Aboseif, S. R., H. E. O'Connell, et al. (1996). "Collagen injection for intrinsic sphincteric deficiency in men." J Urol 155(1): 10-13.

PURPOSE: We evaluated the efficacy of collagen injections in the treatment of male urinary incontinence due to intrinsic sphincteric deficiency. MATERIALS AND METHODS: A total of 88 men (mean age 68 years) with mild to severe intrinsic sphincter deficiency underwent a mean of 3.5 transurethral injections of collagen (mean total volume injected 25 ml.). Patients were subdivided into 2 groups based on use of more than 3 or 3 or fewer pads per day. Patient age, pad use before treatment, duration of leakage, number of injections, volume of collagen used and etiology of incontinence were compared for the 2 groups. RESULTS: Of the patients 42 became nearly completely dry, 19 had substantial improvement but still required 1 to 3 pads per day, 14 consistently used fewer pads but still more than 3 per day and 13 showed no improvement. Most injections were performed with the patient under local anesthesia and no significant morbidity occurred. CONCLUSIONS: In select patients collagen injections appear to be effective, easy to deliver and safe. Pretreatment incontinence severity, concomitant detrusor abnormalities and etiology of intrinsic sphincteric deficiency other than radical retropubic prostatectomy were associated with a worse response to collagen therapy.

Abruzzo, L. V., A. J. Thornton, et al. (1992). "Cytokine-induced gene expression of interleukin-8 in human transitional cell carcinomas and renal cell carcinomas." Am J Pathol 140(2): 365-373.

Chemotactic cytokines play a critical role in recruiting leukocytes to sites of tissue injury. Interleukin-8 (IL-8) is a chemotactic cytokine secreted by a variety of cells (eg, monocytes, endothelial cells, fibroblasts) during the inflammatory response. In this report, the authors demonstrate that human transitional cell carcinomas and renal cell carcinomas have the capacity to elaborate IL-8 in response to the inflammatory mediators IL-1 beta and tumor necrosis factor (TNF)-alpha. All cell lines expressed high levels of IL-8 mRNA on stimulation with either IL-1 beta or TNF-alpha, but not lipopolysaccharide; one expressed the gene constitutively. The authors selected one transitional cell carcinoma cell line (UM-UC-9) and one renal cell carcinoma cell line (UM-RC-5) for further study. Both displayed a time- and dose-dependent increase in steady-state levels of IL-8 mRNA in response to IL-1 beta and TNF-alpha. Specific mRNA was detectable by 1 hour after stimulation. Secretion of antigenic IL-8 measured by enzyme-linked immunosorbent assay into culture supernatants reflected the kinetics of mRNA expression. Because heat-inactivated TNF-alpha failed to induce synthesis of IL-8 mRNA, and cycloheximide augmented TNF-alpha-induced synthesis, IL-8 expression appears to be a stimulus-specific primary induction phenomenon. As with other inflammatory mediators whose mRNA contains a 3' AU-rich sequence (eg, IL-2, TNF-alpha), the half-life of IL-8 mRNA was short, less than 1 hour. Our data suggest that secretion of IL-8 by malignant cells may partly account for the inflammatory infiltrates associated with some malignant neoplasms.

Ahmed, M. M., K. Venkatasubbarao, et al. (1996). "EGR-1 induction is required for maximal radiosensitivity in A375-C6 melanoma cells." J Biol Chem 271(46): 29231-29237.

Exposure to ionizing radiation leads to induction of the immediate-early gene, early growth response-1 (Egr-1). Previous studies have suggested distinct cell type- and inducer-specific roles for EGR-1 protein in cellular growth inhibition. The present study was undertaken to determine the functional role of EGR-1 in growth inhibition caused by exposure of tumor cells to ionizing radiation. Exposure to ionizing radiation caused induction of EGR-1 protein in human melanoma cells A375-C6. Inhibition of either the function of EGR-1 protein by stable transfection with a dominant-negative mutant or the expression of EGR-1 by transient transfection with an antisense oligomer resulted in a diminished growth-inhibitory response to ionizing radiation. Because previous studies have suggested that mutations in the tumor-suppressor gene p53 confer radio-resistance, we examined the p53 status of A375-C6 cells. Interestingly, both the parental and the transfected A375-C6 cells showed trisomy for wild-type p53 alleles. Exposure to ionizing radiation resulted in induction of p53 protein that localized to the nucleus in A375-C6 cells. These data suggest that inhibition of EGR-1 function confers radio resistance despite the induction of wild-type nuclear p53. Thus, EGR-1 is required for the growth-inhibitory response to ionizing radiation in A375-C6 cells.

Aisen, A. M., D. A. Ohl, et al. (1992). "MR of an adrenal pseudocyst." Magn Reson Imaging 10(6): 997-1000.

We describe the appearance of an adrenal pseudocyst on MRI and CT. The MR characteristics of the lesion were noteworthy in that the lesion had two components with different imaging characteristics. The larger component was of low signal intensity on both T1- and T2-weighted images and might have been confused with an adrenal adenoma.

Akech, J., J. J. Wixted, et al. (2010). "Runx2 association with progression of prostate cancer in patients: mechanisms mediating bone osteolysis and osteoblastic metastatic lesions." Oncogene 29(6): 811-821.

Runx2, a bone-specific transcriptional regulator, is abnormally expressed in highly metastatic prostate cancer cells. Here, we identified the functional activities of Runx2 in facilitating tumor growth and osteolysis. Our studies show that negligible Runx2 is found in normal prostate epithelial and non-metastatic LNCaP prostate cancer cells. In the intra-tibial metastasis model, high Runx2 levels are associated with development of large tumors, increased expression of metastasis-related genes (MMP9, MMP13, VEGF, Osteopontin) and secreted bone-resorbing factors (PTHrP, IL8) promoting osteolytic disease. Runx2 siRNA treatment of PC3 cells decreased cell migration and invasion through Matrigel in vitro, and in vivo shRunx2 expression in PC3 cells blocked their ability to survive in the bone microenvironment. Mechanisms of Runx2 function were identified in co-culture studies showing that PC3 cells promote osteoclastogenesis and inhibit osteoblast activity. The clinical significance of these findings is supported by human tissue microarray studies of prostate tumors at stages of cancer progression, in which Runx2 is expressed in both adenocarcinomas and metastatic tumors. Together these findings indicate that Runx2 is a key regulator of events associated with prostate cancer metastatic bone disease.

Albert, N. E., F. C. Sparks, et al. (1977). "Effect of pelvic and retroperitoneal surgery on the urethral pressure profile and perineal floor electromyogram in dogs." Invest Urol 15(2): 140-142.

Study of the urethral pressure profile and perineal floor electromyogram in 12 dogs subjected to colonic resection, abdominal vascular stripping, and pudenal nerve transection suggest that specific defects in urethral continence function may follow pelvic and retroperitoneal surgical dissection. These alterations, attributable to damage of the pudendal nerves and the sympathetic fibers in the posterior peritoneum, must be accurately evaluated before treatment of postoperative urodynamic problems.

Ambani, S. N., B. L. Jacobs, et al. (2009). "Case of a concurrent renal mass and extragonadal retroperitoneal teratoma." Can J Urol 16(2): 4607-4610.

The presentation of a synchronous renal cell carcinoma (RCC) and germ cell tumor (GCT) is rare. We report the case of a 57 year-old male who presented with a right renal mass and retroperitoneal lymphadenopathy. He underwent a successful right partial nephrectomy and retroperitoneal lymph node dissection, and the subsequent pathology revealed a stage I clear cell RCC and a retroperitoneal teratoma with a component of benign prostatic tissue. We briefly discuss the rarity of this occurrence, the pathological features that helped support this diagnosis, and the likely etiologies of these synchronous lesions.

Amundadottir, L. T., P. Sulem, et al. (2006). "A common variant associated with prostate cancer in European and African populations." Nat Genet 38(6): 652-658.

With the increasing incidence of prostate cancer, identifying common genetic variants that confer risk of the disease is important. Here we report such a variant on chromosome 8q24, a region initially identified through a study of Icelandic families. Allele -8 of the microsatellite DG8S737 was associated with prostate cancer in three case-control series of European ancestry from Iceland, Sweden and the US. The estimated odds ratio (OR) of the allele is 1.62 (P = 2.7 x 10(-11)). About 19% of affected men and 13% of the general population carry at least one copy, yielding a population attributable risk (PAR) of approximately 8%. The association was also replicated in an African American case-control group with a similar OR, in which 41% of affected individuals and 30% of the population are carriers. This leads to a greater estimated PAR (16%) that may contribute to higher incidence of prostate cancer in African American men than in men of European ancestry.

Amundsen, C., M. Lau, et al. (1999). "Do urinary symptoms correlate with urodynamic findings?" J Urol 161(6): 1871-1874.

PURPOSE: We determined whether urinary symptomatology correlates with video urodynamic findings. MATERIALS AND METHODS: A total of 115 women with complaints of urinary incontinence completed a 27-item questionnaire. Pelvic examination and video urodynamic study were performed. Subjective findings were scored from 0 to 5, with 5 representing the most severe symptomatology. Patients were divided into 5 subgroups based on etiology of incontinence, and analyzed by Student's t test with p < 0.05 considered statistically significant. RESULTS: Among the 115 patients 11% had normal studies, 38% proximal urethral hypermobility with stress urinary incontinence, 33% intrinsic sphincter deficiency, 11% significant pelvic prolapse and stress urinary incontinence, and 10% detrusor instability. Subjective complaints, such as incontinence during physical activity, were prominent in both stress urinary incontinence groups as well as the prolapse group with stress urinary incontinence. Questions about nocturia, frequency, urgency, urge incontinence, number of pads, number of vaginal deliveries and incomplete emptying were not statistically significant for any group. CONCLUSIONS: Subjective complaints were not helpful in differentiating the etiology of incontinence. Few questions were helpful in predicting which patients would have a normal video urodynamic study.

Angermeier, K. W. and J. E. Montie (1989). "Perioperative complications of adrenal surgery. [Review] [76 refs]." Urologic Clinics of North America 16(3): 597-606.

Complications of adrenal surgery may be medical or surgical. The latter are related to the operative approach as well as to the type and extent of the adrenal lesion and are in general similar to those seen in other open procedures. The medical complications include adrenal insufficiency as a result of bilateral adrenalectomy or continuing contralateral suppression, as well as more specific problems resulting from the physiological derangements of Cushing's syndrome, pheochromocytoma, and primary aldosteronism. Nevertheless, with meticulous preoperative management and postoperative care, adrenal surgery can be performed with low morbidity and mortality rates. [References: 76] <156>

Angermeier, K. W., A. C. Novick, et al. (1990). "Nephron-sparing surgery for renal cell carcinoma with venous involvement." Journal of Urology 144(6): 1352-1355.

A nephron-sparing operation recently has been shown to provide extended survival free of disease in selected patients with localized renal cell carcinoma, particularly for tumors of lower stage. To define better the role of conservative surgical treatment in more locally advanced renal cell carcinoma we reviewed 9 patients with venous tumor involvement in solitary functioning kidneys who underwent a nephron-sparing operation. Complete tumor resection with adequate preservation of renal function was accomplished in all cases. Of the 9 patients 5 had no evidence of disease 7 to 93 months (mean 33.2 months) postoperatively. The remaining 4 patients died of metastatic renal cell carcinoma 17 to 47 months (mean 35.5 months) postoperatively, 2 of whom had concomitant local recurrences in the renal remnant. Based on previously reported results of total nephrectomy for renal cell carcinoma with venous involvement and the morbidity associated with renal replacement therapy, we believe that a nephron-sparing operation is a viable option in the management of these patients. <145>

Angulo, C. J., C. M. Sanchez, et al. (1996). "[Prognosis prediction in patients with transitional cell carcinoma of the urinary bladder]. [Spanish]." Archivos Espanoles de Urologia 49(4): 374-384.

OBJECTIVES: Many attempts have been made during decades to identify factors predictive of prognosis in patients with transitional cell carcinoma (TCC) of the bladder. The present study attempts to determine the predictive factors in a large series of patients with long follow-up homogeneously treated at three institutions from 1983 to 1992. METHODS: The clinical and histological factors with presumed prognostic value were retrospectively evaluated in a series of 331 patients with a mean follow-up of 7.2 years, and a study of survival was performed. RESULTS: Univariate analysis showed tumor stage, growth pattern, grade, size, coexisting dysplasia, histologic type, topography of the lesion and patient age are useful parameters for the prediction of prognosis. The Cox analysis revealed tumor stage is the most important prognostic variable (Beta = 1.23, p < .001), followed by growth pattern as determined by the presence or absence of a papillary phenotype (Beta = 1.18, p < .001), tumor size (Beta = .98, p < .001), WHO modified histologic grading considering persistence or loss of cell polarity (Beta = .73, p < .01), tumor location (Beta = .48, p < .05), and histology (presence or absence of phenotypes other than pure TCC, Beta = .45, p < .05). Coexisting dysplasia, tumor multiplicity, age and sex did not independently influence survival. CONCLUSION: Despite the advancements in the field of molecular biology relative to prognostic markers in bladder cancer, the conventional morphological parameters and tumor stage continue to be the main source of prognostic information in clinical practice. <90>

Angulo, J. C., A. Akdas, et al. (1998). "[Comparison among patients considered candidates for radical prostatectomy in academic institutes in different countries]." Arch Esp Urol 51(10): 957-964.

OBJECTIVE: Radical prostatectomy is performed in potentially curable prostatic cancers, but surgical indication might somehow depend on the idiosyncrasies of a population. Herein we compare the characteristics of patients undergoing radical prostatectomy in teaching University Hospitals of different countries. METHODS: We conducted a retrospective review on 250 consecutive patients who underwent radical prostatectomy before January 1997 in five teaching University Hospitals in Europe (Spain, Sweden, Switzerland, Turkey) and the United States (Detroit, MI). Clinicopathological data were recorded and compared, and a questionnaire investigated whether patient and physician attitudes towards surgery differed. RESULTS: The number of surgeries per month at each institution ranged from 0.9 to 10 and the proportion of newly diagnosed patients that undergo surgery from 0.14 to 0.36. The Kruskal-Wallis test revealed both median age and preoperative prostate-specific antigen (PSA) levels were different between groups. Similarly, despite standardized surgery and histologic work-up, differences in the detection of extracapsular invasion and the rate of detectable PSA after surgery were observed between institutions. Diagnosis in the Swedish and Swiss groups was more often based on digital rectal examination, while the rest were more confident with transrectal ultrasound. Doctors at some institutions were more inclined to recommend radical surgery, either by not mentioning or disapproving other therapeutic strategies. The proportion of patients who said they would elect surgery again ranged from 72% to 92%, and the proportion of doctors who said they would perform surgery again ranged from 78% to 100%. Patients' and doctors' degree of satisfaction with the decision made were also different. CONCLUSIONS: (i) Candidates for radical prostatectomy in teaching hospitals of several countries are different. Might therefore have practical implications on the design of clinical trials and the interpretation of the results of treatment. (ii) Patient and physician acceptance of surgery varies according to countries and is more established firm in those countries where it is more frequently performed.

Angulo, J. C., J. E. Montie, et al. (1996). "Interobserver consistency of digital rectal examination in clinical staging of localized prostatic carcinoma." Urol Oncol 1(5): 199-205.

Appell, R. A., D. H. Bagley, et al. (1978). "Calyceal injury due to external ureteric compression during urography." Br J Urol 50(3): 214.

Appell, R. A., H. R. England, et al. (1980). "The effects of epidural anesthesia on the urethral closure pressure profile in patients with prostatic enlargement." J Urol 124(3): 410-411.

In 10 patients with obstructive manifestations of prostatic enlargement the urethral closure pressure profile was observed before and after the effective blockade of thoracolumbar sympathetic outflow by epidural anesthesia. While epidural anesthesia significantly decreased urethral closure pressure considerable profile responses still remained in these patients. This fact suggests that the bulk of the prostatic tissue is responsible for the bladder outlet obstruction, since urethral closure pressure persists despite urethral smooth and skeletal muscular relaxation as a result of epidural anesthesia. After transurethral resection of the prostatic tissue in these patients the urethral closure pressure did decrease to zero. The result of the prostatic resection is to decrease the urethral closure pressure and, thereby, increase the efficiency of voiding.

Appell, R. A., D. E. Shield, et al. (1977). "Thioridazine-induced priapism." Br J Urol 49(2): 160.

Aranha, O., R. Grignon, et al. (2003). "Suppression of human prostate cancer cell growth by ciprofloxacin is associated with cell cycle arrest and apoptosis." Int J Oncol 22(4): 787-794.

For hormone resistant prostate cancer (HRPC), chemotherapy is used but the mortality is 100% with a mean survival time of 7-8 months. Our previous studies have shown the chemotherapeutic effect of ciprofloxacin in bladder cancer. At doses 50-400 micro g/ml ciprofloxacin, the concentrations that are normally achieved at doses currently used for the treatment of anti-bacterial infections, inhibited bladder cancer cell growth and induced S/G2M arrest with modulation of key cell cycle regulatory genes and ultimately activated apoptotic processes. In this study, we investigated the effect of ciprofloxacin on androgen independent prostate carcinoma, PC3 cells and compared our results with non-tumorigenic prostate epithelial cells. The main advantage of this fluroquinolone antibiotic is its relative non-toxicity as compared to current chemotherapy, which is not very effective, for the treatment of advanced hormone resistant prostate cancer. PC3 cells as well as normal prostate epithelial cells (MLC8891) were treated with 25-400 micro g/ml ciprofloxacin, and cell counting was done during 3 days of treatment. The cell death was determined using DAPI staining of cell nuclei, 7AAD-staining followed by flow cytometric analysis as well as by activation of caspase-3, a member of the ICE family of enzymes involved in the apoptotic cascade. The cell lysates were analyzed by immunoblotting techniques for the expression of key genes targeted by ciprofloxacin (p21WAF1, Bax and Bcl-2). Translocation of bax was visualized using a fluorescence staining procedure followed by laser confocal microscopic imaging. Treatment of prostate cancer cells with ciprofloxacin resulted in a dose- and time-dependent inhibition of cell growth (70-100% with 50-400 micro g/ml of the drug). There was a concomitant induction of cell cycle arrest at the S and G2/M phases of the cell cycle as well as induction of apoptosis. The CDK inhibitor p21WAF1 was down-regulated as early as 12 h following ciprofloxacin treatment (100-200 micro g/ml for 12-24 h). There was a significant increase in the Bax/Bcl-2 ratio with translocation of Bax, a pro-apoptotic protein, to mitochondria with concomitant activation of caspase 3. These results suggest the potential usefulness of the fluroquinolone, ciprofloxacin as a chemotherapeutic agent for advanced prostate cancer. The fluroquinolone ciprofloxacin showed anti-proliferative and apoptosis inducing activity on prostate cancer cells but not on non-tumorigenic prostate epithelial cells. These effects of ciprofloxacin were mediated by cell cycle arrest at S-G2/M phase of the cell cycle, Bax translocation to mitochondrial membrane and by increasing the Bax/Bcl-2 ratio in PC3 prostate cancer cells. Based on our in vitro results, further in-depth in vivo animal or human investigations are warranted.

Aranha, O., D. P. Wood, Jr., et al. (2000). "Ciprofloxacin mediated cell growth inhibition, S/G2-M cell cycle arrest, and apoptosis in a human transitional cell carcinoma of the bladder cell line." Clin Cancer Res 6(3): 891-900.

The second most prevalent urological malignancy in middle aged and elderly men is bladder cancer, with 90% of the cases being transitional cell carcinomas. The success of current systemic and intravesical therapeutic agents, such as cisplatin, thiotepa, Adriamycin, mitomycin C, and bacillus Calmette-Guerin, is limited with recurrence rates reduced to 17-44%. In addition, most of these agents require instrumentation of the urinary tract and are delivered at a significant cost and potential morbidity to the patient. Fluroquinolone antibiotics such as ciprofloxacin, which can be administered p.o., may have a profound effect in bladder cancer management. This is primarily based on limited in vitro studies on tumor cells derived from transitional cell carcinoma of the bladder that revealed a dose- and time-dependent inhibition of cell growth by ciprofloxacin at concentrations that are easily attainable in the urine of patients. However, the mechanism(s) by which ciprofloxacin elicits its biological effects on bladder cancer cells is not well documented. Our experimental data confirm previous studies showing the in vitro cell growth inhibition of the transitional cell carcinoma of the bladder cell line HTB9 and further showed the induction of cell cycle arrest at the S/G2-M checkpoints. In addition, we found down-regulation of cyclin B, cyclin E, and dephosphorylation of cdk2 in ciprofloxacin-treated bladder tumor cells. There was also an up-regulation of Bax, which altered the Bax:Bcl-2 ratio, which may be responsible for mitochondrial depolarization reported to be involved prior to the induction of apoptosis. The cyclin-dependent kinase inhibitor p21WAF1 level was found to be decreased within 12 h of ciprofloxacin treatment and disappeared completely when HTB9 cells were treated with 200 microg/ml ciprofloxacin for 24 h. The down-regulation of p21WAF1 closely correlated with poly(ADP-ribose) polymerase cleavage and CPP32 activation. Recent studies revealed that p21WAF1 protects cells from apoptosis by arresting them in G1 and further binds to pro-caspase-3, preventing its activation and thus, inhibiting the apoptotic cascade. Hence, the down-regulation of p21WAF1, together with the alterations in Bax and cdk2 as observed in our studies, may define a novel mechanism by which ciprofloxacin inhibits tumor cell growth and induces apoptotic cell death. The results of our current studies provide strong experimental evidence for the use of ciprofloxacin as a potential preventive and/or therapeutic agent for the management of transitional cell carcinoma of the bladder.

Aranha, O., L. Zhu, et al. (2002). "Role of mitochondria in ciprofloxacin induced apoptosis in bladder cancer cells." J Urol 167(3): 1288-1294.

PURPOSE: In our earlier series we showed that ciprofloxacin inhibits bladder tumor cell growth with concomitant S/G2M cell cycle arrest and reported an increased Bax-to-Bcl-2 ratio in cells undergoing cell death. In the current series we elucidated the molecular mechanisms by which ciprofloxacin induces apoptotic processes. MATERIALS AND METHODS: Ciprofloxacin mediated mitochondrial depolarization was detected by flow cytometry in HTB9 cells. Mitochondrial permeability transition was measured by spectrophotometry in isolated mitochondria treated with ciprofloxacin in the presence and absence of cyclosporin. The consequential decrease in mitochondrial calcium, cytochrome c release and Bax translocation to mitochondria, which resulted in the activation of caspase 3 leading to apoptotic cell death, was measured by biochemical and confocal microscopy. RESULTS: Mitochondrial depolarization was observed during ciprofloxacin induced apoptotic processes. Cyclosporin A, a known inhibitor of the mitochondrial permeability transition pore, protected cells against decreased mitochondrial potential. Also, ciprofloxacin induced an alteration of mitochondrial calcium as early as 5 minutes and this disruption of intracellular calcium homeostasis was prevented by cyclosporin. Ciprofloxacin also had a direct effect on swelling of isolated mitochondria, which was absent in the presence of cyclosporin. Mitochondrial changes were accompanied by cytochrome c release and caspase 3 activation. Our findings also showed Bcl-2 dependent subcellular redistribution of Bax to the mitochondrial membrane in ciprofloxacin treated bladder tumor cells. CONCLUSIONS: The disruption of calcium homeostasis, mitochondrial swelling and redistribution of Bax to the mitochondrial membrane are key events in the initiation of apoptotic processes in ciprofloxacin treated bladder cancer cells.

Armstrong, A. P., R. E. Miller, et al. (2008). "RANKL acts directly on RANK-expressing prostate tumor cells and mediates migration and expression of tumor metastasis genes." Prostate 68(1): 92-104.

BACKGROUND: Metastases to bone are a frequent complication of human prostate cancer and result in the development of osteoblastic lesions that include an underlying osteoclastic component. Previous studies in rodent models of breast and prostate cancer have established that receptor activator of NF-kappaB ligand (RANKL) inhibition decreases bone lesion development and tumor growth in bone. RANK is essential for osteoclast differentiation, activation, and survival via its expression on osteoclasts and their precursors. RANK expression has also been observed in some tumor cell types such as breast and colon, suggesting that RANKL may play a direct role on tumor cells. METHODS: Male CB17 severe combined immunodeficient (SCID) mice were injected with PC3 cells intratibially and treated with either PBS or human osteprotegerin (OPG)-Fc, a RANKL antagonist. The formation of osteolytic lesions was analyzed by X-ray, and local and systemic levels of RANKL and OPG were analyzed. RANK mRNA and protein expression were assessed on multiple prostate cancer cell lines, and events downstream of RANK activation were studied in PC3 cells in vitro. RESULTS: OPG-Fc treatment of PC3 tumor-bearing mice decreased lesion formation and tumor burden. Systemic and local levels of RANKL expression were increased in PC3 tumor bearing mice. PC3 cells responded to RANKL by activating multiple signaling pathways which resulted in significant changes in expression of genes involved in osteolysis and migration. RANK activation via RANKL resulted in increased invasion of PC3 cells through a collagen matrix. CONCLUSION: These data demonstrate that host stromal RANKL is induced systemically and locally as a result of PC3 prostate tumor growth within the skeleton. RANK is expressed on prostate cancer cells and promotes invasion in a RANKL-dependent manner.

Armstrong, M. B., O. O. Nafiu, et al. (2005). "Testicular chloroma in a nonleukemic infant." J Pediatr Hematol Oncol 27(7): 393-396.

Extramedullary myeloid cell tumors (EMCT) are localized collections of immature myeloid cells that occur outside of the bone marrow. Usually observed concurrently with bone marrow disease, EMCT also may occur in the absence of overt marrow leukemia. In this report, we describe an infant with a testicular mass that was identified as an EMCT after orchiectomy. Unlike the only previously reported case of infantile testicular chloroma, this patient did not exhibit bone marrow disease at diagnosis. Because systemic chemotherapy is considered to be superior to local control (surgery, radiation therapy), the patient was treated with intensively timed induction chemotherapy followed by 3 cycles of maintenance treatment (according to CCG protocol #2891) but no radiation therapy. The patient remains disease-free 18 months after diagnosis.

Arredouani, M. S., S. S. Tseng-Rogenski, et al. (2010). "Androgen ablation augments human HLA2.1-restricted T cell responses to PSA self-antigen in transgenic mice." Prostate 70(9): 1002-1011.

BACKGROUND: In recent years, there has been an increasing interest in targeting human prostate tumor-associated antigens (TAAs) for prostate cancer immunotherapy as an alternative to other therapeutic modalities. However, immunologic tolerance to TAA poses a significant obstacle to effective, TAA-targeted immunotherapy. We sought to investigate whether androgen deprivation would result in circumventing immune tolerance to prostate TAA by impacting CD8 cell responses. METHODS: To this end, we generated a transgenic mouse that expresses the human prostate-specific antigen (PSA) specifically in the prostate, and crossed it to the HLA-A2.1 transgenic mouse to evaluate how androgen deprivation affects human HLA A2.1-resticted T cell responses following immunization of PSA-expressing mice by vaccinia-PSA (PROSTVAC). RESULTS: Our PSA transgenic mouse showed restricted expression of PSA in the prostate and detectable circulating PSA levels. Additionally, PSA expression was androgen-dependent with reduced PSA expression in the prostate within 1 week of castration, and undetectable PSA by day 42 after castration as evaluated by ELISA. Castration of the PSA/A2.1 hybrid mouse prior to immunization with a PSA-expressing recombinant vaccinia virus resulted in a significant augmentation of PSA-specific cytotoxic lymphocytes. CONCLUSIONS: This humanized hybrid mouse model provides a well-defined system to gain additional insight into the mechanisms of immune tolerance to PSA and to test novel strategies aiming at circumventing immune tolerance to PSA and other TAA for targeted prostate cancer immunotherapy.

Artz, A. S., D. Fergusson, et al. (2004). "Mechanisms of unexplained anemia in the nursing home." J Am Geriatr Soc 52(3): 423-427.

OBJECTIVES: To characterize anemia in elderly nursing home residents. DESIGN: Prospective multiinstitutional cohort study. SETTING: Five nursing homes. PARTICIPANTS: From retrospective analysis, residents found to be anemic using chart review were prospectively randomized. Of the 81 residents enrolled, 60 were anemic. MEASUREMENTS: Chart review for medical history and factors related to treatment or history of anemia, extensive laboratory evaluation for causes of anemia, and classification of anemia by two hematologists. RESULTS: Among the 60 anemic residents, the causes of anemia were idiopathic (n=27), iron-deficiency (n=14), anemia associated with chronic disease (n=8), anemia of renal insufficiency (n=6), and other (n=5). The eryrthropoietin (EPO) response to anemia was lower in residents with idiopathic anemia (IA) than in those with iron-deficiency anemia, and this correlated with renal function as estimated using calculated creatinine clearance. In this elderly population, advancing age was not correlated with lower EPO response. CONCLUSION: IA is common in nursing home residents. A lower EPO response contributes to the high prevalence of anemia in this setting and may be due, in part, to occult renal dysfunction.

Asahi, H., A. Mizokami, et al. (2006). "Bisphosphonate induces apoptosis and inhibits pro-osteoclastic gene expression in prostate cancer cells." Int J Urol 13(5): 593-600.

AIM: Bisphosphonates are well established for the management of cancer-induced skeletal complications. Recent studies suggest that bisphosphonates promote apoptosis of cancer cells as well as osteoclasts in bone metastatic sites. To determine the direct effects of bisphosphonate on prostate cancer, we examined the effects of minodronate on prostatic cancer cell growth and the expression of apoptosis-related proteins and osteoclastogenic factors. METHODS: PC-3, DU145 and LNCaP cells were treated with amino-bisphosphonate minodronate. Then proliferation, apoptosis and expression of bcl-2, bax, poly (ADP)-ribose polymerase (PARP), caspase-3, receptor activator of nuclear factor-kappaB ligand (RANKL), osteoprotegerin (OPG), matrix metalloproteinases-2 (MMP-2), and parathyroid hormone related protein (PTHrP) were assessed. RESULTS: The proliferation of prostatic cancer cells was inhibited by minodronate. DNA fragmentation and TUNEL-positive nuclei were observed in minodronate-treated PC-3 cells. Minodronate decreased bcl-2 expression and induced bax expression, caspase-3 activity and degradation of PARP in DU145 and PC-3 cells. Minodronate decreased expression of RANKL, PTHrP and MMP-2 in PC-3 cells. CONCLUSIONS: Our results suggest that bisphosphonate not only promotes apoptosis directly but also decreases pro-osteoclastic gene expression in prostate cancer cells.

Atiemo, H. and F. Daneshgari (2006). "Surgical innovations in pelvic organ prolapse and incontinence." Clin Geriatr Med 22(3): 605-621.

Pelvic organ prolapse (POP) and urinary incontinence (UI) are common problems facing the geriatric woman. Many patients may find great benefit from medical or conservative treatments; however, surgical options are commonly used in many cases. This article examines the current medical and surgical innovations for POP and UI that have the potential to improve the patient's quality of life.

Atiemo, H., T. L. Griebling, et al. (2006). "Advances in geriatric female pelvic surgery." BJU Int 98 Suppl 1: 90-94; discussion 95-96.

Atiemo, H., J. Wynes, et al. (2005). "Effect of botulinum toxin on detrusor overactivity induced by intravesical adenosine triphosphate and capsaicin in a rat model." Urology 65(3): 622-626.

OBJECTIVES: To assess the effects of intravesical injection of botulinum toxin type A (BTX) on a model of detrusor overactivity induced by intravesical infusions of adenosine triphosphate (ATP) and capsaicin. BTX has recently been used clinically to treat overactive bladder syndromes without a precise knowledge of the mechanism of action. METHODS: Twelve Sprague-Dawley rats underwent BTX injections. Six received 1.0 U and 6 received 0.5 U. BTX injections were done at bladder tube placement. Ten rats received saline injections as controls. After 48 hours of recovery, all 22 animals underwent awake, conscious cystometrography (CMG), performed using both saline and ATP (20 mM) intravesical infusion at 0.074 mL/min. In another 4 rats, capsaicin (100 microM) was infused intravesically before and after the BTX injections. The CMG parameters calculated included bladder contraction pressures and contraction frequencies (contractions per minute or Herz). RESULTS: Intravesical saline CMG produced a contraction frequency of 0.78 +/- 0.10 Hz. Intravesical ATP doubled this voiding frequency to 1.45 +/- 0.18 Hz (P = 0.003). BTX treatment at 1.0 U reduced the frequency to 0.91 +/- 0.13 Hz (P = 0.02). BTX injection significantly decreased the bladder contraction pressure during saline and ATP CMG. However, 0.5 U BTX did not decrease ATP-induced overactivity; therefore, in the capsaicin experiments, 1.0 U BTX was used. Although BTX tended to reverse detrusor overactivity secondary to intravesical capsaicin, this difference was not statistically significant. CONCLUSIONS: Intravesical infusion of either ATP or capsaicin can induce detrusor overactivity. BTX was more effective in blocking the effect of ATP than of capsaicin, although BTX injection did show a trend in reducing the contraction frequencies and amplitudes induced by capsaicin. The clinical utility of using BTX to treat overactive bladder syndromes and bladder hypersensory states, especially those that may be caused by an augmentation of the purinergic pathway, should be studied further.

Atiemo, H. O. (2010). "Should an anti-incontinence procedure be routinely performed at the time of pelvic organ prolapse repair? An evidence-based review." Curr Urol Rep 11(5): 304-309.

The concept of prophylactic anti-incontinence surgery for women undergoing prolapse repair has been a popular and controversial debate in recent years. This article provides an evidence-based review of the current literature to determine the proper evaluation of the patient with prolapse, the predictive quality of preoperative urodynamics, and the selection of the appropriate anti-incontinence procedure. Based on this review, the midurethral sling predominates as the procedure of choice; however, there is poor evidence to suggest that routine usage of a prophylactic sling is warranted in treatment of the patient with pelvic organ prolapse.

Atiemo, H. O., D. Nonaka, et al. (2003). "Xanthogranulomatous adrenalitis." J Urol 170(1): 177.

Atiemo, H. O., M. J. Szostak, et al. (2003). "Salvage of sildenafil failures referred from primary care physicians." J Urol 170(6 Pt 1): 2356-2358.

PURPOSE: Sildenafil citrate is an effective first line agent for most causes of erectile dysfunction. Primary care providers (PCPs) write the majority of these prescriptions and most failures of sildenafil therapy are subsequently referred to urologists for alternative therapies. Often it is concluded that the drug is ineffective when in actuality the failure is do to inadequate patient education. We examined patients referred from PCPs who were nonresponders to sildenafil therapy and attempted to convert them to responders through reeducation. MATERIALS AND METHODS: In a 2-year period 253 sildenafil nonresponders were evaluated by the same urologist (GNS). Patient reeducation consisted of viewing a brief videotape, personal instruction and detailed instruction sheets for the patient and his partner. Outcome measures were obtained through patient self-reporting of the Sexual Health Inventory for Men and a global assessment question. Responders were identified as those who answered positively latter or had a statistical improvement in the score of the former. RESULTS: Of the 253 patients reeducated 17 were excluded due to contraindications. Of the remaining nonresponders 41.5% achieved salvage with reeducation. Incorrect administration accounted for 81% of the failures. Average time with the physician was 12 minutes and 94% of the patients continued to respond at 26 months. CONCLUSIONS: Approximately 40% of patients with sildenafil failures referred from PCPs can be converted to responders through reeducation. Incorrect drug administration was the most common reason for correctable failure. Reeducation can be done in an efficient manner. New package materials may improve sildenafil outcomes and compliance.

Attie, M. F., M. D. Fallon, et al. (1985). "Bone and parathyroid inhibitory effects of S-2(3-aminopropylamino)ethylphosphorothioic acid. Studies in experimental animals and cultured bone cells." Journal of Clinical Investigation 75(4): 1191-1197.

S-2-(3-aminopropylamino)ethylphosphorothioic acid (WR 2721) is a radio- and chemoprotective agent which produces hypocalcemia in humans. Intravenous injection of 30 mg/kg WR 2721 in rats and 15 mg/kg in dogs lowers serum calcium by 19 and 25%, respectively. Hypocalcemia in dogs is associated with a fall in serum immunoreactive parathyroid hormone (PTH), which suggests that the mechanism of its hypocalcemic effect is acute hypoparathyroidism. Despite this effect on PTH, in eight chronically parathyroidectomized rats on a low phosphate diet, WR 2721 reduced serum calcium from 9.4 +/- 0.6 to 7.7 +/- 0.5 mg/dl (P less than 0.01) at 3 h. Furthermore, in dogs rendered hypercalcemic by continuous infusion of PTH, WR 2721 reduced serum calcium from 11.0 +/- 0.5 to 10.6 +/- 0.5 mg/dl (P less than 0.01). To determine whether WR 2721 causes hypocalcemia by enhancing the exit of calcium from the circulation or inhibiting its entry, the drug was infused 3 h after administration of 45Ca to rats. WR 2721 did not significantly increase the rate of disappearance of 45Ca from the circulation even though serum calcium fell by 19%. However, serum 45Ca specific activity was higher at 1.5 h (P less than 0.01) and 3 h (P less than 0.05) in rats given WR 2721 than in rats given vehicle alone, which suggests that WR 2721 blocks the entry of nonradioactive calcium into the circulation, presumably from bone. In incubations with fetal rat long bone labeled in utero with 45Ca, 10(-3) M WR 2721 inhibited PTH-stimulated, but not base-line release of 45Ca. Bone resorption by primary culture of chick osteoclasts was inhibited by WR 2721 at concentrations as low as 10(-4) M in the absence of hormonal stimulation. These studies suggest that WR 2721 lowers serum calcium predominantly by blocking calcium release from bone. This acute hypocalcemic effect is at least in part independent of its effect on the parathyroid glands, and is most likely a direct effect of the agent on bone resorption. <37>

Austin, P. F., O. L. Westney, et al. (2001). "Advantages of rectus fascial slings for urinary incontinence in children with neuropathic bladders." J Urol 165(6 Pt 2): 2369-2371; discussion 2371-2362.

PURPOSE: Many surgical procedures to improve outlet resistance in children with neuropathic bladders are obstructive and increase the detrusor leak point pressure. In contrast, fascial slings are designed to achieve continence by increasing the Valsalva or stress leak point pressure without altering the detrusor leak point pressure. We evaluate the effectiveness of fascial slings in achieving continence in pediatric patients with neuropathic bladder. MATERIALS AND METHODS: From October 1994 until February 1999, 10 females and 8 males with neuropathic bladder secondary to myelodysplasia or traumatic spinal cord injury underwent fascial sling procedures. Mean patient age was 14 years (range 8 to 18) and all were incontinent despite aggressive medical management. Urodynamic evaluation was performed preoperatively and postoperatively. Specific urodynamic measurements included detrusor leak point pressure, stress leak point pressure and detrusor compliance. Compliance was only compared in the 12 nonaugmented cases. RESULTS: With a mean followup of 21.2 months (range 6 to 57), preoperative and postoperative urodynamics revealed little change in mean detrusor leak point pressure (23.2 versus 23.22 cm. H2O) but a substantial increase in mean stress leak point pressure (41.6 versus 64.5 cm. H2O). Mean compliance was unchanged in the nonaugmented group (22.00 versus 26.78 ml/cm. H2O). Four patients (22.22%) remained wet after surgery, of whom 2 were successfully treated with a repeat sling procedure and 1 with collagen injection for an overall continence rate of 94.44%. CONCLUSIONS: Fascial slings can be effectively used in pediatric patients for neuropathic incontinence. Furthermore, stress urinary incontinence is corrected by increasing the Valsalva or stress leak point pressure with preservation of the detrusor leak point pressure. Preservation of detrusor leak point pressure is particularly advantageous because other forms of bladder outlet procedures achieve continence at the expense of increasing detrusor pressures, thus placing the upper tracts at risk for damage.

Bagley, D., R. Appell, et al. (1980). "Renal angiomyolipoma: diagnosis and management." Urology 15(1): 1-5.

Renal angiomyolipoma is a benign tumor. Use of excretory urography, plain tomography, arteriography, ultrasound, and computerized tomography can usually provide the diagnosis. Appropriate operative or nonoperative management can then be determined for the individual patient.

Bagley, D. H., E. Herlihy, et al. (1980). "Infections and antibiotic prophylaxis in the fulgurated rat bladder." Invest Urol 17(4): 277-283.

A model is described for establishing infection in a fulgurated rat bladder. Persistence of bacteriuria was dependent upon the size of the bacterial inoculum. Infection in an injured bladder exposed to a single predictable bacterial inoculum may be prevented by a single dose of antibiotic. The appropriate timing of antibiotic administration varies with the infecting organism.

Bajaj, S., D. Fink-Bennett, et al. (2008). "Intestinal malrotation in adult seen on hepatobiliary scintigraphy." Clin Nucl Med 33(12): 861-863.

Hepatobiliary scintigraphy is primarily used to diagnose acute and chronic biliary tract disorders. However, its potential role in diagnosing unsuspected extrahepatic pathology is not well described. We present 2 adult patients with chronic abdominal pain who underwent hepatobiliary scintigraphy for evaluation of cystic duct patency. In both cases, the proximal small bowel was located on the right side of the abdomen, which suggested the diagnosis of malrotation. Retrospective review of abdominal CT scan, upper gastrointestinal series, and subsequent laparotomy confirmed malrotation. The diagnosis of malrotation in both these patients was first suggested on hepatobiliary scintigraphy, which significantly impacted their subsequent management.

Banerjee, M., D. Biswas, et al. (2000). "Recursive partitioning for prognostic grouping of patients with clinically localized prostate carcinoma." Cancer 89(2): 404-411.

BACKGROUND: Patients treated with radical prostatectomy for clinically localized prostate carcinoma present considerable heterogeneity in terms of disease free survival outcome. Multiple studies have attempted to create prognostic groupings of these patients in the perioperative phase, using information available regarding several clinicopathologic variables. Such groupings allow physicians to make early yet prudent decisions regarding adjuvant combination therapies. The current study presents results from a statistical analysis that enables the natural identification of such prognostic groups. METHODS: Examination of consecutive radical prostatectomy specimens was performed between January 1991 and December 1995 at Wayne State University, Harper Hospital, Detroit, Michigan. Disease free survival in a cohort of 485 of these men was analyzed using recursive partitioning and amalgamation technique. Clinicopathologic parameters evaluated included age, race, preoperative prostate specific antigen (PSA) level, clinical and pathologic stage, and Gleason grade of the fine-needle biopsy as well as the radical prostatectomy specimen. RESULTS: A binary decision tree representation was generated for classifying patients based on the clinicopathologic variables mentioned earlier. The worst prognosis was for patients with either advanced stage and a PSA level > 24.1 ng/mL or advanced stage, a PSA level </= 24.1 ng/mL, and age </= 65 years. This group had an estimated median disease free survival of only 10.3 months. Patients with lower pathologic stage, prostatectomy Gleason scores of </= 7, and a preoperative PSA level </= 22.7 ng/mL had the best prognosis. CONCLUSIONS: The recursive partitioning analyses allows easy characterization of a patient for prognosis shortly after radical prostatectomy. This will enable a physician to make more prudent decisions regarding whether to employ watchful waiting, proceed with accepted adjuvant therapy (radiotherapy or hormonal therapy), or refer patients to a research center that is able to administer experimental adjuvant therapy. [See editorial counterpoint on pages 232-3 and reply to counterpoint on pages 234-5, this issue.]

Banowsky, L. H., J. E. Montie, et al. (1974). "Renal transplantation. III. Prevention of wound infections." Urology 4(6): 656-659.

Barbieri, E. A., E. B. Bawle, et al. (2005). "A syndrome of hypoplastic sinuses, hydrocephalus, bronchiectasis, and hypogammaglobulinemia with functional antibody deficiency in twin girls." Ann Allergy Asthma Immunol 94(6): 693-699.

BACKGROUND: A variety of syndromes are known to be associated with immune deficiency, some as a major part of the syndrome and some as an occasional finding. OBJECTIVES: To report a newly defined syndrome of hydrocephalus, hypoplastic sinuses, cartilaginous webbing of the bronchi, bronchiectasis, and hypogammaglobulinemia with functional antibody deficiency in identical twin girls. METHODS: Spirometry, radiography, computed tomography (CT), bronchoscopy, and laboratory tests were performed for diagnosis. RESULTS: A girl (twin A) was evaluated at the age of 7 years for chronic cough and wheeze that worsened with exercise. Hydrocephalus had been diagnosed a year before evaluation. She was treated for cough variant asthma and was lost to follow-up until the age of 10 years. The cough had worsened progressively, and dyspnea was now apparent. Spirometry was consistent with reversible airway obstruction. A chest radiograph was suggestive of bronchiectasis. A chest CT scan showed bilateral upper lobe bronchiectasis. Hypogammaglobulinemia and functional antibody deficiency were noted. A CT scan of the sinuses revealed aplasia or severe hypoplasia of all the paranasal sinuses. Bronchoscopy revealed a grossly abnormal bronchial structure and atrophic-appearing bronchial mucosa. Twin B also had a history of hydrocephalus. Although she had no respiratory symptoms, chest CT revealed bronchiectasis, and she had obstruction on spirometry. Laboratory analysis revealed hypogammaglobulinemia and functional antibody deficiency. She became symptomatic 2 years after twin A. CONCLUSIONS: This is a newly reported syndrome of hydrocephalus, absent sinuses, abnormalities of the bronchi, and functional antibody deficiency, which initially presented as cough and wheeze.

Bardot, S. F. and J. E. Montie (1992). "Renal angiomyolipoma: current concepts of diagnosis and management." AUA Update Series 11(4): 306-311.

Bardot, S. F., J. E. Montie, et al. (1992). "Laparoscopic surgical technique for internal drainage of pelvic lymphocele." J Urol 147(3 Pt 2): 908-909.

A previously unreported technique of internal drainage of a pelvic lymphocele is described using a laparoscopic approach to create the peritoneal window for drainage in 2 patients. The technique avoids a larger incision and permits a shorter recovery period.

Barrett, J. M., M. A. Rovedo, et al. (2006). "Prostate cancer cells regulate growth and differentiation of bone marrow endothelial cells through TGFbeta and its receptor, TGFbetaRII." Prostate 66(6): 632-650.

BACKGROUND: The underlying mechanisms permitting prostate cancer bone metastasis are poorly understood. We previously showed that the highly metastatic prostate cancer cell line, PC-3, inhibits bone marrow endothelial (HBME-1) cell growth in collagen gels and induces them to differentiate into cords, resembling angiogenesis in vivo. METHODS: cDNA microarray analysis was performed to identify cytokines responsible for the effects of PC-3 cells on HBME-1 cells. Cytokine and neutralizing antibody studies were done to further investigate specific angiogenic factors, such as transforming growth factor beta (TGFbeta). TGFbeta RNA and protein were detected by real-time RT-PCR and enzyme-linked immunosorbent assay (ELISA) analysis to measure their production by prostate cancer cell lines. Conditioned media experiments using TGFbeta neutralizing antibodies were used to analyze TGFbeta activation by prostate cancer cells. RESULTS: PC-3 conditioned media altered the expression of several TGFbeta-regulated or -associated genes in HBME-1 cells. Low concentrations of TGFbeta cytokines inhibited HBME-1 cell growth to a similar level as PC-3 conditioned media and partially induced differentiation. Inhibitors and neutralizing antibodies directed against TGFbeta isoforms and TGFbeta receptor type 2 (TGFbetaRII) reversed the growth inhibition of HBME-1 cells conferred by PC-3 conditioned media. Yet, only TGFbetaRII neutralizing antibodies significantly inhibited HBME-1 differentiation. Also, prostate cancer cell lines produced low levels of TGFbeta RNA and protein, and were shown to activate serum-derived TGFbeta. CONCLUSIONS: These results suggest that prostate cancer cells mediate growth inhibition and differentiation of bone marrow endothelial cells both through production and activation of TGFbeta as well as alteration of TGFbetaRII-mediated signal transduction. This could contribute to the establishment and growth of bone metastases.

Barth, R. J., Jr., J. J. Mule, et al. (1991). "Identification of unique murine tumor associated antigens by tumor infiltrating lymphocytes using tumor specific secretion of interferon-gamma and tumor necrosis factor." Journal of Immunological Methods 140(2): 269-279.

Stimulation of multiple CD8+ murine tumor infiltrating lymphocyte (TIL) lines and one TIL clone with the tumor of origin of the TIL induced at least three-fold more secretion of TNF and/or INF-gamma than was elicited by other syngeneic, methylcholanthrene (MCA) induced sarcomas. TIL which specifically secreted lymphokines were generated from three different sarcomas. Specific lymphokine secretion was a stable characteristic of the lines over time. IL-2 was necessary for maximal lymphokine secretion by TIL. These investigations demonstrate that lymphokine secretion by CD8+ lymphocytes derived from tumor bearing mice can be used to define unique tumor associated antigens on at least three different sarcomas and may be valuable in studies of the biologic nature of these antigens and of the adoptive immunotherapy of cancer. <142>

Baru, J. S., D. A. Bloom, et al. (2001). "John Holter's shunt." J Am Coll Surg 192(1): 79-85.

Bassily, N. H., C. J. Vallorosi, et al. (2000). "Coordinate expression of cytokeratins 7 and 20 in prostate adenocarcinoma and bladder urothelial carcinoma." Am J Clin Pathol 113(3): 383-388.

We studied the expression of cytokeratin (CK)-7 and CK-20 in prostate adenocarcinoma and urothelial carcinoma and evaluated their usefulness for distinguishing high-grade forms of these tumors. We examined prostate adenocarcinoma in 59 radical prostatectomy specimens and in 10 autopsy specimens showing metastatic disease, and urothelial carcinoma of the bladder in 28 cystectomy specimens. Immunohistochemical staining for CK-7, CK-20, and prostate-specific antigen (PSA) was performed on paraffin sections. For prostate adenocarcinoma, 5 cases had only CK-7 positivity, 5 had only CK-20 focal positivity, 1 stained for both markers, and 48 were negative for both. PSA was positive in all but 1 poorly differentiated prostatic carcinoma. In the autopsy cases, PSA was expressed in the prostate and the metastatic tumors in most cases; few cases were focally positive for CK-7 or CK-20, but none was positive for both markers. For the urothelial tumors, CK-7 was the sole positive marker in 6 cases, and CK-20 in 1 case; 17 cases were positive for both, and 4 were negative for both. All urothelial carcinomas were PSA negative. Although PSA is useful for differentiating prostatic from urothelial carcinoma, CK-7 and CK-20 are helpful when both are positive, supporting the diagnosis of urothelial carcinoma. However, if only 1 marker is positive or both are negative, these markers have limited usefulness for distinguishing these carcinomas.

Bassily, N. H., C. J. Vallorosi, et al. (2000). "Coordinate expression of cytokeratins 7 and 20 in prostate adenocarcinoma and bladder urothelial carcinoma. [see comments.]." American Journal of Clinical Pathology 113(3): 383-388.

We studied the expression of cytokeratin (CK)-7 and CK-20 in prostate adenocarcinoma and urothelial carcinoma and evaluated their usefulness for distinguishing high-grade forms of these tumors. We examined prostate adenocarcinoma in 59 radical prostatectomy specimens and in 10 autopsy specimens showing metastatic disease, and urothelial carcinoma of the bladder in 28 cystectomy specimens. Immunohistochemical staining for CK-7, CK-20, and prostate-specific antigen (PSA) was performed on paraffin sections. For prostate adenocarcinoma, 5 cases had only CK-7 positivity, 5 had only CK-20 focal positivity, 1 stained for both markers, and 48 were negative for both. PSA was positive in all but 1 poorly differentiated prostatic carcinoma. In the autopsy cases, PSA was expressed in the prostate and the metastatic tumors in most cases; few cases were focally positive for CK-7 or CK-20, but none was positive for both markers. For the urothelial tumors, CK-7 was the sole positive marker in 6 cases, and CK-20 in 1 case; 17 cases were positive for both, and 4 were negative for both. All urothelial carcinomas were PSA negative. Although PSA is useful for differentiating prostatic from urothelial carcinoma, CK-7 and CK-20 are helpful when both are positive, supporting the diagnosis of urothelial carcinoma. However, if only 1 marker is positive or both are negative, these markers have limited usefulness for distinguishing these carcinomas. <58>

Beach, S., H. Tang, et al. (2008). "Snail is a repressor of RKIP transcription in metastatic prostate cancer cells." Oncogene 27(15): 2243-2248.

Diminished expression of the metastasis suppressor protein RKIP was previously reported in a number of cancers. The underlying mechanism remains unknown. Here, we show that the expression of RKIP negatively correlates with that of Snail zinc-transcriptional repressor, a key modulator of normal and neoplastic epithelial-mesenchymal transition (EMT) program. With a combination of loss-of-function and gain-of-function approaches, we showed that Snail repressed the expression of RKIP in metastatic prostate cancer cell lines. The effect of Snail on RKIP was on the level of transcriptional initiation and mediated by a proximal E-box on the RKIP promoter. Our results therefore suggest that RKIP is a novel component of the Snail transcriptional regulatory network important for the progression and metastasis of cancer.

Beduschi, R., M. C. Beduschi, et al. (1999). "Pneumoperitoneum does not potentiate the nephrotoxicity of aminoglycosides in rats." Urology 53(2): 451-454.

OBJECTIVES: Pneumoperitoneum is associated with transient renal dysfunction. To our knowledge, the safety of administering nephrotoxins such as aminoglycosides during pneumoperitoneum has not been studied. Our hypothesis was that pneumoperitoneum potentiates the nephrotoxicity of aminoglycosides. METHODS: From 29 rats we obtained preprocedure 24-hour urine collections. In the pneumoperitoneum group (n = 7), carbon dioxide was insufflated intra-abdominally at 15 mm Hg pressure for 2 hours. In the gentamicin group (n = 7), 10 mg/kg gentamicin was administered intravenously. In the combined pneumoperitoneum/gentamicin group (n = 8), the same dose of gentamicin was administered 10 minutes before pneumoperitoneum. Sham rats (n = 7) received anesthesia only. Urine was collected for the 24 hours after the procedure, and 1 week later blood for creatinine determination and final 24-hour urine collections were obtained. All urine samples were assayed for creatinine and N-acetyl-beta-glucosaminidase (NAG). RESULTS: Only the gentamicin and combined pneumoperitoneum/gentamicin groups presented day 1 values for NAG excretion that were significantly greater than same day sham or paired preprocedure values; the rest of the urinary creatinine and NAG day 1 levels and all the day 7 levels were not significantly different from same day sham or paired preprocedure levels. Day 7 serum creatinine and creatinine clearance did not differ significantly among the groups. CONCLUSIONS: We found that intravenous gentamicin transiently increased urinary excretion of NAG in rats, which resolved within 1 week. Pneumoperitoneum for 2 hours at 15 mm Hg did not increase urinary NAG, either alone or in gentamicin-treated rats. Moreover, our data are sufficient to refute with 95% certainty the possibility that gentamicin plus pneumoperitoneum decreases creatinine clearance more than approximately 60%. These results do not support the hypothesis that pneumoperitoneum potentiates the nephrotoxicity of aminoglycosides.

Beduschi, R., M. C. Beduschi, et al. (1999). "Antifibrinolytic additives to fibrin glue for laparoscopic wound closure in urinary tract." J Endourol 13(4): 283-287.

BACKGROUND AND OBJECTIVES: Fibrinolytic activity of urine may rapidly degrade fibrin glue used in the urinary tract, thereby limiting tissue adhesion. The goals of this study were to verify the ability of antifibrinolytic agents to delay the degradation of fibrin glue in the urinary tract and to assess the results of this delay on subsequent wound healing. MATERIALS AND METHODS: In 25 domestic pigs, a 3.5-cm incision in the urinary bladder was left open (N = 6) or closed laparoscopically with fibrin glue alone (N = 6), fibrin glue containing aprotinin 5000 KIU/mL (N = 6), or fibrin glue containing aprotinin 2500 KIU/mL with (N = 4) or without (N = 3) aminocaproic acid 12.5 mg/mL. At harvest 7 days later, the bladder was tested for leakage. Histologic features were scored by a pathologist blinded to the closure method. RESULTS: There were no significant differences among the groups in the amount of leakage at harvest. Significant fibrin glue material in the wound was noted more often in the pigs treated with fibrin glue plus aprotinin (7 of 13) than in the fibrin glue-only group (0 of 6; P = 0.04). The presence of significant fibrin material in the wound correlated well with absence of granulation tissue (P < 0.001), such that granulation tissue bridging the wound edges was found more often in the fibrin glue-only group (6 of 6) than in the groups treated with fibrin glue plus aprotinin (4 of 13; P = 0.01). CONCLUSIONS: Although aprotinin +/- aminocaproic acid did delay the degradation of fibrin glue used to close a bladder wound, it was associated with inhibition of granulation tissue in the glued wound. These findings suggest that aprotinin alone and aprotinin plus aminocaproic acid are not useful additives to fibrin glue used for wound closure in the urinary tract.

Beduschi, R. and J. E. Montie (2000). "Current indiations for new possibilities for organ preservation in carcinoma of the bladder." Brazilian Journal of Urology 26(3): 234-241.

Beduschi, R. and J. S. Wolf, Jr. (1997). "Fragment of a catheter as a foreign body in the kidney." Tech Urol 3(4): 222-224.

Foreign bodies in the kidney are unusual. A review of the literature disclosed few reports of renal foreign body from nontraumatic causes. In this article, we report a case of gross hematuria due to iatrogenic foreign body in the kidney from ureteral endoscopy. The catheter fragment eluded diagnosis for 18 months until it was discovered and retrieved by means of a flexible ureteroscope. To our knowledge, this is the first report of this complication and presentation following endoscopic manipulation of the upper ureteral tract.

Beebe-Dimmer, J. L., R. L. Dunn, et al. (2007). "Features of the metabolic syndrome and prostate cancer in African-American men." Cancer 109(5): 875-881.

BACKGROUND: Metabolic syndrome refers to a cluster of conditions that includes hypertension, dyslipidemia, central adiposity, and high blood glucose levels. Over the past decade, a growing body of literature suggests that metabolic syndrome may be associated with several different forms of cancer. Because prostate cancer risk is highest among African Americans, and these men, similarly, are more prone to developing specific features of the metabolic syndrome, including hypertension and type-2 diabetes, any relationships would have a significant impact on developing strategies for the primary prevention of prostate cancer. METHODS: The Flint Men's Health Study is a community-based, case-control study of prostate cancer conducted exclusively among African Americans. Prostate cancer cases and controls completed an interviewer-administered questionnaire that asked about the respondent's history of high blood pressure and diabetes. All men also participated in a physical examination in which several measures of body composition, including waist circumference, were collected. RESULTS: Hypertension was reported more commonly among men with prostate cancer (cases) compared with men in the control group (odds ratio [OR]. 2.4; 95% confidence interval [95% CI], 1.5-3.7), and cases were more likely to have a waist circumference >102 cm (OR, 1.8; 95% CI, 1.2-2.9). However, self-reported diabetes was not associated with prostate cancer risk. The men with prostate cancer also were more likely than controls to exhibit multiple syndrome characteristics (OR, 1.9; 95% CI, 1.2-3.0). CONCLUSIONS: The current results indicated that features of the metabolic syndrome, specifically abdominal obesity and hypertension, are associated with prostate cancer in African-American men. This relationship, if it is proved causal, suggests that prevention or control of these conditions eventually may lead to a reduction in the incidence of prostate cancer in this high-risk minority group.

Beebe-Dimmer, J. L., G. J. Faerber, et al. (2008). "Body composition and serum prostate-specific antigen: review and findings from Flint Men's Health Study." Urology 71(4): 554-560.

Recent studies have suggested that obesity is associated with lower serum prostate-specific antigen levels, perhaps influencing the recommendation for prostate biopsy and potentially explaining part of the observed poorer prognosis among obese men. African-American men have the greatest rates of prostate cancer and are more likely to die of the disease, making early detection a priority in this group. We present findings from the Flint Men's Health Study, a study of African-American men, that are consistent with most studies suggesting that overweight men have prostate-specific antigen levels that are 0.15 to 0.30 ng/mL lower than those who are not overweight. We have coupled our results with a systematic review of publications in this area.

Beebe-Dimmer, J. L., L. A. Lange, et al. (2006). "Polymorphisms in the prostate-specific antigen gene promoter do not predict serum prostate-specific antigen levels in African-American men." Prostate Cancer Prostatic Dis 9(1): 50-55.

A major problem with the use of serum prostate-specific antigen (PSA) in predicting prostate cancer risk is the considerable variability of such measurements. Cramer et al. identified a set of single-nucleotide polymorphisms (SNPs) in the upstream regulatory region of the PSA gene that were each associated with increased promoter activity and serum PSA, further suggesting that genotyping these SNPs could be useful in improving the predictive value of PSA screening. In order to replicate this finding, DNA samples from 475 African-American men were genotyped for the same SNPs and no association was observed with either serum PSA level or prostate cancer diagnosis.

Beebe-Dimmer, J. L., D. P. Wood, Jr., et al. (2004). "Risk perception and concern among brothers of men with prostate carcinoma." Cancer 100(7): 1537-1544.

BACKGROUND: It is important for clinicians, researchers, and others who shape public health policy to understand the demographic correlates and psychologic factors that drive health behaviors, such as screening for early detection of cancer, particularly among individuals at high risk for developing the disease. METHODS: One-hundred eleven men whose brothers were diagnosed with prostate carcinoma completed a computer-assisted telephone interview aimed to assess their perception of absolute risk and concern about developing prostate carcinoma over the next 10 years and across their lifetime. Comparisons were made between selected demographic, behavioral, family pedigree characteristics, and measures of perceived risk and concern. RESULTS: The majority of men perceived their personal risk of developing prostate carcinoma to be > or =50%. Men who at the time of the interview were younger than their affected brother were significantly more concerned about prostate carcinoma and perceived their risk to be higher than men who were older than their brother. Estimates of personal risk and concern were also uniformly higher among men with more than one first-degree relative affected with prostate carcinoma compared to men with only one affected first-degree relative. Risk perception and concern about an impending prostate carcinoma diagnosis were associated with the use of supplements marketed for prostate health. CONCLUSIONS: The findings indicated that birth order in relation to a brother diagnosed with prostate carcinoma is significantly associated with risk perception and concern in unaffected family members. These results highlight the need for further study of the familial dynamics and characteristics that drive health behaviors and stress importance of public health education to inform men of personal risk assessment as well as the risks and benefits of screening. These studies ultimately can contribute to the success of strategies for the primary prevention and early detection of cancer.

Beebe-Dimmer, J. L., D. P. Wood, Jr., et al. (2004). "Use of complementary and alternative medicine in men with family history of prostate cancer: a pilot study." Urology 63(2): 282-287.

OBJECTIVES: To describe the use of complementary and alternative medicines (CAMs) among men with a family history of prostate cancer and to evaluate the relationship between selected sociodemographic and behavioral characteristics and the use of CAMs. METHODS: Unaffected brothers of men diagnosed with prostate cancer were asked to participate in a short computer-assisted telephone interview. The survey focused primarily on the use of different vitamins, herbal supplements, and medications, some of which are marketed for prostate health or prostate cancer prevention. RESULTS: A total of 111 men completed the survey, representing 66% of eligible study subjects. Of the 111 men, 61 (55%) reported currently taking some form of CAM, with 30% taking a vitamin or supplement purported to have prostate-specific benefits. The prevalence of CAM use generally increased with increasing age; however, men who were younger than their affected brother at the time of the diagnosis of prostate cancer were more likely to use CAMs than were older brothers. CONCLUSIONS: Most men with a family history of prostate cancer take vitamins and supplements, some of which are believed to prevent future cancer occurrence. The results of this study and others provide some insight into the determinants of potentially beneficial health behaviors in high-risk individuals.

Beekman, K. W., A. D. Colevas, et al. (2006). "Phase II evaluations of cilengitide in asymptomatic patients with androgen-independent prostate cancer: scientific rationale and study design." Clin Genitourin Cancer 4(4): 299-302.

Two randomized trials demonstrated an improvement in survival with docetaxel-based chemotherapy for patients with metastatic, androgen-independent prostate disease. However, the effect of current therapy is suboptimal in that it is complicated by toxicities and has no curative potential. Cilengitide (EMD121974; NSC 707544), is a potent selective alphavbeta3 and alphavbeta5 integrin antagonist. Integrins are cell surface receptors that mediate a variety of cell activities including endothelial cell proliferation and migration. Blocking the ligation of integrins by antagonists promotes apoptosis of proliferative angiogenic cells, thereby suspending new blood vessel formation, which is essential for the growth of malignant disease. In prostate cancer specifically, integrins are known to be involved in metastases with differential expression on tumor cells. Tumors and vascular endothelial cells produce factors, such as vascular endothelial growth factor and basic fibroblast growth factor, that promote neovascularization, which has been implicated in prostate cancer progression. Cilengitide has been shown to inhibit alphavbeta3- and alphavbeta5-mediated cell adhesion and block in vitro endothelial cell migration. In vivo experiments demonstrated that cilengitide inhibited cytokine-induced basic fibroblast growth factor- and vascular endothelial growth factor-mediated angiogenesis in a dose-dependent manner. Cilengitide also inhibited tumor growth in various in vivo systems. Two Cancer Therapy Evaluation Program-sponsored, multicenter, phase II trials are designed to evaluate the safety and efficacy of this agent in patients with androgen-independent prostate cancer. National Cancer Institute trial 6735 is evaluating cilengitide at 2000 mg in patients with nonmetastatic androgen-independent prostate cancer, and National Cancer Institute trial 6372 is evaluating 2 dose levels of cilengitide, 500 mg or 2000 mg, intravenously twice weekly in patients with metastatic prostate cancer.

Begley, L., D. Keeney, et al. (2006). "Concordant copy number and transcriptional activity of genes mapping to derivative chromosomes 8 during cellular immortalization in vitro." Genes Chromosomes Cancer 45(2): 136-146.

Deletion, rearrangement, or amplification of sequences mapping to chromosome 8 are frequently observed in human prostate and other tumors. However, it is not clear whether these events alter the transcriptional activity of the affected genes. To examine this question, we have utilized oligonucleotide microarray technology and compared the transcriptional patterns of normal human prostate tissues and five immortalized cell lines carrying either two normal chromosomes 8 or one normal and one derivative chromosome 8. Comparison of the transcriptional profiles of the tissues and cell lines identified 125 differentially expressed transcripts specific to chromosome 8, with 46 transcripts mapping to 8p and 79 transcripts mapping to 8q. The majority of genes mapping to 8p (44/46, 96%) were transcriptionally down-regulated in cells hemizygous for 8p, whereas the majority of genes mapping to 8q (58/79, 73%) were up-regulated in cells carrying three copies of 8q. Moreover, hemizygous alleles on 8p exhibited sub-haploinsufficient transcript levels for several genes that could be induced to haploinsufficient levels under hypomethylating conditions, suggesting that epigenetic regulation is a common mechanism for gene silencing in cells deleted for one copy of 8p. The results of these studies clearly demonstrate that alterations of gene copy number and transcriptional activity are directly correlated in cell lines harboring derivative chromosomes 8, and that these events are commonly observed during cellular immortalization in vitro.

Begley, L., C. Monteleon, et al. (2005). "CXCL12 overexpression and secretion by aging fibroblasts enhance human prostate epithelial proliferation in vitro." Aging Cell 4(6): 291-298.

The direct relationship between the aging process and the incidence and prevalence of both benign prostatic hyperplasia (BPH) and prostate cancer (PCa) implies that certain risk factors associated with the development of both diseases increase with the aging process. In particular, both diseases share an overly proliferative phenotype, suggesting that mechanisms that normally act to suppress cellular proliferation are disrupted or rendered dysfunctional as a consequence of the aging process. We propose that one such mechanism involves changes in the prostate microenvironment, which 'evolves' during the aging process and disrupts paracrine interactions between epithelial and associated stromal fibroblasts. We show that stromal fibroblasts isolated from the prostates of men 63-81 years of age at the time of surgery express and secrete higher levels of the CXCL12 chemokine compared with those isolated from younger men, and stimulate CXCR4-mediated signaling pathways that induce cellular proliferation. These studies represent an important first step towards a mechanistic elucidation of the role of aging in the etiology of benign and malignant prostatic diseases.

Begley, L. A., S. Kasina, et al. (2008). "The inflammatory microenvironment of the aging prostate facilitates cellular proliferation and hypertrophy." Cytokine 43(2): 194-199.

Benign Prostatic Hypertrophy (BPH, also known as benign prostatic hyperplasia or benign prostatic enlargement), is one of the most common benign proliferative conditions associated with aging in men and is pathologically characterized by the proliferation of fibroblast/myofibroblast and epithelial cell types in the prostate. Previous studies from our laboratory have shown that the CXC-type chemokines, CXCL5 and CXCL12, are secreted by aging prostate stroma and promote both proliferative and transcriptional responses from prostate epithelial cells. Using array-based gene expression profiling and quantitative reverse-transcriptase polymerase chain reaction, we now show that the transcriptome of the aging prostate stroma is characterized by the up-regulation of several genes that encode secreted inflammatory mediators, including secreted CXC-type chemokines (CXCL1, CXCL2, CXCL5, CXCL6, CXCL12), interleukins (IL11, IL33), and transcripts with cytokine homology (CYTL1). At the protein level, ELISA experiments demonstrated that CXCL1, CXCL5, and CXCL6 were secreted by primary prostate stromal fibroblasts explanted from aging prostate stroma. Dose-response assays confirmed that, like CXCL5 and CXCL12, CXCL1 and CXCL6 promote low-level proliferative responses from both prostate stromal fibroblasts and epithelial cells. Taken together, these data suggest that inflammatory mediators are secreted by prostatic stroma consequent to aging, that the levels of these mediators are sufficient to promote low-level increases in the proliferative rate of both epithelial and stromal fibroblast cell types. Moreover, these processes may account for the low-level, but cumulative, proliferation of both epithelial and fibroblastic/myofibroblastic cell types that characterizes the aging-associated development of benign prostatic hypertophy.

Begley, L. A., S. Kasina, et al. (2008). "CXCL5 promotes prostate cancer progression." Neoplasia 10(3): 244-254.

CXCL5 is a proangiogenic CXC-type chemokine that is an inflammatory mediator and a powerful attractant for granulocytic immune cells. Unlike many other chemokines, CXCL5 is secreted by both immune (neutrophil, monocyte, and macrophage) and nonimmune (epithelial, endothelial, and fibroblastic) cell types. The current study was intended to determine which of these cell types express CXCL5 in normal and malignant human prostatic tissues, whether expression levels correlated with malignancy and whether CXCL5 stimulated biologic effects consistent with a benign or malignant prostate epithelial phenotype. The results of these studies show that CXCL5 protein expression levels are concordant with prostate tumor progression, are highly associated with inflammatory infiltrate, and are frequently detected in the lumens of both benign and malignant prostate glands. Exogenous administration of CXCL5 stimulates cellular proliferation and gene transcription in both nontransformed and transformed prostate epithelial cells and induces highly aggressive prostate cancer cells to invade through synthetic basement membrane in vitro. These findings suggest that the inflammatory mediator, CXCL5, may play multiple roles in the etiology of both benign and malignant proliferative diseases in the prostate.

Begley, L. A., J. W. MacDonald, et al. (2007). "CXCL12 activates a robust transcriptional response in human prostate epithelial cells." J Biol Chem 282(37): 26767-26774.

CXCL12 is a CXC-type chemokine that plays important roles in hematopoiesis, development, and organization of the immune system and supports the survival or growth of a variety of normal or malignant cell types. Our laboratory recently showed that CXCL12 is secreted by aging stromal fibroblast cells and is a major paracrine factor that specifically stimulates the proliferation of prostate epithelial cells. The current study shows that this CXCL12-mediated proliferative response may be either ERK-dependent or ERK-independent. Moreover, CXCL12 initiates a previously undefined and complex global transcriptional response in prostate epithelial cells. This CXCL12-mediated transcriptional response directly stimulates the expression of genes encoding proteins that are involved in the promotion of cellular proliferation and progression through the cell cycle, tumor metastasis, and cellular motility, and directly represses the transcription of genes encoding proteins involved in cell-cell adhesion and resistance to apoptosis. Thus, CXCL12 may play a major role in the etiology of benign proliferative disease in the context of an aging tissue microenvironment.

Belldegrun, A., N. H. Bander, et al. (2001). "Society of Urologic Oncology Biotechnology Forum: new approaches and targets for advanced prostate cancer." J Urol 166(4): 1316-1321.

PURPOSE: We provide an overview of advances in molecular based therapeutic strategies for prostate cancer and summarize the studies presented at the Society of Urologic Oncology Biotechnology Forum in 2000. MATERIALS AND METHODS: Three promising new treatment strategies are presented, and a critique of the advantages and limitations of each is offered by a leading expert in the field. RESULTS: Treatment results and the current state of dendritic cell based immunotherapy, monoclonal antibody therapy and anti-apoptotic treatment approaches are presented. CONCLUSIONS: Currently patients with advanced prostate carcinoma have expanded therapeutic options available in the form of molecular based phases II and III clinical trials.

Belldegrun, A. S., T. Klatte, et al. (2008). "Cancer-specific survival outcomes among patients treated during the cytokine era of kidney cancer (1989-2005): a benchmark for emerging targeted cancer therapies." Cancer 113(9): 2457-2463.

BACKGROUND: The management of renal cell carcinoma (RCC) is evolving toward less extirpative surgery and the use of targeted therapy. The authors set out to provide a benchmark against which emerging therapies should be measured. METHODS: A prospective database including clinical and pathological variables for 1632 patients with RCC treated between 1989 and 2005 was queried. Patients were stratified using the University of California-Los Angeles Integrated Staging System (UISS) into low-, intermediate-, and high-risk groups. Disease-specific survival (DSS) was measured. Response to systemic therapy for patients with advanced disease was assessed. RESULTS: Nephrectomy was performed in 1492 patients. Overall 5-, 10-, and 15-year DSS was 55%, 40%, and 29%. For localized disease, 5- and 10-year DSS for UISS low-, intermediate-, and high-risk groups was 97% and 92%, 81% and 61%, and 62% and 41%, respectively. For metastatic disease, 5- and 10-year DSS for UISS low-, intermediate-, and high-risk groups was 41% and 31%, 18% and 7%, and 8% and 0%, respectively. Patients with metastatic disease receiving immunotherapy (n=453) had complete response in 7% (median survival [MS], 120+ months), partial response in 15% (MS, 42.8 months), stable disease in 33% (MS, 38.6 months), and progressive disease in 45% (MS, 11.6 months). CONCLUSIONS: Most patients with localized RCC do well with surgery alone, but effective adjuvant therapy is needed for patients identified as at high risk for recurrence. For advanced disease, newer targeted and potentially less toxic treatments should be at least as effective as those achieved with aggressive surgical resection and immunotherapy.

Belville, W. D., J. M. Park, et al. (1994). "Perineal xanthogranulomatous pseudotumor due to intermittent catheterization: a liposarcoma mimic. Case report." Paraplegia 32(9): 624-626.

A large perineal fatty tissue mass shown to be an encapsulated xanthogranulomatous reaction was found in a spinal cord injured man whose neuropathic bladder was for a long time being managed by clean intermittent catheterization, but who had chronic urinary tract infection. He was also known to be a chronic alcoholic. We would say that an alcohol numbed sensorium and multiple catheterizations led to recurrent small urethral perforations which in the setting of chronic bacteriuria promoted the unusual inflammatory mass. Appreciating the increasing use of clean intermittent catheterization for the spinal cord injured, we suspect that similar cases of 'xanthogranulomatous pseudotumors' will be found, and therefore we describe this most unusual clinical presentation.

Belville, W. D., S. J. Swierzewski, 3rd, et al. (1993). "Synchronous cystoscopy and cystometry in the management of neurogenic bladder dysfunction." J Urol 150(2 Pt 1): 431-433.

The physical difficulties associated with cystoscopy and cystometry in the spinal cord injury patient led to a clinical trial of synchronous cystoscopy and cystometry in these individuals. Following a disappointing experience with external transducer methodology, a recently available fiberoptic microtransducer system was used and an effective system was developed. A total of 20 individuals with spinal cord injury underwent a standard water cystometrogram on an examination table followed by synchronous flexible cystoscopy and cystometry using a 5F fiberoptic microtransducer while seated in a chair. The results showed both pressure tracings to be clinically identical. Uninhibited contraction spikes, compliance curves and leak point pressures were essentially the same by both methods and artifact was not a problem. Given the speed, ease and reproducibility of this method, the difficulties with patient transfer for these studies have been virtually eliminated. Two urethral instrumentations have been replaced by 1. Examination room time was decreased from 60 to approximately 10 to 15 minutes with half of the required personnel. Perhaps more importantly, these occasionally problematic individuals clearly prefer this streamlined approach and patient compliance with followup has improved.

Belville, W. D., S. J. Swierzewski, 3rd, et al. (1993). "Fiberoptic microtransducer pressure technology: urodynamic implications." Neurourol Urodyn 12(2): 171-178.

The FST 200 is a novel commercially available pressure measurement system that combines microtechnology and fiberoptics and is particularly well suited for invasive urodynamic studies. Pressure recording with this system is highly accurate and reproducible. The pressure curves obtained parallel those from standard water cystometry. Being small and portable, the system lends itself to invasive transurethral monitoring in the privacy of an examination room. Additionally, the 5F catheter size allows the performance of leak point pressures and pressure/flow voiding studies with minimal urethral stenting artifact often seen with larger catheters. The technical aspects of this system are presented.

Ben Yoseph, Y., D. A. Mitchell, et al. (1992). "Mucolipidoses II and III variants with normal N-acetylglucosamine 1-phosphotransferase activity toward alpha-methylmannoside are due to nonallelic mutations." American Journal of Human Genetics 50(1): 137-144.

Normal N-acetylglucosamine 1-phosphotransferase activity toward mono- and oligosaccharide acceptor substrates was detected in cultured skin fibroblasts from mucolipidoses II and III patients who were designated as variants (one of four mucolipidosis II and three out of six mucolipidosis III patients examined). The activity toward natural lysosomal protein acceptors was absent or deficient in cell preparations from all patients with classical as well as variant forms of mucolipidoses II and III. Complementation analysis, using fused and cocultivated mutant fibroblast combinations, revealed that, while cell lines with variant mucolipidosis III constituted a complementation group distinct from that of classical forms of mucolipidoses II and III, the variant mucolipidosis II cell line belonged to the same complementation group as did the classical forms. In contrast to the mutant enzyme from variant mucolipidosis III patients that failed to recognize lysosomal proteins as the specific acceptor substrates, the activity toward alpha-methylmannoside in the variant mucolipidosis II patient could be inhibited by exogenous lysosomal enzyme preparations (bovine beta-glucuronidase and human hexosaminidase A). These findings suggest that N-acetylglucosamine 1-phosphotransferase is composed of at least two distinct polypeptides: (1) a recognition subunit that is defective in the mucolipidosis III variants and (2) a catalytic subunit that is deficient or altered in the classical forms of mucolipidoses II and III as well as in the mucolipidosis II variant. <137>

Bennett, C., M. Robinson, et al. (1990). "Electroejaculation: new therapy for neurogenic infertility." Contemporary Urology 2: 25-28.

Bennett, C. J., J. W. Ayers, et al. (1987). "Electroejaculation of paraplegic males followed by pregnancies." Fertil Steril 48(6): 1070-1072.

Semen obtained by electroejaculation was used to achieve pregnancies in the spouses of T5-6 and T4-5 paraplegics. Viable semen was recovered in both an antegrade and retrograde fashion. In both cases, the SPA test was positive. Semen recovered for AIH IUI was washed and swum up prior to insemination.

Bennett, C. J., S. W. Seager, et al. (1987). "Electroejaculation for recovery of semen after retroperitoneal lymph node dissection: case report." J Urol 137(3): 513-515.

Electroejaculation with a rectal probe was used successfully for semen recovery 8 years after bilateral suprarenal hilar lymph node dissection for stage IIB embryonal cell cancer. An adequate ejaculate was obtained in relation to total sperm count, motility and normal morphology. Prior use of sympathomimetic drugs, including imipramine and ephedrine, was unsuccessful in producing an ejaculation. Electrostimulation via a rectal probe seems to be a useful technique for semen recovery in the patient with anejaculation after retroperitoneal lymph node dissection.

Bennett, C. J., S. W. Seager, et al. (1988). "Sexual dysfunction and electroejaculation in men with spinal cord injury: review." J Urol 139(3): 453-457.

Bennett, C. L., D. K. Price, et al. (2002). "Racial variation in CAG repeat lengths within the androgen receptor gene among prostate cancer patients of lower socioeconomic status." J Clin Oncol 20(17): 3599-3604.

PURPOSE: To evaluate (1) whether there were racial differences in the androgen receptor gene CAG repeat length and in clinical or laboratory attributes of prostate cancer at the time of diagnosis; (2) whether there were differences in race, Gleason score, prostate-specific antigen (PSA) level, and stage at diagnosis by androgen receptor gene CAG repeat length; and (3) whether sociodemographic, clinical, and laboratory based factors might be associated with advanced-stage prostate cancer. To our knowledge, our study is the first to report on CAG repeat lengths in a cohort of prostate cancer patients, which includes large numbers of African-American men. METHODS: CAG repeat lengths on the androgen receptor gene were evaluated for 151 African-American and 168 white veterans with prostate cancer. The chi(2) test, t test, and logistic regression analyses were used to evaluate the associations between CAG repeat lengths and race, stage, histologic grade, and PSA levels at diagnosis. RESULTS: The mean age of the cohort at the time of diagnosis was 68.7 years. At presentation, 42.0% had stage D prostate cancer, 26.5% had Gleason scores of 8 to 10, and 53.0% had PSA levels >/= 10 ng/dL. Mean androgen receptor gene CAG repeat length for white veterans was 21.9 (SD, 3.5) versus 19.8 (SD, 3.2) for African-American veterans (P =.001). Men with shorter CAG repeats were more likely to have stage D prostate cancer (P =.09) but were not more likely to have a higher PSA concentration or Gleason score. CONCLUSION: In this cohort of men with prostate cancer, short CAG repeat length on the androgen receptor gene was associated with African-American race and possibly with higher stage but not with other clinical or pathologic findings.

Bent, A. E., J. Foote, et al. (2001). "Collagen implant for treating stress urinary incontinence in women with urethral hypermobility." J Urol 166(4): 1354-1357.

PURPOSE: We evaluated the use of collagen in women with stress urinary incontinence and urethral hypermobility. MATERIALS AND METHODS: We treated 90 patients with stress urinary incontinence and urethral hypermobility with 1 to 3 injections of Contigen implant (C. R. Bard, Inc., Covington, Georgia) between June 1996 and October 1998. Observations at 3, 6 and 12 months included continence grade, 7-day voiding diaries and quality of life questionnaires. Abdominal leak point pressure was determined at baseline and 12 months. RESULTS: At the 6-month followup 68 patients remained in the study, of whom 30 (44%) were dry and 24 (35%) were improved. Of the 58 patients who reached the 12-month followup 19 (33%) were dry and 19 (33%) were improved. Considering all patients entered into the study at 6 months 30 (33%) were dry and 24 (27%) were improved. Of the original 90 patients 19 (21%) were dry and 19 (21%) were improved at 12 months. The probability of maintaining initial improvement for 12 months was 44%. The success of bulking agent therapy was not predicted by the initial incontinence grade. Improved continence grade correlated with improved leak point pressure. CONCLUSIONS: This therapy is appropriate in women with urethral hypermobility who wish to avoid surgical risks and in those in whom surgery is ill advised.

Bentley, G., J. Dey, et al. (2000). "Significance of the Gleason scoring system after neoadjuvant hormonal therapy." Mol Urol 4(3): 125-;discussion 131.

Neoadjuvant hormonal therapy (NHT) induces morphologic changes in prostate adenocarcinoma that result in the assignment of higher Gleason scores on average than in pretreatment biopsy specimens. This outcome has led to the recommendation that the Gleason scoring system not be applied to prostate adenocarcinoma specimens after NHT. We reviewed the radical prostatectomy specimens of 116 patients who had received NHT. Gleason scores were assigned on the post-treatment specimens by applying the usual criteria; in addition, an estimated pretreatment Gleason score was assigned on the basis of knowledge of the morphologic alterations associated with NHT. Finally, an estimate of the degree of therapy effect was assigned: little or no evidence of hormonal effect (grade 1) to marked therapy-related changes (grade 3). Both the post-treatment and the estimated pretreatment Gleason score correlated significantly with biochemical progression (P = 0.03 and P = 0.03, respectively; log-rank test). The degree of therapy effect did not correlate with progression (P = 0.46; log-rank test). This limited analysis suggests that despite the morphologic alterations induced by NHT, post-treatment Gleason score remains a significant prognostic measure. Further studies in more uniformly treated populations are required to confirm this observation.

Bernstein, A. M., H. P. Koo, et al. (1999). "Beyond the Trendelenburg position: Friedrich Trendelenburg's life and surgical contributions." Surgery 126(1): 78-82.

Friedrich Trendelenburg (1844-1924) was a giant figure in the formative years of modern surgical practice. His name lives on in the Trendelenburg position, a pelvis-up, head-down position that is of great use in surgical practice. That position, however, was certainly well known before Trendelenburg and the linkage of his name was by no means the greatest of Trendelenburg's achievements. Trendelenburg was a world class surgeon, innovator, and educator who made novel advances that spanned the entire range of surgical practice.

Berry, S. H., L. M. Bogart, et al. (2010). "Development, validation and testing of an epidemiological case definition of interstitial cystitis/painful bladder syndrome." J Urol 183(5): 1848-1852.

PURPOSE: No standard case definition exists for interstitial cystitis/painful bladder syndrome for patient screening or epidemiological studies. As part of the RAND Interstitial Cystitis Epidemiology study, we developed a case definition for interstitial cystitis/painful bladder syndrome with known sensitivity and specificity. We compared this definition with others used in interstitial cystitis/painful bladder syndrome epidemiological studies. MATERIALS AND METHODS: We reviewed the literature and performed a structured, expert panel process to arrive at an interstitial cystitis/painful bladder syndrome case definition. We developed a questionnaire to assess interstitial cystitis/painful bladder syndrome symptoms using this case definition and others used in the literature. We administered the questionnaire to 599 women with interstitial cystitis/painful bladder syndrome, overactive bladder, endometriosis or vulvodynia. The sensitivity and specificity of each definition was calculated using physician assigned diagnoses as the reference standard. RESULTS: No single epidemiological definition had high sensitivity and high specificity. Thus, 2 definitions were developed. One had high sensitivity (81%) and low specificity (54%), and the other had the converse (48% sensitivity and 83% specificity). These values were comparable or superior to those of other epidemiological definitions used in interstitial cystitis/painful bladder syndrome prevalence studies. CONCLUSIONS: No single case definition of interstitial cystitis/painful bladder syndrome provides high sensitivity and high specificity to identify the condition. For prevalence studies of interstitial cystitis/painful bladder syndrome the best approach may be to use 2 definitions that would yield a prevalence range. The RAND Interstitial Cystitis Epidemiology interstitial cystitis/painful bladder syndrome case definitions, developed through structured consensus and validation, can be used for this purpose.

Bhat, I., J. M. Zerin, et al. (2003). "Unusual presentation of osteoid osteoma mimicking osteomyelitis in a 27-month-old infant." Pediatr Radiol 33(6): 425-428.

Osteoid osteoma is an uncommon, benign disorder of bone that is most often encountered in school-age children and in adolescents. It is quite rare in children under the age of 3 years. We report a case of osteoid osteoma with unusual clinical and imaging features in a 27-month-old toddler who presented with a limp and swelling of the right knee. Initial clinical evaluation, plain films, and computed tomography (CT) were strongly suggestive of chronic osteomyelitis involving the distal right femoral metadiaphysis. The appearance on nuclear medicine bone scan, however, was typical of osteoid osteoma. A biopsy of the lesion was taken and histological examination confirmed the diagnosis of osteoid osteoma. The misleading clinical and imaging features in this case are discussed.

Bianco, F. J., Jr., D. C. Gervasi, et al. (1998). "Matrix metalloproteinase-9 expression in bladder washes from bladder cancer patients predicts pathological stage and grade." Clin Cancer Res 4(12): 3011-3016.

The matrix metalloproteinases (MMPs), in particular the gelatinases (MMP-2 and MMP-9) have been associated with tumor cell invasion and metastasis in many human cancers. Here we examined the expression of proMMP-2 (gelatinase A) and proMMP-9 (gelatinase B) proteins in the cellular component of bladder washes obtained from 65 patients. Twenty-six patients had active bladder cancer, 24 had a history of bladder cancer but no evidence of active disease at the time of cystoscopy (recurrence-free), and 15 patients had lesions other than bladder cancer (controls). The results were correlated with the cytological findings of the bladder wash and the histopathological results of the tumor resection when performed. In patients with active transitional cell carcinoma of the bladder, 71 and 38% had expression and overexpression of the latent form of MMP-9 (proMMP-9), respectively. In contrast, neither latent nor active MMP-2 could be detected in any of the samples examined, regardless of tumor status. Overexpression of proMMP-9 correlated with higher grade (P = 0.003) and pathological stage (P = 0.04) of disease in the active bladder cancer group. No significant gelatinase expression was detected in the recurrence-free and control cases. Compared with urine cytology, proMMP-9 expression had an overall higher sensitivity for bladder cancer identification (71 versus 54%, P = 0.11). Detection of proMMP-9 in bladder washes may be a novel approach for the identification of patients with more aggressive forms of bladder cancer.

Bianco, F. J., Jr., D. Justa, et al. (2004). "Management of clinical T1 bladder transitional cell carcinoma by radical cystectomy." Urol Oncol 22(4): 290-294.

High-grade bladder cancer involving the lamina propria is considered superficial disease. This spectrum is generally treated with TUR plus intravesical therapy. However, significant understaging jeopardizes long-term survival and improvements and radical surgery represents a provocative alternative. We evaluated disease-free and cancer-specific survival (CSS) in our cohort of patients with high-grade T1 tumors. A total of 318 patients with bladder cancer underwent radical cystectomy between 1990 and 2000 at our institution. Of these, 66 had cT1 tumors with or without Carcinoma in-situ (CIS). Our multidisciplinary bladder cancer database was queried to perform a multivariate analysis on clinical parameters such as: age, race, sex, cystectomy year, intravesical therapy, angiolymphatic-invasion and tumor upstage in relation to recurrence and survival. The clinical stage was accurate in 44 of the cases (66%). However, 27% were upstaged by cystectomy and 12% of the cT1 + CIS patients had nodal disease. Patients with cT1 tumors plus CIS had a significantly worse CSS. Those with persistent disease after an initial course of BCG therapy appeared to have worse CSS also. At a median follow up of 4 years, overall cancer-specific mortality was 22%, however, pathologic T1 +/- CIS had 92% CSS at 10 years. Our data suggests that some cT1 bladder cancer tumors have assiduous clinical courses evidenced in staging discrepancies. For high-grade tumors, early cystectomy and orthotopic diversion increases life expectancy significantly and should be carry out early rather than late.

Bianco, F. J., Jr., M. W. Kattan, et al. (2003). "Radical prostatectomy nomograms in black American men: accuracy and applicability." J Urol 170(1): 73-76; discussion 76-77.

PURPOSE: Nomograms have been developed to allow the prediction of disease recurrence based on clinical and pathological parameters in patients with clinically localized prostate cancer. However, they have been constructed using predominantly white American male (CAM) cohorts. We have previously shown that black American males (AAMs) have worse disease-free survival after radical prostatectomy after controlling for known prognostic factors. We tested the accuracy of prognostic nomograms in a population of AAMs with prostate cancer treated with radical prostatectomy. MATERIALS AND METHODS: We tested the performance of published preoperative and postoperative prognostic nomograms in a cohort of patients treated with radical prostatectomy as monotherapy for localized prostate cancer at Wayne State University in the prostate specific antigen era. Predictions made with the nomogram were stratified by race and compared with actual outcomes. The summary statistic used to evaluate the nomogram was the concordance index. A value of 0.5 indicates no predictive discrimination, whereas a value of 1.0 indicates perfect discrimination. RESULTS: A total of 1,043 patients, including 331 AAMs (32%) and 712 CAMs (68%), comprised the study cohort. Treatment failure was defined as increasing prostate specific antigen, which occurred in 193 patients (18.5%). The preoperative concordance index for CAMs and AAMs was 0.78 and 0.74, respectively (p = 0.8). The postoperative index was 0.85 and 0.83, respectively (p = 0.9). CONCLUSIONS: Preoperative and postoperative nomograms can be applied accurately to an individual regardless of race.

Bianco, F. J., Jr., I. J. Powell, et al. (2002). "Presence of circulating prostate cancer cells in African American males adversely affects survival." Urol Oncol 7(4): 147-152.

African-Americans (AAM) with prostate cancer are more likely to relapse than Caucasian-Americans (CAM) despite controlling for known prognostic factors. One explanation may be that micrometastatic disease in AAM behaves more aggressively than in CAM. We tested this hypothesis by comparing the reverse transcriptase polymerase chain reaction amplification of the Prostatic Specific Antigen-mRNA (RTPCR PSA-mRNA) results from peripheral blood samples of AAM and CAM with respect to disease outcome. We evaluated the peripheral blood of 246 consecutive patients at the time of radical prostatectomy. The RTPCR PSA-mRNA test for determination of circulating prostate cancer cells was performed. The results were stratified by races and correlated with standard clinico-pathological variables and disease free survival. 27% and 23% of AAM and CAM patients were RTPCR PSA-mRNA positive, respectively. The RTPCR PSA-mRNA status correlated with the pathologic stage in CAM but not in AAM, (p = 0.05). There was no association with Gleason score, PSA level, or clinical stage with the RTPCR PSA-mRNA status in either group. AAM with organ-confined prostate cancer were marginally more likely to have circulating prostate cells than similarly staged CAM (24% vs. 17%). In AAM but not CAM who had prostate cancer, the RTPCR PSA-mRNA status correlated with and was an independent predictor of disease-free survival. Our data suggests that, though the likelihood of having circulating prostate cells is the same in AAM and CAM, the presence of circulating prostate cells in AAM is predictive of a worse outcome. This may partially explain the worse prognosis in AAM vs. CAM with clinically localized prostate cancer.

Bianco, F. J., Jr., D. P. Wood, Jr., et al. (2003). "Ten-year survival after radical prostatectomy: specimen Gleason score is the predictor in organ-confined prostate cancer." Clin Prostate Cancer 1(4): 242-247.

Pathologic stage is a major prognostic factor in patients with clinically localized prostate cancer. However, disease recurrence occurs even in patients with organ-confined disease. With the advent of prostate-specific antigen (PSA) testing, the percentage of patients with pathologically organ-confined tumors has increased significantly. We studied clinical/pathologic factors that will predict disease recurrence in patients with pathologically organ-confined tumors. Patients with clinically localized newly diagnosed prostate cancer who had not received prior therapeutic intervention but who underwent radical prostatectomy as definitive treatment between 1990 and 1999, were included in this study. Clinical/pathologic parameters including age, race, clinical stage, preoperative PSA, and biopsy and specimen Gleason scores (grouped as 2-6, 7, and 8-10) were correlated with disease-free survival in patients with organ-confined disease. Metastasis-free and cancer-specific survival for the cohort was also assessed. A total of 1045 patients fulfilled our inclusion criteria. Overall, the 10-year estimates of PSA progression-free, metastasis-free, and cancer-specific survival were 75%, 91%, and 92%, respectively. Cancer was confined to the prostate in 532 of 1045 patients (51%), of whom 96% (511 of 532) remain PSA progression-free, compared to 65% (335 of 513) with extraprostatic disease (P = 0.0001). Interestingly, in patients with organ-confined disease, the specimen Gleason score was the only prognostic factor for disease recurrence after multivariable analysis. Radical prostatectomy provided excellent cancer control. For patients with pathologically organ-confined tumors, the specimen Gleason score is the only factor predictive of disease-free survival. Of note, Gleason scores of 8-10 are uncommon in these patients.

Bianco, F. J., Jr., D. P. Wood, Jr., et al. (2001). "Proliferation of prostate cancer cells in the bone marrow predicts recurrence in patients with localized prostate cancer." Prostate 49(4): 235-242.

BACKGROUND: Reverse-transcription polymerase chain reaction (RT-PCR) amplification of prostate specific antigen (PSA) mRNA has been used to detect the presence of prostate cancer cells in the peripheral blood and bone marrow of patients with clinically localized disease. Some studies have demonstrated a correlation between detection of PSA-mRNA and disease recurrence. However, many RT-PCR-positive patients remain disease-free. We propose that phenotypic characterization of individual micrometastatic cells may provide more prognostic information than mere detection of such cells. METHODS: We studied 58 patients undergoing radical prostatectomy for clinically localized disease whose bone marrow had been found to contain PSA-mRNA by RT-PCR. Immunohistochemical detection and phenotypic characterization of micrometastatic cells was performed using a two-color technique: cytokeratin antibody for detection and the MIB-1 antibody for proliferation. The clinical endpoint was disease recurrence. RESULTS: One or more micrometastatic cells were proliferating in 36.2% of the patients; the disease-free survival rate was 76.2% in this group. In contrast, in the patients with non-proliferating cells, 97.3% remained disease-free (P = 0.025). Multivariate analysis demonstrated that the presence of proliferating cells was the only preoperative variable that correlated with disease-free survival (P = 0.05). CONCLUSIONS: Determination of the phenotype of individual micrometastatic cells can contribute prognostic information above and beyond the mere determination of their presence or absence. Phenotypic characterization of individual micrometastatic cells may ultimately be used to select patients for systemic therapy given either alone or in combination with local therapy.

Bianco, F. J., Jr., D. P. Wood, Jr., et al. (2002). "Prostate cancer stage shift has eliminated the gap in disease-free survival in black and white American men after radical prostatectomy." J Urol 168(2): 479-482.

PURPOSE: The initiation of prostate specific antigen (PSA) testing has led to increased public awareness, early detection and a stage shift in prostate cancer. We have previously reported that black American men have worse disease-free survival independently of pathological or clinical factors. We tested the stage shift effects on disease-free survival in our cohort of patients treated with radical prostatectomy. MATERIALS AND METHODS: A total of 1,042 consecutive patients underwent radical prostatectomy performed by Wayne State University full-time faculty. The cohort was divided by the year of surgery as before (585 men in group 1) or after (457 in group 2) 1996. Clinicopathological and disease-free survival data were obtained from the Karmanos Cancer Institute multidisciplinary prostate cancer database. RESULTS: Improvements in clinical stage, preoperative PSA and biopsy Gleason score were observed in group 2 (p = 0.0001). Pathological organ confined disease increased in group 2 versus 1 in the 2 races, including 89 of 153 (58%) from 66 of 178 (37%) in black men and 189 of 304 (62%) from 194 of 407 (48%) in white men (p = 0.003 and 0.001, respectively). Calculated cancer recurrence-free median probability in group 1 at 42 months was 81% and 68% in white and black men, respectively (log rank test p = 0.001). These differences became insignificant in group 2 patients at 42 months with a median probability of 90% and 88% in white and black men, respectively (log rank test p = 0.39), representing a net increase in disease-free survival of 20% in black men. Specimen Gleason score, PSA and pathological stage were independent predictors of survival in the 2 groups. In contrast, race was an independent predictor only in group 1. CONCLUSIONS: The increased rate of pathological organ confined disease is translating into improved disease-free survival rates. These early data suggest that the survival gap in black and white American men is narrowing and may become statistically insignificant.

Binkley, N., G. Ellison, et al. (1999). "Rib biopsy technique for cortical bone evaluation in rhesus monkeys (Macaca mulatta)." Lab Anim Sci 49(1): 87-89.

Old World primates are often studied to model human skeletal physiology. An important advantage of monkeys over other animal models (i.e., rodents) is the presence of cortical bone Haversian remodeling. Seventy-five female rhesus monkeys (Macaca mulatta) were subjected to bone biopsy. With monkeys in lateral decubitus position, the tenth rib was surgically exposed and freed from periosteum by use of careful sharp and blunt dissection. The rib section was resected, using bone cutters, and the surgical wound was closed. This procedure was repeated for the contralateral rib at a later time point in 65 monkeys. There was no mortality or appreciable morbidity. The bone specimens were (mean +/- SD) 2.50 +/- 0.25 cm long, with 5.5 +/- 1.0 mm2 total cross-sectional area. They were adequate for histologic, immunohistochemical, and quantitative histomorphometric examinations. Prevalence of pneumothorax was approximately 8.0% for the 140 procedures. This complication was immediately and successfully corrected by insertion of a small thoracic tube, evacuation of pneumothorax, and closure of the incision. This well-tolerated, repeatable procedure yields excellent specimens for performance of cortical bone histologic examination without euthanasia, allowing longitudinal evaluation.

Birkmeyer, J. D. and D. C. Miller (2009). "Surgery: can checklists improve surgical outcomes?" Nat Rev Urol 6(5): 245-246.

In the quest to reduce the incidences of morbidity and mortality associated with surgery, a number of initiatives are being explored. Could a simple checklist provide an effective means of improving surgical outcome?

Blaivas, J., E. J. McGuire, et al. (2010). "Management of difficult cases in female urology and neurourology at the Reed M. Nesbit society meeting festschrift in honor of Edward J. McGuire, MD." Neurourol Urodyn 29 Suppl 1: S2-12.

This is a panel discussion of seven complex urologic cases in female urology and neurourology. Differences in diagnosis and management are discussed by this international panel of experts.

Blaivas, J. G., R. A. Appell, et al. (1997). "Definition and classification of urinary incontinence: recommendations of the Urodynamic Society." Neurourol Urodyn 16(3): 149-151.

Blaivas, J. G., R. A. Appell, et al. (1997). "Standards of efficacy for evaluation of treatment outcomes in urinary incontinence: recommendations of the Urodynamic Society." Neurourol Urodyn 16(3): 145-147.

Blane, C. E., M. Barr, et al. (1991). "Renal obstructive dysplasia: ultrasound diagnosis and therapeutic implications." Pediatr Radiol 21(4): 274-277.

57 cases of renal obstructive dysplasia (defined as the abnormal development of nephronic and ductal structures due to in utero obstruction of the urinary tract) were evaluated in terms of sonographic findings, renal and other associated anomalies, and current status of the child. More than one-third of the cases had bilateral disease and although not uniformly fatal bilateral involvement was associated with significant morbidity and mortality. In 12 of the 33 cases with unilateral dysplasia there was an association with contralateral renal problems including uretero-pelvic junction obstruction, vesicoureteral reflux and aplasia. Almost one-half of the cases had congenital anomalies, these included VACTERL association, congenital heart disease, cranial abnormalities and gastrointestinal malformations. Fifteen stillborns and 12 of the patients with bilateral involvement and four with unilateral involvement have died. Four patients are on dialysis (two with bilateral involvement and two with unilateral renal obstructive dysplasia). Only one-quarter are otherwise normal. More serious problems are reported in this mixed age population of patients with obstructive renal dysplasia than has been identified in previous studies. Management decisions of the fetus and child must be based on this new age-expanded population.

Blane, C. E., M. A. DiPietro, et al. (1988). "Percutaneous nephrostogram in the newborn with bilateral renal cystic disease." Am J Dis Child 142(12): 1349-1351.

Percutaneous antegrade pyelography should be considered in the few, select, critically ill newborns with bilateral renal cystic disease when the diagnosis is critical to management and difficult with the usual imaging procedures. Two extremely ill newborns with severe oliguria and cystic abnormalities in both kidneys by ultrasound underwent sonographic guidance for percutaneous antegrade nephrostograms in the first week of life. With injection of contrast medium, definitive diagnoses were made of a multicystic dysplastic kidney on one side and an obstructed hydronephrotic kidney on the other, thereby directing decompression of the obstructed kidney to preserve native renal function. This procedure can provide a definitive diagnosis in these rare but difficult cases.

Blane, C. E., M. A. DiPietro, et al. (2003). "Pediatric renal pelvic fullness: an ultrasonographic dilemma." J Urol 170(1): 201-203.

PURPOSE: We conducted a prospective study to define normal renal pelvic size in children. MATERIALS AND METHODS: Institutional Review Board approved consent was obtained to perform renal ultrasound during excretory urography (IVP) scheduled for medical management. Mean patient age (17 females, 11 males) was 5.2 years. Renal ultrasound was conducted concurrent with 10-minute IVP. RESULTS: Fifty kidneys were imaged with 51 collecting systems. IVP defined 44 collecting systems as normal. Mean anteroposterior pelvic diameter on sonography for these 44 systems was 3.3 mm. One normal collecting system on IVP had a diameter greater than 10 mm on ultrasound (14 mm). No sonographic caliceal dilatation was seen in any kidney appearing normal on IVP. The 7 dilated systems on IVP had a mean ultrasound diameter of 17.1 mm. Two dilated collecting systems smaller than 10 mm in diameter on sonography had caliceal distention on ultrasound. CONCLUSIONS: Normal renal pelvis threshold diameter was 10 mm in asymptomatic children. We recommend further evaluation in children with caliceal dilatation and/or dilatation of the anteroposterior renal pelvis greater than 10 mm. Using these criteria, no system appearing abnormal on IVP would have been missed.

Blane, C. E., M. A. DiPietro, et al. (1993). "Renal sonography is not a reliable screening examination for vesicoureteral reflux." J Urol 150(2 Pt 2): 752-755.

A retrospective analysis of 493 infants and children was performed to determine the reliability of renal sonography for identifying vesicoureteral reflux. Sonography was done in all cases within 8 hours of a voiding cystourethrogram. Vesicoureteral reflux was documented in 272 of 986 kidneys on voiding cystourethrography and there were 201 refluxing kidneys with normal ultrasound (25 with grade I reflux, 119 with grade II, 50 with grade III, 6 with grade IV and 1 with grade V). In 71 of the refluxing kidneys the ultrasound was abnormal due to pelvicaliceal dilatation in 45, a duplication anomaly in 6 and renal fossae abnormality in 20. Of the kidneys with vesicoureteral reflux 74% were sonographically normal. Sonography was not sufficiently sensitive or specific for detecting vesicoureteral reflux, since 28% of the missed refluxing kidneys had grade III or higher reflux.

Blane, C. E., M. L. Ritchey, et al. (1992). "Single system ectopic ureters and ureteroceles associated with dysplastic kidney." Pediatr Radiol 22(3): 217-220.

Eight children forming an uncommon subgroup of renal obstructive dysplasia are presented. Each child had a nonfunctioning dysplastic kidney with a single collecting system with ectopic ureteral insertion and/or ureterocele. Five of the children had classic multicystic dysplastic kidneys, one had the hydronephrotic type of multicystic dysplastic kidney and two had hypoplastic kidneys. Other significant medical problems in 5 of the 8 children (63%) included VACTERL association, congenital heart disease and other genitourinary malformations. Unlike some children with unilateral multicystic dysplastic kidney, this subgroup of children has an increased risk of infection. They must be correctly identified on imaging so that tailored clinical management decisions can be made and associated anomalies detected.

Blane, C. E., J. M. Zerin, et al. (1994). "Bladder diverticula in children." Radiology 190(3): 695-697.

PURPOSE: The frequency, number, and underlying associations of bladder diverticula were studied in a pediatric population. MATERIALS AND METHODS: Eighty-five children with bladder diverticula (31 girls and 54 boys) were retrospectively identified in a pediatric genitourinary data base of 5,084 children. RESULTS: Primary bladder diverticula were seen in 20 children with vesicoureteral reflux and 14 children without reflux. Fifty-one of the 85 children (60%) had associated neurogenic dysfunction of the bladder (n = 26), outlet obstruction (n = 14), or a syndrome (n = 9) or were postoperative (n = 2). A single child of the 26 with multiple bladder diverticula had no associated condition. CONCLUSION: In this population, bladder diverticula were found in 1.7% of the children. The presence of more than one diverticulum on a side was usually associated with neurogenic dysfunction of the bladder, bladder outlet obstruction, or syndromes such as Williams, Menkes, prune-belly, or Ehlers-Danlos type 9 syndromes.

Blei, L., S. Sihelnik, et al. (1983). "Ultrasonographic analysis of chronic intratesticular pathology." Journal of Ultrasound in Medicine 2: 17-23.

Bloom, D. A. (1979). "Update in clinical pathology: the odontogenic keratocyst." J Macomb Dent Soc 16(5): 7-11.

Bloom, D. A. (1991). "Two-step orchiopexy with pelviscopic clip ligation of the spermatic vessels." J Urol 145(5): 1030-1033.

Ten boys with nonpalpable testes located in the peritoneal cavity underwent celiopelviscopy and clip ligation of the spermatic vessels with the intent of augmenting vasal collateral blood flow. After intervals in excess of 6 months, 7 patients underwent vas-based orchiopexy following division of the occluded spermatic vessels. Six boys had good results as judged by size of the relocated testes. In 1 boy the testis atrophied. He had undergone previous inguinal-only exploration before referral to us for celiopelviscopy and at stage 2 orchiopexy a silk suture was found on the vas deferens.

Bloom, D. A. (1995). "Digestive mucosal graft in urethroplasty." Eur Urol 28(3): 266.

Bloom, D. A. (1997). "Hippocrates and urology: the first surgical subspecialty." Urology 50(1): 157-159.

Hippocrates, who is generally considered a focal point for the start of western medical tradition, left behind a corpus of medical writings that constituted the first recorded comprehensive health system. The pivotal point of the Hippocratic corpus was the Hippocratic Oath, which outlined the duties of healers of his school, but demarcated lithotomy as a practice that was off limits to his fellow physicians. Surgery for bladder stone, urology in essence, was thus the first specifically identified surgical subspecialty.

Bloom, D. A. (1997). "Testicular descent and ascent in the first year of life." Urology 50(5): 826.

Bloom, D. A. (1999). "Wombat uroflowmetry." BJU Int 83(3): 365.

Bloom, D. A. (2000). "Acronyms, abbreviations and initialisms." BJU Int 86(1): 1-6.

Bloom, D. A. (2000). "Overactive bladder: paediatric aspects." BJU Int 85 Suppl 3: 43-44; discussion 45-46.

Bloom, D. A. (2003). "State-of-the Section Address: American Academy of Pediatrics, Section on Urology. The origin of a species: pediatric urology." J Urol 170(4 Pt 2): 1488-1492.

Bloom, D. A. (2010). "Editorial comment." J Urol 183(5): 2019.

Bloom, D. A. (2010). "A gentle reminder." Pediatr Radiol 40(8): 1323.

Bloom, D. A., B. H. Adler, et al. (2003). "Congenital piriform fossa sinus tract presenting as an asymptomatic neck mass in an infant." Pediatr Radiol 33(5): 360-363.

BACKGROUND: A 5-month-old girl with an asymptomatic left-sided neck mass was demonstrated by ultrasound and upper gastrointestinal series (UGI), and confirmed at surgery, to have a congenital piriform fossa sinus tract (CPFST) that communicated with an intrathyroidal cyst. OBJECTIVE: To demonstrate a case of CPFST presenting as an asymptomatic neck mass. Nearly all cases of CPFST present with infection or pain, making this case unique. MATERIALS AND METHODS: Case report and review of the literature. CONCLUSIONS: CPFST with an associated cyst should be added to the differential diagnosis of asymptomatic cystic neck masses in infants, especially if the cyst is intrathyroidal by ultrasound.

Bloom, D. A., K. E. Applegate, et al. (1996). "Pediatric case of the day. Ectopic cervical thymus." Radiographics 16(1): 204-206.

Bloom, D. A., J. W. Ayers, et al. (1988). "The role of laparoscopy in management of nonpalpable testes." J Urol (Paris) 94(9-10): 465-470.

Laparoscopy is the ideal first operative step in management of boys with nonpalpable testes. No other investigation is as reliable in locating a nonpalpable testis or in confirming its absence. Whatever the laparoscopic findings, further operative intervention is generally necessary and the laparoscopic findings determine the subsequent operative steps. Laparoscopy also permits endoscopic manipulation such as application of a spermatic vessel clip for staged Fowler-Stephens orchidopexy. Herein we report our experiences with laparoscopy in 30 patients with nonpalpable testes.

Bloom, D. A. and S. Brosman (1978). "The multicystic kidney." J Urol 120(2): 211-215.

Bloom, D. A., C. Buonomo, et al. (1999). "Allergic colitis: a mimic of Hirschsprung disease." Pediatr Radiol 29(1): 37-41.

BACKGROUND: Allergy to cow milk protein is a common cause of gastrointestinal symptoms in infancy. Milk allergy is usually a clinical diagnosis, and thus there have been few reports of the radiographic findings. OBJECTIVE: To describe the barium enema findings of allergic colitis and differentiate them from Hirschsprung disease. Materials and methods. Four infants (age range 7 days-5 weeks) with constipation underwent barium enema to exclude Hirschsprung disease. Radiographic findings were correlated with the pathologic specimens from suction rectal biopsy. RESULTS: All enemas revealed irregular narrowing of the rectum and a transition zone. Rectal biopsies in each case demonstrated ganglion cells and evidence of an allergic colitis, with inflammatory infiltrates in the lamina propria. A diagnosis of milk allergy colitis was made and symptoms resolved after removal of milk from the diet. CONCLUSIONS: Milk allergy is common in infancy. The rectum is a primary target organ, with allergic colitis often diagnosed on clinical grounds alone. However, a child with allergic colitis may be referred to radiology for barium enema, especially if constipation is present. The radiologist should be aware of the unique imaging findings of allergic colitis, so as to avoid confusion with Hirschsprung disease and perhaps an unnecessary rectal biopsy.

Bloom, D. A., J. W. Burnett, et al. (1998). "Partial purification of box jellyfish (Chironex fleckeri) nematocyst venom isolated at the beachside." Toxicon 36(8): 1075-1085.

Chironex fleckeri, the northern Australian box jellyfish produces one of, if not, the most potent animal venoms. Study of the venom has been hampered by the limits of the animals' range and the venom's thermolability. Using retained lethality and native polyacrylamide gel electrophoresis (NPAGE), we show that lyophilization of autolysis isolated nematocysts is an effective method of transporting the venom. In addition, Sephadex G-200 chromatography, spin concentration, and NPAGE fail to demonstrate the presence of a 600 kDa protein to which the bulk of the lethal activity has been ascribed. Sodium dodecyl sulfate capillary electrophoresis of crude venom yields several protein bands with a molecular weight range of 30-200 kDa. Freeze-thaw studies show a loss of activity and NPAGE bands after two freeze thaw cycles.

Bloom, D. A., J. W. Burnett, et al. (1999). "Effects of verapamil and CSL antivenom on Chironex fleckeri (box-jellyfish) induced mortality." Toxicon 37(11): 1621-1626.

Ovine antivenom prolonged survival in mice challenged with intravenous Chironex fleckeri venom over a limited dose range. Verapamil enhanced the beneficial effect of ovine antivenom. This data suggests that there may be an, as yet undefined, optimal antivenom dose for humans and that verapamil, used in combination with antivenom is an effective agent.

Bloom, D. A., R. V. Clayman, et al. (1999). "Stents and related terms: a brief history." Urology 54(4): 767-771.

Bloom, D. A., M. A. DiPietro, et al. (1987). "Extratesticular dermoid cyst and fibrous dysplasia of epididymis." J Urol 137(5): 996-997.

Bloom, D. A. and R. M. Ehrlich (1993). "Omental evisceration through small laparoscopy port sites." J Endourol 7(1): 31-32; discussion 32-33.

Two children developed omental evisceration through small periumbilical port sites after peritoneal endoscopy for nonpalpable testes. Factors that predispose to this complication include decompression of the pneumoperitoneum by suction. These factors and steps to avoid it such as closure of all endoscopic fascial defects under direct vision are described.

Bloom, D. A., G. Faerber, et al. (1995). "Urinary incontinence in girls. Evaluation, treatment, and its place in the standard model of voiding dysfunctions in children." Urol Clin North Am 22(3): 521-538.

Urinary incontinence is the principle voiding dysfunction of childhood. This can be viewed as one among many dysfunctions in our standard model of voiding dysfunction. A careful elimination history is essential to manage any voiding dysfunction.

Bloom, D. A. and E. W. Fonkalsrud (1974). "Surgical management of pheochromocytoma in children." J Pediatr Surg 9(2): 179-184.

Bloom, D. A., E. W. Fonkalsrud, et al. (1976). "Malignant hyperpyrexia during anesthesia in childhood." J Pediatr Surg 11(2): 185-190.

Malignant hyperpyrexia is a highly lethal complication of general anesthesia. It occurs with sufficient frequency, particularly in children and young adults, to justify use of continuous temperature monitoring during adminnstration of general anesthesia. Fever may be a late manifestation of the malignant hyperpyrexia syndrome, and it is important to be aware of the early signs. Prompt recognition and aggressive management should lower the high mortality known to occur with this complication. Family members should be screened for CPK elevations to determine possible susceptibility to malignant hyperpyrexia. Two case reports illustrate these points of diagnosis and management.

Bloom, D. A., W. D. Foster, et al. (1985). "Cost-effective uroflowmetry in men." J Urol 133(3): 421-424.

A simple method of timed urine flow measurement performed at home by the patient is compared to instrumental measurements of peak flow rate. The timed method correlates well with the peak flow rate. Timed uroflowmetry is free, can be done in the privacy of the home and provides multiple measurements. This is a valid technique to document a weak stream and is a useful screening test for patients with lower urinary tract obstruction.

Bloom, D. A., E. J. Guiney, et al. (1994). "Normal and abnormal pelviscopic anatomy at the internal inguinal ring in boys and the vasal triangle." Urology 44(6): 905-908.

OBJECTIVES. We sought to explain and define normal and abnormal laparoscopic pelvic anatomy, which has only recently become the target of much attention. METHODS. The embryology, normal anatomic landmarks, and abnormal findings of the male pelvis, as discerned from more than 350 laparoscopic investigations in boys, were analyzed. RESULTS. The medial umbilical ligament, the wishbone at the internal inguinal ring, the transverse vesical fold, and the vasal triangle are principal laparoscopic landmarks of the male pelvis. Deficient spermatic vessels, abnormal gonadal locations, patent processus vaginalis, single medial umbilical ligament, and transverse testicular ectopia were the abnormal findings. CONCLUSIONS. Laparoscopic familiarity with the male pelvis permits safe and efficient diagnostic and therapeutic navigation in this new surgical arena.

Bloom, D. A. and T. Hensle (2000). "A chat with John Lattimer." Urology 56: 179-181.

Bloom, D. A. and F. Hinman, Jr. (2003). "Frank Hinman, Sr: a first generation urologist." Urology 61(4): 876-881.

Bloom, D. A., W. Husser, et al. (2002). "A conversation with Earl Nation." Urology 59(6): 983-986.

Bloom, D. A., K. Iwamoto, et al. (1981). "Management of malignant hyperthermia." J Urol 125(4): 594-597.

A case of malignant hyperthermia in a young girl with vesicoureteral reflux and multiple congenital abnormalities is discussed. Malignant hyperthermia is a relatively newly defined problem that is associated with anesthesia. It is being recognized with increasing frequency, particularly in children with multiple musculoskeletal anomalies. The term itself is a misnomer. It is a drug-induced syndrome of hypermetabolism that may represent an inborn error of metabolism. Recognition, prophylaxis and crisis management are reviewed, and the use of dantrolene sodium in the care of patients with malignant hyperthermia is discussed. Because recognition of malignant hyperthermia is an important concern for the practicing urologist, the principles of identifying the patient at risk, as well as managing the crisis, should be familiar to the clinician.

Bloom, D. A. and A. K. Jaiswal (2003). "Phosphorylation of Nrf2 at Ser40 by protein kinase C in response to antioxidants leads to the release of Nrf2 from INrf2, but is not required for Nrf2 stabilization/accumulation in the nucleus and transcriptional activation of antioxidant response element-mediated NAD(P)H:quinone oxidoreductase-1 gene expression." J Biol Chem 278(45): 44675-44682.

The antioxidant response element (ARE) and transcription factor Nrf2 regulate basal expression and antioxidant induction of NAD(P)H:quinone oxidoreductase-1 (NQO1) and other detoxifying genes. Under normal conditions, Nrf2 is targeted for proteasomal degradation by INrf2. Oxidative stress causes release of Nrf2 from INrf2. Nrf2 translocates to the nucleus, binds to the ARE, and activates gene expression. In this study, we demonstrate that protein kinase C (PKC) plays a significant role in the regulation of ARE-mediated NQO1 gene expression and induction in response to t-butylhydroquinone. Treatment of HepG2 cells with the PKC inhibitors staurosporine and calphostin C repressed ARE-mediated induction of a luciferase reporter as well as that of the endogenous NQO1 gene. Similar experiments with inhibitors of MEK/ERK, p38, phosphatidylinositol 3-kinase, and tyrosine kinases failed to repress ARE-mediated gene expression. The PKC inhibitor staurosporine blocked the nuclear translocation of Nrf2, suggesting that Nrf2 might be the target for PKC regulation. A Prosite search revealed the presence of seven putative PKC sites in mouse Nrf2. The PKC site at Ser40 is conserved among species and lies in the Neh2 domain, which interacts with INrf2. We demonstrate that phosphorylation of Ser40 is necessary for Nrf2 release from INrf2, but is not required for Nrf2 stabilization/accumulation in the nucleus and transcriptional activation of ARE-mediated NQO1 gene expression. A peptide that competes with endogenous Nrf2 for INrf2 binding was able to induce ARE activity more effectively than t-butylhydroquinone, and Nrf2 that accumulated in the nucleus as a result was not phosphorylated.

Bloom, D. A., J. J. Kaufman, et al. (1981). "Late recurrence of renal tubular carcinoma." J Urol 126(4): 546-548.

Bloom, D. A., J. M. Knechtel, et al. (1990). "Urethral dilation improves bladder compliance in children with myelomeningocele and high leak point pressures." J Urol 144(2 Pt 2): 430-433; discussion 443-434.

Among 350 children with myelomeningocele 18 with elevated leak point pressures were managed by urethral dilation and followed for 1 to 5 years. Longitudinal measurements of bladder compliances revealed durable improvement in the pressure-volume relationships after dilation. These data suggest that noncompliant bladders are acquired because of high outlet resistance, and early intervention may improve long-term bladder storage characteristics.

Bloom, D. A. and B. A. Kogan (2001). "Conversations with Frank Hinman, Jr." Urology 57(4): 843-846.

Bloom, D. A. and H. P. Koo (1997). "Comments on bilateral neonatal testicular torsion." Clin Pediatr (Phila) 36(11): 657-658.

Bloom, D. A. and H. P. Koo (1999). "The circumcision issue." Clin Pediatr (Phila) 38(4): 243-244.

Bloom, D. A. and H. P. Koo (2000). "Routine and ritual circumcision is a multi-cultural phenomenon." Clin Pediatr (Phila) 39(2): 129.

Bloom, D. A., J. Lapides, et al. (1995). "Reed Nesbit and pediatric urology." Urology 45(2): 296-307.

OBJECTIVES. To ascertain the pediatric urology experience and contributions of Reed Nesbit, a urologist known primarily as an educator, transurethral resectionist, and prostate expert. METHODS. The writings of Nesbit and appropriate background references were analyzed. RESULTS. Nesbit's contributions to pediatric urology, particularly the Cabot-Nesbit orchidopexy, the buttonhole preputial transposition, the dorsal tunical tuck for chordee, and the elliptical anastomosis were significant. CONCLUSIONS. Nesbit's contributions to pediatric urology were innovative and enduring.

Bloom, D. A., R. L. Lebowitz, et al. (1997). "Correlation of cystographic bladder morphology and neuroanatomy in boys with posterior urethral valves." Pediatr Radiol 27(6): 553-556.

PURPOSE: We have observed a difference in the radiographic appearance of the body of the bladder (trabeculated) and its base (smooth) in boys with severely obstructing posterior urethral valves. We wanted to determine if (1) this was a reproducible finding and (2) there was an anatomic and/or physiologic explanation for it. MATERIALS AND METHODS: We reviewed the initial voiding cystourethrogram in 47 boys with severe posterior urethral valves. The interureteric ridge was used as the division between the body and base of the bladder. The presence of trabeculation for each region was recorded. RESULTS: Ages ranged from 1 day to 6 years at the time of initial cystographic evaluation (median 14 days). The body of the bladder was trabeculated and the base smooth in 72 % (34 patients). In the remaining patients, both the body and base were smooth. In no patient was the base trabeculated. CONCLUSIONS: The cystographic morphology of the urinary bladder in boys with posterior urethral valves can be explained by its neuroanatomy. The body of the bladder, which contracts during voiding because of parasympathetic (cholinergic) stimulation, becomes trabeculated. The bladder base relaxes during voiding due to sympathetic (alpha adrenergic) stimulation and remains smooth. Thus, this difference in the cystographic appearance of the two parts of the urinary bladder reflects the normal innervation and the mechanics of micturition in boys with urethral obstruction.

Bloom, D. A., G. Lieskovsky, et al. (1983). "The Turnbull loop stoma." J Urol 129(4): 715-718.

The stoma is the weak link of external urinary diversion. Improper stomal position or configuration produces the unnecessary burden of leakage for the patient with diversion. Stomal bleeding, incrustation and peristomal dermatitis cause inconvenience and expense. Stomal stenosis is the most common reason for repeat operation of an ileal conduit. The Turnbull loop stoma obviates many of these problems. We have performed 100 urinary diversions using this stoma with minimal stomal complications and no episodes of stomal stenosis from 1 to 7 years postoperatively. The significant complication has been parastomal hernia. Minor modifications of the technique have lowered the incidence of hernia. Loop stomas are our principal form of stomal construction.

Bloom, D. A. and E. McGuire (1989). "Practical management of children with myelomeningocele." Dialogues in Pediatric Urology 12: 3-4.

Bloom, D. A. and E. McGuire (1991). "Collagen injection therapy in children with myelodysplasia." Dialogues in Pediatric Urology 14: 2.

Bloom, D. A., E. J. McGuire, et al. (2005). "Rudolph Hohenfellner." J Urol 174(4 Pt 2): 1517-1518, cover.

Bloom, D. A., E. J. McGuire, et al. (1994). "A brief history of urethral catheterization." J Urol 151(2): 317-325.

Bloom, D. A., M. T. Milen, et al. (1999). "Claudius Galen: from a 20th century genitourinary perspective." J Urol 161(1): 12-19.

PURPOSE: We review the life and contributions of Claudius Galen from a 20th century perspective and examine his genitourinary observations. MATERIALS AND METHODS: All obtainable English translations of Galen's works were explored in addition to relevant commentaries. RESULTS: Galen's remarkable observations and novel concepts expanded medical knowledge in general and contributed to fundamental genitourinary principles in particular. Galen was one of the first to describe correctly the function of kidneys and explain micturition. Among his many neologisms he coined the term ureter, and he was probably the first to recognize the value of a competent ureterovesical valve. Galen advocated catheterization for urinary obstruction. He was a teacher, practitioner and philosopher, and wrote voluminously. CONCLUSIONS: Galen's influence on medical theory, terminology and practice remained unquestioned in Europe and the Middle East throughout the Middle Ages and Renaissance.

Bloom, D. A., R. J. Morgan, et al. (1989). "Thomas Hillier and percutaneous nephrostomy." Urology 33(4): 346-350.

Bloom, D. A., R. N. Mory, et al. (1992). "Dilation vs. dilatation: a brief history." J Urol 147(6): 1682.

Bloom, D. A. and J. M. Park (2003). "Dryness and the urological armamentarium." J Urol 169(1): 330.

Bloom, D. A., J. M. Park, et al. (1998). "Comments on pediatric elimination dysfunctions: the Whorf hypothesis, the elimination interview, the guarding reflex and nocturnal enuresis." Eur Urol 33 Suppl 3: 20-24.

AIMS OF STUDY: This paper addresses pediatric elimination disorders including nocturnal enuresis from the perspectives of terminology (the Whorf hypothesis), the elimination interview, and the guarding reflex. METHODS: The elimination interview and a modern model of normal voiding function, including the guarding reflex, are explained. RESULTS: The language of voiding dysfunction influences our perception of it. Nocturnal enuresis, and all other voiding dysfunctions, should be evaluated by a careful elimination interview. The guarding reflex may fit into an evolving etiologic paradigm for nocturnal enuresis. CONCLUSIONS: (1) Words and phrases of eliminology should aim for simplicity, clarity and accuracy. (2) Urologists need to perfect their eliminology skills vis-a-vis the elimination interview. (3) The role of the guarding reflex in nocturnal enuresis and all other voiding dysfunctions should be critically examined.

Bloom, D. A., F. F. Radwan, et al. (2001). "Toxinological and immunological studies of capillary electrophoresis fractionated Chrysaora quinquecirrha (Desor) fishing tentacle and Chironex fleckeri Southcott nematocyst venoms." Comp Biochem Physiol C Toxicol Pharmacol 128(1): 75-90.

Repeated runs of capillary electrophoresis (CE) were used to study partially-purified jellyfish nematocyst venom protein in concentrations sufficient to perform toxinological assays. Nematocyst venoms from Chironex fleckeri (Cf) and Chysaora quinquecirrha were processed. The CE eluate was divided into quadrants by scanning protein content. The fourth fraction of both jellyfish venoms, contained proteins with the smallest molecular weight components, which were responsible for the highest hemolysins and the humoral and cell-mediated immunological activity. Cytotoxic Cf lethal factor activity against human liver cells was widely dispersed throughout both venoms but more prominent in fraction 4. A V(beta) receptor human T-cell repertoire was not species-specific for either crude or fractionated jellyfish nematocyst venom.

Bloom, D. A., M. L. Ritchey, et al. (1993). "Pediatric peritoneoscopy (laparoscopy)." Clin Pediatr (Phila) 32(2): 100-104.

Bloom, D. A. and P. T. Scardino (2009). "Peter Lester Scardino--a genitourinary surgeon in third generation of the specialty: part 1." Urology 73(5): 940-943.

Bloom, D. A. and P. T. Scardino (2009). "Peter Lester Scardino--a genitourinary surgeon in third generation of the specialty: part 2." Urology 73(5): 944-946.

Bloom, D. A., P. T. Scardino, et al. (1982). "The significance of lymph nodal involvement in renal angiomyolipoma." J Urol 128(6): 1292-1295.

Renal angiomyolipoma, a benign tumor, can involve regional lymph nodes. Although this phenomenon has been reported previously followup information has been scant. We have treated 3 patients who had renal angiomyolipoma with nodal involvement and all had further evidence of tuberous sclerosis. Each patient had hematuria with flank pain and required nephrectomy. In the ensuing 3 to 11 years none of these patients has had evidence of further disease progression. Nodal involvement may reflect the multicentricity of angiomyolipoma or may represent a form of "benign metastasis" but it does not appear to be a harbinger of disease progression.

Bloom, D. A., D. Schofield, et al. (1997). "Radiologic-pathologic conference of Children's Hospital Boston: a palpable pelvic mass in an adolescent girl." Pediatr Radiol 27(11): 888-891.

Bloom, D. A., W. W. Seeley, et al. (1993). "Toilet habits and continence in children: an opportunity sampling in search of normal parameters." J Urol 149(5): 1087-1090.

An opportunity sampling of 1,192 children regarding parameters of toilet training and elimination status was obtained by interview and questionnaire. Toilet training ages ranged from 0.75 to 5 years, with a mean of 2.4 +/- 0.6 years (standard deviation). Voiding frequency was inversely related to age; most children between 3 and 12 years old urinated 5 to 6 times per day. Influences of gender, urinary infections and parental recall were investigated. Nocturnal and diurnal enuresis was reported in 18% and 10% of our sample, respectively. Bowel movements per week ranged from 1 to 21, with a mean of 6.8 +/- 2.5.

Bloom, D. A., G. Uznis, et al. (1998). "Charles B.G. de Nancrede: academic surgeon at the fin de siecle." World J Surg 22(11): 1175-1181.

At the last turn of the century American surgery was in the midst of a number of paradigm shifts, involving transitions in technology, surgical practice, surgical specialization, patient care, surgical training, and medical economics. Charles B. G. de Nancrede was a leader during this formative period. A key figure in the transition from antiseptic to sterile technique in American medicine, he was also a prolific writer, a bold surgeon, and a great surgical educator. De Nancrede created one of the earliest prototypes of the modern multispecialty surgical departments. The coming turn of the century promises new transitions comparable to those of the past.

Bloom, D. A., G. Uznis, et al. (1998). "Frederick C. McLellan and clinical cystometrics." Urology 51(1): 168-172.

Precise analysis of lower urinary tract function was an unfulfilled dream only a century ago. By the late 19th century, water manometers and plethysmographs were utilized to measure bladder pressures. In the early 1900s, Rose developed a cystometer that was later improved by Munro. In 1938 Frederick C. McLellan, active in clinical research under Reed Nesbit at the University of Michigan, was the first to apply the earlier principles and cystometric tools to a large group of patients and created the first modern paradigm of bladder dysfunction. McLellan's work brought clinical relevance to the cystometer and thus precision to the analysis of lower urinary tract function.

Bloom, D. A., J. Wan, et al. (1993). "Distal intussusception of processus vaginalis: a cause of acute hydrocele." Urology 42(1): 76-78.

Acute obstruction of a patent processus vaginalis occurred in two boys, mimicking incarceration of an inguinal hernia. In fact, obstruction was caused by an intussusception of the processus vaginalis forming an intussuscipiens that occluded the hernia sac. This lesion, described previously in 1896 and in 1974, is one of the mechanisms by which an asymptomatic hernia or hydrocele becomes acutely symptomatic.

Bloom, D. A., J. Wan, et al. (2000). "Barometers and bladders: a primer on pressures." J Urol 163(3): 697-704.

PURPOSE: We develop a "consilient" (unified) view of pressure as a physical phenomenon and "clinimetric" tool, making a connection between barometers and bladders. MATERIALS AND METHODS: The philosophy, physics and clinical applications of pressure during the last 2 millennia were examined from Lucretius to the modern medical subspecialties. RESULTS: A variety of units and systems of pressure quantification developed as the physics of pressure became understood. Applications of pressure in clinical medicine with distinct physiological relevance have been created for organ systems across the subspecialties. Some measurements have become useful for management of urinary tract and other diseases. CONCLUSIONS: Despite a broad range of units, systems and applications, a consilient view of pressure in medicine can be approached. This perspective is fundamental to understanding the significance of pressures in the expanding clinimetric arena and should mitigate against misplaced concreteness that is tempting in modern medical practice, whereby laboratory tests become virtual realities and are mistaken for patients.

Blute, M. L., E. J. Bergstralh, et al. (2000). "Validation of Partin tables for predicting pathological stage of clinically localized prostate cancer." J Urol 164(5): 1591-1595.

PURPOSE: The accurate prediction of pathological stage of prostate cancer using preoperative factors is a critical aspect of treatment. In 1997 Partin et al published tables predicting pathological stage using clinical stage, Gleason score and prostate specific antigen (PSA). We tested the validity of the Partin tables. MATERIALS AND METHODS: From 1990 to 1996 inclusively 5,780 patients underwent bilateral pelvic lymphadenectomy and radical prostatectomy for prostate cancer at the Mayo Clinic. However, only 2,475 of these patients met all inclusion criteria of no preoperative treatment, known biopsy Gleason score, available preoperative PSA done either before biopsy or more than 28 days after biopsy and clinical stage T1, T2 or T3a. Among the 2,475 patients 15 had positive lymph nodes and planned prostatectomy was abandoned. The receiver operating characteristics (ROC) curve area, observed and predicted Partin rates of each pathological stage, and positive and negative predictive values were used to compare the Mayo study to the Partin tables. RESULTS: The distribution of pathological stage was organ confined in 67% of Mayo cases versus 48% in the Partin study, extracapsular without seminal vesicle or node involvement in 18% versus 40%, seminal vesicle involvement without nodes in 9% versus 7% and were positive nodes in 6% versus 5%. Using the predicted probabilities of Partin et al the ROC curve area for predicted node positive disease was 0.84 for Mayo cases compared to an estimated 0. 82 in the Partin series. The ROC curve area for predicting organ confined cancer was 0.76 for the Mayo Clinic compared to an estimated 0.73 for the Partin series. The observed rates of node positive disease were similar to those predicted (Partin) based on clinical stage, PSA and Gleason score. For organ confined disease Mayo rates were consistently higher than those predicted from the Partin series using a cut point of 0.50 or greater. Positive and negative predictive values were 0.83 and 0.49 versus 0.63 and 0.70 for the Mayo Clinic and Partin series. CONCLUSIONS: Our study provides strong evidence that sensitivity and specificity of the Partin tables for external clinical sites are similar to what was reported.

Blute, M. L., E. J. Bergstralh, et al. (2000). "Validation of Partin tables for predicting pathological stage of clinically localized prostate cancer. [see comments.]." Journal of Urology 164(5): 1591-1595.

PURPOSE: The accurate prediction of pathological stage of prostate cancer using preoperative factors is a critical aspect of treatment. In 1997 Partin et al published tables predicting pathological stage using clinical stage, Gleason score and prostate specific antigen (PSA). We tested the validity of the Partin tables. MATERIALS AND METHODS: From 1990 to 1996 inclusively 5,780 patients underwent bilateral pelvic lymphadenectomy and radical prostatectomy for prostate cancer at the Mayo Clinic. However, only 2,475 of these patients met all inclusion criteria of no preoperative treatment, known biopsy Gleason score, available preoperative PSA done either before biopsy or more than 28 days after biopsy and clinical stage T1, T2 or T3a. Among the 2,475 patients 15 had positive lymph nodes and planned prostatectomy was abandoned. The receiver operating characteristics (ROC) curve area, observed and predicted Partin rates of each pathological stage, and positive and negative predictive values were used to compare the Mayo study to the Partin tables. RESULTS: The distribution of pathological stage was organ confined in 67% of Mayo cases versus 48% in the Partin study, extracapsular without seminal vesicle or node involvement in 18% versus 40%, seminal vesicle involvement without nodes in 9% versus 7% and were positive nodes in 6% versus 5%. Using the predicted probabilities of Partin et al the ROC curve area for predicted node positive disease was 0.84 for Mayo cases compared to an estimated 0. 82 in the Partin series. The ROC curve area for predicting organ confined cancer was 0.76 for the Mayo Clinic compared to an estimated 0.73 for the Partin series. The observed rates of node positive disease were similar to those predicted (Partin) based on clinical stage, PSA and Gleason score. For organ confined disease Mayo rates were consistently higher than those predicted from the Partin series using a cut point of 0.50 or greater. Positive and negative predictive values were 0.83 and 0.49 versus 0.63 and 0.70 for the Mayo Clinic and Partin series. CONCLUSIONS: Our study provides strong evidence that sensitivity and specificity of the Partin tables for external clinical sites are similar to what was reported. <45>

Bochner, B. H., M. W. Kattan, et al. (2006). "Postoperative nomogram predicting risk of recurrence after radical cystectomy for bladder cancer." J Clin Oncol 24(24): 3967-3972.

PURPOSE: Radical cystectomy and pelvic lymphadenectomy (PLND) remains the standard treatment for localized and regionally advanced invasive bladder cancers. We have constructed an international bladder cancer database from centers of excellence in the management of bladder cancer consisting of patients treated with radical cystectomy and PLND. The goal of this study was the development of a prognostic outcomes nomogram to predict the 5-year disease recurrence risk after radical cystectomy. PATIENTS AND METHODS: Institutional radical cystectomy databases containing detailed information on bladder cancer patients were obtained from 12 centers of excellence worldwide. Data were collected on more than 9,000 postoperative patients and combined into a relational database formatted with patient characteristics, pathologic details of the pre- and postcystectomy specimens, and recurrence and survival status. Patients with available information for all selected study criteria were included in the formation of the final prognostic nomogram designed to predict 5-year progression-free probability. RESULTS: The final nomogram included information on patient age, sex, time from diagnosis to surgery, pathologic tumor stage and grade, tumor histologic subtype, and regional lymph node status. The predictive accuracy of the constructed international nomogram (concordance index, 0.75) was significantly better than standard American Joint Committee on Cancer TNM (concordance index, 0.68; P < .001) or standard pathologic subgroupings (concordance index, 0.62; P < .001). CONCLUSION: We have developed an international bladder cancer nomogram predicting recurrence risk after radical cystectomy for bladder cancer. The nomogram outperformed prognostic models that use standard pathologic subgroupings and should improve our ability to provide accurate risk assessments to patients after the surgical management of bladder cancer.

Bochner, B. H., J. E. Montie, et al. (2003). "Follow-up strategies and management of recurrence in urologic oncology bladder cancer: invasive bladder cancer." Urol Clin North Am 30(4): 777-789.

A surveillance program following cystectomy should consider a patient's individual risk for the development of local and distant recurrences and any specific needs related to the urinary tract reconstruction performed (Table 1). Well-documented recurrence patterns following cystectomy are available from many large surgical series and provide the background information needed for tailoring follow-up based on pathologic criteria. Economic issues also must be considered, given that the health care-related expenses of treating and following patients with bladder cancer is twice as much as that expended for the treatment of prostate cancer. Because of the ever-increasing fiscal constraints placed on clinicians, risk-adjusted follow-up strategies are reasonable, but will require prospective evaluation to validate their appropriateness.

Bock, C. H., P. A. Peyser, et al. (2005). "Decreasing age at prostate cancer diagnosis over successive generations in prostate cancer families." Prostate 64(1): 60-66.

BACKGROUND: The decline in age at prostate cancer diagnosis over the past decade is partially attributable to prostate specific antigen (PSA) screening. We examined age at diagnosis over successive generations within prostate cancer families. METHODS: Families with at least two affected men were selected from the University of Michigan Prostate Cancer Genetics Project. The 1,345 individuals from 489 families were grouped into three generations. RESULTS: Risk of prostate cancer diagnosis at a given age was estimated to increase 1.31 (95% CI: 1.13-1.51) times from one generation to the next. Among men diagnosed prior to the PSA era, inferences were similar (hazard ratio = 1.28, 95% CI: 0.97-1.68). No maternal versus paternal disease transmission effect was observed. CONCLUSIONS: Age at prostate cancer diagnosis was observed to decrease over successive generations in families from an ongoing familial prostate cancer study. This finding, if confirmed, may have important implications for familial prostate cancer risk assessment.

Bodie, B., A. C. Novick, et al. (1989). "The Cleveland Clinic experience with adrenal cortical carcinoma." Journal of Urology 141(2): 257-260.

Between 1936 and 1987, 82 patients with adrenal cortical carcinoma were seen at our clinic. Of these patients 49 (72 per cent) have been seen during the last 25 years. A total of 40 patients (48.8 per cent) presented with a hormonally functional tumor and 42 (51.2 per cent) had a nonfunctional tumor. Forty patients (48.8 per cent) presented with localized disease, 12 (14.6 per cent) with regional disease and 30 (36.6 per cent) with distant metastases. Complete surgical removal of all gross tumor was achieved in 49 patients. Over-all 3 and 5-year patient survival rates in this series were 37.5 and 25.1 per cent, respectively. Survival was significantly improved (43.9 per cent at 5 years, p equals 0.0001) in patients with localized disease that was completely removed surgically; postoperative adjuvant therapy with op'-DDD was of no benefit in these patients. Survival in patients with metastatic disease was poor and was not improved by treatment with op'-DDD, cytotoxic chemotherapy or radiation therapy. <164>

Bogart, L. M., S. H. Berry, et al. (2007). "Symptoms of interstitial cystitis, painful bladder syndrome and similar diseases in women: a systematic review." J Urol 177(2): 450-456.

PURPOSE: In women symptoms of interstitial cystitis are difficult to distinguish from those of painful bladder syndrome and they appear to overlap with those of urinary tract infection, chronic urethral syndrome, overactive bladder, vulvodynia and endometriosis. This has led to difficulties in formulating a case definition for interstitial cystitis, and complications in the treatment and evaluation of its impact on the lives of women. We performed a systematic literature review to determine how best to distinguish interstitial cystitis from related conditions. MATERIALS AND METHODS: We performed comprehensive literature searches using the terms diagnosis, and each of interstitial cystitis, painful bladder syndrome, urinary tract infection, overactive bladder, chronic urethral syndrome, vulvodynia and endometriosis. RESULTS: Of 2,680 screened titles 604 articles were read in full. The most commonly reported interstitial cystitis symptoms were bladder/pelvic pain, urgency, frequency and nocturia. Interstitial cystitis and painful bladder syndrome share the same cluster of symptoms. Chronic urethral syndrome is an outdated term. Self-reports regarding symptoms and effective antibiotic use can distinguish recurrent urinary tract infections from interstitial cystitis in some but not all women. Urine cultures may also be necessary. Pain distinguishes interstitial cystitis from overactive bladder and vulvar pain may distinguish vulvodynia from interstitial cystitis. Dysmenorrhea distinguishes endometriosis from interstitial cystitis, although many women have endometriosis plus interstitial cystitis. CONCLUSIONS: In terms of symptoms interstitial cystitis and painful bladder syndrome may be the same entity. Recurrent urinary tract infections may be distinguished from interstitial cystitis and painful bladder syndrome via a combination of self-report and urine culture information. Interstitial cystitis and painful bladder syndrome may be distinguished from overactive bladder, vulvodynia and endometriosis, although identifying interstitial cystitis and painful bladder syndrome in women with more than 1 of these diseases may be difficult.

Bolenz, C., S. F. Shariat, et al. (2009). "Risk stratification of patients with nodal involvement in upper tract urothelial carcinoma: value of lymph-node density." BJU Int 103(3): 302-306.

OBJECTIVE: To determine the risk factors associated with clinical outcome in patients with lymph node (LN)-positive urothelial carcinoma of the upper urinary tract (UTUC) treated with radical nephroureterectomy (RNU) and lymphadenectomy, focusing on the concept of LN density (LND). PATIENTS AND METHODS: Patients undergoing RNU with regional lymphadenectomy were identified through multi-institutional databases. All pathology slides were re-evaluated by genitourinary pathologists unaware of the clinical data. The exposure variable used was LND (continuously coded and that of all possible thresholds) with recurrence-free and disease-specific survival (DSS) serving as the outcome measures. RESULTS: Of 432 patients undergoing RNU with lymphadenectomy, 135 (31%) had LN metastases. Within a median follow-up of 4.1 years, 90 of the 135 patients with LN metastases (68%) had disease recurrence and 76 (58%) died from UTUC. The mean (sem) 5-year recurrence-free and DSS probabilities were 27 (4)% and 33 (5)%, respectively. The median (range) LND was 50 (3-100)%. The most informative threshold for LND in relation to outcome was 30%. In multivariable analyses that adjusted for the effects of tumour stage and grade, patients with a LND of > or =30% were at greater risk of both cancer recurrence, with 5-year rates of 25 (5)% vs 38 (8)% (hazard ratio 1.8, P = 0.021) and mortality, with 5-year rates of 30 (6)% vs 48 (9)% (1.7, P = 0.032) compared to those with a LND of <30%. Our results are primarily limited by a lack of standardization in the lymphadenectomy template. CONCLUSION: We evaluated the concept of LND for the first time in UTUC. LND provides additional prognostic information in patients with node-positive disease after RNU. The use of LND in clinical trials might provide an additional insight into the value of LN dissection in patients undergoing RNU.

Bomalaski, M. D., J. G. Anema, et al. (1999). "Delayed presentation of posterior urethral valves: a not so benign condition." J Urol 162(6): 2130-2132.

PURPOSE: Posterior urethral valves are usually detected during infancy by prenatal sonography. Rarely they may be diagnosed during later childhood, adolescence or even adulthood. Less is known about presentation and outcome in these older patients. We reviewed our experience at 4 institutions with the late presentation of posterior urethral valves. MATERIALS AND METHODS: A 13-year retrospective review revealed the late presentation of posterior urethral valves in 47 patients 5 to 35 years old (mean age 8). Data collected included presenting symptomatology, radiographic findings and renal function. Statistical analysis determined the relationships among presenting symptoms, patient age at diagnosis and renal function. RESULTS: The most common presenting symptoms were diurnal enuresis in 60% of the cases, urinary tract infection in 40% and voiding pain in 13%. Other presenting symptoms in less than 10% of the cases included poor stream, gross hematuria and proteinuria. At diagnosis hydronephrosis and vesicoureteral reflux were present in 40 and 33% of the patients, respectively, while serum creatinine was elevated in 35% and end stage renal disease had developed in 10%. The severity of presenting signs and symptoms was significantly associated with renal impairment, while patient age at diagnosis was not. CONCLUSIONS: Posterior urethral valves is not merely a disease of infancy. Voiding cystourethrography should be considered in boys older than 5 years who have voiding complaints, especially in association with diurnal enuresis or urinary tract infection. Patients who present late with posterior urethral valves are at risk for progression to end stage renal disease.

Bomalaski, M. D. and D. A. Bloom (1997). "Urodynamics and massive vesicoureteral reflux." J Urol 158(3 Pt 2): 1236-1238.

PURPOSE: Urodynamic studies are the key to management and reconstruction of bladder pathology. In the face of high grade vesicoureteral reflux measured pressures and volumes reflect the combined storage characteristics of the upper and lower tracts. We examined the influence of high grade reflux on measured volume and compliance (change in volume/change in pressure). MATERIALS AND METHODS: A total of 18 children with high grade vesicoureteral reflux underwent urodynamic evaluation with and without ureteral occlusion. Occlusion was created in the operative suite using ureteral occlusion balloons. After fluoroscopic confirmation of the absence of reflux bladder pressure was measured during filling at a rate of 12.5 cc per minute. During ureteral occlusion bladder capacity was defined as leakage around the urethral catheter, bladder pressure greater than 40 cm. water or volume exceeding estimated bladder capacity for age, as determined by the formula, bladder capacity in ml. = (age + 2) x 30. The ureteral occlusion balloons were removed and similar measurements were obtained in the presence of reflux. Compliance was calculated for the first and last 50% (initial and terminal compliance, respectively) of bladder capacity. RESULTS: Mean initial compliance without and with ureteral occlusion was 19.6 versus 13.2 cm. water (33% decrease). Mean terminal compliance without and with occlusion was 12.9 versus 8.6 cm. water (33% decrease, p < 0.005). Bladder capacity decreased a median of 16%. Underlying bladder pathology was evaluated to determine the patients who would benefit most from ureteral occlusion studies. Patients with neurogenic bladder, posterior urethral valves and primary reflux had similar changes in measured compliance with ureteral occlusion. Patients with poor terminal compliance without occlusion and those with bilateral vesicoureteral reflux had greater changes in compliance with occlusion but these changes were not statistically significant (p < 0.05). Age was indicative of a significant decrease in terminal compliance with ureteral occlusion, since older patients had the greatest change in terminal compliance (p < 0.005). CONCLUSIONS: High grade vesicoureteral reflux influences measured lower tract volume and compliance.

Bomalaski, M. D., D. A. Bloom, et al. (1996). "Glutaraldehyde cross-linked collagen in the treatment of urinary incontinence in children." J Urol 155(2): 699-702.

PURPOSE: Prospective analysis was done to assess the efficacy of glutaraldehyde cross-linked collagen in the treatment of pediatric structural urinary incontinence. MATERIALS AND METHODS: A total of 40 pediatric patients (average age 12.1 years) with structural urinary incontinence received 70 glutaraldehyde cross-linked collagen injections. Of the 40 patients 25 had spina bifida, 12 had the exstrophy/epispadias complex, 2 had continent reservoirs and 1 had bilateral ureteral ectopia. Average followup was 2.1 years (range 3 months to 6.3 years), and included urodynamic evaluation and assessment of change in continence grade, daily pad use and dry interval. Patient satisfaction was evaluated by questionnaire concerning self-esteem, activity level and patient assessment of overall benefit. RESULTS: Complete cure of incontinence was reported by 22% of patients, improvement by 54% and no change by 24%. There was statistically significant postoperative improvement of continence grade (exstrophy/epispadias p < or = 0.004, spina bifida p < or = 0.0001), decreased daily use of pads (exstrophy/epispadias p < or = 0.008, spina bifida p < or = 0.002) and dry interval (exstrophy/epispadias p < or = 0.008, spina bifida p < or = 0.004). Greater success occurred in cases of the exstrophy/epispadias complex (91%) than spina bifida (71%). No patient had unsafe bladder pressures as a result of collagen treatment. Reevaluation of a 1992 study group with an initial 88% cure or improvement rate showed that after a mean followup of 4.5 years the cure or improvement rate remained 86%. CONCLUSIONS: Collagen improves continence in the majority of children with anatomically based urinary incontinence. Exstrophy/epispadias patients have the best outcome from collagen treatment. Glutaraldehyde cross-linked collagen is durable in most patients who have an initially positive outcome.

Bomalaski, M. D., R. B. Hirschl, et al. (1997). "Vesicoureteral reflux and ureteropelvic junction obstruction: association, treatment options and outcome." J Urol 157(3): 969-974.

PURPOSE: We investigated the association, treatment options and outcomes of patients with ureteropelvic junction obstruction and concomitant vesicoureteral reflux. MATERIALS AND METHODS: We analyzed 6,790 consecutive pediatric urology records at our university. Treatment options included observation, and primary pyeloplasty, ureteroneocystostomy and nephroureterectomy. Hydronephrosis, reflux and obstruction were judged as resolved, improved, unchanged or worse. RESULTS: A total of 1,140 patients had vesicoureteral reflux, 224 had ureteropelvic junction obstruction and 41 had both conditions (39 ipsilateral and 6 contralateral kidneys). There was no increased risk of obstruction in patients with reflux when all grades of reflux were grouped (odds ratio 1.26, confidence interval 0.91 to 1.71). In contrast, subgroup analysis of patients with high grade reflux demonstrated a 5-fold increased risk of obstruction (odds ratio 5.0, confidence interval 2.4 to 10.8). One patient was lost to followup. Observation of 6 kidneys led to resolution of reflux in 3 (50%), resolution of obstruction in 3 (50%) and resolution or improvement of hydronephrosis in 4 (67%). Primary pyeloplasty was done on 29 kidneys with 10 (35%) requiring subsequent ureteroneocystostomy. At latest followup hydronephrosis resolved or improved in 24 patients (83%), vesicoureteral reflux resolved or improved in 19 (66%) and ureteropelvic junction obstruction resolved in all. Primary ureteroneocystostomy was performed on 5 kidneys, all of which required subsequent pyeloplasty. Hydronephrosis resolved in 3 patients (60%), and reflux and obstruction resolved in all. Two patients treated with primary nephroureterectomy, and 1 who underwent concomitant pyeloplasty and ureteroneocystostomy have had no subsequent urological problems. One patient awaits primary pyeloplasty. CONCLUSIONS: High grade vesicoureteral reflux is associated with ureteropelvic junction obstruction. No association with low or intermediate grade reflux was demonstrated. While some patients may be monitored expectantly, in our series pyeloplasty or nephrectomy was required in 81% and ureteroneocystostomy was required in 36%. In no case did primary ureteroneocystostomy protect against the subsequent need for pyeloplasty.

Bomalaski, M. D., M. L. Ritchey, et al. (1997). "What imaging studies are necessary to determine outcome after ureteroneocystostomy?" J Urol 158(3 Pt 2): 1226-1228.

PURPOSE: After ureteroneocystostomy we have performed renal ultrasonography within the first 3 months to exclude hydronephrosis, voiding cystography after 3 months to exclude vesicoureteral reflux and subsequent ultrasonography to monitor the upper tracts. This study attempted to determine those patients at risk for hydronephrosis or recurrent vesicoureteral reflux. MATERIALS AND METHODS: We studied the records of patients who underwent ureteroneocystostomy in the last decade at our institutions to find the incidence and degree of preoperative and postoperative hydronephrosis and vesicoureteral reflux. Results of initial postoperative imaging were compared to radiological imaging throughout followup (mean 2.3 years). Patients with postoperative reflux were evaluated for risk factors that differentiated them from others. RESULTS: Excluding patients with neuropathic bladder or ureterocele, 167 underwent 278 ureteroneocystostomies at a mean followup of 26.5 months. Persistent vesicoureteral reflux was noted in 4 kidneys (1.4%) and contralateral reflux developed in 3 of the 48 cases (6.3%) of unilateral ureteroneocystostomy. There was no statistical difference in success rates among cross-trigonal, ureteral advancement or extravesical techniques. New onset mild hydronephrosis in 13 kidneys (4.7%) at the initial followup study (mean 1.6 months) completely resolved in 12 and remained mild in 1. No patient had progression of existing hydronephrosis and 1 had recurrent vesicoureteral reflux after initial negative cystography. Risk factors for postoperative reflux or hydronephrosis were preoperative dysfunctional voiding, preoperative hydronephrosis or scarring on sonography and postoperative urinary tract infection. None of the 88 patients without these risk factors had postoperative hydronephrosis or reflux. All patients with persistent, contralateral or recurrent reflux were selected using these criteria (p < 0.003). CONCLUSIONS: Complication rates after nontapered ureteroneocystostomy in children without neuropathic bladder are quite low. Mild postoperative hydronephrosis was not clinically significant in our patients. Children with abnormal preoperative ultrasound or dysfunctional voiding are identified as a high risk group for postoperative hydronephrosis or recurrent reflux. All other patients received little benefit from postoperative imaging, suggesting that further evaluation of this group is necessary only in the presence of a postoperative urinary tract infection.

Bonner, R. B., M. Liebert, et al. (1996). "Characterization of the DD23 tumor-associated antigen for bladder cancer detection and recurrence monitoring. Marker Network for Bladder Cancer." Cancer Epidemiol Biomarkers Prev 5(12): 971-978.

Bladder cancer detection, monitoring, and prevention represent major problems that could be addressed with sensitive and specific biomarkers. The antigen recognized by the DD23 antibody, previously developed against a tumor-related antigen, was partially biochemically characterized, and its sensitivity and specificity in cancer detection and recurrence monitoring was evaluated. Quantitative fluorescence image analysis was used to quantify antigen content in exfoliated urothelial cells in a cross-section of patients with bladder cancers of all grades and stages and control populations. The antigen was found in tumor cells as well as normal-appearing urothelial cells, suggesting it represents a marker induced by the altered growth factor environment of a cancer-containing bladder. When used as a quantitative marker, the sensitivity for bladder cancer detection was 85%, and the specificity was 95%. No significant difference was seen between symptomatic and asymptomatic control populations, including patients with previous bladder cancers in the absence of a recurrence. In bladder cancer recurrence monitoring, results were consistently negative until just before detection of a recurrence. The biomarker reflects a "field effect" that occurs very late in tumorigenesis and seems to represent events common to most cancers involving the genitourinary tract. Western blotting showed the antibody recognized a dimeric protein. DD23 quantification in single cells may be particularly useful in targeting cystoscopic intervention for recurrence monitoring and, because of its high specificity, could be a tool for bladder cancer screening in high-risk groups.

Borden, T. A., E. J. McGuire, et al. (1981). "Urinary undiversion in patients with myelodysplasia and neurogenic bladder dysfunction. Report of a workshop." Urology 18(3): 223-228.

This workshop was conducted in an attempt to analyze critically the role of reconstruction of the myelodysplastic patient who had undergone urinary diversion and to develop guidelines for selecting those patients in whom urinary undiversion might be undertaken safely. The collective experience initially seems to be acceptable; however, the authors emphasize the gravity of the decision and the complexity of the evaluation which must be undertaken prior to embarking on such reconstructive surgery. Contrary to some reports, we believe that the defunctionalized bladder frequently can be evaluated. Further, many of the contraindications to urinary undiversion have been identified and several of the hazards involved therein can be avoided. We believe that the neurogenic bladder is no longer an absolute contraindication to undiversion. Our experience suggests that undiversion is a reasonable surgical treatment in select patient with neurogenic bladder dysfunction. But, the decision to remove a satisfactorily functioning conduit must not be undertaken lightly. Patients should be selected only after a thorough, detailed, and properly conducted evaluation. A protocol has been developed which will hopefully assist in this evaluation. Perhaps additional shared experience will further refine and delineate the circumstances appropriate for reconstruction of these patients.

Borer, J. G., J. M. Park, et al. (1999). "Heparin-binding EGF-like growth factor expression increases selectively in bladder smooth muscle in response to lower urinary tract obstruction." Lab Invest 79(11): 1335-1345.

Heparin-binding epidermal growth factor-like growth factor (HB-EGF), an activating ligand for the epidermal growth factor receptor (ErbB1) tyrosine kinase and at least one isoform of the ErbB4 receptor tyrosine kinase, is synthesized by the smooth muscle of the human bladder wall. In this study we tested the hypothesis that HB-EGF plays a role in the bladder-wall thickening that occurs in response to obstructive syndromes affecting the lower urinary tract, possibly by acting as an autocrine smooth muscle cell (SMC) growth factor. HB-EGF was mitogenic for primary culture human bladder SMC, and cell growth in serum-containing medium was inhibited more than 70% by [Glu52]-diphtheria toxin/CRM197, a specific HB-EGF inhibitor, consistent with a physiologic role for HB-EGF as an autocrine bladder SMC mitogen. Human and mouse bladder SMC in vivo and cultured human bladder SMC expressed the primary HB-EGF receptor, ErbB1, but not mRNA for the secondary HB-EGF receptor, ErbB4, thereby identifying ErbB1 as the cognate HB-EGF receptor in the bladder wall. Reverse transcription-polymerase chain reaction analysis also demonstrated ErbB2 and ErbB3 expression in human bladder muscle tissue, suggesting the possibility of receptor cross-talk after ErbB1 activation. Urethral ligation in mice resulted in an increase in steady-state HB-EGF mRNA expression up to 24 hours in whole bladder tissue in comparison with ErbB1 and glyceraldehyde 3-phosphate dehydrogenase mRNA levels, which did not change in a demonstrable pattern. HB-EGF protein increased coordinately with HB-EGF mRNA levels. Dissection of bladder tissue into muscle and mucosal layers demonstrated that the increase in HB-EGF mRNA occurred predominantly in the muscle layer, with peak levels (13-fold higher than sham controls) occurring 12 hours after obstruction. These data support a physiologic role for HB-EGF as a mediator of hypertrophic bladder tissue growth.

Borofsky, M., R. B. Shah, et al. (2009). "Nephron-sparing diagnosis and management of renal keratinizing desquamative squamous metaplasia." J Endourol 23(1): 51-55.

BACKGROUND AND PURPOSE: Keratinizing desquamative squamous metaplasia (KDSM) of the upper urinary tract is a rare condition for which there is no defined management plan. A condition historically treated with extirpative surgery, conservative management would be preferable, because this is almost certainly a benign condition. We report the favorable clinical course of two cases of renal KDSM diagnosed and managed with a nephron-sparing approach, relying on ureteroscopy and serial imaging. PATIENTS AND METHODS: Retrospective chart review was performed to obtain history, physical examination results, radiographic imaging, and diagnostic procedures. RESULTS: Both patients were referred to our institution for evaluation of complex cystic renal masses. Both reported passing flaky material in their urine. Flexible ureteroscopy revealed waxy sediment in the collecting system, which broke up easily with manipulation and proved to be squamous keratin debris on cytologic and histologic examination. In 1 patient, we obtained a percutaneous needle biopsy as well, which revealed benign keratinizing squamous epithelium. All findings were consistent with KDSM. Each patient has since been followed conservatively with CT. In 1 case, there has been slight growth of the mass but no worrisome changes after 42 months. In the other case, there were several new renal collecting system filling defects on CT 17 months after diagnosis. Another ureteroscopy revealed the same findings as the original, with the addition of keratin debris draining out of the lesion into the rest of the kidney. CONCLUSIONS: Our two cases of KDSM confirm the feasibility of nephron-sparing management using a combination of diagnostic ureteroscopy and imaging surveillance. The duration of follow-up without adverse events suggests that the finding of renal KDSM is not necessarily an indication for extirpative surgery, and that conservative management is an appropriate option.

Borza, T., R. B. Shah, et al. (2010). "Localized amyloidosis of the upper urinary tract: a case series of three patients managed with reconstructive surgery or surveillance." J Endourol 24(4): 641-644.

OBJECTIVE: To evaluate the clinical presentation, diagnosis, treatment, and prognosis of primary localized amyloidosis of the upper urinary tract. METHODS: Patients with primary localized amyloidosis of the upper urinary tract were identified by database inquiry, and their medical records were reviewed. RESULTS: Primary localized amyloidosis was identified in the ureter in two patients and in the renal pelvis in one patient. Systemic disease and amyloidosis secondary to a medical condition were excluded. All three patients presented with gross painless hematuria, and two also reported flank pain. None endorsed irritative urinary symptoms. Initial evaluation consisted of renal ultrasonography or intravenous urogram, and subsequently additional imaging and ureteroscopies with biopsies were performed. Congo red staining of the biopsies displayed apple green birefringence under polarized light. One patient was treated with distal ureterectomy and Boari flap ureteroneocystostomy, whereas the other two were followed with surveillance imaging. None of the patients have developed progressive disease or recurrence of their symptoms during follow-up of 15 months, 6 years, and 8 years. CONCLUSIONS: Primary localized amyloidosis of the upper urinary tract is a rare condition that is of interest because the clinical presentation and radiographic and endoscopic appearance mimic malignancy. Many commonalities exist between upper urinary tract and bladder amyloidosis, but obstructive features, like flank pain and hydronephrosis, are unique to upper urinary tract lesions. In the absence of significant obstruction, early eradication of an upper urinary tract lesion may not be necessary. Rather, follow-up with serial imaging is sufficient to monitor for disease progression.

Bradford, T. J. and J. S. Wolf, Jr. (2005). "Percutaneous injection of fibrin glue for persistent nephrocutaneous fistula after partial nephrectomy." Urology 65(4): 799.

We report a case of persistent urinary leak of nearly 4 months' duration after open surgical partial nephrectomy. The urinary leak was refractory to ureteral stenting, urethral catheter placement, and ureteroscopic fulguration. Fibrin glue was injected percutaneously under fluoroscopic guidance into the nephrocutaneous fistula tract, which resulted in its prompt and complete resolution.

Brede, C., J. M. Hollingsworth, et al. (2010). "Medical expulsive therapy for ureteral calculi in the real world: targeted education increases use and improves patient outcome." J Urol 183(2): 585-589.

PURPOSE: In controlled trials medical expulsive therapy has improved outcomes in patients with ureteral stones but its real-world use and effectiveness outside a clinical trial have not been thoroughly examined. We studied the impact of targeted education of emergency department physicians about medical expulsive therapy and analyzed its impact on patient outcomes and cost. MATERIALS AND METHODS: In 2006 emergency department physicians at our institution were formally educated about medical expulsive therapy. Retrospective emergency department data were collected on patients with ureteral stones from 2003 and 2005 (before educational intervention), and 2007 (after intervention). Cost and 90-day post-emergency department event data were gathered from a health maintenance organization owned and operated by our medical center. Medical expulsive therapy prescribing trends, adverse outcome (repeat emergency department visit, hospital admission or surgery) and total cost related to ureteral calculus diagnosis were analyzed. RESULTS: Of 166 health maintenance organization patients with ureteral calculi who met all study requirements 97 (58.4%) were prescribed medical expulsive therapy and 53 (31.9%) filled the medical expulsive therapy prescription, while 113 did not. Analysis revealed a 2-fold increase in medical expulsive therapy prescribing and a 4-fold increase in prescribing alpha-blockers in each time increment. Bivariate analysis showed that the frequency of adverse outcomes was lower in the medical expulsive therapy group (37.7% vs 53.1%) and medical expulsive therapy was associated with a lower mean total cost per patient ($1,805 vs $2,372). CONCLUSIONS: Targeted educational intervention can increase the use of preferred medical expulsive therapy (alpha-blockers) in the emergency department. Medical expulsive therapy decreases the incidence of adverse events by 29% and decreases the total cost associated with ureteral stones by 24%.

Brenner, P. C., P. Russo, et al. (1995). "Salvage radical prostatectomy in the management of locally recurrent prostate cancer after 125I implantation." Br J Urol 75(1): 44-47.

OBJECTIVE: To define the role of salvage prostatectomy in patients who have locally recurrent prostate cancer following pelvic lymph node dissection and 125I implantation. PATIENTS AND METHODS: Over 1000 patients underwent 125I implantation for localized prostate cancer at the Memorial Sloan Kettering Cancer Center between 1970 and 1986. Salvage radical prostatectomy was performed in a highly selected group of 10 patients with locally recurrent disease. RESULTS: Three of the 10 patients had organ-confined residual prostate cancer following salvage radical prostatectomy. The remaining seven patients had extra-prostatic disease including four patients with positive surgical margins. Two patients with organ-confined disease and one with extracapsular tumour had no evidence of locally recurrent or metastatic disease and continue to have undetectable prostate-specific antigen (PSA) levels at 50, 44, and 31 months following salvage radical prostatectomy. After a mean follow-up of 30 months, the remaining seven patients had a rising PSA level consistent with locally persistent and/or metastatic disease (median 5 ng/mL; range 1.0-144). This PSA elevation occurred within 20 months of salvage radical prostatectomy (median 6 months). Two of these patients developed clinically evident bone metastases. CONCLUSION: Salvage radical prostatectomy, although technically feasible in highly selected patients, should not be widely advocated as an effective treatment option for patients with locally recurrent prostate cancer after 125I implantation.

Bruce, B., G. Khanna, et al. (2007). "Expression of the cytoskeleton linker protein ezrin in human cancers." Clin Exp Metastasis 24(2): 69-78.

Expression of the metastasis-associated protein, ezrin, in over 5,000 human cancers and normal tissues was analyzed using tissue microarray immunohistochemistry. Ezrin staining was compared between cancers and their corresponding normal tissues, between cancers of epithelial and mesenchymal origin, in the context of the putative inhibitor protein, merlin, and against clinicopathological data available for breast, lung, prostate cancers and sarcomas. Ezrin was found in most cancers and normal tissues at varying levels of intensity. In general ezrin was expressed at higher levels in sarcomas than in carcinomas. By normalizing the expression of ezrin in each cancer using ezrin expression found in the corresponding normal tissue, significant associations between ezrin were found in advancing histological grade in sarcomas (P = 0.02) and poor outcome in breast cancer (P = 0.025). Clinicopathologic associations were not changed by simultaneous assessment of ezrin and merlin in each patient sample for the cancer types examined. These data support a role for ezrin in the biology of human cancers and the need for additional studies in breast cancer and sarcoma patients that may validate ezrin as a marker of cancer progression and as a potential target for cancer therapy.

Bruce, R. G., W. R. Rankin, et al. (1996). "Single focus of adenocarcinoma in the prostate biopsy specimen is not predictive of the pathologic stage of disease." Urology 48(1): 75-79.

OBJECTIVES: To determine whether a very small focus of prostate cancer in a needle biopsy specimen correlates with organ-confined disease or with favorable disease parameters. METHODS: Of 598 needle biopsies of the prostate performed from January 1990 through June 1994, 49 specimens (8.2%) contained a microscopic focus (less than 2 mm in length of the entire biopsy core specimen) of adenocarcinoma. For these 49 patients, the clinical and pathologic features were correlated. RESULTS: Of these 49 patients, 27 (55.1%) underwent either radical prostatectomy, with or without pelvic lymph node dissection (26), or pelvic lymph node dissection alone (1). Seven of these 27 patients (25.9%) had extraprostatic disease: lymph node involvement (1), positive surgical margins (5), or seminal vesicle invasion (1). Ten of the 49 patients (20.4%) underwent radiotherapy, and 12 (24.5%) chose hormonal therapy. The pathologic stage for these 22 patients could not be ascertained. However, despite the limited amount of disease in the biopsy specimen, 2 patients treated with radiotherapy suffered a relapse (mean interval to recurrence, 11.5 months), and 3 patients treated with hormonal therapy (early or delayed) had bony metastasis at the time of diagnosis. Overall, 12 of the 49 patients (24.5%) had unfavorable disease (as defined by extraprostatic disease on pathologic specimen, relapse after radiotherapy, or bony metastasis at the time of diagnosis). CONCLUSIONS: These findings suggest that a microscopic focus of prostatic adenocarcinoma in a needle biopsy specimen, per se, does not predict the pathologic stage or the biologic behavior of a tumor.

Bu, G., W. Lu, et al. (2008). "Breast cancer-derived Dickkopf1 inhibits osteoblast differentiation and osteoprotegerin expression: implication for breast cancer osteolytic bone metastases." Int J Cancer 123(5): 1034-1042.

Most breast cancer metastases in bone form osteolytic lesions, but the mechanisms of tumor-induced bone resorption and destruction are not fully understood. Although it is well recognized that Wnt/beta-catenin signaling is important for breast cancer tumorigenesis, the role of this pathway in breast cancer bone metastasis is unclear. Dickkopf1 (Dkk1) is a secreted Wnt/beta-catenin antagonist. In the present study, we demonstrated that activation of Wnt/beta-catenin signaling enhanced Dkk1 expression in breast cancer cells and that Dkk1 overexpression is a frequent event in breast cancer. We also found that human breast cancer cell lines that preferentially form osteolytic bone metastases exhibited increased levels of Wnt/beta-catenin signaling and Dkk1 expression. Moreover, we showed that breast cancer cell-produced Dkk1 blocked Wnt3A-induced osteoblastic differentiation and osteoprotegerin (OPG) expression of osteoblast precursor C2C12 cells and that these effects could be neutralized by a specific anti-Dkk1 antibody. In addition, we found that breast cancer cell conditioned media were able to block Wnt3A-induced NF-kappaB ligand reduction in C2C12 cells. Finally, we demonstrated that conditioned media from breast cancer cells in which Dkk1 expression had been silenced via RNAi were unable to block Wnt3A-induced C2C12 osteoblastic differentiation and OPG expression. Taken together, these results suggest that breast cancer-produced Dkk1 may be an important mechanistic link between primary breast tumors and secondary osteolytic bone metastases.

Buchanan, M. and J. S. Wolf (1986). "A comprehensive study of learning disabled adults." Journal of Learning Disabilities 19(1): 34-38.

Bude, R. O., J. F. Platt, et al. (1991). "Dilated renal collecting systems: differentiating obstructive from nonobstructive dilation using duplex Doppler ultrasound." Urology 37(2): 123-125.

Two patients with ileal loop urinary diversions, studied with real-time and Doppler sonography ("duplex sonography") of the kidneys, were shown to have dilated intrarenal collecting systems. Resistive index measurements calculated from the Doppler signal correctly identified obstructive dilatation in 1 case and nonobstructive dilatation in the other.

Bukowski, R. M., G. W. Smith, et al. (1988). "Combination chemotherapy including VP-16 for poor prognosis germ cell neoplasms." Urology 31(5): 403-407.

Fifteen patients with germ cell neoplasms (9 testicular primary, 4 extragonadal, 2 adult teratoma syndrome) with features indicative of a poor prognosis were treated with chemotherapy followed by surgery. In patients with testicular primary sites, 2 patients have relapsed and all 9 remain alive (median follow-up 36 months). In patients with extragonadal tumors 2/4 are alive without disease, and both patients with the adult teratoma syndrome have died. Combination chemotherapy and surgery can be employed successfully in this subset of patients with germ cell neoplasms. <169>

Bukowski, R. M., M. Wolf, et al. (1993). "Alternating combination chemotherapy in patients with extragonadal germ cell tumors. A Southwest Oncology Group study." Cancer 71(8): 2631-2638.

BACKGROUND: Extragonadal germ cell tumors (EGGCT) are uncommon, occur primarily in the mediastinum and retroperitoneum, and have been noted to have variable response rates to cisplatin-based chemotherapy regimens. METHODS: The Southwest Oncology Group (SWOG) has completed a prospective trial of combination chemotherapy followed by surgical removal of residual disease in patients with this type of germ cell neoplasm. Chemotherapy consisted of alternating cycles of vinblastine, bleomycin, and cisplatin with etoposide, bleomycin, doxorubicin, and cisplatin. Four cycles of therapy were given followed by surgical removal of residual disease where appropriate. RESULTS: Fifty patients were entered into the trial, and 41 were eligible, with 4 patients excluded by pathology review. Of the 41 eligible patients, 24 had mediastinal tumors, 15 had retroperitoneal tumors, and 2 had unknown primary sites. Complete response rates (chemotherapy +/- surgery) for the various sites were as follows: mediastinum, 18 of 24 (75%); retroperitoneum, 10 of 15 (67%); and unknown primary, 2 of 2 (100%). At 2 years, the disease-free survival rate for all patients was 87%. At a median follow-up of 6.8 years, 26 of 41 patients (63%) are alive. The toxicity of the chemotherapy regimen was substantial, with neutropenic fever developing in 17 of 41 patients (41%) during treatment. Additional side effects included nausea and vomiting (76%), mucositis (27%), and pulmonary toxicity (5%). CONCLUSIONS: This prospective trial of chemotherapy in patients with EGGCT demonstrates a significant response in patients with either mediastinal or retroperitoneal tumors and a 4-year survival rate of more than 60% and 70%, respectively.

Bukowski, T. P., A. Chakrabarty, et al. (1995). "Acquired rectourethral fistula: methods of repair. [Review] [28 refs]." Journal of Urology 153(3:Pt 1): t-3.

Rectourethral fistulas are a rare but devastating complication of urinary or rectal surgery, trauma or inflammation. Historically repair has posed a challenge because of technical difficulties and the high incidence of recurrent fistulas. We report 7 cases of acquired rectourethral fistulas of varying etiology (3 after prostatectomy, 3 after trauma and 1 after recurrent perineal abscess), which were managed by various means. Our data and those in the literature suggest that the first attempt at repair is the best and subsequent repairs become increasingly difficult; the York Mason approach allows easy accessibility with minimal risk of complications and the best chance for a functionally successful outcome when a vascularized flap is not required, and some cases may have such a low probability of successful resolution of the fistula as well as maintenance of urinary continence that cystectomy and supravesical diversion are appropriate considerations. [References: 28] <104>

Buonocore, E., C. Hesemann, et al. (1984). "Clinical and in vitro magnetic resonance imaging of prostatic carcinoma." American Journal of Roentgenology 143(6): 1267-1272.

Magnetic resonance imaging (MRI) of the prostate was accomplished in 10 patients who subsequently had surgical exploration for histologic confirmation and tumor staging. Eight patients were found to have carcinoma of the prostate. Two patients had malignancies of the urinary bladder and were treated with radical resection of the bladder and prostate. The prostatic glands in the latter two patients were free of tumor. One gland was entirely normal; the other had extensive acute and chronic prostatitis. Two resected prostates with carcinoma and one normal prostate were available for in vitro MRI in a clinical magnetic resonance unit. The MRI finding of prostatic carcinoma was heterogeneous signal patterns, seen best on T2-weighted studies. A similar pattern was identified in the gland with acute and chronic prostatitis. There was a homogeneous MRI signal pattern of the normal prostate gland examined in vitro. In two instances, the MRI studies were accurate for the identification of tumor spread to the seminal vesicles, not diagnosed at the time of surgical resection. Microscopic metastatic disease of the lymph nodes in four patients was not identified by MRI. <189>

Burnett, A. L., G. Aus, et al. (2007). "Erectile function outcome reporting after clinically localized prostate cancer treatment." J Urol 178(2): 597-601.

PURPOSE: In conjunction with the assignment to update the Guidelines for Management of Clinically Localized Prostate Cancer, the American Urological Association Prostate Cancer Guideline Update Panel performed a side analysis of the reporting of erectile function outcomes in this clinical context as published in the medical literature. MATERIALS AND METHODS: Four National Library of Medicine PubMed(R) Services literature searches targeting articles published from 1991 through early 2004 were done to derive outcome reporting (efficacy or side effects) for the treatment of clinical stage T1 or T2 N0M0 prostate cancer. A database was constructed containing descriptions relating to erectile function as well as numerical frequency rates of complete erectile dysfunction, and partial and intact erectile function for various treatments. A literature review was also done, consisting of a PubMed Services search of current measures and protocols used for assessing erectile function outcomes and a survey of consensus opinion sources on the management of male sexual dysfunctions. RESULTS: Based on inclusion criteria 436 articles were selected. Of these articles database extraction from 100 pertaining to radical prostatectomy garnered various characterizations of erectile function, including qualitative descriptions, generic terminology and rating systems. Database extraction from 31 articles, in which results for at least 50 patients were reported, yielded ranges of rates for complete erectile dysfunction, partial erectile function and intact erectile function that were 26% to 100%, 16% to 48% and 9% to 86% for radical prostatectomy, 8% to 85%, 21% to 47% and 36% to 63% for external beam radiation, and 14% to 61%, 21% and 18% for interstitial radiation, respectively. The literature review showed an evolution in standards for studying and reporting erectile function outcomes. CONCLUSIONS: Clinical studies reporting erectile function outcomes after localized prostate cancer treatment often demonstrate poorly interpretable and inconsistent manners of assessment as well as widely disparate rates of erectile dysfunction and erectile function. Future studies must apply scientifically rigorous methodology and standard outcomes measures to advance this field of study.

Burnett, J. W., D. A. Bloom, et al. (1996). "Coelenterate venom research 1991-1995: clinical, chemical and immunological aspects." Toxicon 34(11-12): 1377-1383.

Important clinical, chemical, and immunological advances in coelenterate venom research have been made in recent years. Perhaps the most dramatic advance has been in the communication of research data and clinical cases between investigators in this field. Results have been processed by the International Consortium for Jellyfish Stings through their newsletter and the forthcoming publication of the Marine Stinger Book by the University of New South Wales Press.

Burnett, J. W., D. Weinrich, et al. (1998). "Autonomic neurotoxicity of jellyfish and marine animal venoms." Clin Auton Res 8(2): 125-130.

Venoms and poisons of jellyfish and other marine animals can induce damage to the human nervous and circulatory systems. Clues to the pathogenesis and clinical manifestations of these lesions can be obtained from data of human envenomations and animal experimentation. Because many investigators are unaware that marine animal venoms have autonomic actions, this paper aims to elucidate the broad antagonistic or toxic effects these compounds have on the autonomic nervous system. Marine venoms can affect ion transport of particularly sodium and calcium, induce channels or pores in neural and muscular cellular membranes, alter intracellular membranes of organelles and release mediators of inflammation. The box jellyfish, particularly Chironex fleckeri, in the Indo-Pacific region, is the world's most venomous marine animal and is responsible for autonomic disorders in patients. The symptoms induced by these venoms are vasospasm, cardiac irregularities, peripheral neuropathy, aphonia, ophthalmic abnormalities and parasympathetic dysautonomia. Cases of Irukandji syndrome, caused by the jellyfish Carukia barnesi, have symptoms that mimic excessive catecholamine release. Coelenterate venoms can also target the myocardium, Purkinje fiber, A-V node or aortic ring. Actions on nerves, as well as skeletal, smooth or cardiac muscle occur. Recent studies indicate that the hepatic P-450 enzyme family may be injured by these compounds. The multiplicity of these venom activities means that a thorough understanding of the sting pathogenesis will be essential in devising effective therapies.

Bush, N. C. and J. Q. Clemens (2007). "Urinary tract infection in females: Case and comment." Contemporary Urology 19: 14-23.

Cadeddu, J. A., A. Bzostek, et al. (1997). "A robotic system for percutaneous renal access." J Urol 158(4): 1589-1593.

PURPOSE: Percutaneous renal access can be challenging, particularly when the collecting system is not distended. Precise entry into a selected calyx facilitates subsequent percutaneous manipulations, but this skill requires extensive experience. In an attempt to improve accuracy while decreasing technical challenges, we developed a robotic system that automates the task of fluoroscopic image-guided percutaneous needle placement. MATERIALS AND METHODS: The prototype system consisted of a three degree-of-freedom robot with a needle injector end-effector. Imaging was provided by a biplanar fluoroscope. After correction of image distortion and fluoroscope calibration, robot to image-space registration was completed. To validate the system's ability to insert a needle into a calyx, ex vivo porcine kidneys suspended in agarose gel and distended with iodinated contrast solution were used as a model. In situ renal access tests with three 20 kg. pigs were performed. Access was confirmed by passing a flexible wire or aspirating iodinated contrast from the collecting system. RESULTS: The diameter of target calyces ranged from 3 to 7 mm. The in vitro accuracy of final needle tip positioning was 0.43 mm. In the ex vivo model, successful "one stick" access occurred on 10 of 12 attempts (83%). In situ access on the first attempt was successful for 6 of 12 target calyces (50%). Needle or tissue deflection accounted for each failure. CONCLUSION: The feasibility of a robotic system to assist in the percutaneous access of small and delicate renal calyces has been demonstrated. Additional work in reducing procedural steps and correcting for tissue deflection during needle passage is necessary to improve accuracy and to allow for clinical application.

Cadeddu, J. A., J. S. Wolfe, Jr., et al. (2001). "Complications of laparoscopic procedures after concentrated training in urological laparoscopy." J Urol 166(6): 2109-2111.

PURPOSE: To increase the safety and efficiency of laparoscopic surgery clinical training programs have been developed to increase the skill and efficiency of urological trainees. We evaluated the impact of dedicated laparoscopy training on the rate and type of complications after trainees entered clinical practice. MATERIALS AND METHODS: Data were obtained from 13 centers where laparoscopy was performed by a single surgeon with at least 12 months of training in urological laparoscopy before clinical practice. Data included training experience, laparoscopic procedures performed after commencing clinical practice and associated complications. Procedures were classified as easy, moderate and difficult. RESULTS: During training each surgeon participated in a mean of 71 cases. In clinical practice a total of 738 laparoscopic cases were performed with the group reporting an overall complication rate of 11.9%. The rate was unchanged when the initial 20, 30 and 40 cases per surgeon were compared with all subsequent cases (12%, 11.9% and 12% versus 11.8 to 12%, respectively). The re-intervention rate was 1.1%. The complication rate increased with case difficulty. Overall and early complication rates attributable to laparoscopic technique in the initial 20, 30 and 40 cases were identical. The most common complications were neuropathy in 13 patients, urine leakage/urinoma in 9, transfusion in 7 and ileus in 5. CONCLUSIONS: The complication rate of surgeons who completed at least 12 months of laparoscopy training did not differ according to initial versus subsequent surgical experience. Intensive training seems to decrease the impact of the learning curve for laparoscopy.

Caird, M. S., J. M. Hall, et al. (2007). "Outcome study of children, adolescents, and adults with sacral agenesis." J Pediatr Orthop 27(6): 682-685.

Musculoskeletal functional outcome was assessed in children and adults with sacral agenesis and no myelomeningocele. General health, musculoskeletal function, and psychosocial adjustment were assessed in 16 sacral agenesis patients (10 males, 6 females; mean age, 14 +/- 5 years) using previously validated patient and parent self-report questionnaires. Radiographs were reviewed to classify each patient by Renshaw type. Most patients were happy with their looks, and all felt that their general health was good to excellent. Patients reported being limited in function by their low back and distal lower extremities. Half were limited by pain. They reported problems functioning in physically demanding situations, although most were able to participate in low-demand physical activities. No relationship was found between pain and Renshaw type nor between overall satisfaction and Renshaw type.

Calhoun, E. A., J. Q. Clemens, et al. (2009). "Primary care physician practices in the diagnosis, treatment and management of men with chronic prostatitis/chronic pelvic pain syndrome." Prostate Cancer Prostatic Dis 12(3): 288-295.

To describe practice patterns of primary care physicians (PCPs) for the diagnosis, treatment and management of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), we surveyed 556 PCPs in Boston, Chicago, and Los Angeles (RR=52%). Only 62% reported ever seeing a patient like the one described in the vignette. In all, 16% were 'not at all' familiar with CP/CPPS, and 48% were 'not at all' familiar with the National Institutes of Health classification scheme. PCPs reported practice patterns regarding CP/CPPS, which are not supported by evidence. Although studies suggest that CP/CPPS is common, many PCPs reported little or no familiarity, important knowledge deficits and limited experience in managing men with this syndrome.

Cameron, A., D. E. Fenner, et al. (2010). "Self-report of difficult defecation is associated with overactive bladder symptoms." Neurourol Urodyn.

AIMS: The association of dysfunctional bowel elimination with lower urinary tract symptoms is well known in children, but not in adults. It was our objective to assess lower urinary tract symptoms (LUTS) in women who report difficult defecation (DD). METHODS: This is a secondary analysis of 2,812 women, aged 35-64, who participated in a telephone interview. All subjects were asked "When you move your bowels, does the stool come out easily?" DD was considered present in those answering "no." All subjects were queried regarding LUTS, urinary infections in the past year, self-perceived health status, medical history, and demographics. Symptoms of stress incontinence (five items), urge incontinence (five items), and the impact of these symptoms on their quality of life were solicited from subjects reporting more than 12 episodes of incontinence in 1 year. RESULTS: DD was reported by 10.4% (290/2,790) of women. Women with DD had higher LUTS than those who did not: nocturia (mean 1.8 +/- 0.1 vs. 1.3 +/- 0.0), urgency (47.6% vs. 29.2%), increased daytime frequency (mean 8.2 +/- 0.3 vs. 7.2 +/- 0.1), dysuria (22.9% vs. 13.7%), and a sensation of incomplete bladder emptying (55.6% vs. 28.2%). DD women were more often menopausal, reported a fair or poor self-reported health status, and had a higher number of comorbidities, less formal education, and lower annual household income. CONCLUSIONS: Women with symptoms of DD have an increased rate of LUTS, consistent with the diagnosis of overactive bladder without incontinence. The pathophysiology underlying this association is worthy of future research. Neurourol. Urodynam. (c) 2009 Wiley-Liss, Inc.

Cameron, A. P., Latini, Jerilyn M. (2008). "Management of acute and chronic urinary complications of radiation therapy for prostate cancer (review article)." AUA Update Series 32.

Cameron, A. P. and H. O. Atiemo (2009). "Unusual presentation of an obstetrical urethrovaginal fistula secondary to improper catheter placement." Can Urol Assoc J 3(4): E21-E22.

Vesicovaginal and urethrovaginal fistulas related to obstetrical causes are exceptionally rare in the developed world. We report a case of 23-year-old woman with a urethrovaginal fistula, which developed after a cesarean delivery because of an inappropriately placed urethral catheter. Diagnostic evaluation and surgical approach are discussed.

Cameron, A. P., J. Q. Clemens, et al. (2009). "Combination drug therapy improves compliance of the neurogenic bladder." J Urol 182(3): 1062-1067.

PURPOSE: Typical management of increased bladder storage pressures and decreased compliance related to neurogenic bladder dysfunction consists of antimuscarinic therapy with or without clean intermittent catheterization. However, these measures are often unsuccessful. In this patient group we commonly use combination therapy consisting of antimuscarinics combined with imipramine and/or an alpha-blocker. MATERIALS AND METHODS: A retrospective chart review was performed identifying all patients with neurogenic bladder dysfunction who were initially on no drug therapy or antimuscarinic therapy alone and were later switched to 2 or 3 drug therapy. RESULTS: In the group initially on no therapy and subsequently on 2 drugs (22) mean bladder pressure at capacity decreased 52% and mean compliance increased 5.0-fold. Similarly in the group starting without therapy but ending up on 3 drugs (28) bladder pressure decreased 67% and compliance increased 9.7-fold. In the group initially on an antimuscarinic agent alone (27) triple drug therapy decreased bladder pressure 60% and compliance increased 3.0-fold (all p <0.01). There were also improvements in incontinence, vesicoureteral reflux, detrusor overactivity and detrusor sphincter dyssynergia. CONCLUSIONS: In this highly selected group of patients with neurogenic bladder dysfunction and poor bladder compliance combination medical therapy with 2 or 3 drugs improved compliance, decreased bladder pressures at capacity and improved clinical outcomes. Combination therapy requires further study of the side effect profile but these results suggest that it should be considered for patients in whom antimuscarinic agents alone fail.

Cameron, A. P. and J. B. Gajewski (2009). "Bladder outlet obstruction in painful bladder syndrome/interstitial cystitis." Neurourol Urodyn 28(8): 944-948.

AIMS: Obstructive symptoms such as slow stream, dribbling and straining are often reported by painful bladder syndrome and interstitial cystitis (PBS/IC) patients. Our hypothesis was that some patients with PBS/IC have an associated measurable bladder outlet obstruction (BOO) secondary to dysfunctional voiding and that those patients with more severe PBS/IC are more likely to have BOO. METHODS: This is a retrospective chart review of female patients diagnosed with PBS/IC based on the NIDDK research definition. Charts were reviewed for clinical symptom severity, ulcer or non-ulcer PBS/IC on cystoscopy, and pressure-flow urodynamics (UDPF). Patients were excluded if they had a urinary infection at the time of urodynamics or did not meet study entry requirements. The cut-off values of <or=12 ml/sec and >or=25 cm of water was used to define BOO. RESULTS: Of the 231 women: 38 had ulcer PBS/IC and 193 had non-ulcer PBS/IC. MCC was 269 ml in non-ulcer PBS/IC and 200 ml in ulcer PBS/IC (P = 0.006). One hundred eleven women (48%) met criteria for obstruction. MCC was 298 ml in the non-obstructed group and 214 ml in the obstructed group (P < 0.0001). The maximum flow with non-ulcer PBS/IC was 11.0 ml/sec and in ulcer PBS/IC 8.9 ml/sec (P = 0.04) Detrusor pressure at maximum flow was 33.3 cm H(2)O, in non-ulcer, and 37.4 cm H(2)O in ulcer PBS/IC (P = 0.01). CONCLUSIONS: Forty-eight percent of our PBS/IC patients have BOO, and increasing severity of PBS/IC is associated with higher voiding pressure.

Cameron, A. P., L. P. Wallner, et al. (2010). "Bladder management after spinal cord injury in the United States 1972 to 2005." J Urol 184(1): 213-217.

PURPOSE: Studies have shown that bladder management with an indwelling catheter for patients with spinal cord injury is associated with more urological complications such as stones, urinary infection, urethral strictures and bladder cancer. However, little is known about actual bladder management for these patients in clinical practice. MATERIALS AND METHODS: Using the National Spinal Cord Injury Database the bladder management method was determined at discharge from rehabilitation and at each 5-year followup period for 30 years. RESULTS: At discharge from rehabilitation (24,762 patients) the selection of bladder management with a condom catheter decreased steadily from a peak of 34.6% in 1972 to a low of 1.50% in 2001. The use of clean intermittent catheterization increased from 12.6% in 1972 to a peak of 56.2% in 1991. Indwelling catheter use initially decreased from 33.1% in 1972 to 16.5% in 1991 but increased to 23.1% in 2001. Of 12,984 individuals with followup data those originally using an indwelling catheter for bladder management were unlikely to switch to another method, with 71.1% continuing to use an indwelling catheter at 30 years. Individuals using clean intermittent catheterization and condom catheterization at discharge home did not continue to use these methods with only 20% and 34.6% remaining on the same management, respectively. CONCLUSIONS: With time bladder management with clean intermittent catheterization has increased in popularity. However, only 20% of patients initially on clean intermittent catheterization remained on this form of bladder management. More research on the safety of each of these methods needs to be performed to provide better guidance to aid with this decision.

Campbell, T., J. Blasko, et al. (2001). "Clinical staging of prostate cancer: reproducibility and clarification of issues." Int J Cancer 96(3): 198-209.

The American Joint Committee on Cancer (AJCC) staging system for prostate cancer adopted in 1992 is based on tumor-node-metastasis (TNM) designations. It has been widely accepted for use in local and advanced disease. The purpose of this study was to assess reproducibility of staging among observers and to help clarify staging issues. Twelve prostate cancer cases were sent to 20 physicians with special expertise in prostate cancer including eight urologists, eight radiation oncologists, and four medical oncologists. Physicians were asked to assign a stage based on the 1992 AJCC clinical staging. The most frequently reported stage assigned to each case was taken to be the consensus. Agreement was the percentage of physicians who reported that particular stage. Seventy-five percent of the physicians responded. The overall agreement for assignment of T stage was 63.9%. Differences were found by specialty for inclusion of available information in designating a T stage. The overall agreement for N stage was 73.8%. The most common designation was Nx regardless of availability of a computed tomography scan. The overall agreement for M stage was 76.6%. Without a bone scan the most common designation was Mx regardless of Gleason grade or prostate-specific antigen (PSA). A frequent comment was that PSA was more indicative of disease extent than current clinical staging. The reproducibility of the 1992 clinical AJCC staging is poor even among experts in the field. This problem arises primarily from disagreement regarding which studies are included in assigning a stage. Some of these difficulties are addressed in the 1997 revision. However, the clinical staging does not address the true biological significance of disease in many instances.

Caoili, E. M., R. H. Cohan, et al. (2005). "MDCT urography of upper tract urothelial neoplasms." AJR Am J Roentgenol 184(6): 1873-1881.

OBJECTIVE: The purpose of our study was to review the MDCT urography appearance of pathologically proven transitional cell carcinomas of the renal collecting system and ureter and to correlate the MDCT urography findings with pathology findings. MATERIALS AND METHODS: Of 370 MDCT urography examinations performed over an 18-month period, 18 patients were diagnosed with 27 renal collecting system or ureteral urothelial neoplasms at endoscopic biopsy (n = 8) or surgery (n = 19). Initial MDCT reports were reviewed to determine the sensitivity of original reviewers in detecting these neoplasms. Two radiologists also retrospectively reviewed these scans and characterized the CT appearance of the neoplasms on both axial CT and 3D reformatted images. Findings at retrospective review were correlated with pathology results to determine whether any CT features could be used to predict tumor grade. RESULTS: Eighteen of 27 neoplasms were prospectively identified on MDCT urography, and an additional six neoplasms were detected on retrospective review. Three ureteral neoplasms could not be visualized. The 24 retrospectively detected neoplasms had three distinct MDCT appearances: circumferential urothelial wall thickening (n = 14), small masses (> 5 mm in maximal diameter) (n = 5), and large masses (> 5 mm in maximal diameter) (n = 5). All detected lesions could be seen on axial excretory phase images provided wide window settings were reviewed; however, only six were detected on 3D reconstructions. MDCT urography appearance did not correlate with tumor grade. CONCLUSION: MDCT urography is a promising technique for detecting upper urinary tract neoplasms. The static 3D reconstructions used in this study are insufficient for visualization. Axial image review remains essential for tumor identification.

Caoili, E. M., R. H. Cohan, et al. (2002). "Urinary tract abnormalities: initial experience with multi-detector row CT urography." Radiology 222(2): 353-360.

PURPOSE: To evaluate multi-detector row computed tomographic (CT) urography for detection of urinary tract abnormalities. MATERIALS AND METHODS: Sixty-five patients referred from the urology service, in whom urinary tract abnormalities were strongly suspected, underwent multi-detector row CT urography. The technique included unenhanced, nephrographic, compression, and excretory-phase images through the abdomen and pelvis. Transverse images and three-dimensional reformations were reviewed by one of two radiologists. Findings were retrospectively compared with results of urinalysis, cystoscopy and/or ureteroscopy, and/or surgery. RESULTS: Multi-detector row CT urography depicted many clinically diagnosed urinary tract abnormalities, including 15 of 16 uroepithelial malignancies, five congenital anomalies, five urinary tract calculi, and 18 calyceal and/or papillary, 30 renal pelvic and/or ureteral, and 25 bladder abnormalities. All abnormalities were detected on transverse images. These abnormalities included diffuse urothelial wall thickening in four patients (three of whom had transitional cell carcinoma), a renal abscess, a colovesical fistula, and incidentally detected extrarenal disease (a liver mass, hepatic metastases, lymph node metastases, an aortic dissection, and a pheochromocytoma; each of these findings was seen in one patient). CONCLUSION: Multi-detector row CT urography is a useful method for detecting urinary tract abnormalities.

Caoili, E. M., R. H. Cohan, et al. (2002). "Urinary tract abnormalities: initial experience with multi-detector row CT urography. [see comments.]." Radiology 222(2): 353-360.

PURPOSE: To evaluate multi-detector row computed tomographic (CT) urography for detection of urinary tract abnormalities. MATERIALS AND METHODS: Sixty-five patients referred from the urology service, in whom urinary tract abnormalities were strongly suspected, underwent multi-detector row CT urography. The technique included unenhanced, nephrographic, compression, and excretory-phase images through the abdomen and pelvis. Transverse images and three-dimensional reformations were reviewed by one of two radiologists. Findings were retrospectively compared with results of urinalysis, cystoscopy and/or ureteroscopy, and/or surgery. RESULTS: Multi-detector row CT urography depicted many clinically diagnosed urinary tract abnormalities, including 15 of 16 uroepithelial malignancies, five congenital anomalies, five urinary tract calculi, and 18 calyceal and/or papillary, 30 renal pelvic and/or ureteral, and 25 bladder abnormalities. All abnormalities were detected on transverse images. These abnormalities included diffuse urothelial wall thickening in four patients (three of whom had transitional cell carcinoma), a renal abscess, a colovesical fistula, and incidentally detected extrarenal disease (a liver mass, hepatic metastases, lymph node metastases, an aortic dissection, and a pheochromocytoma; each of these findings was seen in one patient). CONCLUSION: Multi-detector row CT urography is a useful method for detecting urinary tract abnormalities. <4>

Capitanio, U., S. F. Shariat, et al. (2009). "Comparison of oncologic outcomes for open and laparoscopic nephroureterectomy: a multi-institutional analysis of 1249 cases." Eur Urol 56(1): 1-9.

BACKGROUND: Data regarding the oncologic efficacy of laparoscopic nephroureterectomy (LNU) compared to open nephroureterectomy (ONU) are scarce. OBJECTIVE: We compared recurrence and cause-specific mortality rates of ONU and LNU. DESIGN, SETTING, AND PARTICIPANTS: Thirteen centers from three continents contributed data on 1249 patients with nonmetastatic upper tract urothelial carcinoma (UTUC). MEASUREMENTS: Univariable and multivariable survival models tested the effect of procedure type (ONU [n=979] vs LNU [n=270]) on cancer recurrence and cancer-specific mortality. Covariables consisted of institution, age, Eastern Cooperative Oncology Group (ECOG) performance status score, pT stage, pN stage, tumor grade, lymphovascular invasion, tumor location, concomitant carcinoma in situ, ureteral cuff management, previous urothelial bladder cancer, and previous endoscopic treatment. RESULTS AND LIMITATIONS: Median follow-up for censored cases was 49 mo (mean: 62). Relative to ONU, LNU patients had more favorable pathologic stages (pT0/Ta/Tis: 38.1% vs 20.8%, p<0.001) and less lymphovascular invasion (14.8% vs 21.3%, p=0.02) and less frequently had tumors located in the ureter (64.5 vs 71.1%, p=0.04). In univariable recurrence and cancer-specific mortality models, ONU was associated with higher cancer recurrence and mortality rates compared to LNU (hazard ratio [HR]: 2.1 [p<0.001] and 2.0 [p=0.008], respectively). After adjustment for all covariates, ONU and LNU had no residual effect on cancer recurrence and mortality (p=0.1 for both). CONCLUSIONS: Short-term oncologic data on LNU are comparable to ONU. Since LNU was selectively performed in favorable-risk patients, we cannot state with certainty that ONU and LNU have the same oncologic efficacy in poor-risk patients. Long-term follow-up data and morbidity data are necessary before LNU can be considered as the standard of care in patients with muscle-invasive or high-grade UTUC.

Carey, T. E., T. S. Nair, et al. (1993). "Blood group antigens and integrins as biomarkers in head and neck cancer: is aberrant tyrosine phosphorylation the cause of altered alpha 6 beta 4 integrin expression?" J Cell Biochem Suppl 17F: 223-232.

Head and neck cancer is a capricious disease that varies greatly in its clinical behavior. The development of biomarkers that can distinguish between biologically aggressive and indolent tumors has been a long term goal of our laboratories. Predictive markers applicable to biopsy specimens should facilitate clinical management through early identification of patients at greatest risk for early relapse or metastatic spread. Two prominent cell surface markers that we identified by raising monoclonal antibodies to squamous cell carcinomas are blood group antigens and the A9 antigen/alpha 6 beta 4 integrin. Both of these markers are abnormally displayed in squamous cancers of the head and neck and serve as indicators of early relapse. Loss of blood group antigen expression is a stronger single indicator than is overexpression of the alpha 6 beta 4 integrin. However, use of both markers together is a stronger predictive indicator than is either alone. We know little about the function of the blood group antigens in squamous cells except that the mature antigens are associated with differentiation. Similarly, the function of the alpha 6 beta 4 integrin is also not fully understood. Integrin alpha 6 beta 4 is thought to serve as an extracellular matrix receptor, but its ligand has not been confirmed. In resting epithelium, the alpha 6 beta 4 integrin is polarized to the basal aspect of the basal cell as a component of the hemidesmosome, the anchoring structures of the epithelia. This basal polarization is lost in migrating normal squamous cells and squamous carcinomas. Tyrosine phosphorylation of the beta 4 subunit is absent or greatly reduced in malignant cells and this may be a critical signal for subcellular localization of alpha 6 beta 4 and cell anchoring. On the basis of our current experimental results, we postulate that tyrosine phosphorylation of the beta 4 subunit is a reversible signal that regulates cell migration in normal and malignant cells, and may therefore be an important initial event in the metastatic cascade.

Carroll, P. R., J. W. McAninch, et al. (1994). "Outcome after temporary vascular occlusion for the management of renal trauma." J Urol 151(5): 1171-1173.

To determine the impact of temporary vascular occlusion on patient outcome after surgery for renal trauma, we reviewed the records of 30 patients managed since 1977 whose injuries represented 17% of a total of 181 injuries in 175 patients. Reconstruction was judged to be adequate in 25 patients, while the remaining 5 underwent immediate nephrectomy. Compared with patients whose renal injuries did not require temporary occlusion, these 30 were more likely to have renovascular trauma, shock at presentation and higher transfusion requirements. Postoperatively, of 20 patients renal imaging (9) and radionuclide scanning (11) demonstrated preservation of significant renal parenchyma or function in 18 (90%). Although complications were more common in patients whose renal injuries required temporary vascular occlusion, only 2 were related to the renal injury or its method of repair (urinary extravasation in 1 patient and azotemia in 1 with bilateral injury). Temporary vascular occlusion can be performed expeditiously and safely, and may have an important role in preserving renal function. Our results support the routine use of early vascular control and the selective use of temporary vascular occlusion in renal injuries requiring exploration.

Casey, J. T., R. Patel, et al. (2010). "Infectious complications in patients with chronic bacteriuria undergoing major urologic surgery." Urology 75(1): 77-82.

OBJECTIVES: To review our perioperative antibiotic management of patients with chronic bacteriuria who underwent urological procedures, and the relationship to postoperative infectious complications. METHODS: Between January 2002 and January 2007, 77 patients with chronic bacteriuria underwent 94 major open procedures, including ileocystoplasty (n = 53), ileal conduit (n = 19), and pubovaginal sling placement (n = 18). Admission urine cultures were classified as "sensitive" (sensitive to admission antibiotics or no growth), "resistant" (resistant to admission antibiotics), and "unknown" (multiple unspeciated organisms present or no admission culture data available). RESULTS: Our rate of multidrug resistance bacteriuria was 46.3%. There were 7 febrile urinary tract infections, 12 wound infections, 1 episode of sepsis, and no intra-abdominal abscesses, yielding an infectious complication rate of 20.2%. There was no statistical relationship between urine culture status and the rate of febrile urinary tract infections or sepsis, but wound infections were less common in patients with "sensitive" urine cultures. Of the patients who had urine cultures that demonstrated multiple unspeciated organisms, 32% were complicated by wound infections. On multivariate analysis, gender, age, and body mass index were associated with the development of infectious complications. CONCLUSIONS: In a medically complex population of patients, those with neurogenic bladder and frequent catheterization undergoing major abdominal surgery, we demonstrate an infectious complication rate of 20.2%. Wound infections were as common in patients whose urine cultures revealed multiple unspeciated organisms as those that were resistant to the perioperative antibiotics, and in this population, further characterization may allow for more appropriate perioperative coverage and a decreased rate of wound infections.

Catalona, W. J., J. E. Montie, et al. (1994). "The outlook for preserving continence and potency during radical prostatectomy." Contemporary Urology 6(5): 18-28.

Cespedes, R. D., C. A. Cross, et al. (1996). "Modified Ingelman-Sundberg bladder denervation procedure for intractable urge incontinence." J Urol 156(5): 1744-1747.

PURPOSE: We determined the efficacy of the modified Ingelman-Sundberg procedure in women with urge incontinence and intractable detrusor instability. MATERIALS AND METHODS: Women with urge incontinence and detrusor instability, in whom medical and behavioral therapy failed, received transvaginal local anesthesia to block the terminal pelvic nerve branches to the bladder. Urge incontinence resolved temporarily in 25 patients, who subsequently underwent modified Ingelman-Sundberg transvaginal bladder denervation. All patients underwent preoperative urodynamic evaluation but documented detrusor instability was not a requirement for surgery. RESULTS: Of the patients 16 (64%) were cured of urge incontinence with substantial relief of detrusor instability, 2 (8%) had temporary improvement and 7 (28%) had no change. No patient who was cured required further surgery (mean followup 14.8 months, range 4 to 30). Use of anticholinergic agents also decreased dramatically: 5 patients used no, 9 used 1 and 2 used 2 medications. Detrusor instability was documented in 44% of the patients and was not predictive of operative outcome. There were no major complications of the procedure. Operative time was approximately 15 minutes. CONCLUSIONS: In patients with urge incontinence and medically refractory detrusor instability, with few simple choices for treatment, the modified Ingelman-Sundberg procedure is an excellent surgical option that yields good results with minimal morbidity.

Cespedes, R. D., C. A. Cross, et al. (1997). "Pubovaginal fascial slings." Tech Urol 3(4): 195-201.

The first pubovaginal fascial sling was reported in 1907, however, until recently this procedure was rarely utilized except after other incontinence procedures had failed. Currently, a pubovaginal sling is indicated as the primary incontinence procedure if intrinsic sphincter deficiency or coexisting intrinsic sphincter deficiency and urethral hypermobility are diagnosed preoperatively. Additionally, incontinence secondary to urethral hypermobility should be treated with a pubovaginal sling if the patient has a high risk of postoperative failure due to obesity, chronic cough, or repetitive strenuous activity. Pubovaginal slings are relatively easy to perform and yield reliably good results with minimal morbidity. We describe our current technique and results using pubovaginal slings for stress incontinence in women.

Cespedes, R. D., W. W. Leng, et al. (1999). "Collagen injection therapy for postprostatectomy incontinence." Urology 54(4): 597-602.

Cespedes, R. D., E. J. McGuire, et al. (1996). "Bladder preservation and continent urinary diversion in T3b transitional cell carcinoma of the bladder." Semin Urol Oncol 14(2): 103-111.

The patient with T3b transitional cell carcinoma (TCC) of the bladder has traditionally been treated with radical cystectomy and urinary diversion, but initial success with systemic chemotherapy and renewed interest in quality-of-life issues has increased interest in bladder preservation treatments. Unfortunately, despite multiple trials using limited surgical procedures and neoadjuvant or adjuvant chemotherapy, no combined modality has consistently improved survival over the achieved with radical cystectomy alone in patients with T3b disease. Additionally, continent stomal diversions and orthotopic neobladders allow almost normal continence and voiding in both male and female patients, which calls into question the need for bladder preservation. Although no single treatment modality or urinary diversion is right for all patients, a radical cystectomy with continent diversion provides the best chance for survival and allows the best postoperative quality of life. If bladder preservation treatments are used, inclusion in a clinical trial is recommended.

Cespedes, R. D., L. L. Pisters, et al. (1997). "Long-term followup of incontinence and obstruction after salvage cryosurgical ablation of the prostate: results in 143 patients." J Urol 157(1): 237-240.

PURPOSE: We report long-term followup of patients with incontinence and obstruction after salvage cryosurgical ablation of the prostate. MATERIALS AND METHODS: We reviewed the records of 143 patients who underwent cryosurgical ablation of the prostate for treatment failure after radiation therapy. Data were collected by telephone interview with each patient and chart review. Median followup was 27 months (range 12 to 42). RESULTS: Of 107 patients who underwent cryosurgical ablation of the prostate using a commercially available urethral warmer 15 (14%) had significant obstruction or retention that required transurethral resection of the prostate in 10, of whom 6 became incontinent. Urinary incontinence occurred in 45 patients (42%) and resolved in 21 (47%), for an overall 28% long-term incontinence rate. Of 28 patients who underwent cryosurgical ablation of the prostate using an alternative urethral warmer 13 (46%) had incontinence and 15 (54%) had significant obstruction or retention. Resolution was rare and 89% of the patients are currently incontinent. Eight patients underwent 2 separate cryosurgical ablations with an 88% incontinence rate (43% overall). The double freezing technique did not increase postoperative obstruction or incontinence. CONCLUSIONS: Incontinence and urinary retention rates are increased in patients undergoing cryosurgical ablation of the prostate after failure of radiation therapy but spontaneous resolution occurs in half of the patients within 1 year if an effective urethral warmer is used. Incontinence treatments should be delayed until after this period. Postoperative incontinence and obstruction rates are significantly greater when an effective urethral warmer is not used and spontaneous resolution is rare.

Chai, T., A. K. Chung, et al. (1995). "Compliance and complications of clean intermittent catheterization in the spinal cord injured patient." Paraplegia 33(3): 161-163.

The optimal management of the neuropathic bladder secondary to spinal cord injury remains unsettled. Some have advocated the use of chronic indwelling catheters in tetraplegic patients supposedly due to comparable complication rates with non-indwelling catheter management. We assessed the urological complication and compliance rates in a group of spinal cord injured patients followed over a mean of 5.9 years. Complication rates from clean intermittent catheterization were comparable if not better than the rates previously reported for clean intermittent catheterization and significantly better than chronically catheterized patients. The compliance rate in our series was 71% as determined by the number of patients remaining on clean intermittent catheterization at their last urological follow-up. We conclude that the use of clean intermittent catheterization can provide optimal management of the lower urinary tract in spinal cord injured patients.

Chai, T. C., W. D. Belville, et al. (1993). "Specificity of the American Urological Association voiding symptom index: comparison of unselected and selected samples of both sexes." J Urol 150(5 Pt 2): 1710-1713.

The American Urological Association voiding symptom index questionnaire for benign prostatic hypertrophy was administered to an elderly unselected sample and a selected urology clinic sample of both sexes to investigate the ability of this instrument to identify prostatic pathological conditions. The female subjects in these cohorts provided a control. In the large unselected sample the male subjects scored statistically higher in only 2 categories, weak stream (487 subjects) and strain (507) (p < 0.05 for both categories). The clinical significance of these scores is questionable, however, since they were low (less than 2 of 5). In the selected group (145 subjects) the female subjects showed a higher total mean score due to the contribution of statistically higher irritative scores (p < 0.05). We conclude that the American Urological Association voiding symptom index does not specifically identify prostatic pathological conditions, and that elderly men and women have similar voiding symptom scores. Therefore, treatment that results in improvement in symptom scores may not specifically affect the prostate. Other factors, such as an aging detrusor, changes in physiological production of urine or other unknown factors, may contribute to the symptoms.

Chai, T. C. and D. A. Ohl (1995). "Difficult urethral catheterization due to ectopic ureter: an unusual presentation of ureteral ectopia in a man." J Urol 153(6): 1899-1900.

We report the unusual presentation of an ectopic ureter in a man with a solitary kidney. The presenting symptom was the inability to place a Foley catheter into the bladder because of preferential passage into the ectopic ureteral opening in the prostatic urethra. Flexible cystoscopy was helpful in diagnosis and management of the problem. The differential diagnosis of a difficult urethral catheterization should include occult congenital genitourinary anomalies.

Chaib, H., E. K. Cockrell, et al. (2001). "Profiling and verification of gene expression patterns in normal and malignant human prostate tissues by cDNA microarray analysis." Neoplasia 3(1): 43-52.

cDNA microarray technology allows the "profiling" of gene expression patterns for virtually any cellular material. In this study, we applied cDNA microarray technology to profile changes in gene expression associated with human prostate tumorigenesis. RNA prepared from normal and malignant prostate tissue was examined for the expression levels of 588 human genes. Four different methods for data normalization were utilized. Of these, normalization to ACTB expression proved to be the most rigorous technique with the least probability of producing spurious results. After normalization to ACTB expression, 15 of 588 (2.6%) genes examined by array analysis were differentially expressed by a factory of 2x or more in malignant compared to normal prostate tissues. The expression patterns for 8 of 15 genes have been reported previously in prostate tissues (TGFbeta3, TGFBR3, IGFII, IGFBP2, VEGF, FGF7, ERBB3, MYC), but those of seven genes are reported here for the first time (MLH1, CYP1B1, RFC4, EPHB3, MGST1, BTEB2, MLP). These genes describe at least four metabolic and signaling pathways likely disrupted in human prostate tumorigenesis. Reverse transcriptase polymerase chain reaction (RT-PCR) and Northern blot analyses quantitated with reference to ACTB expression levels verified the trends in gene expression levels observed by array analysis for 14/15 and 8/8 genes, respectively. However, RT-PCR and Northern blot analyses accurately verified the "fold" differences in expression levels for only 6/15 (40%) and 7/8 (88%) of genes examined, respectively, demonstrating the need to better validate quantitative differences in gene expression revealed by array-based techniques.

Chaib, H., J. W. MacDonald, et al. (2003). "Haploinsufficiency and reduced expression of genes localized to the 8p chromosomal region in human prostate tumors." Genes Chromosomes Cancer 37(3): 306-313.

Cytogenetic and molecular studies have suggested that deletion or rearrangement of sequences that map to the short arm of chromosome 8 may be permissive for tumorigenesis in several organ systems, and in human prostate tumors in particular. In this study, we hypothesized that genes deleted for one copy and localized to the 8p chromosomal region may be transcriptionally down-regulated or ablated in affected human prostate tumor tissues. To test this hypothesis, we used cDNA microarray analysis to determine the transcriptional profiles for 259 transcribed sequences mapping to the 8p chromosomal region for seven human prostate tumor xenografts, completely characterized for numerical and structural alterations on chromosome 8, and five normal human prostate tissues. These experiments identified 33 genes differentially expressed between normal and malignant prostate tissues, the majority of which (28/33, 85%) were transcriptionally down-regulated in malignant compared to normal human prostate tissues. These findings, that haploinsufficiency and transcriptional down-regulation for genes mapping to 8p are largely coincident in human prostate tumors, should provide a powerful tool for the identification of tumor-suppressor genes associated with human prostate cancer initiation and progression.

Chaib, H., M. A. Rubin, et al. (2001). "Activated in prostate cancer: a PDZ domain-containing protein highly expressed in human primary prostate tumors." Cancer Res 61(6): 2390-2394.

Critical events in prostate tumorigenesis and metastasis likely include the abnormal activation and expression of specific genes. Using RNA expression profiling techniques, we have identified a transcript originating from the activated in prostate cancer (AIPC) gene, the expression of which is preferentially up-regulated in several cultured prostate tumor cell lines and human primary prostate tumors. Sequence analysis revealed that the AIPC protein encodes six PDZ domains, which are protein-protein binding domains likely involved in protein clustering and scaffolding. Immunohistochemical analysis of a tissue microarray comprising 158 tumor, 18 high-grade prostatic intraepithelial neoplasia, and 91 normal prostate specimens with an anti-AIPC antibody demonstrated abundant AIPC protein expression in 75% of tumors, 83% of prostatic intraepithelial neoplasia lesions, and 3% of normal tissues (P < 0.0001). These data suggest that the accumulation of AIPC protein may be closely associated with the initiation or early promotion of prostate tumorigenesis.

Chamberlain, D. H., M. P. Hopkins, et al. (1991). "The effects of early removal of indwelling urinary catheter after radical hysterectomy." Gynecol Oncol 43(2): 98-102.

Radical hysterectomy has long been a primary mode of therapy for selected gynecologic malignancies. The lower urinary tract is an area associated with complications following this procedure. Lack of satisfactory reflex micturition and urinary retention, diminished bladder sensation, infection, and fistula formation are common adverse sequelae. Prolonged indwelling catheterization is a cornerstone of postoperative management after radical hysterectomy. An alternative regimen consisting of early postoperative catheter removal, with a strict voiding schedule, and intermittent self-catheterization (ISC) for postvoid residuals (PVR) was prospectively investigated. Intermittent self-catheterization was initiated only if the PVR 12 hr after catheter removal was greater than 75 ml. Twenty-six patients who underwent radical hysterectomy were studied. Catheters were removed between the fifth and ninth postoperative day. Eighteen patients (69%) had PVRs less than 75 ml at 12 hr and were successfully managed with a strict voiding schedule only. Eight patients (31%) had 12-hr PVRs greater than 75 ml and were managed with a strict voiding schedule and ISC until the PVR was less than 75 ml for two consecutive voids. These patients were evaluated with fluorourodynamics and none had an abnormal study. Compared to 25 historical control patients, study group median indwelling catheter duration was less (6.0 days compared to 30.0 days) with no increase in postoperative complications. On the basis of these data, early removal of indwelling urinary catheters after radical hysterectomy appears to be an acceptable alternative to long-term catheterization.

Chan, P. K., D. A. Bloom, et al. (1999). "The N-terminal half of NPM dissociates from nucleoli of HeLa cells after anticancer drug treatments." Biochem Biophys Res Commun 264(1): 305-309.

NPM (nucleophosmin/B23) is a nucleolar phosphoprotein abundant in tumor cells. It dissociates from nucleoli of cells after treatments with various anticancer drugs. To determine the domain of NPM responsible for nucleolar binding, the N- and C-terminal halves of NPM were fused to GFP (green fluorescent protein) and introduced into HeLa cells. The N-terminal half (aa 1-150) of NPM (GFP-NPM(N)) was found localized in the nucleoli. A stable transformant of GFP-NPM(N) in HeLa cells was prepared and tested for association to nucleoli after anticancer drug treatments. GFP-NPM(N) dissociates from nucleoli after treatments with daunomycin, actinomycin D, camptothecin, and toyocamycin. The dissociation is time- and dose-dependent, and correlates with the cytotoxicity induced by the drugs. These results indicate that a stable transformant of GFP-NPM(N) in HeLa cells may be useful for the screening of anticancer drugs.

Chander, S., E. L. Ergun, et al. (2004). "Diaphragmatic and crural FDG uptake in hyperventilating patients: a rare pattern important to recognize." Clin Nucl Med 29(5): 296-299.

The authors describe various patterns of F-18 fluorodeoxyglucose (FDG) accumulation in the diaphragm and crura. They present 6 patients in whom incidental diaphragmatic and crural uptake of FDG was observed during positron emission tomography (PET). Hyperventilation is thought to be the potential underlying mechanism of this condition.

Chander, S., P. Lee, et al. (2005). "PET imaging of gallbladder carcinoma." Clin Nucl Med 30(12): 804-805.

Chander, S., S. M. Westphal, et al. (2004). "Retroperitoneal malignant peripheral nerve sheath tumor: evaluation with serial FDG-PET." Clin Nucl Med 29(7): 415-418.

Retroperitoneal malignant peripheral nerve sheath tumor (MPNST), a rare type of neurogenic tumor, was diagnosed in a 14-year-old girl with a history of neurofibromatosis type 1 (NF1). Immunochemistry demonstrated spindle cells positive for S-100 protein. The patient had multiple tumor recurrences and she was evaluated with serial F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET). A tumor in the right iliac wing showed increased FDG uptake on PET. FDG-PET played an important role in therapy planning and subsequent follow up. This case emphasizes the important role FDG-PET could play in the staging, restaging, and posttherapy follow up of MPNST.

Chander, S., A. P. Zingas, et al. (2004). "Positron emission tomography in primary thyroid lymphoma." Clin Nucl Med 29(9): 572-573.

Chang, C., A. Saltzman, et al. (1995). "Androgen receptor: an overview." Crit Rev Eukaryot Gene Expr 5(2): 97-125.

The action of androgens in regulating development and growth is mediated by androgen receptor (AR). AR is a member of the steroid hormone receptor superfamily, a class of receptors that function through their ability to regulate the transcription of specific genes. The AR is located in various target tissues, with its levels and activity altered with the onset of various cellular events (e.g., sexual development, malignant transformation). The modulation of AR levels occurs through a number of mechanisms, including transcription, and is regulated by various factors (e.g., androgens). The ability of AR to modulate gene transcription is through its interaction with specific DNA sequences located near or within the target gene promoter. The importance of the AR in reproductive physiology has been emphasized by the finding of AR mutations, leading to a variety of disorders, including testicular feminization syndrome. In this article, we review the structure and function of AR and the role AR plays in the function of the mammalian system.

Chang, S. S., B. Jacobs, et al. (2004). "Increased body mass index predicts increased blood loss during radical cystectomy." J Urol 171(3): 1077-1079.

PURPOSE: Historically obesity has been thought to impact negatively patients undergoing surgery. We evaluated the impact of body mass index (BMI), an objective measure of obesity, on operative and perioperative outcomes in patients undergoing radical cystectomy. MATERIAL AND METHODS: We reviewed the records of 304 consecutive patients who underwent radical cystectomy and urinary diversion between October 1995 and July 2000. Factors analyzed included BMI, clinical demographic characteristics, comorbidities, operative variables (eg estimated blood loss [EBL], transfusion requirement and operative time), length of stay and postoperative complications. Results were analyzed using the nonpaired heteroscedastic Student t test assuming unequal variances to determine statistical significance. RESULTS: Of the patients 61% were overweight or obese (BMI 25 or greater). BMI did not correlate with type of urinary diversion, gender or race. On univariate analysis the preoperative variables age, American Society of Anesthesiologists score and BMI correlated with EBL. However, on multivariate analysis BMI was the only preoperative or operative variable that significantly correlated with EBL (p = 0.01). Mean EBL in patients with a normal BMI (less than 25) was 595 ml compared to the mean EBL for overweight and obese patients (25 or greater of 811 ml (p <0.001). However, BMI did not correlate with the complication rate or hospital stay. CONCLUSIONS: On multivariate analysis considering preoperative and operative variables BMI was the only preoperative variable that predicted increased blood loss. Despite this finding overweight or obese patients in this series did not have a higher complication rate or longer hospital stay.

Charles, L. G., Y. C. Xie, et al. (2000). "Antitumor efficacy of tumor-antigen-encoding recombinant poxvirus immunization in Dunning rat prostate cancer: implications for clinical genetic vaccine development." World Journal of Urology 18(2): 136-142.

One potential use for prostate-cancer-associated genes discovered through ongoing genetics studies entails the construction of virus- or plasmid-based recombinant vector vaccines encoding these new tumor-associated antigens (TAA) to induce TAA-specific immune responses for the prevention or therapy of prostate cancer. Clinical trials evaluating prototypes of such recombinant vaccines are under way. TAA-encoding recombinant vector vaccines, however, have not previously been evaluated in a prostate-cancer animal model. For assessment of the potential susceptibility of prostate cancer to genetic immunization strategies using TAA-encoding recombinant vectors, the antitumor efficacy of a model recombinant viral vector encoding a TAA was evaluated in rat Dunning prostate cancer. Recombinant vaccinia was chosen as a prototype virus vector encoding a TAA for these studies, and beta-galactosidase was chosen as a model target TAA. Dunning AT-2 cells were transduced with a retroviral vector to express beta-galactosidase, and the susceptibility of tumorigenic AT-2-lacZ cells to immunization with vaccinia-lacZ was measured using protection studies in Copenhagen and nu/nu rats. Stably transduced AT-2-lacZ cells expressing beta-galactosidase as measured by enzymatic substrate-based assays were found to retain their tumorigenicity in vivo despite abundant expression of rat major histocompatibility complex (MHC) class I. Immunization with model TAA-encoding recombinant vaccinia-lacZ conferred significant protection against subsequent growth of AT-2-lacZ cells in vivo (P = 0.01); however, the efficacy of such immunization was markedly dependent on the volume of tumor challenge. The antitumor efficacy of TAA-encoding recombinant vaccinia immunization was abrogated in nu/nu rats, suggesting a T-cell-dependent mechanism of activity. These studies suggest that prostate cancer may be a suitable target for immunization strategies using TAA-encoding recombinant vectors. Such immunization strategies may be more effective in settings of minimal cancer burden. <52>

Chatterjee, D., Y. Bai, et al. (2004). "RKIP sensitizes prostate and breast cancer cells to drug-induced apoptosis." J Biol Chem 279(17): 17515-17523.

Cancer cells are more susceptible to chemotherapeutic agent-induced apoptosis than their normal counterparts. Although it has been demonstrated that the increased sensitivity results from deregulation of oncoproteins during cancer development (Evan, G. I., and Vousden, K. H. (2001) Nature 411, 342-348; Green, D. R., and Evan, G. I. (2002) Cancer Cell 1, 19-30), little is known about the signaling pathways leading to changes in the apoptotic threshold in cancer cells. Here we show that low RKIP expression levels in tumorigenic human prostate and breast cancer cells are rapidly induced upon chemotherapeutic drug treatment, sensitizing the cells to apoptosis. We show that the maximal RKIP expression correlates perfectly with the onset of apoptosis. In cancer cells resistant to DNA-damaging agents, treatment with the drugs does not up-regulate RKIP expression. However, ectopic expression of RKIP resensitizes DNA-damaging agent-resistant cells to undergo apoptosis. This sensitization can be reversed by up-regulation of survival pathways. Down-regulation of endogenous RKIP by expression of antisense and small interfering RNA (siRNA) confers resistance on sensitive cancer cells to anticancer drug-induced apoptosis. Our studies suggest that RKIP may represent a novel effector of signal transduction pathways leading to apoptosis and a prognostic marker of the pathogenesis of human cancer cells and tumors after treatment with clinically relevant chemotherapeutic drugs.

Chechile, G., E. A. Klein, et al. (1992). "Functional equivalence of end and loop ileal conduit stomas." Journal of Urology 147(3): 582-586.

A total of 458 patients underwent ileal conduit urinary diversion between 1970 and 1984. An end stoma was constructed in 44% of the patients and a Turnbull loop stoma in 56%. The median interval between appliance changes for all patients was 5 days. Patients with an end stoma had a longer median interval between appliance changes than those with a loop stoma. A total of 51 patients had 66 complications. Operations for stomal revisions were required in 5.5% of the patients. There was no difference in interval until initial complication between the end and loop stoma groups, although the end stoma was more prone to ischemic complications than the loop stoma. We conclude that the ileal conduit stoma constructed in an end or loop fashion yielded clinically equivalent long-term function. <136>

Chen, B., M. Zhou, et al. (2002). "Port site, retroperitoneal and intra-abdominal recurrence after laparoscopic acrenalectomy for apparently isolated metastasis." J Urol 168(6): 2528-2529.

Chen, B. T. and D. P. Wood, Jr. (2003). "Salvage prostatectomy in patients who have failed radiation therapy or cryotherapy as primary treatment for prostate cancer." Urology 62 Suppl 1: 69-78.

Asymptomatic prostate-specific antigen (PSA) recurrence after radiation therapy for prostate carcinoma poses a diagnostic and therapeutic dilemma for clinicians. Patients with locally recurrent disease can consider treatment options of salvage surgery, cryotherapy, watchful waiting, or androgen deprivation. Of these options, only salvage surgery has been shown to result in long-term disease-free survival for selected patients. However, salvage surgery is associated with significant morbidity, including urinary incontinence and rectal injuries. Ideally, salvage surgery outcomes can be optimized with careful patient selection according to clinical stage, serum PSA levels before radiation and surgery, the medical condition of the patient, and clear expectations of the physician and patient. Among patients with locally recurrent disease, those with localized prostate carcinoma amenable to radical prostatectomy before radiation or cryotherapy would be the most suitable candidates for salvage surgery.

Chen, C., A. J. Koh, et al. (2004). "Impact of the mitogen-activated protein kinase pathway on parathyroid hormone-related protein actions in osteoblasts." J Biol Chem 279(28): 29121-29129.

Parathyroid hormone-related protein (PTHrP) regulates proliferation and differentiation of osteoblastic cells via binding to the parathyroid hormone receptor (PTH-1R). The cAMP-dependent protein kinase A pathway governs the majority of these effects, but recent evidence also implicates the MAPK pathway. MC3T3-E1 subclone 4 cells (MC4) were treated with the MAPK inhibitor U0126 and PTHrP. In differentiated MC4 cells, osteocalcin and bone sialoprotein gene expression were both down-regulated by PTHrP and also by inhibition of the MAPK pathway. PTHrP-mediated down-regulation of PTH-1R mRNA and up-regulation of c-fos mRNA were MAPK-independent, whereas PTHrP stimulation of fra-2 and interleukin-6 (IL-6) mRNA was MAPK-dependent. Luciferase promoter assays revealed that regulation of IL-6 involved the cAMP-dependent protein kinase A and MAPK pathways with a potential minor role of the protein kinase C pathway, and a promoter region containing an activator protein-1 site was necessary for PTHrP-induced IL-6 gene transcription. An alternative pathway, through cAMP/Epac/Rap1/MAPK, mediated ERK phosphorylation but was not sufficient for IL-6 promoter activation. Phosphorylation of the transcription factor CREB was also necessary but not sufficient for PTHrP-mediated IL-6 promoter activity. Most interesting, a bidirectional effect was found with PTHrP increasing phosphorylated ERK in undifferentiated MC4 cells but decreasing phosphorylated ERK in differentiated cells. These data indicate that inactivation of the MAPK pathway shows differential regulation of PTHrP-stimulated activator protein-1 members, blocks PTHrP-stimulated IL-6, and synergistically down-regulates certain osteoblastic markers associated with differentiation. These novel findings indicate that the MAPK pathway plays a selective but important role in the actions of PTHrP.

Cheng, X., H. Zhang, et al. (2004). "Cyclooxygenase-2 inhibitor preserves medullary aquaporin-2 expression and prevents polyuria after ureteral obstruction." J Urol 172(6 Pt 1): 2387-2390.

PURPOSE: Renal obstruction causes impairment of urinary concentrating ability, partly by decreasing aquaporin-2 (AQP-2) water channel level in the collecting ducts. We reported previously that ureteral obstruction induced cyclooxygenase-2 (COX-2) in the medullary collecting duct cells by increased mechanical stretch. In this study we investigated whether AQP-2 decrease after obstruction was regulated by COX-2. MATERIALS AND METHODS: Sprague-Dawley rats were subjected to bilateral ureteral obstruction for 24 to 48 hours. During obstruction rats were given NS398, a COX-2 specific inhibitor, by oral gavage (2 mg/kg per day). COX-2 and AQP-2 levels were assessed in the inner medulla using Western blot. Urine output was measured after releasing obstruction to assess the degree of polyuria. RESULTS: With obstruction COX-2 protein levels increased and AQP-2 levels decreased in the inner medulla. Corresponding to the loss of AQP-2, urine output increased 4.2-fold after obstruction. The obstructed rats receiving NS398 exhibited significant preservation of AQP-2 level (72% of control), as well as significant normalization of urine output. The sham operated rats receiving NS398 exhibited an increased amount of AQP-2 protein level. CONCLUSIONS: These findings suggest that COX-2 mediated prostaglandin has an important role in the down-regulation of AQP-2 water channel level in the medullary collecting duct cells after ureteral obstruction.

Cher, M. L., F. J. Bianco, Jr., et al. (1998). "Limited role of radionuclide bone scintigraphy in patients with prostate specific antigen elevations after radical prostatectomy." J Urol 160(4): 1387-1391.

PURPOSE: Bone scintigrams of patients with increasing serum prostate specific antigen (PSA) after radical prostatectomy are only rarely positive. We identify clinical parameters that would improve our ability to select patients for this imaging study. MATERIALS AND METHODS: We reviewed all bone scintigrams done at our institution between 1991 and 1996 in patients with persistently increasing serum PSA after radical prostatectomy. What prompted the clinician to obtain the bone scintigram was trigger PSA (tPSA). The rate of increase in PSA to tPSA was measured by tPSA/time from radical prostatectomy (slope 1) and tPSA/time from last undetectable PSA (slope 2). These parameters were evaluated together with standard clinicopathological data in univariate and multivariate analyses to determine the ability to predict the bone scintigram result. RESULTS: In univariate analysis tPSA (p = 0.003), slope 1 (p = 0.005) and slope 2 (p = 0.004) were useful in predicting the bone scintigram result but pathological stage, Gleason score, preoperative PSA and time to recurrence were not. In multivariate analysis the single most useful parameter in predicting the bone scintigram result was tPSA (p = 0.01). Based on a logistic regression model the probability of a positive bone scintigram was less than 5% until tPSA increased to 40 to 45 ng./ml. CONCLUSIONS: In patients with increasing serum PSA after radical prostatectomy current serum PSA is the best predictor of the bone scintigram result. Furthermore, there is limited usefulness of bone scintigraphy until PSA increases above 30 to 40 ng./ml.

Cher, M. L., J. G. de Oliveira, et al. (1999). "Cellular proliferation and prevalence of micrometastatic cells in the bone marrow of patients with clinically localized prostate cancer." Clin Cancer Res 5(9): 2421-2425.

The presence of prostate cancer cells in the bone marrow (BM) of patients with clinically localized disease is associated with an increased chance of disease recurrence; however, not all patients develop recurrence. We therefore sought to determine the phenotype of individual micrometastatic cells as a potential method to better predict disease outcome. Immunostaining was performed on BM cells from 46 patients whose BM RNA fraction had been identified to contain prostate-specific antigen mRNA. The prevalence of micrometastatic cells among BM mononuclear cells was determined using an anticytokeratin antibody. Mib-1 antibody was used to determine the percentage of micrometastatic cells that were proliferating. Micrometastatic cells were found in 96% of patient samples, with a 30-fold variation in prevalence ranging from 0.1-3.26/10(5) BM cells. Prior androgen ablation was associated with a reduced prevalence of micrometastatic cells (P = 0.010). In 68% of patients, some micrometastatic cells were judged to be proliferating at proportions ranging from 1 of 11 (9%) to 4 of 4 (100%). Higher Gleason score of the primary tumor was associated with a higher proliferative proportion of micrometastatic cells (P = 0.038). We conclude that, in patients with clinically localized disease, there is wide variability in the prevalence of micrometastatic cells and the proportion which are proliferating. Long-term follow-up will determine whether the development of clinically obvious metastatic disease is related to higher prevalence of micrometastatic cells in the marrow or the proportion that are proliferating.

Cher, M. L., D. A. Towler, et al. (2006). "Cancer interaction with the bone microenvironment: a workshop of the National Institutes of Health Tumor Microenvironment Study Section." Am J Pathol 168(5): 1405-1412.

Chintala, K., D. A. Bloom, et al. (2004). "Images in cardiology: Pericardial yolk sac tumor presenting as cardiac tamponade in a 21-month-old child." Clin Cardiol 27(7): 411.

Chiu, K. M., C. D. Arnaud, et al. (2000). "Correlation of estradiol, parathyroid hormone, interleukin-6, and soluble interleukin-6 receptor during the normal menstrual cycle." Bone 26(1): 79-85.

Rodent models suggest that estradiol deficiency promotes bone loss through increasing interleukin-6 (IL-6) activity. However, it is controversial as to whether these findings are applicable to humans. To evaluate estradiol-mediated modulation of IL-6 activity in relation to bone metabolism in humans, we measured serum IL-6, soluble interleukin-6 receptor (sIL-6R), estradiol (E2), progesterone, luteinizing hormone, follicle-stimulating hormone, intact parathyroid hormone (PTH), serum and urine Ca, and bone biochemical markers (serum bone-specific alkaline phosphatase, osteocalcin, and serum and urine deoxypyridinoline [Dpd]) across one menstrual cycle for 211 women. Neither IL-6 nor sIL-6R levels differed between the follicular phase (FP) and the luteal phases (LP). However, IL-6 was negatively correlated with E2 during the FP (p =0.003). Furthermore, IL-6 correlated positively with serum Ca over the entire cycle (p = 0.0091. Serum Ca correlated positively with serum (p = 0.040) and urine (p = 0.006) Dpd. PTH was significantly higher during the FP than in the LP (p = 0.004). PTH was negatively related to E2 (p = 0.002), serum Ca (p < 0.001), and urine Ca (p = 0.036), whereas it was positively correlated with IL-6 (p = 0.027). These data demonstrate that IL-6 and PTH fluctuate with E2, and serum II-6 is associated with PTH levels during the menstrual cycle. However, the role of 11-6 in bone remodeling during the normal menstrual cycle remains to be determined.

Chiu, K. M., E. T. Keller, et al. (1999). "Carnitine and dehydroepiandrosterone sulfate induce protein synthesis in porcine primary osteoblast-like cells." Calcif Tissue Int 64(6): 527-533.

Age-related bone loss eventually leads to osteopenia in men and women. The etiology of age-related bone loss is currently unknown; however, decreased osteoblast activity contributes to this phenomenon. In turn, osteoblast proliferation and function is dependent on energy production, thus the loss of energy production that occurs with age may account for the deficient osteoblast activity. Carnitine and dehydroepiandrosterone-sulfate (DHEAS), both of which decline with age, promote energy production through fatty acid metabolism. Thus, we hypothesized that carnitine and DHEAS would increase osteoblast activity in vitro. Accordingly, we measured the effect of carnitine and DHEAS on palmitic acid oxidation as a measure of energy production, and alkaline phosphatase (ALP) activity and collagen type I (COL) as indices of osteoblast function in primary porcine osteoblast-like cell cultures. Carnitine (10(-3) and 10(-1) M) but not DHEAS (10(-9), 10(-8), and 10(-7) M) increased carnitine levels within the cells. Carnitine alone and in combination with DHEAS increased palmitic acid oxidation. Both carnitine and DHEAS alone and in an additive fashion increased ALP activity and COL levels. These results demonstrate that in osteoblast-like cells in vitro, energy production can be increased by carnitine and osteoblast protein production can be increased by both carnitine and DHEAS. These data suggest that carnitine and DHEAS supplementation in the elderly may stimulate osteoblast activity and decrease age-related bone loss.

Chiu, K. M., M. J. Schmidt, et al. (1999). "Correlation of serum L-carnitine and dehydro-epiandrosterone sulphate levels with age and sex in healthy adults." Age Ageing 28(2): 211-216.

OBJECTIVES: L-carnitine and dehydro-epiandrosterone (DHEA) independently promote mitochondrial energy metabolism. We therefore wondered if an age-related deficiency of L-carnitine or DHEA may account for the declining energy metabolism associated with age. METHODS: we evaluated serum levels of L-carnitine and the sulphated derivative of DHEA (DHEAS) in cross-sectional study of 216 healthy adults, aged 20-95. RESULTS: serum DHEAS levels declined, while total carnitine levels increased with age (P < 0.0001). Total and free carnitine and DHEAS levels were lower in women than men (P < 0.0001). Esterified/free (E/F) carnitine (inversely related to carnitine availability) increased with age in both sexes (P=0.012). CONCLUSION: reduced carnitine availability correlates with the age-related decline of DHEAS levels. These results are consistent with the hypothesis that decreased energy metabolism with age relates to DHEAS levels and carnitine availability.

Christ, G. J. and M. Liebert (2005). "Proceedings of the Baltimore smooth muscle meeting: identifying research frontiers and priorities for the lower urinary tract." J Urol 173(4): 1406-1409.

PURPOSE: The myocyte is a major parenchymal cell of the lower urinary tract (LUT) in men and women. Significant phenotypic diversity ensures that myocytes subserve their important role in the physiologically distinct tissues and organs of the LUT, including the ureters, bladder, urethra, prostate, penis, vagina and myometrium. Coordinated contraction and relaxation of myocytes is required for normal organ function, while alterations in myocyte structure/function are implicated in the etiology of various LUT diseases/disorders. LUT diseases/disorders will continue to increase in an ever aging American population. The purpose of the Baltimore Smooth Muscle Meeting was to begin to identify some research frontiers and priorities. MATERIALS AND METHODS: A 1-day conference of some of the leading world experts in smooth muscle research was held at American Urological Association headquarters. These experts gave presentations in their areas of expertise and extensively discussed their work. This report details those interactions. RESULTS: There is astonishing diversity in the contribution of the myocyte to LUT physiology and dysfunction. Novel tools, technologies and ideas have produced increased understanding and identified new frontiers. CONCLUSIONS: An improved understanding of urogenital myocyte physiology, function and dysfunction is required better to elucidate disease mechanisms and develop novel therapeutics. The First Annual Baltimore Smooth Muscle Meeting provided the first step in this direction. More coordinated LUT myocyte funding initiatives, the further development of research resources, tools and technologies, and exploration of the urogenital system as a model system for studying systems biology and integrative physiology are among the highest research priorities.

Claeys, G. B., A. V. Sarma, et al. (2005). "INSPstI polymorphism and prostate cancer in African-American men." Prostate 65(1): 83-87.

BACKGROUND: Both prostate cancer and diabetes mellitus are common diseases in African-American men. High insulin levels and insulin resistance have been implicated in prostate cancer development, which has prompted a recent investigation of a possible role for germline variation in the insulin gene (INS) and prostate cancer risk. METHODS: Four hundred sixty-six African-American men with and without prostate cancer from the Flint Men's Health Study were typed for the INS Pst1 genotype using restriction digest and direct sequencing. An association between the Pst1 genotype and prostate cancer was examined using crude and age-adjusted logistic regression models. RESULTS: African-American men who were homozygous for the INS PstI CC genotype were 1.59 times more likely to be diagnosed with prostate cancer compared to men with the TT or TC genotypes (95% CI = 0.93-2.72). The association appeared stronger among diabetics compared to non-diabetics; however this observation was not statistically significant. CONCLUSIONS: Our study, taken together with the report of Ho et al., suggests that the INS Pst1 CC genotype is associated with prostate cancer risk in African-American men. Germline variation in the INS gene should be more fully explored in multiethnic studies to elucidate the molecular variant(s) associated with prostate carcinogenesis.

Clark, P. E., L. R. Schover, et al. (2001). "Quality of life and psychological adaptation after surgical treatment for localized renal cell carcinoma: impact of the amount of remaining renal tissue." Urology 57(2): 252-256.

OBJECTIVES: To analyze the quality of life and psychological adjustment after surgical therapy for localized renal cell carcinoma. METHODS: Postal questionnaires including measures of quality of life (SF-36) and the impact of the stress of cancer (Impact of Events Scale) were completed by 97 patients who had undergone radical or partial nephrectomy for localized renal cell carcinoma. Data were analyzed for the group as a whole and comparing the partial nephrectomy and radical nephrectomy groups. The variables examined included the impact of the type of partial nephrectomy (elective versus mandatory) and the amount of self-reported renal tissue remaining. RESULTS: The quality of life for the group as a whole was good, with no significant differences between the sample and U.S. norms for an age and sex-matched community sample on both the mental and physical health composite scores. Having undergone a partial versus a radical nephrectomy did not influence the patients' overall quality of life. Multiple linear regression modeling demonstrated that having more remaining renal parenchyma was an independent predictor of better self-reported physical health on the SF-36 (P <0.001). The entire sample had low mean scores on both avoidance and intrusion on the Impact of Events Scale, suggesting a lack of daily anxiety about cancer. Multiple linear regression modeling showed that patients who reported having more remaining renal parenchyma had lower intrusion and avoidance scores (P = 0.002 and 0.01, respectively). Multiple logistic regression modeling also demonstrated that the patients' perception of their remaining renal parenchyma was associated with less concern about cancer recurrence (P = 0.018) and less impact of cancer on patients' overall health (P <0.001). CONCLUSIONS: Most survivors of localized kidney cancer have normal physical and mental health regardless of the type of nephrectomy performed. The quality of life is better for patients with more renal parenchyma remaining after surgery for localized renal cell carcinoma.

Clemens, J. Q. (1999). "The bulbourethral sling procedure: Northwestern University experience." Contemporary Urology 11: 68-73.

Clemens, J. Q. (2005). "Is patient reporting of interstitial cystitis symptoms comparable between two disease-specific indices?" Nat Clin Pract Urol 2: 278-279.

Clemens, J. Q. (2008). "Male and female pelvic pain disorders--is it all in their heads?" J Urol 179(3): 813-814.

Clemens, J. Q. (2010). "Afferent neurourology: A novel paradigm." Neurourol Urodyn 29 Suppl 1: S29-31.

The term "afferent neurourology" is introduced to describe the study of sensory processing related to the genitourinary tract. Urologic disorders that are characterized by abnormal sensory processing are reviewed, and unique challenges to our understanding of these disorders are described. A paradigm which separates afferent urologic disorders from efferent disorders and structural abnormalities is presented.

Clemens, J. Q. (2010). "Afferent neurourology: an epidemiological perspective." J Urol 184(2): 432-439.

PURPOSE: Multiple urological conditions are characterized by bothersome sensations such as pain or urinary urgency. There is significant confusion about the etiology and pattern of these symptoms. MATERIALS AND METHODS: The term afferent neurourology is introduced to describe the study of sensory processing related to the genitourinary tract. Epidemiological studies related to afferent neurourology are reviewed and unique challenges to our understanding of these disorders are described. RESULTS: Afferent urological disorders are characterized by urological pain or urinary urgency. Conceptually these afferent disorders can be differentiated from efferent urological disorders and structural urological abnormalities. Afferent urological disorders are common in men and women, although symptom severity is variable. Study of the entire disease spectrum may provide insight into pathogenesis and prevention. The natural history of these symptoms is poorly understood. Afferent urological disorders commonly co-occur with other poorly understood somatic symptoms, suggesting that symptoms may be due to a systemic disorder in certain individuals. Mechanisms responsible for these sensory abnormalities are poorly understood and may arise from central and peripheral abnormalities. CONCLUSIONS: Urinary pain and urgency are common, bothersome symptoms that are currently understood poorly and managed ineffectively. Intentional recognition of sensory urological abnormalities as a separate field of study may enhance research efforts into these conditions and improve treatment outcomes.

Clemens, J. Q. and D. A. Bloom (2010). "Dr. McGuire has been honored and revered nationally and internationally." Neurourol Urodyn 29 Suppl 1: S1.

Clemens, J. Q., S. O. Brown, et al. (2008). "Mental health diagnoses in patients with interstitial cystitis/painful bladder syndrome and chronic prostatitis/chronic pelvic pain syndrome: a case/control study." J Urol 180(4): 1378-1382.

PURPOSE: We compared the rate of mental health disorders in male and female patients with pelvic pain and control subjects. MATERIALS AND METHODS: Male patients with chronic prostatitis/chronic pelvic pain syndrome (174) and female patients with interstitial cystitis/painful bladder syndrome (111) were identified from a urology tertiary care clinic population. A control group consisting of 72 men and 175 women was also recruited. Subjects completed self-administered questionnaires that included items about demographics, medical history, medication use and urological symptoms. The Patient Health Questionnaire was used to identify depression and panic disorder. Multiple logistic regression was used to determine odds ratios for the presence of a mental health diagnosis. RESULTS: Mental health disorders were identified in 13% of the chronic prostatitis/chronic pelvic pain syndrome cases and 4% of male controls (OR 2.0, p = 0.04), as well as in 23% of interstitial cystitis/painful bladder syndrome cases and 3% of female controls (OR 8.2, p <0.0001). Disease status (case vs control) (OR 10.4, p = 0.001) and income greater than $50,000 (OR 0.34, p = 0.008) were the only 2 variables independently predictive of the presence of a mental health diagnosis. Age, gender, race/ethnicity and education were not predictive. Medications for anxiety, depression or stress were being taken by 18% of patients with chronic prostatitis/chronic pelvic pain syndrome, 37% of those with interstitial cystitis/painful bladder syndrome, 7% of male controls and 13% of female controls. CONCLUSIONS: Depression and panic disorder are significantly more common in men and women with pelvic pain conditions than in controls. Medication use data suggest that anxiety and depression may be more difficult to treat in patients with urological pain syndromes than in controls.

Clemens, J. Q., S. O. Brown, et al. (2006). "Predictors of symptom severity in patients with chronic prostatitis and interstitial cystitis." J Urol 175(3 Pt 1): 963-966; discussion 967.

PURPOSE: Numerous studies have been performed to identify potential risk factors for CP/CPPS and IC. However, few studies have been done to identify predictors of disease severity. MATERIALS AND METHODS: A total of 174 men with CP/CPPS and 111 women with IC completed questionnaires to quantify symptom severity and identify demographic, medical and psychosocial characteristics. Symptom severity was assessed with the National Institutes of Health CPSI in men, and the O'Leary-Sant ICSI and problem index in women. Univariate and multivariate analyses were performed to identify characteristics predictive of worse symptoms. RESULTS: The mean National Institutes of Health CPSI score in men was 15.32, and the mean O'Leary-Sant ICSI and problem index in women was 19.17. The most commonly reported comorbidities were allergies, sinusitis, erectile dysfunction and irritable bowel syndrome in men, and allergies, urinary incontinence, sinusitis and irritable bowel syndrome in women. In the 2 sexes self-reported urinary frequency and urgency, worse depression scores and lower education level were independent predictors of worse symptom severity. In men additional independent predictors were self-reported pelvic pain, fibromyalgia and previous heart attack, and in women an additional independent predictor was postmenopausal status. CONCLUSIONS: There are several common medical conditions associated with urological pelvic pain syndromes in men and women. Few of them were predictive of symptoms severity in this analysis. Self-reported pelvic pain symptoms, education and depression severity were the factors most strongly predictive of symptom severity in patients with CP/CPPS and IC.

Clemens, J. Q., W. Bushman, et al. (1999). "Questionnaire based results of the bulbourethral sling procedure." J Urol 162(6): 1972-1976.

PURPOSE: The success rate of the bulbourethral sling procedure to treat post-radical prostatectomy incontinence has been reported in a previous chart review analysis. We present further evaluation of the procedure using postoperative mailed questionnaires. MATERIALS AND METHODS: Between October 1994 and October 1997, 66 men underwent the bulbourethral sling procedure at our hospital. Postoperatively all patients with indwelling bolsters were mailed questionnaires to assess continence status, discomfort and voiding patterns. RESULTS: Of the 66 patients 4 required bolster removal for infection (2), erosion (1) or pain (1), and 1 died. These patients were not assessed further. Questionnaire data were obtained from the remaining 61 patients. At a median followup of 9.6 months (mean 11.9, range 3 to 30) 25 patients (41%) reported complete cure of incontinence, 32 (53%) required no pad for protection and 52 (85%) required 2 pads or less. Persistent perineal numbness or discomfort was present in 32 patients (52%). Of 12 patients who received adjuvant radiation therapy only 1 (8%) was cured. CONCLUSIONS: The short-term success rate following the bulbourethral sling procedure is high but persistent perineal discomfort is common. Adjuvant radiation predisposes to treatment failure.

Clemens, J. Q., W. Bushman, et al. (1999). "Urodynamic analysis of the bulbourethral sling procedure." J Urol 162(6): 1977-1981; discussion 1981-1972.

PURPOSE: The bulbourethral sling procedure is successful in correcting incontinence following radical prostatectomy. However, the mechanism of action of the sling is not intuitively clear. We analyze the results of urodynamic testing on a cohort of men who underwent the bulbourethral sling procedure. MATERIALS AND METHODS: Between October 1994 and October 1997, 66 men underwent the bulbourethral sling procedure at our hospital. All but 1 patient underwent preoperative video urodynamic testing. Intraoperative urethral pressure profilometry and abdominal leak point pressure measurements were performed. Additionally, all patients were invited to undergo followup video urodynamic testing. Results were correlated with current continence status. RESULTS: Preoperatively all patients demonstrated intrinsic sphincter deficiency. Following sling placement postoperative Valsalva leak point pressure values were significantly increased but maximum resting urethral pressures were unchanged. Preoperative and postoperative Abrams-Griffiths nomograms were not consistent with postoperative bladder outlet obstruction. Postoperative voiding pressures were consistently less than corresponding Valsalva leak point pressures. CONCLUSIONS: Patients undergoing video urodynamic testing following the bulbourethral sling procedure demonstrated unobstructed voiding patterns, despite significant increases in Valsalva leak point pressures.

Clemens, J. Q., E. A. Calhoun, et al. (2009). "Rescoring the NIH chronic prostatitis symptom index: nothing new." Prostate Cancer Prostatic Dis 12(3): 285-287.

The National Institutes of Health-chronic prostatitis symptom index (NIH-CPSI) is a commonly used 13-item questionnaire for the assessment of symptom severity in men with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). For each item, score ranges are 0-1 (6 items), 0-3 (2 items), 0-5 (3 items), 0-6 (1 item) and 0-10 (1 item). This scoring system is straightforward, but items with wider score ranges are de facto weighted more, which could adversely affect the performance characteristics of the questionnaire. We rescored the NIH-CPSI so that equal weights were assigned to each item, and compared the performance of the standard and rescored questionnaires using the original validation dataset. Both the original and revised versions of the scoring algorithm discriminated similarly among groups of men with CP (n=151), benign prostatic hyperplasia (n=149) and controls (n=134). The internal consistency of the questionnaire was slightly better with the revised scoring, but values with the standard scoring were sufficiently high (Cronbach's >or=0.80). We conclude that although the rescored NIH-CPSI provides better face validity than the standard scoring algorithm, it requires additional calculation efforts and yields only marginal improvements in performance.

Clemens, J. Q., E. A. Calhoun, et al. (2009). "Validation of a modified National Institutes of Health chronic prostatitis symptom index to assess genitourinary pain in both men and women." Urology 74(5): 983-987, quiz 987 e981-983.

OBJECTIVES: To date, separate condition-specific instruments have been used to assess severity of symptoms, in men and women with urological pain conditions. We developed a single instrument that can be used to assess treatment response in clinical trials and cohort studies that involve both genders. METHODS: We developed the Genitourinary Pain Index (GUPI) by modifying and adding questions to the National Institutes of Health-Chronic Prostatitis Symptom Index. To assess discriminant validity, concurrent validity, and reliability, we administered the GUPI to 1653 men and 1403 women in a large managed care population. To assess responsiveness, we administered the GUPI to 47 men and women who completed a National Institutes of Health-sponsored trial of pelvic floor physical therapy. RESULTS: The GUPI discriminated between men with chronic prostatitis or interstitial cystitis, those with other symptomatic conditions (dysuria, frequency, chronic cystitis), and those with none of these diagnoses (P <.05). It also discriminated between women with interstitial cystitis, those with incontinence, and those with none of these diagnoses (P <.05). The GUPI demonstrated good internal consistency within subscale domains, and GUPI scores correlated highly with scores on the Interstitial Cystitis Symptom Index and Problem Index. The GUPI was highly responsive to change, and the change in score was similar in both male and female responders. A reduction of 7 points robustly predicted being a treatment responder (sensitivity 100%, specificity 76%). CONCLUSIONS: The GUPI is a valid, reliable, and responsive instrument that can be used to assess the degree of symptoms in both men and women with genitourinary pain complaints.

Clemens, J. Q., E. A. Calhoun, et al. (2010). "A Survey of Primary Care Physician Practices in the Diagnosis and Management of Women With Interstitial Cystitis/Painful Bladder Syndrome." Urology.

OBJECTIVES: To describe the practice patterns among primary care physicians' (PCPs) managing patients with symptoms suggestive of interstitial cystitis/painful bladder syndrome (IC/PBS). METHODS: We developed a clinical vignette describing a woman with typical IC/PBS symptoms to elicit questions about etiology, management strategies, and familiarity with this syndrome. We mailed the questionnaire to 556 PCPs, including academicians and community physicians, in Boston, Los Angeles, and Chicago. RESULTS: We received 290 completed questionnaires (response rate, 52%). Nineteen percent of respondents reported they had "never" seen a patient like the one described in the vignette. Two-thirds of respondents correctly identified the hallmark symptom of IC/PBS (bladder pain/pressure). Regarding etiology, 90% correctly indicated that IC/PBS was a noninfectious disease, 76% correctly reported that it was not caused by a sexually transmitted infection, and 61% correctly indicated that it was not caused by a psychiatric illness. Common treatments included antibiotics and nonsteroidal anti-inflammatory agents. Referrals were often made to a specialist. CONCLUSIONS: Although most PCPs indicate familiarity with IC/PBS, they manage the condition infrequently. They also appear to have significant knowledge deficits about the clinical characteristics of IC/PBS, and they indicate variable practice patterns in the diagnosis and treatment of the condition. Educational efforts directed at PCPs will likely improve the care of patients with IC/PBS.

Clemens, J. Q., J. O. DeLancey, et al. (2000). "Urinary tract erosions after synthetic pubovaginal slings: diagnosis and management strategy." Urology 56(4): 589-594.

OBJECTIVES: To review our experience with the diagnosis and management of genitourinary tract erosions after pubovaginal sling placement. METHODS: Clinic and operative records from the urology and gynecology services at two university hospitals were reviewed, and 14 patients were identified who underwent surgical treatment for a urogenital tract erosion after pubovaginal sling placement. The presenting symptoms, physical findings, diagnostic procedures, surgical treatments, and outcomes were reviewed. RESULTS: Six vaginal erosions, six urethral and vaginal erosions, and two bladder erosions occurred. All were associated with synthetic sling or suture materials. Common symptoms included vaginal and urethral pain, irritative voiding symptoms, vaginal discharge and/or bleeding, and recurrent urinary tract infections. All vaginal and urethral erosions were detected by physical examination and cystoscopy. Symptoms resolved after removal of the eroded sling component. Of the 12 patients with vaginal or urethral erosions, 7 developed recurrent postoperative stress incontinence. CONCLUSIONS: Persistent painful or irritative symptoms after pubovaginal sling placement may be due to urogenital tract erosion, especially if synthetic materials were used. Appropriate evaluation and treatment will result in dramatic symptomatic improvement, although recurrent stress incontinence may occur.

Clemens, J. Q., C. L. Link, et al. (2007). "Prevalence of painful bladder symptoms and effect on quality of life in black, Hispanic and white men and women." J Urol 177(4): 1390-1394.

PURPOSE: The prevalence of painful bladder symptoms is poorly defined, especially in racial and ethnic minority groups. We estimated the prevalence of painful bladder symptoms in a community based sample, assessed symptom variation by age, gender, race/ethnicity and socioeconomic status, and estimated their impact on quality of life. MATERIALS AND METHODS: A population based cross-sectional survey of individuals was done in the Boston area using a multistage stratified cluster sample. A 2-hour in person interview performed by a bilingual interviewer was done, generally in the home of the subject. The research design was for equal numbers of subjects in each of 24 design cells, as defined by age (30 to 39, 40 to 49, 50 to 59 and 60 to 79 years), gender and race/ethnicity (black, Hispanic and white). The sample of 5,506 subjects was recruited from April 2002 through June 2005. Multiple definitions of painful bladder symptoms were used based on consensus statements, research definitions and published articles. The effect of gender, age, race/ethnicity and socioeconomic status on symptom prevalence was assessed. RESULTS: The prevalence of painful bladder syndrome symptoms was 0.83% to 2.71% in women and 0.25% to 1.22% in men depending on the definition used. Multivariate analyses revealed that symptoms were significantly more common in women, middle-aged individuals (40 to 59 years old) and lower socioeconomic status groups. For most definitions there were no variations by race or ethnicity. The presence of symptoms was associated with a significant adverse impact on quality of life. CONCLUSIONS: Painful bladder symptoms are more common than suggested by coded physician diagnoses. Although most bladder pain research cohorts have included predominantly white women, these population based findings indicate no racial/ethnic disparity and limited gender disparity in the prevalence of painful bladder symptoms. This suggests that the burden of painful bladder syndrome may be greater in nonwhite individuals and men than previously suspected.

Clemens, J. Q., T. Markossian, et al. (2009). "Comparison of economic impact of chronic prostatitis/chronic pelvic pain syndrome and interstitial cystitis/painful bladder syndrome." Urology 73(4): 743-746.

OBJECTIVES: To perform a comparison of the economic impact of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and interstitial cystitis/painful bladder syndrome (IC/PBS) because limited information is available. Furthermore, no direct comparisons of the costs of these 2 conditions have been performed. Such a comparison is relevant because the distinction between the 2 conditions is not always clear. METHODS: We recruited 62 men with CP/CPPS and 43 women with IC/PBS from a tertiary care outpatient urology clinic. Information about hospitalizations, laboratory tests, physician visits, telephone calls, medication use, and lost productivity was obtained from written questionnaires. Direct medical cost estimates were determined from hospital cost accounting data, the 2005 Physician Fee Schedule Book, and the 2005 Redbook for pharmaceuticals. Indirect costs were determined from patient-reported annual income and patient-reported hours lost from work during the most recent 3-month period. RESULTS: Using Medicare rates, the annualized direct costs per person were $3631 for IC/PBS and $3017 for CP/CPPS. Using non-Medicare rates for outpatient visits and tests/procedures, the annual per person costs increased substantially to $7043 for IC/PBS and $6534 for CP/CPPS. Sixteen patients with CP/CPPS (26%) and 8 with IC/PBS (19%) reported lost wages as a result of their condition in the previous 3 months. CONCLUSIONS: Both CP/CPPS and IC/PBS have very similar and substantial direct and indirect costs. The greater costs reflected by the non-Medicare rates may more accurately reflect the true costs, given that a large proportion of these patients were <65 years old.

Clemens, J. Q., T. W. Markossian, et al. (2007). "Overlap of voiding symptoms, storage symptoms and pain in men and women." J Urol 178(4 Pt 1): 1354-1358; discussion 1358.

PURPOSE: We quantified the degree of symptomatic overlap in individuals who reported urological symptoms and compared these patterns between men and women. MATERIALS AND METHODS: A questionnaire was mailed to a random sample of the Kaiser Permanente Northwest membership with no medical record evidence of pelvic malignancy or neurological disease. The questionnaire included the International Prostate Symptom Scale, Interstitial Cystitis Symptom Index and Problem Index, and National Institutes of Health Chronic Prostatitis Symptom Index. The 701 men and 745 women who reported urological symptoms were selected for analysis. The degree of overlap of storage symptoms, voiding symptoms and pain symptoms was assessed. Multiple logistic regression was used to determine symptom predictors. RESULTS: There was a high degree of overlap among the 3 symptom categories with few observed differences between men and women. Of individuals with storage or voiding symptoms 34% of men and 43% of women also had pain symptoms. Of those with pain 90% of men and 94% of women also had voiding or storage symptoms. Logistic regression results indicated that frequency, urgency and any storage symptoms were statistically more common in women than in men, while a slow stream was more common in men than in women. CONCLUSIONS: As previously reported, there are limited differences in the degree and distribution of lower urinary tract symptoms in men and women. To our knowledge the novel finding of this study is that pain symptoms commonly coincide with voiding and storage symptoms in the 2 genders. This suggests that categorizing patients into disease categories, such as lower urinary tract symptoms or bladder conditions, may ignore the pain components of symptoms. A symptom based classification symptom may more accurately identify and address all patient complaints.

Clemens, J. Q., R. T. Meenan, et al. (2005). "Prevalence of interstitial cystitis symptoms in a managed care population." J Urol 174(2): 576-580.

PURPOSE: We calculated the prevalence of symptoms typically associated with interstitial cystitis (IC) in men and women in a managed care population in the Pacific Northwest. MATERIALS AND METHODS: International Classification of Diseases-9 based queries of the Kaiser Permanente Northwest, Portland, Oregon database were used to identify subjects with IC exclusion criteria, who were excluded from further analysis. A total of 10,000 questionnaires, including 5,000 for women and 5,000 for men, were mailed to subjects with codes indicating bladder symptoms and to those with none of the codes. The questionnaires included questions about the presence of IC symptoms and the O'Leary-Sant interstitial cystitis questionnaire. IC symptoms were defined in 2 ways, that is as 1) pelvic pain at least 3 months in duration plus urgency or frequency at least 3 months in duration and 2) the same criteria plus pain increasing as the bladder fills and/or pain relieved by urination. RESULTS: The prevalence of IC symptoms according to definitions 1 and 2 was 11.2% and 6.2% in women, and 4.6% and 2.3% in men, respectively. Symptoms were long-standing (duration greater than 1 year in 80% of cases) and bothersome (severity score 5 or greater in greater than 50%). Mean O'Leary-Sant interstitial cystitis questionnaire scores were 15.94 in subjects with definition 1 IC symptoms, 18.97 in those with definition 2 IC symptoms and 6.69 in those with no IC symptoms (p <0.001). Symptoms were most common and most severe in subjects previously diagnosed with IC. CONCLUSIONS: The prevalence of IC symptoms is 30 to 50-fold higher in women and 60 to 100-fold higher in men than the prevalence of a coded physician diagnosis of IC in the same population. Although these findings are not conclusive, they imply that IC may be significantly under diagnosed.

Clemens, J. Q., R. T. Meenan, et al. (2005). "Incidence and clinical characteristics of National Institutes of Health type III prostatitis in the community." J Urol 174(6): 2319-2322.

PURPOSE: Few population-based epidemiological studies of prostatitis have been performed. We used coded physician diagnoses and subsequent chart reviews to estimate the incidence and clinical characteristics of physician diagnosed National Institutes of Health (NIH) type III prostatitis. MATERIALS AND METHODS: Computer searches of the Kaiser Permanente Northwest (Portland, Oregon) database were performed on the 2-year interval May 2002 to May 2004 to identify new diagnoses of chronic prostatitis (International Classification of Diseases, 9th Revision code 601.1) and prostatitis not otherwise specified (International Classification of Diseases, 9th Revision code 601.9). Of the 1,223 men identified with these coded diagnoses, chart reviews were performed on a random subset of 413 (33.8%). Patients were categorized based on NIH prostatitis definitions of type I/II-evidence of pyuria and/or bacteriuria on urinalysis or culture, type III-presence of at least 1 of the pain or urinary symptoms in the NIH Chronic Prostatitis Symptom Index (pain in the perineum, testicles, tip of penis, pubic or bladder area, dysuria, ejaculatory pain, incomplete emptying, urinary frequency), type IV-inflammation on prostate biopsy and Other-symptoms other than those listed. RESULTS: Of the 413 patients 57 were previously diagnosed with prostatitis (prevalent cases), 46 had no evidence of a prostatitis diagnosis in the medical record and 7 were treated by physicians outside of the Kaiser Permanente Northwest plan. Of the remaining 303 the distribution was 58 type I/II, 189 type III, 33 type IV and 23 Other. The incidence of physician diagnosed type III prostatitis was 3.3 per 1,000 person-years. If those with isolated urinary symptoms were excluded from analysis, the incidence decreased to 2.8 per 1,000 person-years. The mean age of those with type III prostatitis was 52.9 years (range 29 to 82). The most common presenting symptoms were dysuria, urinary frequency and perineal pain. Symptom duration at presentation was less than 3 months in 44%, 3 months or greater in 31% and unspecified in 25%. The majority (78%) of new prostatitis diagnoses was made by primary care physicians. CONCLUSIONS: These data indicate that prostatitis is commonly diagnosed in the community setting, and that type III prostatitis accounts for the majority of these diagnoses. The duration and complexity of symptoms are less than those reported in established prostatitis research cohorts. Most prostatitis diagnoses in the community are made by nonurologists.

Clemens, J. Q., R. T. Meenan, et al. (2007). "Prevalence of and risk factors for prostatitis: population based assessment using physician assigned diagnoses." J Urol 178(4 Pt 1): 1333-1337.

PURPOSE: Previous studies to assess risk factors for prostatitis used patient self-reported data and, therefore, they were subject to recall bias. We 1) used coded physician diagnoses to calculate the prevalence of prostatitis and 2) compared these patients with matched controls to identify medical conditions that are associated with prostatitis. Subjects were male enrollees in the Kaiser Permanente Northwest, Portland, Oregon health maintenance organization. MATERIALS AND METHODS: A computer search of the Kaiser Permanente Northwest administrative database was performed for May 1, 1998 to April 30, 2004 to identify men with a coded diagnosis of prostatitis. Prostatitis cases were each age matched with 3 controls and the medical diagnoses (using 3-digit International Classification of Diseases, 9th Revision codes) assigned to these 2 groups were compared. RESULTS: A prostatitis diagnosis was present in 4.5% of the male population. There were 37 diagnoses that were significantly more common in cases than in controls (p <0.0001). Most of them were other urological codes to describe prostatitis symptoms, unexplained physical symptoms in other organ systems and psychiatric diagnoses. The strongest observed associations were with benign prostatic hyperplasia (OR 2.7), functional digestive disorders (OR 2.6), dyspepsia (OR 2.1), anxiety disorders (OR 2.0), other soft tissue disorders (OR 2.0), esophageal reflux (OR 1.8) and mood disorders (OR 1.8). CONCLUSIONS: Prostatitis is a commonly diagnosed condition in the community setting, affecting approximately 1/22 men. The diagnosis is associated with multiple other unexplained physical symptoms and certain psychiatric conditions. Studies to explore possible biological explanations for these associations are needed.

Clemens, J. Q., R. T. Meenan, et al. (2008). "Case-control study of medical comorbidities in women with interstitial cystitis." J Urol 179(6): 2222-2225.

PURPOSE: We used physician assigned diagnoses in an electronic medical record to assess comorbidities associated with interstitial cystitis. MATERIALS AND METHODS: A computer search of the administrative database at Kaiser Permanente Northwest, Portland, Oregon was performed for May 1, 1998 to April 30, 2003. All women with a medical record diagnosis of interstitial cystitis (ICD-9 code 595.1) were identified. These cases were then matched with 3 controls each based on age and duration in the health plan. The medical diagnoses (using ICD-9 codes restricted to 3 digits) assigned to these 2 groups were compared using the OR. RESULTS: A total of 239 cases and 717 matched controls were analyzed. There were 23 diagnoses that were significantly more common in cases than in controls (p < or = 0.005). Seven of these 23 diagnoses were other urological or gynecological codes used to describe pelvic symptoms. Additional specific conditions associated with interstitial cystitis were gastritis (OR 12.2), child abuse (OR 9.3), fibromyalgia (OR 3.0), anxiety disorder (OR 2.8), headache (OR 2.5), esophageal reflux (OR 2.2), unspecified back disorder (OR 2.2) and depression (OR 2.0). CONCLUSIONS: A diagnosis of interstitial cystitis was associated with multiple other unexplained physical symptoms and certain psychiatric conditions. Studies to explore the possible biological explanations for these associations are needed. Interstitial cystitis was also associated with a history of child abuse, although 96% of patients with IC did not have this diagnosis.

Clemens, J. Q., R. T. Meenan, et al. (2006). "Prevalence of prostatitis-like symptoms in a managed care population." J Urol 176(2): 593-596; discussion 596.

PURPOSE: We calculated the prevalence of symptoms typically associated with chronic prostatitis/chronic pelvic pain syndrome in men in a managed care population in the Pacific Northwest. MATERIALS AND METHODS: A questionnaire mailing to 5,000 male enrollees 25 to 80 years old in the Kaiser Permanente Northwest (Portland, Oregon) health plan was performed. The questionnaires included screening questions about the presence, duration and severity of pelvic pain, and the National Institutes of Health Chronic Prostatitis Symptom Index. Chronic prostatitis/chronic pelvic pain syndrome symptoms were defined in 2 ways: 1) presence of any of the following for a duration of 3 or more months: pain in the perineum, testicles, tip of penis, pubic or bladder area, dysuria, ejaculatory pain; and 2) perineal and/or ejaculatory pain, and a National Institutes of Health Chronic Prostatitis Symptom Index total pain score of 4 or more. Prevalence estimates were age adjusted to the total Kaiser Permanente Northwest male population. RESULTS: A total of 1,550 questionnaires were returned. The prevalence of chronic prostatitis/chronic pelvic pain syndrome symptoms was 7.5% for definition 1 and 5.9% for definition 2. Mean National Institutes of Health Chronic Prostatitis Symptom Index scores were 17 for definitions 1 and 2. Of those with prostatitis-like symptoms, 30% met criteria for having both definitions present. The prevalence of prostatitis-like symptoms using either of the 2 diagnoses was 11.2%. CONCLUSIONS: This population based study indicates that approximately 1 in 9 men have prostatitis-like symptoms. Application of 2 different definitions for prostatitis-like symptoms identified unique groups of men, with limited overlap in the groups.

Clemens, J. Q., R. T. Meenan, et al. (2005). "Prevalence and incidence of interstitial cystitis in a managed care population." J Urol 173(1): 98-102; discussion 102.

PURPOSE: We calculated the prevalence and incidence of physician diagnosed interstitial cystitis (IC) in men and women in a managed care population in the Pacific Northwest. MATERIALS AND METHODS: A computer search of the Kaiser Permanente Northwest (Portland, Oregon) database was performed for January 1998 to May 2002. The prevalence of IC in patients 25 to 80 years old was calculated using the 4 definitions of 1) patients assigned a diagnosis of IC, 2) patients assigned a diagnosis of IC without any of the consensus IC exclusion criteria, 3) patients who had also had undergone cystoscopy and 4) patients who had specifically undergone cystoscopy with hydrodistention for IC. A second database search was performed 1 year later (May 2003) to identify incident cases of IC. RESULTS: The prevalence of IC was 197 per 100,000 women and 41 per 100,000 men for definition 1, 158 per 100,000 women and 28 per 100,000 men for definition 2, 99 per 100,000 women and 19 per 100,000 men for definition 3, and 45 per 100,000 women and 8 per 100,000 men for definition 4. Using definition 2 the 1-year incidence of IC was 21 per 100,000 women and 4 per 100,000 men. The female-to-male ratio for each estimate was 5:1. CONCLUSIONS: The prevalence and incidence of interstitial cystitis is significantly higher for women and men than previously published estimates. Men account for a higher proportion of patients with IC than has previously been recognized.

Clemens, J. Q., R. T. Meenan, et al. (2008). "Costs of interstitial cystitis in a managed care population." Urology 71(5): 776-780; discussion 780-771.

OBJECTIVES: To assess the direct medical costs, medication, and procedure use associated with interstitial cystitis (IC) in women in the Kaiser Permanente Northwest (KPNW) managed care population. METHODS: The KPNW electronic medical record was used to identify women diagnosed with IC (n = 239). Each of these patients was matched with three controls according to age and duration in the health plan. Health plan cost accounting data were used to determine the inpatient, outpatient, and pharmacy costs for 1998 to 2003. An analysis of the prescription medication use and cystoscopic and urodynamic procedures commonly associated with IC was also performed. To evaluate for co-morbidities, an automated risk-adjustment model linked to 28 chronic medical conditions was applied to the administrative data sets from both groups. RESULTS: The mean duration from the date of IC diagnosis to the end of the study period was 36.6 months (range 1.4 to 60). The mean yearly costs were 2.4-fold greater for the patients than for the controls ($7100 versus $2994), and the median yearly costs were 3.8-fold greater ($5000 versus $1304). These cost differences were predominantly due to outpatient and pharmacy expenses. Medication and procedure use were significantly greater for the patients than for the controls. These findings were consistent across risk-adjustment model categories, which suggest that the observed cost differences are IC specific. CONCLUSIONS: The direct per-person costs of IC are high, with average yearly costs approximately $4000 greater than for the age-matched controls. This cost differential is an underestimate, because the costs preceding the diagnosis, the use of alternative therapies, indirect costs, and the costs of those with IC that is not diagnosed were not included.

Clemens, J. Q., R. B. Nadler, et al. (2000). "Biofeedback, pelvic floor re-education, and bladder training for male chronic pelvic pain syndrome." Urology 56(6): 951-955.

OBJECTIVES: Pelvic floor tension myalgia may contribute to the symptoms of male patients with chronic pelvic pain syndrome (CPPS). Therefore, measures that diminish pelvic floor muscle spasm may improve these symptoms. Based on this hypothesis, we enrolled 19 patients with CPPS in a 12-week program of biofeedback-directed pelvic floor re-education and bladder training. METHODS: Pre-treatment and post-treatment symptom assessments included daily voiding logs, American Urological Association (AUA) symptom score, and 10-point visual analog pain and urgency scores. Pressure-flow studies were obtained before treatment in most patients. Instruction in pelvic floor muscle contraction and relaxation was achieved using a noninvasive form of biofeedback at biweekly sessions. Home exercises were combined with a progressive increase in timed-voiding intervals. RESULTS: Mean age of the 19 patients was 36 years (range 18 to 67). Four patients completed less than three treatment sessions, 5 patients completed three to five sessions, and 10 attended all six sessions. Mean follow-up was 5.8 months. Median AUA symptom scores improved from 15.0 to 7.5 (P = 0.001), and median bother scores decreased from 5.0 to 2.0 (P = 0.001). Median pain scores decreased from 5.0 to 1.0 (P = 0.001), and median urgency scores decreased from 5.0 to 2.0 (P = 0.002). Median voiding interval increased from 0.88 hours to 3.0 hours (P = 0.003). Presence of detrusor instability, hypersensitivity to filling, or bladder-sphincter pseudodyssynergia on pretreatment urodynamic studies was not predictive of treatment results. CONCLUSIONS: This preliminary study confirms that a formalized program of neuromuscular re-education of the pelvic floor muscles together with interval bladder training can provide significant and durable improvement in objective measures of pain, urgency, and frequency in patients with CPPS.

Clemens, J. Q., T. G. Schuster, et al. (2001). "Revision rate after artificial urinary sphincter implantation for incontinence after radical prostatectomy: actuarial analysis." J Urol 166(4): 1372-1375.

PURPOSE: We determined the actuarial revision rate for artificial urinary sphincters implanted in patients who were incontinent after radical prostatectomy. MATERIALS AND METHODS: We reviewed the records of 70 consecutive patients who were incontinent after radical prostatectomy and who underwent primary artificial urinary sphincter implantation at the University of Michigan between 1984 and 1999. Questionnaires were mailed to all patients with an indwelling device, and telephone calls were placed to those who did not respond to the mailing. Information about surgical revision and current continence status was obtained from chart review and questionnaire response. The Kaplan-Meier curves for actuarial freedom from operative revision were constructed. RESULTS: Of the 66 patients with available postoperative data 24 (36%) required reoperation at a mean followup of 41 months. The 5-year actuarial rate for freedom from any operative revision was 50%, and the corresponding rate for cuff revision was 60%. A single operative revision did not predispose the patient to further revision. Questionnaire data indicated a continence rate of 80% (range 0 to 2 pads). CONCLUSIONS: Approximately half of the patients who were incontinent after radical prostatectomy may expect to undergo operative revision within 5 years after artificial urinary sphincter implantation. Despite this high reoperation rate, an excellent level of continence is maintained.

Clemens, J. Q., J. A. Stern, et al. (1998). "Long-term results of the Stamey bladder neck suspension: direct comparison with the Marshall-Marchetti-Krantz procedure." J Urol 160(2): 372-376.

PURPOSE: We performed followup of a cohort of women who underwent the Stamey endoscopic needle suspension (group 1) or the Marshall-Marchetti-Krantz vesicourethropexy (group 2) between 1975 and 1983. MATERIALS AND METHODS: Telephone interviews were performed to assess current continence status and time to failure. Risk factors for recurrence of incontinence were correlated with long-term results. RESULTS: Long-term data were obtained for 32 of 41 women (78%) in group 1 and 36 of 54 (67%) in group 2. Range of followup was 9.4 to 19.9 years (median 15.0, mean 15.2) in group 1 and 13.2 to 21.9 (median 16.8, mean 17.0) in group 2. Of group 1 patients 44% remained dry compared to 33% of group 2 patients. Persistent local side effects were reported by 9% of group 1 and 0% of group 2. Urinary urgency was present in 70% of group 1 patients and 23% of group 2. There was no relationship between long-term operative success and age at surgery, degree of preoperative incontinence, parity, obesity, prior incontinence surgery or prior hysterectomy for either procedure. CONCLUSIONS: The Stamey and the Marshall-Marchetti-Krantz procedures yield high initial cure rates with progressive, parallel declines in continence status with time.

Cole, D. J., M. G. Sanda, et al. (1994). "Phase I trial of recombinant human macrophage colony-stimulating factor administered by continuous intravenous infusion in patients with metastatic cancer." Journal of the National Cancer Institute 86(1): 39-45.

BACKGROUND: Macrophage colony-stimulating factor is a bone marrow-derived glycoprotein that can stimulate monocytes and macrophages, resulting in production of factors involved in immune response. In vitro and in vivo preclinical studies in animals have demonstrated that recombinant human macrophage colony-stimulating factor (rHuM-CSF) can have antitumor activity. PURPOSE: A phase I clinical trial was undertaken to evaluate the toxicity, pharmacokinetics, and immunologic effects of rHuM-CSF given by continuous intravenous infusion in patients with cancer. METHODS: Eighteen patients with metastatic solid tumors refractory to conventional therapy were treated with rHuM-CSF. Twelve patients received two 14-day cycles of rHuM-CSF by continuous infusion, with a 2-week interval. Dose escalation levels were 50, 100, and 150 micrograms/kg over 24 hours. Consecutive cohorts of three to six patients were planned at each dose level. Six patients received a modified regimen of four 7-day periods of infusion at 100 micrograms/kg over 24 hours, with 1-week intervals. RESULTS: Dose-limiting toxicity was grade 4 thrombocytopenia at a dose of 150 micrograms/kg over 24 hours in two patients receiving the 2-week regimen. Platelet count nadirs and concomitant monocytosis were seen on days 7-9, but recovery occurred during the treatment period. Macrophage colony-stimulating factor serum levels were maximal on day 1 and returned to near baseline on day 7 of infusion. Patients treated with four 7-day infusions had no treatment-limiting thrombocytopenia. There were no cumulative effects on platelet or monocyte counts or significant constitutional symptoms. Subclinical conjunctival injection was noted in five of 10 patients receiving screening ophthalmologic evaluation. Grade 2 episcleritis was diagnosed in one patient, and asymptomatic perilimbal and retinal hemorrhages were seen in two. Two patients developed sepsis caused by the intravenous line, which required cessation of therapy. No objective responses were documented. CONCLUSION: The maximum tolerated dose of rHuM-CSF given by continuous intravenous infusion for 14 days was 100 micrograms/kg over 24 hours, with rapidly reversible, dose-limiting thrombocytopenia at 150 micrograms/kg over 24 hours. A regimen alternating weekly cycles of infusion avoids dose-limiting toxicity and allows long-term treatment. IMPLICATIONS: The regimen of repeated 7-day infusions may be useful for future studies evaluating rHuM-CSF-activated monocytes in therapy for long-term infectious diseases or in investigation of new modes of cancer therapy using rHuM-CSF in conjunction with a tumor-specific antibody. <124>

Comstock, K. E., C. L. Hall, et al. (2009). "A bioluminescent orthotopic mouse model of human osteosarcoma that allows sensitive and rapid evaluation of new therapeutic agents In vivo." In Vivo 23(5): 661-668.

Osteosarcoma (OSA) is the most common primary malignant bone tumor in children, 30% of whom develop lung metastases despite aggressive treatment. Our objective was to develop a mouse model of OSA for preclinical studies that (i) incorporates the natural history of OSA including tumor growth in bone and development of lung metastasis and (ii) is amenable to non-invasive detection methods. A human OSA cell line that expresses high levels of luciferase was created. Following subcutaneous injection, nine out of ten mice showed tumor growth. Eight out of ten mice showed tumor growth following orthotopic injection into the proximal tibia. Thirty percent of mice showed pulmonary metastasis by bioluminescent imaging eight to 10 weeks following orthotopic injection. Animals receiving cisplatin treatment showed reduced tumor volume compared to animals treated with vehicle alone. This model allows real-time detection of tumors and can be used to study mechanisms of OSA metastasis and test new therapeutic agents.

Connolly, L. P., D. A. Bloom, et al. (1996). "Localization of Tc-99m MDP in neuroblastoma metastases to the liver and lung." Clin Nucl Med 21(8): 629-633.

Localization of skeletal tracer in a neuroblastoma primary is common but localization in extraskeletal metastatic sites has not received recognition. Tc-99m MDP concentration in hepatic or pulmonary metastases was noted in three of ten patients with such metastases. Lesion size appears to be important for demonstrating these metastases with Tc-99m MDP. This was particularly true for hepatic metastases, which were identified only when they were 5 cm or greater in diameter.

Conti, D. J., R. Andersen, et al. (1987). "Comparison of clinical response of DR-matched, MLC-compatible cadaver renal allografts and those from HLA-identical related donors." Transplantation Proceedings 19(1:Pt 1): t-4.

Cooney, K. A., J. D. McCarthy, et al. (1997). "Prostate cancer susceptibility locus on chromosome 1q: a confirmatory study." J Natl Cancer Inst 89(13): 955-959.

BACKGROUND: Recent recognition that a predisposition to prostate cancer can be inherited has led to a search for specific genes associated with the disease. Through a study of families with three or more affected first-degree relatives, a region on the long arm of chromosome 1 (i.e., 1q24-25) has been tentatively identified as containing a gene, HPC1, involved in the development of hereditary prostate cancer. Confirmation of this finding is needed, however, before attempts are made to isolate and characterize the putative HPC1 gene. PURPOSE: To confirm that chromosome 1q24-25 contains a gene relevant to hereditary prostate cancer, we analyzed an independent set of families, each with two or more affected individuals. METHODS: Fifty-nine unrelated families were selected for analysis on the sole criterion that more than one living family member was affected by prostate cancer. DNA samples were subsequently isolated from 130 individuals with the disease. These samples were genotyped at six polymorphic marker sequences (D1S215, D1S2883, D1S466, D1S158, D1S518, and D1S2757) covering the chromosomal region proposed to contain HPC1. The resulting data were analyzed by nonparametric multipoint linkage (NPL) methods, yielding NPL Z scores and corresponding one-sided P values. RESULTS: When the entire set of 59 families was considered, the occurrence of prostate cancer (and, presumably, the HPC1 gene) was most tightly linked to marker D1S466 (NPL Z score = 1.58; P = .0574). Analysis of the 20 families (51 affected individuals) fulfilling one or more of the proposed clinical criteria for hereditary prostate cancer (i.e., three or more affected individuals within one nuclear family; affected individuals in three successive generations [maternal or paternal lineage]; and/or clustering of two or more individuals affected before the age of 55 years) revealed more convincing evidence of disease linkage to chromosome 1q24-25 (maximum NPL Z score [at marker D1S466] = 1.72; P = .0451). The 39 families (79 affected individuals) that did not meet the clinical criteria for hereditary prostate cancer exhibited no significant evidence of disease linkage to DNA sequences at chromosome 1q24-25 (maximum NPL Z score [at marker D1S466] = 0.809; P = .208). The six African-American families in our study contributed disproportionately to the observation of linkage, with a maximum NPL Z score at marker D1S158 of 1.39 (P = .0848) for these families. CONCLUSIONS AND IMPLICATIONS: Our data confirm that chromosome 1q24-25 is likely to contain a prostate cancer susceptibility gene. Future efforts at positional cloning of the HPC1 gene should focus on families who meet the proposed clinical criteria for hereditary prostate cancer.

Cooney, K. A., J. D. McCarthy, et al. (1997). "Prostate cancer susceptibility locus on chromosome 1q: a confirmatory study. [see comments.]." Journal of the National Cancer Institute 89(13): 955-959.

BACKGROUND: Recent recognition that a predisposition to prostate cancer can be inherited has led to a search for specific genes associated with the disease. Through a study of families with three or more affected first-degree relatives, a region on the long arm of chromosome 1 (i.e., 1q24-25) has been tentatively identified as containing a gene, HPC1, involved in the development of hereditary prostate cancer. Confirmation of this finding is needed, however, before attempts are made to isolate and characterize the putative HPC1 gene. PURPOSE: To confirm that chromosome 1q24-25 contains a gene relevant to hereditary prostate cancer, we analyzed an independent set of families, each with two or more affected individuals. METHODS: Fifty-nine unrelated families were selected for analysis on the sole criterion that more than one living family member was affected by prostate cancer. DNA samples were subsequently isolated from 130 individuals with the disease. These samples were genotyped at six polymorphic marker sequences (D1S215, D1S2883, D1S466, D1S158, D1S518, and D1S2757) covering the chromosomal region proposed to contain HPC1. The resulting data were analyzed by nonparametric multipoint linkage (NPL) methods, yielding NPL Z scores and corresponding one-sided P values. RESULTS: When the entire set of 59 families was considered, the occurrence of prostate cancer (and, presumably, the HPC1 gene) was most tightly linked to marker D1S466 (NPL Z score = 1.58; P = .0574). Analysis of the 20 families (51 affected individuals) fulfilling one or more of the proposed clinical criteria for hereditary prostate cancer (i.e., three or more affected individuals within one nuclear family; affected individuals in three successive generations [maternal or paternal lineage]; and/or clustering of two or more individuals affected before the age of 55 years) revealed more convincing evidence of disease linkage to chromosome 1q24-25 (maximum NPL Z score [at marker D1S466] = 1.72; P = .0451). The 39 families (79 affected individuals) that did not meet the clinical criteria for hereditary prostate cancer exhibited no significant evidence of disease linkage to DNA sequences at chromosome 1q24-25 (maximum NPL Z score [at marker D1S466] = 0.809; P = .208). The six African-American families in our study contributed disproportionately to the observation of linkage, with a maximum NPL Z score at marker D1S158 of 1.39 (P = .0848) for these families. CONCLUSIONS AND IMPLICATIONS: Our data confirm that chromosome 1q24-25 is likely to contain a prostate cancer susceptibility gene. Future efforts at positional cloning of the HPC1 gene should focus on families who meet the proposed clinical criteria for hereditary prostate cancer. <81>

Cooney, K. A., M. S. Strawderman, et al. (2001). "Age-specific distribution of serum prostate-specific antigen in a community-based study of African-American men." Urology 57(1): 91-96.

OBJECTIVES: Previous studies have observed higher age-specific serum prostate-specific antigen (PSA) values in African-American (AA) men without prostate cancer compared to white men, leading some to recommend race-specific PSA reference ranges for the early detection of prostate cancer. The primary objective of the Flint Men's Health Study was to determine age-specific PSA reference values in a community-based sample of AA men, aged 40 to 79 years. METHODS: A probability sample of 943 AA men was selected from households in Genesee County, Michigan. Men without a prior history of prostate cancer/surgery were invited to participate in a prostate cancer screening protocol, consisting of measurement of serum total PSA, free/total PSA ratio, and digital rectal examination. Sextant biopsies were recommended, based on total PSA greater than 4.0 ng/mL and/or an abnormal digital rectal examination. RESULTS: From the sample of 943 men, 732 were eligible, 432 had blood drawn for PSA testing, and 374 completed all phases of the clinical examination. The 95th percentile PSA values were estimated to range from 2.36 ng/mL for men in the fifth decade to 5.59 ng/mL for men in the eighth decade. The 95th percentile values for age-specific PSA were comparable to those observed in a similar study of white men in Olmsted County, Minnesota. The median and 5th percentile values for free/total PSA did not vary significantly across age. CONCLUSIONS: The minor differences in PSA reference ranges between AA and white men may not be of sufficient magnitude to recommend the use of race-specific PSA reference ranges for screening.

Cooney, K. A., J. C. Wetzel, et al. (1996). "Distinct regions of allelic loss on 13q in prostate cancer." Cancer Res 56(5): 1142-1145.

Loss of heterozygosity (LOH) involving the long arm of chromosome 13 has been reported to occur in as many as one third of primary prostate cancers. Candidate tumor suppressor genes on 13q that may be important in the development of prostate cancer include the retinoblastoma susceptibility gene (RBI) and a gene associated with inherited breast cancer (BRCA2). To define the pattern of allelic loss of 13q in prostate cancer, LOH analysis was performed using nine mapped polymorphic markers spanning the entire chromosomal arm. Nineteen (48%) of 40 prostate cancer cases obtained following radical prostatectomy demonstrated atllelic loss with at least one marker. Furthermore, 13 (33%) of 40 cases had evidence of allelic loss involving a region of 13q14 containing RB1. To test the hypothesis that RB1 is the targeted tumor suppressor gene in this region, 37 of 40 cases were assessed for expression of pRB, the protein product of RB1 using immunohistochemical techniques. By this analysis, 8 (22%) of 37 prostate tumors demonstrated no pRB expression. However, allelic loss at RB1, assessed with an intragenic marker, did not correlate with absent pRB expression (Fisher's exact test, P=0.375). Taken together, these data confirm that allelic loss of a common region of 13q14 occurs in approximately one third of prostate cancers. Lack of correlation of LOH at RB1 with absent pRB expression suggests the existence of another tumor suppressor gene in this region important in prostate cancer.

Cooper, C. R., C. H. Chay, et al. (2003). "Stromal factors involved in prostate carcinoma metastasis to bone." Cancer 97(3 Suppl): 739-747.

BACKGROUND: Prostate carcinoma (PC) frequently metastasizes to bone, where it causes significant morbidity and mortality. Stromal elements in the primary and metastatic target organs are important mediators of tumor cell intravasation, chemoattraction, adhesion to target organ microvascular endothelium, extravasation, and growth at the metastatic site. METHODS: The role of stromal factors in bone metastasis was determined with a cyclic DNA microarray comparison of a bone-derived cell PC cell line with a soft tissue-derived cell PC cell line and by evaluating the effects of selected stromal components on PC cell chemotaxis, cell adhesion to human bone marrow endothelium (HBME), and PC cell growth. RESULTS: The authors demonstrate that PC cells express protease-activated receptor 1 (PAR1; thrombin receptor), and its expression is up-regulated in PC compared with normal prostate tissue. In addition, this overexpression was very pronounced in bone-derived PC cell lines (VCaP and PC-3) compared with soft tissue PC cell lines (DUCaP, DU145, and LNCaP). The authors report that bone stromal factors, including stromal cell-derived factor 1 (SDF-1) and collagen Type I peptides, are chemoattractants for PC cells, and they demonstrate that some of these factors (e.g., extracellular matrix components, transforming growth factor beta, bone morphogenic proteins [BMPs], and SDF-1) significantly alter PC-HBME interaction in vitro. Finally, stromal factors, such as BMPs, can regulate the proliferation of PC cells in vitro. CONCLUSIONS: Soluble and insoluble elements of the stroma are involved in multiple steps of PC metastasis to bone. The authors hypothesize that PAR1 may play a central role in prostate tumorigenesis.

Cooper, C. R., B. Graves, et al. (2008). "Novel surface expression of reticulocalbin 1 on bone endothelial cells and human prostate cancer cells is regulated by TNF-alpha." J Cell Biochem 104(6): 2298-2309.

An unbiased cDNA expression phage library derived from bone-marrow endothelial cells was used to identify novel surface adhesion molecules that might participate in metastasis. Herein we report that reticulocalbin 1 (RCN1) is a cell surface-associated protein on both endothelial (EC) and prostate cancer (PCa) cell lines. RCN1 is an H/KDEL protein with six EF-hand, calcium-binding motifs, found in the endoplasmic reticulum. Our data indicate that RCN1 also is expressed on the cell surface of several endothelial cell lines, including human dermal microvascular endothelial cells (HDMVECs), bone marrow endothelial cells (BMEC), and transformed human bone marrow endothelial cells (TrHBMEC). While RCN1 protein levels were highest in lysates from HDMVEC, this difference was not statistically significant compared BMEC and TrHBMEC. Given preferential adhesion of PCa to bone-marrow EC, these data suggest that RCN1 is unlikely to account for the preferential metastasis of PCa to bone. In addition, there was not a statistically significant difference in total RCN1 protein expression among the PCa cell lines. RCN1 also was expressed on the surface of several PCa cell lines, including those of the LNCaP human PCa progression model and the highly metastatic PC-3 cell line. Interestingly, RCN1 expression on the cell surface was upregulated by tumor necrosis factor alpha treatment of bone-marrow endothelial cells. Taken together, we show cell surface localization of RCN1 that has not been described previously for either PCa or BMEC and that the surface expression on BMEC is regulated by pro-inflammatory TNF-alpha.

Cordes, L. G., A. M. Wiesenthal, et al. (1981). "Isolation of Legionella pneumophila from hospital shower heads." Annals of Internal Medicine 94(2): 195-197.

Legionella pneumophila serogroup 6 was isolated from nine of 16 shower heads in a Chicago hospital ward where three patients had contracted Legionnaires' disease caused by serogroup 6 L. pneumophila. Each patient had showered there 2 to 10 days before the onset of disease symptoms. We also isolated the bacteria in two other hospitals, and found the same serogroups as had been causing Legionnaires' disease in those hospitals: serogroup 1 in Pittsburgh and serogroups 1 and 4 in Los Angeles. However, showers from hospital wards where no patients had contracted Legionnaires' disease also yielded L. pneumophila. Shower heads at the Chicago hospital were sterilized with ethylene oxide but rapidly became recontaminated, suggesting that the potable water at these hospitals may have contained the organism. The question of whether aerosols of shower water or other exposures to potable water containing L. pneumophila may cause nosocomial Legionnaires' disease has not been resolved but deserves further study. <41>

Corey, E., J. E. Quinn, et al. (2003). "LuCaP 35: a new model of prostate cancer progression to androgen independence." Prostate 55(4): 239-246.

BACKGROUND: Generation of suitable in vivo models is critical for understanding of processes associated with development and progression of prostate cancer (CaP). METHODS: Lymph nodes containing metastatic androgen-independent CaP were implanted into athymic mice. A xenograft designated LuCaP 35 and its hormone-independent variant LuCaP 35V were established and characterized. RESULTS: LuCaP 35 is an androgen-sensitive, prostate-specific antigen (PSA)-producing xenograft. It expresses the wild-type androgen receptor and exhibits deletions in chromosome 8p, but not in chromosome 10. The response of LuCaP 35 to androgen ablation is similar to that observed in man. Using recurring LuCaP 35 tumors we have also established an androgen-insensitive variant of LuCaP 35. CONCLUSIONS: The availability of hormone-dependent and -independent variants of LuCaP 35, which exhibit many properties analogous to those of CaP in man, provides an excellent model system to study the processes associated with development of androgen independence and to evaluate new treatment modalities.

Crane, G. M. and D. A. Bloom (2010). "Ramon Guiteras: founder of the American Urological Association, surgeon, sportsman and statesman." J Urol 184(2): 447-452.

PURPOSE: We conducted an extensive search to learn more about Ramon Guiteras, the founder of the American Urological Association. MATERIALS AND METHODS: Scientific publications, newspaper articles, and historical documents and texts were reviewed. Institutions and organizations of which Ramon Guiteras was a member were contacted. RESULTS: Guiteras' career peaked at the turn of the century, just as genitourinary surgery was emerging as an independent field. The American Urological Association began as an organization of the members of Guiteras' clinic with the dream of becoming an inclusive organization for the benefit of all ethical physicians with an interest in the urinary sciences. Guiteras contributed to advances in urological treatments, including improving and helping to bring a method of suprapubic prostatectomy to worldwide attention. He authored numerous scientific articles and a comprehensive, fully illustrated, 2-volume textbook that was widely translated. He pursued adventure through travel and sport, and participated in missions to Cuba and France during President Wilson's term of office. CONCLUSIONS: Ramon Guiteras died at age 59 years but his legacy lives on through the American Urological Association, a detailed textbook, contributions to urological instruments and techniques, and a vibrant elementary school in Bristol, Rhode Island that bears his name.

Crawford, E. D., J. T. Batuello, et al. (2000). "The use of artificial intelligence technology to predict lymph node spread in men with clinically localized prostate carcinoma." Cancer 88(9): 2105-2109.

BACKGROUND: The current study assesses artificial intelligence methods to identify prostate carcinoma patients at low risk for lymph node spread. If patients can be assigned accurately to a low risk group, unnecessary lymph node dissections can be avoided, thereby reducing morbidity and costs. METHODS: A rule-derivation technology for simple decision-tree analysis was trained and validated using patient data from a large database (4,133 patients) to derive low risk cutoff values for Gleason sum and prostate specific antigen (PSA) level. An empiric analysis was used to derive a low risk cutoff value for clinical TNM stage. These cutoff values then were applied to 2 additional, smaller databases (227 and 330 patients, respectively) from separate institutions. RESULTS: The decision-tree protocol derived cutoff values of < or = 6 for Gleason sum and < or = 10.6 ng/mL for PSA. The empiric analysis yielded a clinical TNM stage low risk cutoff value of < or = T2a. When these cutoff values were applied to the larger database, 44% of patients were classified as being at low risk for lymph node metastases (0.8% false-negative rate). When the same cutoff values were applied to the smaller databases, between 11 and 43% of patients were classified as low risk with a false-negative rate of between 0.0 and 0.7%. CONCLUSIONS: The results of the current study indicate that a population of prostate carcinoma patients at low risk for lymph node metastases can be identified accurately using a simple decision algorithm that considers preoperative PSA, Gleason sum, and clinical TNM stage. The risk of lymph node metastases in these patients is < or = 1%; therefore, pelvic lymph node dissection may be avoided safely. The implications of these findings in surgical and nonsurgical treatment are significant.

Crawford, E. D., D. P. Wood, et al. (2003). "Southwest Oncology Group studies in bladder cancer." Cancer 97(8 Suppl): 2099-2108.

Over 50,000 patients are diagnosed annually with bladder cancer, and approximately 10,000 eventually will die of their disease. Thus, the Southwest Oncology Group (SWOG) Genitourinary Cancer Committee is committed to the study of therapeutic interventions in patients with superficial, invasive, and metastatic bladder cancer. In the past 15 years, SWOG has completed six Phase III, randomized trials. Studies in patients with superficial disease have established the role of bacillus Calmette-Guerin in patient management; and a large, randomized trial has outlined the value of neoadjuvant chemotherapy and cystectomy in patients with advanced disease. SWOG plans to build on this model by evaluating patients with residual disease after chemotherapy for possible bladder preservation while evaluating more chemotherapy for patients with persistent disease. The Genitourinary Cancer Committee will continue to seek new, active agents for metastatic disease and will participate in and support large, Phase III, international trials that seek to improve current regimens. SWOG accomplishments in bladder cancer are highlighted, and future strategies are discussed.

Cross, C. A., R. D. Cespedes, et al. (1997). "Paravaginal vault suspension for the treatment of vaginal and uterovaginal prolapse." J Pelvic Surg 3(2): 81-85.

Cross, C. A., R. D. Cespedes, et al. (1998). "Transvaginal urethrolysis for urethral obstruction after anti-incontinence surgery." J Urol 159(4): 1199-1201.

PURPOSE: Urethral obstruction following a stress incontinence procedure occurs in 5 to 20% of patients. We examine the success of transvaginal urethrolysis in resolving voiding dysfunction. MATERIALS AND METHODS: A retrospective chart review was performed on 39 patients who had undergone transvaginal urethrolysis for urethral obstruction following an anti-incontinence procedure. Preoperatively, a history was taken, and pelvic examination and either video urodynamics or cystoscopy were done. RESULTS: All 39 patients complained of urge incontinence, 13% had urinary retention, 51% had incomplete bladder emptying and 36% voided to completion but had irritative voiding symptoms. Previous surgery included retropubic urethropexy in 41% of the cases, pubovaginal sling in 38% and bladder neck suspension in 21%. Mean length of followup after urethrolysis was 16 months. Of the 39 patients 33 (85%) had resolution of urge incontinence but 5 still required occasional intermittent catheterization. The remaining 6 patients had continued urge incontinence. An augmentation procedure was performed in 4 patients with improvement of symptoms. CONCLUSIONS: Our data support transvaginal urethrolysis for the treatment of iatrogenic urethral obstruction. It is a rapid, effective and minimally invasive technique that should be considered if voiding dysfunction does not resolve spontaneously.

Cross, C. A., R. D. Cespedes, et al. (1997). "Treatment results using pubovaginal slings in patients with large cystoceles and stress incontinence." J Urol 158(2): 431-434.

PURPOSE: We determined the efficacy of performing a pubovaginal sling concurrently with a formal cystocele repair in patients with grade III to IV cystoceles. MATERIALS AND METHODS: We studied 42 women with grade III to IV cystoceles diagnosed by physical examination and video urodynamics. Of the patients 9 (22%) had intrinsic sphincter deficiency diagnosed by an abdominal leak point pressure of less the 60 cm. water, and 24 (57%) had type II stress incontinence with urethral hypermobility and an abdominal leak point pressure greater than 90 cm. water. A pubovaginal sling and anterior colporrhaphy were performed and, if indicated, other vaginal procedures were done at that time. RESULTS: A total of 36 patients (86%) was available for postoperative pelvic examinations performed at 3-month intervals, for a mean followup of 20.4 months (range 12 to 39). Only 3 patients had symptomatic grade III cystoceles and 2 had enteroceles. Two patients required collagen injections and 2 underwent a repeat pubovaginal sling. Therefore, all patients were continent at the time of followup. CONCLUSIONS: This study confirms that in patients with large cystoceles and stress urinary incontinence a pubovaginal sling and anterior colporrhaphy effectively treat the incontinence and reduce the cystocele. In addition, the fascial sling appears to provide additional support to the bladder base, improving the durability of the anterior colporrhaphy.

Cross, C. A., R. D. Cespedes, et al. (1998). "Our experience with pubovaginal slings in patients with stress urinary incontinence." J Urol 159(4): 1195-1198.

PURPOSE: Pubovaginal slings successfully treat stress urinary incontinence in women with intrinsic sphincter deficiency. Because of its durability, it has been an attractive procedure in select patients with urethral hypermobility. We examine our experience with pubovaginal sling. MATERIALS AND METHODS: A total of 150 patients were evaluated for pelvic prolapse and urinary incontinence. An abdominal leak point pressure was determined in all patients. Of patients with type II stress urinary incontinence, 36 patients (80%) underwent additional gynecological procedures at the time of the pubovaginal sling, compared to 29% with intrinsic sphincter deficiency and 33% with coexisting urethral hypermobility and intrinsic sphincter deficiency. RESULTS: The overall cure rate was 93% with a mean followup of 22 months. At 1 week postoperatively spontaneous voiding was accomplished by 56% of the patients with urethral hypermobility and 57% with intrinsic sphincter deficiency. Only 2.8% of patients required surgical therapy for prolonged urinary retention. De novo urgency/urge incontinence occurred in 19% of women with a 3% incidence of persistent urge incontinence. CONCLUSIONS: Pubovaginal slings are effective and durable. Voiding dysfunction is uncommon and is temporary in most patients.

Cross, C. A., S. F. English, et al. (1998). "A followup on transurethral collagen injection therapy for urinary incontinence." J Urol 159(1): 106-108.

PURPOSE: Transurethral collagen injection therapy has been used successfully in treating stress urinary incontinence due to intrinsic sphincter deficiency since United States Food and Drug Administration approval in October 1993. MATERIALS AND METHODS: Telephone interview and chart review were performed on 139 women with intrinsic sphincter deficiency documented using video urodynamics, of whom 73% had grade 3 incontinence (leakage without effort). Median followup was 18 months (range 6 to 36). Median patient age was 72 years. RESULTS: A total of 103 patients (74%) was substantially improved after collagen therapy, 29 (20%) were improved and 7 had no improvement. Of the substantially improved group 72% obtained continence after 2 or fewer injections. Of the patients 11% required a "booster" injection more than 6 months after initial treatment. Complications, such as hematuria, urinary tract infections or transient urinary retention, were rare. CONCLUSIONS: Our results confirm the safety and efficacy of transurethral collagen. Once continence is achieved further collagen therapy is rarely necessary.

Cude, K. J., J. S. Montgomery, et al. (2002). "The role of an androgen receptor polymorphism in the clinical outcome of patients with metastatic prostate cancer." Urol Int 68(1): 16-23.

The androgen receptor plays a major role in the development and function of normal and malignant prostate cells. Due to the relationship of the androgen receptor and prostatic growth, it has been proposed that polymorphisms within the androgen receptor may play a role in an individual's susceptibility to developing prostate cancer. An inverse relationship has been established between a highly polymorphic trinucleotide repeat located in the first exon of the androgen receptor and the transactivaton function of the receptor. Serum samples were collected from 131 patients with histologically confirmed adenocarcinoma of the prostate, DNA was isolated, and the polymorphic CAG repeat was amplified by PCR and sequenced. The CAG repeat lengths were then compared with age at diagnosis, age at time of study, baseline log(10) PSA, Gleason score, time from diagnosis to initiation of hormonal therapy, time to progression after androgen ablation, and overall survival time. No correlation was found between CAG length and time to progression or overall survival time, but a significant correlation was found between Gleason score and CAG length suggesting that shorter CAG lengths may predict a higher histological grade of prostate cancer.

Curtis, M. R., E. A. Gormley, et al. (1997). "Prospective development of a cost-efficient program for the pubovaginal sling." Urology 49(1): 41-45.

OBJECTIVES: We designed and implemented a cost-containment program for patients undergoing a pubovaginal sling procedure. We sought to test the hypothesis that preoperative patient education could reduce the length of hospital stay in these patients. Our goal was to decrease hospital charges while maintaining quality of care. METHODS: A multidisciplinary group of clinic and hospital staff identified factors that contribute to a patient's hospital charges for a pubovaginal sling procedure. A program of preoperative patient education to teach intermittent self-catheterization was combined with the elimination or control of items considered unnecessary to the delivery of safe, efficient care. Patient care was standardized from the preoperative visit to discharge planning. The difference in the mean values of 38 prestudy patients was compared with 15 study patients with a Wilcoxon rank sum test. RESULTS: Length of hospital stay was reduced from a mean of 2.8 to 1.1 days after implementation of the program (P < 0.0001). This decreased length of stay, combined with a reduction in routine laboratory studies (97% decrease; P < 0.0001), operating room charges (11% decrease; P < 0.01), and medications (35% decrease; P < 0.01), led to significantly reduced hospital charges. Total hospital charges decreased by 35%, from a mean of $4862 to a mean of $3153 (P < 0.0001). There was no increase in morbidity. Patient satisfaction with length of hospital stay did not change significantly following implementation of the program. CONCLUSIONS: With a program of preoperative patient education combined with a critical review of the factors contributing to a patient's hospital charges, it is possible to implement a cost-efficient program for a pubovaginal sling, leading to a 35% reduction in mean total hospital charges. This approach directed toward other incontinence procedures could be expected to yield comparative results.

Dahm, P., A. D. Silverstein, et al. (2003). "A longitudinal assessment of bowel related symptoms and fecal incontinence following radical perineal prostatectomy." J Urol 169(6): 2220-2224.

PURPOSE: Recent studies have suggested an increased incidence of fecal incontinence following radical perineal prostatectomy. We provide a prospective and longitudinal assessment of bowel related symptoms of patients undergoing radical perineal prostatectomy. MATERIALS AND METHODS: A total of 78 patients who underwent radical perineal prostatectomy between January 1 and December 31, 2001 and had a minimal followup of 6 months were included in the analysis. Patient information was obtained from the chart and the bowel domain specific questions of a validated quality of life questionnaire, the Expanded Prostate Cancer Index Composite. The questionnaire was administered to the candidates preoperatively, at 4 weeks following surgery and subsequently at 3-months intervals. A mean bowel function, bother and summary health related quality of life score was calculated at each interval. The duration of new or worsened symptoms with respect to baseline was evaluated using Kaplan-Meier analysis. RESULTS: Symptoms of involuntary stool leakage and rectal urgency were reported by 11.5% (9 of 78) and 19.2% (15) of patients preoperatively. While all bowel related symptoms transiently increased following surgery, rectal urgency was the most persistent symptom, yet normalized in more than 90% of patients within 9 1/2 months. Compared to individual baseline 15.4%, 7.7%, 5.1% and 3.9% of patients reported worsened symptoms of fecal incontinence after 3, 6, 9 and 12 months, respectively. In the subset of 69 patients who denied preoperative fecal incontinence the incidence of involuntary stool leakage was 2.9% by 12 months following radical perineal prostatectomy. Of 10 patients 9 recovered individual health related quality of life score by 6 months after prostatectomy. CONCLUSIONS: Longitudinal assessment of self-reported questionnaire data suggests that fecal incontinence and bowel related symptoms are more prevalent following radical perineal prostatectomy compared to baseline, yet resolve in the majority of patients with time in the early postoperative period.

Dai, J., C. L. Hall, et al. (2008). "Prostate cancer induces bone metastasis through Wnt-induced bone morphogenetic protein-dependent and independent mechanisms." Cancer Res 68(14): 5785-5794.

Prostate cancer (PCa) is frequently accompanied by osteosclerotic (i.e., excessive bone production) bone metastases. Although bone morphogenetic proteins (BMP) and Wnts are mediators of PCa-induced osteoblastic activity, the relation between them in PCa bone metastases is unknown. The goal of this study was to define this relationship. Wnt3a and Wnt5a administration or knockdown of DKK-1, a Wnt inhibitor, induced BMP-4 and 6 expression and promoter activation in PCa cells. DKK-1 blocked Wnt activation of the BMP promoters. Transfection of C4-2B cells with axin, an inhibitor of canonical Wnt signaling, blocked Wnt3a but not Wnt5a induction of the BMP promoters. In contrast, Jnk inhibitor I blocked Wnt5a but not Wnt3a induction of the BMP promoters. Wnt3a, Wnt5a, and conditioned medium (CM) from C4-2B or LuCaP23.1 cells induced osteoblast differentiation in vitro. The addition of DKK-1 and Noggin, a BMP inhibitor, to CM diminished PCa CM-induced osteoblast differentiation in a synergistic fashion. However, pretreatment of PCa cells with DKK-1 before collecting CM blocked osteoblast differentiation, whereas pretreatment with Noggin only partially reduced osteoblast differentiation, and pretreatment with both DKK-1 and Noggin had no greater effect than pretreatment with DKK-1 alone. Additionally, knockdown of BMP expression in C4-2B cells inhibited Wnt-induced osteoblastic activity. These results show that PCa promotes osteoblast differentiation through canonical and noncanonical Wnt signaling pathways that stimulate both BMP-dependent and BMP-independent osteoblast differentiation. These results show a clear link between Wnts and BMPs in PCa-induced osteoblast differentiation and provide novel targets, including the noncanonical Wnt pathway, for therapy of PCa.

Dai, J., J. Keller, et al. (2005). "Bone morphogenetic protein-6 promotes osteoblastic prostate cancer bone metastases through a dual mechanism." Cancer Res 65(18): 8274-8285.

Prostate cancer frequently metastasizes to bone where it forms osteoblastic lesions through unknown mechanisms. Bone morphogenetic proteins (BMP) are mediators of skeletal formation. Prostate cancer produces a variety of BMPs, including BMP-6. We tested the hypothesis that BMP-6 contributes to prostate cancer-induced osteosclerosis at bone metastatic sites. Prostate cancer cells and clinical tissues produced BMP-6 that increased with aggressiveness of the tumor. Prostate cancer-conditioned medium induced SMAD phosphorylation in the preosteoblast MC3T3 cells, and phosphorylation was diminished by anti-BMP-6 antibody. Prostate cancer-conditioned medium induced mineralization of MC3T3 cells, which was blocked by both the BMP inhibitor noggin and anti-BMP-6. Human fetal bones were implanted in severe combined immunodeficient mice and after 4 weeks, LuCaP 23.1 prostate cancer cells were injected both s.c. and into the bone implants. Anti-BMP-6 or isotype antibody administration was then initiated. Anti-BMP-6 reduced LuCaP 23.1-induced osteoblastic activity, but had no effect on its osteolytic activity. This was associated with increased osteoblast numbers and osteoblast activity based on bone histomorphometric evaluation. As endothelin-1 has been implicated in bone metastases, we measured serum endothelin-1 levels but found they were not different among the treatment groups. In addition to decreased bone production, anti-BMP-6 reduced intraosseous, but not s.c., tumor size. We found that BMP-2, BMP-4, BMP-6, and BMP-7 had no direct effect on prostate cancer cell growth, but BMP-2 and BMP-6 increased the in vitro invasive ability of prostate cancer cell. These data show that prostate cancer promotes osteoblastic activity through BMP-6 and that, in addition to its bone effects, suggest that BMPs promote the ability of the prostate cancer cells to invade the bone microenvironment.

Dai, J., Y. Kitagawa, et al. (2004). "Vascular endothelial growth factor contributes to the prostate cancer-induced osteoblast differentiation mediated by bone morphogenetic protein." Cancer Res 64(3): 994-999.

Human prostate cancer has a high predisposition to metastasize to bone, resulting in the formation of osteoblastic metastases. The mechanism through which prostate cancer cells promote osteoblastic lesions is undefined. Vascular endothelial growth factor (VEGF) has been implicated as a mediator of osteoblast activity. In the present study, we examined if prostate cancer cells promote osteoblastic activity through VEGF. We found that LNCaP and C4-2B prostate cancer cell lines and primary tumor and metastatic prostate cancer tissues from patients expressed VEGF. Bone morphogenetic proteins (BMPs), which are normally present in the bone environment, induced VEGF protein and mRNA expression in C4-2B cells. Furthermore, BMP-7 activated the VEGF promoter. Noggin, a BMP inhibitor, diminished VEGF protein expression and promoter activity in C4-2B cells. Conditioned media (CM) from C4-2B cells induced pro-osteoblastic activity (increased alkaline phosphatase, osteocalcin, and mineralization) in osteoblast cells. Both noggin alone and anti-VEGF antibody alone diminished C4-2B CM-induced pro-osteoblastic activity. Transfection of C4-2B cells with VEGF partially rescued the C4-2B CM-induced pro-osteoblastic activity from noggin inhibition. These observations indicate that BMPs promote osteosclerosis through VEGF in prostate cancer metastases. These results suggest a novel function for VEGF in skeletal metastases. Specifically, VEGF promotes osteoblastic lesion formation at prostate cancer bone metastatic sites.

Dai, J., D. Lin, et al. (2000). "Chronic alcohol ingestion induces osteoclastogenesis and bone loss through IL-6 in mice." J Clin Invest 106(7): 887-895.

To investigate the role of IL-6 in alcohol-mediated osteoporosis, we measured a variety of bone remodeling parameters in wild-type (il6(+/+)) or IL-6 gene knockout (il6(-/-)) mice that were fed either control or ethanol liquid diets for 4 months. In the il6(+/+) mice, ethanol ingestion decreased bone mineral density, as determined by dual-energy densitometry; decreased cancellous bone volume and trabecular width and increased trabecular spacing and osteoclast surface, as determined by histomorphometry of the femur; increased urinary deoxypyridinolines, as determined by ELISA; and increased CFU-GM formation and osteoclastogenesis as determined ex vivo in bone marrow cell cultures. In contrast, ethanol ingestion did not alter any of these parameters in the il6(-/-) mice. Ethanol increased receptor activator of NF-kappaB ligand (RANKL) mRNA expression in the bone marrow of il6(+/+) but not il6(-/-) mice. Additionally, ethanol decreased several osteoblastic parameters including osteoblast perimeter and osteoblast culture calcium retention in both il6(+/+) and il6(-/-) mice. These findings demonstrate that ethanol induces bone loss through IL-6. Furthermore, they suggest that IL-6 achieves this effect by inducing RANKL and promoting CFU-GM formation and osteoclastogenesis.

Dash, A., R. L. Dunn, et al. (2004). "Patient, surgeon, and treatment characteristics associated with homologous blood transfusion requirement during radical retropubic prostatectomy: multivariate nomogram to assist patient counseling." Urology 64(1): 117-122.

OBJECTIVES: To identify the preoperative patient, treatment, and surgeon factors associated with the administration of homologous blood transfusion during or after radical retropubic prostatectomy (RRP) to be able to better inform patients regarding the probability of transfusion. Homologous blood transfusion is sometimes required during or after RRP, but predictive models for estimating transfusion probability using patient and surgical characteristics are lacking. METHODS: Data were prospectively collected regarding patient characteristics, cancer severity, surgeon experience, anesthetic used, operative blood loss, and transfusion among 1123 consecutive RRP cases. Multivariate regression analysis identified baseline factors associated with a homologous transfusion requirement and generated a model for predicting the likelihood of perioperative homologous transfusion. RESULTS: Homologous transfusion was administered in 3.8% of subjects; the mean estimated blood loss was 953 mL. Multivariable regression analysis identified prostate size (P <0.0001, odds ratio [OR] 1.74), use of general anesthesia (P = 0.01, OR 2.22), use of neoadjuvant hormonal therapy (P = 0.006, OR 3.35), and surgeon expertise (P <0.0001, OR 8.63) as independent risk factors associated with a need for perioperative homologous transfusion. The most influential factor, surgical expertise, clustered among surgeons who performed more than 15 RRPs annually, because these surgeons had lower transfusion rates and lower estimated blood loss more consistently than did surgeons who performed fewer RRPs annually. CONCLUSIONS: Larger prostate size, use of general anesthesia, use of neoadjuvant hormonal therapy, and annual surgeon case volume were independently associated with an increased probability that an individual patient would receive homologous transfusion during or after RRP. A nomogram indicating the probability of homologous transfusion based on these factors provides a benchmark of expected homologous transfusion rates according to individual patient and treatment parameters.

Dash, A., M. G. Sanda, et al. (2002). "Prostate cancer involving the bladder neck: recurrence-free survival and implications for AJCC staging modification. American Joint Committee on Cancer." Urology 60(2): 276-280.

OBJECTIVES: In the American Joint Committee on Cancer (AJCC) TNM staging system, prostate cancer involving the bladder neck after radical prostatectomy is considered pT4 disease, suggesting a high risk of recurrence. The recurrence risk with pathologic invasion of the bladder neck, however, has not been definitively compared with that associated with extra-organ disease. We therefore compared the recurrence risk in cases with bladder neck involvement with that of cases with extraprostatic extension and/or seminal vesicle invasion. METHODS: The study cohort was composed of 1123 men with clinically localized prostate cancer treated with prostatectomy as monotherapy. The preoperative prostate-specific antigen (PSA) level, bladder neck involvement, margin positivity, Gleason score, and other pathologic categories were assessed as covariates contributing to the PSA-recurrence risk in univariate and multivariable models. RESULTS: Bladder neck involvement was found in 60 (5%) of 1123 cases. In univariate analysis, the bladder neck was the site-specific margin with the greatest PSA-recurrence risk of focal involvement (relative risk 1.52, 95% confidence interval [CI] 1.15 to 2.00, P = 0.0030). The PSA-recurrence relative risk with extraprostatic extension was 3.05 (95% CI 2.13 to 4.38, P <0.0001) and with seminal vesicle invasion was 8.59 (95% CI 5.76 to 12.82, P <0.0001). In the multivariable model, the PSA-recurrence risk with bladder neck involvement (relative risk 1.19, 95% CI 0.72 to 1.96, P = 0.5) was not a significant independent prognostic factor. Extraprostatic extension (relative risk 2.25, 95% CI 1.54 to 3.27, P <0.0001) and seminal vesicle invasion (relative risk 4.12, 95% CI 2.57 to 6.62, P <0.0001) were significant independent predictors of PSA recurrence. CONCLUSIONS: Any staging system should be evidence based. The current AJCC system for staging bladder neck involvement, however, is contrary to the available evidence. Reclassification of bladder neck involvement as part of the pT3 category should be considered. <8>

Dash, A., T. G. Schuster, et al. (2002). "Ureteroscopic treatment of renal calculi in morbidly obese patients: a stone-matched comparison." Urology 60(3): 393-397; discussion 397.

OBJECTIVES: To report a matched comparison of morbidly obese (MO) patients and normal weight (NW) patients who underwent ureteroscopic (URS) treatment of renal calculi. Shock wave lithotripsy and percutaneous nephrostolithotomy may be precluded in MO patients, and URS treatment offers a minimally invasive alternative. METHODS: We retrospectively reviewed the charts of patients who underwent URS at our institution between 1997 and 2000. Fifty-four patients underwent URS treatment solely for renal calculi. Sixteen MO patients underwent 18 procedures. Thirty-eight NW patients, who underwent 39 procedures, were matched to the MO patients by stone location and size. Stones were categorized by location and size, less than 10 mm or 10 mm or greater. The factors and outcomes assessed were stone length, operative time, presence of a ureteral stent, success, and complications. RESULTS: The overall success rate was 83% (15 of 18 procedures) for MO patients and 67% (26 of 39 procedures) for NW patients, but this difference was not significant (P = 0.23). The difference in the success rate for renal calculi 10 mm or greater (100% versus 38%) approached significance (P = 0.09). This may be related to other distinctions between the groups. URS treatment was often a salvage therapy in the NW group after other modalities failed. No significant differences were found between the other outcomes. CONCLUSIONS: URS treatment of renal calculi when matched for location and size is as successful and no more morbid in MO than in NW patients. URS treatment of renal calculi is a safe and effective first-line treatment for renal calculi in MO patients.

Dash, A. and J. S. Wolf (2005). "Percutaneous treatment of renal cystic nephroma." J Endourol 19(6): 724-725.

Cystic nephroma is a rare, presumed benign, renal tumor that occurs in both children and adults. When its presence is suspected preoperatively, nephron-sparing surgery can be applied. We describe treatment of a cystic nephroma that is the first reported, to our knowledge, using endoscopic techniques.

Davis, D. E. and J. S. Wolf (2005). "Laparoscopic pyelovesicostomy for ureteropelvic junction obstruction in a pelvic kidney." J Endourol 19(4): 469-470.

Pyelovesicostomy is an attractive option for treatment of ureteral obstruction in a congenital pelvic kidney or a renal allograft. We describe the first laparoscopic performance of this procedure. The total operative time was 207 minutes.

Davis, J. N. and M. L. Day (2002). "The convergence of hormone regulation and cell cycle in prostate physiology and prostate tumorigenesis." Mol Biotechnol 22(2): 129-138.

Despite the intense research focused on prostate cancer, it remains the most frequently diagnosed malignancy in men over 40-yr-of-age, and the second most frequent cause of cancer-related deaths in men in the United States (1). In 1990, the National Cancer Institute convened 50 experts and leaders from various disciplines in the prostate cancer field to discuss research directions that would help elucidate the molecular basis of this disease and reduce the incidence and mortality of prostate cancer (2). Critical issues identified at this meeting included the role of androgens and the regulation of cell cycle in prostate tumorigenesis and its progression to androgen-independence. Hormones and cell cycle clearly play important roles in normal and cancerous prostate physiology; however, little information has emerged that clearly delineates their function in the etiology of prostate cancer. Some of the mutational events that occur during prostate tumorigenesis and its progression to androgen-independence involve alterations to normal growth, developmental and apoptotic programs regulated by androgen, and the cell cycle. As such, the delineation of events by which prostate cancer cells circumvent these regulatory mechanisms will be central to our understanding of prostate tumorigenesis and to the development of new modalities to treat this disease. This article is then intended to summarize the functional convergence of androgen regulation and cell cycle in normal prostate physiology and prostate tumorigenesis.

Davis, J. N., M. T. McCabe, et al. (2005). "Disruption of Rb/E2F pathway results in increased cyclooxygenase-2 expression and activity in prostate epithelial cells." Cancer Res 65(9): 3633-3642.

The loss of the retinoblastoma tumor suppressor gene (RB) is common in many human cancers, including prostate. We previously reported that engineered deletion of RB in prostate epithelial cells results in sustained cell growth in serum-free media, a predisposition to develop hyperplasia and dysplasia in prostate tissue recombinant grafts, and sensitization to hormonal carcinogenesis. Examining the molecular consequence of RB loss in this system, we show that cyclooxygenase-2 (COX-2) is significantly up-regulated following RB deletion in prostate tissue recombinants. To study the effect of RB deletion on COX-2 regulation, we generated wild-type (PrE) and Rb-/- (Rb-/-PrE) prostate epithelial cell lines rescued by tissue recombination. We show elevated COX-2 mRNA and protein expression in Rb-/-PrE cell lines with increased prostaglandin synthesis. We also find that loss of Rb leads to deregulated E2F activity, with increased expression of E2F target genes, and that exogenous expression of E2F1 results in elevated COX-2 mRNA and protein levels. COX-2 promoter studies reveal that E2F1 transcriptionally activates COX-2, which is dependent on the transactivation and DNA-binding domains of E2F1. Further analysis revealed that the E2F1 target gene, c-myb, is elevated in Rb-/-PrE cells and E2F1-overexpressing cells, whereas ectopic overexpression of c-myb activates the COX-2 promoter in prostate epithelial cells. Additionally, cotransfection with E2F1 and a dominant-negative c-myb inhibited E2F1 activation of the COX-2 promoter. Taken together, these results suggest activation of a transcriptional cascade by which E2F1 regulates COX-2 expression through the c-myb oncogene. This study reports a novel finding describing that deregulation of the Rb/E2F complex results in increased COX-2 expression and activity.

Davis, J. N., K. J. Wojno, et al. (2006). "Elevated E2F1 inhibits transcription of the androgen receptor in metastatic hormone-resistant prostate cancer." Cancer Res 66(24): 11897-11906.

Activation of E2F transcription factors, through disruption of the retinoblastoma (Rb) tumor-suppressor gene, is a key event in the development of many human cancers. Previously, we showed that homozygous deletion of Rb in a prostate tissue recombination model exhibits increased E2F activity, activation of E2F-target genes, and increased susceptibility to hormonal carcinogenesis. In this study, we examined the expression of E2F1 in 667 prostate tissue cores and compared it with the expression of the androgen receptor (AR), a marker of prostate epithelial differentiation, using tissue microarray analysis. We show that E2F1 expression is low in benign and localized prostate cancer, modestly elevated in metastatic lymph nodes from hormone-naive patients, and significantly elevated in metastatic tissues from hormone-resistant prostate cancer patients (P = 0.0006). In contrast, strong AR expression was detected in benign prostate (83%), localized prostate cancer (100%), and lymph node metastasis (80%), but decreased to 40% in metastatic hormone-resistant prostate cancer (P = 0.004). Semiquantitative reverse transcription-PCR analysis showed elevated E2F1 mRNA levels and increased levels of the E2F-target genes dihyrofolate reductase and proliferating cell nuclear antigen in metastatic hormone-independent prostate cancer cases compared with benign tissues. To identify a role of E2F1 in hormone-independent prostate cancer, we examined whether E2F1 can regulate AR expression. We show that exogenous expression of E2F1 significantly inhibited AR mRNA and AR protein levels in prostate epithelial cells. E2F1 also inhibited an AR promoter-luciferase construct that was dependent on the transactivation domain of E2F1. Furthermore, using chromatin immunoprecipitation assays, we show that E2F1 and the pocket protein family members p107 and p130 bind to the AR promoter in vivo. Taken together, these results show that elevated E2F1, through its ability to repress AR transcription, may contribute to the progression of hormone-independent prostate cancer.

Day, K. C., M. T. McCabe, et al. (2002). "Rescue of embryonic epithelium reveals that the homozygous deletion of the retinoblastoma gene confers growth factor independence and immortality but does not influence epithelial differentiation or tissue morphogenesis." J Biol Chem 277(46): 44475-44484.

The ability to rescue viable prostate precursor tissue from retinoblastoma-deficient (Rb-/-) fetal mice has allowed for the isolation and characterization of the first Rb-/- prostate epithelial cell line. This cell line, designated Rb-/-PrE, was utilized for experiments examining the consequences of Rb loss on an epithelial population. These findings demonstrated that Rb deletion has no discernible effect on prostatic histodifferentiation in Rb-/-PrE cultures. When Rb-/-PrE cells were recombined with embryonic rat urogenital mesenchyme and implanted into athymic male, nude mouse hosts, the recombinants developed into fully differentiated and morphologically normal prostate tissue. The Rb-/-PrE phenotype was characterized by serum independence in culture and immortality in vivo, when compared with wild type controls. Cell cycle analysis revealed elevated S phase DNA content accompanied by increased expression of cyclin E1 and proliferating cell nuclear antigen. Rb-/-PrE cultures also exhibited a diminished ability to growth arrest under high density culture conditions. We believe that the development of Rb-/- prostate tissue and cell lines has provided a unique experimental platform with which to investigate the consequences of Rb deletion in epithelial cells under various physiological conditions. Additionally, the development of this technology will allow similar studies in other tissues and cell populations rescued from Rb-/- fetuses.

Day, M. L., T. J. Fahrner, et al. (1990). "The zinc finger protein NGFI-A exists in both nuclear and cytoplasmic forms in nerve growth factor-stimulated PC12 cells." J Biol Chem 265(25): 15253-15260.

The NGFI-A gene, which encodes a zinc finger protein with a predicted molecular mass of congruent to 54 kDa, is rapidly activated in PC12 cells by nerve growth factor (NGF). As a transcription factor, NGFI-A is a potentially important mediator of the cellular response to this growth factor. To characterize this protein, antibodies to four different domains of NGFI-A were raised. Immunogens included a bacterial trpE/NGFI-A fusion protein (A310) and three peptides predicted from the NGFI-A cDNA nucleotide sequence. Three of these antisera recognize two predominant NGFI-A species in NGF-stimulated PC12 cells: a 54-kDa form and a closely spaced doublet at 84 kDa. However, one of these antisera, directed against the last 15 carboxyl terminal residues of NGFI-A, recognizes only the 84-kDa species. Both NGFI-A species are rapidly induced in PC12 cells by NGF, phorbol ester, and the calcium ionophore A23187. Pulse-chase analysis revealed no obvious precursor-product relationship between these two forms and demonstrated that both the 54- and 84-kDa species are short-lived proteins. V8 protease digestion of the 54- and 84-kDa forms resulted in the formation of several small peptides that were common to both species. The digest of each species also contained one large, relatively V8 protease-resistant fragment that was substantially larger in digests of the 84-kDa form. These two fragments contained common epitopes and were derived from the amino-terminal portion of the NGFI-A protein. When NGFI-A was incubated with alkaline phosphatase, the 84-kDa doublet resolved into a single band with slightly increased mobility, indicating that this form is phosphorylated. Cell fractionation studies demonstrated that the 84-kDa species are found exclusively in the nucleus, while the 54-kDa form resides solely in the cytoplasm. It therefore appears that the 54-kDa form lacks the signal necessary for nuclear localization and is missing a portion of the carboxyl terminal domain.

Day, M. L., R. G. Foster, et al. (1997). "Cell anchorage regulates apoptosis through the retinoblastoma tumor suppressor/E2F pathway." J Biol Chem 272(13): 8125-8128.

Epithelial cells are dependent upon adhesion to extracellular matrix for survival. We show that loss of beta1 integrin receptor contact with extracellular matrix signals the inhibition of G1 cyclin-dependent kinase activity. This loss of cyclin-dependent kinase activity leads to accumulation of the hypophosphorylated (active) form of the retinoblastoma tumor suppressor protein (Rb). We present evidence that in epithelial cells deprived of matrix contact, the growth suppression signal elicited by hypophosphorylated Rb opposes stimulatory signals from serum growth factors, leading to a cell cycle conflict that triggers apoptosis. This apoptotic pathway is modulated by Bcl-2 through a novel mechanism that regulates Rb phosphorylation. We present evidence that the Rb-dependent apoptotic pathway functions in vivo in the apoptosis of the prostate glandular epithelium following castration.

Day, M. L., D. Schwartz, et al. (1987). "Ventricular atriopeptin. Unmasking of messenger RNA and peptide synthesis by hypertrophy or dexamethasone." Hypertension 9(5): 485-491.

Left ventricular hypertrophy or treatment with dexamethasone caused a 2.5-fold to threefold increase in both immunoreactive atriopeptin (AP) and AP messenger RNA (mRNA), primarily in left ventricular tissue. The combined treatments increased immunoreactive AP and AP mRNA more than either treatment alone. In the animals in which cardiac hypertrophy had been produced by abdominal aortic constriction, there was a decrease in atrial levels of AP and an increase in plasma levels of immunoreactive AP. The increase in left ventricular immunoreactive AP was confirmed by immunohistochemical staining of tissue from hypertrophied and/or dexamethasone-treated rats. The mRNA accumulated in the left ventricle was identical to atrial AP mRNA, as judged by transcriptional start site and by size on Northern blots. Because the mass of ventricular tissue is substantially greater than that of atrial tissue, the induced mRNA levels may represent a total abundance approaching one third of the total AP mRNA in the atria. High performance liquid chromatographic purification of ventricular extracts primarily demonstrated the presence of the high molecular precursor and small amounts of C-terminal peptide AP. Induction of ventricular AP (mRNA and peptide) may represent regression of the tissue to an earlier developmental form. These data provide a unique example of regulation of AP biosynthesis in nonatrial tissue.

Day, M. L., S. Wu, et al. (1993). "Prostatic nerve growth factor inducible A gene binds a novel element in the retinoblastoma gene promoter." Cancer Res 53(23): 5597-5599.

We are investigating the role of the early response transcription factor, nerve growth factor inducible A gene (NGFI-A), as a modulator of retinoblastoma (RB) gene transcription in prostate cells. Examination of the RB promoter reveals a novel element GCGGGGGAG located at nucleotides 152-144 upstream of the methionine initiation codon. This sequence shares strong homology with the consensus NGFI-A binding element GCGGGGGCG varying by a single nucleotide. In DNA binding assays, an NGFI-A fusion protein and the native protein product of the NGFI-A gene purified from prostate cancer cells bound specifically to an oligonucleotide containing the RB promoter element. Gene expression studies in rat ventral prostate demonstrated a 1.9-fold increase in RB mRNA following castration that parallels a 2.7-fold induction of NGFI-A mRNA. In summary, the in vitro DNA binding data and the transient coregulation of rat NGFI-A and RB following castration suggests that the RB gene may be transcriptionally regulated by NGFI-A in prostate cells.

Day, M. L., X. Zhao, et al. (1999). "E-cadherin mediates aggregation-dependent survival of prostate and mammary epithelial cells through the retinoblastoma cell cycle control pathway." J Biol Chem 274(14): 9656-9664.

E-cadherin and the retinoblastoma tumor suppressor (Rb) are traditionally associated with diverse regulatory aspects of cell growth and differentiation. However, we have discovered new evidence, which suggests that these proteins are functionally linked in a physiologic pathway required for cell survival and programmed cell death. Pharmacological activation of protein kinase C (PKC) or inducible overexpression and activation of the alpha isozyme of PKC (PKCalpha) resulted in approximately 60% apoptosis of mammary and prostate epithelial cells. Interestingly, the surviving cells had undergone dramatic aggregation concurrent with increased E-cadherin expression. When aggregation was inhibited by the addition of an E-cadherin-blocking antibody, apoptosis increased synergistically. We hypothesized that survival of the aggregated population was associated with contact-inhibited growth and that apoptosis might result from aberrant growth regulatory signals in non-aggregated, cycling cells. This hypothesis was confirmed by experiments that demonstrated that E-cadherin-dependent aggregation resulted in Rb-mediated G1 arrest and survival. Immunoblot analysis and flow cytometry revealed that hypophosphorylated Rb was present in non-aggregated, S phase cultures concurrent with synergistic cell death. We have also determined that the loss of membrane E-cadherin and subsequent hypophosphorylation of Rb in luminal epithelial cells preceded apoptosis induced by castration. These findings provide compelling evidence that suggests that E-cadherin-mediated aggregation results in Rb activation and G1 arrest that is critical for survival of prostate and mammary epithelial cells. These data also indicate that Rb can initiate a fatal growth signal conflict in non-aggregated, cycling cells when the protein is hypophosphorylated as these epithelial cells enter S phase.

Day, M. L., X. Zhao, et al. (1994). "Phorbol ester-induced apoptosis is accompanied by NGFI-A and c-fos activation in androgen-sensitive prostate cancer cells." Cell Growth Differ 5(7): 735-741.

We have previously demonstrated the induction of the early response transcription factor NGFI-A in castration-induced regression of the rat ventral prostate. We have developed an in vitro model to investigate the role of kinase signal transduction and early transcriptional regulation in apoptosis of androgen-sensitive prostate cells. Cell death was induced in the androgen-sensitive human prostate line, LNCaP, by addition of the protein kinase activator, 12-tetradecanoylphorbol 13-acetate (TPA). TPA-induced death of LNCaP cells was asynchronous and exhibited morphological and ultrastructural features indicative of apoptosis. Specifically, cytoplasmic contraction, condensation of nuclear chromatin, and formation of membrane-bound "apoptotic bodies" were observed. Additionally, the characteristic endonuclease-generated DNA ladder, commonly associated with apoptosis, was observed in TPA-treated LNCaP cultures. TPA-induced LNCaP apoptosis was preceded by rapid yet transient induction of the early response transcription factors NGFI-A and c-fos. In dose-response experiments, NGFI-A and c-fos gene activation parallels the induction of death in LNCaP cells. TPA-induced expression of NGFI-A and c-fos and death of LNCaP cultures were blocked by pretreatment with staurosporine, a potent inhibitor of several protein kinases. Based on these studies, we suggest that activation of a TPA-inducible kinase(s) mediates apoptosis of androgen-sensitive prostate cells by means of an intracellular pathway that may involve the transient activation of the early response transcription factors NGFI-A and c-fos.

Dean, R., E. Herlihy, et al. (1978). "The accuracy of antimicrobial disk sensitivity testing in urinary tract infections." J Urol 120(1): 80-81.

Fifty bacterial strains shown resistant to ampicillin, cephalothin or tetracycline by Kirby-Bauer disk diffusion susceptibility testing were isolated from patients with urinary infections. Inhibitory activity in urine of volunteers given these antimicrobial agents and tube dilution sensitivity testing indicated that agar disk diffusion gradients do not provide sufficiently high antimicrobial concentrations to predict accurately clinical efficacy.

DeHaan, A. M., N. M. Wolters, et al. (2009). "EGFR ligand switch in late stage prostate cancer contributes to changes in cell signaling and bone remodeling." Prostate 69(5): 528-537.

BACKGROUND: Bone metastasis occurs frequently in advanced prostate cancer (PCa) patients; however, it is not known why this happens. The epidermal growth factor receptor (EGFR) ligand EGF is available to early stage PCa; whereas, TGF-alpha is available when PCa metastasizes. Since the microenvironment of metastases has been shown to play a role in the survival of the tumor, we examined whether the ligands had effects on cell survival and proliferation in early and late PCa. METHODS: We used LNCaP cells as a model of early stage, non-metastatic PCa and the isogenic C4-2B cells as a model of late stage, metastatic PCa. RESULTS: We found that the proliferation factor MAPK and the survival factor AKT were differentially activated in the presence of different ligands. TGF-alpha induced growth of C4-2B cells and not of the parental LNCaP cells; however, LNCaP cells expressing a constitutively active AKT did proliferate with TGF-alpha. Therefore, AKT appeared to be the TGF-alpha-responsive factor for survival of the late stage PCa cells. LNCaP cells exposed to EGF produced more osteoprotegerin (OPG), an inhibitor of bone remodeling, than C4-2B cells with TGF-alpha, which had increased expression of RANKL, an activator of bone remodeling. In concordance, TGF-alpha-treated C4-2B conditioned medium was able to differentiate an osteoclast precursor line to a greater extent than EGF-treated C4-2B or TGF-alpha-treated LNCaP conditioned media. CONCLUSION: The switch in EGFR ligand availability as PCa progresses affects cell survival and contributes to bone remodeling.

Deierhoi, M. H., R. M. Radvany, et al. (1981). "Correlation of B-cell antibodies and clinical course in DRw-typed renal allograft recipients." Transplantation Proceedings 13(1:Pt 2): t-4.

Delvecchio, F. C., B. K. Auge, et al. (2003). "In vitro analysis of stone fragmentation ability of the FREDDY laser." J Endourol 17(3): 177-179.

BACKGROUND AND PURPOSE: The Frequency-Doubled Double-Pulse Nd:Yag) (FREDDY) laser (World of Medicine, Berlin Germany) is a short-pulsed, double-frequency solid-state laser with wavelengths of 532 and 1064 nm. This low-power, low-cost laser was developed for intracorporeal lithotripsy. We designed an experimental set-up to test its fragmentation efficiency at different energy and frequency settings. MATERIALS AND METHODS: Forty previously weighed plaster-of-Paris stone phantoms were divided into four groups in order to test fragmentation at 5 and 10 Hz for 2 and 4 minutes. A hands-off underwater laboratory set-up including a holder to keep the stone phantom in contact with the quartz laser fiber was utilized. The 280-microm laser fiber was cleaved and stripped between runs to ensure optimal energy delivery. After fragmentation was completed, all of the stone fragments remaining within the holder were allowed to desiccate for 48 hours and reweighed. Fragmentation was measured as the percentage weight loss. RESULTS: Stone phantoms fragmented at 5 Hz for 2 minutes sustained a mean 24% loss of weight, whereas the 4-minute treatment at 5 Hz reduced stone weight by 54%. Treatment at 10 Hz for 2 minutes demonstrated results similar to those of stones treated for 4 minutes at 5 Hz, reducing stone weight by 51%. Fragmentation at 10 Hz for 4 minutes revealed a 64% loss of mass, less than expected for these power settings. Fiber deterioration observed at the higher energy settings may be the cause of the reduced stone-fragmentation efficiency. CONCLUSIONS: Fragmentation with the FREDDY laser in the 5 Hz, 4 minutes and 10 Hz, 2 minutes protocols is comparable, suggesting that stone fragmentation correlates well with the total energy delivered to the stone. The slight drop in fragmentation efficiency at 10 Hz, 4 minutes is most likely explained by fiber damage occurring consistently at these higher energy settings. The safety profile and low investment and running costs of this laser are advantages that suggest the laser warrants further clinical trials.

Delvecchio, F. C., B. K. Auge, et al. (2002). "Computed tomography urography, three-dimensional computed tomography and virtual endoscopy." Curr Opin Urol 12(2): 137-142.

Spiral computed tomography technology allows an entire body region to be imaged as a continuous volume of computed tomography data. The acquisition of genitourinary images can be performed at different intervals after intravenous contrast injection in order to characterize the renal vasculature, the renal parenchyma or the collecting system. Computed tomography scanning as contrast is excreted into the collecting system is termed a 'computed tomography urogram'. Volumetric data from spiral computed tomography can be rendered into conventional two-dimensional images or even reformatted into three-dimensional views of organ systems or hollow structures, as in 'fly-through' virtual endoscopy. Although virtual endoscopy of the urinary tract remains in its infancy, three-dimensional imaging is currently a useful adjunct in the evaluation of renal transplant and donor patients and partial nephrectomy candidates. The role of computed tomography urography compared with intravenous urography in the evaluation of hematuria is discussed.

Demers, R. Y., A. Tiwari, et al. (2001). "Trends in the utilization of androgen-deprivation therapy for patients with prostate carcinoma suggest an effect on mortality." Cancer 92(9): 2309-2317.

BACKGROUND: After a surge in the incidence of prostate carcinoma in the early 1990s, diminishing rates of mortality became apparent in 1993. This decrease in mortality is unlikely to be explained entirely by treatment with curative intent alone following screen-detected cases, because the time frame between detection and mortality remains relatively brief. METHODS: This study used incidence and initial treatment data from the Detroit area SEER registry between 1973 and 1998 in addition to mortality data covering the Metropolitan Detroit area obtained from the Michigan Department of Community Health. Data for Caucasian and African-American men were analyzed. The use of androgen-deprivation therapy, which evolved during the study period, was evaluated in conjunction with mortality and incidence trend data for consideration of etiologic contributions. RESULTS: The incidence of prostate carcinoma, as noted previously in national data, increased sharply in 1988, peaking in 1992 in Southeast Michigan, whereas mortality rates began to decrease in approximately 1993, with a sustained decrease to the latest recorded data in 1998. These trends were identical in Caucasians and African Americans. A sharp increase in the use of androgen-deprivation therapy began in 1990. This use of androgen-deprivation therapy is high and sustained for patients with early-stage disease, increases for several years, and then diminishes for patients with regional disease. The use also diminished through the 1990s for patients with late-stage disease, paralleling the decrease in the incidence rate for late-stage disease. CONCLUSIONS: The pattern of androgen-deprivation therapy usage was consistent with that for hormonal monotherapy and adjuvant and neoadjuvant therapy. These findings suggest that androgen-deprivation therapy may contribute, along with advances in diagnostic techniques and curative therapy with radiation or surgery, toward decreasing prostate carcinoma mortality rates in Southeast Michigan.

Demichelis, F., H. Greulich, et al. (2008). "SNP panel identification assay (SPIA): a genetic-based assay for the identification of cell lines." Nucleic Acids Res 36(7): 2446-2456.

Translational research hinges on the ability to make observations in model systems and to implement those findings into clinical applications, such as the development of diagnostic tools or targeted therapeutics. Tumor cell lines are commonly used to model carcinogenesis. The same tumor cell line can be simultaneously studied in multiple research laboratories throughout the world, theoretically generating results that are directly comparable. One important assumption in this paradigm is that researchers are working with the same cells. However, recent work using high throughput genomic analyses questions the accuracy of this assumption. Observations by our group and others suggest that experiments reported in the scientific literature may contain pre-analytic errors due to inaccurate identities of the cell lines employed. To address this problem, we developed a simple approach that enables an accurate determination of cell line identity by genotyping 34 single nucleotide polymorphisms (SNPs). Here, we describe the empirical development of a SNP panel identification assay (SPIA) compatible with routine use in the laboratory setting to ensure the identity of tumor cell lines and human tumor samples throughout the course of long term research use.

Demiralp, B., H. L. Chen, et al. (2002). "Anabolic actions of parathyroid hormone during bone growth are dependent on c-fos." Endocrinology 143(10): 4038-4047.

PTH has anabolic and catabolic actions in bone that are not clearly understood. The protooncogene c-fos and other activating protein 1 family members are critical transcriptional mediators in bone, and c-fos is up-regulated by PTH. The purpose of this study was to examine the mechanisms of PTH and the role of c-fos in PTH-mediated anabolic actions in bone. Mice with ablation of c-fos (-/-) and their wild-type (+/+) and heterozygous (+/-) littermates were administered PTH for 17 d. The +/+ mice had increased femoral bone mineral density (BMD), whereas -/- mice had reduced BMD after PTH treatment. PTH increased the ash weight of +/+ and +/-, but not -/-, femurs and decreased the calcium content of -/-, but not +/+ or +/-, femurs. Histomorphometric analysis showed that PTH increased trabecular bone volume in c-fos +/+, +/- vertebrae, but, in contrast, decreased trabecular bone in -/- vertebrae. Serum calcium levels in +/+ mice were greater than those in -/- mice, and PTH increased calcium in -/- mice. Histologically, PTH resulted in an exacerbation of the already widened growth plate and zone of hypertrophic chondrocytes but not the proliferating zone in -/- mice. PTH also increased calvarial thickness in +/+ mice, but not -/- mice. The c-fos -/- mice had lower bone sialoprotein and osteocalcin (OCN), but unaltered PTH-1 receptor mRNA expression in calvaria, suggesting an alteration in extracellular matrix. Acute PTH injection (8 h) resulted in a decrease in osteocalcin mRNA expression in wild-type, but unaltered expression in -/-, calvaria. These data indicate that c-fos plays a critical role in the anabolic actions of PTH during endochondral bone growth.

Deng, X., H. Liu, et al. (2008). "Ionizing radiation induces prostate cancer neuroendocrine differentiation through interplay of CREB and ATF2: implications for disease progression." Cancer Res 68(23): 9663-9670.

Radiation therapy is a first-line treatment for prostate cancer patients with localized tumors. Although some patients respond well to the treatment, approximately 10% of low-risk and up to 60% of high-risk prostate cancer patients experience recurrent tumors. However, the molecular mechanisms underlying tumor recurrence remain largely unknown. Here we show that fractionated ionizing radiation (IR) induces differentiation of LNCaP prostate cancer cells into neuroendocrine (NE)-like cells, which are known to be implicated in prostate cancer progression, androgen-independent growth, and poor prognosis. Further analyses revealed that two cyclic AMP-responsive element binding transcription factors, cyclic AMP-response element binding protein (CREB) and activating transcription factor 2 (ATF2), function as a transcriptional activator and a repressor, respectively, of NE-like differentiation and that IR induces NE-like differentiation by increasing the nuclear content of phospho-CREB and cytoplasmic accumulation of ATF2. Consistent with this notion, stable expression of a nonphosphorylatable CREB or a constitutively nuclear-localized ATF2 in LNCaP cells inhibits IR-induced NE-like differentiation. IR-induced NE-like morphologies are reversible, and three IR-resistant clones isolated from dedifferentiated cells have acquired the ability to proliferate and lost the NE-like cell properties. In addition, these three IR-resistant clones exhibit differential responses to IR- and androgen depletion-induced NE-like differentiation. However, they are all resistant to cell death induced by IR and the chemotherapeutic agent docetaxel and to androgen depletion-induced growth inhibition. These results suggest that radiation therapy-induced NE-like differentiation may represent a novel pathway by which prostate cancer cells survive the treatment and contribute to tumor recurrence.

Denil, J., D. A. Ohl, et al. (1992). "Motility longevity of sperm samples processed for intrauterine insemination." Fertil Steril 58(2): 436-438.

This study demonstrates that sperm from men with male factor infertility and sperm obtained by electroejaculation have reduced motility longevity when compared with normal specimens. After 24 hours, normal samples lost only 34% of initial motility, whereas male factor patients lost 48%, and electroejaculation patients dropped 66%. Based on these data and previous clinical studies of insemination timing, it is recommended that sperm retrieval and artificial insemination for male factor infertility, especially when electroejaculation is necessary, be performed 24 to 36 hours after urinary detection of the LH surge or as close to the time of ovulation as possible.

Denil, J., D. A. Ohl, et al. (1992). "Die Elektroejakulation in der Behandlung von neurogen Ejakulationsstorungen [Electroejaculation in the treatment of neurogenic ejaculation disorders]." Aktuelle Urologie 23: 276-286.

Denil, J., D. A. Ohl, et al. (1992). "Treatment of anejaculation with electroejaculation." Acta Urol Belg 60(3): 15-25.

Male infertility caused by anejaculation is common after spinal cord injury (SCI) and following retroperitoneal lymph node dissection (RPLND) for testicular cancer. Other conditions sometimes associated with neurogenic ejaculation loss are diabetes mellitus, multiple sclerosis, extensive pelvic surgery and adult myelodysplasia. Primary absence of ejaculation also has been described. Few treatment options exist for these patients, if they wish to father a child. With electroejaculation (EEJ), or the low-current stimulation of the ejaculatory organs via a rectal probe, emission of semen can be initiated in these men. In non-SCI-patients EEJ requires general anaesthesia. The collected semen is washed and the motile sperm fraction isolated before artificial insemination (AI) of the partner. At the University of Michigan 198 men have been treated between 1986 and December 1991. An ejaculate could be obtained from nearly all patients. A major obstacle to success is the severe asthenozoospermia and the poor functional quality of the obtained sperm samples. This can be caused by the EEJ-technique itself, as well as by the long anejaculatory status. A semen sample with at least 10 million progressively motile sperm cells, useful for AI, was obtained in 75% of the SCI men and in 87% of the men following RPLND. In the couples wishing insemination, 49 pregnancies were induced, accounting for an overall pregnancy rate of 35% per couple. Thirty five healthy babies have been born. Only three complications were encountered. At Hannover Medical School only few patients have been stimulated to date. We could obtain an adequate sperm sample for AI from all of them. No complications were seen. As the first couple has just entered the phase of AI with husband sperm, an analysis of these results would be premature. Electroejaculation combined with artificial insemination is an efficient and safe treatment of male infertility due to neurogenic anejaculation.

Denil, J., D. A. Ohl, et al. (1992). "Functional characteristics of sperm obtained by electroejaculation." J Urol 147(1): 69-72.

Sperm obtained by electroejaculation in 32 anejaculatory men were examined for functional characteristics. Raw specimens showed high sperm counts but motility averaged only 11%. Average viability was 10% for antegrade and 5% for retrograde fractions. Bovine cervical mucus penetration was normal (30 mm. or more in 30 minutes) in only 24% of the electroejaculation samples but it was normal in all of the donor samples tested. Processed sperm motility averaged 30% with 71% forward progression. At 20 hours patient samples retained 46% of the original motility, while donor controls retained 81%. In the hamster egg penetration assay patient sperm penetrated 14% of the oocytes while donor sperm penetrated 40%. Therefore, we identified 4 characteristics of sperm obtained by electroejaculation: 1) low viability, 2) poor survival after overnight incubation, 3) moderately impaired cervical mucus penetration and 4) moderately poor fertilizing capability as measured by the hamster egg penetration assay. Poor sperm survival and impaired function may explain the low pregnancy rates from insemination with electroejaculated sperm.

Denil, J., D. A. Ohl, et al. (1996). "Vacuum erection device in spinal cord injured men: patient and partner satisfaction." Arch Phys Med Rehabil 77(8): 750-753.

OBJECTIVE: To assess the efficacy of and patient and partner satisfaction with a vacuum erection device (VED) to treat erectile dysfunction of spinal cord injury. DESIGN: Case series. SETTING: University hospital outpatient clinic. PATIENTS: Twenty spinal cord injured men with erectile dysfunction and their heterosexual partners, recruited from outpatient population and by advertisement. INTERVENTION: Use of a VED to obtain erections for sexual activity. MAIN OUTCOME MEASURES: Efficacy in obtaining adequate penile erection, and patient and partner satisfaction with the device (survey). RESULTS: At 3 months, 93% of the men and 83% of the women reported rigidity sufficient for vaginal penetration, with an average duration of 18 minutes. These numbers decreased somewhat at the 6-month control. At 6 months, 41% of the men and 45% of the women were satisfied with the device, with premature loss of rigidity during intercourse the most commonly reported complaint. Sixty percent of men and 42% of women indicated an improvement of the sexual relationship. Minor side effects, such as petechiae and penile skin edema, occurred frequently, but there were no complications that required treatment. CONCLUSION: The VED is effective in many couples in the treatment of erectile dysfunction associated with spinal cord injury. The devices were not universally accepted, but had a significant impact on sexual activity and sexual satisfaction for nearly half the couples. Vacuum erection devices should be presented to SCI men along with other options for treatment of erectile dysfunction.

Dhakshinamoorthy, S., A. K. Jain, et al. (2005). "Bach1 competes with Nrf2 leading to negative regulation of the antioxidant response element (ARE)-mediated NAD(P)H:quinone oxidoreductase 1 gene expression and induction in response to antioxidants." J Biol Chem 280(17): 16891-16900.

The antioxidant response element (ARE) and Nrf2 are known to regulate the expression and coordinated induction of genes encoding detoxifying enzymes including NAD(P)H:quinone oxidoreductase1 (NQO1) in response to antioxidants. In this report, we demonstrate that overexpression of the transcription factor Bach1 in Hep-G2 cells negatively regulated NQO1 gene expression and induction in response to antioxidant t-BHQ. Bandshift and supershift assays revealed that Bach1 binds to the ARE as a heterodimer with small Maf proteins but not as a homodimer or heterodimer with Nrf2. The transfection and ChIP assays revealed that Bach1 and Nrf2 competed with each other to regulate ARE-mediated gene expression. Heme, a negative regulator of Bach1 relieved the Bach1 repression of NQO1 gene expression in transfected cells. The transcription of Bach1 and Nrf2 did not change in response to t-BHQ. Immunofluorescence assays and Western blot analysis revealed that both Bach1 and Nrf2 localized in the cytoplasm and nucleus of the untreated cells. The treatment of cells with t-BHQ resulted in the nuclear accumulation of both Bach1 and Nrf2. Interestingly, the t-BHQ-induced nuclear accumulation of Bach1 was significantly delayed over that of Nrf2. These results led to the conclusion that a balance of Nrf2 versus Bach1 inside the nucleus influences up- or down-regulation of ARE-mediated gene expression. The results further suggest that antioxidant-induced delayed accumulation of Bach1 contributes to the down-regulation of ARE-regulated genes, presumably to reduce the antioxidant enzymes to normal levels.

Diamond, D. A., H. M. Price, et al. (1995). "Retroperitoneal laparoscopic nephrectomy in children." J Urol 153(6): 1966-1968.

Retroperitoneal pediatric laparoscopic nephrectomy is described in 3 patients requiring 3 to 5 hours with an estimated blood loss of 10 to 60 cc. The children returned to school within 7 days postoperatively. Advantages of this procedure include the avoidance of intraoperative repositioning of the patient and easy conversion to an open lumbodorsal approach, if necessary; early laparoscopic visualization of the renal artery; applicability in cases of previous abdominal surgery, and avoidance of intraperitoneal adhesion.

Diaz, A., M. Roach, 3rd, et al. (1994). "Indications for and the significance of seminal vesicle irradiation during 3D conformal radiotherapy for localized prostate cancer." Int J Radiat Oncol Biol Phys 30(2): 323-329.

PURPOSE: To evaluate the use of pretreatment prostate specific antigen, Gleason score, and clinical stage as predictors of the risk of seminal vesicle involvement in patients with clinically localized prostatic cancer, and to determine the impact of excluding the seminal vesicles on the dose received by surrounding normal tissues. METHODS AND MATERIALS: An empirically derived equation combining the preoperative prostate specific antigen and Gleason score was applied to 188 patients treated with radical prostatectomy, for whom pathologic evaluation of the seminal vesicles was available. High and low risk groups for seminal vesicle involvement were defined using this equation. The observed risks of seminal vesicle involvement was compared to the predicted risk using the preoperative prostate specific antigen, Gleason score or clinical stage alone or using the empirical equation. Dose-volume histograms for five patients treated using six-field conformal radiotherapy were compared including and excluding the seminal vesicles. RESULTS: Using the empirically derived equation, a low risk group of 109 patients was identified with a calculated risk of seminal vesicle involvement of < or = 13% and an observed incidence of 7.3%. Among the high risk group of 79 patients, which included all patients with a calculated risk > 13%, 37% had seminal vesicle involvement (p < 0.001 low vs. high risk). Twenty percent of the rectal volume received on average above 86% of the total dose for the five plans which included the seminal vesicles compared to 68% for the five plans excluding the seminal vesicles. The doses to 40% of the rectal volume were 64% and 37% if the seminal vesicles were included and excluded, respectively. The dose to the bladder and femoral heads was also decreased but to a lesser extent. CONCLUSION: The empirical formula predicts risk of seminal vesicle involvement with a higher degree of significance for a larger number of patients than either Gleason score, clinical stage, or prostate specific antigen alone. Based on an analysis of our first 100 patients treated with definitive conformal therapy alone, approximately 47% of those patients could have been treated excluding the seminal vesicles. Excluding the seminal vesicles may allow us to go to a higher total dose with less rectal toxicity.

Diehl, K. M., E. T. Keller, et al. (2007). "Why should we still care about oncogenes?" Mol Cancer Ther 6(2): 418-427.

Although oncogenes and their transformation mechanisms have been known for 30 years, we are just now using our understanding of protein function to abrogate the activity of these genes to block cancer growth. The advent of specific small-molecule inhibitors has been a tremendous step in the fight against cancer and their main targets are the cellular counterparts of viral oncogenes. The best-known example of a molecular therapeutic is Gleevec (imatinib). In the early 1990s, IFN-alpha treatment produced a sustained cytologic response in approximately 33% of chronic myelogenous leukemia patients. Today, with Gleevec targeting the kinase activity of the proto-oncogene abl, the hematologic response rate in chronic myelogenous leukemia patients is 95% with 89% progression-free survival at 18 months. There are still drawbacks to the new therapies, such as drug resistance after a period of treatment, but the drawbacks are being studied experimentally. New drugs and combination therapies are being designed that will bypass the resistance mechanisms.

Dinney, C. P., R. C. Babkowski, et al. (1998). "Relationship among cystectomy, microvessel density and prognosis in stage T1 transitional cell carcinoma of the bladder." J Urol 160(4): 1285-1290.

PURPOSE: The selection of therapy for stage T1 bladder cancer is controversial, and reliable biomarkers that identify patients likely to require cystectomy for local disease control have not been established. We evaluated our experience with T1 bladder cancer to determine whether early cystectomy improves prognosis, and whether microvessel density has prognostic value for T1 lesions and could be used for patient selection. MATERIALS AND METHODS: We retrospectively reviewed the records of 88 patients with T1 transitional cell carcinoma of the bladder. Patient outcome was correlated with therapeutic intervention. Paraffin embedded tissue from 54 patients was available for factor VIII immunohistochemical staining for microvessel density quantification. RESULTS: Median followup was 48 months (range 12 to 239). Of the patients 34% had no tumor recurrence. The rates of recurrence only and progression to higher stage disease were 41 and 25%, respectively. The survival of patients in whom disease progressed was diminished (p = 0.0002). Grade did not predict recurrence or progression nor did cystectomy provide a survival advantage. Microvessel density did not correlate with recurrence or progression. CONCLUSIONS: Patients with T1 bladder cancer have a high risk of recurrence and progression. Tumor progression has a significant negative impact on survival. Neither grade nor early tumor recurrence predicted disease progression. Because early cystectomy did not improve patient outcome, we suggest reserving cystectomy for patients with progression or disease refractory to local therapy. Microvessel density is not a prognostic marker for T1 bladder cancer and has no value in selecting patients with T1 disease for cystectomy.

Ditah, F., R. B. Shah, et al. (2008). "Renal cell carcinoma with synchronous gallbladder metastasis treated with laparoscopic radical nephrectomy and cholecystectomy in the same setting." UroToday International Journal 1(5).

Doehring, C. B., M. G. Sanda, et al. (1996). "Histopathologic characterization of hereditary benign prostatic hyperplasia." Urology 48(4): 650-653.

OBJECTIVES: Recent studies suggest the presence of a hereditary form of benign prostatic hyperplasia (H-BPH). This study was undertaken to characterize the histopathologic features of BPH in these men. METHODS: Because study subjects with H-BPH were young (mean age 59 years) and had a large prostate (mean prostate weight 61 g), we compared the histopathologic findings in these men with those in two different control groups: (1) age-matched control subjects (mean age 59 years; mean prostate weight 31 g), and (2) prostate weight-matched control subjects (mean age 70 years; mean prostate weight 61 g). Using a color video image analysis system, we morphometrically determined stromal/epithelial ratios in histologic sections taken from 12 men with H-BPH, 36 age-matched control subjects, and 36 prostate weight-matched control subjects. RESULTS: The stromal/epithelial ratio was 2.6 +/- 1.4 in the men with H-BPH, 2.7 +/- 1.7 in the age-matched control subjects, and 1.7 +/- 0.9 in the prostate weight-matched control subjects. Regression analysis, which controlled for the differences in prostate weight or patient age between men with H-BPH and age-matched and prostate weight-matched control subjects, respectively, revealed a significant difference between men with H-BPH and prostate weight-matched control subjects (P = 0.015) but no difference from age-matched control subjects (P = 0.36). CONCLUSIONS: The larger prostates in young men with H-BPH are characterized by a higher stromal/epithelial ratio than are similar-sized prostates in older men with sporadic BPH. This finding gives rise to speculation that H-BPH is associated with an increase in stromal elements. <88>

Donald, C. D., C. Q. Sun, et al. (2003). "Cancer-specific loss of beta-defensin 1 in renal and prostatic carcinomas." Lab Invest 83(4): 501-505.

In a previous large-scale gene expression profiling study of renal epithelial neoplasms, human beta-defensin-1 (DEFB1) was found to be significantly down-regulated in conventional clear cell (renal) carcinoma. We have now completed an expanded expression analysis of this gene. We performed immunohistochemical analysis for the DEFB1 protein in clinical specimens of both renal cell carcinoma and prostate cancer. In a subset of prostate cancers, we performed laser capture microdissection and RT-PCR to correlate mRNA levels with protein levels. Overall, 82% of prostate cancers exhibit either complete loss of protein expression or only minimal expression, whereas the adjacent benign epithelium retained expression in all cases. Similarly, 90% of renal cell carcinomas show cancer-specific loss of DEFB1 protein. In the prostate cancer subset analysis, mRNA levels correlate with protein levels. We have thus demonstrated the cancer-specific down-regulation of DEFB1 in a large sample of prostatic and renal carcinomas and validated one of the key findings of previous cancer gene profiling studies of prostatic and renal neoplasia.

Douglas, J. A., A. M. Levin, et al. (2007). "Common variation in the BRCA1 gene and prostate cancer risk." Cancer Epidemiol Biomarkers Prev 16(7): 1510-1516.

Rare inactivating mutations in the BRCA1 gene seem to play a limited role in prostate cancer. To our knowledge, however, no study has comprehensively assessed the role of other BRCA1 sequence variations (e.g., missense mutations) in prostate cancer. In a study of 817 men with and without prostate cancer from 323 familial and early-onset prostate cancer families, we used family-based association tests and conditional logistic regression to investigate the association between prostate cancer and single nucleotide polymorphisms (SNPs) tagging common haplotype variation in a 200-kb region surrounding (and including) the BRCA1 gene. We also used the Genotype-Identity-by-Descent Sharing Test to determine whether our most strongly associated SNP could account for prostate cancer linkage to chromosome 17q21 in a sample of 154 families from our previous genome-wide linkage study. The strongest evidence for prostate cancer association was for a glutamine-to-arginine substitution at codon 356 (Gln(356)Arg) in exon 11 of the BRCA1 gene. The minor (Arg) allele was preferentially transmitted to affected men (P = 0.005 for a dominant model), with an estimated odds ratio of 2.25 (95% confidence interval, 1.21-4.20). Notably, BRCA1 Gln(356)Arg is not in strong linkage disequilibrium with other BRCA1 coding SNPs or any known HapMap SNP on chromosome 17. In addition, Genotype-Identity-by-Descent Sharing Test results suggest that Gln(356)Arg accounts (in part) for our prior evidence of prostate cancer linkage to chromosome 17q21 (P = 0.022). Thus, we have identified a common, nonsynonymous substitution in the BRCA1 gene that is associated with and linked to prostate cancer.

Douglas, J. A., K. A. Zuhlke, et al. (2005). "Identifying susceptibility genes for prostate cancer--a family-based association study of polymorphisms in CYP17, CYP19, CYP11A1, and LH-beta." Cancer Epidemiol Biomarkers Prev 14(8): 2035-2039.

Polymorphisms in genes that code for enzymes or hormones involved in the synthesis and metabolism of androgens are compelling biological candidates for prostate cancer. Four such genes, CYP17, CYP19, CYP11A1, and LH-beta, are involved in the synthesis and conversion of testosterone to dihydrotestosterone and estradiol. In a study of 715 men with and without prostate cancer from 266 familial and early-onset prostate cancer families, we examined the association between prostate cancer susceptibility and common single-nucleotide polymorphisms in each of these four candidate genes. Family-based association tests revealed a significant association between prostate cancer and a common single-nucleotide polymorphism in CYP17 (P=0.004), with preferential transmission of the minor allele to unaffected men. Conditional logistic regression analysis of 461 discordant sibling pairs from these same families reaffirmed the association between the presence of the minor allele in CYP17 and prostate cancer risk (odds ratio, 0.51; 95% confidence interval, 0.28-0.92). These findings suggest that variation in or around CYP17 predicts susceptibility to prostate cancer. Family-based association tests may be especially valuable in studies of genetic variation and prostate cancer risk because this approach minimizes confounding due to population substructure, which is of particular concern for prostate cancer given the tremendous variation in the worldwide incidence of this disease.

Duffey, D. C., Z. Chen, et al. (1999). "Expression of a dominant-negative mutant inhibitor-kappaBalpha of nuclear factor-kappaB in human head and neck squamous cell carcinoma inhibits survival, proinflammatory cytokine expression, and tumor growth in vivo." Cancer Research 59(14): 3468-3474.

We demonstrated recently that constitutive expression of proinflammatory cytokines interleukin (IL)-1alpha, IL-6, IL-8, and granulocyte-macrophage colony-stimulating factor in head and neck squamous cell carcinoma is correlated with activation of transcription factor nuclear factor (NF)-kappaB/Rel A (p50/p65), which binds the promoter region within each of the genes encoding this repertoire of cytokines. NF-kappaB can be activated after signal-dependent phosphorylation and degradation of inhibitor-kappaBalpha and has been reported to promote cell survival and growth. In the present study, we expressed a phosphorylation site mutant of inhibitor-kappaBalpha (IkappaBalphaM) in head and neck squamous cell carcinoma lines UM-SCC-9, -11B, and -38 to determine the effect of inhibition of NF-kappaB on cytokine expression, cell survival in vitro, and growth in vivo. After transfection with IKBalphaM, only a few UM-SCC-9 clones were obtained that stably expressed the mutant IkappaB, suggesting that expression of a mutant IkappaBalpha may affect survival of the transfected UM-SCC cell lines. After cotransfection of IkappaBalphaM with a Lac-Z reporter, we found that the number of surviving beta-galactosidase-positive cells in the three cell lines was reduced by 70-90% when compared with controls transfected with vector lacking the insert. In UM-SCC-9 cells that stably expressed IkappaBalphaM, inhibition of constitutive and tumor necrosis factor-a induced NF-kappaB activation, and production of all four cytokines was observed. Although UM-SCC-9 IkappaBalphaM-transfected cells proliferated at the same rate as vector-transfected cells in vitro, a significant reduction in growth of tumor xenografts was observed in SCID mice in vivo. The decreased growth of UM-SCC-9 IkappaBalphaM-transfected tumor cells accompanied decreased immunohistochemical detection of the activated form of NF-kappaB in situ. These results provide evidence that NF-KB and IkappaBalpha play an important role in survival, constitutive and inducible expression of proinflammatory cytokines, and growth of squamous cell carcinoma. NF-kappaB could serve as a potential target for therapeutic intervention against cytokine and other immediate-early gene responses that contribute to the survival, growth, and pathogenesis of these cancers. <13>

Dunn, M. D., A. J. Portis, et al. (2000). "Clinical effectiveness of new stent design: randomized single-blind comparison of tail and double-pigtail stents." J Endourol 14(2): 195-202.

BACKGROUND AND PURPOSE: Stent morbidity appears to be secondary to lower urinary tract irritation. In an effort to decrease stent morbidity, a "one size fits all" Tail stent (Microvasive [Boston Scientific] Natick, MA) was developed with a 7F proximal pigtail and 7F shaft which tapers to a lumenless straight 3F tail. PATIENTS AND METHODS: We randomized 60 patients in a single-blind fashion to a 7F tail stent or 7F double-pigtail Percuflex stent. Patients were evaluated at the time of stent removal and 2 weeks later with a standardized questionnaire assessing: irritative lower tract symptoms individually and on a total scale of 0 (no symptoms) to 30 (worst symptoms), obstructive lower tract symptoms (on a total scale of 0-20), and upper tract irritative symptoms (on a total scale of 0-10). RESULTS: Patient age, weight, and height were similar in the two groups. Complications, including fever, urinary tract infections, emergency room visits, and the need for antispasmodics and pain medication, also demonstrated no significant difference. At the time of stent removal, patients who received a tail stent had significantly less urinary frequency and a statistically significant (21%) decrease in overall irritative voiding symptoms (12.2 v 15.4; p = 0.048). Two weeks after stent removal, the total irritative voiding symptoms was markedly decreased in both groups (7.1 in the Tail v 5.3 in the double-pigtail group; p = 0.15). Obstructive bladder and flank symptoms were not significantly different in the two stent groups, either at the time of stent removal or at 2 weeks after removal. CONCLUSION: In this randomized, single-blind study, the 7F Tail stent produced significantly less irritative symptoms than did the standard 7F double-pigtail stent. Obstructive symptoms tended to be less with the new stent, while flank symptoms were similar.

Eisner, B., T. Schuster, et al. (2004). "A randomized clinical trial of the effect of intraoperative saline perfusion on postvasectomy azoospermia." Ann Fam Med 2(3): 221-223.

BACKGROUND: We wanted to determine whether a saline flush during vasectomy would reduce the time needed to reach azoospermia. METHODS: During vasectomy men were randomly assigned to flush the prostatic end of the vas deferens with 10 mL of normal saline (intervention group, n = 50), while the remaining men (n = 56) served as controls. Sperm counts were performed on the immediate postprocedure urine specimen and on semen samples at 1, 6, and 12 weeks after vasectomy. RESULTS: The postprocedure urine specimens from the intervention and control groups contained 29.2 x 106 and 0.004 x 106 sperm, respectively (P < .001). Total sperm counts in the ejaculate for intervention and control groups at 1, 6, and 12 weeks were (in millions of sperm): 14.1 and 13.8, 0.4 and 8.0, and 0.0 and 0.011, respectively (P > .05 at all time points). There was no difference in the rate at which the men in the 2 groups achieved azoospermia. CONCLUSIONS: Vasal perfusion with saline during vasectomy was effective in removing sperm from the distal vas; however, perfusion did not increase the rate at which men achieve azoospermia.

Eisner, B. H. and D. A. Bloom (2002). "Wolff and Muller: fundamental eponyms of embryology, nephrology and urology." J Urol 168(2): 425-428.

PURPOSE: Kaspar Friedrich Wolff and Johannes Petrus Muller, German physicians in the 18th and 19th centuries, respectively, contributed significantly to the study of the biological sciences, specifically embryology and the development of the genitourinary tract. Their eponyms are a part of daily conversation in medical education, practice and research. We reviewed their lives and works. MATERIALS AND METHODS: Commentaries on the works of these scientists as well as available English translations of their works were analyzed. RESULTS: Wolff and Muller were pioneers in their fields. Wolff gained renown for his Theoria Generatonis, a great embryological treatise, produced in 1759. Muller performed significant studies in the fields of anatomy, pathology, physiology and embryology. In 1834 he became editor of the physiology journal that later came to be known as Muller's Archiv. CONCLUSIONS: Studies of and inferences about the development of the urogenital system a century apart by these 2 men contributed greatly to the current understanding of embryology. Their names remain a part of everyday medical dialogue.

Elashry, O. M., S. Y. Nakada, et al. (1996). "Comparative clinical study of port-closure techniques following laparoscopic surgery." J Am Coll Surg 183(4): 335-344.

BACKGROUND: Recently, a number of laparoscopic port-closure techniques have been reported to avoid the complications associated with the port closure after laparoscopic surgery. To evaluate these port-closure techniques, we compared seven new laparoscopic port-closure techniques with the standard technique of a hand-sutured closure. STUDY DESIGN: In a prospective, randomized study, 95, 12-mm port sites in 32 patients undergoing transperitoneal laparoscopic procedures were randomized to one of eight different port-site closure techniques. The port-closure techniques included: the Carter-Thomason Needle-Point Suture Passer, Maciol suture needle set, eXit Disposable Puncture Closure device, Endoclose suture carrier, Tahoe Surgical Instruments Ligature device, a long 14-gauge angiocatheter with looped polypropylene suture, Lowsley retractor with hand-sutured closure, and the standard technique of hand-sutured closure. We evaluated the time, the security, and the auxiliary instrumentation required for each closure. RESULTS: Of the port-closure techniques, the Carter-Thomason device was faster overall, resulted in fewer port-closure-related complications and provided a leak proof closure. CONCLUSIONS: The Carter-Thomason device is our preferred method for the closure of port sites after laparoscopic surgery.

Elashry, O. M., S. Y. Nakada, et al. (1996). "Ureterolysis for extrinsic ureteral obstruction: a comparison of laparoscopic and open surgical techniques." J Urol 156(4): 1403-1410.

PURPOSE: We evaluated the role of laparoscopy in the management of extrinsic ureteral obstruction due to benign retroperitoneal fibrosis or ovarian pathology. The results of laparoscopic ureterolysis were compared to those of a contemporary series of open ureterolysis performed for the same pathological conditions. MATERIALS AND METHODS: We compared 6 patients undergoing unilateral laparoscopic ureterolysis for extrinsic ureteral obstruction to 7 undergoing open unilateral ureterolysis for similar pathological conditions. Patient demographic, operative, and early and late postoperative data were collected. RESULTS: Laparoscopic ureterolysis was associated with less intraoperative blood loss and need for parenteral pain medications, and significantly shorter hospital stay and convalescence than open surgery. Although there were no intraoperative or postoperative complications in the laparoscopy group, 1 patient in the open surgery group had an intraoperative ureteral avulsion and 4 had minor postoperative complications (blood transfusion, ileus and/or wound cellulitis). Operative time was longer in the laparoscopy group (255 versus 232 minutes). Subjective followup with an analog pain scale and/or telephone interview showed improvement in all patients in the laparoscopy group and all 6 contacted in the open surgery group. Likewise, excretory urography and/or renal scan showed improved renal function and relief of obstruction in all patients. CONCLUSIONS: Laparoscopic unilateral ureterolysis for extrinsic ureteral obstruction is a less morbid, yet equally effective procedure with several clinical advantages over conventional open surgical ureterolysis.

Elashry, O. M., S. Y. Nakada, et al. (1996). "Laparoscopy for adult polycystic kidney disease: a promising alternative." Am J Kidney Dis 27(2): 224-233.

The purpose of this study was to evaluate the efficacy of laparoscopy in managing patients with abdominal symptoms from autosomal dominant polycystic kidney disease (ADPKD). From April 1993 to July 1995, four patients with ADPKD underwent seven laparoscopic procedures: five cyst decortications were performed in two patients using a laparoscopic ultrasound unit and two laparoscopic nephrectomies were performed in two patients with end-stage renal failure. The mean operative time was 207 minutes for laparoscopic cyst decortication and 272 minutes for laparoscopic nephrectomy. The two nephrectomy specimens were 2,200 g and 1,750 g, respectively. The mean intraoperative blood loss was 85 mL. The patients resumed their oral intake within 10 hours after laparoscopic cyst decortication and within 16 hours after laparoscopic nephrectomy. The mean amount of parenteral analgesics required postoperatively was 12 mg morphine sulfate for cyst decortication and 30 mg morphine sulfate for nephrectomy. The mean hospital stay was 3 days for cyst decortication and 3.5 days for nephrectomy. The patients returned to their usual activities after an average of 2 weeks. Based on pain analog scales, all the patients have shown marked reduction in their symptoms (average, 90%) during an average follow-up period of 6.6 months. Laparoscopic cyst decortication and nephrectomy are effective minimally invasive treatment options for patients with adult polycystic kidney disease who are experiencing abdominal symptoms due to marked renal enlargement. We believe that by using a laparoscopic ultrasound unit, most renal cysts may be safely removed, and if need be, even "giant" kidneys can be removed laparoscopically. To the best of our knowledge, the two nephrectomy specimens in this study represent the largest kidneys removed laparoscopically to date and the first laparoscopic nephrectomies in ADPKD patients.

Elashry, O. M., J. S. Wolf, et al. (1997). "Laparoscopic radial partial nephrectomy of a renal tumor: Initial case report." Min Invas Ther & Allied Technol 6: 252-257.

Elashry, O. M., J. S. Wolf, Jr., et al. (1997). "Recent advances in laparoscopic partial nephrectomy: comparative study of electrosurgical snare electrode and ultrasound dissection." J Endourol 11(1): 15-22.

Although technically feasible, laparoscopic partial nephrectomy (LPN) using conventional instrumentation presents the intraoperative challenge of hemostasis, creating a flush (i.e., precise guillotine) incision, and closure of the collecting system. In an effort to resolve these technical problems, we used a unique electrosurgical snare electrode (ESE) in combination with an ERBE electrosurgical generator and compared its effectiveness with that of two ultrasonic dissectors (Cavitron Ultrasonic Surgical Aspirator [CUSA] and harmonic scalpel [HS]) in performing LPN. Twelve female minipigs underwent right lower-pole LPN using one of the aforementioned modalities. Six weeks later, in the same animals, a left lower-pole LPN was performed using the same device, thereby providing an acute and chronic renal remnant to examine. The animals were harvested, and transverse and perpendicular histologic sections were prepared of the cut surface of each specimen. The weights of the LPN specimens and the remaining kidney were also recorded. The time required for partial nephrectomy, degree of hemostasis (i.e., blood loss), ease of excising the targeted tissue, changes in renal function, tissue reactivity, and depth of damage to the surface of the remaining renal parenchyma were measured for each device. All 12 procedures were successful using the ultrasonic dissection, and 11 procedures were successful using the ESE. The ESE was significantly faster than the two forms of ultrasonic dissection (p < 0.0001) and produced less intraoperative bleeding (P = 0.002). Both forms of ultrasonic energy produced significantly deeper parenchymal injury in the acute surgical specimen (P = 0.03) and more parenchymal fibrosis and chronic inflammation in the chronic surgical specimens (P = 0.007) than the ESE. None of the animals exhibited any extravasation from the incised collecting system when studied by retrograde pyelography 6 weeks postoperatively at the time of left LPN and harvest. The function of the renal remnant was consistent with the size of the partial nephrectomy specimen. No hypertension developed in any of the study animals. Our results using a unique electrosurgical snare probe show it to have potential advantages as a rapid, hemostatic method for performing a partial nephrectomy. We believe that this instrument may represent an important tool for performing nephron-sparing surgery via an open or laparoscopic approach. Clinical trials are in progress.

Elhilali, M. M., M. L. Stoller, et al. (1996). "Effectiveness and safety of the Dornier compact lithotriptor: an evaluative multicenter study." J Urol 155(3): 834-838.

PURPOSE: We evaluated the efficacy and safety of the Dornier compact lithotriptor for management of renal stones. MATERIALS AND METHODS: We administered 191 treatments to 169 patients with renal stones on 176 occasions with the patient under combined parental sedation and analgesia. The Dornier Compact lithotriptor is mobile and ultrasound guided, and uses an electromagnetic energy source. RESULTS: A total of 22 patients required a second treatment (13%), 123 (72.8%) were stone-free, 26 (15.4%) had fragments less than 4 mm. large, 16 (9.5%) had stone fragments larger than 4 mm, and 4 (2.4%) required auxiliary therapy (treatment failures). The side effects were mostly mild to moderate, with nausea and/or vomiting reported in 26 patients (14%), colic or pain in 66 (39%), ureteral obstruction in 2, steinstrasse in 7 (4%) and fever in 1. Our clinical results indicate that extracorporeal shock wave lithotripsy was effective for treatment of stones in the kidney, with a low incidence of complications and adverse effects. The lithotriptor used is much smaller, less expensive and user friendly with no installation requirements, rendering it mobile. CONCLUSIONS: The success rate with newer generation devices compares well with results obtained using other stationary and larger versions.

Elias, L., D. Lew, et al. (2000). "Infusional interleukin-2 and 5-fluorouracil with subcutaneous interferon-alpha for the treatment of patients with advanced renal cell carcinoma: a southwest oncology group Phase II study." Cancer 89(3): 597-603.

BACKGROUND: A Phase II trial was conducted to determine the response rate of patients with advanced renal cell carcinoma to a three-drug combination of 5-fluorouracil (5-FU), interleukin-2 (IL-2), and interferon-alpha-2b (IFN-alpha). METHODS: A 2-stage accrual plan was used that was designed to determine whether response to this regimen was consistent with a true response rate of >/= 30%. The regimen was comprised of 5 treatment days weekly for 4 weeks every 6 weeks. Each weekly treatment was comprised of 5-FU, 1750 mg/m(2), continuous intravenous (i.v.) infusion over 24 hours followed by IL-2, 6 MIU/m(2)/day, continuous i.v. infusion for 4 days. IFN-alpha, 6 MU/m(2), was given subcutaneously on Days 1, 2, and 5. RESULTS: Thirty-eight patients were entered on study, 3 of whom were ineligible. Among the 35 eligible patients there were 3 confirmed partial responses (PR) and 1 complete response (CR), for an overall response rate of 11% (95% confidence interval, 3-27%). One patient considered as having a PR had minimal evidence of residual disease and was free from disease progression at > 2.5 years of follow-up, as was the patient with CR. Three additional patients not qualified as having a PR were showing signs of response at the time they were removed from protocol, and another patient who was removed from protocol early for management of an infection subsequently responded to the same regimen off protocol. Thirteen patients were considered nonassessable (NASS) for response, many of whom had multiple poor risk features and were unable to complete 1 cycle of treatment. CONCLUSIONS: This multicenter study failed to confirm an advantageous overall response rate for this three-drug regimen. However, there were two durable responses and indications of responsiveness not scored as PRs among patients with more favorable risk factor patterns, and many poor risk NASS patients. For these reasons, the response rate reported in the current study may be a conservative reflection of the effectiveness of this regimen.

Elkins, T. E., J. O. DeLancey, et al. (1990). "The use of modified Martius graft as an adjunctive technique in vesicovaginal and rectovaginal fistula repair." Obstet Gynecol 75(4): 727-733.

The use of the Martius graft, a labial fibro-fatty tissue graft, is described as an adjunctive technique in the repair of 37 complex fistulas in 35 patients. The graft was used to repair three groups of patients with non-radiation-induced vesicovaginal fistulas: 12 patients with large (greater than 4 cm) obstetric fistulas, six patients with obstetric fistulas that caused urethral sloughing, and six patients with recurrent obstetric or post-hysterectomy fistulas. Five other patients had radiation-induced fistulas, and six others had rectovaginal fistulas. The overall success rate was 86.5%. Anatomical studies undertaken of the graft in a cadaver demonstrated that it is composed of fibroadipose tissue from the labium majus, and not from the bulbocavernosus muscle. It receives its blood supply anteriorly from the external pudendal artery and posteriorly from the internal pudendal artery. These vessels form a plexus within the graft. The prominence of fibrous tissue in this fibroadipose tissue arises from a superficial tunic of fibrous tissue similar to the tunica dartos in the male, as well as from the considerable fibrous septa within the adipose tissue itself. Although the labial graft used today differs from that originally described by Heinrich Martius, it remains a safe, simple, and helpful technique in difficult fistula repairs.

Elkins, T. E., R. J. Stocker, et al. (1994). "Surgery for ovarian remnant syndrome. Lessons learned from difficult cases." J Reprod Med 39(6): 446-448.

Ten cases of ovarian remnant syndrome jointly managed by gynecology and urology departments are presented. Complications of the surgery included a high incidence of ureteral and bowel injury. Preoperative, intraoperative and postoperative considerations may reduce the complications or minimize their significance. One case of ovarian cancer developed among the instances of ovarian remnant syndrome in this series. Preoperative, intraoperative and postoperative considerations can reduce the complications of surgery for ovarian remnant syndrome.

Ellis, J. H., R. P. Campo, et al. (1995). "Positional variation in the Whitaker test." Radiology 197(1): 253-255.

PURPOSE: To describe positional variation in the outcome of the Whitaker test. MATERIALS AND METHODS: The authors retrospectively reviewed the cases of six patients in whom the pressure gradient during Whitaker testing varied by at least 10 cm of water and changed from normal ( < or = 13 cm of water) to abnormal ( > 13 cm of water) when patients were placed in different positions. RESULTS: Four patients had obstruction only in nonstandard positions. All had intermittent symptoms, and three had ureteral kinks at fluoroscopy. Two patients with ileal conduits had abnormal results in the standard position but normal results at repositioning related to compression of the conduits (seen as conduit distention at fluoroscopy). All six had undergone urinary tract surgery. Gradient differences with positional change ranged from 10 to > 38 cm of water. CONCLUSIONS: Whitaker testing in different positions may help identify intermittent obstructions that might otherwise go undetected or prevent inappropriate diagnosis of obstruction. Intermittent or unexplained symptoms, tortuous ureters, malpositioned kidneys, or previous surgery are indications for provocative positional testing.

Eng, M. H., L. G. Charles, et al. (1999). "Early castration reduces prostatic carcinogenesis in transgenic mice." Urology 54(6): 1112-1119.

OBJECTIVES: To test the hypothesis that transgenic mouse models of prostate cancer could be useful for testing chemoprevention strategies by evaluating the effects of early castration on prostate carcinogenesis in TRAMP mice. Human prostate cancer, unlike other cancers, requires androgens for oncogenesis yet acquires partial androgen independence in the castrated milieu. This paradigm is the basis for an ongoing clinical trial using selective androgen deprivation for prostate cancer chemoprevention. However, preclinical correlates for hormonal prevention or other chemoprevention strategies of prostate cancer have not previously been demonstrated in autochthonous models of prostate carcinogenesis. METHODS: Magnetic resonance imaging was used to longitudinally measure prostate growth in castrated and noncastrated TRAMP mice, and mice were prospectively examined for the onset of advanced, palpable prostate cancer. Modulation of androgen-responsive oncogene expression, as well as oncogene expression in refractory cancers, was evaluated by Western blot. RESULTS: Early castration significantly reduced prostate tumor growth as measured by magnetic resonance imaging and improved cancer-free survival. Prevention of prostate cancer development in these mice was associated with durable suppression of androgen-responsive oncogene expression (T-antigen expression not detectable by Western blot); prostate cancers refractory to the hormonal prevention strategy demonstrated androgen-independent oncogene expression. CONCLUSIONS: These findings suggest that carcinogenesis related to androgen-responsive oncogene expression can be prevented in some cases by hormonal manipulation and that transgenic TRAMP mice are useful for the preclinical evaluation of hormonal and possibly other strategies of prostate cancer chemoprevention. <62>

English, S. F., M. Liebert, et al. (1998). "The incidence of Helicobacter pylori in patients with interstitial cystitis." J Urol 159(3): 772-773.

PURPOSE: The cause of interstitial cystitis is unknown. We evaluated the incidence of Helicobacter pylori antibodies in patients with interstitial cystitis to determine whether such infection may be a causative factor. MATERIALS AND METHODS: We obtained serum samples from 23 patients with interstitial cystitis and 23 control subjects. Samples were analyzed for the presence of H. pylori IgG antibodies. RESULTS: The incidence of positive tests for H. pylori antibodies was 22% in the interstitial cystitis group and 35% in controls. CONCLUSIONS: The incidence of infection with H. pylori is not increased in interstitial cystitis, and so it is unlikely to be a causative factor.

English, S. F., L. L. Pisters, et al. (1998). "The use of the appendix as a continent catheterizable stoma." J Urol 159(3): 747-749.

PURPOSE: We review the results of 5 years of using the unmodified appendix for reconstruction of neobladders and native bladders, and describe the mechanism of continence. MATERIALS AND METHODS: Between 1993 and 1997, 24 patients have undergone continent urinary diversion using the unaltered appendix. Median patient age at the time of surgery was 62 years. Patients were followed at the urological outpatient clinic for a mean of 18 months (range 7 to 47). Video urodynamic studies were performed once in the first 6 months postoperatively and repeated if there was any history of incontinence or bladder problems. RESULTS: Of the patients with an appendicovesicostomy onto the native bladder 80% were dry during the day and night. This figure was improved to 94% when 2 patients with incontinence catheterized more frequently. Patients with a neobladder were more likely to be continent and had a longer interval between catheterizations, which reflects the larger reservoir volume rather than better continence mechanism in these patients. The level of continence is at the appendiceal bladder junction in the native bladder and the appendicocecal junction in the neobladder, which is able to withstand reservoir pressures of 30 to 40 cm. water. Stress incontinence driven by abdominal pressure did not occur. Instead incontinence occurred when the bladder became over full and the pressure increased, or during an unstable contraction. CONCLUSIONS: The appendix does not need to be tunneled through the bladder wall to achieve satisfactory continence. In a low pressure reservoir continence may be achieved simply by anastomosing the appendix directly onto the bladder or leaving it in situ when creating a neobladder.

Erickson, B. A., R. P. Dorin, et al. (2007). "Is nasogastric tube drainage required after reconstructive surgery for neurogenic bladder dysfunction?" Urology 69(5): 885-888.

OBJECTIVES: To determine whether the routine use of nasogastric tubes (NGTs) after bowel surgery for neurogenic bladder dysfunction improves outcomes. METHODS: We retrospectively evaluated 54 consecutive patients (30 women, 24 men) with neurogenic bladder who underwent bladder reconstruction or replacement with bowel segments by one surgeon from December 2000 to August 2005. The first 32 [NGT(+)] had NGTs placed during the procedure, whereas the subsequent 22 [NGT(-)] did not. We compared short-term postoperative outcomes between groups. RESULTS: Patient age ranged from 17 to 74 years (mean, 42.6 years). Procedures included augmentation cystoplasty with or without creation of catheterizable stoma (31), ileovesicostomy (13), and ileal conduit (9). Mean age or mean operative time did not differ between the NGT(+) and NGT(-) groups. The NGT(-) patients experienced less time to oral intake (3.1 versus 4.4 days, P <0.01), fewer days to flatus (2.9 versus 4.0 days, P = 0.01), and fewer days to first bowel movement (4.4 versus 5.9 days, P = 0.01). We found no statistical differences in the incidence of postoperative complications. Overall hospital days were less in the NGT(-) patients, but this did not reach statistical significance (9.9 versus 11.0, P = 0.2). CONCLUSIONS: Routine use of NGTs in patients undergoing bladder reconstruction or replacement for neurogenic bladder dysfunction seems to confer no benefit. The omission of NGTs in this population is possible without increasing overall morbidity. These findings parallel those previously reported in neurologically intact patients undergoing urinary diversion.

Ernst, C. B., J. J. Bookstein, et al. (1972). "Renal vein renin ratios and collateral vessels in renovascular hypertension." Arch Surg 104(4): 496-502.

Ershler, W. B., A. S. Artz, et al. (2006). "Issues of aging and geriatric medicine: relevance to cancer treatment and hematopoietic reconstitution." Biol Blood Marrow Transplant 12(1 Suppl 1): 100-106.

Aging is not a disease. Nevertheless, diseases, including most malignancies, increase in frequency with advancing age. Although there are many reasons why this might be the case, perhaps most important is that it takes time to progress through the many steps of carcinogenesis and growth to reach a threshold for diagnosis. Other factors, including accumulated nonlethal damage to DNA (eg, by free radicals), increased proinflammatory factors, and age-associated declines in DNA repair and immune competence, are to some degree important. The median age for all cancer is approximately 70 years and will become even older over the next several decades. Myelodysplasia and hematologic malignancies, including lymphoma, myeloma, and leukemia, can be effectively treated in older age groups, but advanced age presents a number of additional challenges. With appropriate pretreatment assessment of organ reserve, physical performance, and cognitive function, individualized (tailored) therapy may ultimately prove to offer the greatest chance for successful outcomes. Such assessment would also identify those who are likely to benefit from more aggressive treatments, including bone marrow or stem cell transplantation.

Ershler, W. B., S. M. Harman, et al. (1997). "Immunologic aspects of osteoporosis." Dev Comp Immunol 21(6): 487-499.

Osteoporosis is a major cause of morbidity in older people. There are a large number of risk factors for the development of osteoporosis. However, these risk factors eventually must mediate their effects through modulation of bone remodeling. A variety of compounds including hormones and nutrients modulate bone remodeling. In addition to these well-characterized substances, the immune system plays a role in bone remodeling through pro-inflammatory cytokines. Specifically, interleukin-1 (IL-1), IL-11, interferon-g are known to influence osteoclasts and osteoblasts. Recently, the cytokine IL-6 has joined ranks with these cytokines as a bone reactive agent. IL-6 has been shown to increase with age and menopause. Additionally, murine models suggest that IL-6 plays a central role in bone resorption. Finally, in vitro studies demonstrate that IL-6 induces osteoclast activity. In this review, we will discuss the pathogenesis of osteoporosis in the context of aging and IL-6.

Ershler, W. B. and E. T. Keller (2000). "Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty." Annu Rev Med 51: 245-270.

Interleukin-6 (IL-6) is a proinflammatory cytokine that is normally tightly regulated and expressed at low levels, except during infection, trauma, or other stress. Among several factors that down-regulate IL-6 gene expression are estrogen and testosterone. After menopause or andropause, IL-6 levels are elevated, even in the absence of infection, trauma, or stress. IL-6 is a potent mediator of inflammatory processes, and it has been proposed that the age-associated increase in IL-6 accounts for certain of the phenotypic changes of advanced age, particularly those that resemble chronic inflammatory disease [decreased lean body mass, osteopenia, low-grade anemia, decreased serum albumin and cholesterol, and increased inflammatory proteins such as C-reactive protein (CRP) and serum amyloid A]. Furthermore, the age-associated rise in IL-6 has been linked to lymphoproliferative disorders, multiple myeloma, osteoporosis, and Alzheimer's disease. This overview discusses the data relating IL-6 to age-associated diseases and to frailty. Like the syndrome of inappropriate antidiuretic hormone, it is possible that certain clinically important late-life changes are due to an inappropriate presence of IL-6.

Eyre, S. J., D. P. Ankerst, et al. (2009). "Validation in a multiple urology practice cohort of the Prostate Cancer Prevention Trial calculator for predicting prostate cancer detection." J Urol 182(6): 2653-2658.

PURPOSE: The Prostate Cancer Prevention Trial prostate cancer risk calculator was developed in a clinical trial cohort that does not represent men routinely referred for prostate biopsy. We assessed the generalizability of the Prostate Cancer Prevention Trial calculator in a cohort more representative of patients referred for consideration of prostate biopsy in American urology practice. MATERIALS AND METHODS: Patients undergoing prostate biopsy by 12 urologists at 5 sites were enrolled in an Early Detection Research Network cohort. The Prostate Cancer Prevention Trial risk calculator was validated by examining area underneath the receiver operating characteristic curve, sensitivity, specificity and calibration comparing observed vs predicted risk of prostate cancer detection. RESULTS: Cancer incidence was greater (43% vs 22%, p = 0.001) in the Early Detection Research Network validation cohort (645) compared to the Prostate Cancer Prevention Trial group (5,519). Early Detection Research Network participants were younger and more racially diverse, and had more abnormal digital rectal examinations and higher prostate specific antigen than Prostate Cancer Prevention Trial participants (all p <0.001). Cancer severity was worse in the Early Detection Research Network cohort than in the Prostate Cancer Prevention Trial (Gleason 7 or higher 60% vs 21%, p <0.001). Nevertheless, the Prostate Cancer Prevention Trial risk calculator was superior to prostate specific antigen alone for predicting cancer in the Early Detection Research Network (AUC 0.691 vs 0.655, p = 0.009) and calibration confirmed that the Prostate Cancer Prevention Trial risk score accurately predicted individual risks in the Early Detection Research Network cohort. CONCLUSIONS: Differences between the Early Detection Research Network validation cohort and the Prostate Cancer Prevention Trial cohort underscore the importance of validating calculator performance in the multicenter urology practice setting. Our findings extend the applicability of the Prostate Cancer Prevention Trial calculator for measuring the risk of prostate cancer detection on biopsy to the routine American urology practice setting.

Faerber, G. J. (1996). "Endoscopic collagen injection therapy in elderly women with type I stress urinary incontinence." J Urol 155(2): 512-514.

PURPOSE: The safety and efficacy of collagen injection therapy for the treatment of type I stress urinary incontinence were determined. MATERIALS AND METHODS: A total of 12 women 68 to 85 years old (mean age 76) with type I stress urinary incontinence underwent collagen injection. Incontinence was subjectively categorized as grades 0 to 3, and Valsalva leak point pressures were measured before and after injection. RESULTS: At a mean of 10.3 months (range 3 to 24) 10 of the 12 women (83%) were cured, while the remaining 2 noticed subjective improvement in incontinence. Average number of injections per patient was 1.25 (1 injection in 9 and 2 in 3), average total collagen injected per patient was 2.2 cc (range 1.0 to 3.5) and average increase in Valsalva leak point pressure after collagen injection was 22 cm. water (range 0 to 40). CONCLUSIONS: Collagen injection appears to be an effective alternative method for the treatment of type I stress urinary incontinence in elderly women.

Faerber, G. J. (1998). "Urethral diverticulectomy and pubovaginal sling for simultaneous treatment of urethral diverticulum and intrinsic sphincter deficiency." Tech Urol 4(4): 192-197.

The purpose of this article is to determine the efficacy and safety of simultaneous urethral diverticulectomy and placement of a pubovaginal sling in patients with concomitant urethral diverticula and intrinsic sphincter deficiency (ISD). Sixteen women (mean age of 53 years) underwent simultaneous urethral diverticulectomy and pubovaginal sling. ISD was determined by fluorourodynamic evaluation and Valsalva leak point pressures. Treatment outcome was determined by resolution of the diverticula and change in individual incontinence grades before and after surgical repair. All 16 who underwent urethral diverticulectomy had symptomatic resolution at a mean follow-up of 25 months. Fourteen of 16 patients (88%) had no physical or radiologic evidence of residual or recurrent diverticula, while 2 of 16 (12%) had small, stable residual diverticula. All 16 patients reported significant improvement in incontinence status after placement of the pubovaginal sling, with 14 of 16 (88%) cured and 2 of 16 (12%) significantly improved. Five of 16 (31%) had mixed incontinence preoperatively: 2 of 5 had resolution of detrusor instability (DI) after surgery, 3 of 5 had persistent DI. De novo DI developed in two patients. No patient had erosion of the sling despite its close proximity to the urethral mucosal suture line. The average time to complete bladder emptying was approximately 5 weeks, and no patient developed permanent urinary retention. Simultaneous pubovaginal sling and urethral diverticulectomy can be performed safely without increased risk to the urethral reconstruction, yet with excellent continence rates.

Faerber, G. J. (1999). "Management of failed suspension procedure for the treatment of stress urinary incontinence." Mediguide to Urology 11: 1-7.

Faerber, G. J. (2001). "Pediatric urolithiasis." Curr Opin Urol 11(4): 385-389.

Urinary lithiasis in the pediatric population has evolved from a mere clinical curiosity to a disease process worthy of thoughtful and rigorous scientific study. All aspects of urinary lithiasis have undergone this evolution, including the epidemiology of stone formation in children, defining new modalities of radiologic imaging, and refining surgical techniques for stone treatment. These advancements and observations in pediatric stone disease are highlighted.

Faerber, G. J., M. M. Ahmed, et al. (1997). "Contemporary diagnosis and treatment of fibroepithelial ureteral polyp." J Endourol 11(5): 349-351.

Fibroepithelial polyps of the ureter are rare, benign tumors often not easily distinguished from malignant transitional-cell carcinomas by radiologic means. Historically, many patients have undergone unnecessary nephroureterectomy for these lesions. With recent advancement in endourologic instrumentation, a biopsy-proven diagnosis of suspect upper-tract lesions can be made prior to definitive therapy. We describe a typical case of fibroepithelial ureteral polyp wherein the diagnosis and surgical treatment was accomplished entirely by endoscopic means.

Faerber, G. J., W. D. Belville, et al. (1998). "Comparison of transurethral versus periurethral collagen injection in women with intrinsic sphincter deficiency." Tech Urol 4(3): 124-127.

Two different injection techniques for collagen injection have been described for the treatment of intrinsic sphincter deficiency (ISD) in women: periurethral and transurethral. The purpose of this review was-to compare these two different techniques to determine whether or not one method clearly is superior. Forty-five women, ages 43 to 88 years (mean 67 years), with ISD underwent collagen injection therapy using either the periurethral or transurethral route. A retrospective analysis was performed comparing initial and final incontinence grades, change in daily pad use, initial Valsalva leak point pressure (VLPP), total amount of collagen used, number of treatment sessions performed, anesthesia required, and complications related to injections. Twenty-four patients underwent transurethral injection, and 21 underwent periurethral injection. There was no significant difference in preoperative incontinence grade, initial VLPP, or age between the two groups. At a mean follow-up of 6.3 months, 11 (46%) of the transurethral group were cured, 12 (50%) improved, and 1 (4%) unchanged. The periurethral group with a mean follow-up of 8.8 months experienced a 33% cure rate and 67% improvement rate (p > .05). The average amount of collagen injected was 4.7 cc (1.5-12.5) transurethrally and 10.1 cc (5-20) periurethrally (p < .001). The number of treatment sessions was identical (1.3) regardless of the method used. Complications were minimal [minor bleeding (2), urinary tract infection (1) in periurethral vs. minor bleeding (2), urinary tract infection (1) in the transurethral group, and not significant between the two groups]. Overall, success was equivalent using either method. The amount of collagen injected was significantly more when utilizing the periurethral method. The transurethral method appears to offer similar results as the more commonly described periurethral technique. The transurethral method is an acceptable technique for collagen injection therapy in women.

Faerber, G. J. and D. A. Bloom (1999). "The origin and utility of Bergman's sign." Contemporary Urology 11: 16-17.

Faerber, G. J. and M. Goh (1997). "Percutaneous nephrolithotripsy in the morbidly obese patient." Tech Urol 3(2): 89-95.

From 1989 to 1995, 530 patients underwent percutaneous nephrolithotripsy, of which 93 were identified as morbidly obese. A retrospective study was performed comparing results of nephrolithotripsy in patients with near normal ideal body weight versus those patients considered morbidly obese. Outcome parameters measured included size, configuration, and number of calculi, location and number of access sites required, stone-free rates, operative time, number of ancillary procedure, hospital stay, and complications. Stone number was similar between the normal weight and morbidly obese groups; however, the morbidly obese group had smaller stones treated percutaneously. Operative time was similar between the two groups if a single access was required, but then was significantly higher in the morbidly obese group if multiple access sites were necessary. Stone-free rates were not statistically different between normal weight versus obese patients (89% vs. 82%). However, hospital stay was longer (3.5 days vs. 4.4 days) and the overall rate of complications was higher (16% vs. 37%) in the morbidly obese group compared to normal weight group.

Faerber, G. J. and J. W. Konnak (1993). "Results of combined Nesbit penile plication with plaque incision and placement of Dacron patch in patients with severe Peyronie's disease." J Urol 149(5 Pt 2): 1319-1320.

We treated 9 men with severe curvature of the penis secondary to Peyronie's disease with penile plication and a previously unreported technique of incision of the Peyronie plaque and placement of Dacron patch. All men were potent before penile straightening. At a mean followup of 17.5 months all men achieved good to excellent correction of the deformity and they have remained potent. One patient initially complained of numbness of the glans penis and decreased penile rigidity distal to the Dacron patch but potency returned and the numbness resolved.

Faerber, G. J., J. M. Park, et al. (1994). "Treatment of pediatric urethral stricture disease with the neodymium:yttrium-aluminum-garnet laser." Urology 44(2): 264-267.

OBJECTIVES. The aim of this study was to assess the efficacy and safety of the neodymium:yttrium-aluminum-garnet (Nd:YAG) laser in the treatment of pediatric urethral stricture disease. METHODS. Twelve boys who had previously undergone unsuccessful cold-knife internal urethrotomy or serial urethral dilation for urethral stricture disease underwent endoscopic laser internal urethrotomy utilizing a contact-tip fiber for recurrent urethral stricture. RESULTS. At a mean follow-up of 12 months, 10 of the 12 boys are free of stricture disease for an overall success rate of 83%. Two boys were considered failures and underwent successful open urethroplasty. There were no treatment complications. CONCLUSIONS. The Nd:YAG laser utilizing the contact-tip fiber was successful in treating recurrent urethral stricture disease. The hemostatic characteristic of the laser allowed bloodless urethrotomy, which was particularly useful when operating with the smaller pediatric endoscopic instruments.

Faerber, G. J. and T. D. Richardson (1997). "Long-term results of transurethral collagen injection in men with intrinsic sphincter deficiency." J Endourol 11(4): 273-277.

Male stress urinary incontinence (SUI) secondary to intrinsic sphincter deficiency (ISD) is a well-recognized potential complication of various forms of therapy for both benign and malignant conditions of the prostate. Short-term efficacy of collagen therapy for SUI in men has been demonstrated; however, little information exists on the long-term durability of this minimally invasive treatment modality. Herein, we present our long-term experience with transurethral collagen injection therapy in men with SUI. Sixty-eight men ages 45 to 75 years underwent collagen injection for treatment of urinary incontinence secondary to ISD. Incontinence resulted from radical prostatectomy (N = 47), external-beam radiation (8), cryotherapy (4), salvage radical prostatectomy (4), and transurethral resection of the prostate (TURP) (5). Response was judged according to changes in the number of pads used daily and the incontinence grade. The average amount of collagen injected was 36 cc (range 8-125 cc), and the average number of treatment sessions was 5 (range 3-15). With a mean follow-up of 38 (6-46) months, 10% of the patients were cured (no pads, Grade 0 incontinence), 10% were greatly improved (> 50% decrease in pads used or improved incontinence grade), 67% had minimal to no improvement (< 50% decrease in pads used or no change in continence grade), and 13% reported worsening of their incontinence. Patients with incontinence after TURP were most likely to achieve a favorable outcome, whereas patients with incontinence after salvage prostatectomy responded poorly. Complications were minimal and included hematuria (N = 10), transient urinary retention (8), and urinary tract infection (5). Collagen injection therapy is a safe, relatively noninvasive method of treatment for ISD in male patients. However, long-term success with collagen is disappointing in all groups with the exception of men with SUI after TURP.

Faerber, G. J., T. D. Richardson, et al. (1997). "Retrograde treatment of ureteropelvic junction obstruction using the ureteral cutting balloon catheter." J Urol 157(2): 454-458.

PURPOSE: We assessed the efficacy and safety of a new cutting balloon catheter to treat symptomatic ureteropelvic junction obstruction in adults. MATERIALS AND METHODS: A total of 32 adults (mean age 40 years, range 18 to 79) underwent retrograde balloon incision for symptomatic ureteropelvic junction obstruction (27 primary and 5 secondary cases). Treatment outcome was based on improvement of symptoms and resolution of obstruction by excretory urography or diuretic renal scintigraphy. RESULTS: A total of 36 retrograde endopyelotomies was performed on 32 patients. Of 4 patients who underwent repeat endopyelotomy 2 had resolution of persistent obstruction. At a mean followup of 14 months (range 3 to 28) 28 of 32 patients (87.5%) were rendered symptom-free and had no obstruction on excretory urography or diuretic renography. Average hospital stay was 1.8 days (range 0 to 6) and the complication rate was 15.6% (postoperative bleeding, fever and ileus). Treatment failed in 4 patients and subsequent open pyeloplasty was successful. CONCLUSIONS: Retrograde balloon incision endopyelotomy appears to be a safe and effective treatment for ureteropelvic junction obstruction.

Faerber, G. J., M. L. Ritchey, et al. (1995). "Percutaneous endopyelotomy in infants and young children after failed open pyeloplasty." J Urol 154(4): 1495-1497.

PURPOSE: We assessed the efficacy and safety of percutaneous endopyelotomy in infants and young children with secondary ureteropelvic junction obstruction after previous open pyeloplasty. MATERIALS AND METHODS: Three boys and 2 girls with persistent ureteropelvic junction obstruction after open pyeloplasty underwent percutaneous antegrade cold knife endopyelotomy via an 18F nephrostomy tract. RESULTS: Percutaneous endopyelotomy was successfully performed in all 5 children with minimal complications. At a mean followup of 2.5 years endopyelotomy was successful in 4 of the 5 children based on the absence of symptoms, normal pressure-perfusion studies and normal or improved diuretic renal scintigraphy studies. One child in whom endopyelotomy failed underwent successful ureterocalicostomy. CONCLUSIONS: Percutaneous antegrade endopyelotomy is a safe and efficacious method of treating secondary ureteropelvic junction obstruction in children. This method offers a minimally invasive alternative to conventional repeat open pyeloplasty.

Faerber, G. J. and M. B. Tchetgen (1998). "Expeditious method of difficult ureteral stent change with preservation of ureteral access." J Urol 160(5): 1781-1783.

Faerber, G. J. and A. R. Vashi (1998). "Variations in Valsalva leak point pressure with increasing vesical volume." J Urol 159(6): 1909-1911.

PURPOSE: Although leak point pressure testing is a valuable tool in the diagnosis of female stress urinary incontinence, little standardization in methodology exists. We examined the effect of vesical volume on leak point pressure to assess the need for determining an optimal volume for leak point pressure testing. MATERIALS AND METHODS: Video urodynamic testing was performed in 52 consecutive women with a mean age of 52 years who presented with stress urinary incontinence. By fluoroscopic criteria stress urinary incontinence was type I in 12 patients, type II in 20 and type III in 20. Leak point pressure determined at 50 cc volume increments was correlated with fluoroscopic criteria. RESULTS: Women with type I stress urinary incontinence had high leak point pressure, which remained high at increasing vesical volumes, and those with type III had low leak point pressure, which remained low at increasing volumes. In patients with type II incontinence initially high leak point pressure decreased significantly at increasing vesical volumes. The most appropriate classification of patients occurred at a volume of 250 to 300 cc. CONCLUSIONS: Leak point pressure is affected by vesical volume. At a volume of 250 to 300 cc leak point pressure correlates best with fluoroscopic findings, and it may be used to guide therapy in women presenting with stress urinary incontinence.

Faerber, G. J., J. Wan, et al. (1992). "Percutaneous extraction of calculi from continent augmentation cystoplasty." J Endourol 6(6): 417-419.

Fagan, J. F., III, L. T. Singer, et al. (1986). "Selective screening device for the early detection of normal or delayed cognitive development in infants at risk for later mental retardation." Pediatrics 78(6): 1021-1026.

The present study tested the predictive validity at 3 years of age of a screening device for the early identification of later cognitive delay. The screening device, administered between 3 and 7 months of age, is based on the infant's differential fixation "to novel" over previously shown pictures. The sample was composed of 62 infants suspected to be at risk for later mental retardation. The prevalence of delayed cognitive development (IQ less than or equal to 70) at 3 years of age was 13%. Novelty preference scores correctly identified six of eight (75%) of the delayed children. The test identified 49 of 54 (91%) of the normal children. Validity for predicting cognitive delay was 55%. Validity for the prediction of normality was 96%. The screening device proved to be equally sensitive, specific, and valid when the sample was divided into infants born at term or born preterm. The results of the present study and of a previous study indicate that detection of cognitive delay based on early novelty preferences is as easily accomplished for infants who will later be mildly delayed (IQ scores 60 to 70) as it is for those who will later be severely delayed (IQ scores less than or equal to 50). Moreover, such results are in contrast to those obtained with conventional tests tapping sensorimotor development. <176>

Fagerlin, A., D. Rovner, et al. (2004). "Patient education materials about the treatment of early-stage prostate cancer: a critical review." Ann Intern Med 140(9): 721-728.

BACKGROUND: To ensure that patients make informed medical decisions, patient education materials must communicate treatment risks and benefits. OBJECTIVE: To survey publicly available patient education materials and assess their suitability to support informed decision making in early-stage prostate cancer. DESIGN: Cross-sectional review of Internet, print, and multimedia sources. SETTING: University data analysis laboratory. MEASUREMENTS: The content of 44 materials that described all standard treatment options was reviewed. Top-rated documents underwent plain-language review. Total score on 54 content items and accuracy, balance, and plain-language evaluation was measured. RESULTS: 502 of 546 patient education materials did not describe all standard treatments (watchful waiting, surgery, radiation, and hormone therapy). Eighty percent of the 44 materials that addressed standard treatments and underwent content review described anatomy, physiology, stage, and grade of cancer. Half of the materials fully described radical prostatectomy and radiation therapy. One third of the materials included risks and benefits of each treatment; none explicitly compared outcomes of all treatments in a single summary. Information was accurate and balanced but did not include key content for informed consent. LIMITATIONS: The search was restricted to publicly available materials and did not include books or materials written in languages other than English. The accuracy, balance, and plain-language reviews were evaluated by 1 reviewer. The criteria reflect the authors' focus on informed decision making. Other aspects of health education may require a different evaluation template. CONCLUSIONS: Currently available patient education materials on early-stage prostate cancer treatment do not contain comprehensive information about the risks and benefits of each treatment. To assist patients and physicians in choosing among prostate cancer treatment options, a new generation of materials is needed.

Feitz, W. F., M. L. Ritchey, et al. (1994). "Ureterocele associated with a single collecting system of the involved kidney." Urology 43(6): 849-851.

OBJECTIVE. This is a study concerning ureteroceles associated with a single collecting system of the involved kidney. METHODS. Over an eight-year period 9 children (5 boys, 4 girls) had a ureterocele subtending a single collecting system, whereas 63 children had duplex ureteroceles. Malformations of other organ systems were present in only 1 patient. RESULTS. Three patients have undergone surgical interventions: a transurethral incision of bilateral obstructive ureteroceles in 1 and nephroureterectomy in 2. In 4 cases cystic/dysplastic kidneys involuted and were reabsorbed with collapse of the ureteroceles. The last 2 patients have received antibiotic treatment for single episodes of a urinary tract infection. CONCLUSIONS. Earlier reports of a high incidence of concomitant anomalies and male predominance in patients with single-system ectopic ureteroceles could not be verified by our experience. Our current policy for a patient is careful evaluation, individualized therapy, and long-term surveillance.

Feng, M. R., M. Liebert, et al. (1991). "Effect of verapamil on the uptake and efflux of etoposide (VP16) in both sensitive and resistant cancer cells." Sel Cancer Ther 7(2): 75-83.

The effect of calcium antagonist verapamil on the uptake and efflux of Etoposide (VP16), a semi-synthetic derivative of podophylotoxin and a broad spectrum antineoplastic agent, has been investigated and compared in sensitive (UM-UC-2) and resistant (UM-UC-9) human bladder cancer cells, and L1210 leukemia cells, by using both radioisotope (3[H]-VP16) liquid scintillation and high performance liquid chromatography assay with electrochemical detection. The uptake of VP16 was rapid in all three cell lines, showing an initial rapid linear phase followed by a second slower phase, but at steady state the ratios of intracellular to extracellular VP16 concentrations were only 0.004-0.006. No significant difference in drug uptake was observed in sensitive UM-UC-2 and resistant UM-UC-9 cells at all concentrations studied. Verapamil at a concentration of 10 microM enhanced the intracellular VP-16 levels in all sensitive and resistant cell lines. The increments were 21.5% for UM-UC-2, 11.8% for UM-UC-9, and 31.0% for L1210 cells after 30 minutes incubation with 1 microM VP16. A slower efflux of VP16 was observed in verapamil treated cells in all three cell lines. There was a small increase in the nonexchangeable components in verapamil treated cells, although only 5-10% of VP16 was retained. No peak other than that of VP16 was detected in the HPLC chromatogram of extracts from both cell pellet and influx or efflux medium.

Fergany, A. F., I. S. Gill, et al. (2001). "Laparoscopic intracorporeally constructed ileal conduit after porcine cystoprostatectomy." J Urol 166(1): 285-288.

PURPOSE: We present our technique of laparoscopic ileal conduit creation after cystoprostatectomy in a porcine model performed in a completely intracorporeal manner. METHODS AND METHODS: After developing the technique in 5 acute animals laparoscopic cystoprostatectomy with intracorporeally performed ileal conduit urinary diversion was performed in 10 surviving male pigs. A 5-port transperitoneal technique was used. All steps of the technique applied during open surgery were duplicated intracorporeally. Specifically cystectomy, isolation of an ileal conduit, restoration of bowel continuity and mucosa-to-mucosa stented bilateral ileoureteral anastomosis formation were performed by exclusively intracorporeal laparoscopic techniques. RESULTS: Surgery was successful in all 10 study animals without intraoperative or immediate postoperative complications. Blood loss was minimal and average operative time was 200 minutes. Stenosis of the end ileal stoma specifically at the skin level was noted in 6 animals. Three deaths occurred 2 to 3 weeks postoperatively. At sacrifice renal function was normal in all surviving animals. No ileo-ureteral anastomotic strictures were noted on pre-sacrifice radiography of the loop or at autopsy examination of the anastomotic sites. CONCLUSIONS: Laparoscopic ileal conduit urinary diversion after cystoprostatectomy may be performed completely intracorporeally in the porcine model. Clinical application of this technique is imminent.

Fergany, A. F., K. S. Hafez, et al. (2000). "Long-term results of nephron sparing surgery for localized renal cell carcinoma: 10-year followup." J Urol 163(2): 442-445.

PURPOSE: Partial nephrectomy is effective for renal cell carcinoma when preservation of renal function is a concern. We present the 10-year followup of patients treated with nephron sparing surgery at our institution. MATERIALS AND METHODS: Partial nephrectomy was performed in 107 patients with localized sporadic renal cell carcinoma before December 1988. Tumors were symptomatic in 73 patients (68%) and indications for surgery were imperative in 96 (90%). Of the patients 42 (39%) had renal insufficiency preoperatively. All patients were followed a minimum of 10 years or until death. RESULTS: At the end of the followup interval 32 patients (30%) had no evidence of recurrence, 28 (26%) died of metastatic renal cell carcinoma and 46 (42%) died of unrelated causes. Cancer specific survival was 88.2% at 5 and 73% at 10 years, and was significantly affected by tumor stage, symptoms, tumor laterality and tumor size. Long-term renal function was stable in 52 patients (49%). CONCLUSIONS: Partial nephrectomy is effective for localized renal cell carcinoma, providing long-term tumor control with preservation of renal function.

Fernandez, M. I., S. F. Shariat, et al. (2009). "Evidence-based sex-related outcomes after radical nephroureterectomy for upper tract urothelial carcinoma: results of large multicenter study." Urology 73(1): 142-146.

OBJECTIVES: To assess the sex differences in the clinical and pathologic characteristics of upper tract urothelial carcinoma (UTUC) and to determine the effect on prognosis after radical nephroureterectomy (RNU) in a large multicenter series. METHODS: The records of 1363 patients who had undergone RNU were reviewed from the UTUC Collaboration database. The median follow-up was 47 months (range 0-250). The pathologic slides were re-evaluated by genitourinary pathologists unaware of the original findings from the slides and the clinical outcomes. The endpoints were freedom from tumor recurrence and disease-specific survival. RESULTS: The male-to-female ratio was 2.1:1. The women were older than the men at diagnosis (70 +/- 11 vs 68 +/- 11 years; P < .001). No significant sex-related differences were found in the presence of symptoms at presentation (P = .70), pathologic stage (P = .98), tumor grade (P = .28), tumor architecture (P = .27), presence of lymphovascular invasion (P = .42), presence of concomitant carcinoma in situ (P = .08), or the presence of lymph node metastases (P = .24). Recurrence developed in 379 patients (28%), and 313 patients (23%) died of their disease. Sex was not associated with disease recurrence (P = .07) or disease-specific survival (P = .13). An adjustment for the effects of the pathologic features did not change the lack of association of sex with the clinical outcomes. CONCLUSIONS: To our knowledge, this is the largest series analyzing the effect of sex on the outcomes after RNU. No difference was found in the clinicopathologic features or prognosis between women and men treated with RNU for UTUC. The results of this large, international series show that RNU provides durable local control and disease-specific survival for both men and women with UTUC.

Ferro, F. and D. A. Bloom (1998). "Medical photography and genitourinary surgery." Br J Urol 82(3): 325-330.

Fesseha, T., W. Sakr, et al. (1999). "Prognostic implications of a positive apical margin in radical prostatectomy specimens." J Urol 158(6): 2176-2179.

Finley, D. S., F. Pouliot, et al. (2010). "Primary and salvage cryotherapy for prostate cancer." Urol Clin North Am 37(1): 67-82, Table of Contents.

Cryotherapy is a technique to ablate tissue by local induction of extremely cold temperatures. Recently, the American Urological Association Best Practice Statement recognized cryoablation of the prostate as an established treatment option for men with newly diagnosed or radiorecurrent organ-confined prostate cancer. Emerging data suggest that, in select cases, cryoablation may have a role in focal ablation of prostate. The current state of the art of cryoablation in these applications is reviewed.

Fischer, M. C., M. T. Milen, et al. (2005). "Thomas Annandale and the first report of successful orchiopexy." J Urol 174(1): 37-39.

PURPOSE: We investigate the surgeon and factors behind the first report of successful orchiopexy. MATERIALS AND METHODS: We reviewed the first reports of orchiopexy, and the work and writings concerning Thomas Annandale and the time in which he practiced. RESULTS: Annandale was a surgeon in Edinburgh, Scotland, in the late 19th century. In 1877 he successfully brought down an ectopic testicle in a 3-year-old boy. This first reported successful orchiopexy was due in large part to Lister's antiseptic technique. CONCLUSIONS: Annandale performed the first successful orchiopexy by integrating the surgical and antiseptic ideas of his predecessors and contemporaries.

Fisher, C. and M. Park (2004). "Penile torsion repair using dorsal dartos flap rotation." J Urol 171(5): 1903-1904.

PURPOSE: Counterclockwise penile torsion is a frequently noted congenital deformity. Previously proposed techniques of torsion repair are ineffective or pose significant operative risks. We introduce a novel technique using dorsal dartos flap rotation. MATERIALS AND METHODS: The penis is first degloved completely and a broad based dartos flap is mobilized from the dorsal penile skin. The flap is rotated around the right side of the penile shaft and attached to the ventral aspect, causing clockwise penile rotation. Final slight adjustments are made during skin closure. We applied this technique in 8 patients undergoing circumcision (2), chordee (4) or hypospadias (2) repair. RESULTS: This technique was effective for correcting penile torsion in all patients. At a mean followup of 8.3 months the cosmetic outcome was satisfactory with the complete correction of penile torsion. CONCLUSIONS: Rotational repositioning of a dorsal dartos flap is an effective technique for correcting penile torsion and it is easily applicable with other penile reconstruction procedures.

Fisher, P. C., B. K. Hollenbeck, et al. (2004). "Inguinal bladder hernia masking bowel ischemia." Urology 63(1): 175-176.

Displacement of the bladder outside of the pelvis by way of the inguinal canal represents an infrequent presentation of an inguinal hernia that rarely causes urinary tract obstruction. However, bladder hernias can become bothersome, painful, and potentially dangerous. We report a 56-year-old man with a chronic bladder hernia who became acutely unable to empty his bladder from its position in the right hemiscrotum after a motor vehicle accident. At hernia repair, bladder and ischemic bowel were discovered, mandating significant small bowel resection. This case presents interesting considerations and potential pitfalls when evaluating a patient with a bladder hernia.

Fisher, P. C., J. S. Montgomery, et al. (2006). "200 consecutive hand assisted laparoscopic donor nephrectomies: evolution of operative technique and outcomes." J Urol 175(4): 1439-1443.

PURPOSE: Despite the popularity of hand assisted laparoscopic donor nephrectomy published experience is less than that with standard laparoscopic donor nephrectomy and few critical assessments of operative maneuvers have been described. MATERIALS AND METHODS: We describe the impact of changes in operative technique made by a single surgeon during 200 hand assisted laparoscopic donor nephrectomies. RESULTS: With a mean operative time of 229 minutes and hospital stay of 1.9 days the rates of conversion to open surgery, intraoperative complications and major postoperative complications were 1%, 1.5% and 6%, respectively. Lasting changes in technique were dissection of a ureteral/gonadal packet, bipolar cautery use on gonadal/adrenal/lumbar veins and resting the kidney before removal. The incidence of ureteral complications decreased from 8% to 5.1% with dissection of the ureter in conjunction with the gonadal vein rather than isolating it. Warm ischemia time decreased from a mean of 186 to 143 seconds with bipolar electrocautery instead of clips to control gonadal/adrenal/lumbar veins. After starting to rest the kidney before removal the incidence of primary graft nonfunction and delayed function decreased from 6.7% to 0% and 30% to 11.8%, respectively, with a corresponding improvement in 2-year graft survival from 83% to 95%. CONCLUSIONS: This large series of hand assisted donor laparoscopic nephrectomies with a mean followup approaching 3 years demonstrates that the procedure is safe for the donor and procures a good specimen. Decreases in ureteral complications, warm ischemia time and graft dysfunction might be attributable to specific changes in our operative technique.

FitzGerald, M. P., R. U. Anderson, et al. (2009). "Randomized multicenter feasibility trial of myofascial physical therapy for the treatment of urological chronic pelvic pain syndromes." J Urol 182(2): 570-580.

PURPOSE: We determined the feasibility of conducting a randomized clinical trial designed to compare 2 methods of manual therapy (myofascial physical therapy and global therapeutic massage) in patients with urological chronic pelvic pain syndromes. MATERIALS AND METHODS: We recruited 48 subjects with chronic prostatitis/chronic pelvic pain syndrome or interstitial cystitis/painful bladder syndrome at 6 clinical centers. Eligible patients were randomized to myofascial physical therapy or global therapeutic massage and were scheduled to receive up to 10 weekly treatments of 1 hour each. Criteria to assess feasibility included adherence of therapists to prescribed therapeutic protocol as determined by records of treatment, adverse events during study treatment and rate of response to therapy as assessed by the patient global response assessment. Primary outcome analysis compared response rates between treatment arms using Mantel-Haenszel methods. RESULTS: There were 23 (49%) men and 24 (51%) women randomized during a 6-month period. Of the patients 24 (51%) were randomized to global therapeutic massage, 23 (49%) to myofascial physical therapy and 44 (94%) completed the study. Therapist adherence to the treatment protocols was excellent. The global response assessment response rate of 57% in the myofascial physical therapy group was significantly higher than the rate of 21% in the global therapeutic massage treatment group (p = 0.03). CONCLUSIONS: We judged the feasibility of conducting a full-scale trial of physical therapy methods and the preliminary findings of a beneficial effect of myofascial physical therapy warrants further study.

Fitzgerald, M. P., N. K. Janz, et al. (2007). "Prolapse severity, symptoms and impact on quality of life among women planning sacrocolpopexy." Int J Gynaecol Obstet 98(1): 24-28.

OBJECTIVES: To explore the relationship between severity of pelvic organ prolapse (POP), symptoms of pelvic dysfunction and quality of life using validated measures. METHOD: Baseline data from 314 participants in the Colpopexy And Urinary Reduction Efforts (CARE) trial were analyzed. Pelvic symptoms and impact were assessed using the Pelvic Floor Distress Inventory (PFDI) and the Pelvic Floor Impact Questionnaire (PFIQ). PFDI and PFIQ scores were compared by prolapse stage and history of incontinence or POP surgery. Regression analyses were performed to identify other predictors of symptoms and impact. RESULTS: Women were predominantly (90%) Caucasian and had mean age of 61 years. Women with stage II POP, especially those with prior surgery, reported more symptoms and impact than women with more advanced POP. There were no other significant predictors of symptoms or life impact. CONCLUSIONS: Women planning sacrocolpopexy with stage II prolapse and prior pelvic surgery reported more symptoms and quality of life impact than those with more advanced prolapse.

Fitzpatrick, C., J. Delancey, et al. (1994). "Experience of a combined gynecology/urology clinic in the University of Michigan Medical Center." Internl Urogynecol 5(3): 160-163.

Fitzpatrick, C., H. Flood, et al. (1995). "Bladder dysfunction after repeat laparoscopic uterine nerve ablation " Intnl Urogynecol 6(1): 31-33.

Fitzpatrick, C., S. J. Swierzewski, 3rd, et al. (1993). "Stress urinary incontinence and genital prolapse after female pelvic trauma." Intl Urogynecol 4: 301-303.

Fitzpatrick, C., S. J. Swierzewski, 3rd, et al. (1993). "Periurethral collagen for urinary incontinence after gender reassignment surgery." Urology 42(4): 458-460.

We report on 2 patients, one female and one male transsexual; in both, Type III stress urinary incontinence developed after gender reassignment surgery. Both patients were treated by periurethral injection of gluteraldehyde cross-linked collagen resulting in a marked symptomatic improvement in association with a significant rise in abdominal leak point pressures. We believe these are the first reported cases of collagen injection being used for urinary incontinence after gender reassignment surgery.

Flechner, S. M. and K. Hafez (1999). "Use of a cadaveric donor aorta for vascular replacement in kidney transplantation." J Urol 161(3): 909-910.

Flint, A., H. B. Grossman, et al. (1995). "DNA and PCNA content of renal cell carcinoma and prognosis." Am J Clin Pathol 103(1): 14-19.

Robson stage I or II renal carcinomas have a heterogenous clinical outcome. A variety of morphologic features and other parameters have been proposed as prognostically useful. The authors measured the DNA content and PCNA expression of 47 stage I or II renal carcinomas, and assessed the association of these measures with pathologic stage, nuclear grade, and clinical course. Approximately 56% of stage I neoplasms and 40% of stage II neoplasms were diploid. Five of 9 neoplasms in which multiple samples were analyzed manifested both aneuploid and diploid regions. PCNA expression was noted in 20 of 32 stage I neoplasms and 9 of 15 stage II neoplasms, and varied greatly among the neoplasms. Neither ploidy nor PCNA expression is associated with clinical behavior in these data. These results are different from some of those previously reported by others. These discrepancies are likely to be due to differences in methodology and the fact that there were only eight cases of metastatic disease. No single parameter will serve as a completely accurate prognostic indicator. Most individuals with these neoplasms will do well because all of the tumor has been excised.

Flood, H. D., S. J. Malhotra, et al. (1995). "Long-term results and complications using augmentation cystoplasty in reconstructive urology." Neurourol Urodyn 14(4): 297-309.

One hundred and twenty-two augmentation cystoplasties performed over an 8-year period were reviewed. Mean age at surgery was 37 years (range 2-82 years). There were 82 female patients. The primary urodynamic diagnosis was reduced compliance in 92 (77%) patients and detrusor hyperreflexia/instability in the remainder. The clinical diagnostic groups were: spinal cord injury/disease in 32 (27%), myelodysplasia in 27 (22%), interstitial cystitis in 21 (17%), idiopathic detrusor instability in 13 (11%), radiation cystitis in 8 (7%), Hinman-Allen syndrome in 5 (4%), and miscellaneous in 11 (9%). A detubularized ileal augmentation was used in 82 (67%) patients. In 36 (30%) a detubularized ileocecocystoplasty was fashioned and in the remainder detubularized sigmoid was used. In 19 patients augmentation accompanied undiversion. Sixteen patients had a simultaneous fascial sling for urethral incompetence. Mean follow-up was 37 months (range 6-96 months). There was no postoperative mortality. During follow-up 4 patients died from unrelated causes, 11 have been lost to follow-up, and 5 patients await planned transplantation. Bladder capacity was increased from a preoperative mean of 108 ml (range 15-500 ml) to 438 ml (200-1,200 ml) postoperatively. Of the 106 assessable patients, 80 (75%) had an excellent result, 21 (20%) were improved, and 5 (5%) had major ongoing problems. During the period of follow-up, 17 (16%) patients underwent revision of their augmentation. Twenty-four (21%) patients developed bladder stones and 30% of these did so more than once. Urinary incontinence became manifest in 15 (13%) patients but required surgical treatment in only half of these. Pyelonephritis occurred in 13 (11%) patients. Five patients developed small bowel obstruction following discharge from hospital. There were 7 instances of reservoir rupture in 5 (4%) patients. Augmentation cystoplasty has a pivotal role in the treatment of a broad range of lower and upper urinary tract problems. Careful patient selection and close follow-up are essential.

Flood, H. D., M. L. Ritchey, et al. (1994). "Outcome of reflux in children with myelodysplasia managed by bladder pressure monitoring." J Urol 152(5 Pt 1): 1574-1577.

From June 1984 to December 1992 voiding cystourethrography performed on 209 patients with myelodysplasia revealed vesicoureteral reflux in 57 (27%). High grade reflux (3 to 5/5) occurred in 33 patients (58%). Bladder pressure at typical capacity, defined as the pressure at average catheterization volume or bladder leak point pressure, was determined urodynamically. After a mean of 56 months vesicoureteral reflux resolved or improved in 55% of patients and remained unchanged in 28%. There was no correlation between the grade of reflux and the rate of spontaneous resolution. Pressure at typical capacity of 40 cm. water or more was significantly more common in patients with reflux (44%) than in those with no reflux (20%) (p < 0.001). There was a strong association between pressure at typical capacity of 40 cm. water or more and upper tract deterioration (p < 0.0001). However, there was no correlation between pressure at typical capacity and grade of reflux (p = 0.18). Treatment of pressure at typical capacity of 40 cm. water or more led to resolution or improvement of vesicoureteral reflux in 8 of 10 reevaluated patients. Hydronephrosis resolved (7) or improved (1) in 8 of 9 cases. Measurement of intravesical pressure is of paramount importance in the management of spina bifida patients with vesicoureteral reflux. Maintaining the pressure at typical capacity at less than 40 cm. water is associated with increased spontaneous resolution of vesicoureteral reflux and a lower incidence of upper tract deterioration.

Flum, A. S. and J. S. Wolf, Jr. (2010). "Laparoscopic partial nephrectomy for multiple ipsilateral renal tumors using a tailored surgical approach." J Endourol 24(4): 557-561.

BACKGROUND AND PURPOSE: Laparoscopic partial nephrectomy (LPN) is safe and effective for solitary renal masses, but its application to multiple ipsilateral renal tumors has been reported infrequently. We review our experience with LPN for multiple ipsilateral renal tumors to assess its role in current practice. MATERIALS AND METHODS: We have managed seven patients with multiple ipsilateral renal tumors with LPN. Of the patients, four had an imperative indication for nephron-sparing surgery. RESULTS: Among the 16 tumors resected, with a mean size of 2.1 cm, 9 (in five patients) were renal cell carcinoma on final pathology. LPN was performed without hilar clamping in four patients (no-clamp group), and with hilar clamping and a sutured bolster in three patients (clamp-suture group). The no-clamp group had a lower mean operative time than the clamp-suture group (185 vs. 225 minutes), similar mean estimated blood loss (363 vs. 417 mL), and shorter hospital stay (1.8 vs. 3 days). The only complication was an intraoperative hemorrhage necessitating blood transfusion, and there was one focal-positive margin, both in patients in the clamp-suture group. Among the five patients with cancer, there have been no local recurrences or metastases during a mean radiographic follow-up of 48 months. CONCLUSIONS: LPN, with a tailored approach that spares some patients from renal ischemia, appears to be safe and effective in this small series of selected patients with multiple ipsilateral renal tumors.

Foote, J., K. Glavind, et al. (2005). "Treatment of overactive bladder in the older patient: pooled analysis of three phase III studies of darifenacin, an M3 selective receptor antagonist." Eur Urol 48(3): 471-477.

AIM: To evaluate the efficacy, tolerability and safety of darifenacin, an M(3) selective receptor antagonist, in the subgroup of older patients from a pooled analysis of three phase III, multicentre, randomized, double-blind clinical trials in patients with overactive bladder (OAB). PATIENTS AND METHODS: 317 patients aged > or =65 years with OAB symptoms (urge incontinence, urgency and frequency) received up to 12 weeks' oral treatment with darifenacin 7.5 mg or 15 mg once daily or matching placebo. Efficacy was evaluated from daily electronic diary records. Safety endpoints included withdrawal rates and treatment-related adverse events. RESULTS: Darifenacin treatment of patients aged > or =65 years was associated with a dose-related, significant improvement of all the major symptoms of OAB. At week 12, the median reduction in incontinence episodes/week was greater with darifenacin 7.5 mg or 15 mg than in the corresponding placebo arms (66.7% vs. 34.8% and 75.9% vs. 44.8%, respectively, both p < 0.001). Both doses were also significantly superior to placebo in improving micturition frequency (both p < 0.001), bladder capacity (volume voided) (darifenacin 7.5 mg, p = 0.018, darifenacin 15 mg, p < 0.001), and the frequency of urgency episodes (both p < 0.001). Darifenacin was well tolerated. The most common treatment-related adverse events were dry mouth (7.5 mg, 20.6%; 15 mg, 30.9%; placebo, 4.5%) and constipation (7.5 mg, 18.6%; 15 mg, 23.6%; placebo, 6.4%), typically mild or moderate. Use of constipation remedies (laxatives, stool softeners or fibre supplements) was low and similar between groups (7.5 mg, 10.3%; 15 mg, 16.4%; placebo, 10.0%). There were few withdrawals due to treatment-related adverse events (7.5 mg, 1.0%; 15 mg, 9.1%; placebo, 2.7%), and no nervous system or cardiovascular safety concerns. CONCLUSIONS: The results demonstrate excellent efficacy, tolerability and safety with darifenacin 7.5 mg and 15 mg once-daily treatment for OAB in older patients.

Forman, J. D., R. Kumar, et al. (1995). "Neoadjuvant hormonal downsizing of localized carcinoma of the prostate: effects on the volume of normal tissue irradiation." Cancer Invest 13(1): 8-15.

A prospective evaluation of neoadjuvant hormonal downsizing in patients with localized carcinoma of the prostate was undertaken to assess its effect on normal tissue irradiation. Twenty patients with stage T1 or T2 (A, B) carcinoma of the prostate received 3 months of Lupron prior to definitive radiotherapy. The volumes of the prostate, seminal vesicles, bladder, and rectum from both the pre- and posthormone treatment planning CT were entered onto a 3-D treatment-planning system. The treatment planning parameters were standardized to facilitate comparison of the pre- and posthormonal volumes. Following the three monthly injections of Lupron, the average volume of the prostate was reduced by 37%. As a consequence, the volume of the bladder receiving at least 40, 52, and 64 Gy was reduced by an average of 15, 18, and 20%, respectively. In addition, the volume of the rectum receiving at least 40, 52, and 64 Gy was reduced by an average of 13, 20, and 34%, respectively. In conclusion, in patients with localized prostate cancer, downsizing of the prostate resulted in a reduction in the volume of bladder and rectum receiving high radiation doses. This approach may result in an improvement in the therapeutic ratio by reducing the morbidity of treatment.

Forman, J. D., Y. Lee, et al. (1993). "Advantages of CT and beam's eye view display to confirm the accuracy of pelvic lymph node irradiation in carcinoma of the prostate." Radiology 186(3): 889-892.

Possible advantages of computed tomography (CT) and beam's eye view (BEV) display in the design of pelvic irradiation fields were studied in 20 consecutive patients with localized adenocarcinoma of the prostate. Pelvic fields were designed with standard four-field techniques. Then, CT and BEV display were done to define the reduced prostate tumor volumes. With treatment-planning CT, the location of the pelvic vascular structures (internal and external iliac artery and vein) was outlined. These were used as an approximation of the location of the lymph nodes. A BEV display of these lymph node volumes was then compared with the pelvic fields designed without CT and BEV display. Nineteen of the 20 patients had part of the CT-defined lymph node volume (a portion of the internal iliac lymph node volume) excluded from the original field design. Thirteen patients also had part of the external iliac nodal volume excluded. Dose-volume histograms showed that up to 30% of the lymph node volume received only 56% of the prescribed dose. <128>

Forman, J. D., T. Oppenheim, et al. (1993). "Frequency of residual neoplasm in the prostate following three-dimensional conformal radiotherapy." Prostate 23(3): 235-243.

The incidence of residual neoplastic cells on prostatic biopsy following conventional external beam radiotherapy is reported to range from 40-90%. As a result, it has been stated that current modalities of radiotherapy may carry an unacceptable local failure rate even in patients irradiated for low stage disease. In order to assess the potential benefits of three-dimensional (3-D) treatment planning, an unselected, consecutive group of patients with localized adenocarcinoma of the prostate was evaluated. This study was designed to determine the frequency of residual cancer in the prostate two years following definitive external beam radiotherapy designed, using a 3-D planning system. Between February 1988 and February 1989, 30 consecutive patients with localized (Stage T1-T3NxMo) adenocarcinoma of the prostate received definitive external beam radiotherapy. All treatment fields were designed with a computed tomography (CT)-based 3-D treatment planning system, resulting in a static conformal radiotherapy plan. The minimum dose delivered to the target volume, which included the prostate, periprostatic tissues, and a 1 cm margin, was between 65 and 69 cGy. Twenty-six patients had Stage T1, T2NxMo primary tumors and four were T3NxMo. Two years following the completion of treatment, all patients underwent digital rectal examination, transrectal ultrasound examination of the prostate with multiple biopsies, bone scan, and serum prostate specific antigen (PSA) determinations. Residual prostate cancer was proven by biopsy in six of 30 patients (20%). Four of 26 (15%) with Stage T1 and T2 tumors had a positive biopsy. However, two of the four Stage T3 tumors had postradiation biopsies positive for cancer (50%). Only one patient with a positive biopsy had an abnormal rectal examination. Five of the eight patients with elevated serum PSA levels after two years had residual neoplasia identified on biopsy. One of six patients with an abnormal postradiation ultrasound had residual tumor. Only one of the 22 patients (5%) with a normal serum PSA at two years had a positive postradiation biopsy. In patients with localized prostate cancer, the use of 3-D static conformal radiotherapy followed by multiple ultrasound guided biopsies confirmed the efficacy of external beam radiotherapy in low stage disease. We believe that the low incidence of positive biopsies in this study resulted from the benefits of 3-D treatment planning as well as the fact that all patients were evaluated, whereas past studies have been in selected patient groups when suspicion of residual disease existed prior to biopsy.(ABSTRACT TRUNCATED AT 400 WORDS)

Forrest, J. B., J. Q. Clemens, et al. (2009). "AUA Best Practice Statement for the prevention of deep vein thrombosis in patients undergoing urologic surgery." J Urol 181(3): 1170-1177.

Foster, H., M. Ritchey, et al. (1992). "Adventitious knots in urethral catheters: report of 5 cases." J Urol 148(5): 1496-1498.

Urethral catheterization with 5 or 8F feeding tubes in 5 boys was complicated by stochastic knotting within the bladder thereby impeding removal. The common factor in these patients was insertion of excessive length within the bladder. Percutaneous endoscopic retrieval was done successfully in 1 child. This technique may avoid urethral trauma associated with catheter removal, particularly in younger boys.

Foster, H. E. and E. J. McGuire (1993). "Management of urethral obstruction with transvaginal urethrolysis." J Urol 150(5 Pt 1): 1448-1451.

Transvaginal urethrolysis was performed in 48 patients with urethral obstruction following 1 or more urethral suspension procedures. A needle suspension procedure had been performed in 19 patients (40%), retropubic urethropexy in 17 (35%) and pubovaginal sling in 10 (21%). A good response as indicated by normal voiding with minimal or no irritative symptoms was achieved in 33 patients (65%). The most common presenting complaints were irritative voiding symptoms (71%) and urinary retention (60%). Fluoroscopic urodynamic evaluation frequently demonstrated urethral hypersuspension, a cystocele and/or elevated voiding pressures. No patient had stress urinary incontinence as a result of the procedure. Urethral obstruction should be recognized as a potential complication following surgical correction of female stress urinary incontinence. Transvaginal urethrolysis is a safe and effective method to manage this problem.

Freeman, E. R., D. A. Bloom, et al. (2001). "A brief history of testosterone." J Urol 165(2): 371-373.

PURPOSE: We explore the history of testosterone in the context of medical and scientific developments. MATERIALS AND METHODS: A review of the scientific and historical literature was conducted. RESULTS: The origins and effects of testosterone have been recognized throughout the history of humankind. Hunter performed testicular transplantation experiments in 1767 while studying tissue transplantation techniques, and almost a century later Berthold linked the physiological and behavioral changes of castration to a substance secreted by the testes. Brown-Sequard gave birth to the field of organotherapy in 1889 when he announced that his auto-injection of testicular extracts resulted in rejuvenated physical and mental abilities. Steinach and Niehans expanded upon Brown-Sequard's work with rejuvenation treatments involving vasoligation, tissue grafts and cellular injections. In 1935 David et al isolated the critical ingredient in organotherapeutic treatments, testosterone. CONCLUSIONS: The effects of the powerful hormone testosterone continue to inspire research and controversy 65 years later.

Fried, N. M., W. W. Roberts, et al. (2002). "Focused ultrasound ablation of the epididymis with use of thermal measurements in a canine model." Fertil Steril 78(3): 609-613.

OBJECTIVE: To explore the epididymis as an alternative anatomical target to the vas deferens for noninvasive male sterilization using therapeutic focused ultrasound. DESIGN: Controlled preclinical study. SETTING: Canine animal model in an academic research environment. PATIENT(S): Four healthy male mongrel dogs (30-35 kg). INTERVENTION(S): A transducer mounted on a plastic clip delivered ultrasound energy to the canine epididymis. Thermocouples placed transcutaneously into the epididymis, intradermally, and on the skin surface recorded temperatures during ablation with a wide range of acoustic powers and sonication times (control, 3 W/120 s, 5 W/90 s, 7 W/60 s). MAIN OUTCOME MEASURE(S): Thermocouple temperature measurements determined the optimal range of ablation parameters that produced successful thermal occlusion of the epididymis without adverse effects (e.g., skin burns, testicular injury). RESULT(S): A large "therapeutic window" was determined (power = 3-7 W, time = 20-120 seconds) over which noninvasive thermal occlusion of the epididymis can be achieved. Thermal occlusion rates were higher, and complications lower, than found previously with vas deferens ablation. CONCLUSION(S): The epididymis represents a larger and easier target than the vas deferens for performing noninvasive male sterilization using focused ultrasound. Long-term azoospermia studies will be necessary to confirm permanent sterilization with this technique.

Fried, N. M., Y. D. Sinelnikov, et al. (2001). "Noninvasive vasectomy using a focused ultrasound clip: thermal measurements and simulations." IEEE Trans Biomed Eng 48(12): 1453-1459.

INTRODUCTION: Conventional surgical vasectomy may lead to complications including bleeding, infection, and scrotal pain. Noninvasive transcutaneous delivery of therapeutic focused ultrasound has previously been shown to thermally occlude the vas deferens. However, skin burns and inconsistent vas occlusion have presented complications. This study uses bio-heat transfer simulations and thermocouple measurements to determine the optimal ablation dosimetry for vas occlusion without skin burns. METHODS: A 2-rad ultrasound transducer mounted on a vasectomy-clip-delivered ultrasound energy at 4 MHz to the canine vas deferens co-located at the focus between the clip jaws. Chilled degassed water was circulated through an attached latex balloon, providing efficient ultrasound coupling into the tissue and active skin cooling to prevent skin burns. Thermocouples placed at the vas, intradermal, and skin surface locations recorded temperatures during ablation. Procedures were performed with transducer acoustic powers of 3-7 W and sonication times of 60-120 s on both the left and right vas deferens (n = 2) in a total of four dogs (precooling control, 3 W/120 s, 5 W/90 s, 7 W/60 s). Measurements were compared with bio-heat transfer simulations modeling the effects of variations in power and sonication time on tissue temperatures and coagulation zones. RESULTS: Active skin cooling produces a thermal gradient in the tissue during ablation, allowing sufficient thermal doses to be delivered to the vas without skin burns. However, low-power, long-duration heating produced excessive tissue necrosis due to thermal diffusion, while high power and short heating times reduced the therapeutic window and produced skin burns presumably due to direct ultrasound absorption. CONCLUSIONS: Both simulations and experiments suggest that a therapeutic window exists in which thermal occlusion of the vas may be achieved without the formation of skin burns in the canine model (power = 5-7 W, surface intensity = 1.4-1.9 W/cm2, time = 20-50 s). This range of ablation parameters will help guide future experiments to refine incisionless vasectomy using focused ultrasound.

Friedman, J., R. L. Dunn, et al. (2008). "Neoadjuvant docetaxel and capecitabine in patients with high risk prostate cancer." J Urol 179(3): 911-915; discussion 915-916.

PURPOSE: Docetaxel is the most active cytotoxic agent in hormone refractory prostate cancer. Preclinically docetaxel increases expression of thymidine phosphorylase, an enzyme responsible for activation of capecitabine to 5-fluorouracil resulting in increased antitumor activity. We assessed activity and safety of neoadjuvant docetaxel and capecitabine in patients with high risk prostate cancer. MATERIALS AND METHODS: Patients with either clinical stage greater than T2, prostate specific antigen 15 ng/ml or more, or Gleason sum 8 or greater received 3 to 6 cycles of docetaxel (36 mg/m2 intravenously on days 1, 8 and 15) and capecitabine (1,250 mg/m2 per day orally divided twice a day on days 5 to 18) every 28 days, followed by local therapy. The primary end point was rate of 50% or greater prostate specific antigen decrease. Correlative studies included qualitative changes in histology, tissue thymidine phosphorylase and survivin expression, and CK18Asp396 (serum apoptosis marker). RESULTS: A total of 15 patients were treated, of whom 6 (40%) experienced a 50% or greater decrease in prostate specific antigen with infrequent diarrhea or hand-foot syndrome. Eleven patients underwent radical prostatectomy. There were no pathological complete responses and 4 patients demonstrated mild histological changes, including focal necrosis and vacuolated cytoplasm. While there was no discernable pattern of increased thymidine phosphorylase expression, 4 specimens showed decreased survivin expression, suggesting a possible mechanism for chemotherapy induced apoptosis. There was no correlation of prostate specific antigen response and survivin expression, and no increase in serum CK18Asp396. CONCLUSIONS: Neoadjuvant docetaxel and capecitabine is well tolerated but is not associated with significant pathological and prostate specific antigen responses.

Frohlich, D. A., M. T. McCabe, et al. (2008). "The role of Nrf2 in increased reactive oxygen species and DNA damage in prostate tumorigenesis." Oncogene 27(31): 4353-4362.

The impact of oxidative stress in human cancer has been extensively studied. It is accepted that elevated reactive oxygen species (ROS) promote mutagenic DNA damage. Even with an extensive armament of cellular antioxidants and detoxification enzymes, alterations to DNA occur that initiate cellular transformation. Erythroid 2p45 (NF-E2)-related factor 2 (Nrf2) is a basic-region leucine zipper transcription factor that mediates the expression of key protective enzymes through the antioxidant-response element (ARE). By analysing 10 human prostate cancer microarray data sets, we have determined that Nrf2 and members of the glutathione-S-transferase (GST) mu family are extensively decreased in human prostate cancer. Using the TRAMP transgene and Rb and Nrf2 knockout murine models, we demonstrated that the loss of Nrf2 initiates a detrimental cascade of reduced GST expression, elevated ROS levels and ultimately DNA damage associated with tumorigenesis. Based on overwhelming data from clinical samples and the current functional analysis, we propose that the disruption of the Nrf2-antioxidant axis leads to increased oxidative stress and DNA damage in the initiation of cellular transformation in the prostate gland.

Fu, Z., I. M. Dozmorov, et al. (2002). "Osteoblasts produce soluble factors that induce a gene expression pattern in non-metastatic prostate cancer cells, similar to that found in bone metastatic prostate cancer cells." Prostate 51(1): 10-20.

BACKGROUND: Progressive prostate cancer typically metastasizes to bone where prostate cancer cells gain an osteoblast-like phenotype and induce osteoblastic metastases through unknown mechanisms. To investigate the biology of prostate cancer skeletal metastases, we compared gene expression between the non-metastatic LNCaP cell line and its derivative cell line C4-2B that metastasizes to bone. METHODS: Total RNA from LNCaP and C4-2B cell lines was isolated and used to probe membrane-based gene arrays (Comparison 1). Additionally, LNCaP cells were incubated in the absence or presence of conditioned media (CM) from a human osteoblast-like cell line (HOBIT) and total RNA from these cells was used to probe gene arrays (Comparison 2). Differential expression of genes was confirmed by RT-PCR. RESULTS: Of the 1,176 genes screened, 35 were differentially expressed between LNCaP and C4-2B cells (Comparison 1). HOBIT-CM induced differential expression of 30 genes in LNCaP cells (Comparison 2). Interestingly, 19 genes that were differentially expressed in C4-2B vs. LNCaP also displayed a similar expression pattern in LNCaPs grown in HOBIT-CM. These genes are primarily involved in motility, metabolism, signal transduction, tumorigenesis, and apoptosis. CONCLUSIONS: These results suggest that osteoblasts produce soluble factors that contribute to the progression of prostate cancer skeletal metastases, including their transition to an osteoblast-like phenotype. Additionally, these data provide targets to explore for further investigations towards defining the biology of skeletal metastases.

Fu, Z., Y. Kitagawa, et al. (2006). "Metastasis suppressor gene Raf kinase inhibitor protein (RKIP) is a novel prognostic marker in prostate cancer." Prostate 66(3): 248-256.

BACKGROUND: Diminished expression of Raf kinase inhibitor protein (RKIP), an inhibitor of the Raf signaling cascade, promotes prostate cancer (PCa) metastasis in a murine model, suggesting that it is a metastasis suppressor gene. However, the prognostic significance of RKIP expression and its association with metastasis in PCa patients is unknown. METHODS: To investigate RKIP protein expression is a prognostic marker in PCa we performed immunohistochemical staining for RKIP expression in tissue microarrays consisting of 758 non-neoplastic prostate tissues, primary tumors and metastases from 134 PCa patients. The Cox proportional-hazards model was used to adjust for covariates including Gleason score, tumor volume, tumor weight, clinical stage, digital rectal exam findings, serum PSA level and surgical margins. RESULTS: RKIP expression was low in approximately 5%, 48%, and 89% of non-neoplastic prostate, primary tumors and metastases, respectively. Low RKIP expression in primary tumors was a strong positive predictive factor for PCa recurrence based on PSA levels. In patients whose primary tumors expressed high RKIP levels, the 7-year PSA recurrence rate was <10%; whereas in patients with tumors with low RKIP expression the recurrence rate was 50% (P<0.001). Multivariate analysis revealed RKIP was an independent prognostic factor (P<0.001). CONCLUSION: In contrast to increased expression of pro-tumorigenic genes, these results demonstrate decreased protein expression of a gene, for example, RKIP, can serve as a prognostic marker in PCa patients.

Fu, Z., P. C. Smith, et al. (2003). "Effects of raf kinase inhibitor protein expression on suppression of prostate cancer metastasis." J Natl Cancer Inst 95(12): 878-889.

BACKGROUND: Raf kinase inhibitor protein (RKIP), an inhibitor of Raf-mediated activation of mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK), is expressed at lower levels in human C4-2B metastatic prostate cancer cells than in the parental non-metastatic LNCaP prostate cancer cells from which they were derived. We examined whether RKIP functions as a suppressor of metastasis. METHODS: Immunohistochemistry was used to detect RKIP expression in clinical samples of primary prostate cancer and prostate cancer metastases. LNCaP and C4-2B cells were stably transfected with plasmids that constitutively expressed antisense and sense RKIP cDNA, respectively, or with empty vector. Assays of cell proliferation, soft-agar colony formation, and in vitro cell invasion were used to examine the malignant phenotypes of the transfected cells. An orthotopic murine model was used to examine the effect of expressing RKIP in C4-2B cells on the development of spontaneous metastasis. RESULTS: Clinical samples of primary prostate cancer had detectable RKIP expression, whereas clinical samples of prostate cancer metastases did not. There were no differences in the in vitro proliferation rate or colony-forming ability between the control vector-transfected and sense RKIP vector-transfected C4-2B cells or between the control vector-transfected and the antisense RKIP vector-transfected LNCaP cells. Overexpression of RKIP in C4-2B cells was associated with decreased in vitro cell invasion, decreased development of lung metastases in vivo, and decreased vascular invasion in the primary tumor but did not affect primary tumor growth in mice. CONCLUSIONS: RKIP does not influence the tumorigenic properties of human prostate cancer cells. It appears to be a novel and clinically relevant suppressor of metastasis that may function by decreasing vascular invasion.

Fugita, O. E., D. Y. Chan, et al. (2004). "Laparoscopic radical nephrectomy in obese patients: outcomes and technical considerations." Urology 63(2): 247-252; discussion 252.

OBJECTIVES: To review our technique and experience with laparoscopic radical nephrectomy (LRN) in the obese patient population. Obesity has been considered a potential risk factor for poor outcomes in a variety of surgical procedures and has been considered a relative contraindication to laparoscopy. Since 1996, with increased experience and technical modifications, obesity has not been considered a contraindication for laparoscopy at our institution. METHODS: Retrospective data were obtained for all patients who underwent LRN from January 1997 to December 2000. A body mass index (Quetelet's index) greater than 30 was used to define obese patients. Technical modifications included slightly greater insufflation pressures and a lateral shift in trocar sites. The obese laparoscopic group was compared with the nonobese laparoscopic group. RESULTS: Of 101 patients who underwent LRN, 69 were not obese and 32 were obese. No statistically significant differences were observed in any of the analyzed operative data between the nonobese laparoscopic group and obese laparoscopic group, including a mean operative time of 220 and 242 minutes, respectively. Other factors assessed were the time to ambulation, length of hospital stay, conversion rate to an open procedure, and complication rate, which also demonstrated no statistically significant difference. Only one conversion to an open procedure was required in both the obese and the nonobese laparoscopic groups. CONCLUSIONS: With minor technical modifications, LRN can be safely performed in obese patients. Proper trocar site selection and greater insufflation pressures were critical for success. The differences in the intraoperative and postoperative course of LRN in obese and nonobese patients were not statistically significant. Obesity should not be considered a contraindication to laparoscopic nephrectomy.

Fujita, H., K. Koshida, et al. (2002). "Cyclooxygenase-2 promotes prostate cancer progression." Prostate 53(3): 232-240.

BACKGROUND: Cyclooxygenase (COX) -2, an inducible isoform of COX, has been observed to be expressed in prostate cancer. Several studies have reported that COX-2 overexpression is associated with carcinogenesis, cell growth, angiogenesis, apoptosis, and invasiveness in a variety of tumor types. METHODS: To investigate the function of COX-2 in prostate cancer directly, we stably transfected human full-length COX-2 cDNA into LNCaP cells (LNCaP-COX-2), which express low levels of endogenous COX-2. RESULTS: The level of COX-2 mRNA and protein and the COX activity in COX-2 LNCaP-COX-2 cells was significantly increased compared with parent and control-transfected cells. Overexpression of COX-2 increased both proliferation in vitro and tumor growth rate in vivo. However, the pro-tumor effect was neither associated with changes of androgen receptor (AR) expression level nor AR activity. Furthermore, addition of the major metabolites of COX-2-mediated arachidonic acid metabolism did not alter the proliferation of LNCaP-COX-2 cells in vitro. LNCaP-COX-2 cells had increased secretion of vascular endothelial growth factor (VEGF) protein, suggesting that angiogenesis induced by COX-2 stimulates tumor growth in vivo. CONCLUSION: These data demonstrate that COX-2 contributes to prostate cancer progression and suggest that it mediates this effect, in part, through increased VEGF.

Fukunaga-Johnson, N., S. W. Lee, et al. (1996). "Molecular analysis of a gene, BB1, overexpressed in bladder and breast carcinoma." Anticancer Res 16(3A): 1085-1090.

The AN43 antigen is a new bladder tumor marker which is present in bladder cancer specimens as well as breast cancer specimens (1). Our objective was to clone the AN43 gene and determine its possible role in bladder and breast tumorigenesis. A bladder tumor cell cDNA expression library was made and screened with a murine monoclonal antibody to the AN43 antigen. A 1897 bp cDNA clone was isolated following expression screening with the AN43 antibody and named BB1. Following DNA sequencing, the BB1 cDNA clone was determined to have no homology to any known gene when screened through GenBank. RNA analysis demonstrated increased expression of BB1 mRNA in metastatic breast and bladder carcinomas relative to normal breast epithelium and urothelium. Treatment with gamma-interferon resulted in decreased mRNA expression. BB1 mRNA expression is increased in malignant cells relative to normal cells and is down-regulated following gamma-interferon treatment and therefore may have a role in tumor progression. Further characterization and functional analysis of this novel gene will be useful in understanding tumor development and metastatic potential.

Gabr, A. H., Y. Gdor, et al. (2009). "Radiographic surveillance of minimally and moderately complex renal cysts." BJU Int 103(8): 1116-1119.

OBJECTIVE: To assess the effectiveness of radiographic surveillance for managing minimally and moderately complex renal cysts. PATIENTS AND METHODS: Forty-three patients with 50 minimally or moderately complex renal cysts underwent radiographic surveillance at our institution. Study inclusion criteria were surveillance for >2 years (36 patients, mean follow-up 3.0 years) or surveillance for >6 months with subsequent surgical excision (seven patients, mean follow-up 3.3 years). RESULTS: The complexity of the renal cysts was in the form of high attenuation before contrast-enhanced imaging ('hyperdense') in 29 patients, thin septations in nine, borderline enhancement in six, thin calcifications in five, and a thick wall in one. The mean initial largest dimension was 2.9 cm and the mean final dimension was 3.0 cm, with the size increased in 29 cysts, decreased in 14 and with no change in seven. The cyst character worsened in seven patients, improved in four and did not change in 39. Eventually seven patients had surgery (laparoscopic partial nephrectomy in five and laparoscopic radical nephrectomy in two), which revealed renal cancer in five. Surgical intervention was prompted by growth alone in two patients, growth and worsening of cyst characteristics in two, new onset of flank pain in one, and appearance of an enhancing nodule in the wall or septa in two. CONCLUSION: Radiographic surveillance is an effective method for managing patients with minimally or moderately complex renal cysts. Malignant lesions can be identified and removed while still of low grade and contained, and surgery can be avoided in most patients.

Gabr, A. H., Y. Gdor, et al. (2009). "Approach and specimen handling do not influence oncological perioperative and long-term outcomes after laparoscopic radical nephrectomy." J Urol 182(3): 874-880.

PURPOSE: We assessed the impact of approach (standard vs hand assisted) and specimen handling (morcellation vs intact extraction) on laparoscopic radical nephrectomy short-term recovery and long-term oncological outcome. MATERIALS AND METHODS: Of 255 patients with pathologically confirmed and presumed localized renal cell carcinoma 147 underwent standard and 108 underwent hand assisted laparoscopic radical nephrectomy. Specimen handling was done by intact extraction in 132 cases and morcellation in 123. Perioperative data were recorded prospectively and oncological surveillance was reviewed retrospectively. RESULTS: Despite significant differences in body mass index, mass size, T stage and pathological risk between the groups there were no statistically significant differences in perioperative outcome by approach or specimen handling except greater estimated blood loss (mean 406 vs 283 ml), longer hospital stay (mean 2.8 vs 2.4 days) and greater time to recovery (mean 13 vs 9.9 days) in the hand assisted vs the standard group. Discovery of pT3 disease was not significantly different between the specimen handling groups after controlling for mass size. Multivariate analysis of 5-year Kaplan-Meier survival curves revealed that neither approach nor specimen handling impacted recurrence-free, cancer specific or overall survival. CONCLUSIONS: Differences in perioperative outcomes attributable to the specific approach (standard vs hand assisted) and the method of specimen handling (morcellation vs intact extraction) at laparoscopic radical nephrectomy have minimal clinical significance. There are no discernible differences in long-term oncological efficacy. The choice of approach and specimen handling for laparoscopic radical nephrectomy can be based on surgeon and patient preference, cosmetic considerations and other factors.

Gabr, A. H., Y. Gdor, et al. (2009). "Patient and pathologic correlates with perioperative and long-term outcomes of laparoscopic radical nephrectomy." Urology 74(3): 635-640.

OBJECTIVES: To comprehensively analyze and compare patient and pathologic correlates with perioperative events and with the long-term results of laparoscopic radical nephrectomy. METHODS: Laparoscopic radical nephrectomy was performed in 255 patients with renal cell carcinoma. Mean follow-up time was 35.2 months; for 39 patients, it was 5 or more years. RESULTS: Multivariate analysis revealed that major intraoperative complications were associated with increased body mass index and that major postoperative complications were associated with a higher American Society of Anesthesiologists (ASA) score. Older age and higher ASA score were associated with longer hospitalization. Patients were classified using a risk group stratification that incorporated grade and stage; 118 patients were low risk, 93 were intermediate risk, and 44 patients were high risk. No pathologic features were associated with perioperative outcomes. Kaplan-Meier recurrence-free, cancer-specific, and overall survival at 5 years were 79.2%, 88%, and 76.2%, respectively. Multivariate analysis revealed that pathologic risk group, mass size, and high-risk histologic subtype were associated with recurrence-free survival, and cancer-specific survival was associated with pathologic risk group and mass size. Age, high-risk pathologic risk group, and a high-risk histologic subtype were associated with overall survival. CONCLUSIONS: Our results indicate that perioperative outcomes of laparoscopic radical nephrectomy are associated with body mass index, ASA score, and age, but not with tumor characteristics. Recurrence-free and cancer-specific survival rates were associated with the expected pathologic parameters, confirming the oncologic efficacy of the procedure. Overall survival is associated not only with tumor pathology but also with age, suggesting that competing-cause mortality is important in this setting.

Gadzinski, A. J., W. W. Roberts, et al. (2010). "Long-term outcomes of nephroureterectomy versus endoscopic management for upper tract urothelial carcinoma." J Urol 183(6): 2148-2153.

PURPOSE: We compared outcomes in patients treated with nephroureterectomy vs nephron sparing endoscopic surgery for upper tract urothelial carcinoma. MATERIALS AND METHODS: Patients treated at our institution for upper tract urothelial carcinoma from 1996 to 2004 were monitored for upper tract and bladder recurrence, metastasis, and cancer specific and overall survival. Outcomes were compared between treatment groups by univariate and multivariate analyses based on pertinent pathological and demographic variables. RESULTS: Of 96 renal units 62 underwent immediate nephroureterectomy and 34 were managed endoscopically. Median followup in all survivors was 77 months. Overall nephroureterectomy and endoscopy complication rates were 29% and 9.3%, respectively. In patients with low grade tumors the 5-year metastasis-free survival rate after nephroureterectomy and endoscopy was 88% and 94%. The corresponding 5-year cancer specific and overall survival rates were 89% vs 100% and 72% vs 75%, respectively. Of endoscopic cases 84% had at least 1 ipsilateral recurrence. Multivariate analysis revealed that only tumor grade was significantly associated with metastasis-free survival while grade and body mass index correlated with cancer specific survival, and Charlson Comorbidity index and grade impacted overall survival. Treatment group was not associated with survival outcome. CONCLUSIONS: When technically feasible and in select patients, endoscopic management provides cancer related and overall survival equivalent to that of nephroureterectomy in patients with low grade upper tract urothelial carcinoma at the cost of frequent re-treatments in many patients. Nephroureterectomy is standard treatment for high grade cancer when there is a normal contralateral kidney but endoscopy should be considered when there are imperative indications for nephron sparing.

Galetti, T. P., J. E. Pontes, et al. (1989). "Neoadjuvant intra-arterial chemotherapy in the treatment of advanced transitional cell carcinoma of the bladder: results and followup." J Urol 142(5): 1211-1214; discussion 1214-1215.

The long-term results of regional chemotherapy plus intra-arterial cisplatin with or without doxorubicin as an adjuvant before cystectomy and urinary diversion in patients with invasive transitional cell carcinoma of the bladder were evaluated. A total of 27 patients with T3aNxMo (8), T3bNxMo (14) and T4NxMo (5) disease participated in a phase II trial completed in 1985. Of the patients 19 received cisplatin and doxorubicin intra-arterially, and cyclophosphamide intravenously, and the remaining 8 received 70 to 100 mg. per m.2 cisplatin intra-arterially. A total of 19 patients underwent cystectomy after chemotherapy. Patients in this group had a pathological complete response (no evidence of disease after surgical restaging) or the presence of residual disease at operation that could (surgical complete response) or could not (pathological partial response) be completely resected. Of the 19 patients undergoing cystectomy surgical complete response was observed in 47.4%, pathological complete response in 26.3% and pathological partial response in 26.3%. At a median followup of 27 months for the group 66% of the patients with a surgical complete response, 100% with a pathological complete response and 40% with a pathological partial response were alive with no evidence of disease. The over-all survival for patients with a pathological or surgical complete response is 76.9%. In the patients not operated upon because of persistent or advanced disease after chemotherapy survival was brief (less than 4 months). Prolonged survival in patients achieving a pathological or surgical complete response with neoadjuvant chemotherapy occurs, and this modality may have a role in patients with invasive tumors.

Gallagher, B. L., N. T. Dwyer, et al. (2007). "Objective and quality-of-life outcomes with bone-anchored male bulbourethral sling." Urology 69(6): 1090-1094.

OBJECTIVES: To investigate the success rates and quality-of-life outcomes with the male bulbourethral sling using the validated Male Urogenital Distress Inventory (MUDI) and Male Urinary Symptom Impact Questionnaire (MUSIQ). These validated incontinence questionnaires for men have not been reported in the sling population. METHODS: A total of 31 consecutive patients underwent placement of a male bulbourethral bone-anchoring sling from October 2002 through May 2005. The preoperative information included history and physical examination, pad history, urodynamic findings, and MUDI and MUSIQ results. Postoperatively, the patients were evaluated clinically and completed a MUDI and MUSIQ every 6 months. RESULTS: Of the 31 patients, 24 completed the questionnaires and follow-up protocol. Of the other 7 patients, 4 underwent sling removal and 3 were lost to follow-up. The average follow-up time was 15 months (range 9 to 21). After surgery, the pad use decreased from a median of 3.7 pads/day (range 1 to 12) to 1.3 pads/day (range 0 to 6). Of the 24 analyzed patients, 18 (75%) were dry or using 1 pad or less per day, and 9 (38%) no longer needed pads. Subjectively, 75% of the patients were satisfied. The mean MUDI and MUSIQ scores decreased from 56.8 and 29.9 preoperatively to 44.8 (P <0.0001) and 14.6 (P = 0.002) after sling placement, respectively. When all 31 patients were included, our clinical success rate of 1 pad/day or less decreased to 58%. CONCLUSIONS: Of the 24 patients with follow-up data, 75% were satisfied and were clinically cured. A significant improvement was seen after surgery in the MUDI and MUSIQ scores, severity of incontinence, and average pad use. The MUDI and MUSIQ scores paralleled patient satisfaction and clinical success after male bulbourethral sling placement.

Gandy, S., R. B. DeMattos, et al. (2004). "Alzheimer's Abeta vaccination of rhesus monkeys (Macaca mulatta)." Mech Ageing Dev 125(2): 149-151.

Recent preliminary data suggest that vaccination with Alzheimer's Abeta might reduce senile plaque load and stabilize cognitive decline in human Alzheimer's disease. To examine the mechanisms and consequences of anti-Abeta-antibody formation in a species more closely related to humans, rhesus monkeys (Macaca mulatta) were vaccinated with aggregated Abeta(1-42). Immunized monkeys developed anti-Abeta titers exceeding 1:1000, and their plasma Abeta levels were 5-10-fold higher than the plasma Abeta levels observed in monkeys vaccinated with aggregated amylin. These data support the use of non-human primates to model certain phenomena associated with vaccination of humans with aggregated Alzheimer's Abeta.

Garcia, V. F. and D. A. Bloom (1986). "Inversion appendectomy." Urology 28(2): 142-143.

Gardner, S. M., J. S. Wolf, Jr., et al. (1996). "The unintubated ureterotomy endourologically revisited." J Urol 156(3): 1160-1163.

PURPOSE: The duration of stenting after endoureterotomy is a controversial issue. An even more basic question, however, is whether stent placement is needed at all. We performed a porcine study to address this question. METHODS: A unilateral midureteral stricture was created in 20 minipigs. Six weeks later, 15 pigs underwent endoureterotomy. In 10 animals, a 7F ureteral stent was placed for 1 week. Five pigs remained unstented. Three months later, all 20 ureters were studied radiographically and were harvested. RESULTS: Three of 5 control animals and 2 of 10 stented animals has strictures. In the unstented study group, all 5 animals had a nonobstructing dilation at the site of endoureterotomy. This was corroborated by a normal furosemide washout renal scan in all 3 animals so tested. CONCLUSIONS: The result of unstented endoureterotomy in the porcine model suggests that, after endoureterotomy of secondary midureteral strictures, stenting may be unnecessary.

Gardner, T. A., D. P. Poppas, et al. (1994). "Volvulus of the ileal conduit: a late complication." J Urol 152(3): 948-950.

We report 2 cases of ileal conduit volvulus presenting as a late complication. The importance of early diagnosis and surgical intervention is discussed.

Gardy, M., M. Kozminski, et al. (1991). "Stress incontinence and cystoceles." J Urol 145(6): 1211-1213.

We studied prospectively 62 women with cystoceles by video-urodynamics before and after operative repair. Of 29 women with grades 1 and 2 cystoceles 8 had residual urine, 14 had urge incontinence and 24 had symptoms of stress urinary incontinence. Of these women 23 had urodynamic evidence of stress incontinence, as did 3 of 5 without stress incontinence symptoms. Of 33 women with large cystoceles 22 had symptoms of stress urinary incontinence but 10 more had urodynamic evidence of stress urinary incontinence. Of these 33 women 18 had significant residual urine and 24 had urge incontinence. Operative repair resolved stress incontinence in 51 of 54 women, urge incontinence in 33 of 38 and residual urine in 24 of 26. Cystoceles recurred in 3 patients, and enteroceles developed in 3 and recurred in 2. These findings indicate that cystoceles may cause voiding dysfunction and lack of symptoms of stress incontinence is unreliable in patients with cystoceles. In addition, cystoceles are associated with other symptoms, most of which actually resolve after operative repair.

Garg, M. K., S. Tekyi-Mensah, et al. (1998). "Impact of postprostatectomy prostate-specific antigen nadir on outcomes following salvage radiotherapy." Urology 51(6): 998-1002.

OBJECTIVES: To evaluate the relationship between the postprostatectomy prostate-specific antigen (PSA) nadir and the outcome of patients treated with salvage radiotherapy. METHODS: Seventy-eight patients received definitive external beam radiation for recurrence following radical prostatectomy (RP). The PSA nadir was undetectable in 41 patients (less than 0.05 ng/mL). All patients received salvage radiotherapy (median dose 66 Gy) for a median of 19 months (range 2 to 149) following prostatectomy. The median follow-up time was 25 months (range 1 to 59) from the date of completion of radiation. RESULTS: Among patients having an undetectable or detectable postoperative PSA, 78% and 68% were free of disease, respectively, at the last follow-up. At 3 years, the disease-free survival rates were 65% and 60%, respectively (P = 0.6). Overall, the disease-free survival rate at 3 years was 78% in patients with a PSA level 2 ng/mL or less at the time of radiotherapy compared to 31% with a PSA greater than 2 ng/mL (P < 0.0001). CONCLUSIONS: Many patients who never achieve an undetectable postprostatectomy PSA level may still be salvaged with therapeutic radiotherapy. The best predictor of a favorable outcome is a low (2 ng/mL or less) PSA level at the time of radiation.

Gdor, Y., A. H. Gabr, et al. (2008). "Success of laser endoureterotomy of ureteral strictures associated with ureteral stones is related to stone impaction." J Endourol 22(11): 2507-2511.

PURPOSE: Since the holmium:yttrium-aluminum-garnet (Ho:YAG) laser is the flexible lithotrite of choice for ureteral stones, its application to ureteral strictures associated with ureteral calculi is convenient. The results of Ho:YAG laser endoureterotomy in this specific setting have not been defined. We report our experience with Ho:YAG laser endoureterotomy of ureteral strictures associated with ureteral stone treatment, with or without a history of stone impaction. METHODS: We reviewed the medical records of 13 patients with ureteral stricture related to stone treatment, with (n = 9) or without (n = 4) a history of impacted ureteral stones, who were managed with Ho:YAG laser endoureterotomy. Follow-up was obtained with radiographic imaging and renal scans. RESULTS: The overall success rate was 62%, with a mean follow-up of 21 months in successful cases and a mean recurrence time of 1.6 months in failures. Outcome was not associated with length or location of the stricture. Among the nine strictures associated with impacted stones, treatment was successful in only 5 (56%). Of the four strictures that occurred after stone removal but without history of impaction, the success rate was 75%. Success was also greater for strictures managed with post-procedure stents >or=8 Fr (75%), compared to stents <or=7 Fr. (56%). CONCLUSIONS: Our results suggest that laser endoureterotomy of ureteral strictures due to ureteral stone treatment without a history of impaction is associated with a reasonable success rate (75%), but that laser endoureterotomy for strictures related to impacted stones is associated with a success rate of only 56%. Larger caliber stents might be preferred in this setting.

Gdor, Y., A. H. Gabr, et al. (2008). "Holmium:yttrium-aluminum-garnet laser endoureterotomy for the treatment of transplant kidney ureteral strictures." Transplantation 85(9): 1318-1321.

BACKGROUND: The management of ureteral strictures in transplanted kidney is challenging. Open surgical treatment is effective but entails significant convalescence. Holmium:yttrium-aluminum-garnet (Ho:YAG) laser endoureterotomy is useful for other types of ureteral obstruction, and we aimed to assess its long-term success for strictures of transplant kidney ureters. METHODS: We reviewed the course of 12 kidney transplant patients managed with Ho:YAG laser endoureterotomy and/or percutaneous ureteroscopic balloon dilatation for ureterovesical anastomotic strictures or ureteropelvic junction obstruction. Success was defined as stable serum creatinine and no hydronephrosis on follow-up. RESULTS: Of the patients, nine had ureterovesical anastomotic strictures. Of the six treated with balloon dilatation and Ho:YAG laser endoureterotomy, the success rate was 67% (58 months mean follow-up). Both strictures with failure were longer than 10 mm. Of the three patients treated with balloon dilatation only, there was success in only one (14 months follow-up) and both strictures with failure were shorter than 10 mm. There were three patients treated for ureteropelvic junction obstruction, one with balloon dilatation and two with balloon dilatation plus Ho:YAG laser endoureterotomy, all successfully (57 months mean follow-up). Overall, of the eight strictures 10 mm or shorter, there was success rate in six (75%), with 52 months mean follow-up, including five of five (100%) treated with laser endoureterotomy and one of three (33%) treated with only balloon dilation. CONCLUSIONS: Our results suggest that Ho:YAG laser endoureterotomy should be a first line treatment for ureteral strictures of length 10 mm or shorter in kidney transplant patients.

Gerhard, G. S., R. L. Malek, et al. (2004). "Zebrafish, killifish, neither fish, both fish?" J Gerontol A Biol Sci Med Sci 59(9): B873-875.

Gerig, N. E., R. B. Meacham, et al. (1997). "Use of electroejaculation in the treatment of ejaculatory failure secondary to diabetes mellitus." Urology 49(2): 239-242.

OBJECTIVES: To describe the experience of two male fertility programs using electroejaculation (EEJ) in the management of men with ejaculatory failure secondary to diabetes mellitus. METHODS: Twenty-nine EEJ procedures were performed in 7 diabetic men with ejaculatory failure. Results were reviewed with attention paid to sperm characteristics in both antegrade and retrograde specimens as well as pregnancy rates. RESULTS: Retrograde semen specimens retrieved from the bladder following EEJ contained a mean of 3444.5 million sperm (range 269.2 to 4996 million). Antegrade specimens contained a mean of 698.8 million sperm (range 226.8 to 1961 million). Mean sperm motility was 4% for retrograde specimens (range 0% to 11%) and 7% for antegrade specimens (1% to 15%). In all but 1 case, semen specimens were used for intrauterine insemination. The total number of motile sperm contained in the processed, inseminated specimens ranged from 1 to 87.2 million. In 1 case, the sperm obtained through EEJ was used in an in vitro fertilization procedure. CONCLUSIONS: EEJ can be successfully used to obtain sperm from men with ejaculatory failure due to diabetes mellitus. The procedure requires general anesthesia, and pregnancy rates after intrauterine insemination with the processed sperm are low. Advanced reproductive technologies may offer a feasible alternative, providing higher success rates with fewer procedures.

Gheiler, E. L., J. Lovisolo, et al. (1999). "Results of a clinical care pathway for radical prostatectomy patients in an open hospital: Multiphysician system." Eur Urol 35: 210-216.

Gheiler, E. L., M. V. Tefilli, et al. (1998). "Management of primary urethral cancer." Urology 52(3): 487-493.

OBJECTIVES: To determine the best therapeutic approach for treatment of patients with urethral cancer according to tumor location and clinical-pathologic stage. METHODS: A retrospective review of 21 consecutive patients diagnosed with primary urethral carcinoma was performed. Clinical-pathologic staging, treatment modality, and outcome were analyzed. RESULTS: The overall survival rate was 62%. In patients with clinical Stage Ta-2N0M0 tumors, 8 of 9 patients (89%) are free of disease compared to 5 of 12 patients (42%) with Stage T3-4N0-2M0 tumors (P = 0.03). Best treatment outcome for patients with Stage T3 disease or higher was obtained when multimodality therapy (neoadjuvant chemotherapy and radiation therapy with or without surgery) was administered, with a disease-free survival rate of 60%. CONCLUSIONS: Clinical-pathologic stage was a strong predictor of disease-free survival rate. For patients with Ta-2N0M0 tumors, multimodality therapy may not be required. Conversely, best treatment outcomes in patients with T3-4N0-2M0 tumors are obtained by administering a multimodal therapy combining chemotherapy and radiation therapy with surgical resection.

Gheiler, E. L., M. V. Tefilli, et al. (1998). "Predictors for maximal outcome in patients undergoing salvage surgery for radio-recurrent prostate cancer." Urology 51(5): 789-795.

OBJECTIVES: To determine preradiation and preoperative clinical staging and postoperative pathologic factors that can predict disease-free survival in patients undergoing salvage surgery for radio-recurrent prostate cancer. METHODS: A retrospective review was performed on 40 patients who underwent salvage surgery for radio-recurrent prostate cancer. Preradiation and preoperative clinical staging factors, as well as pathologic stage were analyzed as predictors of disease-free survival. Biochemical failure was defined as a persistent serum prostate-specific antigen (PSA) elevation greater than 0.4 ng/mL. RESULTS: As a group, salvage surgery provided excellent clinical disease control in 35 of 40 patients (87.5%). Overall, 18 of 38 (47.4%) patients analyzed had no evidence of biochemical progression. Preradiation clinical stage and pathologically organ-confined disease were statistically significant predictors of disease-free survival (P = 0.03 and P = 0.02, respectively). Seminal vesicle invasion and positive lymph nodes were the worst pathologic prognostic factors. Preoperative clinical T1c disease approached statistical significance in predicting pathologically organ-confined disease and disease-free survival (P = 0.08 and P = 0.07, respectively). CONCLUSIONS: Ideal candidates for salvage surgery should have preradiation and preoperative clinically organ-confined disease. All patients with pathologically organ-confined disease following salvage prostatectomy were disease free at a mean follow-up of 36.1 months. Salvage surgery, although technically feasible, should not be widely advocated as an effective curative treatment in patients with locally advanced disease at the time of diagnosis.

Gheiler, E. L., D. P. Wood, Jr., et al. (1997). "Orthotopic urinary diversion is a viable option in patients undergoing salvage cystoprostatectomy for recurrent prostate cancer after definitive radiation therapy." Urology 50(4): 580-584.

OBJECTIVES: To evaluate whether orthotopic urinary diversion is a viable option for patients undergoing cystoprostatectomy for radio-recurrent prostate cancer (RRPC). METHODS: Between 1990 and 1996, we performed 34 salvage surgeries for RRPC, including 26 radical retropubic prostatectomies and 8 cystoprostatectomies. We determined the operative and postoperative complication rates and pathologic stage for the 8 patients undergoing cystoprostatectomy. RESULTS: Of the 8 patients in whom cystoprostatectomy was performed, 5 underwent ileal conduit diversion and 3 underwent orthotopic neobladder reconstruction. There were no intraoperative complications or perioperative mortalities. In the group with orthotopic neobladder, postoperative complications included pyelonephritis in 1 patient and prolonged ileus in another. In the group with ileal conduit, no short-term complications occurred; 1 patient developed an incisional hernia on long-term follow-up. All patients with neobladder reconstruction are continent during the day. One patient wears one pad at night. The other 2 are continent at night. CONCLUSIONS: Orthotopic urinary diversion is a valid option for selected patients with RRPC who require a cystoprostatectomy. This procedure can be performed with minimal complications, resulting in good continence and good quality of life. <78>

Ghoniem, G. M., D. A. Bloom, et al. (1989). "Bladder compliance in meningomyelocele children." J Urol 141(6): 1404-1406.

The 2 components of detrusor compliance were analyzed in 32 children with myelomeningocele and compared to compliance in 15 age-matched controls with nonneuropathic enuresis. In myelomeningocele initial compliance was variable, whereas terminal compliance was relatively constant. Low terminal compliance corresponded with vesicoureteral reflux, deterioration of upper tract morphology and diminished renal function.

Gibbons, E. P., B. L. Jacobs, et al. (2009). "Dosimetric outcomes in prostate brachytherapy: is downsizing the prostate with androgen deprivation necessary?" Brachytherapy 8(3): 304-308.

OBJECTIVES: A large prostate volume has historically been a relative contraindication to prostate brachytherapy (PB) because of concerns of toxicity and potential pubic arch interference. Common practice has been to downsize large prostates with androgen deprivation therapy (ADT) before proceeding with brachytherapy. The present study compares postimplant dosimetry in patients with prostate volumes >50 cc with those with prostate volumes </=50 cc. METHODS: A review of all patients who underwent PB at our institution from 2001 to 2006 was performed. Postimplant dosimetry was obtained approximately 4 weeks after brachytherapy. RESULTS: One-hundred forty-five out of a total of 148 patients had available dosimetry. In the 113 patients with prostate volumes </=50 cc (mean, 35.4 cc, range, 14.2-49.7 cc); the mean D(90) (dose which covers 90% of the prostate), V(100) (volume of prostate receiving 100% of the prescribed dose), V(150) (volume of prostate receiving 150% of the prescribed dose), and V(200) (volume of prostate receiving 200% of the prescribed dose) was 128.9%, 95.6%, 73.9%, and 51.2%, respectively. In the 32 patients with prostate volumes >50 cc (mean 58.1 cc, range 50.2-86.0 cc); the mean D(90), V(100), V(150), and V(200) was 125.1%, 95.2%, 68.2%, and 41.7%, respectively. The rectal V(100) was 1.0 cc for both cohorts. There was no statistically significant difference between the cohorts with respect to postimplant dosimetry for D(90), V(100), and V(150). The V(200) for prostate volumes >50 cc was significantly lower (p<0.05). CONCLUSIONS: In the present study, patients with prostate volumes >50 cc have postimplant dosimetry parameters similar to patients with prostate volumes </=50 cc for D(90), V(100), and V(150); and significantly lower values for V(200). These results suggest that patients with large prostate volumes may not need to be routinely placed on hormonal therapy; sparing patients the side effects of hormonal therapy, and sparing the health care system the costs of luteinizing hormone-releasing hormone agonist injections.

Gibbons, R. P., J. E. Monte, et al. (1976). "Manifestations of renal cell carcinoma." Urology 8(3): 201-206.

Patients with renal cell carcinoma often have no specific localizing symptoms or signs, and their presentation will often involve many organ systems. Since 40 per cent of these patients do not have genitourinary symptoms, care must be taken to avoid being misled by normal findings on urinalysis. More than 50 per cent of patients with renal cell carcinoma have vague symptoms suggesting a gastrointestinal origin; thus if primary gastrointestinal studies do not disclose a cause for these symptoms, excretory urography must be included as a screening procedure.

Gilbert, S. M., S. Daignault, et al. (2008). "The use of tumor markers in testis cancer in the United States: a potential quality issue." Urol Oncol 26(2): 153-157.

BACKGROUND: Performance measurement is currently being implemented at various levels to address issues related to quality of care. Administrative data and cancer registries provide a measure of health care delivery (processes) at the population level. In testis cancer, the use of tumor markers is an important component of care and may represent a measurable quality indicator. We analyzed the use of testis cancer tumor markers across the United States. METHODS: Incident germ cell testis cancer cases between 1998 and 2002 were abstracted from the Surveillance, Epidemiology, and End Results (SEER) program. Tumor marker codes were categorized as performed and not performed. Bivariate and multivariable analyses were performed. Logistic regression was used to determine the independent association of demographic and clinical factors with the failure to measure or document tumor markers. RESULTS: In 4,742 testis cancer cases, performance of both alpha fetoprotein and human chorionic gonadotropin was recorded in 44.7% of cases, while performance of alpha fetoprotein, human chorionic gonadotropin, and lactate dehydrogenase together occurred in only 16%. Tumor marker use did not increase considerably between 1998 and 2002, and significant variation existed between SEER sites. In multivariable models, disease stage and the interaction between SEER site and year were significantly associated with tumor marker use. CONCLUSIONS: We have identified low and variable rates of tumor marker use in testis cancer cases recorded in SEER. As pay-for-performance evolves, standardized metrics for recommended processes of care (e.g., measurement of tumor markers in patients with testis cancer) may be tied to reimbursement. In this context, failure to document the use of tumor markers will be interpreted as less than optimal care.

Gilbert, S. M., R. L. Dunn, et al. (2010). "Development and validation of the Bladder Cancer Index: a comprehensive, disease specific measure of health related quality of life in patients with localized bladder cancer." J Urol 183(5): 1764-1769.

PURPOSE: We developed and validated a reliable, responsive multidimensional instrument to measure disease specific health related quality of life in bladder cancer survivors treated with local cancer therapy. MATERIALS AND METHODS: Instrument content was based on qualitative information obtained from a panel of bladder cancer providers and from patient focus groups. Draft items were piloted and revised, resulting in the 36-item Bladder Cancer Index consisting of urinary, bowel and sexual health domains. Internal consistency, test-retest reliability, convergent validity, concurrent validity and criterion validity were then assessed. RESULTS: Internal consistency was high at 0.77 to 0.91. Test-retest reliability was also high at 0.73 to 0.95. Correlations among the 3 domains were low (r < or = 0.39), indicating interscale independence. Health outcome discrimination was apparent in clinically distinct treatment groups. Moderate correlation was observed with existing external measures, indicating that the Bladder Cancer Index detects aspects of health related quality of life related to bladder cancer treatments that are not recorded by more general measures. CONCLUSIONS: The Bladder Cancer Index is a robust, multidimensional measure of bladder cancer specific health related quality of life and to our knowledge is the first available validated instrument to assess health outcomes across a range of local treatments commonly used for bladder cancer.

Gilbert, S. M., R. L. Dunn, et al. (2008). "Mortality after urologic cancer surgery: impact of non-index case volume." Urology 71(5): 906-910.

OBJECTIVES: To quantify the degree to which overall urologic oncology volume either reduces or enhances the effect of single procedure volume on short-term outcomes after urologic oncology surgery. METHODS: Urologic oncology procedures for prostate, kidney, and bladder cancer performed between 1988 and 2003 were identified in the Nationwide Inpatient Sample. Procedure-specific volume and urologic oncology volume (excluding the procedure of interest) were determined for each cancer and each hospital. Multivariable logistic regression models were constructed to measure the independent effect of urologic oncology volume (non-index procedures) on operative mortality after prostatectomy, cystectomy, and nephrectomy (index procedures) after adjusting for patient and hospital factors. RESULTS: Unadjusted operative mortality for prostatectomy, cystectomy, and nephrectomy was 0.2%, 2.8%, and 1.4%, respectively. For prostatectomy and cystectomy, the magnitude of the volume-mortality association was reduced after adjusting for non-index urologic oncology case volume. For example, the relationship between surgical volume and mortality was reduced by 20% for radical prostatectomy and 60% for radical cystectomy. CONCLUSIONS: The volume-outcome effect for index urologic oncology procedures is modified by experience with other non-index specialty-related procedures. Efforts to identify transferable, effective processes of care should focus on a subset of high-volume centers.

Gilbert, S. M., R. L. Dunn, et al. (2007). "Re: Zoledronic acid initiated during the first year of androgen deprivation therapy increases bone mineral density in patients with prostate cancer: C. W. Ryan, D. Huo, L. M. Demers, T. M. Beer and L. V. Lacerna. J Urol 2006; 176: 972-978." J Urol 177(4): 1584-1585; author reply 1585.

Gilbert, S. M. and B. K. Hollenbeck (2009). "Limitations of lymph node counts as a measure of therapy." J Natl Compr Canc Netw 7(1): 58-61.

For several cancers, the number of lymph nodes removed during surgery is associated with survival. Observational studies supporting this association have prompted considerable debate regarding the extent of lymphadenectomy, and in some dieases, absolute lymph node counts have been suggested as a measure of the quality of cancer care. However, for most cancers, lymph node counts may not directly influence survival in a causal manner. In fact, several randomized clinical trials addressing the question in lung, gastric, and pancreatic cancers have not shown more extensive lymph node dissections to be linked with improved survival. Despite this negative evidence, however, lymph node counts have remained a target process in quality initiatives. Misinterpretation of the evidence may be driving some of the pressure to broadly implement more extended lymph node dissections. As a process for more accurate disease staging and as a potential marker for the completeness of surgery, lymph node counts are likely linked to quality, at least indirectly. However, a causal association between lymph node counts (and extented lymphadenectomy) and survival is tenuous and has not been supported by high-level evidence.

Gilbert, S. M. and C. T. Lee (2006). "A case of T2 muscle-invasive bladder cancer treated with neoadjuvant chemotherapy." Nat Clin Pract Urol 3(12): 675-679.

BACKGROUND: A 61-year-old woman with a substantial history of smoking presented with gross hematuria. Cystoscopic evaluation revealed a large bladder tumor. INVESTIGATIONS: Cystoscopic evaluation, histological examination, crosssectional imaging. DIAGNOSIS: High-grade muscle-invasive transitional cell carcinoma (clinical stage T2N0M0, later confirmed as pathologic stage T3aN0M0). MANAGEMENT: Transurethral resection of the bladder tumor, clinical trialbased neoadjuvant treatment with paclitaxel, carboplatin and gemcitabine, and radical cystectomy.

Gilbert, S. M., D. C. Miller, et al. (2008). "Cancer survivorship: challenges and changing paradigms." J Urol 179(2): 431-438.

PURPOSE: We summarize the potential issues faced by cancer survivors, define a conceptual framework for cancer survivorship, describe challenges associated with improving the quality of survivorship care and outline proposed survivorship programs that may be implemented going forward. MATERIALS AND METHODS: We performed a nonsystematic review of current cancer survivorship literature. Given the comprehensive scope and high profile, the recent report by the Institute of Medicine, From Cancer Patient to Cancer Survivor: Lost in Transition, served as the principal guide for the review. RESULTS: In recognition of the increasing number of cancer survivors in the United States survivorship has become an important health care concern. The recent report by the Institute of Medicine comprehensively outlined deficits in the care provided to cancer survivors, and proposed mechanisms to improve the coordination and quality of followup care for this increasing number of Americans. Measures to achieve these objectives include improving communication between health care providers through a survivorship care plan, providing evidence based surveillance guidelines and assessing different models of survivorship care. Implementing coordinated survivorship care broadly will require additional health care resources, and commitment from health care providers and payers. Research demonstrating the effectiveness of survivorship care will be important on this front. CONCLUSIONS: Potential shortcomings in the recognition and management of ongoing issues faced by cancer survivors may impact the overall quality of long-term care in this increasing population. Although programs to address these issues have been proposed, there is substantial work to be done in this area.

Gilbert, S. M. and J. E. Montie (2008). "Determining when to recommend continent urinary diversion." Can Urol Assoc J 2(4): 407-409.

Gilbert, S. M., D. P. Wood, et al. (2007). "Measuring health-related quality of life outcomes in bladder cancer patients using the Bladder Cancer Index (BCI)." Cancer 109(9): 1756-1762.

BACKGROUND: Health-related quality of life (HRQOL) has not been adequately measured in bladder cancer. A recently developed reliable and disease-specific quality of life instrument (Bladder Cancer Index, BCI) was used to measure urinary, sexual, and bowel function and bother domains in patients with bladder cancer managed with several different interventions, including cystectomy and endoscopic-based procedures. METHODS: Patients with bladder cancer were identified from a prospective bladder cancer outcomes database and contacted as part of an Institutional Review Board-approved study to assess treatment impact on HRQOL. HRQOL was measured using the BCI across stratified treatment groups. Bivariate and multivariable analyses adjusted for age, gender, income, education, relationship status, and follow-up time were performed to compare urinary, bowel, and sexual domains between treatment groups. RESULTS: In all, 315 bladder cancer patients treated at the University of Michigan completed the BCI in 2004. Significant differences were seen in mean BCI function and bother scores between cystectomy and native bladder treatment groups. In addition, urinary function scores were significantly lower among cystectomy patients treated with continent neobladder compared with those treated with ileal conduit (all pairwise P<.05). CONCLUSIONS: The BCI is responsive to functional and bother differences in patients with bladder cancer treated with different surgical approaches. Significant differences between therapy groups in each of the urinary, bowel, and sexual domains exist. Among patients treated with orthotopic continent urinary diversion, functional impairments related to urinary incontinence and lack of urinary control account for the low observed urinary function scores.

Gobet, R., J. M. Park, et al. (1999). "Renal renin-angiotensin system dysregulation caused by partial bladder outlet obstruction in fetal sheep." Kidney Int 56(5): 1654-1661.

BACKGROUND: To determine whether fetal renal obstruction activates the renal renin-angiotensin system (RAS), an important mediator in normal kidney development and obstructive nephropathy, we used a model of fetal partial bladder outlet obstruction (PBOO). METHODS: Total RNA and protein was extracted from kidney of sheep fetuses with partial bladder outlet obstruction created at 95 days gestation, after 2 (N = 6) and 5 weeks of obstruction (term; N = 6), and from normal fetal sheep at various time points between 60 and 135 days of gestation (total N = 19). Relative levels of mRNA for renin, angiotensinogen, type 1 and 2 angiotensin II (Ang II) receptors (AT-1 and AT-2), and transforming growth factor-beta1 (TGF-beta1) were assessed by semiquantitative reverse transcription-polymerase chain reaction. Expression levels of AT-2 receptor protein were measured by Western blot analysis. RESULTS: Renin mRNA expression was increased (250%) after two weeks of obstruction. In normal fetuses, AT-1 expression was low at 60 to 75 days of gestation and increased toward the end of gestation, whereas AT-2 expression showed a reversed pattern. At 109 days, PBOO caused an increased expression of AT-2 mRNA compared with normals (400%). Correspondingly, AT-2 receptor protein was more abundant in obstructed kidneys. TGF-beta1 mRNA expression was significantly increased in obstructed kidneys at 109 days gestation. CONCLUSIONS: These observations confirm the reciprocal developmental regulation of AT-1 and AT-2 receptors' expression, suggesting their functional role in renal development. Partial bladder outlet obstruction produces specific alterations: increased renin expression and altered balance of receptor subtypes, which may induce altered functional and vascular regulation of the obstructed fetal kidney. TGF-beta1, a mediator of Ang II-induced fibrosis, may play a role in inducing and propagating interstitial fibrosis.

Goh, M., A. H. Tekchandani, et al. (1998). "Metastatic Crohn's disease involving penile skin." J Urol 159(2): 506-507.

Goh, M. and J. S. Wolf, Jr. (1999). "Almost totally tubeless percutaneous nephrolithotomy: further evolution of the technique." J Endourol 13(3): 177-180.

BACKGROUND AND OBJECTIVES: There is renewed interest in the concept of foregoing placement of the postoperative nephrostomy tube (PNT) after percutaneous nephrolithotomy (PCNL) with the intent of reducing postoperative discomfort and hospital stay. We have omitted the PNT and placed an internal ureteral stent or externalized ureteral catheter after PCNL in selected patients. We reviewed our experience in order to assess the efficacy and safety of this practice. PATIENTS AND METHODS: Primary PCNL was performed in 26 renal units in 21 patients (5 bilateral PCNL, 4 of which were simultaneous) by one surgeon at the University of Michigan and the Ann Arbor Veterans Affairs Medical Center. A postoperative nephrostomy tube was placed if the stone burden was >3 cm, more than one access site was used, the renal anatomy was obstructive, significant bleeding or perforation was noted, or a second look was required. RESULTS: No PNT was placed in 10 renal units in 8 patients (no-PNT group). In six no-PNT kidneys, internal ureteral stents were used, and in four, externalized ureteral stents were placed for 1 to 2 days. The mean stone size in the PNT and no-PNT patients was 3.0 and 1.8 cm, respectively. Of the 16 kidneys in the PNT group, 4 were initially eligible for omission of PNT, but a PNT was placed because of bleeding or other access-related problem. All patients were rendered stone free except for three (one PNT and two no-PNT) patients, who each had a fragment < or =4 mm. Omission of PNT placement resulted in decreased mean length of stay (2.3 days in the no-PNT group v 3.6 days in the PNT group). There were four complications, all managed with delayed stenting (one in a no-PNT patient and the remaining three in the PNT group). CONCLUSION: Omission of PNT placement in selected patients may reduce morbidity without compromising efficacy and safety, but further study is needed.

Goldfarb, D. A., A. C. Novick, et al. (1989). "Experience with extra-adrenal pheochromocytoma." Journal of Urology 142(4): 931-936.

From 1955 to 1985, 20 patients presented with a total of 22 extra-adrenal pheochromocytomas (2 had multiple tumors and 2 had a malignant extra-adrenal pheochromocytoma). There were 13 male and 7 female patients, and the highest incidence was in the second decade. Although most patients presented with symptoms typical of pheochromocytoma, several presented with unusual features related to the anatomical location, such as mediastinal mass (chest tumor), upper airway obstruction (neck tumor) or gross hematuria (bladder tumor). In 5 of 6 patients in whom plasma catecholamine levels were fractionated epinephrine levels were elevated. The most common tumor location was the superior para-aortic region (13 patients). In 16 patients the location of tumors was established before treatment. Computerized tomography (9 patients) was the most accurate imaging study for tumor localization. A total of 19 patients underwent complete excision of all pheochromocytomas. Postoperative followup information (median interval 120 months) was available for 15 of these patients. Three patients had recurrent pheochromocytoma that was treated successfully. One patient had essential hypertension. No patient had metastatic disease. The low incidence of malignancy suggests a benign course for extra-adrenal pheochromocytoma and represents a departure from the previously reported higher incidence of malignancy with extra-adrenal pheochromocytoma. <155>

Goldfarb, D. A., A. C. Novick, et al. (1990). "Magnetic resonance imaging for assessment of vena caval tumor thrombi: a comparative study with venacavography and computerized tomography scanning." Journal of Urology 144(5): 1100-1103.

We assessed the accuracy of magnetic resonance imaging in demonstrating the presence and extent of vena caval tumor thrombi. The study group included 20 patients with vena caval thrombi from renal cell carcinoma (18), renal pelvic transitional cell carcinoma (1) and adrenal pheochromocytoma (1). Preoperative diagnostic studies included magnetic resonance imaging in all patients, inferior venacavography in 16 and computerized tomography scanning in 15. All patients underwent an operation in which the presence and extent of the vena caval thrombus were confirmed. Magnetic resonance imaging accurately delineated the presence and extent of the thrombus in all 20 patients (100%). Venacavography was accurate in 15 patients (94%) but 8 (50%) required a retrograde and antegrade study. Computerized tomography scanning demonstrated the presence of a tumor thrombus in all 15 patients but accurately delineated the cephalad extent of the thrombus in only 5 (33%). In patients with vena caval tumor thrombi magnetic resonance imaging can provide accurate information regarding the extent of vena caval involvement while avoiding the need for an invasive contrast imaging study. <147>

Goldman, S. M., C. M. Sandler, et al. (1997). "Blunt urethral trauma: a unified, anatomical mechanical classification." J Urol 157(1): 85-89.

PURPOSE: We propose a simple, anatomically based classification of blunt urethral injury as a replacement for currently used classifications, which are not comprehensive, anatomically inconsistent or based on a mixed anatomical/mechanistic formula. The latter are difficult to learn and use, and have not been universally adopted. MATERIALS AND METHODS: We reviewed most of the currently used general uroradiological, emergency radiological and urological textbooks to define the classification of urethral injuries that is most widely accepted. Most authors use the Colapinto and McCallum classification, modifications thereof or the older surgical classification of urethral injuries, which simply divides such injuries anatomically into anterior and posterior. However, there is little consensus about the best classification and none includes all of the blunt injuries of the urethra. To correct these difficulties we devised a comprehensive and anatomically consistent classification. RESULTS: The proposed classification categorizes blunt urethral trauma as I-posterior urethra intact but stretched (Colapinto and McCallum type I), II-partial or complete pure posterior injury with tear of membranous urethra above the urogenital diaphragm (Colapinto and McCallum type II), III-partial or complete combined anterior/posterior urethral injury with disruption of the urogenital diaphragm (Colapinto and McCallum type III), IV-bladder neck injury with extension into the urethra, IVA-injury of the base of the bladder with periurethral extravasation simulating a true type IV urethral injury and V-partial or complete pure anterior urethral injury. CONCLUSIONS: The proposed classification is anatomically valid and includes all of the common types of blunt urethral injuries. Universal adoption of this system should permit comparison of various management/treatment modalities at various institutions.

Gonzalez, C. M., D. Penson, et al. (2007). "Pay for performance: rationale and potential implications for urology." J Urol 178(2): 402-408.

PURPOSE: Pay for performance represents a new paradigm for physician reimbursement based on the value based purchasing of health care services. Government and private payers have expressed an interest in moving toward this system with several pay for performance programs already in place. The rationale behind this initiative and what it means for the practicing urologist are discussed. MATERIALS AND METHODS: MEDLINE and Internet based research focusing on the topics of health care quality, measures used to implement pay for performance, and private and public sector experience with pay for performance to date were reviewed. RESULTS: Health care quality can be assessed through 3 types of measures, including structure, process and outcome. Structure measures involve the environment where services are provided, whereas process measures capture how a particular provider delivers health care. Outcome assessment involves the results of the services provided. These measures are best used when they are used in coordination with each other, and when they are risk adjusted. Most pay for performance systems in use today are based on these measures. However, there are little data that show whether this reimbursement paradigm actually improves the quality of heath care provided. CONCLUSIONS: Many questions remain regarding the implementation of a pay for performance system in the field of urology. Government and private payers are motivated to implement pay for performance. However, specific evidence based metrics for urology that fairly and accurately define quality are currently lacking. Given that implementation of a nationwide pay for performance system appears to be inevitable, urology involvement in the development and implementation of these health care quality metrics is essential.

Gormley, E. A., D. A. Bloom, et al. (1994). "Pubovaginal slings for the management of urinary incontinence in female adolescents." J Urol 152(2 Pt 2): 822-825; discussion 826-827.

A pubovaginal sling is an effective treatment for type III incontinence secondary to poor proximal urethral sphincter function. We used a pubovaginal sling to treat incontinence in 15 female adolescents. The etiology of incontinence was spinal dysraphism in 10 patients and prior trauma in 3. Simultaneous bladder augmentation was performed in the remaining 2 patients for poor bladder compliance. Three patients required additional procedures including repeat slings in 2 and repeat augmentation in 1. Of 13 patients followed for more than 6 months 11 remain dry, 1 leaks small amounts and wears 1 pad per day, and 1 did not achieve acceptable continence and was subsequently managed with bladder augmentation and a Mitrofanoff procedure. The upper urinary tracts have remained normal in all 13 patients. The pubovaginal sling has proved to be safe and successful in these children. The overall continence rate of 92% compares favorably to other available modalities.

Graham, C. W., R. R. Dmochowski, et al. (2002). "Pubic osteomyelitis following bladder neck surgery using bone anchors: a report of 9 cases." J Urol 168(5): 2055-2057; discussion 2057-2058.

PURPOSE: We reviewed 9 cases of pubic osteomyelitis associated with placement of bone anchors for bladder neck suspension procedures for risk factors, bacterial speciation and sensitivities, and interventions performed. MATERIALS AND METHODS: Nine women were treated for pubic osteomyelitis following the use of bone anchors for bladder neck suspension surgery. In 8 cases the bone anchors had been placed through a suprapubic incision and in 1 the bone anchors were placed by a vaginal route. RESULTS: Patient ages ranged from 36 to 74 years (mean 51.8). Symptomatic presentation ranged from 2 to 18 months following initial operation. Presenting symptoms included pain over the pubis and/or a draining wound. Staphylococcus species were cultured in all cases, most commonly Staphylococcus epidermidis. Resistance to methicillin was present in 7 cases (78%). Wound debridement and removal of the anchors provided definitive treatment in all but 1 patient, who eventually required partial pubectomy. Pain (3 of 9 cases) and mild incontinence (5 of 9) were present at last followup. CONCLUSIONS: Bone anchors used in surgery for urinary incontinence can be associated with pubic osteomyelitis. Infection characteristics are similar to those seen with other urological prosthetic implantation procedures. Aggressive treatment with surgical debridement and long-term antibiotics is usually effective. Staphylococcus species, especially methicillin resistant strains, are the most common bacteria identified in this setting. Careful attention to implantation technique, including appropriate perioperative antibiotic selection, should be considered when using this technique.

Green, D., H. D. Mitcheson, et al. (1983). "Management of the bladder by augmentation ileocecocystoplasty." J Urol 130(1): 133-134.

Use of cecum and ileum to construct a large capacity, urinary reservoir with provision for easy intermittent catheterization is described. The technique is useful in the management of hypertonic or hyperreflexic vesical dysfunction.

Green, D. F., E. J. McGuire, et al. (1986). "A comparison of endoscopic suspension of the vesical neck versus anterior urethropexy for the treatment of stress urinary incontinence." J Urol 136(6): 1205-1207.

Endoscopic suspension of the vesical neck has been reported to be as effective as anterior urethropexy in the treatment of female stress urinary incontinence. We compared our first 29 patients treated with endoscopic suspension of the vesical neck between 1982 and 1985 to our last 21 patients treated with anterior urethropexy between 1979 and 1985. Both groups were comparable in regard to age, parity, duration of symptoms and previous surgery for stress urinary incontinence. All patients underwent thorough preoperative urodynamic testing. Endoscopic suspension of the vesical neck successfully cured stress urinary incontinence in 26 patients (90 per cent), while anterior urethropexy resolved the incontinence in 20 (95 per cent). Of the 3 failures of endoscopic suspension 2 probably were related to technique or material failure. Hospitalization was reduced for endoscopic suspension versus anterior urethropexy (mean 4.04 versus 6.00 days, respectively). The most common complication after endoscopic suspension of the vesical neck was transient urinary retention (34 per cent). We conclude that endoscopic suspension of the vesical neck is an effective method to treat stress urinary incontinence, and that it also reduces hospital stay and postoperative recovery.

Greenberg, R. E., R. R. Bahnson, et al. (1997). "Initial report on intravesical administration of N-trifluoroacetyladriamycin-14-valerate (AD 32) to patients with refractory superficial transitional cell carcinoma of the urinary bladder." Urology 49(3): 471-475.

OBJECTIVES: This study was designed to assess the pharmacokinetics, safety, and antitumor activity of intravesically administered AD 32, a novel anthracycline, in patients with transitional cell carcinoma (TCC) of the bladder. METHODS: Six weekly doses of AD 32 (200 to 900 mg) were administered to 32 patients with superficial TCC who were candidates for intravesical treatment. Serum drug levels were measured during the 6-hour period after administration of the first, third, and sixth doses. Patients underwent bladder evaluations at 3-month intervals to determine responses to treatment. RESULTS: Very low levels of unmetabolized AD 32 and its two primary metabolites were measured in serum. The lack of systemic exposure was confirmed by the finding of only a few minor systemic adverse events. Local bladder irritation, the main toxicity associated with intravesical administration of AD 32, persisted for several days after each instillation. The maximum tolerated dose was 800 mg. Thirteen patients had complete responses to treatment, including 8 who remained disease free for 12.1 to 38.5 months. CONCLUSIONS: AD 32 is an active drug for the treatment of superficial bladder cancer. Further studies of intravesical administration of AD 32 are warranted.

Greenfield, S. P., J. J. Griswold, et al. (1993). "Ureteral reimplantation in infants." J Urol 150(5 Pt 1): 1460-1462.

Between 1984 and 1990, 30 infants (46 ureters) 8 weeks to 6 months old (mean age 4 months) underwent ureteral reimplantation. Weight at operation ranged from 4.9 to 9.5 kg. (mean 6.9). Underlying abnormalities were primary vesicoureteral reflux (28 ureters), primary ureterovesical junction obstruction (11), ectopic ureterocele (4) and ectopic ureter (3). Patients with reflux underwent surgery because of high grade reflux (grade IV or V) or breakthrough infection. Infants with primary ureterovesical junction obstruction underwent obstructive diethylenetriaminepentaacetic acid diuretic renograms. Reimplantations performed included 44 Glenn-Anderson advancements, 1 Cohen cross-trigonal advancement and 1 Politano-Leadbetter procedure. Of the ureters 30 (65%) were tapered intravesically. Ureteral stents were used in all instances. Transient ureteral obstruction developed in 2 children following stent removal and 1 required temporary percutaneous nephrostomy drainage. No permanent ureterovesical obstruction was noted in any patient. Followup at 18 months revealed no postoperative reflux in 43 of 46 ureters (93%). One infant required repeat reimplantation to correct a vesicoureteral fistula and the remaining 2 patients (2 ureters) with low grade reflux (grade I and II) are being observed. Surgery was successful in 27 of 30 tapered ureters (90%) and in all 16 of the nontapered ureters (100%). While the majority of infants with ureterovesical junction abnormalities may be observed, some may require surgery. Reimplantation, when necessary in this age group, can be performed with a high degree of success and diverting procedures such as vesicostomy or ureterostomy can be avoided.

Greenfield, S. P., W. Lewis, 3rd, et al. (1995). "Regional renal blood flow measurements using radioactive microspheres in a chronic porcine model with unilateral vesicoureteral reflux." J Urol 154(2 Pt 2): 816-819.

95Niobium labeled radioactive microspheres were used to determine regional renal blood flows in a porcine model of chronic sterile vesicoureteral reflux. Unilateral vesicoureteral reflux was surgically created in 5 mini-pigs and regional renal blood flows were determined by microsphere injection 6 months later. The contralateral nonrefluxing kidney acted as a control. There was a significant reduction of flow in the inner cortical regions of the middle (78% of control, p < or = 0.0437) and lower poles (69% of control, p < or = 0.0274), and the juxta-medullary cortical region of the lower pole (67% of control, p < or = 0.0124). There was no difference in flow in the other regions or when comparing whole kidneys. There were no differences between refluxing and nonrefluxing kidneys when comparing ratios of inner to outer cortical flow level by level. These observations are in contrast to those in acutely created vesicoureteral reflux in a porcine model, which had no significant differences in flow in any region using the microsphere technique. Decreases of blood flow in certain cortical regions may help explain some of the physiological changes in vesicoureteral reflux in children and experimental models of reflux.

Greenfield, S. P., M. Ng, et al. (1997). "Experience with vesicoureteral reflux in children: clinical characteristics." J Urol 158(2): 574-577.

PURPOSE: We reviewed our 9-year experience with a large population of children with vesicoureteral reflux who were evaluated and treated according to contemporary concepts. MATERIALS AND METHODS: From 1985 to 1993 we followed 288 boys and 752 girls with vesicoureteral reflux. If surgery was not performed, patients were on antibiotic prophylaxis and evaluation was done every 18 months with contrast voiding cystography and radionuclide renal imaging. Urine cultures were obtained every 4 months. Two negative voiding cystourethrograms 1 year apart were required to discontinue prophylaxis. RESULTS: The major reasons for initial evaluation were urinary tract infection in 560 children (54%), voiding dysfunction without urinary tract infection in 156 (15%), sibling surveys in 122 (12%) and prenatal hydronephrosis in 23 (2%). In 150 kidneys (10%) in 132 children scarring at presentation was grade 0 in 10 (7%), I in 18 (12%), II in 27 (18%), III in 30 (20%), IV in 48 (32%) and V in 17 (11%). Of these 132 patients 17 presented at ages less than 1 year (13%), 29 at ages 1 to 3 (22%), 50 at ages 4 to 6 (38%), 24 at ages 7 to 9 (18%) and 12 at ages greater than 10 (9%). No new scars were seen in children on prophylaxis without breakthrough infection. After 1 negative voiding cystourethrogram reflux was noted again in 27% of the cases. Breakthrough infections developed in 62 children of whom a third were older than 7 years. Reimplantation in 205 children (20%) was performed for grade IV to V reflux (101), breakthrough infection (62), advanced age (18), large periureteral diverticulum (12) and noncompliance (3). Five boys and 57 girls (30% of all children) had urinary tract infections after successful reimplantation. CONCLUSIONS: Almost half of the children with vesicoureteral reflux have no history of culture proved urinary tract infection. Scarring may be associated with any reflux grade and it may be initially diagnosed at any age. Only half of the scars are noted with higher grades of reflux (IV and V). Continuous prophylaxis prevents new scarring. Breakthrough infections are rare but they can occur at ages greater than 7 years. Two consecutive negative cystograms are necessary before discontinuing prophylaxis. Children should be monitored after reimplantation for recurrent urinary tract infection.

Greenfield, S. P., M. Ng, et al. (1997). "Resolution rates of low grade vesicoureteral reflux stratified by patient age at presentation." J Urol 157(4): 1410-1413.

PURPOSE: Most children with grades I to III primary vesicoureteral reflux are monitored for years on antibiotic prophylaxis until reflux resolves. While the overall resolution rate of these grades is known, the rates for various patient ages at presentation are unknown. Therefore, we examined resolution rates of these grades for different ages at presentation. MATERIALS AND METHODS: From 1985 through 1990, 168 boys (245 ureters) and 433 girls (590 ureters) with all grades of reflux were enrolled in the study and monitored through the end of 1993. Urine cultures were obtained every 4 months and contrast voiding cystourethrography was repeated every 18 months. Age at presentation was stratified into groups younger than 1, 1 to 3, 4 to 6, 7 to 9, and 10 years and older. Resolution rates were then calculated for grades I to III reflux for each age at presentation. Time to resolution was also evaluated for each age and grade. RESULTS: There were no significant differences between rates of resolution at different ages for each grade. Children less than 10 years old had as high a likelihood of resolution as infants. Neither sex nor bilaterality versus unilaterality was a helpful predictor of resolution. Time to resolution varied widely and it was also not helpful for identifying the cases of reflux that resolved. CONCLUSIONS: Low grade vesicoureteral reflux may not resolve until adolescence and age at presentation is not a reliable predictive factor. Children should remain on prophylaxis for many years unless definitive correction is undertaken.

Greenfield, S. P., P. Seville, et al. (2002). "Experience with varicoceles in children and young adults." J Urol 168(4 Pt 2): 1684-1688; discussion 1688.

PURPOSE: Varicocele ligation in children and adolescents has been advocated for left testicular growth arrest. We report our experience with this population as well as the results of the microscopic inguinal technique. MATERIALS AND METHODS: Between 1994 and 1999, 184 children and young adults presented with unilateral left varicoceles. At presentation 171 patients were asymptomatic and 13 had pain. Testicular measurement was assessed with calipers in 158 cases and ultrasound in 26. Surgery was performed using a microscopic inguinal technique in 58 patients and loupes in 16 of those who presented with left testicular growth arrest initially or who had growth arrest while under observation. Only one child underwent surgery for pain alone. RESULTS: Patient age at presentation ranged from 5 to 22 years, and 70% presented between the ages of 12 and 16 years. Of the 13 patients with pain ages ranged from 13 to 22 years and 6 (46%) also had left testicular growth arrest. Initially, 109 (60%) boys were found not to have left testicular growth arrest and were followed, while 56 (30%) with left testicular growth arrest (ages 9 to 22 years) underwent surgery and 19 were lost to followup. Left testicular growth arrest developed in 17 (15%) of the followed group (ages 11 to 17 years) after 6 to 41 months (average 22) of observation and they underwent surgery. Postoperatively, varicocele disappeared in 66 (89%) patients and it was smaller in 8, in whom 8 loupes were used in 2 and the microscope was used in 6. Of the 36 patients who returned for postoperative measurement 30 (83%) had catch-up growth, while 6 did not. No hydroceles were noted. CONCLUSIONS: Varicoceles can be found in boys as young as 5 years and left testicular growth arrest as early as 9 years. As left testicular growth arrest can develop if not present initially, these boys must be followed with serial testicular measurements before and after puberty until late adolescence. Microscopic inguinal ligation results in complete resolution of the varicocele in almost 90% of patients with no complicating hydroceles. Left testicular catch-up growth can be expected in more than 80% of patients at any age.

Greenfield, S. P. and J. Wan (1996). "Vesicoureteral reflux: practical aspects of evaluation and management." Pediatr Nephrol 10(6): 789-794.

The efficacy of both medical and surgical therapy for vesicoureteral reflux (VUR) has been well established. Controversy remains, however, regarding who should be evaluated for the presence of VUR, who should undergo corrective surgery, who should be treated medically and for how long. Medical treatment requires many years of continuous antibiotic prophylaxis, so compliance with therapy is essential. Many children are lost to followup, however, and remain untreated after a medical regimen is started. This large number of untreated children raises issues of the appropriateness of blanket therapeutic recommendations for all children with VUR and challenges the clinician to devise more effective treatment strategies.

Gringon, D. J., F. S. Sakr, et al. (1998). "Polycoprotein expression in the normal and neoplastic prostate gland." Jrnl Urol Path 7: 167-176.

Grossfeld, G. D., M. S. Litwin, et al. (2001). "Evaluation of asymptomatic microscopic hematuria in adults: the American Urological Association best practice policy--part I: definition, detection, prevalence, and etiology. [see comments.]." Urology 57(4): 599-603.

Grossfeld, G. D., J. S. Wolf, Jr., et al. (2001). "Asymptomatic microscopic hematuria in adults: summary of the AUA best practice policy recommendations." Am Fam Physician 63(6): 1145-1154.

The American Urological Association (AUA) convened the Best Practice Policy Panel on Asymptomatic Microscopic Hematuria to formulate policy statements and recommendations for the evaluation of asymptomatic microhematuria in adults. The recommended definition of microscopic hematuria is three or more red blood cells per high-power microscopic field in urinary sediment from two of three properly collected urinalysis specimens. This definition accounts for some degree of hematuria in normal patients, as well as the intermittent nature of hematuria in patients with urologic malignancies. Asymptomatic microscopic hematuria has causes ranging from minor findings that do not require treatment to highly significant, life-threatening lesions. Therefore, the AUA recommends that an appropriate renal or urologic evaluation be performed in all patients with asymptomatic microscopic hematuria who are at risk for urologic disease or primary renal disease. At this time, there is no consensus on when to test for microscopic hematuria in the primary care setting, and screening is not addressed in this report. However, the AUA report suggests that the patient's history and physical examination should help the physician decide whether testing is appropriate.

Grossman, H. B., C. Lee, et al. (2000). "Expression of the alpha6beta4 integrin provides prognostic information in bladder cancer." Oncol Rep 7(1): 13-16.

Integrins are cell surface receptors for extracellular matrix components that may participate in metastatic processes. Normal urothelial tissues show a polarized expression of alpha6beta4 integrin on basal cells at their junction with the lamina propria. We have previously shown that bladder cancers frequently overexpress one member of the integrin family, the alpha6beta4 integrin. In this study, we evaluated the level of alpha6beta4 integrin expression in bladder cancer specimens from 57 patients and correlated the expression level with patient survival. Expression was evaluated by immunoperoxidase staining. Three patterns of alpha6beta4 expression were observed: negative (13 patients); strong overexpression throughout the tumor cells (21 patients); and weak expression that most closely resembled expression in normal urothelium (23 patients). Individuals with weak staining tumors had a statistically significantly better survival (p=0.041) than patients whose tumors exhibited either no expression or strong overexpression. These data indicate that evaluation of the expression of alpha6beta4 integrin may provide valuable prognostic information on clinical outcome in patients with bladder cancer.

Grossman, H. B., M. Liebert, et al. (1998). "p53 and RB expression predict progression in T1 bladder cancer." Clin Cancer Res 4(4): 829-834.

The optimal clinical management of minimally invasive (stage T1) bladder cancer is controversial. T1 bladder cancers share characteristics of both noninvasive (Ta) papillary cancer and high stage, muscle-invasive bladder cancers. Patients with T1 bladder cancer have a higher risk of cancer progression and death than do patients with Ta bladder cancer. However, this risk is much lower than that of patients with high-stage bladder cancers. Methods of identifying T1 bladder cancer patients at greatest risk for progression may significantly improve clinical management. We retrospectively evaluated two tumor suppressor genes, p53 and RB, as potential prognostic markers for progression in a cohort of 45 patients with pT1 bladder cancer. Median follow-up for these individuals was greater than 3.5 years. Of this group, 58% had altered p53 expression based on positive p53 immunostaining. Three patterns for RB nuclear protein staining were observed: absent, heterogeneous (normal), and strongly homogeneous. Progression-free survival was similar for patients with loss of RB protein expression and those with apparent overexpression of RB protein. Therefore, both staining patterns were considered abnormal. Patients with normal expression of both proteins (i.e., p53 negative and RB heterogeneously positive) had an excellent outcome, with no patient showing disease progression, whereas patients with abnormal expression of either or both proteins had a significant increase in progression (P = 0.04 and P = 0.005, respectively). These data support the stratification of T1 bladder cancer patients based on p53 and RB nuclear protein status and suggest that patients with normal protein expression for both genes can be managed conservatively, whereas patients with alterations in one and particularly both genes require more aggressive treatment.

Grossman, H. B., M. Liebert, et al. (1994). "Decreased connexin expression and intercellular communication in human bladder cancer cells." Cancer Res 54(11): 3062-3065.

Connexins make up a gene family encoding proteins that form intercellular channels known as gap junctions. Decreases in connexin expression and loss of intercellular communication have been associated with the malignant phenotype in some animal and human cells. The expression of connexin 26 and 43 mRNA was evaluated in cultured normal and malignant human urothelial cells. The normal urothelial cells were shown by Northern analysis to express both connexins. Increased confluence of the cultured normal human urothelial cells was associated with upregulation of connexin 26 mRNA. Connexin 26 mRNA expression was decreased in the bladder cancer cells. Using a human connexin 26 complementary DNA probe, nuclear run-on assays demonstrated that the decreased expression in the cancer cells was due to a failure of transcription. Southern blot analysis did not reveal any alterations in the genomic DNA. Assessment of gap junction function by scrape loading of lucifer yellow demonstrated dye transfer in normal urothelial cells but not in bladder cancer cells. Downregulation of connexin 26 mRNA was associated with functional loss of intercellular communication in the human bladder cancer cells. Connexin 43 expression varied considerably in the bladder cancer cell lines and did not correlate with dye transfer of lucifer yellow. These data suggest that alterations in the regulation of connexin 26 expression are associated with and may contribute to the malignant phenotype in bladder cancer.

Grossman, H. B., M. Liebert, et al. (1990). "Fibronectin distribution in normal and malignant urothelium." J Urol 143(2): 418-420.

Fibronectin is a glycoprotein that mediates the attachment of BCG to the murine bladder. To assess the potential role of fibronectin on bladder cancer cells as a specific substrate for BCG binding in man, a semi-quantitative method was employed to evaluate the presence of fibronectin on normal urothelium and bladder cancer. Monoclonal anti-fibronectin binding to normal and malignant urothelial tissues was evaluated by an immunoperoxidase assay. Human tumor cell lines were evaluated with mixed hemadsorption and immunoperoxidase assays. In both systems, immunoreactive fibronectin had low expression on unfixed normal and malignant urothelium. With fixation, immunoreactive fibronectin decreased on supporting stroma and increased in normal and malignant urothelium. Fibronectin distribution did not show tumor specificity either with fixed or unfixed specimens.

Grossman, H. B., R. B. Natale, et al. (2003). "Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer." N Engl J Med 349(9): 859-866.

BACKGROUND: Despite aggressive local therapy, patients with locally advanced bladder cancer are at significant risk for metastases. We evaluated the ability of neoadjuvant chemotherapy to improve the outcome in patients with locally advanced bladder cancer who were treated with radical cystectomy. METHODS: Patients were enrolled if they had muscle-invasive bladder cancer (stage T2 to T4a) and were to be treated with radical cystectomy. They were stratified according to age (less than 65 years vs. 65 years or older) and stage (superficial muscle invasion vs. more extensive disease) and were randomly assigned to radical cystectomy alone or three cycles of methotrexate, vinblastine, doxorubicin, and cisplatin followed by radical cystectomy. RESULTS: We enrolled 317 patients over an 11-year period, 10 of whom were found to be ineligible; thus, 154 were assigned to receive surgery alone and 153 to receive combination therapy. According to an intention-to-treat analysis, the median survival among patients assigned to surgery alone was 46 months, as compared with 77 months among patients assigned to combination therapy (P=0.06 by a two-sided stratified log-rank test). In both groups, improved survival was associated with the absence of residual cancer in the cystectomy specimen. Significantly more patients in the combination-therapy group had no residual disease than patients in the cystectomy group (38 percent vs. 15 percent, P<0.001). CONCLUSIONS: As compared with radical cystectomy alone, the use of neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin followed by radical cystectomy increases the likelihood of eliminating residual cancer in the cystectomy specimen and is associated with improved survival among patients with locally advanced bladder cancer.

Grossman, H. B., R. W. Washington, Jr., et al. (1992). "Alterations in antigen expression in superficial bladder cancer." J Cell Biochem Suppl 16I: 63-68.

Bladder cancer can be viewed as a prototype for carcinogen-induced neoplasia. This has been demonstrated experimentally in a variety of systems and in man through epidemiological studies of occupational exposure to putative carcinogens. The natural history of this neoplasm demonstrates recurrence in time and space, i.e., multifocal disease. This clinical scenario is precisely what would be expected if a target tissue, e.g., urothelium, was continuously exposed to a weak carcinogen. The detection of gross disease is clinically easy. However, the ability to intervene at early stages and monitor the success of this treatment requires the definition of early markers for bladder cancer. Integrins are a family of cell surface proteins, many of which function as receptors for extracellular matrix components. Normal epithelial cells express the integrin alpha 6 beta 4 in association with an anchoring structure known as the hemidesmosome. Urothelium expresses alpha 6 beta 4 on the basal layer of cells similar to the distribution seen on other epithelial surfaces. Even early stages of bladder cancer demonstrate an alteration in the expression of this integrin. Low-stage bladder tumors express alpha 6 beta 4 diffusely throughout the tumor as well as at the invading margin. Altered expression of alpha 6 beta 4 may be an early marker for bladder cancer which may contribute to an invasive phenotype. A second potential marker is detected by DD23, an IgG1 murine monoclonal antibody triggered by the immunization of a BALB/c mouse with a fresh human bladder tumor specimen. The antigen detected by DD23 is not present on normal urothelial specimens.(ABSTRACT TRUNCATED AT 250 WORDS)

Gruenenfelder, J., E. J. McGuire, et al. (2002). "Acute urinary retention associated with the use of cyclooxygenase-2 inhibitors." J Urol 168(3): 1106.

Gudziak, M. R., E. J. McGuire, et al. (1996). "Urodynamic assessment of urethral sphincter function in post-prostatectomy incontinence." J Urol 156(3): 1131-1134; discussion 1134-1135.

PURPOSE: Direct measurement of maximum urethral pressure by urethral profilometry has been used widely to assess urethral sphincter function. We attempted to determine if there was any relationship between maximum urethral pressure, which is measured at the level of the membranous urethra, or extrinsic urethral sphincter function, and the amount of abdominal pressure needed to cause leakage (abdominal leak point pressure) in men with post-prostatectomy incontinence. We also examined the relationship between external sphincter function and continence or incontinence. MATERIALS AND METHODS: We retrospectively evaluated fluoro-urodynamics performed in 37 men with post-prostatectomy incontinence. Urodynamic study consisted of measurement of maximum urethral and abdominal leak point pressures, and assessment of extrinsic sphincter function by pressure measurements and radiographically. RESULTS: Data were analyzed on 27 patients for whom abdominal leak point and maximum urethral pressures were available. Mean maximum urethral pressure was 52.5 cm. water (range 20 to 165) and mean abdominal leak point pressure was 77.8 cm. water (range 27 to 132). Regression analysis was performed between maximum urethral and abdominal leak point pressures. A Pearson correlation coefficient of 0.13834 was calculated (p = 0.4914) indicating virtually no correlation between the 2 measurements in our sample. Extrinsic urethral sphincter was normal in all patients. Only 1 of 37 patients had no evidence of intrinsic sphincter deficiency, that is there was no urine leakage with increases in abdominal pressure and the patient was incontinent solely based on bladder dysfunction (detrusor instability). CONCLUSIONS: Our study indicates that incontinence after prostatectomy due to an increase in abdominal pressure (stress incontinence) does not depend on extrinsic sphincter function and is not related to maximal urethral pressure. We conclude that post-prostatectomy incontinence due to sphincter dysfunction results from intrinsic sphincter deficiency. In our experience bladder dysfunction is rarely the sole cause of post-prostatectomy incontinence.

Gumucio, D. L., S. Fagoonee, et al. (2008). "Tissue stem cells and cancer stem cells: potential implications for gastric cancer." Panminerva Med 50(1): 65-71.

Gastric cancer remains the second leading cause of death in the world today, making the search for its molecular and cellular basis an important priority. Though recognition of the tight link between inflammation and tumorigenesis is centuries old, only recently are the pieces of the etiological puzzle beginning to fall together. Recent advances in gastric stem cell biology appear to be central to this slowly resolving puzzle. At least two types of stem cells may be important. Resident adult or tissue stem cells may, in a chronically inflamed environment, slowly acquire a series of genetic and epigenetic changes that lead to their emergence as ''cancer stem cells''. This scenario has not yet been proven experimentally, although the first step, prospective recognition of a gastric stem cell has recently been conquered. Alternatively, the setting of chronic inflammatory stress and injury may lead to loss of the indigenous gastric stem cells from their niches; bone marrow derived stem cells may then be recruited to and engraft into the gastric epithelium. Such recruited cells have the potential to contribute to the tumor mass. Indeed, evidence supporting this scenario has been published. Here, we review these recent findings and discuss implications for the future.

Gunaratnam, N. T., A. V. Sarma, et al. (2001). "A prospective study of EUS-guided celiac plexus neurolysis for pancreatic cancer pain." Gastrointest Endosc 54(3): 316-324.

BACKGROUND: Celiac plexus neurolysis, a chemical splanchnicectomy of the celiac plexus, is used to treat pain caused by pancreatic cancer. Most commonly, celiac plexus neurolysis is performed percutaneously under CT or fluoroscopic guidance, but can also be performed with EUS. The aim of this study was to prospectively assess the efficacy of EUS celiac plexus neurolysis in the management of pain caused by pancreatic cancer. METHODS: In this prospective study conducted in a community-based referral hospital, 58 patients with painful and inoperable pancreatic cancer were evaluated at 8 observation points before and after EUS celiac plexus neurolysis for up to 6 months. The following data were collected: age, gender, tumor location, vascular invasion, adjuvant therapy, and laboratory tests including prothrombin time, and complete blood counts were obtained at baseline (before EUS celiac plexus neurolysis); pain scores, morphine use, and adjuvant therapy were assessed at each observation. RESULTS: Pain scores were lower (p = 0.0001) 2 weeks after EUS celiac plexus neurolysis, an effect that was sustained for 24 weeks when adjusted for morphine use and adjuvant therapy. Forty-five of the 58 patients (78%) experienced a decline in pain scores after EUS celiac plexus neurolysis. Chemotherapy with and without radiation also decreased pain after EUS celiac plexus neurolysis (p = 0.002). Procedure-related transient abdominal pain was noted in 5 patients; there were no major complications. CONCLUSIONS: EUS celiac plexus neurolysis is safe and controls pain caused by unresectable pancreatic cancer.

Gupta, M., D. M. Bolton, et al. (1995). "The effect of newer generation lithotripsy upon renal function assessed by nuclear scintigraphy." J Urol 154(3): 947-950.

PURPOSE: We studied the effect of second generation lithotripsy on renal function. MATERIALS AND METHODS: We evaluated 42 patients with unilateral renal calculi by nuclear renography, serum creatinine levels, renal ultrasonography and plain radiographs. RESULTS: There was no significant change in glomerular filtration rate at 1 or 3 months. Split function of the treated kidneys was lower at 1 month (mean 47.2%, p = 0.01) and 3 months (47.3%, p = 0.01) than before treatment (49.1%). A greater than 5% decrease in split function of the treated kidney occurred at 1 month in 6 patients (16.2%) and at 3 months in 3. Of the patients 23 (62.2%) were stone-free and 11 had residual fragments less than 4 mm., with a 19% retreatment rate for an overall success rate of 91.9%. CONCLUSIONS: Newer generation lithotriptors may limit renal damage while permitting satisfactory treatment of renal calculi.

Guz, B., S. B. Streem, et al. (1991). "Role of percutaneous nephrostomy in patients with upper urinary tract transitional cell carcinoma." Urology 37(4): 331-336.

Percutaneous nephrostomy has become a well-established procedure for a wide variety of urologic disorders. However, its role in the management of patients with upper urinary tract transitional cell carcinoma has not been defined. We utilized percutaneous nephrostomy in 23 renal units for the evaluation or treatment of 21 patients in whom standard techniques were inconclusive or inadequate. The percutaneous nephrostomy provided adequate relief of obstruction in the face of significant azotemia or infection. Diagnostic abilities were improved through the use of antegrade pyelography, selective cytologic examination, and, at times, by providing direct access for endoscopic visualization and biopsy. In select cases, the percutaneous access provided a route for definitive or adjunctive treatment of the lesion. Complications were few and seeding of the tract or local tumor spread has not occurred at follow-up ranging from one to one hundred twenty-one (mean 27.8) months. <143>

Guz, B. V., D. P. Wood, Jr., et al. (1989). "Retroperitoneal neural sheath tumors: Cleveland Clinic experience." Journal of Urology 142(6): 1434-1437.

Retroperitoneal neural sheath tumors are a rare clinical entity with a variable and nonspecific presentation, whose accurate preoperative diagnosis often can be difficult. Since July 1984, 9 retroperitoneal neural sheath tumors, including 3 benign schwannomas, 3 malignant schwannomas and 3 neurofibromas, were evaluated at our institution. Preoperative evaluation included a computerized tomography scan in all patients and magnetic resonance imaging in 4. Magnetic resonance imaging offered better resolution and anatomical definition in certain cases. Preoperative computerized tomography-guided needle biopsy, performed in 3 patients, yielded inaccurate or inconclusive results. The 6 patients with surgically resected benign schwannomas and neurofibromas had no local recurrences and all 6 had no evidence of disease (mean followup 17.3 and 14 months, respectively). Malignant tumors, especially when associated with von Recklinghausen's disease, offered a poor prognosis. Surgical considerations include complete tumor excision with free margins of resection and proper pathological evaluation to determine biological potential. <154>

Haas, G. P., J. E. Montie, et al. (1993). "The state of prostate cancer screening in the United States." Eur Urol 23(3): 337-347.

Habib, A. S., T. J. Polascik, et al. (2009). "Lidocaine patch for postoperative analgesia after radical retropubic prostatectomy." Anesth Analg 108(6): 1950-1953.

In a prospective, double-blind, placebo-controlled study, patients undergoing radical retropubic prostatectomy under general anesthesia were randomly assigned to receive a lidocaine patch or placebo applied on each side of the wound at the end of surgery. Data were collected for 24 h after surgery. Seventy patients completed the study (36 lidocaine group, 34 placebo group). Demographics and postoperative morphine consumption were not different between the groups. However, the lidocaine patch group reported significantly less pain on coughing (19%-33% reduction) over all time periods (treatment vs placebo P < 0.0001, time x treatment P = 0.3056) and at rest (17%-32% reduction) for up to 6 h (treatment vs placebo P = 0.0003, time x treatment P = 0.0130).

Haden, H. T., W. K. Stacy, et al. (1975). "Scintiphotography in diagnosis of urinary fistula after renal transplantation." Journal of Nuclear Medicine 16(7): 612-615.

Scintiphotographic studies in six patients with ureteral fistula following renal transplantation are presented. Images were obtained using 99m-Tc-Sn-DTPA or 131-I-orthoiodohippurate. Urinary leakage was accurately detected in each case but the pattern of extravasation is highly variable. When carefully performed, radionuclide scintiphotography is a safe and effective method for detecting urinary leakage after renal transplantation. <49>

Hafez, K. S., H. A. El Fettouh, et al. (2000). "Management of synchronous renal neoplasm and abdominal aortic aneurysm." J Vasc Surg 32(6): 1102-1110.

OBJECTIVES: Renal neoplasm (RN) and abdominal aortic aneurysm (AAA) are occasionally discovered concurrently. The approach to synchronous malignancy and aortic aneurysm is controversial. METHODS: Between 1981 and 1999, concurrent RN and AAA were diagnosed in 50 patients at the Cleveland Clinic Foundation. Twenty-three patients were managed conservatively because of small asymptomatic AAA or metastatic disease; these patients were excluded from the study. The remaining 27 patients underwent operative management of both entities with a staged or simultaneous approach, and they form the basis of this article. RESULTS: AAA diameter ranged from 4.8 to 13 cm (mean, 6.0+/-1.8 cm). RNs were managed with radical nephrectomy in 11 patients (41%), partial nephrectomy in 10 patients (37%), or both in 6 patients with bilateral renal tumors (22%). The AAA repair was performed at the time of the urologic procedure in 11 patients (41%), before the urologic procedure in 13 patients (48%), or after the urologic procedure in 3 patients (11%). The AAA was addressed with open surgical repair in 24 patients (89%); recently, three patients (11%) underwent endovascular repair of the aneurysm and staged partial nephrectomy. The incidence of major perioperative complications was 23% (6 patients). Acute renal failure was the most common complication (3 [11%]) followed by acute respiratory failure (2 [7.4%]), pulmonary embolism (1 [3.7%]), and stroke (1 [3.7%]). At the mean follow-up of 57 months, there were no graft infections reported. The 5-year overall and cancer-specific survival rates were 62% and 81%, respectively. There was a significant difference in 5-year cancer-specific survival when comparing patients managed simultaneously versus staged (80% versus 35%, P =.007). CONCLUSIONS: The concurrent presentation of RN and AAA should not discourage one from treating both entities simultaneously because long-term survival is common. Endovascular repair of AAA holds promise as an attractive strategy in these complex patients.

Hafez, K. S., A. F. Fergany, et al. (1999). "Nephron sparing surgery for localized renal cell carcinoma: impact of tumor size on patient survival, tumor recurrence and TNM staging." J Urol 162(6): 1930-1933.

PURPOSE: We studied the impact of tumor size on patient survival and tumor recurrence following nephron sparing surgery for localized sporadic renal cell carcinoma. In addition, we evaluated the usefulness of the new TNM staging system in which T1 versus T2 tumor status is delineated by tumor size 7 or less versus more than 7 cm., respectively. MATERIALS AND METHODS: The results of nephron sparing surgery for localized sporadic renal cell carcinoma in 485 patients treated before 1997 were reviewed. Patients were divided into groups according to tumor size as 1--2.5 or less (142), 2--2.5 to 4.0 (168), 3--more than 4 to 7 (125) and 4--more than 7 cm (50). Mean postoperative followup was 47 months. RESULTS: Overall and cancer specific 5-year survival for the entire series was 81 and 92%, respectively. Of 44 patients with recurrent renal cell carcinoma 16 (3.2%) had local recurrence and 28 (5.8%) had metastatic disease. There was no difference in 5-year cancer specific survival or tumor recurrence between groups 1 and 2 or groups 3 and 4. However, these outcome measures were significantly more favorable in groups 1 and 2 combined (tumors 4 cm. or less) compared to groups 3 and 4 combined (tumors more than 4 cm.) (p = 0.001). CONCLUSIONS: Following nephron sparing surgery for localized sporadic renal cell carcinoma cancer-free survival is significantly better in patients with tumors 4 cm. or less compared to those with larger tumors. The usefulness of the current TNM staging system can be improved by subdividing T1 tumors into T1a (4 cm. or less) and T1b (4 to 7 cm.).

Hafez, K. S., S. R. Inman, et al. (1996). "Renal hemodynamic effects of lovastatin in a renal ablation model." Urology 48(6): 862-867.

OBJECTIVES: Patients with renal mass reduction of more than 50% are at increased risk for progressive renal failure. Lipid-lowering agents have been shown to preserve renal function in various models of chronic renal failure. This study was performed to evaluate the hemodynamic effects of lovastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, in the remnant kidney model. METHODS: Two groups of animals were studied. Group 1 (n = 9) served as controls and group 2 (n = 14) received lovastatin, 15 mg/kg/day orally, for 2 weeks after renal ablation. Glomerular filtration rate (GFR, inulin clearance), renal blood flow (RBF, ultrasonic flow probe), and 24-hour protein excretion were measured in anesthetized rats. RESULTS: Two weeks after renal ablation, GFR was 0.28 +/- 0.09 mL/min/gkw (gram kidney weight) in group 1, whereas in group 2, lovastatin preserved GFR at 0.58 +/- 0.3 mL/min/gkw (P < 0.05). RBF in group 1 was 1.2 +/- 0.2 mL/min/gkw and increased to 2.1 +/- 0.4 mL/min/gkw in group 2 (P < 0.05), representing a 43% increase. Protein excretion decreased significantly to 13 +/- 1.7 mg/24 hr in group 2. The lovastatin-treated group had a lower serum cholesterol (59 +/- 3 mg/dL versus 71 +/- 2 mg/dL, P < 0.05), but serum triglyceride levels were not different between the two groups. CONCLUSIONS: Lovastatin preserves renal function in a renal ablation model after 2 weeks of treatment. It specifically increased total RBF. Therefore, in addition to its known cholesterol lowering effect, lovastatin also has the direct renal hemodynamic effect of increasing RBF and maintaining GFR.

Hafez, K. S., V. Krishnamurthi, et al. (2000). "Contemporary management of renal cell carcinoma with coexistent renal artery disease: update of the Cleveland Clinic experience." Urology 56(3): 382-386.

OBJECTIVES: To treat concurrent renal cell carcinoma (RCC) and renal artery disease (RAD), which pose an unusual and challenging management dilemma. METHODS: Before June 1998, 48 patients presented with localized RCC and RAD affecting all the functioning renal parenchyma. These patients were grouped into four distinct categories: group 1, a solitary kidney with RCC and RAD (n = 8); group 2, bilateral RCC and coexistent RAD (n = 9); group 3, unilateral RCC and contralateral RAD (n = 15); and group 4, unilateral RCC and bilateral RAD (n = 16). The most common cause of RAD was atherosclerosis (n = 40), followed by medial fibroplasia (n = 5), renal artery aneurysm (n = 2), and arteriovenous malformation (n = 1). RESULTS: All patients underwent complete surgical excision of RCC. A nephron-sparing operation was performed preferentially (44 patients), and bilateral renal cancer operations were staged. Eleven patients underwent surgical renal vascular reconstruction in conjunction with either partial (n = 9) or radical (n = 2) nephrectomy. In 2 patients, renal revascularization was accomplished by percutaneous transluminal angioplasty before tumor excision. No perioperative deaths occurred. Postoperatively, preservation of renal function was achieved in 47 patients; 1 patient required chronic dialysis. The overall and cancer-specific 5-year patient survival rates in this series were 66% and 90%, respectively. At a mean follow-up of 58 months, 28 patients were alive with no evidence of malignancy. Six patients died of metastatic RCC, and 14 died of unrelated causes with no evidence of malignancy. CONCLUSIONS: Nephron-sparing surgery combined with selective renal arterial reconstruction can yield gratifying results in this complex patient population.

Hafez, K. S., A. C. Novick, et al. (1998). "Management of small solitary unilateral renal cell carcinomas: impact of central versus peripheral tumor location." J Urol 159(4): 1156-1160.

PURPOSE: Recent studies have suggested that nephron sparing surgery and radical nephrectomy provide equally effective therapy for patients with small (less than 4 cm.), solitary, unilateral renal cell carcinoma and a normal contralateral kidney. We evaluate whether central versus peripheral tumor location in the involved kidney is a significant factor affecting treatment outcome in these patients. MATERIALS AND METHODS: Patients with a single, small (less than 4 cm.), localized, unilateral, sporadic renal cell carcinoma were identified from our institutional registry. From 1972 to 1995, 145 patients fulfilling these criteria were treated with either nephron sparing surgery (86) or radical nephrectomy (59). Mean postoperative followup was 51.4 months. Tumor characteristics and outcome measures were analyzed in 35 patients with central versus 110 with peripheral renal cell carcinomas according to the type of treatment. RESULTS: We detected 27 central (77%) and 75 peripheral renal cell carcinomas (68%) incidentally. Nephron sparing surgery was used to treat 19 central (54%) and 67 peripheral (61%) carcinomas. Pathological tumor stage was T1 to 2 in 33 central (94%) and 91 peripheral (82%) cases. Grade 1 to 2 renal cell carcinoma was present in 28 central (80%) and 85 peripheral (77%) tumors. Postoperatively, when comparing patients with central versus peripheral renal cell carcinomas there was no difference in 5-year cancer specific survival (100 versus 97%), tumor recurrence (5.7 versus 4.5%) or renal function (mean serum creatinine 1.43 mg./dl. in both groups). These parameters were also equivalent in patients treated with nephron sparing surgery versus radical nephrectomy overall and within the central versus peripheral renal cell carcinoma subgroups. Nephron sparing surgery was technically more complicated in central renal cell carcinomas with a longer renal ischemia time (55 versus 34 minutes, p <0.05) and more frequent entry of the collecting system (74 versus 47%, p <0.05) compared to peripheral carcinomas. Two patients (2.3%, 1 central, 1 peripheral) had local tumor recurrence after nephron sparing surgery. CONCLUSIONS: There were no significant biological differences between centrally versus peripherally located small solitary unilateral renal cell carcinomas. Nephron sparing surgery is technically more demanding in patients with central tumors. However, treatment with nephron sparing surgery or radical nephrectomy is equally effective regardless of tumor location.

Hafez, K. S., A. C. Novick, et al. (1997). "Patterns of tumor recurrence and guidelines for followup after nephron sparing surgery for sporadic renal cell carcinoma." J Urol 157(6): 2067-2070.

PURPOSE: We delineated patterns of tumor recurrence and developed guidelines for followup after nephron sparing surgery for sporadic renal cell carcinoma. MATERIALS AND METHODS: Before December 1994, 327 patients underwent nephron sparing surgery for sporadic localized renal cell carcinoma at our clinic. Mean postoperative followup was 55.6 months. The course and outcome for patients with postoperative recurrent renal cell carcinoma were reviewed in detail. RESULTS: Renal cell carcinoma recurred after nephron sparing surgery in 38 patients (11.6%), including 13 (4.0%) who had local tumor recurrence with (7) or without (6) metastatic disease and 25 (7.6%) who had metastatic disease without local tumor recurrence. Recurrent renal cell carcinoma was detected by associated symptoms in 25 patients and by a followup chest x-ray or abdominal computerized tomography (CT) in 13. The respective incidences of postoperative local tumor recurrence and metastatic disease according to initial pathological tumor stage were 0 and 4.4% for stage T1, 2.0 and 5.3% for stage T2, 8.2 and 11.5% for stage T3a, and 10.6 and 14.9% for stage T3b disease. The peak postoperative intervals until local tumor recurrence were 6 to 24 months (7 of 10 patients with stage T3 renal cell carcinoma) and longer than 48 months (all 3 with stage T2 disease). Patients with isolated local tumor recurrence had better survival compared to those with local tumor recurrence and metastatic disease or metastases only. CONCLUSIONS: Followup for recurrent malignancy after nephron sparing surgery for renal cell carcinoma can be tailored according to the initial pathological tumor stage. All patients should be evaluated yearly with a medical history, physical examination and select laboratory studies. Patients with stage T1 renal cell carcinoma require no additional monitoring, while those with stage T2 disease should also undergo a yearly chest x-ray and abdominal CT every 2 years. The same recommendations are offered for patients with stage T3 renal cell carcinoma except that abdominal CT should be done every 6 months for the first 2 years postoperatively.

Haggman, M. J., J. Adolfsson, et al. (2000). "Clinical management of premalignant lesions of the prostate. WHO Collaborative Project and Consensus Conference on Public Health and Clinical Significance of Premalignant Alterations in the Genitourinary Tract." Scandinavian Journal of Urology & Nephrology.Supplementum(205): 44-49.

The presence of high-grade prostatic intraepithelial neoplasia (PIN) in a prostate biopsy is a considerable risk factor for the presence of prostate cancer, with up to 73% of patients having cancer on rebiopsy. The risk is related to the clinical setting (screening vs urological practice) and patient factors such as prostatic serum antigen (PSA) and findings on digital rectal examination (DRE). Thus, high-grade PIN has serious clinical implications. The aim of this paper is to propose practical guidelines for the clinical management of PIN. Based on current knowledge we recommend that: Only patients considered for curative treatment of prostate cancer be further investigated for a PIN biopsy finding; A palpable nodule or tumor-suspicious transrectal ultrasonography (TRUS) finding, in conjunction with a finding of high-grade PIN on prostate biopsy, should prompt rebiopsy; An elevated PSA level or an elevated PSA density should also warrant repeat biopsy, as the most likely cause of PSA elevation is concomitant prostate cancer; The presence of high-grade PIN on biopsy without concomitant prostate cancer in patients suitable for curative treatment, notwithstanding normal DRE, TRUS or PSA, should prompt repeat biopsies, as the association with prostate cancer is significant; The presence of PIN alone on biopsy does not warrant treatment, as a substantial number of rebiopsies yield only PIN. <40>

Haggman, M. J., J. A. Macoska, et al. (1997). "The relationship between prostatic intraepithelial neoplasia and prostate cancer: critical issues." J Urol 158(1): 12-22.

PURPOSE: Prostatic intraepithelial neoplasia (PIN) is often considered to be a premalignant lesion and the main precursor of invasive carcinoma of the prostate. We evaluated the evidence for and against PIN as a premalignant lesion and determined guidelines for the clinical management of PIN. MATERIALS AND METHODS: Literature analysis of histopathological, morphometric, phenotypic and molecular genetic evidence of progression and of clinical findings regarding PIN was done. Literature searches were performed on MEDLINE with relevant key words. RESULTS: PIN, like prostate cancer, occurs most frequently in the peripheral zone of the prostate and is usually located in close proximity to prostate cancer. The relative PIN and prostate cancer volumes vary inversely. Prostate specific antigen in cases of PIN appears to be intermediate between prostate cancer and normal levels, although this elevation may be explained by concomitant prostate cancer or benign prostatic hyperplasia. Deoxyribonucleic acid ploidy in PIN follows the aneuploid proportion as in the concomitant prostate cancer. Prostate cancer and PIN show evidence of loss of putative tumor suppressor genes on chromosome 8p. The clinical relevance of PIN biopsy findings is based on the association of neoplasia and prostate cancer. High grade PIN in core biopsies without concomitant prostate cancer has a substantial risk for prostate cancer in subsequent biopsies (24 to 73%, up to 100% when the digital rectal examination is suspicious) and should cause further biopsy sampling. CONCLUSIONS: There is convincing evidence that PIN is a precursor lesion to prostate cancer, with a close association of PIN and prostate cancer in biopsy and prostatectomy specimens. A biopsy finding of high grade PIN necessitates further investigation in patients who are candidates for radical treatment for localized prostate cancer.

Haggman, M. J., K. J. Wojno, et al. (1997). "Allelic loss of 8p sequences in prostatic intraepithelial neoplasia and carcinoma." Urology 50(4): 643-647.

OBJECTIVES: Previous work has suggested that prostatic intraepithelial neoplasia (PIN) may be a premalignant lesion important in tumorigenesis of the prostate. However, to adequately test this hypothesis at the genetic level, it is necessary to determine whether lesions in close proximity demonstrate similar genetic alterations and, hence, whether an "evolutionary" relationship might exist between PIN and tumor in the same prostate. Therefore, the purpose of this study was to examine at least two PIN lesions per prostate (one adjacent to and another distant from malignant lesions in the same prostate) for similarities or differences in the types and frequencies of genetic alterations. METHODS: To accomplish this goal, DNA was extracted from microdissected PIN, tumor, and normal epithelial tissue samples from 48 radical prostatectomies and amplified using polymerase chain reaction techniques at highly polymorphic microsatellite repeat sequences at proximal (D8S87, 8p12) and distal (NEFL, 8p21) loci on the short arm of chromosome 8. PIN specimens were either adjacent to (within one high-power microscopic field [HPF]) or distant from (separated by two or more HPFs) tumor specimens from the same patients. RESULTS: Similar fractional allelic loss frequencies were observed for informative tumor (10 [35%] of 29) and PIN (6 [21%] of 29) samples at the NEFL locus, but allelic loss at the D8S87 locus was observed only in tumors (8 [22%] of 36 informative samples). Moreover, allelic loss at the NEFL locus involved the same allele in 4 cases and different alleles in 3 cases. Interestingly, all 4 cases with the same allele loss were from adjacent PIN and tumor tissues, and all 3 with different allele loss were from distant PIN and tumor. CONCLUSIONS: These results suggest that PIN and invasive cancer share common genetic events (eg, deletion at the NEFL locus) along the same pathway of development in the prostrate.

Halajian, E. B., T. A. Wheat, et al. (2006). "Arpad G Gerster, MD, and the first photographic surgical textbook." J Am Coll Surg 203(1): 116-123.

Hall, C. L., A. Bafico, et al. (2005). "Prostate cancer cells promote osteoblastic bone metastases through Wnts." Cancer Res 65(17): 7554-7560.

Prostate cancer produces painful osteoblastic bone metastases. Although prostate cancer cells produce numerous osteogenic factors, to date, none have been shown to mediate osteoblastic bone metastases in an in vivo model of prostate cancer. Wnts are a large family of proteins that promote bone growth. Wnt activity is antagonized by endogenous proteins including dickkopf-1 (DKK-1). We explored if prostate cancer cells mediate osteoblastic activity through Wnts using DKK-1 as a tool to modify Wnt activity. A variety of Wnt mRNAs were found to be expressed in prostate cancer cell lines and Wnt mRNA expression was increased in primary prostate cancer compared with nonneoplastic prostate tissue. In addition to expressing Wnts, PC-3 prostate cancer cells expressed the Wnt inhibitor DKK-1. To determine if DKK-1 masked Wnt-mediated osteoblastic activity in osteolytic PC-3 cells, the cells were stably transfected with DKK-1 short hairpin RNA. Decreasing DKK-1 enabled PC-3 cells to induce osteoblastic activity, including alkaline phosphatase production and mineralization, in murine bone marrow stromal cells indicating that DKK-1 blocked Wnt-mediated osteoblastic activity in PC-3 cells. Another prostate cancer cell line, C4-2B, induces mixed osteoblastic/osteolytic lesions. To determine if Wnts contribute to C4-2B's ability to induce mixed osteoblastic/osteolytic lesions, C4-2B cells were stably transfected with either empty vector or DKK-1 expression vector to block Wnt activity. The cells were then injected in the tibiae of mice and allowed to grow for 12 weeks. Blocking Wnt activity converted the C4-2B cells to a highly osteolytic tumor. Taken together, these data show that Wnts contribute to the mechanism through which prostate cancer induces osteoblastic activity.

Hall, C. L., J. Dai, et al. (2006). "Type I collagen receptor (alpha 2 beta 1) signaling promotes the growth of human prostate cancer cells within the bone." Cancer Res 66(17): 8648-8654.

The most frequent site of prostate cancer metastasis is the bone. Adhesion to bone-specific factors may facilitate the selective metastasis of prostate cancer to the skeleton. Therefore, we tested whether prostate cancer bone metastasis is mediated by binding to type I collagen, the most abundant bone protein. We observed that only bone metastatic prostate cancer cells bound collagen I, whereas cells that form only visceral metastases failed to bind collagen. To confirm the relationship between collagen adhesion and bone metastatic potential, a collagen-binding variant of human LNCaP prostate cancer cells was derived through serial passage on type I collagen (LNCaP(col)). Fluorescence-activated cell sorting analysis showed that LNCaP(col) cells express increased levels of the integrin collagen I receptor alpha(2)beta(1) compared with LNCaP cells. Antibodies to the alpha(2)beta(1) complex inhibited LNCaP(col) binding to collagen, confirming that integrins mediated the attachment. Correspondingly, LNCaP(col) cells displayed enhanced chemotactic migration toward collagen I compared with LNCaP cells, an activity that could be blocked with alpha(2)beta(1) antibodies. To directly test the role of alpha(2)beta(1)-dependent collagen binding in bone metastasis, LNCaP and LNCaP(col) cells were injected into the tibia of nude mice. After 9 weeks, 7 of 13 (53%) mice injected with LNCaP(col) developed bone tumors, whereas 0 of 8 mice injected with LNCaP cells had evidence of boney lesions. LNCaP(col) cells were found to express increased levels of the metastasis-promoting RhoC GTPase compared with parental LNCaP. We conclude that collagen I attachment mediated by alpha(2)beta(1) initiates motility programs through RhoC and suggest a mechanism for prostate cancer metastasis to the bone.

Hall, C. L., S. D. Daignault, et al. (2008). "Dickkopf-1 expression increases early in prostate cancer development and decreases during progression from primary tumor to metastasis." Prostate 68(13): 1396-1404.

BACKGROUND: Prostate cancer (PCa) frequently metastasizes to the bone and induces osteoblastic lesions. We previously demonstrated through over-expression of the Wnt inhibitor dickkopf-1 (DKK-1) that Wnts contribute to the osteoblastic component of PCa osseous lesions in vivo. METHODS: To test the clinical significance of DKK-1 expression during PCa progression, tissue microarrays were stained for DKK-1 protein by immunohistochemistry. RESULTS: DKK-1 expression index (EI) was found to increase in PIN and primary lesions compared to non-neoplastic tissue (106 +/- 10 vs. 19 +/- 6, respectively, where the EI is the product of the percent expression and staining intensity). DKK-1 expression was also found to be higher in all PCa metastatic lesions (56 +/- 21 EI) compared to non-neoplastic tissues but was significantly decreased versus primary PCa lesions (P < 0.008). The decline in DKK-1 correlated with a shift of beta-catenin staining from the nucleus to the cytoplasm suggesting possible mechanism for the observed decrease in DKK-1 levels during PCa progression. Within metastatic lesions, DKK-1 expression was least abundant in PCa bone metastases relative to all soft tissue PCa metastatic lesions except lymph node metastases. High DKK-1 expression within PCa metastases was further associated with shorter over-all patient survival. CONCLUSIONS: Taken together, these data demonstrate that elevated DKK-1 expression is an early event in PCa and that as PCa progresses DKK-1 expression declines, particularly in advanced bone metastases. The decline of DKK-1 in bone metastases can unmask Wnts' osteoblastic activity. These data support a model in which DKK-1 is a molecular switch that transitions the phenotype of PCa osseous lesions from osteolytic to osteoblastic.

Hall, C. L., C. W. Dubyk, et al. (2008). "Type I collagen receptor (alpha2beta1) signaling promotes prostate cancer invasion through RhoC GTPase." Neoplasia 10(8): 797-803.

The most frequent site of metastasis in human prostate cancer (PCa) is the bone. Preferential adhesion of PCa cells to bone-specific factors may facilitate the selective metastasis of the skeleton. The most abundant protein within the skeleton is type I collagen. We previously demonstrated that PCa cells selected in vitro for collagen I binding (LNCaP(col)) are highly motile and acquired the capacity to grow within the bone compared to nontumorigenic LNCaP parental cells. Treatment with alpha(2)beta(1)-neutralizing antibodies selectively blocked collagen-stimulated migration, suggesting that integrin signaling mediates PCa migration. To elucidate the mechanism of collagen-stimulated migration, we evaluated integrin-associated signaling pathways in non-collagen-binding LNCaP parental cells and in collagen-binding isogenic C4-2B and LNCaP(col) PCa cells. The expression and activity of RhoC guanosine triphosphatase was increased five- to eightfold in collagen-binding LNCaP(col) and C4-2B cells, respectively, compared to parental LNCaP cells. RhoC activation was selectively blocked with antibodies to alpha(2)beta(1) where treatment with a small hairpin RNA specific for RhoC suppressed collagen-mediated invasion without altering the PCa cells' affinity for collagen I. We conclude that the ligation of alpha(2)beta(1) by collagen I activates RhoC guanosine triphosphatase, which mediates PCa invasion, and suggests a mechanism for the preferential metastasis of PCa cells within the bone.

Hall, C. L., S. Kang, et al. (2006). "Role of Wnts in prostate cancer bone metastases." J Cell Biochem 97(4): 661-672.

Prostate cancer (CaP) is unique among all cancers in that when it metastasizes to bone, it typically forms osteoblastic lesions (characterized by increased bone production). CaP cells produce many factors, including Wnts that are implicated in tumor-induced osteoblastic activity. In this prospectus, we describe our research on Wnt and the CaP bone phenotype. Wnts are cysteine-rich glycoproteins that mediate bone development in the embryo and promote bone production in the adult. Wnts have been shown to have autocrine tumor effects, such as enhancing proliferation and protecting against apoptosis. In addition, we have recently identified that CaP-produced Wnts act in a paracrine fashion to induce osteoblastic activity in CaP bone metastases. In addition to Wnts, CaP cells express the soluble Wnt inhibitor dickkopf-1 (DKK-1). It appears that DKK-1 production occurs early in the development of skeletal metastases, which results in masking of osteogenic Wnts, thus favoring osteolysis at the metastatic site. As metastases progress, DKK-1 expression decreases allowing for unmasking of Wnt's osteoblastic activity and ultimately resulting in osteosclerosis at the metastatic site. We believe that DKK-1 is one of the switches that transitions the CaP bone metastasis activity from osteolytic to osteoblastic. Wnt/DKK-1 activity fits a model of CaP-induced bone remodeling occurring in a continuum composed of an osteolytic phase, mediated by receptor activator of NFkB ligand (RANKL), parathyroid hormone-related protein (PTHRP) and DKK-1; a transitional phase, where environmental alterations promote expression of osteoblastic factors (Wnts) and decreases osteolytic factors (i.e., DKK-1); and an osteoblastic phase, in which tumor growth-associated hypoxia results in production of vascular endothelial growth factor and endothelin-1, which have osteoblastic activity. This model suggests that targeting both osteolytic activity and osteoblastic activity will provide efficacy for therapy of CaP bone metastases.

Hall, C. L. and E. T. Keller (2006). "The role of Wnts in bone metastases." Cancer Metastasis Rev 25(4): 551-558.

Wnts are a large family of secreted glycoproteins that mediate bone development in the embryo and promote bone production in the adult. Autocrine Wnt signaling within tumor cells has been shown to promote tumorigenesis by enhancing tumor cell proliferation and survival. We recently demonstrated that prostate cancer cells (CaP) produce Wnts which act in a paracrine fashion to induce osteoblastic activity in CaP bone metastases. The ability of tumor-derived Wnts to influence bone development is regulated by multiple families of secreted antagonists including soluble frizzled related receptors (sFrp) and dickkopfs (DKK). CaP cells appear to produce DKK-1 early in the development of skeletal metastases, which masks osteogenic Wnts and thus favors an osteolytic environment at the metastatic site. As the metastases progresses, DKK-1 expression is lost allowing for a Wnt mediated osteoblastic response which predominates CaP boney lesions. Interestingly, blocking DKK-1 expression early in CaP metastasis prevents tumor establishment within the bone suggesting that osteolysis is a required first step in the development of CaP bone metastases. In this review, we discuss our data on the Wnt inhibitor DKK-1 in CaP bone metastasis in the context of current literature evidence that demonstrate that Wnt inhibitors can function as both tumor suppressors and tumor promoters. We provide a model that the affect of Wnt inhibitors on tumor development is dependent on the tumor micro-environment and suggest that DKK-1 is a switch which transitions CaP bone metastases from osteolytic to osteoblastic.

Hall, M. C., S. S. Chang, et al. (2007). "Guideline for the management of nonmuscle invasive bladder cancer (stages Ta, T1, and Tis): 2007 update." J Urol 178(6): 2314-2330.

Hall, T. L., C. R. Hempel, et al. (2009). "Histotripsy of the prostate: dose effects in a chronic canine model." Urology 74(4): 932-937.

OBJECTIVES: To develop the technique of histotripsy ultrasound therapy as a noninvasive treatment for benign prostatic hyperplasia and to examine the histotripsy dose-tissue response effect over time to provide an insight for treatment optimization. We have previously demonstrated the feasibility of prostate histotripsy fractionation in a canine model. METHODS: Various doses of histotripsy were applied transabdominally to the prostates of 20 canine subjects. Treated prostates were then harvested at interval time points from 0 to 28 days and assessed for histologic treatment response. RESULTS: The lowest dose applied was found to produce only scattered cellular disruption and necrosis, whereas higher doses produced more significant regions of tissue effect that resulted in sufficient fractionation of tissue so the material could be voided with urination. Urethral tissue was more resistant to the lower histotripsy doses than was parenchymal tissue. Treatment of the urethra at the lowest doses appeared to heal, with minimal long-term sequelae. CONCLUSIONS: Histotripsy was effective at fractionating parenchymal and urethral tissue in the prostate, in the presence of a sufficient dose. Further development of this technique could lead to a noninvasive method for debulking the prostate to relieve symptoms associated with benign prostatic hyperplasia.

Hall, T. L., K. Kieran, et al. (2007). "Histotripsy of rabbit renal tissue in vivo: temporal histologic trends." J Endourol 21(10): 1159-1166.

BACKGROUND AND PURPOSE: Histotripsy is defined as noninvasive, nonthermal, mechanical (cavitational) tissue ablation. We previously demonstrated the predictable acute tissue effects of histotripsy in rabbit kidney and other tissues. We sought to characterize the appearance and natural history of renal tissue after histotripsy. MATERIALS AND METHODS: Following Institutional Animal Care Committee approval, the left kidneys of 29 rabbits were treated with 60,000 750-kHz, 15-cycle bursts of ultrasound energy from an 18-element phased-array transducer at a 1-kHz pulse-repetition frequency. The treated kidneys were harvested at 0, 1, 2, 7, 21, or 60 days; fixed in Formalin; then prepared for microscopic analysis with hematoxylin and eosin and trichrome stains. RESULTS: For kidneys harvested acutely (day 0), a contiguous area of finely disrupted tissue was observed containing no recognizable cells or cellular components. Along the boundary of architectural disruption, a border several tubules wide contained cells that were not visibly disrupted but appeared damaged (pyknotic nuclei). At subsequent time intervals, an inflammatory response developed in association with a steadily decreasing area of cellular and architectural disruption. By day 60, only a small fibrous scar persisted adjacent to a wedge of tubular dilation and fibrosis underlying a surface-contour defect. CONCLUSIONS: Histotripsy produces mechanical fractionation of cellular and architectural structures. The resultant acellular material appears to be readily reabsorbed within 60 days in the rabbit. This may prove to be a significant advantage for imaging assessment of residual tumor after ablation of renal malignancy.

Hamburger, M. D., J. S. Wolf, et al. (2000). "Appropriateness of routine postoperative chest radiography after tracheotomy." Archives of Otolaryngology -- Head & Neck Surgery 126(5): 649-651.

OBJECTIVE: To determine the appropriateness of postoperative chest radiography after adult tracheotomy. DESIGN: Retrospective case series. SETTING: Tertiary care academic medical center. PATIENTS: The records of 379 consecutive adult patients who underwent tracheotomy by the Otolaryngology-Head and Neck Surgery Service from January 1992 to December 1996 were available for review and met inclusion criteria. All patients underwent postoperative chest radiography. MAIN OUTCOME MEASURES: Frequency of postoperative tracheotomy-associated complications, most significantly pneumothorax. RESULTS: The patients had no pneumothorax on postoperative chest films. Minor complications, which were found in 7.1% of the patients, included small bleeds, wound infection, and subcutaneous emphysema. Tracheostomy-associated death occurred in 2 patients (0.5%). CONCLUSIONS: Routine postoperative chest radiography is unnecessary after adult tracheotomy. Chest radiography may be indicated by clinically suspicious signs or symptoms. <11>

Harada, S., E. T. Keller, et al. (2001). "Long-term exposure of tumor necrosis factor alpha causes hypersensitivity to androgen and anti-androgen withdrawal phenomenon in LNCaP prostate cancer cells." Prostate 46(4): 319-326.

BACKGROUND: One of the mechanisms through which prostate cancers relapse during anti-androgen therapy may involve adaptation to low concentrations of androgen induced by anti-androgen therapies. Recent studies from our laboratory have reported that tumor necrosis factor-alpha (TNFalpha) is secreted from prostate cancer epithelial cells and LNCaP cells. We hypothesized that TNFalpha changes androgen-sensitivity in LNCaP cells. METHODS: We cultured LNCaP cells for more than 3 months in the presence of 50 ng/ml TNFalpha and established TNFalpha-resistant LNCaP cells (LN-TR2). Sensitivity to androgen was examined by the cell proliferation assay. We also transfected LNCaP and LN-TR2 cells with a luciferase reporter plasmid driven by prostate-specific antigen (PSA) promoter and compared PSA promoter activity. Nuclear localization of AR protein that binds to target genes was also examined by Western blotting. RESULTS: LN-TR2 cells had increased sensitivity to dihydrotestosterone (DHT) (i.e., proliferation and PSA promoter activation) than LNCaP cells. Total AR mRNA and AR protein levels were decreased in LN-TR2 cells. However, LN-TR2 cells demonstrated increased levels of nuclear AR compared to LNCaP cells. At 1 nM DHT, the anti-androgen bicalutamide stimulated LN-TR2 and inhibited LNCaP proliferation. CONCLUSIONS: Long-term exposure of TNFalpha causes hypersensitivity to DHT in LNCaP and this was associated with increased nuclear AR protein. Furthermore, hypersensitivity to androgen caused anti-androgen withdrawal phenomenon in the presence of DHT although bicalutamide itself did not stimulate LNCaP proliferation without androgen. This result may be one possible mechanism for the anti-androgen withdrawal phenomenon.

Harney, J. V., M. Liebert, et al. (1991). "The expression of epidermal growth factor receptor on human bladder cancer: potential use in radioimmunoscintigraphy." J Urol 146(1): 227-231.

Monoclonal antibody 425, which binds to an extracellular domain of the epidermal growth factor receptor, was used to evaluate the expression of this antigen on bladder cancer cells. Epidermal growth factor receptor was found on all bladder cancer cell lines tested. Immunoperoxidase staining of fourteen invasive human bladder cancers with monoclonal antibody 425 demonstrated that ten showed strong staining, one showed weak staining and three were negative. Five noninvasive tumors were similarly examined. Four of these were negative and one showed weak staining. Biodistribution experiments with human bladder tumor xenografts in athymic nude mice using radiolabeled monoclonal antibody 425 and an isotype matched control antibody demonstrated specific tumor localization at five and seven days following antibody injection. Successful imaging of a human bladder tumor xenograft was achieved five days post antibody injection. These data confirm that epidermal growth factor receptor expression correlates with bladder cancer stage and suggests that epidermal growth factor receptor may serve as a target antigen for radioimmunoscintigraphy.

Harney, J. V., R. L. Wahl, et al. (1991). "Uptake of 2-deoxy, 2-(18F) fluoro-D-glucose in bladder cancer: animal localization and initial patient positron emission tomography." J Urol 145(2): 279-283.

An orthotopically transplanted, locally metastasizing rat bladder tumor model was developed to evaluate the extent of uptake of fluoro-deoxy-glucose (FDG) in bladder cancer. Significant uptake of FDG in localized bladder tumors in rats was shown, with an average tumor-to-blood ratio of 39 at 2 hours after intravenous FDG administration. Metastases (3 nodal and 1 peritoneal) also showed significant uptake of FDG, with an average metastasis-to-blood ratio of 21.7, and tumor involved-to-normal lymph node ratio of 5.3. Because FDG is excreted in the urine, urinary FDG potentially could prevent the use of FDG/positron emission tomography (FDG/PET) scanning for localized bladder cancer. Bladder lavage successfully reduced the retention of FDG in the normal rat bladder, with an estimated uptake ratio of tumor-to-normal bladder of 13.1 after 5 ml. saline irrigation. Based on these data, we performed an FDG/PET scan of a patient with biopsy proved recurrent intravesical bladder cancer after radiation therapy. Computerized tomography (CT) of the pelvis showed abnormalities consistent with radiation scarring and extravesical tumor. Due to the scarring, the extent of tumor growth could not be determined. The patient also had pulmonary opacities seen on chest radiography. The FDG/PET scan of this patient showed significant extravesical uptake in the pelvis, confirming the abnormality noted on CT. Good images of the clinically apparent metastases in the chest also were obtained. These preliminary data indicate that FDG/PET imaging of bladder cancer is feasible and it may provide new information for the diagnosis and staging of patients with bladder cancer.

Harper, D., D. A. Bloom, et al. (2006). "The high-resolution chest CT findings in an adult with Melnick-Needles syndrome." Clin Imaging 30(5): 350-353.

Melnick-Needles syndrome is an X-linked dominant skeletal dysplasia in which patients often succumb at an early age to chronic pulmonary disease. Radiographic findings of Melnick-Needles syndrome consist of characteristic bony abnormalities and interstitial lung disease. We present the high-resolution computed tomographic (CT) findings in a 39-year-old survivor of Melnick-Needles syndrome. The clinical and physical exam findings also demonstrate an association between Melnick-Needles syndrome and obstructive sleep apnea.

Hart, K. B., D. P. Wood, Jr., et al. (1999). "The impact of race on biochemical disease-free survival in early-stage prostate cancer patients treated with surgery or radiation therapy." Int J Radiat Oncol Biol Phys 45(5): 1235-1238.

PURPOSE: To assess the impact of race on biochemical freedom from recurrence in patients with early-stage prostate cancer treated either by radical prostatectomy or radiation therapy. METHODS: Between July 1989 and December 1994, 693 patients with early-stage prostate cancer were treated with radiation (302 patients) or by radical prostatectomy (391 patients) at Barbara Ann Karmanos Cancer Institute/Wayne State University. Stage, Gleason score, race, pretreatment PSA, and follow-up PSA values were abstracted. There were 387 Caucasian males (CM) and 306 African-American males (AAM). None of the patients received hormone therapy. Radiation therapy was delivered using photon irradiation (249 patients, median dose 69 Gy) or mixed neutron/photon irradiation (53 patients, median dose 10 NGy + 38 PGy). Median follow-up was 36 months (range 2-70) for CM and 35 months (range 1-70) for AAM. RESULTS: Thirty-seven percent of patients treated surgically were AAM, compared to 53% in the radiation group (p = 0001). AAM had a higher median prostate-specific antigen (PSA) than CM (9.78 ng/ml vs. 8.0 ng/ml, p = 0.01). Thirty-three percent of AAM had a pretreatment PSA greater than 15 ng/ml compared to 20% of CM (p = 0.00001). Disease-free survival (DFS) by race was equivalent at 36 months, 81% for CM and 77% for AAM (p = NS). For patients with PSA < or =15, DFS rates were 87% and 85% for CM and AAM, respectively. DFS rates for patients with PSA >15 were 61% for CM and 64% for AAM (p = NS). Significant prognostic factors on multivariate analysis included pretreatment PSA (p = 0.0001) and Gleason score (p = 0.0001). CONCLUSION: Race does not appear to adversely affect biochemical disease-free survival in males treated for early-stage prostate cancer. African-American males with early-stage prostate cancer should expect similar biochemical disease-free survival rates to those seen in Caucasian males.

Hautmann, R. E., H. Abol-Enein, et al. (2007). "Urinary diversion." Urology 69(1 Suppl): 17-49.

A consensus conference convened by the World Health Organization (WHO) and the Societe Internationale d'Urologie (SIU) met to critically review reports of urinary diversion. The world literature on urinary diversion was identified through a Medline search. Evidence-based recommendations for urinary diversion were prepared with reference to a 4-point scale. Many level 3 and 4 citations, but very few level 2 and no level 1, were noted. This outcome supported the clinical practice pattern. Findings of >300 reviewed citations are summarized. Published reports on urinary diversion rely heavily on expert opinion and single-institution retrospective case series: (1) The frequency distribution of urinary diversions performed by the authors of this report in >7000 patients with cystectomy reflects the current status of urinary diversion after cystectomy for bladder cancer: neobladder, 47%; conduit, 33%; anal diversion, 10%; continent cutaneous diversion, 8%; incontinent cutaneous diversion, 2%; and others, 0.1%. (2) No randomized controlled studies have investigated quality of life (QOL) after radical cystectomy. Such studies are desirable but are probably difficult to conduct. Published evidence does not support an advantage of one type of reconstruction over the others with regard to QOL. An important proposed reason for this is that patients are subjected preoperatively to method-to-patient matching, and thus are prepared for disadvantages associated with different methods. (3) Simple end-to-side, freely refluxing ureterointestinal anastomosis to an afferent limb of a low-pressure orthotopic reconstruction, in combination with regular voiding and close follow-up, is the procedure that results in the lowest overall complication rate. The potential benefit of "conventional" antireflux procedures in combination with orthotopic reconstruction seems outweighed by the higher complication and reoperation rates. The need to prevent reflux in a continent cutaneous reservoir is not significantly debated, and this should be done. (4) Most reconstructive surgeons have abandoned the continent Kock ileal reservoir largely because of the significant complication rate associated with the intussuscepted nipple valve.

Havens, A. M., E. A. Pedersen, et al. (2008). "An in vivo mouse model for human prostate cancer metastasis." Neoplasia 10(4): 371-380.

We developed a sensitive real-time polymerase chain reaction (QPCR) assay that allows us to track early lodging/homing events in vivo. We used this technology to develop a metastasis assay of human prostate cancer (PCa) growth in severe combined immunodeficient mice. For this purpose, marked human PCa cell lines were implanted subcutaneously or in the prostate (orthotopically) of severe combined immunodeficient mice as models of primary tumors. Mice were then sacrificed at various time points, and distant tissues were investigated for the presence of metastatic cells. At 3 weeks, a number of tissues were recovered and evaluated by QPCR for the presence of metastatic cells. The data demonstrate that several PCa cell lines are able to spread from the primary lesion and take up residence in distant sites. If the primary tumors were resected at 3 weeks, in several cases, metastatic lesions were identified over the course of 9 months. We propose that this new model may be particularly useful in exploring the molecular events in early metastasis, identifying the metastatic niche, and studying issues pertaining to dormancy.

Hayward, S. W., Y. Wang, et al. (2003). "Rescue and isolation of Rb-deficient prostate epithelium by tissue recombination." Methods Mol Biol 218: 17-33.

The ability to rescue viable prostate precursor tissue from Rb-/-fetal mice has allowed for the generation of Rb-/-prostate tissue and Rb-/-prostate epithelial cell lines. Herein, we provide a protocol for the rescue of urogenital precursor tissue from mouse embryos harboring the lethal Rb-/-mutation. The rescued precursors can matured as subrenal capsule grafts in athymic mice. Subsequently prostatic tissue can be used as a source for Rb-/-epithelium in a tissue recombination protocol for the generation of chimeric prostate grafts in athymic male mouse hosts. We have also provided a detailed description for isolating and propagating the Rb-/-epithelium from such tissue recombinants as established cell lines. Methods for characterizing the grafts and cell lines by determining the retention of prostate-specific epithelial expression markers, including cytokeratins, the androgen receptor, estrogen receptor beta and the dorsolateral prostatic secretory protein (mDLP) are given.

Heaney, M. D., I. R. Francis, et al. (1999). "Orthotopic neobladder reconstruction: findings on excretory urography and CT." American Journal of Roentgenology 172(5): 1213-1220.

OBJECTIVE: The excretory urographic and CT appearance of orthotopic ileal neobladder reconstruction after cystectomy and its complications are described. MATERIALS AND METHODS: We retrospectively reviewed the excretory urograms and CT scans of 32 patients (29 men and three women, 35-76 years old) with transitional cell carcinoma of the bladder who underwent orthotopic neobladder reconstruction with anastomosis to the native urethra after cystectomy. The radiologic review consisted of 25 excretory urograms in 20 patients and 37 CT scans in 21 patients. RESULTS: On excretory urography, the afferent segment of the neobladder was identified as a contrast-filled structure in all 20 patients, and was located in the right lower quadrant in 18 (90%). On CT, the afferent segment and the neobladder were identified in all 21 patients. Delayed imaging performed after initial scanning in 12 (57%) of 21 patients was helpful for revealing detailed anatomy such as the ureteral-afferent limb anastomoses. Complications occurred in two patients and were caused by a lymphocele in one and a urine leak from the neobladder in the other. In six other patients we found evidence of recurrent or metastatic tumor or both: two had local pelvic recurrence and pelvic nodal metastases, two other patients had metastatic nodal disease, one patient had a malignant distal ureteral stricture, and the sixth patient had distant osseous metastases. CONCLUSION: Orthotopic neobladder reconstruction after cystectomy has a characteristic appearance on both excretory urography and CT. Knowledge of this appearance and the altered anatomy is useful to recognize complications and tumor recurrence. Delayed images during excretory urography and CT are useful to define the ureteral-afferent limb anastomosis with the neobladder and also to differentiate between postoperative collections. <69>

Hedgepeth, R. C., S. M. Gilbert, et al. (2010). "Body Image and Bladder Cancer Specific Quality of Life in Patients With Ileal Conduit and Neobladder Urinary Diversions." Urology.

PURPOSE: Patients undergoing radical cystectomy with neobladder for bladder cancer are hypothesized to tolerate worse urinary function than ileal conduit patients because of improved body image. The purpose of this study was to compare body image and quality of life between the 2 diversion types after surgery. MATERIALS AND METHODS: Patients who underwent radical cystectomy at the University of Michigan from November 1999 onwards and completed follow-up between July 2007 and August 2008 were eligible for the study. Patients who had cystoscopy for bladder cancer were enrolled as a reference group. Urinary, bowel, and sexual outcomes were assessed using the Bladder Cancer Index, and body image was evaluated using the EORTC Body Image Scale. Cross-sectional analysis at baseline, 1 month, 6 months, and 1, 2, 4, 6, and 8 years after treatment was performed. RESULTS: A total of 139 neobladder, 85 conduit, and 112 cystoscopy patients were studied. After cystectomy, both conduit and neobladder groups had worse body image scores that improved over time, although the neobladder group did not return to baseline. Age was associated with score but gender was not. Urinary function was better in conduit patients but urinary bother was the same in both diversion types. CONCLUSIONS: Radical cystectomy has a significant impact on body image that improves slowly over time. No difference in body image scores between ileal conduit and neobladder patients exists after surgery. Factors other than just body image are likely involved in the patient's acceptance of worse urinary function associated with a neobladder.

Hedgepeth, R. C., J. Labo, et al. (2009). "Expanded Prostate Cancer Index Composite versus Incontinence Symptom Index and Sexual Health Inventory for Men to measure functional outcomes after prostatectomy." J Urol 182(1): 221-227; discussion 227-228.

PURPOSE: Evaluating quality of life outcomes following prostate cancer treatment is important because different treatments provide similar survival outcomes. A wide variety of quality of life surveys are used with an unknown correlation between domain specific and broad domain instruments. We compared the urinary and sexual outcome measures of the Expanded Prostate Cancer Index Composite, a broad domain instrument, to those of the Incontinence Symptom Index and the Sexual Health Inventory for Men, which are domain specific instruments. MATERIALS AND METHODS: A total of 640 patients undergoing radical prostatectomy at our institution completed a combination of the Expanded Prostate Cancer Index Composite, Incontinence Symptom Index and Sexual Health Inventory for Men questionnaires. Matching functional domains were compared and correlation coefficients were calculated. Subgroup analysis was performed to compare specific information pertinent to recovery from prostatectomy. RESULTS: Correlations between measures of incontinence were 0.26 to 0.84, while indicators of sexual function were 0.70 to 0.84. Subgroup analysis comparing measures of irritative symptoms demonstrated weaker correlations. Analysis in patients reporting no sexual activity also showed a significantly lower correlation of scores than that in patients reporting sexual activity. CONCLUSIONS: Expanded Prostate Cancer Index Composite scores generally demonstrate strong correlations with corresponding Incontinence Symptom Index and Sexual Health Inventory for Men scores, indicating similar measurements of information. Divergent correlations between irritative scores as well as scores in men who are not sexually active may indicate that the Expanded Prostate Cancer Index Composite has more descriptive validity in this population. Wider use of a single broad domain instrument such as the Expanded Prostate Cancer Index Composite to assess outcomes after prostate cancer treatment may improve clinical efficiency and allow comparative quality of life research across treatment types in the future.

Hedgepeth, R. C., J. S. Wolf, Jr., et al. (2009). "Patient-reported recovery after abdominal and pelvic surgery using the Convalescence and Recovery Evaluation (CARE): implications for measuring the impact of surgical processes of care and innovation." Surg Innov 16(3): 243-248.

BACKGROUND: Recovery is an integral part of the surgical process and measuring it provides insight into the impact of surgical innovation. This study used a recently validated instrument, the Convalescence and Recovery Evaluation (CARE), to measure return to baseline health after surgery and explore clinical factors associated with recovery. STUDY DESIGN: Patient health was measured among 96 patients before and after abdominal and pelvic surgery. Patients were grouped by time to recovery of 90% of baseline status. chi2 Tests and logistic models were used to measure relationships between recovery time and patient characteristics, processes of care, and outcomes. RESULTS: Return to baseline health was reached by 44% of patients within 2 weeks, 28% between 2 and 4 weeks, and 28% after 4 weeks. Patients who recovered faster were younger, female, single, and undergoing ambulatory surgery for benign diseases. Patients who were married, underwent surgery for cancer, or had bowel surgery were more likely to require longer recovery time. CONCLUSIONS: Several patient and clinical characteristics were found to be associated with recovery after surgery. CARE appears to be sensitive to these factors and may be useful for informed decision making, assessing changes in processes of care, and evaluating the impact of surgical innovations on recovery.

Helgeson, B. E., S. A. Tomlins, et al. (2008). "Characterization of TMPRSS2:ETV5 and SLC45A3:ETV5 gene fusions in prostate cancer." Cancer Res 68(1): 73-80.

Recurrent gene fusions involving oncogenic ETS transcription factors (including ERG, ETV1, and ETV4) have been identified in a large fraction of prostate cancers. The most common fusions contain the 5' untranslated region of TMPRSS2 fused to ERG. Recently, we identified additional 5' partners in ETV1 fusions, including TMPRSS2, SLC45A3, HERV-K_22q11.23, C15ORF21, and HNRPA2B1. Here, we identify ETV5 as the fourth ETS family member involved in recurrent gene rearrangements in prostate cancer. Characterization of two cases with ETV5 outlier expression by RNA ligase-mediated rapid amplification of cDNA ends identified one case with a TMPRSS2:ETV5 fusion and one case with a SLC45A3:ETV5 fusion. We confirmed the presence of these fusions by quantitative PCR and fluorescence in situ hybridization. In vitro recapitulation of ETV5 overexpression induced invasion in RWPE cells, a benign immortalized prostatic epithelial cell line. Expression profiling and an integrative molecular concepts analysis of RWPE-ETV5 cells also revealed the induction of an invasive transcriptional program, consistent with ERG and ETV1 overexpression in RWPE cells, emphasizing the functional redundancy of ETS rearrangements. Together, our results suggest that the family of 5' partners previously identified in ETV1 gene fusions can fuse with other ETS family members, suggesting numerous rare gene fusion permutations in prostate cancer.

Hellenthal, N. J., S. F. Shariat, et al. (2009). "Adjuvant chemotherapy for high risk upper tract urothelial carcinoma: results from the Upper Tract Urothelial Carcinoma Collaboration." J Urol 182(3): 900-906.

PURPOSE: There is relatively little literature on adjuvant chemotherapy after radical nephroureterectomy in patients with upper tract urothelial carcinoma. We determined the incidence of adjuvant chemotherapy in high risk patients and the ensuing effect on overall and cancer specific survival. MATERIALS AND METHODS: Using an international collaborative database we identified 1,390 patients who underwent nephroureterectomy for nonmetastatic upper tract urothelial carcinoma between 1992 and 2006. Of these cases 542 (39%) were classified as high risk (pT3N0, pT4N0 and/or lymph node positive). These patients were divided into 2 groups, including those who did and did not receive adjuvant chemotherapy, and stratified by gender, age group, performance status, and tumor grade and stage. Cox proportional hazard modeling and Kaplan-Meier analysis were used to determine overall and cancer specific survival in the cohorts. RESULTS: Of high risk patients 121 (22%) received adjuvant chemotherapy. Adjuvant chemotherapy was more commonly administered in the context of increased tumor grade and stage (p <0.001). Median survival in the entire cohort was 24 months (range 0 to 231). There was no significant difference in overall or cancer specific survival between patients who did and did not receive adjuvant chemotherapy. However, age, performance status, and tumor grade and stage were significant predictors of overall and cancer specific survival. CONCLUSIONS: Adjuvant chemotherapy is infrequently used to treat high risk upper tract urothelial carcinoma after nephroureterectomy. Despite this finding it appears that adjuvant chemotherapy confers minimal impact on overall or cancer specific survival in this group.

Henderson, A., D. Murphy, et al. (2008). "Hand-assisted laparoscopic nephrectomy for renal cell cancer with renal vein tumor thrombus." Urology 72(2): 268-272.

OBJECTIVES: To assess outcomes after hand-assisted laparoscopic nephrectomy (HALN) for renal cell cancer tumor thrombus confined to the renal vein and to compare outcomes with published series in this setting. METHODS: Thirteen patients underwent HALN for radiologic T3b disease (tumor thrombus confined to the renal vein on preoperative computed tomography) under the care of three surgeons at two centers between 1997 and 2006. RESULTS: Median patient age was 69 years. Median duration of surgery was 176 minutes. Median blood loss was 250 mL. Median postoperative stay was 3 days. Two patients were converted to open surgery: 1 owing to unsuspected invasion of the subdiaphragmatic vena cava requiring vascular clamping with direct excision and suture, and 1 for control of bleeding. No patients suffered major morbidity associated with surgery, and there was one minor complication (aside from blood transfusion in 5 patients). After 2.7 years median follow-up, 3 of the 12 patients with pT3bN0 disease had metastases, but there were no local recurrences. CONCLUSIONS: These data demonstrate that HALN for renal cell cancer with tumor thrombus limited to the renal vein is feasible. Our outcomes compare favorably to published data on open surgical radical nephrectomy in this setting, and HALN should be considered in centers with experience with this technique.

Herman, J. M., D. C. Smith, et al. (2004). "Prospective quality-of-life assessment in patients receiving concurrent gemcitabine and radiotherapy as a bladder preservation strategy." Urology 64(1): 69-73.

OBJECTIVES: To assess, in a Phase I study, whether bladder preservation with concurrent gemcitabine and radiotherapy (RT) influenced patient-reported quality of life (QOL) as determined by the Functional Assessment of Cancer Therapy-Bladder (FACT-BL). METHODS: Between January 1998 and March 2002, 24 patients with urothelial carcinoma of the bladder were enrolled, and 23 patients underwent transuretheral resection of bladder tumor, followed by twice-weekly gemcitabine with concurrent RT. The initial dose was 10 mg/m2 given twice weekly and increased as tolerated. To assess treatment-related QOL, patients completed the FACT-BL questionnaire. RESULTS: Of the 24 patients enrolled, 23 (96%) were assessed for toxicity and response. The FACT-generic (G) QOL assessment was obtained from 22 (92%) of 23 patients. No statistically significant difference was found in the FACT-G or FACT-BL or the combination before, during, or after treatment. The FACT-BL values were lower in patients who received higher doses of gemcitabine (greater than 20 mg/m2 versus 20 mg/m2 or less). At least one dose-limiting toxicity (DLT) was experienced by 5 (23%) of 22 patients. The FACT-G values were lower for those patients who experienced DLT (difference of -13.1, P = 0.07). The physical well-being scores for patients who experienced DLT were lower after treatment (difference of -5.2, P = 0.03) compared with those without DLT. CONCLUSIONS: Concurrent RT and gemcitabine failed to statistically influence patient-reported QOL, although patients who received higher doses reported lower FACT-BL scores. The results of this study suggest that concurrent gemcitabine with conformal RT is a tolerable treatment regimen for bladder preservation, as demonstrated by the excellent treatment compliance and similar FACT measurements.

Hernandez, D. J., V. A. Sinkov, et al. (2001). "Measurement of bio-impedance with a smart needle to confirm percutaneous kidney access." J Urol 166(4): 1520-1523.

PURPOSE: The traditional method of percutaneous renal access requires freehand needle placement guided by C-arm fluoroscopy, ultrasonography, or computerized tomography. This approach provides limited objective means for verifying successful access. We developed an impedance based percutaneous Smart Needle system and successfully used it to confirm collecting system access in ex vivo porcine kidneys. MATERIALS AND METHODS: The Smart Needle consists of a modified 18 gauge percutaneous access needle with the inner stylet electrically insulated from the outer sheath. Impedance is measured between the exposed stylet tip and sheath using Model 4275 LCR meter (Hewlett-Packard, Sunnyvale, California). An ex vivo porcine kidney was distended by continuous gravity infusion of 100 cm. water saline from a catheter passed through the parenchyma into the collecting system. The Smart Needle was gradually inserted into the kidney to measure depth precisely using a robotic needle placement system, while impedance was measured continuously. RESULTS: The Smart Needle was inserted 4 times in each of 4 kidneys. When the needle penetrated the distended collecting system in 11 of 16 attempts, a characteristic sharp drop in resistivity was noted from 1.9 to 1.1 ohm m. Entry into the collecting system was confirmed by removing the stylet and observing fluid flow from the sheath. This characteristic impedance change was observed only at successful entry into the collecting system. CONCLUSIONS: A characteristic sharp drop in impedance signifies successful entry into the collecting system. The Smart Needle system may prove useful for percutaneous kidney access.

Herr, H., B. Konety, et al. (2009). "Optimizing outcomes at every stage of bladder cancer: do we practice it?" Urol Oncol 27(1): 72-74.

Defining the best practices in treating any disease can lead to optimal treatment. Establishing these best practices is difficult, and relies on clinical trials, expert opinion, and consensus decisions. Bladder cancer is a heterogeneous disease that can be either relatively benign or highly malignant depending on the grade and stage of the tumor. Determining the best practices for bladder cancer is based on the stage, grade, and presentation of the cancer. Herein we identify four clinical scenarios involving bladder cancer and discuss whether best practice guidelines are available for these clinical scenarios, and if so, how often do we follow these guidelines.

Herr, H., C. Lee, et al. (2004). "Standardization of radical cystectomy and pelvic lymph node dissection for bladder cancer: a collaborative group report." J Urol 171(5): 1823-1828; discussion 1827-1828.

PURPOSE: We propose standards for radical cystectomy and pelvic lymph node dissection in the surgical treatment of patients with invasive bladder cancer. MATERIALS AND METHODS: We compiled the consecutive cystectomy experience of 16 experienced surgeons during the last 3 years (2000 to 2002) from 4 institutions. We evaluated patient, tumor and surgical variables of margin status, extent of pelvic node dissection, number of nodes examined and surgeon volume associated with bladder cancer outcomes. RESULTS: A total of 1,091 cystectomy cases were evaluated. Surgical margins and number of nodes retrieved correlated with patient age, prior treatments, pathological tumor stage and extent of node dissection, but not surgeon volume. CONCLUSIONS: Standards for radical cystectomy can be established and achieved by experienced surgeons operating on patients presenting with diverse clinical situations.

Herr, H. W., C. T. Lee, et al. (2001). "Radiographic versus pathologic size of renal tumors: implications for partial nephrectomy." Urology 58(2): 157-160.

OBJECTIVES: To compare the radiographic size with the pathologic size of renal tumors to determine whether these two measurements vary significantly and to evaluate whether any differences in tumor size could have an impact on the decisions regarding partial nephrectomy. METHODS: In 87 renal tumors excised by partial nephrectomy, the maximum transaxial tumor size on computed tomography (CT) was compared with its corresponding pathologic transverse size. Tumors were locally excised after vascular occlusion and hypothermia. The average size of the tumors selected for partial nephrectomy by preoperative CT scan was 3.4 cm (range 1.9 to 9.3). The difference between the CT size and pathologic size was correlated with the histologic type of the renal tumors. RESULTS: Of the 87 tumors, 52 (60%) were classified as clear cell carcinoma and 35 (40%) as other histologic types (papillary, chromophobe, oncocytoma, and angiomyolipoma). Clear cell carcinomas decreased an average of 0.97 cm versus 0.39 cm for the other tumor types. Of 62 tumors greater than 3 cm on CT, 43 averaged 0.87 cm smaller at pathologic evaluation (36 clear cell and 7 other types) and 19 showed no significant (less than 0.5 cm) decrease in size (2 clear cell and 17 other histologic types). Of 30 tumors greater than 4 cm on CT, 22 clear cell carcinomas shrank more than 1 cm and 8 tumors displaying other histologic features showed no decrease in size. CONCLUSIONS: For renal tumors measuring greater than 4 cm, a decrease in tumor size may help facilitate partial nephrectomy, especially for clear cell carcinomas that do not extensively involve major vascular structures or the collecting system.

Hertzer, N. R. and J. E. Montie (1971). "Spigelian hernia. A review of the literature and report of three cases." Cleveland Clinic Quarterly 38(1): 13-18.

Hertzer, N. R., J. E. Montie, et al. (1976). "Revascularization of the kidney after occlusion of the aorta and both renal arteries." Surgery 79(1): 52-56.

A patient who developed acute renal artery thrombosis as a complication of distal abdominal aortic occlusion is described. Because of the presence of an extensive collateral arterial supply, the right kidney survived and revascularization was accomplished successfully with a saphenous vein graft interposed between the superior mesenteric and the right renal arteries. Criteria for revascularization of renal artery occlusion are presented, with emphasis on the importance of collateral circulation and the elective correction of distal aortic thrombosis. <217>

Hochwald, S. N., S. R. Grobmyer, et al. (2010). "Braun enteroenterostomy is associated with reduced delayed gastric emptying and early resumption of oral feeding following pancreaticoduodenectomy." J Surg Oncol 101(5): 351-355.

BACKGROUND AND OBJECTIVES: Morbidity rates following pancreaticoduodenectomy (PD) remain high with delayed gastric emptying (DGE) and slow resumption of oral diet contributing to increased postoperative length of stay. A Braun enteroenterostomy has been shown to decrease bile reflux following gastric resection. We hypothesize that addition of Braun enteroenterostomy during PD would reduce the sequelae of DGE. METHODS: From our PD database, patients were identified that underwent classic PD with partial gastrectomy from 2001 to 2006. All patients with reconstruction utilizing a single loop of jejunum at the University of Florida Shands Hospital were reviewed. Demographics, presenting signs and symptoms, pathologic diagnoses, and postoperative morbidity were compared in those patients undergoing reconstruction with an additional Braun enteroenterostomy (n = 70) to those not undergoing a Braun enteroenterostomy (n = 35). RESULTS: Patients undergoing a Braun had NG tubes removed earlier (Braun: 2 days, no Braun: 3 days, P = 0.002) and no significant change in postoperative vomiting (Braun: 27%, no Braun: 37%, P = 0.37) or NG tube reinsertion rates (Braun: 17%, no Braun: 29%, P = 0.21). Median postoperative day with tolerance of oral liquids (Braun: 5, no Braun: 6, P = 0.01) and solid diets (Braun: 7, no Braun: 9, P = 0.01) were significantly sooner in the Braun group. DGE defined by two criteria including the inability to have oral intake by postoperative day 10 (Braun: 10%, no Braun: 26%, P < 0.05) and the international grading criteria (grades B and C, Braun: 7% vs. no Braun: 31%, P = 0.003) were significantly reduced in those undergoing the Braun procedure. In addition, the median length of stay (Braun: 10 days, no Braun: 12 days, P < 0.05) was significantly reduced in those undergoing the Braun procedure. The rate of pancreatic anastomotic failure was similar in the two groups (Braun: 17% vs. no Braun: 14%, P = 0.79). Median bile reflux was 0% in those undergoing a Braun. CONCLUSIONS: The present study suggests that Braun enteroenterostomy can be safely performed in patients undergoing PD and may reduce the indicence of DGE and its sequelae. Further studies of Braun enteroenterostomy in larger randomized trials of patients undergoing PD are warranted.

Hoffer, F. A., D. A. Bloom, et al. (1999). "Lung abscess versus necrotizing pneumonia: implications for interventional therapy." Pediatr Radiol 29(2): 87-91.

OBJECTIVE: To assess and contrast the role of interventional therapy for two types of cavitating pneumonias: lung abscess and necrotizing pneumonia. MATERIALS AND METHODS: We retrospectively reviewed the imaging, interventional therapy, and outcome of 14 children seen between February 1987 and January 1996 with lung abscess and 9 with necrotizing pneumonia. All children were treated with antibiotics prior to intervention. Pulmonary parenchymal fluid was percutaneously aspirated from ten lung abscesses and three necrotizing pneumonias. Percutaneous catheters drained five lung abscesses. Pleural drainage was performed for three lung abscesses and eight necrotizing pneumonias. RESULTS: All 14 children with lung abscesses had positive Gram stains of the pulmonary fluid; 13 cultures were positive. All 14 defervesced within 48 h of intervention. None developed a bronchopleural fistula. All nine necrotizing pneumonias were presumed to be sequelae of prior pneumonia. Streptococcus pneumoniae was the only organism as documented by pleural fluid latex fixation in three patients, gram stain in two, and culture in only one. Seven of these children developed pneumatoceles, five developed bronchopleural fistulae, and three required long-term chest tubes for persistent pneumothoraces. CONCLUSION: Aggressive interventional therapy can be diagnostic and therapeutic in the infected lung abscess. Interventional therapy can be harmful in postinfectious necrotizing pneumonia.

Hogge, G. S., J. K. Burkholder, et al. (1998). "Development of human granulocyte-macrophage colony-stimulating factor-transfected tumor cell vaccines for the treatment of spontaneous canine cancer." Hum Gene Ther 9(13): 1851-1861.

Cytokine gene-engineered tumor vaccines are currently an area of intense investigation in both basic research and clinical medicine. Our efforts to utilize tumor vaccines in an immunotherapeutic manner involve canines with spontaneous tumors. We hypothesized that canine tumor cells, transfected with human granulocyte-macrophage colony-stimulating factor (hGM-CSF) cDNA in a plasmid vector, would prove nontoxic following intradermal administration, generate biologically relevant levels of protein, effect local histological changes at the sites of vaccination, and create a systemic antitumor response. Sixteen tumor-bearing dogs were admitted to a study of ex vivo gene therapy. Tumor tissue was surgically removed, enzymatically and mechanically dissociated, irradiated, transfected, and intradermally injected back into the patients. The dogs were vaccinated with primary autologous tumor cells transfected with hGM-CSF or a reporter control gene. hGM-CSF protein was detected (0.07 to 14.15 ng/vaccination site) at 24 hr postinjection and dramatic histological changes were observed, characterized by neutrophil and macrophage infiltration at the sites of injection of hGM-CSF-transfected tumor cells. This was in stark contrast to the lesser neutrophilic and eosinophilic infiltrates found at control vaccination sites. Objective evidence of an antitumor response was observed in three animals. These data, in a large animal translational model of spontaneous tumors, demonstrate in vivo biological activity of hGM-CSF-transfected autologous tumor cell vaccines.

Hollenbeck, B. K., N. Bassily, et al. (2000). "Whole mounted radical prostatectomy specimens do not increase detection of adverse pathological features." J Urol 164(5): 1583-1586.

PURPOSE: The optimal method to process radical prostatectomy specimens to maximize the detection of adverse pathological features is unclear and accurate staging is critical. We compare the ability of whole mounted sections to detect these features compared to partially submitted radical prostatectomy specimens. MATERIALS AND METHODS: A total of 93 consecutive radical prostatectomy specimens were processed as whole mounts. Tissue sections were analyzed and the pathological outcomes measured included Gleason score, surgical margin status, and presence or absence of extraprostatic tumor extension and/or seminal vesicle invasion. The pathological outcomes of the preceding cohort were compared to those of a similar cohort consisting of 554 men whose radical prostatectomy specimens were processed as partially submitted glands. RESULTS: A multivariate logistic regression analysis was performed to determine the effect of the method of tissue processing on the pathological outcomes. When considered alone or adjusted for various preoperative patient characteristics (prostate specific antigen, biopsy Gleason score and clinical stage), there were no significant differences in the ability of whole mounted specimens to detect the various outcomes compared to partially submitted specimens (all p >0.4). CONCLUSIONS: Whole mounted sampling of the radical prostatectomy specimen does not improve detection of adverse pathological features.

Hollenbeck, B. K., N. Bassily, et al. (2000). "Whole mounted radical prostatectomy specimens do not increase detection of adverse pathological features. [see comments.]." Journal of Urology 164(5): 1583-1586.

PURPOSE: The optimal method to process radical prostatectomy specimens to maximize the detection of adverse pathological features is unclear and accurate staging is critical. We compare the ability of whole mounted sections to detect these features compared to partially submitted radical prostatectomy specimens. MATERIALS AND METHODS: A total of 93 consecutive radical prostatectomy specimens were processed as whole mounts. Tissue sections were analyzed and the pathological outcomes measured included Gleason score, surgical margin status, and presence or absence of extraprostatic tumor extension and/or seminal vesicle invasion. The pathological outcomes of the preceding cohort were compared to those of a similar cohort consisting of 554 men whose radical prostatectomy specimens were processed as partially submitted glands. RESULTS: A multivariate logistic regression analysis was performed to determine the effect of the method of tissue processing on the pathological outcomes. When considered alone or adjusted for various preoperative patient characteristics (prostate specific antigen, biopsy Gleason score and clinical stage), there were no significant differences in the ability of whole mounted specimens to detect the various outcomes compared to partially submitted specimens (all p >0.4). CONCLUSIONS: Whole mounted sampling of the radical prostatectomy specimen does not improve detection of adverse pathological features. <46>

Hollenbeck, B. K., S. Daignault, et al. (2007). "Getting under the hood of the volume-outcome relationship for radical cystectomy." J Urol 177(6): 2095-2099; discussion 2099.

PURPOSE: Hospital and surgeon volumes independently explain variations in outcomes for a host of surgical procedures. However, the mediators of the volume effect remain unclear. We assessed whether differences among hospitals could explain some or all of the volume effect on short-term outcomes after cystectomy for bladder cancer. MATERIALS AND METHODS: Using the Nationwide Inpatient Sample a 20% sampling of hospital discharges in the United States and the American Hospital Association file we applied International Classification of Diseased, 9th revision, clinical modification procedure codes to identify 1,847 patients who underwent cystectomy for bladder cancer in 2003. Multivariable mixed models were fit to quantify the differences in measures of hospital structure (capacity, staffing and health services) by hospital volume. Separate models were fit to determine the impact of accounting for these differences on the volume-outcome relationship. RESULTS: There were substantial differences in hospital structure according to radical cystectomy volume, including those characterizing capacity, staffing levels and the breadth of available health services. For example, 40.7% of low and 87.8% of high volume hospitals for radical cystectomy offered open heart surgery (OR 10.4, 95% CI 1.3-85.3). After adjusting for case mix patients treated at low volume centers were 3.2 times (95% CI 0.8-13.4) more likely to die postoperatively. Accounting for differences in hospital structure attenuated the volume effect by 59% (OR 1.9, 95% CI 0.4-8.6). CONCLUSIONS: Measurable differences in the availability and breadth of consultative, diagnostic and ancillary services may at least partially explain the association between procedure volume and short-term cystectomy outcomes.

Hollenbeck, B. K., S. Daignault, et al. (2007). "Measuring convalescence after laparoscopic surgery." Urology 69(6): 1025-1029.

OBJECTIVES: To better understand the relationships between case-mix, processes of care, and recovery after laparoscopic surgery. METHODS: Patient recovery was prospectively measured among patients undergoing laparoscopic nephrectomy (n = 308), partial nephrectomy (n = 81), nephroureterectomy (n = 30), and cyst decortication (n = 46). Convalescence was measured using the SF-12 and visual analog pain scales administered preoperatively and at 2 and 6 weeks postoperatively. Patient-reported time to events (eg, driving, normal, nonstrenuous activity) were also measured. Mixed models (SF-12 and pain scores) and Cox proportional hazards models (time to event) were fit to determine the association of case-mix and processes of care with the recovery measures. RESULTS: With the exception of mental health, all convalescence measures demonstrated significant variability across procedure type. The time to return to normal, nonstrenuous activity was 12.8 +/- 9.8, 11.9 +/- 9.2, 21.6 +/- 11.9, and 12.0 +/- 9.0 days for patients undergoing nephrectomy, partial nephrectomy, nephroureterectomy, and cyst decortication, respectively (P < 0.01). The baseline scores were robust predictors of physical, mental, and pain recovery (all P < 0.01). The surgical approach was associated with postoperative pain recovery and return to normal activity (all P < 0.05). Compared with the preoperative characteristics, the perioperative processes of care did not explain the additional variation in any of the recovery measures. CONCLUSIONS: The variation in recovery among the various laparoscopic kidney procedures is significant. The baseline health status of the patient and the preoperative processes (planned procedure, planned surgical approach) strongly influence postoperative recovery.

Hollenbeck, B. K., R. L. Dunn, et al. (2008). "Effects of laparoscopy on surgical discharge practice patterns." Urology 71(6): 1029-1034.

OBJECTIVES: The length of stay (LOS) after surgical procedures often varies regionally and reflects local idiosyncratic practice patterns. We sought to elicit the influence of local pressures (in the form of the technologic imperative exerted by laparoscopy) on discharge physician practice style as measured by LOS. METHODS: Patients undergoing prostatectomy, nephrectomy, and hysterectomy in 2003 were identified from the Nationwide Inpatient Sample using the International Classification of Diseases, Ninth Revision, codes. Within each procedure, the laparoscopy volume was measured and sorted into tertiles. Patients remaining in the hospital longer than the 90th percentile after each surgery were excluded to minimize the influence of imperative indications on LOS. For each procedure, generalized linear models were used to measure the relationship between the hospital laparoscopy volume and log-transformed LOS outcomes among patients undergoing conventional surgery. RESULTS: In 2003, 2%, 19%, and 16% of patients underwent laparoscopic prostatectomy, nephrectomy, and hysterectomy, respectively. A hospital's laparoscopy and conventional volumes were moderately to highly correlated for hysterectomy (r = 0.65) and nephrectomy (r = 0.58) and less so for prostatectomy (r = 0.24). Among patients undergoing conventional prostatectomy and nephrectomy, those treated at high-volume laparoscopy hospitals had 0.41 and 0.30 fewer hospital days, respectively, compared with those treated at hospitals at which only conventional surgery was performed (both P <0.05). This effect was partially explained by a hospital's open procedure volume (both P = 0.07). Similar relationships were not evident for hysterectomy. CONCLUSIONS: These data highlight that patients treated by conventional methods at high-volume laparoscopy centers have shorter hospital stays and suggest that physician practices might susceptible to external influences such as the technologic imperative.

Hollenbeck, B. K., R. L. Dunn, et al. (2007). "Volume-based referral for cancer surgery: informing the debate." J Clin Oncol 25(1): 91-96.

PURPOSE: Mounting evidence suggests a relationship between hospital volume and outcomes after major cancer surgery; however, the absolute benefits of volume-based referral on a national basis are unclear. PATIENTS AND METHODS: Data from the Nationwide Inpatient Sample were used to measure the likelihood of operative mortality and a prolonged length of stay (LOS) after six cancer surgeries (prostatectomy, cystectomy, esophagectomy, pancreatectomy, pneumonectomy, and liver resection) between 1993 and 2003. Using sampling weights, the adjusted likelihood of the outcomes was used to calculate the number of lives saved (or prolonged LOS avoided) in the United States. RESULTS: The magnitude of the volume-operative mortality effect varied from an adjusted odds ratio (OR) of 1.3 (95% CI, 0.8 to 2.3) for cystectomy to 4.9 (95% CI, 2.4 to 10.1) for pancreatectomy. After accounting for varying rates of procedure utilization, the lives saved per 100 surgeries regionalized ranged from 0.2 (95% CI, 0.12 to 0.24 lives saved) for prostatectomy to 9.2 (95% CI, 6.7 to 10.4 lives saved) for pancreatectomy. The volume-prolonged LOS effect varied from an adjusted OR of 0.9 (95% CI, 0.5 to 1.6) for liver resection to 4.8 (95% CI, 3.5 to 6.7) for prostatectomy. After accounting for procedure use, the number of prolonged hospitalizations avoided ranged from -1.7 (95% CI, -11.3 to 3.6 hospitalizations) to 14.3 (95% CI, 12.9 to 15.4 hospitalizations) per 100 surgeries regionalized for liver resection and prostatectomy, respectively. CONCLUSION: For patients undergoing major cancer surgery, the benefits of volume-based referral depend on the interplay between procedure utilization, the magnitude of effect, and the outcome chosen.

Hollenbeck, B. K., R. L. Dunn, et al. (2002). "Neoadjuvant hormonal therapy and older age are associated with adverse sexual health-related quality-of-life outcome after prostate brachytherapy." Urology 59(4): 480-484.

OBJECTIVES: Brachytherapy is increasingly used as a treatment for localized prostate cancer but information regarding long-term, postimplantation, patient-reported sexual health-related quality-of-life (HRQOL) is scant. Neoadjuvant hormonal therapy is commonly administered with brachytherapy, yet its potentially adverse effects on subsequent sexual health have not been described using a validated HRQOL instrument. We used a validated HRQOL survey to characterize the significance of neoadjuvant hormonal therapy and other baseline factors on postimplantation sexual function and impairment. METHODS: A cross-sectional survey using the expanded prostate cancer index composite HRQOL instrument was administered to all 114 localized prostate cancer patients who underwent ultrasound-guided, transperineal brachytherapy during a 4-year period and to 142 age-matched control men. Multivariable models measured the association of baseline factors and covariates with postimplantation sexual HRQOL. RESULTS: Older age (P = 0.01) and neoadjuvant hormonal therapy (P = 0.009) were independently associated with diminished sexual HRQOL after prostate brachytherapy. Among patients younger than 69 years old, 33% reported at least fair sexual function after brachytherapy alone compared with 19% of men after brachytherapy with neoadjuvant hormonal therapy. Of the age-matched control men younger than 69 years old, 78% reported at least fair sexual function. Among patients older than 69 years, 26% reported at least fair sexual function after brachytherapy alone compared with 5% after brachytherapy with neoadjuvant hormonal therapy, and 61% of age-matched controls reported at least fair sexual function. CONCLUSIONS: Patient age and neoadjuvant hormonal therapy are independent, significant determinants of sexual HRQOL after prostate brachytherapy. These factors should be taken into consideration when counseling patients with localized prostate cancer regarding the expected, postimplantation sexual HRQOL outcome. <13>

Hollenbeck, B. K., R. L. Dunn, et al. (2003). "Determinants of long-term sexual health outcome after radical prostatectomy measured by a validated instrument." J Urol 169(4): 1453-1457.

PURPOSE: We combined the strengths of previous patient reported studies (that is use of a validated instrument) with the assets of previous single surgeon, physician reported series (that is prospective collection of operative data) by performing a multiple surgeon study to identify demographic and operative determinants of post-prostatectomy sexual health related quality of life outcomes. MATERIALS AND METHODS: Sexual outcome was measured after prostatectomy in 671 prostate cancer cases with a followup of 4 to 52 months treated by any of 7 urologists at a high volume medical center and 112 age matched controls by cross-sectional health related quality of life assessment using the Expanded Prostate Cancer Index Composite validated questionnaire. Multivariable ANCOVA was done to identify the baseline determinants affecting post-prostatectomy sexual health outcomes among 17 clinical and demographic factors. RESULTS: Factors independently associated with better sexual health outcome in patients included younger age (p <0.0001), nerve sparing technique (p <0.0001), time since prostatectomy (p = 0.0001), smaller prostate size (p = 0.003), higher education level (p = 0.02), and higher household income (p = 0.02). Orgasm was achieved at a higher rate than erection. In controls only age (p = 0.0004) and having a partner (p = 0.04) were significantly associated with sexual health. CONCLUSIONS: Larger prostate size adversely affected sexual health outcome after radical prostatectomy independent of all other measured factors. Patient sexual outcome did not differ significantly among surgeons who performed a broad range of such procedures yearly, suggesting that surgical expertise cannot be measured simply by the number of such operations that a surgeon performs. Stratifying patient reported sexual function by the principal determinants of age, nerve sparing and prostate size provides a basis for counseling patients.

Hollenbeck, B. K., R. L. Dunn, et al. (2004). "Sexual health recovery after prostatectomy, external radiation, or brachytherapy for early stage prostate cancer." Curr Urol Rep 5(3): 212-219.

Each of the three most common contemporary treatments for localized prostate cancer, radical prostatectomy, external beam radiotherapy, and brachytherapy, can have adverse effects on sexual health. Sexual health outcome can be improved by treatment-specific factors, such as the use of nerve-sparing technique during radical prostatectomy, or worsened by the use of androgen deprivation before external beam radiotherapy or brachytherapy. Contemporary studies that have used validated questionnaires to evaluate multiple components of patient-reported sexuality following prostate cancer treatments provide benchmarks of sexual outcome expectations that are of interest to patients selecting their prostate cancer treatment.

Hollenbeck, B. K., R. L. Dunn, et al. (2008). "Development and validation of the convalescence and recovery evaluation (CARE) for measuring quality of life after surgery." Qual Life Res 17(6): 915-926.

PURPOSE: To develop a generic instrument for measuring short-term health status in the recovery period among patients undergoing abdominal and pelvic surgery. METHOD: Instrument content was based on qualitative data ascertained from focus groups of patients and input from an expert panel of clinicians and psychometricians. A draft questionnaire was then piloted and revised, leading to the 27-item Convalescence and Recovery Evaluation (CARE). CARE consists of four individually scored domains, which were identified using factor analysis. Test-retest reliability, internal consistency, and convergent validity were assessed. RESULTS: Test-retest reliability was high, ranging from 0.78 for the activity domain to >0.88 for all others. Internal consistency varied over time postoperatively but was moderate to high for all domains throughout. Correlations between the four domains of CARE were low (each r<or=0.57). Moderate agreement was evident between CARE domains and the appropriate components of validated instruments, providing convergent validity. CONCLUSIONS: CARE is a robust, multi-dimensional measure of convalescence after abdominal and pelvic surgery. CARE can be used to gain a better understanding of the phenomenon of recovery and to measure the impact of new processes of care (e.g., surgical technology adoption) on short-term patient outcomes.

Hollenbeck, B. K., R. L. Dunn, et al. (2010). "Racial differences in treatment and outcomes among patients with early stage bladder cancer." Cancer 116(1): 50-56.

BACKGROUND: Black patients are at greater of risk of death from bladder cancer than white patients. Potential explanations for this disparity include a more aggressive phenotype and delays in diagnosis resulting in higher stage disease. Alternatively, black patients may receive a lower quality of care, which may explain this difference. METHODS: Using Surveillance, Epidemiology, and End Results (SEER)-Medicare data for the years from 1992 through 2002, the authors identified patients with early stage bladder cancer. Multivariate models were fitted to measure relations between race and mortality, adjusting for differences in patients and treatment intensity. Next, shared-frailty proportional hazards models were fitted to evaluate whether the disparity was explained by differences in the quality of care provided. RESULTS: Compared with white patients (n = 14,271), black patients (n = 342) were more likely to undergo restaging resection (12% vs 6.5%; P < .01) and urine cytologic evaluation (36.8% vs 29.7%; P < .01), yet they received fewer endoscopic evaluations (4 vs 5; P < .01). The use of aggressive therapies (cystectomy, systemic chemotherapy, radiation) was found to be similar among black patients and white patients (12% vs 10.2%, respectively; P = .31). Although black patients had a greater risk of death compared with white patients (hazards ratio [HR], 1.23; 95% confidence interval [95% CI], 1.07-1.42), this risk was attenuated only modestly after adjusting for differences in treatment intensity and provider effects (HR, 1.22; 95% CI, 1.06-1.42). CONCLUSIONS: Although differences in initial treatment were evident, they did not appear to be systematic and had unclear clinical significance. Whereas black patients are at greater risk of death, this disparity did not appear to be caused by differences in the intensity or quality of care provided.

Hollenbeck, B. K., J. Hong, et al. (2007). "Misclassification of hospital volume with Surveillance, Epidemiology, and End Results Medicare data." Surg Innov 14(3): 192-198.

Surveillance, Epidemiology, and End Results (SEER)- Medicare data are frequently used for studying relationships between volume and outcomes after cancer surgery; however, because patients often cross SEER boundaries for treatment, SEER-Medicare data may misclassify hospital volume. Thus, we measured the agreement of hospital volume as determined by SEER-Medicare and 100% national Medicare data and determined the extent to which misclassification alters the apparent relationship between volume and operative mortality. This is a retrospective cohort study of SEER-Medicare patients undergoing a major cancer surgery for colon, lung, bladder, and esophageal cancers between 1994 and 1999. Hospital procedure volumes were assessed with both SEER-Medicare and 100% national Medicare data and sorted into terciles. Logistic regression models were fit using generalized estimating equations to assess associations between mortality and volume, as determined from each data source. Compared with 100% Medicare data, SEER-Medicare data misclassified 13% (colectomy) to 36% (esophagectomy) of patients; however, fewer than 3% of patients were misclassified by more than 1 volume stratum. For cystectomy, the apparent association between volume and mortality was relatively weak and not statistically significant based on SEER-Medicare data (adjusted odds ratio, low vs high volume 1.41, 95% confidence interval, 0.89-2.23), but stronger and significant when volume was obtained from 100% Medicare data (odds ratio, 1.82; 95% confidence interval, 1.17 to 2.84). For the other 3 procedures, apparent volume/outcome relationships were similar when volume was assessed from the 2 data sources. Hospital volumes are frequently misclassified with SEER-Medicare data. Such misclassification generally biases volume/outcome associations toward the null, but this effect seems to be small for many procedures. Investigators should be cognizant of this bias and exercise caution when interpreting these relationships when using SEER-Medicare data alone.

Hollenbeck, B. K., E. R. Lipp, et al. (2002). "Concurrent assessment of obstructive/irritative urinary symptoms and incontinence after radical prostatectomy." Urology 59(3): 389-393.

OBJECTIVES: To concurrently evaluate urinary obstructive symptoms and incontinence in men after radical prostatectomy and to determine the effects of these components on urinary impairment and satisfaction. METHODS: Two hundred twenty-eight men after radical prostatectomy were age-matched and zip code-matched to a random sample of 228 men without prostate cancer. Urinary incontinence was assessed by the urinary function domain of the Prostate Cancer Index, and obstructive symptoms were assessed by the American Urological Association Symptom Index. Regression models were constructed to evaluate the impact of obstructive and incontinence symptoms on urinary impairment and satisfaction. RESULTS: The control group reported greater urinary continence (P <0.0001) and less impairment (P <0.0001) than the prostatectomy group, but a difference was not observed for obstructive symptoms. Obstructive urinary symptoms were associated with impairment for both the prostatectomy and the control groups (P <0.0001), and incontinence symptoms were more strongly associated with impairment in the prostatectomy group than in the control group (P = 0.01). Greater obstructive/irritative and incontinence symptoms were associated with lower satisfaction (P <0.0001). CONCLUSIONS: Urinary incontinence was more common in the radical prostatectomy group, but differences were not seen for obstructive symptoms. In addition to incontinence symptoms, obstructive symptoms were associated with urinary impairment and dissatisfaction in the prostatectomy group, suggesting that these symptoms should also be assessed after radical prostatectomy.

Hollenbeck, B. K., D. C. Miller, et al. (2005). "The effects of stage divergence on survival after radical cystectomy for urothelial cancer." Urol Oncol 23(2): 77-81.

INTRODUCTION: Discrepancies between clinical and pathologic staging, herein referred to as stage divergence, are common after radical cystectomy. The implications of stage divergence on survival are ill defined in the context of those treated by surgery alone and would facilitate patient counseling and enhance prognostication. METHODS: There were 78 consecutive radical cystectomy patients with clinical stage T2 or less urothelial carcinoma who comprised our study population. Kaplan-Meier plots were constructed to determine the effects of stage divergence on survival and the log-rank test employed to assess the significance. Regression models were developed to determine predictors of overall and cancer-specific survival. RESULTS: Stage divergence was common after radical cystectomy with downstaging and upstaging occurring in 27% and 49% of patients, respectively. Downstaged patients had better overall (P = 0.003) and bladder cancer-specific (P = 0.0004) survivals. None of the downstaged patient died from bladder cancer (median follow-up 35.9 months). Upstaged patients were five times as likely to succumb from bladder cancer or other illness compared to downstaged patients. This effect was not isolated to patients with lower clinical stages but also demonstrated in patients with clinical stage T2 bladder cancer. CONCLUSIONS: Stage divergence is common after radical cystectomy occurring in 76% of patients in this study. The implications of stage divergence are equally relevant for those who are upstaged or downstaged in terms of survival, and such data is useful when counseling patients postoperatively. Downstaging at the time of radical cystectomy is associated with better overall and cancer-specific survival.

Hollenbeck, B. K., D. C. Miller, et al. (2002). "The utility of lockout valve reservoirs in preventing autoinflation in penile prostheses." Int Urol Nephrol 34(3): 379-383.

INTRODUCTION: Autoinflation is a troublesome complication following penile prosthesis placement that may be potentiated by prevesical scarring following radical prostatectomy. We evaluated the frequency of autoinflation and other complications following penile prosthesis placement in radical prostatectomy patients and controls as a surrogate to establishing the utility of lockout reservoirs in preventing autoinflation. METHODS: 139 prostheses (including 14 with lockout reservoirs) were placed in 132 men (including 35 post-prostatectomy patients) over a 5(1/2) year period at our institution. Outcomes assessed include postoperative complications and the need for revision or replacement of the prosthesis. Multivariable regression analysis was used to determine the association of patient, device-specific, and perioperative characteristics with these outcomes. RESULTS: There was no difference in the postoperative complication and re-operation rates between post-prostatectomy patients and controls (both p > 0.77). The incidence of autoinflation in post-prostatectomy patients and controls was 3% and 5%, respectively (p > 0.99). Patients with prior prostheses were 3 times as likely to develop a postoperative complication or require prosthesis revision (p = 0.02). CONCLUSION: Penile prostheses are well tolerated in post-prostatectomy patients with comparable outcomes to those men with organic erectile dysfunction. The frequency of autoinflation does not appear to be increased in post-prostatectomy patients. Initial results with the lockout valve reservoir in preventing autoinflation are encouraging though additional study is warranted to justify their routine use.

Hollenbeck, B. K., D. C. Miller, et al. (2005). "Identifying risk factors for potentially avoidable complications following radical cystectomy." J Urol 174(4 Pt 1): 1231-1237; discussion 1237.

PURPOSE: Morbidity after radical cystectomy is common and associated with increased health care resource use. Accurate characterization of complications after cystectomy, associated patient specific risk factors, and perioperative processes of care are essential to directing changes in perioperative management that will reduce morbidity and improve the quality of patient care. MATERIALS AND METHODS: The National Surgical Quality Improvement Program (NSQIP) is a prospective quality management initiative of 123 Veterans Affairs Medical Centers nationwide. The NSQIP collects clinical information, intraoperative data and outcomes on a wide variety of surgical procedures from multiple surgical disciplines. Since 1991, 2,538 radical cystectomy procedures have been captured by the NSQIP. Modeling using logistic regression was performed to identify patient specific risk factors and perioperative process measures associated with postoperative morbidity. RESULTS: Of the 2,538 subjects at least 1 postoperative complication developed in 774 (30.5%). The most frequent complication was ileus (10%). Several factors were associated with the development of a complication, including age, dependent functional status, preoperative dyspnea, preoperative acute renal failure, chronic steroid use, preoperative alcohol consumption, American Society of Anesthesiology score, use of general anesthetic, operative time, intraoperative blood requirement and surgeon level of training. CONCLUSIONS: Morbidity remains high after cystectomy with 30.5% of subjects experiencing at least 1 complication. Measurable patient specific risk factors and perioperative processes associated with postoperative morbidity following cystectomy are now delineated which allows for improved risk stratification, patient counseling, and the development of novel processes that may incrementally reduce risk and improve outcomes.

Hollenbeck, B. K., D. C. Miller, et al. (2006). "Risk factors for adverse outcomes after transurethral resection of bladder tumors." Cancer 106(7): 1527-1535.

BACKGROUND: Risk factors for adverse outcomes after transurethral resection of bladder tumors (TURBT) have not been identified to date. Such information would facilitate preoperative risk stratification and case-mix-adjusted outcome comparison, and lead to the development of processes of care directed at improving outcomes and ultimately the quality of care for bladder carcinoma patients. METHODS: The National Surgical Quality Improvement Program (NSQIP) is a prospective quality management initiative of 123 Veterans Affairs Medical Centers nationwide. Since 1991, a total of 21,515 TURBTs have been prospectively registered by the NSQIP; these cases compose the current study population. Using multivariable logistic regression, the authors determined the independent association between preoperative patient risk factors and perioperative elements of structure/process and morbidity, mortality, and prolonged length of stay (LOS) outcomes. RESULTS: The postoperative complication, 30-day, and 90-day mortality rates were 4.3%, 1.3%, and 3.3%, respectively. The median, 75th percentile, and 90th percentile for LOS among patients undergoing TURBT was 2 days, 3 days, and 8 days, respectively. Robust preoperative patient risk factors that were found to be uniformly associated with all adverse outcomes included the presence of disseminated disease (odds ratio [OR], 1.9-5.2) weight loss (OR, 1.8-3.8), low serum albumin (OR, 2.3-7.1), elevated serum creatinine (OR, 1.3-2.9), a dependent functional status (OR, 1.5-2.7), and emergent case status (OR, 1.8-3.1). Compared with models using preoperative patient factors alone, models including perioperative structure and process measures explained further variation in surgical outcomes (each likelihood ratio test, P < .0001). CONCLUSIONS: The findings of the current study highlight the fact that there are a wide array of patient risk factors that are associated with adverse outcomes after TURBT. Validation of those processes implemented to modify such elements can provide a basis for quality metrics in the context of TURBT.

Hollenbeck, B. K., D. C. Miller, et al. (2004). "Aggressive treatment for bladder cancer is associated with improved overall survival among patients 80 years old or older." Urology 64(2): 292-297.

OBJECTIVES: To examine the impact of various treatment modalities on survival among patients with bladder cancer who were 80 years old or older compared with younger patients. A compendium of evidence suggests that bladder cancer surgery is safe among octogenarians; however, the benefit of such treatment in a population with limited life expectancy has not been well documented. METHODS: Subjects with the primary diagnosis of bladder cancer were identified from the National Cancer Institute's Surveillance, Epidemiology, and End Results cancer registry between 1988 and 1999. Of the 13,796 patients diagnosed with bladder cancer, 24% were older than 80 years of age. Proportional hazards regression modeling was performed to determine the independent association of treatment strategy on overall and bladder cancer survival while adjusting for multiple covariates. RESULTS: Of patients 80 years old or older, bladder cancer management included watchful waiting (7%), radiotherapy alone (1%), full or partial cystectomy (12%), and transurethral resection (79%). Patients 80 years old or older were less likely to be treated with extirpative surgery than their younger counterparts (P <0.0001). Cox proportional hazards models demonstrated that, among patients 80 years old or older, radical cystectomy/partial cystectomy had the greatest risk reduction in death from bladder cancer (hazard ratio 0.3) and death from any cause (hazard ratio 0.4) among the primary treatment modalities (both P <0.0001). CONCLUSIONS: Disparities in practice patterns between younger and geriatric patients with bladder cancer exist. We provide compelling evidence that aggressive surgical management of bladder cancer in these patients may improve survival. Risk adjustment tools should be used to identify patients (young and old) who would be better served by less aggressive management.

Hollenbeck, B. K., D. C. Miller, et al. (2006). "The effects of adjusting for case mix on mortality and length of stay following radical cystectomy." J Urol 176(4 Pt 1): 1363-1368.

PURPOSE: Prior studies evaluating quality of care following radical cystectomy have been constrained by the use of retrospective reviews of single institutional series and limited ability to examine risk factors in a comprehensive manner. Characterization of these factors could enhance preoperative patient counseling and facilitate perioperative management, thereby improving the quality of patient care. MATERIALS AND METHODS: The National Surgical Quality Improvement Project is a prospective quality management initiative at 123 Veterans Affairs Medical Centers nationwide. The project collects preoperative clinical and intraoperative data, and outcomes on a wide variety of surgical procedures from multiple surgical disciplines. Since 1991, 2,538 radical cystectomies have been captured by the National Surgical Quality Improvement Project. Modeling using logistic regression was performed to identify preoperative risk factors associated with mortality and prolonged length of stay (greater than 90th percentile) after radical cystectomy. RESULTS: The 30 and 90-day mortality rates following cystectomy were 2.9% and 6.8%, respectively, and median hospital stay was 11 days (90th percentile 30). Robust preoperative factors associated with mortality and prolonged length of stay that uniformly increased risk were older patient age (OR 1.2 to 1.4), American Society of Anesthesiologists class 3 or greater (OR 1.5 to 3.3), dependent functional status (OR 1.7 to 2.0) and low serum albumin (OR 2.1 to 12.0). CONCLUSIONS: A defined set of preoperative risk factors is independently associated with greater mortality and hospital stay following radical cystectomy. The breadth of these factors suggests that complex case mix adjustment is mandatory when comparing outcomes. Implementation of novel processes directed toward minimizing patient risk has the potential to improve outcomes following cystectomy.

Hollenbeck, B. K., D. C. Miller, et al. (2005). "Regionalization of care: centralizing complex surgical procedures." Nat Clin Pract Urol 2(10): 461.

Hollenbeck, B. K. and J. E. Montie (2004). "Early cystectomy for clinical stage T1 bladder cancer." Nat Clin Pract Urol 1(1): 4-5.

Hollenbeck, B. K., W. W. Roberts, et al. (2006). "Importance of perioperative processes of care for length of hospital stay after laparoscopic surgery." J Endourol 20(10): 776-781.

BACKGROUND AND PURPOSE: The technologic imperative has prompted the adoption of complex laparoscopic techniques by physicians with various degrees of skill. We sought to measure the impact of both case mix and physician practice (perioperative process/risk factors) on length of stay (LOS)-a common benchmark- after laparoscopic surgery. PATIENTS AND METHODS: We identified 911 patients undergoing laparoscopic retroperitoneal surgery between 1996 and 2004, who comprise our study population. Patients remaining in the hospital >5 days-the 90th percentile for the sample-were classified as having a prolonged LOS. Adjusted models were developed to determine the independent association of case mix and process measures with a prolonged LOS. The likelihood ratio test was used to discern the improvement of fit of the process model compared with the case-mix model. RESULTS: Among factors related to case mix and structure of care, increasing age (odds ratio [OR] 1.1; 95% CI 1.0, 1.2), less surgeon experience (OR 6.1; 95% CI 2.1, 17.2), male gender (OR 2.1; 95% CI 1.2, 4.0), and American Society of Anesthesiologists score of 3 or 4 (OR 7.2; 95% CI 2.2, 23.3) were independently associated with a prolonged LOS. The need for a transfusion (OR 9.4; 95% CI 33.9, 23.2), the development of a postoperative complication (OR 4.6; 95% CI 2.2, 9.5), and longer operative time (OR 1.5; 95% CI 1.3, 1.8) explained additional variation in prolonged LOS outcomes when considering perioperative process/risk factors in the model. Perioperative factors significantly improved the fit of the model (chi (2) statistic 101.8; p < 0.0001). CONCLUSIONS: Significant variation in outcomes is explained by factors describing aspects of surgical expertise. Variability in the surgical skill set is likely greatest during the laparoscopic learning curve, which raises a quality-of-care concern during the initial implementation of the technique. Policies attempting to smooth the laparoscopic learning curve, such as mentoring and skill measurement prior to credentialing, could improve the quality of care.

Hollenbeck, B. K., T. G. Schuster, et al. (2001). "Comparison of outcomes of ureteroscopy for ureteral calculi located above and below the pelvic brim." Urology 58(3): 351-356.

OBJECTIVES: To compare the safety and efficacy of ureteroscopy performed for proximal and distal ureteral calculi in a contemporary cohort. Ureteroscopy has been used most often for distal ureteral calculi. However, advances in endoscopic equipment have facilitated access to the proximal urinary tract and have broadened the indications for ureteroscopy. METHODS: One hundred ninety-one patients underwent rigid and/or flexible ureteroscopy for ureteral calculi at the University of Michigan between January 1, 1997 and September 30, 1999. Only 7 patients with either bilateral calculi or steinstrasse were excluded. The final cohort consisted of 184 patients who underwent ureteroscopy for distal stones (n = 103) or middle/upper ureteral stones (n = 81). RESULTS: Bivariate analyses of pretreatment and perioperative characteristics were used to assess the sample population. The initial success rate for the distal and proximal ureteral calculi was 96% and 78%, respectively (P = 0.0008). After a "second-look" procedure in 4 and 7 patients with distal and proximal calculi, respectively, the success rate improved to 99% and 88%, respectively (P = 0.004). No differences were noted between groups regarding the intraoperative (P = 0.51) or postoperative (P = 0.85) complication rates. Multivariate logistic regression analysis confirmed that larger stone size (odds ratio 1.2, P = 0.0006) and proximal ureteral location (odds ratio 4.8, P = 0.01) are independent predictors of treatment failure. CONCLUSIONS: Ureteroscopic management of proximal and distal ureteral calculi is highly successful, and the difference in success rates has narrowed substantially. Currently, no greater risk is conferred to the patient for endoscopy of more proximal ureteral calculi.

Hollenbeck, B. K., T. G. Schuster, et al. (2001). "Flexible ureteroscopy in conjunction with in situ lithotripsy for lower pole calculi." Urology 58(6): 859-863.

OBJECTIVES: To demonstrate the efficacy and safety of ureteroscopy as a compromise in treating small and intermediate-size lower pole calculi. The optimal management of lower pole calculi remains controversial. Shock wave lithotripsy is associated with minimal morbidity but with suboptimal stone clearance rates. Conversely, percutaneous nephrostolithotomy has greater morbidity but stone-free rates greater than 90% regardless of size. METHODS: Seventy-two patients underwent ureteroscopy for lower pole calculi 2 cm or less (mean 8.7 mm) during a 3-year period. To minimize confounding, 11 patients with additional calculi at other ipsilateral renal sites and 1 patient with large (2.4 cm each) bilateral calculi were excluded. Two patients with bilateral lower pole calculi and four who required a second procedure were included in the analysis. Thus, the final cohort consisted of 60 patients who underwent 66 procedures. RESULTS: Of patients with follow-up longer than 1 month, 79% were stone free after a single procedure, and this improved to 88% after a second procedure in 4 patients. All 7 patients with follow-up less than 1 month had a reduction in stone burden after successful fragmentation. Overall, 8 patients required an auxiliary procedure. No intraoperative complications, and 7 (11%) postoperative complications occurred. CONCLUSIONS: Ureteroscopy for lower pole calculi is associated with minimal morbidity and stone-free rates comparable to shock wave lithotripsy for smaller stones. The greatest utility of ureteroscopy is in the management of intermediate-size calculi, for which it has substantially higher stone-free rates and lower repeated treatment rates than does shock wave lithotripsy.

Hollenbeck, B. K., T. G. Schuster, et al. (2001). "Routine placement of ureteral stents is unnecessary after ureteroscopy for urinary calculi." Urology 57(4): 639-643.

OBJECTIVES: To report a matched comparison of patients with and without stenting after ureteroscopy for calculi, including middle or proximal ureteral and renal calculi. The elimination of routine stenting after ureteroscopy would prevent stent pain, minimize the need for re-instrumentation, and reduce costs-as long as efficacy and safety are not diminished. METHODS: Of 318 patients who underwent ureteroscopy, 81 (25%) did not have a ureteral stent placed. Of those, 51 were suitable for analysis and included patients with distal ureteral (n = 22), middle or proximal ureteral (n = 11), and renal calculi (n = 18). This cohort was matched to a stented group by stone size and location. RESULTS: The preoperative characteristics of the groups were similar. A stone-free rate of 86% and 94% was achieved in the stented and nonstented groups, respectively (P = 0.32). Complications in the nonstented group were less frequent (flank pain in 3 and postoperative nausea in 1) than in the stented group (hospital visits for flank pain in 12, persistent nausea and vomiting in 1, sepsis in 1, perinephric hematoma in 1, and urinary retention in 1) (total of 4 versus 16, P = 0.025). CONCLUSIONS: Ureteroscopy for distal ureteral stones without ureteral stent placement has been previously described. Our experience expands to include the elimination of stent placement after ureteroscopy for middle or proximal ureteral (22%) and renal (35%) calculi. Our data suggest that after ureteroscopies with short operative times and minimal ureteral trauma, ureteral stents may not be necessary, even if proximal ureteral or renal ureteroscopy has been performed.

Hollenbeck, B. K., T. G. Schuster, et al. (2003). "Safety and efficacy of same-session bilateral ureteroscopy." J Endourol 17(10): 881-885.

PURPOSE: Same-session ureteroscopy for bilateral urinary calculi would potentially reduce costs and the need for a second anesthetic compared with staged procedures. We sought to establish the safety and efficacy of same-session bilateral ureteroscopy relative to procedures for staged bilateral and multiple unilateral calculi in the context of contemporary instrumentation. PATIENTS AND METHODS: A series of 626 consecutive patients underwent ureteroscopy for calculi between January 1997 and August 2001. Among these, 34 patients with bilateral calculi (11 staged and 23 treated in one sitting) and 54 patients with multiple unilateral calculi in distinct locations were included in this study. Multivariable regression was used to determine the association of patient-specific and technical factors with postoperative morbidity. RESULTS: Stone-free rates were similar in the two groups and ranged from 50% to 100% depending on stone location. Postoperative complications occurred in 6 (11%) and 3 (14%) of the patients treated for multiple unilateral and for bilateral calculi in a staged procedure, respectively, compared with 7 (29%) of those undergoing same-session bilateral ureteroscopy (P = 0.12). Logistic regression revealed that same-session bilateral ureteroscopy (odds ratio [OR] 4.0; P = 0.02) and absence of a postoperative stent (OR 1.7; P = 0.03) were associated with added morbidity. However, the cumulative risk of performing staged bilateral procedures (14% per procedure) approximated that of bilateral ureteroscopy in one sitting (29%). CONCLUSION: Bilateral ureteroscopy carries an increased risk of postoperative morbidity. The risk is proportional to the number of renal units treated and may be assumed at once (e.g., same-session) or over time (e.g., staged) as it applies to patients requiring bilateral ureteroscopy.

Hollenbeck, B. K., T. G. Schuster, et al. (2003). "Identifying patients who are suitable for stentless ureteroscopy following treatment of urolithiasis." J Urol 170(1): 103-106.

PURPOSE: Foregoing ureteral stents following ureteroscopy for urinary calculi is an evolving practice. Randomized trials support stent omission in select cases though generalizability is unclear and criteria for stentless ureteroscopy are unknown. Therefore, we sought to identify significant clinical characteristics affecting postoperative morbidity in unstented patients to provide a context for future randomized trials. MATERIALS AND METHODS: Of 837 ureteroscopic procedures for urolithiasis performed at our institution from January 1997 through January 2002 a ureteral stent was not placed in 226 (32%). Among these patients 47 had no stone at the time of the procedure leaving 219 (26%) who were treated for urinary calculus disease. Multivariate logistic regression was used to determine the association of 24 variables with postoperative morbidity. RESULTS: Of the 219 patients treated with ureteroscopy 39 (18%) had a postoperative complication, which was obstructive in 26 (12%), infectious in 10 (5%), and related to patient co-morbidity in 3 (1%). Factors associated with postoperative morbidity included renal pelvic location (p = 0.02), lithotripsy (p = 0.03), bilateral procedure (p = 0.07), history of urolithiasis (p <0.0001), diabetes mellitus (p = 0.06), recent/recurrent infection (p <0.0001), operative time 45 minutes or greater (p = 0.07), operative time 45 minutes or greater plus lithotripsy (p = 0.0004), operative time 45 minutes or greater plus ureteral dilation (p = 0.07) and bilateral stentless procedure (p = 0.005). CONCLUSIONS: Multiple patient and operative factors may predispose a patient to postoperative morbidity after a stentless procedure. Future trials should prospectively validate the role of these factors in either promoting (e.g., history of urolithiasis) or preventing (e.g., preoperative stent) a postoperative complication in the setting of stentless ureteroscopy.

Hollenbeck, B. K., B. D. Seifman, et al. (2004). "Clinical skills acquisition for hand-assisted laparoscopic donor nephrectomy." J Urol 171(1): 35-39.

PURPOSE: The learning curve associated with laparoscopic surgery may be associated with higher patient risk, and in the setting of kidney donation such risk may be unacceptable. We characterize the learning curve for hand-assisted laparoscopic donor nephrectomy in the context of a urology training program, and establish a case volume threshold after which improvements in laparoscopic skill can be demonstrated. MATERIALS AND METHODS: The study included 245 consecutive laparoscopic cases, including 111 donor nephrectomies, performed in 2 (1/2) years to characterize various measures of experience. Documentation of resident involvement in each case was made by a single surgeon and collected prospectively. Outcomes assessed included operative time, blood loss and intraoperative complications. RESULTS: Of the 111 hand-assisted donor nephrectomies the resident was surgeon in 47%. Operative time proved a reliable and sensitive measure of surgeon experience. Increasing laparoscopic experience, as measured by several parameters, was associated with decreasing operative time (each p <0.02). Measurable improvements in laparoscopic skill were realized after participating in 13 (p = 0.007) or serving as surgeon in as few as 6 (p = 0.02) hand-assisted donor nephrectomies. Conversion (2%) and intraoperative complication rates (3%) were low. CONCLUSIONS: Skills for hand-assisted laparoscopic donor nephrectomy can be safely taught in the context of a urology training program independent of resident training level. We documented measurable improvements in laparoscopic skill as gauged by operative time. Our findings provide a basis by which expectations can be set for laparoscopic skill acquisition in the context of a residency program and for the laparoscopically naive surgeon.

Hollenbeck, B. K., S. L. Spencer, et al. (2000). "Use of a working channel catheter during flexible ureteroscopic laser lithotripsy." J Urol 163(6): 1808-1809.

PURPOSE: We describe a technique which protects the working channel of the flexible ureteroscope from damage caused by the laser fiber during laser lithotripsy. MATERIALS AND METHODS: A 2Fr catheter is placed into the working channel of the flexible ureteroscope. A 200 micro. laser fiber is then advanced through the lumen of the catheter and laser lithotripsy is subsequently performed. RESULTS: The catheter provides additional protection to the working channel sheath during passage and firing of the laser fiber. Deflection of the ureteroscope is not affected with the catheter in place. Movement of the laser fiber is augmented by the catheter when compared to movement of the fiber in the working channel alone. Irrigant flow is diminished with the catheter. CONCLUSIONS: The catheter does not appear to hinder performance of the flexible ureteroscope during laser lithotripsy. A catheter also offers additional protection to the working channel sheath, thereby potentially increasing the durability and working life of the flexible ureteroscope.

Hollenbeck, B. K., D. A. Taub, et al. (2005). "Quality of care: partial cystectomy for bladder cancer--a case of inappropriate use?" J Urol 174(3): 1050-1054; discussion 1054.

PURPOSE: Partial cystectomy is perceived to be a less morbid, less technically demanding procedure than radical cystectomy, although only select patients (approximately 6% to 10%) are appropriate candidates (solitary tumor in space/time, absence of carcinoma in situ). From a quality of care perspective, overuse of partial cystectomy may signify inappropriate delivery of health care. MATERIALS AND METHODS: Subjects who underwent extirpative treatment for bladder cancer between 1988 and 2000 were identified within the Surveillance, Epidemiology and End Results (SEER, 3,381) registry and the Nationwide Inpatient Sample (NIS, 22,088). Adjusted models were developed to identify clinical factors independently associated with the use of partial cystectomy for bladder cancer treatment within each sample. RESULTS: Among patients who underwent extirpative surgery for bladder cancer, 18% and 20% of those in SEER and NIS, respectively, underwent partial cystectomy. Significant decreases in use between early and later years were noted in both samples (SEER-22% to 13%, NIS-24% to 17%, both p <0.0001). Partial cystectomy was preferentially used in the elderly, those with stage I disease, females and black patients. Furthermore, partial cystectomy was more commonly provided in rural, nonteaching, low volume hospitals. CONCLUSIONS: Trends in national use of partial cystectomy are consistent between the NIS and SEER with 13% to 17% of patients currently being treated with partial in lieu of radical cystectomy. Partial cystectomy is disproportionately used in certain medical centers (nonteaching, rural, low volume) and patient populations (elderly, black, females, stage I disease) reflecting selective referral or overuse.

Hollenbeck, B. K., D. A. Taub, et al. (2005). "The regionalization of radical cystectomy to specific medical centers." J Urol 174(4 Pt 1): 1385-1389; discussion 1389.

PURPOSE: Regionalization of high risk surgical procedures to larger teaching hospitals has been suggested as a means to improve the quality of care. We established a novel framework for characterizing regionalization, implemented it to determine the extent to which regionalization of radical cystectomy has occurred and delineated whether specific patient characteristics are associated with this phenomenon. MATERIALS AND METHODS: We used the Nationwide Inpatient Sample to identify 22,088 patients who underwent radical cystectomy for bladder cancer from 1988 to 2000. Regionalization was assessed using 5 structural hospital measures, including teaching status, urban location, discharge volume, cystectomy volume and bed capacity. Adjusted models were developed to identify the significance of temporal trends and assess the association of demographic factors with structural qualities. RESULTS: Compared with 1988 to 1990 subjects were more likely to undergo cystectomy at teaching hospitals (OR 1.8), high cystectomy volume hospitals (OR 1.2), high discharge volume hospitals (OR 1.7) and large bed capacity medical centers (OR 1.4) in 1998 to 2000. The concentration of cystectomy to urban medical centers during the study years was 90% to 92%. The proportion of subjects undergoing partial cystectomy decreased from 23.9% to 16.6% as regionalization occurred. Older subjects were less likely to be treated at these regionalized centers. CONCLUSIONS: Without broad legislation from health care payers radical cystectomy has increasingly regionalized to specific medical centers. Despite this regionalization disparities in its use exist among specific, vulnerable patients. Addressing this may facilitate further concentration of this procedure.

Hollenbeck, B. K., D. A. Taub, et al. (2006). "National utilization trends of partial nephrectomy for renal cell carcinoma: a case of underutilization?" Urology 67(2): 254-259.

OBJECTIVES: Partial nephrectomy is perceived to be more technically demanding than radical nephrectomy; concurrently, the increasing incidence of small renal tumors has suggested a greater role for nephron-sparing techniques. From a quality-of-care perspective, the underuse of partial nephrectomy may represent suboptimal delivery of healthcare. METHODS: A total of 66,621 subjects undergoing radical and partial nephrectomy for kidney cancer between 1988 and 2002 were identified from the Nationwide Inpatient Sample, a nationally representative data set of hospital discharges. Adjusted models were developed to identify clinical factors and structural measures independently associated with the use of partial nephrectomy. RESULTS: Overall, 7.5% of patients treated underwent partial nephrectomy. The utilization rates for partial nephrectomy ranged from 0.21 cases per 100,000 U.S. residents in 1988 to 1.6 cases per 100,000 U.S. residents in 2002. The percentage of patients with renal cell carcinoma treated with partial nephrectomy has increased more than threefold during the study interval (3.7% in 1988 to 1990 compared with 12.3% in 2000 to 2002, P <0.0001 for trend). Patients treated at urban (odds ratio 1.1), teaching (odds ratio 1.3), and high nephrectomy volume (odds ratio 2.5) hospitals were more likely to undergo partial nephrectomy (each, P <0.01). CONCLUSIONS: The national use of partial nephrectomy has increased but remains lower than expected in certain settings, suggesting underuse or selective referral. Subjects with kidney cancer are more likely to be treated with partial nephrectomy at teaching institutions with high surgical volumes. The practice patterns of physicians at institutions more commonly using partial nephrectomy may reflect a better quality of care, although additional work in delineating the disparate utilization rates is warranted.

Hollenbeck, B. K., D. A. Taub, et al. (2006). "Use of nephrectomy at select medical centers--a case of follow the crowd?" J Urol 175(2): 670-674.

PURPOSE: Regionalization of high risk surgical procedures to larger, teaching hospitals has been suggested as a means to improve the quality of care. We determined the extent to which the regionalization of nephrectomy has occurred and describe the potential causes and implications of any observed regionalization. MATERIALS AND METHODS: The Nationwide Inpatient Sample comprises a 20% sampling of hospital discharges in the United States yearly. Patients undergoing nephrectomy for kidney cancer between 1988 and 2002 were identified using International Classification of Disease, Ninth Revision, Clinical Modification codes. Regionalization was assessed using 6 structural hospital measures, including teaching status, urban location, discharge volume, nephrectomy volume, bed capacity and for-profit status. Adjusted models were developed to identify the significance of temporal trends in each regionalization measure. RESULTS: We identified 66,621 patients undergoing nephrectomy during the study period. Compared to procedures performed between 1988 and 1990 the likelihood of undergoing nephrectomy at teaching, high nephrectomy volume and high throughput (all diagnoses) hospitals increased by 2.0 (CI 1.9 to 2.2), 7.4 (CI 7.1 to 7.7) and 2.2 times (CI 2.1 to 2.2), respectively, in 2000 to 2002. Conversely nephrectomy was less likely to be performed at for-profit hospitals (OR 0.5, CI 0.5 to 0.6). Patients were more likely to undergo partial nephrectomy at teaching, high volume, high throughput, urban hospitals. CONCLUSIONS: Regionalization of nephrectomy to teaching and high volume (nephrectomy and all diagnoses) hospitals is currently under way. Although the implications are not entirely clear, this study provides further evidence for the crowding of complex surgical procedures into these institutions.

Hollenbeck, B. K., J. T. Wei, et al. (2004). "Neoadjuvant hormonal therapy impairs sexual outcome among younger men who undergo external beam radiotherapy for localized prostate cancer." Urology 63(5): 946-950.

OBJECTIVES: To evaluate the effects of treatment factors and other covariates on sexual health-related quality of life (HRQOL) after radiotherapy (RT) for prostate cancer. The effects of clinical and treatment factors on sexual health after external beam RT have not been fully characterized by patient-reported, validated questionnaires. METHODS: A total of 259 subjects (147 patients who had undergone RT for prostate cancer and 112 age-matched controls) participated in a cross-sectional assessment of HRQOL using the validated expanded prostate cancer index to measure patient-reported sexual function and bother. Multivariable models were used to determine the association of 13 prospectively measured clinical and treatment factors with post-RT sexual HRQOL. RESULTS: Increasing age, time since RT, and use of neoadjuvant hormonal therapy (NHT) were independently associated with sexual function (P <0.01) after RT. The effects of NHT on sexual HRQOL were most notable among the youngest (younger than 67 years) patients and among those closest to treatment. These effects may be conceptualized by examining the distribution of responses to individual Expanded Prostate Cancer Index Composite questions. For example, among the youngest patients, those treated with NHT were less than half as likely to report a fair ability to have erections compared with hormone-naive men. CONCLUSIONS: These patient-reported data, elicited using a validated HRQOL instrument, indicate that older age and NHT significantly and independently hinder post-RT sexual HRQOL outcome among men with localized prostate cancer and provide a framework for counseling patients regarding long-term sexual outcome on the basis of treatment plan and age.

Hollenbeck, B. K., Y. Wei, et al. (2007). "Volume, process of care, and operative mortality for cystectomy for bladder cancer." Urology 69(5): 871-875.

OBJECTIVES: High-volume hospitals have lower mortality rates for a wide range of surgical procedures, including cystectomy for bladder cancer. However, the processes of care that mediate this effect are unknown. We sought to identify the processes that underlie the volume-outcome relationship for cystectomy. METHODS: Within the Surveillance, Epidemiology, and End Results (SEER)-Medicare data set, we used International Classification of Diseases (ICD)-9 procedure codes to identify 4465 patients who underwent cystectomy for bladder cancer between 1992 and 1999. The preoperative and perioperative processes of care were abstracted from the inpatient, outpatient, and physician files using the procedure and diagnosis codes available through 2002. Logistic models were used to assess the relationship between the process and hospital volume, adjusting for differences in patient characteristics. RESULTS: Substantial variation was found in the use of specific processes of care across the hospital volume strata. High-volume hospitals had greater rates of preoperative cardiac testing (odds ratio [OR] 1.57, 95% confidence interval [CI] 1.24 to 1.98), intraoperative arterial monitoring (OR 3.73, 95% CI 3.11 to 4.46), and the use of a continent diversion (OR 4.01, 95% CI 3.03 to 5.30), among many others. Patients treated at low-volume hospitals were 48% more likely to die in the postoperative period (4.9% versus 3.5%, adjusted OR 1.48, 95% CI 1.03 to 2.13). Differences in the use of processes of care explained 23% of this volume-mortality effect. CONCLUSIONS: High-volume and low-volume hospitals differ with regard to many processes of care before, during, and after radical cystectomy. Although these practices have partly explained the volume-outcome relationships for cystectomy, the primary mechanisms underlying this effect remain unclear.

Hollenbeck, B. K. and J. S. Wolf, Jr. (2001). "Laparascopic partial nephrectomy." Semin Urol Oncol 19(2): 123-132.

The role of laparoscopy in urologic surgery has greatly increased over the past decade as has the popularity of elective nephron-sparing surgery. The emergence of these trends in conjunction with improvements in equipment and expertise has led to the increasing application of laparoscopic partial nephrectomy. Initially, this modality was applied in patients with benign diseases, such as chronic pyelonephritis and calculus disease with associated atrophy. Concerns of tumor spillage and local-regional control precluded the application of the laparoscopic modality to small, indeterminate renal masses. However, increasing experience with the technique and advances in intraoperative imaging have prompted its use in removing small renal masses. Herein, we describe the indications for laparoscopic partial nephrectomy, the two approaches (transperitoneal and extraperitoneal) to gain access to the kidney, current options to assist in controlling intraoperative hemorrhage, a comprehensive assessment of the results for benign and malignant resections, and an examination of the similarities and contrasts between open and laparoscopic techniques.

Hollenbeck, B. K., Z. Ye, et al. (2009). "Provider treatment intensity and outcomes for patients with early-stage bladder cancer." J Natl Cancer Inst 101(8): 571-580.

BACKGROUND: Bladder cancer is among the most prevalent and expensive to treat cancers in the United States. In the absence of high-level evidence to guide the optimal management of bladder cancer, urologists may vary widely in how aggressively they treat early-stage disease. We examined associations between initial treatment intensity and subsequent outcomes. METHODS: We used the Surveillance, Epidemiology, and End Results-Medicare database to identify patients who were diagnosed with early-stage bladder cancer from January 1, 1992, through December 31, 2002 (n = 20 713), and the physician primarily responsible for providing care to each patient (n = 940). We ranked the providers according to the intensity of treatment they delivered to their patients (as measured by their average bladder cancer expenditures reported to Medicare in the first 2 years after a diagnosis) and then grouped them into quartiles that contained approximately equal numbers of patients. We assessed associations between treatment intensity and outcomes, including survival through December 31, 2005, and the need for subsequent major interventions by using Cox proportional hazards models. All statistical tests were two-sided. RESULTS: The average Medicare expenditure per patient for providers in the highest quartile of treatment intensity was more than twice that for providers in the lowest quartile of treatment intensity ($7131 vs $2830, respectively). High-treatment intensity providers more commonly performed endoscopic surveillance and used more intravesical therapy and imaging studies than low-treatment intensity providers. However, the intensity of initial treatment was not associated with a lower risk of mortality (adjusted hazard ratio of death from any cause for patients of low- vs high-treatment intensity providers = 1.03, 95% confidence interval 0.97 to 1.09). Initial intensive management did not obviate the need for later interventions. In fact, a higher proportion of patients treated by high-treatment intensity providers than by low-treatment intensity providers subsequently underwent a major medical intervention (11.0% vs 6.4%, P = .02). CONCLUSIONS: Providers vary widely in how aggressively they manage early-stage bladder cancer. Patients treated by high-treatment intensity providers do not appear to benefit in terms of survival or in avoidance of subsequent major medical interventions.

Hollenbeck, B. K., Z. Ye, et al. (2008). "Hospital lymph node counts and survival after radical cystectomy." Cancer 112(4): 806-812.

BACKGROUND: Several studies suggest that patients in whom more lymph nodes are examined have improved survival after radical cystectomy for bladder cancer. Despite growing calls for using lymph node counts as a hospital quality indicator, it has not been established that hospitals that obtain more lymph node have better outcomes. METHODS: Using the national Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database (1992-2003), all patients undergoing radical cystectomy for cancer were identified (n = 3603). Hospitals were ranked and sorted into 3 evenly sized groups: low (no patients with >or=10 lymph nodes removed), medium (up to 20% of patients), and high (greater than 20% of patients). Survival rates were assessed for each hospital group, adjusting for potentially confounding patient and hospital characteristics. RESULTS: On average, low lymph node count hospitals had higher observed mortality rates compared with high lymph node count hospitals (unadjusted hazards ratio [HR], 1.25; 95% confidence interval [95% CI], 1.13-1.39). Low lymph node count hospitals tended to treat patients who were older, had more comorbidity, were of lower socioeconomic status, had higher admission acuity, and had lower procedure volumes. After adjusting for these differences, low lymph node count hospitals tended to have slightly higher mortality (adjusted HR, 1.12; 95% CI, 0.99-1.27), although this finding did not reach statistical significance. Similar findings were evident when other thresholds (lymph node counts >or=5, >or=14, and >or=20) were used. CONCLUSIONS: Hospitals with high lymph node counts tend to have higher survival rates after radical cystectomy for bladder cancer. However, this effect is modest and is explained, in large part, by confounding patient and hospital factors.

Hollingsworth, J. M., M. M. Davis, et al. (2009). "Trends in medical expulsive therapy use for urinary stone disease in U.S. emergency departments." Urology 74(6): 1206-1209.

OBJECTIVES: Between 2000 and 2006, 11 randomized controlled trials were published, demonstrating the efficacy of medical expulsive therapy (MET) for promoting upper tract stone passage. Although its use is gaining traction among urologists, they evaluate a minority of patients who present to the emergency department (ED) for acute renal colic before discharge. As such, measuring the uptake of MET into the broader medical community is important. METHODS: Data were analyzed (2000-2006) from the National Hospital Ambulatory Medical Care Survey. Sampled ED visits for stones were identified. The use of MET was ascertained by the prescription of a calcium channel or alpha blocker at the ED visit. National estimates of the prevalence of MET use were computed. Logistic regression was used to examine linear and nonlinear time trends in MET prescription. RESULTS: The use of MET increased throughout the study period. In fact, the odds of being treated with this approach more than doubled with each successive year (OR, 2.15; 95% CI, 1.31-3.5; P < .001 for the linear trend). However, the overall prevalence of use was exceedingly low at 1.1% (95% CI, 0.6%-1.9%). Given the number needed to treat of 4, this implies a missed opportunity to spare approximately 260,000 individuals annually from stone surgery and its risks. CONCLUSIONS: Despite the growing body of evidence to support its safety and efficacy, our analysis reveals the sluggish dissemination of MET into the broader medical community. The observed underuse represents a block in the translation of clinical science into practice and raises a quality of care concern.

Hollingsworth, J. M., B. K. Hollenbeck, et al. (2009). "Differences in initial benign prostatic hyperplasia management between primary care physicians and urologists." J Urol 182(5): 2410-2414.

PURPOSE: The introduction of efficacious pharmacotherapies has effectively transformed benign prostatic hyperplasia into a chronic disease that requires ongoing medical care. With this transformation primary care physicians have become more involved in the management of benign prostatic hyperplasia. The impact of the increasing role of the primary care physician on the use of benign prostatic hyperplasia related health services remains unknown. MATERIALS AND METHODS: We performed a retrospective cohort study using medical claims from a nonprofit managed care organization. Between 1997 and 2005 we identified incident cases of benign prostatic hyperplasia and the provider responsible for the initial care. We fitted logistic regression models to measure the association between subject receipt of an evaluative process and the treating physician specialty. Furthermore, we examined differences between primary care physicians and urologists with respect to the use of medical therapy. RESULTS: Less than a third of incident cases received initial care from a urologist. Use of office based procedures and urodynamic tests was exclusive to urology. Urologists performed urinalysis testing and transrectal ultrasonography more frequently than primary care physicians (p <0.001). The odds of having a laboratory study doubled with treatment by a urologist (OR 2.03, 95% CI 1.51-2.74). Men seen by a urologist were also more likely to be prescribed a benign prostatic hyperplasia medication (p <0.001). Among those who received medical therapy, prescription of selective alpha-adrenergic blockers, 5alpha-reductase inhibitors and combination therapy was higher among urologists (p = 0.002). CONCLUSIONS: On average, urologists had a higher intensity practice style for benign prostatic hyperplasia than primary care physicians. Further studies are needed to determine how these practice style differences relate to patient clinical outcomes.

Hollingsworth, J. M., B. K. Hollenbeck, et al. (2007). "Operative mortality after renal transplantation--does surgeon type matter?" J Urol 177(6): 2255-2259; discussion 2259.

PURPOSE: Currently there are 64 accredited renal transplantation fellowships in Canada and the United States. Only 27% are limited in scope to kidney transplants. In the remaining fellowships the trainee learns to transplant multiple abdominal organs. Given this evolution to the multiorgan transplant surgeon, we evaluated the effect of the current training paradigm on practice patterns and outcomes for kidney transplants. MATERIALS AND METHODS: Using data from the Nationwide Inpatient Sample, discharge records for kidney transplants (6,674) were abstracted (1993 to 2003). Through the Nationwide Inpatient Sample unique surgeon identifier we determined the proportion of kidney transplants performed by multiorgan and kidney only transplant surgeons. We fit multilevel regression models to examine the relationship between surgeon type and transplant outcome. RESULTS: We identified 99 multiorgan and 196 kidney only transplant surgeons who performed 3,255 and 3,419 kidney transplants, respectively. Kidney only transplant surgeons were more likely than multiorgan surgeons to practice in nonteaching, private, for-profit hospitals (p <0.05). Unadjusted operative mortality was higher in patients treated by kidney only vs multiorgan transplant surgeons (1.7% vs 0.9%, p = 0.002). After adjusting for patient and hospital factors, those who underwent renal transplantation performed by multiorgan transplant surgeons had 55% lower odds of inpatient death (OR 0.45, 95% CI 0.26-0.76) vs kidney only transplant surgeons. CONCLUSIONS: Despite the current training paradigm, kidney only transplant surgeons have a prominent role in renal transplantation. However, given the current donor organ shortage and the implications for quality, the observed mortality difference suggests that additional investigation is needed to determine whether this role should be decreased.

Hollingsworth, J. M., S. L. Krein, et al. (2008). "Understanding variation in the adoption of a new technology in surgery." Med Care 46(4): 366-371.

BACKGROUND: Despite data supporting the superiority of laparoscopy over conventional surgery for donor nephrectomy, prior work reveals that this technology's adoption has been slow. However, the underlying cause for its gradual adoption remains unclear. For this reason, a multilevel analysis was conducted using a population-based cohort to evaluate the amount of variation in laparoscopic donor nephrectomy use attributable to the individual, provider, and hospital levels. METHODS: Using the Nationwide Inpatient Sample (2000-2003), discharges for donor nephrectomies were identified, distinguishing between those surgeries performed by laparoscopic versus conventional approaches. To examine variation in laparoscopy use, we fitted generalized linear mixed models with random intercepts. The principal model had no explanatory variables included and allowed for an understanding of the basic partitioning of the data's variability. Patient-, provider-, and hospital-level factors were then added to the model to determine how much variability at each level might be explained by these covariates. RESULTS: In total, 974 conventional and 516 laparoscopic donor nephrectomies were performed by 157 surgeons at 46 hospitals. Among the different levels of care, the provider and hospital, combined, accounted for the majority of the variation in laparoscopy use (27.6% and 35.2%, respectively). After adjustment, the attributable variation at the provider level was largely unchanged (27.3%), whereas the hospital-level estimate decreased to 26.8%. CONCLUSIONS: These data reveal that the provider and hospital contribute substantially to the variability in laparoscopy use among kidney donors, suggesting that interventions focused at these levels would likely hasten laparoscopy's uptake in the community.

Hollingsworth, J. M., S. L. Krein, et al. (2007). "Payer leverage and hospital compliance with a benchmark: a population-based observational study." BMC Health Serv Res 7: 112.

BACKGROUND: Since 1976, Medicare has linked reimbursement for hospitals performing organ transplants to the attainment of certain benchmarks, including transplant volume. While Medicare is a stakeholder in all transplant services, its role in renal transplantation is likely greater, given its coverage of end-stage renal disease. Thus, Medicare's transplant experience allows us to examine the role of payer leverage in motivating hospital benchmark compliance. METHODS: Nationally representative discharge data for kidney (n = 29,272), liver (n = 7,988), heart (n = 3,530), and lung (n = 1,880) transplants from the Nationwide Inpatient Sample (1993-2003) were employed. Logistic regression techniques with robust variance estimators were used to examine the relationship between hospital volume compliance and Medicare market share; generalized estimating equations were used to explore the association between patient-level operative mortality and hospital volume compliance. RESULTS: Medicare's transplant market share varied by organ [57%, 28%, 27%, and 18% for kidney, lung, heart, and liver transplants, respectively (P < 0.001)]. Volume-based benchmark compliance varied by transplant type [85%, 75%, 44%, and 39% for kidney, liver, heart, and lung transplants, respectively (P < 0.001)], despite a lower odds of operative mortality at compliant hospitals. Adjusting for organ supply, high market leverage was independently associated with compliance at hospitals transplanting kidneys (OR, 143.00; 95% CI, 18.53-1103.49), hearts (OR, 2.84; 95% CI, 1.51-5.34), and lungs (OR, 3.24; 95% CI, 1.57-6.67). CONCLUSION: These data highlight the influence of payer leverage-an important contextual factor in value-based purchasing initiatives. For uncommon diagnoses, these data suggest that at least 30% of a provider's patients might need to be "at risk" for an incentive to motivate compliance.

Hollingsworth, J. M., D. C. Miller, et al. (2006). "Rising incidence of small renal masses: a need to reassess treatment effect." J Natl Cancer Inst 98(18): 1331-1334.

The incidence of kidney cancer has been rising over the last two decades, especially in cases where the disease is localized. Although rates of renal surgery parallel this trend, mortality rates have continued to rise. To investigate the basis of this "treatment disconnect" (i.e., increased rates of treatment accompanied by increased mortality rates), we analyzed patient data from nine registries of the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. We assembled a cohort of 34,503 kidney cancer patients and derived incidence, treatment, and mortality trends for kidney cancer, overall and as a function of tumor size. From 1983 to 2002, the overall age-adjusted incidence rate for kidney cancer rose from 7.1 to 10.8 cases per 100,000 US population; tumors < or = 4 cm in size accounted for most of the increase. Adjusted rates of renal surgery increased concurrently, most notably for tumors < or = 4 cm (0.9-3.6 surgeries per 100,000 US population). However, among kidney cancer patients, all-cause mortality per 100,000 US population increased from 1.5 deaths in 1983 to 6.5 deaths in 2002, with the greatest absolute increase noted for patients with lesions > 7 cm. Our results demonstrate that the rising incidence of kidney cancer is largely attributable to an increase in small renal masses that are presumably curable. The fact that increased detection and treatment of small tumors is not reducing mortality argues for a reassessment of the current treatment paradigm.

Hollingsworth, J. M., D. C. Miller, et al. (2007). "Five-year survival after surgical treatment for kidney cancer: a population-based competing risk analysis." Cancer 109(9): 1763-1768.

BACKGROUND: Kidney cancer's rising incidence is largely attributable to the increased detection of small renal masses. Although surgery rates have paralleled this incidence trend, mortality continues to rise, calling into question the necessity of surgery for all patients with renal masses. Using a population-based cohort, a competing risk analysis was performed to estimate patient survival after surgery for kidney cancer, as a function of patient age and tumor size at diagnosis. METHODS: With data from the Surveillance, Epidemiology, and End Results Program (1983-2002), a cohort was assembled of 26,618 patients with surgically treated, local-regional kidney cancer. Patients were sorted into 20 age-tumor size categories and the numbers of patients that were alive, dead from kidney cancer, and dead from other causes were tabulated. Poisson regression models were fitted to obtain estimates of cancer-specific and competing-cause mortality. RESULTS: Age-specific kidney cancer mortality was stable across all size strata but varied inversely with tumor size. Patients with the smallest tumors enjoyed the lowest cancer-specific mortality (5% for masses<or=4 cm). Competing-cause mortality rose with increasing patient age. The estimated 5-year competing-cause mortality for elderly subjects (>or=70 years) was 28.2% (95% confidence interval [CI]: 25.9%-30.8%), irrespective of tumor size. CONCLUSIONS: Despite surgical therapy, competing-cause mortality for patients with renal masses rises with increasing patient age. After 5 years, one-third of elderly patients (>or=70 years) will die from other causes, suggesting the need for prospective studies to evaluate the role of active surveillance as an initial therapeutic approach for some small renal masses.

Hollingsworth, J. M., D. C. Miller, et al. (2007). "Variable penetrance of a consensus classification scheme for renal cell carcinoma." Urology 69(3): 452-456.

OBJECTIVES: To evaluate the penetrance of the new pathologic standard of care, we characterized the temporal trends in histologic subtype-specific kidney cancer incidence rates. Molecular genetics have refined our understanding of kidney cancer, such that kidney cancer is now recognized as a family of tumors with distinct molecular and clinical characteristics. The histologic classification of kidney cancer has been revised to reflect this new paradigm. METHODS: Using the Surveillance, Epidemiology, and End Results Program, we identified incident cases from 1983 to 2002. Tumor histologic types were assigned, using the International Classification of Disease-Oncology codes. The histologic-specific incidence rates were calculated and directly age-adjusted to the 2000 U.S. population. RESULTS: The histologic type was available for 40,813 cases. Subsequent to the Heidelberg consensus conference, the rate of papillary histologic types rose appropriately from 0.02 in 1998 to 0.89 in 2002 per 100,000 U.S. population, and the incidence of granular cell histologic types remained relatively stable (0.22 to 0.14 cases per 100,000), despite its exclusion as a unique histologic subtype. Paradoxically, the incidence of chromophobe tumors decreased during this interval (0.03 to 0.003 cases per 100,000). CONCLUSIONS: Following the publication of the Heidelberg classification scheme, we have described the differential changes in incidence rates for newly described histologic variants. Our results suggest incomplete penetration of these guidelines. The continued reporting of granular cell histologic types is particularly noteworthy, given that it is no longer recognized as a distinct histologic subtype. Proper categorization of the histologic subtype (eg, chromophobe, papillary, clear cell) is imperative, because it may confer useful information regarding the prognosis, response to adjuvant treatment, and eligibility for clinical trials.

Hollingsworth, J. M., D. C. Miller, et al. (2006). "Surgical management of low-stage renal cell carcinoma: Technology does not supersede biology." Urology 67(6): 1175-1180.

OBJECTIVES: To address the concern that laparoscopic radical nephrectomy (LRN) is being applied in cases of small renal masses in which nephron-sparing surgery (NSS) might be more appropriate. METHODS: From 1998 to 2003, 381 consecutive patients underwent 391 procedures at our institution for renal cell carcinoma, of which 336 were for organ-confined tumors. The temporal trends in the application of LRN and NSS were assessed relative to the clinical stage. RESULTS: During the transition from early (1998 to 2000) to late (2001 to 2003) experience with laparoscopy, the use of LRN among patients with Stage T1a (4 cm or smaller) lesions remained infrequent (21% and 20%, respectively). In contrast, LRN increased among patients with larger lesions during this same interval (Stage T1b, 36% versus 56%, P = 0.017 and Stage T2, 24% versus 41%, P = 0.056). Concurrently, the use of NSS (open surgical or laparoscopic partial nephrectomy) increased for both Stage T1a (25% and 31% versus 34% and 37%, P = 0.082) and T1b (8% and 6% versus 19% and 5%, P = 0.017) tumors. Multivariate analysis demonstrated that the use of both NSS and LRN increased significantly with time (P = 0.002 and P = 0.001, respectively). Neither NSS nor LRN were associated with a greater risk of perioperative complications relative to radical or open surgery (P >0.05 for both). CONCLUSIONS: During a 6-year period at our institution, most Stage T1a lesions were managed with NSS, and a significant increase occurred in the use of NSS for Stage T1b tumors, despite the concurrent increasing application of LRN. These findings suggest that oncologic, rather than technologic, concerns were determining our practice patterns.

Hollingsworth, J. M., D. C. Miller, et al. (2006). "Cost trends for oncological renal surgery: support for a laparoscopic standard of care." J Urol 176(3): 1097-1101; discussion 1101.

PURPOSE: There may be inherent costs associated with the cultivation of laparoscopic expertise. We compared the cost trends for laparoscopy during the development of our program with that of open surgery for renal neoplasms. MATERIALS AND METHODS: We retrospectively reviewed the records of 381 patients treated surgically for renal cortical neoplasms from 1998 to 2003. Demographic information and cancer specific data were recorded on each subject. Direct variable costs, which are directly traceable to the patient care service provided and vary with patient volume, were used to analyze cost. Temporal trends were assessed using multivariate models developed to determine smoothed mean costs by year. RESULTS: Although it was initially more expensive, by 2003 mean costs were lower for laparoscopic than for open radical nephrectomy ($5,157 vs $5,808). This reflected a significantly lower annual increase in direct variable costs for laparoscopy vs open surgery even after adjustment for patient age, sex, race and clinical stage (p = 0.013). Although a similar trend was observed when comparing nephron sparing procedures vs open surgery, this did not attain statistical significance. In addition to surgical technique, only higher clinical stage was independently associated with increased direct variable costs after adjustment for operative year (p <0.0001). CONCLUSIONS: Relative to their open counterparts the costs of laparoscopic treatment of renal cortical neoplasms have increased at a lower rate in the last 6 years. When considered in the context of the well established benefits of laparoscopy, our findings lend additional support in favor of laparoscopy as the standard of care.

Hollingsworth, J. M., D. C. Miller, et al. (2006). "Local anesthesia in transrectal prostate biopsy." Urology 67(6): 1283-1284.

The administration of local anesthesia both topical and injectable before transrectal ultrasound-guided prostate biopsy is safe and efficacious. We describe our technique and review the relevant published data on this topic.

Hollingsworth, J. M., M. A. Rogers, et al. (2006). "Medical therapy to facilitate urinary stone passage: a meta-analysis." Lancet 368(9542): 1171-1179.

BACKGROUND: Medical therapies to ease urinary-stone passage have been reported, but are not generally used. If effective, such therapies would increase the options for treatment of urinary stones. To assess efficacy, we sought to identify and summarise all randomised controlled trials in which calcium-channel blockers or alpha blockers were used to treat urinary stone disease. METHODS: We searched MEDLINE, Pre-MEDLINE, CINAHL, and EMBASE, as well as scientific meeting abstracts, up to July, 2005. All randomised controlled trials in which calcium-channel blockers or alpha blockers were used to treat ureteral stones were eligible for inclusion in our analysis. Data from nine trials (number of patients=693) were pooled. The main outcome was the proportion of patients who passed stones. We calculated the summary estimate of effect associated with medical therapy use using random-effects and fixed-effects models. FINDINGS: Patients given calcium-channel blockers or alpha blockers had a 65% (absolute risk reduction=0.31 95% CI 0.25-0.38) greater likelihood of stone passage than those not given such treatment (pooled risk ratio 1.65; 95% CI 1.45-1.88). The pooled risk ratio for alpha blockers was 1.54 (1.29-1.85) and for calcium-channel blockers with steroids was 1.90 (1.51-2.40). The proportion of heterogeneity not explained by chance alone was 28%. The number needed to treat was 4. INTERPRETATION: Although a high-quality randomised trial is necessary to confirm its efficacy, our findings suggest that medical therapy is an option for facilitation of urinary-stone passage for patients amenable to conservative management, potentially obviating the need for surgery.

Hollingsworth, J. M., T. G. Schuster, et al. (2004). "Seminoma nine years after cardiac transplantation." Transplantation 77(9): 1472.

Hollingsworth, J. M. and J. T. Wei (2006). "Economic impact of surgical intervention in the treatment of benign prostatic hyperplasia." Rev Urol 8 Suppl 3: S9-S15.

The economic burden of benign prostatic hyperplasia (BPH) on our health care system is significant and likely to continue to grow given the burgeoning elderly population. Coincident with the rising number of annual physician office visits and expenditures for BPH has been a dramatic shift in the disease's management, from surgical to medical care. However, long-term cost data call into question the appropriateness of medical therapy as the initial treatment approach for all men with BPH, particularly those with moderate to severe symptoms. Although there has been a paradigm shift away from traditional BPH surgery, there has been renewed interest in the treatment of BPH with novel surgical techniques and minimally invasive surgeries. The economics of surgical interventions for BPH are discussed.

Hollingsworth, J. M. and J. T. Wei (2010). "Does the combination of an alpha1-adrenergic antagonist with a 5alpha-reductase inhibitor improve urinary symptoms more than either monotherapy?" Curr Opin Urol 20(1): 1-6.

BACKGROUND: Alpha1-adrenergic antagonists relieve lower urinary tract symptoms related to benign prostatic hyperplasia. 5alpha-Reductase inhibitors (ARIs) can halt the disease's progression. To assess whether their combined use had an additive benefit, we identified and summarized all randomized controlled trials in which the combination of an alpha1-adrenergic antagonist and ARI was used to treat symptomatic benign prostatic hyperplasia. METHODS: We searched the literature for studies relating to combination medical therapy using the MEDLINE database from 1 January 1993 to 31 December 2008. Only randomized controlled trials were eligible. Data from four trials were examined. The main outcome was a change in a man's lower urinary tract symptom from baseline as measured by validated symptom scores. RESULTS: For men with mean prostate volumes of approximately 36 ml, significant decreases from baseline symptom scores were evident after 1 year when comparing alpha1-adrenergic antagonist monotherapy and combination medical therapy with ARI monotherapy and placebo, but the mean decreases between those receiving alpha1-adrenergic antagonist monotherapy and combination medical therapy were not significantly different. However, at longer follow-up (mean 4.5 years), combination medical therapy demonstrated superiority over alpha1-adrenergic antagonist monotherapy. For men with larger prostates (mean volumes of 55 ml), combination medical therapy resulted in significantly greater improvements in symptoms compared with alpha1-adrenergic antagonist monotherapy after as little as 9 months of treatment. CONCLUSION: Combination medical therapy improves lower urinary tract symptom in men with symptomatic benign prostatic hyperplasia over alpha1-adrenergic antagonist or ARI monotherapy, when prescribed on a long-term basis. Combination medical therapy is efficacious for men with moderately enlarged prostates starting at 25 ml and somewhat better for increasingly larger prostate sizes.

Hollingsworth, J. M., Z. Ye, et al. (2009). "Urologist ownership of ambulatory surgery centers and urinary stone surgery use." Health Serv Res 44(4): 1370-1384.

OBJECTIVES: To understand how physician ownership of ambulatory surgery centers (ASCs) relates to surgery use. DATA SOURCE: Using the State Ambulatory Surgery Databases, we identified patients undergoing outpatient surgery for urinary stone disease in Florida (1998-2002). STUDY DESIGN: We empirically derived a measure of physician ownership and externally validated it through public data. We employed linear mixed models to examine the relationship between ownership status and surgery use. We measured how a urologist's surgery use varied by the penetration of owners within his local health care market. PRINCIPAL FINDINGS: Owners performed a greater proportion of their surgeries in ASCs than nonowners (39.6 percent versus 8.0 percent, p<.001), and their utilization rates were over twofold higher ( p<.001). After controlling for patient differences, an owner averaged 16.32 (95 percent confidence interval [CI], 10.98-21.67; p<.001) more cases annually than did a nonowner. Further, for every 10 percent increase in the penetration of owners within a urologist's local health care market, his annual caseload increased by 3.32 (95 percent CI, 2.17-4.46; p<.001). CONCLUSIONS: These data demonstrate a significant association between physician ownership of ASCs and increased surgery use. While its interpretation is open to debate, one possibility relates to the financial incentives of ownership. Additional work is necessary to see if this is a specialty-specific phenomenon.

Hollingsworth, J. M., Z. Ye, et al. (2010). "Physician-ownership of ambulatory surgery centers linked to higher volume of surgeries." Health Aff (Millwood) 29(4): 683-689.

Many physicians confronting declining reimbursement from insurers have invested in ambulatory surgery centers, where they perform outpatient surgical and diagnostic procedures. An ownership stake entitles physicians to a share of the facility's profits from self-referrals. This arrangement can create a potential conflict of interest between physicians' financial incentives and patients' clinical needs. Our analysis of Florida data for five common procedures revealed a significant association between physician-ownership and higher surgical volume. Possible remedies include revising federal law to require disclosure of investment arrangements; reducing facility payments to dilute ownership incentives; and reforms (such as accountable care organizations) that discourage an excessive rate of procedures.

Hollingsworth, J. M., Y. Zhang, et al. (2010). "Understanding the variation in treatment intensity among patients with early stage bladder cancer." Cancer.

BACKGROUND:: Given the uncertainty surrounding the optimal management for early stage bladder cancer, physicians vary in how they approach the disease. The authors of this report linked cancer registry data with medical claims to identify the sources of variation and opportunities for improving the value of cancer care. METHODS:: By using data from the Surveillance, Epidemiology, and End Results-Medicare database (1992-2005), patients with early stage bladder cancer were abstracted (n = 18,276). The primary outcome was the intensity of initial treatment that patients received, as measured by all Medicare payments for bladder cancer incurred in the 2 years after diagnosis. Multilevel models were fitted to partition the variation in treatment intensity attributable to patient versus provider factors, and the potential savings to Medicare from reducing the physician contribution were estimated. RESULTS:: Provider factors accounted for 9.2% of the variation in treatment intensity. Increasing provider treatment intensity did not correlate with improved cancer-specific survival (P = .07), but it was associated with the subsequent receipt of major interventions, including radical cystectomy (P < .001). If provider-level variation was reduced and clinical practice was aligned with that of physicians who performed in the 25th percentile of treatment intensity, then total payments made for the average patient could be lowered by 18.6%, saving Medicare $18.7 million annually. CONCLUSIONS:: The current results indicated that a substantial amount of the variation in initial treatment intensity for early stage bladder cancer is driven by the physician. Furthermore, a more intensive practice style was not associated with improved cancer-specific survival or the avoidance of major interventions. Therefore, interventions aimed at reducing between-provider differences may improve the value of cancer care. Cancer 2010. (c) 2010 American Cancer Society.

Holmes-Rovner, M., S. Stableford, et al. (2005). "Evidence-based patient choice: a prostate cancer decision aid in plain language." BMC Med Inform Decis Mak 5: 16.

BACKGROUND: Decision aids (DA) to assist patients in evaluating treatment options and sharing in decision making have proliferated in recent years. Most require high literacy and do not use plain language principles. We describe one of the first attempts to design a decision aid using principles from reading research and document design. The plain language DA prototype addressed treatment decisions for localized prostate cancer. Evaluation assessed impact on knowledge, decisions, and discussions with doctors in men newly diagnosed with prostate cancer. METHODS: Document development steps included preparing an evidence-based DA in standard medical parlance, iteratively translating it to emphasize shared decision making and plain language in three formats (booklet, Internet, and audio-tape). Scientific review of medical content was integrated with expert health literacy review of document structure and design. Formative evaluation methods included focus groups (n = 4) and survey of a new sample of men newly diagnosed with prostate cancer (n = 60), compared with historical controls (n = 184). RESULTS: A transparent description of the development process and design elements is reported. Formative evaluation among newly diagnosed prostate cancer patients found the DA to be clear and useful in reaching a decision. Newly diagnosed patients reported more discussions with doctors about treatment options, and showed increases in knowledge of side effects of radiation therapy. CONCLUSION: The plain language DA presenting medical evidence in text and numerical formats appears acceptable and useful in decision-making about localized prostate cancer treatment. Further testing should evaluate the impact of all three media on decisions made and quality of life in the survivorship period, especially among very low literacy men.

Honn, K. V., A. Aref, et al. (1996). "Prostate Cancer - Old Problems and New Approaches. (Part II. Diagnostic and Prognostic Markers, Pathology and Biological Aspects)." Pathol Oncol Res 2(3): 191-211.

Diagnostic and prognostic markers for prostatic cancer (PCa) include conventional protein markers (e.g., PAP, PSA, PSMA, PIP, OA-519, Ki-67, PCNA, TF, collagenase, and TIMP 1), angiogenesis indicator (e.g., factor VIII), neuroendocrine differentiation status, adhesion molecules (E-cadherin, integrin), bone matrix degrading products (e.g., ICPT), as well as molecular markers (e.g., PSA, PSMA, p53, 12-LOX, and MSI). Currently, only PSA is used clinically for early diagnosis and monitoring of PCa. The histological differential diagnosis of prostatic adenocarcinoma includes normal tissues such as Cowper's gland, paraganglion tissue and seminal vesicle or ejaculatory duct as well as pathological conditions such as atypical adenomatous hyperplasia, atrophy, basal cell hyperplasia and sclerosing adenosis. A common PCa is characterized by a remarkable heterogeneity in terms of its differentiation, microscopic growth patterns and biological aggressiveness. Most PCa are multifocal with signi ficant variations in tumor grade between anatomically separated tumor foci. The Gleason grading system which recognizes five major grades defined by patterns of neoplastic growth has gained almost uniform acceptance. In predicting the biologic behavior of PCa clinical and pathological stages are used as the major prognostic indicators. Among the cell proliferation and death regulators androgens are critical survival factors for normal prostate epithelial cells as well as for the androgen-dependent human prostatic cancer cells. The androgen ablation has been shown to increase the apoptotic index in prostatic cancer patients and castration also promotes apoptotic death of human prostate carcinoma grown in mice. The progression of PCa, similarly to other malignancies, is a multistep process, accompanied by genetic and epigenetic changes, involving phenomenons as adhesion, invasion and angiogenesis (without prostate specific features).

Honn, K. V., A. Aref, et al. (1996). "Prostate cancer old problems and new approaches : Part I. epidemiology, incidence and genetic alterations." Pathol Oncol Res 2(1-2): 98-109.

Rates of prostate cancer (PCa) have increased so dramatically over the last decade that the age adjusted incidence rate for PCa is now greater than that any other cancer among men in the United States. This review, published as a three part series, provides a state-of-art assessment of the PCa problem in its divergent aspects.Part 1 covers epidemiology, incidence and progression. Several epidemiological studies have demostrated that first degree male relatives of men with PCa are at increased risk of developing the disease. Familial and genetic factors as well as medical, anthropometric, dietary, hormonal and occupational factors involved in PCa are discussed. Postmortem examination of the prostate in men without evidence of PCa documented a high frequency of adenocarcinoma. Latent disease occurred as early as the second decade of life. Although there is no significant difference in incidence between Caucasian and African-American males, high grade prostatic intraepithelial neoplasia (HGPIN) is higher in the latter group. While dietary fat, androgens and certain environmental factors may be determinants for PCa, the exact mechanism of tumorigenesis is still relatively unknown. The current thinking of the role of genomic instability, chromosomal alterations, tumor suppressor genes and the androgen receptor are explored.

Honn, K. V., A. Aref, et al. (1996). "Prostate Cancer Old Problems and New Approaches. Part III. Prevention and Treatment." Pathol Oncol Res 2(4): 276-292.

In Part Three of this review, we begin with an analysis of prevention strategies for prostate cancer followed by a discussion of the clinical use of molecular techniques for the evaluation and treatment of patients with clinically localized prostate cancer. New developments in neutron and photon therapy of prostate cancer are addressed as well as the use of systemic radiotherapy for the treatment of bone metastases. Finally, we conclude with the role of hormonal therapy in the treatment of prostate cancer and the current status of development of chemo therapeutic regimens for the treatment of prostate cancer.

Hsu, C. X., B. D. Ross, et al. (1998). "Longitudinal cohort analysis of lethal prostate cancer progression in transgenic mice." Journal of Urology 160(4): 1500-1505.

PURPOSE: Human prostate cancer is variably lethal, shows heterogeneous progression, and exhibits a spectrum of histopathology. Traditional rodent models of prostate cancer lack these characteristics. An alternative, autochthonous model of prostate cancer consists of transgenic mice which develop prostate cancer due to prostatic expression of SV40 T antigen. Lethal progression of such cancers in individual mice has not been previously characterized. Studies were undertaken to characterize the longitudinal progression of prostate cancers in these transgenic mice. METHODS: A prospective longitudinal cohort study was undertaken to characterize prostate cancer volume, progression, lethality, and histological heterogeneity in a transgenic mouse model of prostatic adenocarcinoma. Fifty-one transgenic mice were followed prospectively to determine the age at onset of palpable tumor and age at cancer-related death. Tumor volume was followed longitudinally by magnetic resonance imaging (MRI) in a subset of these mice and lethal cancers were evaluated by histopathology. RESULTS: Primary tumors became palpable at 10-38 weeks of age. Palpable tumors always preceded lethal progression. Cancer death followed 2-9 weeks later, and age at cancer death varied from 24 to 39 weeks of age. The histopathological changes were heterogeneous. Primary tumors were detectable by MRI before they became detectable by palpation. MRI showed that, analogous to human prostate cancers, volume of early stage primary tumors did not necessarily predict age at cancer death. CONCLUSION: Prostate cancer in transgenic mice mimics heterogeneic tumor progression in human prostate cancer, providing a uniquely relevant pre-clinical model. Tumor detection by MRI and palpation are valid surrogate measures of tumor progression in this model. <72>

Hume, D. M., H. M. Lee, et al. (1966). "Comparative results of cadaver and related donor renal homografts in man, and immunologic implications of the outcome of second and paired transplants." Annals of Surgery 164(3): 352-397.

Hume, D. M. and J. S. Wolf (1967). "Modification of renal homograft rejection by irradiation." Transplantation 5(4): Suppl-91.

Hume, D. M., J. S. Wolf, et al. (1972). "Liver transplantation." Transplantation Proceedings 4(4): 781-784.

Humphrey, P. A., X. Zhu, et al. (1995). "Hepatocyte growth factor and its receptor (c-MET) in prostatic carcinoma." Am J Pathol 147(2): 386-396.

Hepatocyte growth factor (scatter factor) and its receptor, the c-met proto-oncogene product (c-MET), have been implicated in embryogenesis, tissue reorganization, and tumor progression. Little is known, however, of the expression and functional significance of these molecules in prostatic cells and tissue. In this investigation, we assessed the expression of hepatocyte growth factor (HGF) and c-MET in prostatic tissues and cell lines and also determined the effect of purified recombinant HGF on cell proliferation and scattering of prostatic carcinoma cell lines. HGF was expressed by human prostatic stromal myofibroblasts in primary culture but not by three human prostatic carcinoma cell lines (LNCaP, DU 145, and PC-3) as assessed by Northern blot analysis. HGF was also detected by reverse transcriptase-polymerase chain reaction in both benign and malignant tissues from radical prostatectomy specimens. c-MET transcripts were identified by Northern blot in two androgen-insensitive human prostatic carcinoma cell lines (DU 145 and PC-3) but not the androgen-sensitive LNCaP cell line. Additional evidence of linkage of androgen responsiveness and c-MET was provided by experiments in which androgen deprivation of normal rat prostates via castration produced a marked up-regulation of c-MET expression as determined by Northern blot and immunohistochemistry. c-MET protein was detected by immunohistochemical analysis in a substantial percentage (58 of 128 or 45%) of prostatic carcinomas and was found more often in metastatic growths of human prostatic carcinoma (15 of 20 patients) compared with primary tumors (43 of 108 patients; P < 0.005). Moreover, in Dunning R-3327 rat prostatic carcinoma cell lines, c-MET expression was highest in the androgen-insensitive subline with the highest metastatic capacity. Purified recombinant human HGF induced dose-dependent cellular proliferation and scattering in the DU 145 carcinoma cell line. These data indicate that HGF may function in the prostate gland as a paracrine growth factor, with synthesis by stromal cells and with biological target cells being the epithelial cells. Expression of the HGF receptor, c-MET, is up-regulated by androgen deprivation and c-MET appears to be preferentially expressed on androgen-insensitive, metastatic cells, suggesting a possible linkage of c-MET expression with prostatic carcinoma progression.

Hurd, W. W., S. S. Chee, et al. (2001). "Location of the ureters in relation to the uterine cervix by computed tomography." Am J Obstet Gynecol 184(3): 336-339.

OBJECTIVE: Our aim was to determine the distance of the ureter from the cervix and the influence of age and weight on this distance. STUDY DESIGN: The distance of the ureter from the uterine cervix was determined by evaluating the computed pelvic tomograms from 52 women. Age and body mass index were compared to this distance by means of regression analysis. RESULTS: At the most dorsal reflection of the ureter, the average distance from ureter to cervical margin was 2.3 +/- 0.8 cm (range, 0.1-5.3 cm). There was no relationship to age, but there was a linear relationship between this distance and body mass index (R2 = 0.075; P = .049); thus the ureter was slightly more proximal to the cervical margin in heavier women. CONCLUSIONS: In women with apparently normal pelvic anatomy, the average distance between the ureter and cervix is >2 cm. The finding that this distance is <0.5 cm in 12% of the women studied may explain the relatively common occurrence of ureteral injury during hysterectomy. The relationship between body mass index and location is clinically insignificant.

Hurd, W. W., M. S. Kelly, et al. (1992). "The effect of cocaine on sperm motility characteristics and bovine cervical mucus penetration." Fertil Steril 57(1): 178-182.

OBJECTIVES: To determine the in vitro effects of cocaine on sperm motility and bovine mucus penetration because cocaine abuse is associated with decreased sperm motility, and related compounds, such as procaine, are known to decrease sperm motility. DESIGN: Human semen samples were exposed to a range of cocaine concentrations and the effects quantified using computer-assisted sperm analysis and the bovine mucus penetration test. SETTING: University research laboratory. PATIENTS, PARTICIPANTS: Samples were obtained from 18 healthy volunteers. INTERVENTIONS: Normal semen samples were exposed to concentrations of cocaine ranging from 10(-11) to 10(-4) M. Motility characteristics were evaluated after 2 hours, and bovine mucus penetration was evaluated after 30 minutes, 1 hour, and 2 hours. Mucus penetration by washed sperm was also evaluated. MAIN OUTCOME MEASURES: Motility characteristics were evaluated using computer-assisted sperm analysis, and functional sperm motility was evaluated using the bovine mucus penetration test. RESULTS: Cocaine exposure decreased the percentage of motile sperm in a concentration-dependent manner with a maximum decrease of 23% at 10(-4) M but had no effect on other motility characteristics. Cocaine decreased bovine mucus penetration by 12% at high cocaine concentrations (10(-4) M), but increased penetration by 69% at low concentrations (10(-9) M). Washing sperm before cocaine exposure attenuated the increased sperm penetration. CONCLUSION: The ability of cocaine to decrease the percentage of motile sperm at high concentrations may explain the decreased sperm motility associated with cocaine use. Cocaine's ability to augment sperm penetration at low concentrations suggests an interaction of cocaine with the sperm adrenergic system.

Hurd, W. W., J. F. Randolph, Jr., et al. (1993). "Comparison of intracervical, intrauterine, and intratubal techniques for donor insemination." Fertil Steril 59(2): 339-342.

OBJECTIVE: To compare the efficacy of intracervical insemination (ICI), intrauterine insemination (IUI), and a combination of intratubal and intrauterine insemination (ITI/IUI) for donor insemination. DESIGN: Prospective randomized clinical trial. SETTING: The University of Michigan donor insemination program. PATIENTS, PARTICIPANTS: Forty-one women undergoing donor insemination with cryopreserved sperm for either isolated male factor or male factor plus ovulatory dysfunction corrected by clomiphene citrate. INTERVENTION: Each patient was randomly assigned to receive each of the three insemination techniques in consecutive cycles until pregnancy occurred or the patient dropped from the study. MAIN OUTCOME MEASURES: Cycle fecundity rates were compared using the chi 2 test, and cumulative pregnancy rates (PRs) determined by life table analysis were compared using a log-rank test. RESULTS: Cycle fecundity rate was significantly higher for IUI (18.3%) than for ICI (3.9%) or ITI/IUI (7.3%). By life table analysis, the cumulative PR for IUI was significantly higher than for ICI, but the PR for ITI/IUI was not. CONCLUSION: For donor insemination with cryopreserved sperm, IUI increases cycle fecundity compared with ICI. The addition of ITI to IUI, however, interferes with the apparent beneficial effect of IUI alone.

Hussain, M., M. Banerjee, et al. (2003). "Soy isoflavones in the treatment of prostate cancer." Nutr Cancer 47(2): 111-117.

Epidemiological studies suggest an inverse association between soy intake and prostate cancer (Pca) risk. We have previously observed that soy isoflavone genistein induces apoptosis and inhibits growth of both androgen-sensitive and androgen-independent Pca cells in vitro. To determine the clinical effects of soy isoflavones on Pca we conducted a pilot study in patients with Pca who had rising serum prostate-specific antigen (PSA) levels. Patients with Pca were enrolled in the study if they had either newly diagnosed and untreated disease under watchful waiting with rising PSA (group I) or had increasing serum PSA following local therapy (group II) or while receiving hormone therapy (group III). The study intervention consisted of 100 mg of soy isoflavone (Novasoy) taken by mouth twice daily for a minimum of 3 or maximum of 6 mo. Forty-one patients were enrolled (4 in group I, 18 in group II, and 19 in group III) and had a median PSA level of 13.3 ng/ml. Thirty-nine patients could be assessed for response. Soy isoflavone supplementation was given for a median of 5.5 (range 0.8-6) mo per patient. Although there were no sustained decreases in PSA qualifying for a complete or partial response, stabilization of the PSA occurred in 83% of patients in hormone-sensitive (group II) and 35% of hormone-refractory (group III) patients. There was a decrease in the rate of the rise of serum PSA in the whole group (P = 0.01) with rates of rise decreasing from 14 to 6% in group II (P = 0.21) and from 31 to 9% in group III (P = 0.05) following the soy isoflavone intervention. Serum genistein and daidzein levels increased during supplementation from 0.11 to 0.65 microM (P = 0.00002) and from 0.11 to 0.51 microM (P = 0.00001), respectively. No significant changes were observed in serum levels of testosterone, IGF-1, IGFBP-3, or 5-OHmdU. These data suggest that soy isoflavones may benefit some patients with Pca.

Hussain, M., E. I. Fisher, et al. (2000). "Androgen deprivation and four courses of fixed-schedule suramin treatment in patients with newly diagnosed metastatic prostate cancer: A Southwest Oncology Group Study." J Clin Oncol 18(5): 1043-1049.

PURPOSE: To assess the feasibility of administering a combination of suramin and hydrocortisone in addition to androgen deprivation in a cooperative group setting; to assess the feasibility of treatment with multiple courses of suramin; and to assess progression-free and overall survival in patients with newly diagnosed metastatic prostate cancer who underwent such treatment. PATIENTS AND METHODS: Patients with newly diagnosed metastatic prostate cancer who had adequate hematologic, hepatic, renal, neurologic, and coagulation parameters were treated by combined androgen deprivation and suramin plus hydrocortisone. Suramin was administered on a 78-day fixed dosing schedule (one cycle), and suramin treatment cycles were repeated every 6 months for a total of four cycles. The statistical design was developed on the basis of the feasibility of administering suramin, as judged by the number of patients who developed neurotoxicity of grade 3 or higher or by treatment interruption of 4 weeks or longer due to any persistent suramin-related toxicity. RESULTS: Of the 62 patients enrolled onto the study between August 1994 and January 1997, 59 were eligible and assessable for toxicity on the first cycle. Thirty-two (54%) of 59 patients received a second cycle, 13 (22%) of 59 patients received a third cycle, and only five patients (8%) received a fourth cycle. During the first cycle, 27 patients were removed from the study: 17 because of toxicity, five because of disease progression, two who had died, and three because of other reasons. There was one therapy-related death. Grade 4 toxicities were noted in 11 and three patients during first and second courses, respectively. Neurotoxicity of grade 3 or higher was observed in nine and seven patients during the first and second cycles, respectively. Fifteen patients had treatment interruptions of 4 weeks or longer. Overall, only 54% (95% confidence interval, 41% to 67%) of the patients demonstrated acceptable limits of toxicity. CONCLUSION: Suramin plus hydrocortisone and androgen deprivation has limited applicability in the treatment of patients with newly diagnosed metastatic prostate cancer.

Hussain, M., D. C. Smith, et al. (2003). "Neoadjuvant docetaxel and estramustine chemotherapy in high-risk/locallyadvanced prostate cancer." Urology 61(4): 774-780.

OBJECTIVES: To evaluate the efficacy and safety of neoadjuvant docetaxel and estramustine in patients with high-risk, newly diagnosed, prostate cancer. METHODS: Eligible patients had prostate cancer with one or more of the following criteria: clinical Stage T2b or greater, prostate-specific antigen (PSA) of 15 ng/mL or greater, and/or Gleason score of 8 to 10. Chemotherapy consisted of docetaxel (70 mg/m(2)) on day 1 and estramustine (280 mg three times daily) on days 1 to 3 every 21 days for three to six courses. This was followed by local therapy, as deemed appropriate. RESULTS: Twenty-one patients with a median age of 60 years, median PSA level of 16.1 ng/mL (range 2.4 to 175), and median baseline testosterone of 3.4 ng/mL were enrolled. Seven patients met one of the inclusion criteria, 10 met two, and 4 met three. The Gleason score was 8 or greater in 14 patients. A median of five cycles of chemotherapy was delivered. The most frequent high-grade toxicities were grade 3 (8 patients) and 4 (1 patient) neutropenia and deep venous thrombosis (grade 3 in 2 patients) before institution of low-dose warfarin. All patients responded as determined by protocol-defined criteria. Ten patients underwent radical prostatectomy, with negative surgical margins in 7 patients, and 11 received radiotherapy with negative preradiotherapy biopsies in 2. CONCLUSIONS: Induction docetaxel and estramustine is well tolerated and feasible in patients with newly diagnosed, high-risk prostate cancer. This combination is active; however, its efficacy relative to hormonal therapy will require a controlled randomized trial.

Hussain, M. H., D. P. Wood, et al. (2009). "Bladder cancer: narrowing the gap between evidence and practice." J Clin Oncol 27(34): 5680-5684.

Hussain, S. Z., D. A. Bloom, et al. (2000). "Caroli's disease diagnosed in a child by MRCP." Clin Imaging 24(5): 289-291.

We describe a case of Caroli's disease associated with a choledochal cyst and autosomal recessive polycystic kidney disease in a child whose diagnosis was confirmed with magnetic resonance cholangiopancreatography (MRCP), after initial abnormalities were seen by ultrasonography. Invasive procedures such as liver biopsy or endoscopic retrograde cholangiopancreatography (ERCP) were, therefore, not necessary. Recent radiological advances in the diagnosis of Caroli's disease with particular emphasis on MRCP are discussed.

Hutter, R. V., J. E. Montie, et al. (1996). "Current prognostic factors and their relevance to staging." Cancer 78(2): 369-371.

Ignatoski, K. M., J. F. Escara-Wilke, et al. (2008). "RANKL inhibition is an effective adjuvant for docetaxel in a prostate cancer bone metastases model." Prostate 68(8): 820-829.

BACKGROUND: Docetaxel induces an anti-tumor response in men with advanced prostate cancer (PCa); however, the side effects associated with docetaxel treatment can be severe, resulting in discontinuation of therapy. Thus, identification of an effective adjuvant therapy to allow lower doses of docetaxel is needed. Advanced PCa is typically accompanied by skeletal metastasis. Receptor activator of NFkB ligand (RANKL) is a key pro-osteoclastic factor. Targeting RANKL decreases establishment and progression of PCa growth in bone in murine models. METHODS: The efficacy of inhibiting RANKL, using a recombinant soluble RANK extracellular domain fused with the immunoglobulin Fc domain (RANK-Fc), was tested as an adjuvant therapy with docetaxel for PCa bone metastasis in a murine intra-tibial model. RESULT: The combination of RANK-Fc and docetaxel reduced tumor burden in bone greater than either treatment alone. CONCLUSION: The combination of docetaxel with a RANKL-inhibiting agent merits further investigation for treatment of advance PCa.

Ignatoski, K. M., J. Friedman, et al. (2009). "Change in markers of bone metabolism with chemotherapy for advanced prostate cancer: interleukin-6 response is a potential early indicator of response to therapy." J Interferon Cytokine Res 29(2): 105-112.

Men with androgen-independent prostate cancer (AIPC) frequently have bone metastasis. The effects of chemotherapy on markers of bone metabolism have not been well characterized. We conducted a prospective study of patients with AIPC randomized in the first cycle to receive either docetaxel/estramustine or zoledronic acid, a bisphosphonate, to inhibit osteoclastic activity. Here we report the effects of therapy on markers of bone metabolism in these patients following the first cycle of therapy. Serum levels of several indices of bone remodeling were evaluated using commercial enzyme-linked immunosorbent assays. Changes in markers of bone metabolism were compared in patients receiving initial chemotherapy versus bisphosphonate. There was no significant difference in median change in any of the measured bone markers in patients given zoledronic acid when compared to chemotherapy. When comparing responders to nonresponders, overall interleukin-6 (IL-6) decreased by 35% in prostate-specific antigen responders; whereas, IL-6 levels increased by 76% in nonresponders (p = 0.03). Elevated IL-6 levels and reductions in IL-6 levels early in treatment may reflect ultimate clinical response to docetaxel-based regimens.

Imam, A. A., T. K. Mattoo, et al. (2005). "Calciphylaxis in pediatric end-stage renal disease." Pediatr Nephrol 20(12): 1776-1780.

Calciphylaxis is a rare, but life-threatening complication of end-stage renal disease (ESRD) that has been reported mostly in adult patients. The exact etiology is unknown, but the disease is commonly associated with a high calcium-phosphorus product and elevated levels of parathyroid hormone (PTH). We herein review the published reports on calciphylaxis in ESRD patients less than 18 years old and report the case of a patient with severe calciphylaxis who presented with lower extremity pain, muscle tenderness and difficulty in walking. The serum PTH was low, and the calcium-phosphorus product was normal. The diagnosis of calciphylaxis was confirmed by a muscle biopsy. Treatment with low calcium peritoneal dialysate and substitution of calcium-based phosphorus binders with sevelamer (Renagel) was unsuccessful. The patient's clinical condition progressed to extensive soft tissue calcification and ulcerating skin lesions. Nine months after the onset of symptoms, the patient died of cardiopulmonary arrest.

Imperiale, M. J., H. I. Pass, et al. (2001). "Prospects for an SV40 vaccine. [Review] [39 refs]." Seminars in Cancer Biology 11(1): 81-85.

The identification of SV40 as a possible cause of human cancer leads to the question of whether the unique properties of the virus can be exploited to treat patients with SV40-positive mesotheliomas, which are otherwise refractory to successful intervention. A modified SV40 T antigen, from which the transforming domains have been removed, has been cloned into a vaccinia virus vector and tested in animal tumor model systems. It has been shown to be effective against both subsequent tumor challenge and pre-existing tumors. Thus, the potential exists for use of such a vaccine in mesothelioma patients. Copyright 2001 Academic Press. [References: 39] <33>

Irby, P. B., 3rd, J. S. Wolf, Jr., et al. (1993). "Long-term follow-up of ventriculoureteral shunts for treatment of hydrocephalus." Urology 42(2): 193-197.

Surgical relief of hydrocephalus is achieved mainly with ventriculoperitoneal or ventriculoatrial shunting. In some patients, frequent reoperations are required because of infection, obstruction, or other complications, thus subjecting them to excessive operative morbidity and risk of neurological damage. One option that has been rarely addressed in recent years is drainage of cerebral spinal fluid into the urinary tract by way of a ventriculoureteral shunt. Patients who have endured multiple revisions of standard cerebral spinal fluid shunts may benefit from a relatively lower frequency of reoperation following ventriculoureteral shunting. There are several complications peculiar to this procedure, however, including ascending infection from the bladder, proximal shunt migration out of the ureter or distal migration into the bladder, failed urinary diversion, and electrolyte disturbances associated with volume depletion. Long-term follow-up of patients with ventriculoureteral shunts has not been reported. We describe the course of 4 patients successfully treated with ventriculoureteral shunts for an average of more than five years per patient. Although all eventually required reoperation, the frequency of reoperation with the ventriculoureteral shunts was markedly lower than with the standard shunts in these patients. Ventriculoureteral shunting should be considered for cerebral spinal fluid drainage in selected patients with multiple failures of standard shunts, provided the bladder is a low pressure reservoir with no urine infection.

Izawa, J. I., L. T. Madsen, et al. (2002). "Salvage cryotherapy for recurrent prostate cancer after radiotherapy: variables affecting patient outcome." J Clin Oncol 20(11): 2664-2671.

PURPOSE: To determine the long-term disease-specific survival (DSS) and disease-free survival (DFS) rates after salvage cryotherapy for locally recurrent adenocarcinoma of the prostate and to identify pretreatment factors that have an impact on DSS and DFS. PATIENTS AND METHODS: Between July 1992 and January 1995, 131 patients who had received definitive radiation therapy (XRT) underwent salvage cryotherapy for locally recurrent adenocarcinoma of the prostate. Cryotherapy failure was defined as an increasing postcryotherapy prostate-specific antigen (PSA) level of > or = 2 ng/mL above the postcryotherapy nadir, a positive prostate biopsy, or radiographic evidence of metastatic disease. Clinical variables were studied to determine whether there was an association with the DSS and DFS. RESULTS: The median follow-up was 4.8 years. The 5-year DSS rates were 87% for patients with a precryotherapy Gleason score < or = 8 and 63% for those with Gleason scores of 9 and 10 (P =.012). The 5-year DFS rates were 57% for patients with a precryotherapy PSA level of < or = 10 ng/mL and 23% for those with a PSA level greater than 10 ng/mL (P =.0004). The 5-year DSS rates for patients with a pre-XRT clinical stage of T1 to T2 and those with a clinical stage of T3 to T4 were 94% and 72%, respectively (P =.0041). The 5-year DFS rates for these groups were 90% and 69%, respectively (P =.0057). CONCLUSION: Androgen-independent local recurrences, Gleason score, and pre-XRT clinical stage were important factors that had an impact on DSS and DFS. The subset of patients cured by salvage cryotherapy seems to be small, and patient selection is important.

Izumi, K., A. Mizokami, et al. (2009). "Tranilast inhibits hormone refractory prostate cancer cell proliferation and suppresses transforming growth factor beta1-associated osteoblastic changes." Prostate 69(11): 1222-1234.

BACKGROUND: Tranilast is a therapeutic agent used in treatment of allergic diseases, although it has been reported to show anti-tumor effects on some cancer cells. To elucidate the effects of tranilast on prostate cancer, we investigated the mechanisms of its anti-tumor effect on prostate cancer. METHODS: The anti-tumor effects and related mechanisms of tranilast were investigated both in vitro on prostate cancer cell lines and bone-derived stromal cells, and in vivo on severe combined immunodeficient (SCID) mice. We verified its clinical effect in patients with advanced hormone refractory prostate cancer (HRPC). RESULTS: Tranilast inhibited the proliferation of LNCaP, LNCaP-SF, and PC-3 cells in a dose-dependent manner and growth of the tumor formed by inoculation of LNCaP-SF in the dorsal subcutis and in the tibia of castrated SCID mice. Flow cytometry and TUNEL assay revealed induction of cell cycle arrest and apoptosis by tranilast. Tranilast increased expression of proteins involved in induction of cell cycle arrest and apoptosis. Coculture with bone-derived stromal cells induced proliferation of LNCaP-SF cells. Tranilast also suppressed secretion of transforming growth factor beta1 (TGF-beta1) from bone-derived stromal cells, which induced their differentiation. Moreover, tranilast inhibited TGF-beta1-mediated differentiation of bone-derived stromal cells and LNCaP-SF cell migration induced by osteopontin. In the clinical investigation, PSA progression was inhibited in 4 of 16 patients with advanced HRPC. CONCLUSIONS: These observations suggest that tranilast may be a useful therapeutic agent for treatment of HRPC via the direct inhibitory effect on cancer cells and suppression of TGF-beta1-associated osteoblastic changes in bone metastasis.

Jackman, S. V. and W. W. Roberts (2002). "Where we stand with smart needle technology." Contemporary Urology 14: 32-38.

Jacobs, B. L., E. P. Gibbons, et al. (2009). "Management of bilateral synchronous renal cell carcinoma in a single versus staged procedure." Can J Urol 16(1): 4507-4511.

OBJECTIVES: The presentation of synchronous bilateral renal lesions is rare. We report our experience with the surgical management of these lesions in both a single and staged procedure. METHODS: We retrospectively reviewed the records of all patients with bilateral synchronous renal lesions who underwent surgical management by one surgeon between 2000-2007. We compared characteristics including pre and postoperative renal function, complication rates, and oncological outcomes between the single and staged cohorts. Data were analyzed using descriptive statistics, Student's t-test, and Fisher's exact test. RESULTS: A total of 26 patients (73% male, mean age 65.5 +/- 12.2 years) with bilateral synchronous lesions were identified with a mean follow-up of 25.9 +/- 19.7 months. Of these, 18 (69%) were performed as a single procedure, 5 (19%) were done as a staged procedure, and 3 (12%) had only the first part of the staged procedure performed. The single and staged cohorts were comparable in regards to preoperative creatinine (Cr) (1.1 +/- 0.4 mg/dl versus 1.1 +/- 0.2 mg/dl, p = 0.70), postoperative Cr (1.5 +/- 1.0 mg/dl versus 1.4 +/- 0.5 mg/dl, p = 0.73), and median hospital length of stay (HLOS) (5 days versus 4 days). The complication rate was 22% and 20% for the single and staged cohorts, respectively. One patient had a local recurrence and one patient developed metastatic disease in the single cohort versus no local recurrence or metastatic disease in the staged cohort. CONCLUSION: In the appropriate setting, surgical management of synchronous bilateral renal lesions can be done safely in a single procedure with comparable outcomes to those done in a staged manner.

Jacobs, B. L., E. P. Gibbons, et al. (2008). "Comparison between real-time intra-operative ultrasound-based dosimetry and CT-based dosimetry for prostate brachytherapy using cesium-131." Technol Cancer Res Treat 7(6): 463-469.

The purpose of this study was to evaluate the correlation between real-time intra-operative ultrasound-based dosimetry (USD) and day 0 post-implant CT dosimetry (CTD) (131)Cs permanent prostate brachytherapy. Fifty-two consecutive patients who underwent prostate brachytherapy with (131)Cs were evaluated. Real time operating room planning was performed using VariSeed 7.1 software. Post-needle placement prostate volume was used for real-time planning. Targets for dosimetry were D(90) >110%, V(100) >90%, V(150) <50%, and V(200) <20%. The CT scan for post-operative dosimetry was obtained on day 0. The mean values for USD, CTD, and the linear correlation, respectively, were, for D(90): 114.0%, 105.61%, and 0.15; for V(100): 95.1%, 91.6%, and 0.22; for V(150): 51.5%, 46.4%, and 0.40; and for V(200): 15.8%, 17.9%, and 0.42. The differences between the mean values for USD and CTD for D(90) (p<0.01), V(100) (p<0.01), and V(150) (p<0.05) were statistically significant. For D(90), 30.8% of patients had a >15% difference between USD and CTD and 51.9% of patients had a >10% difference between these values. In contrast, the USD and CTD for V(100) were within 5% in 55.8% of patients and within 10% in 86.5% of patients. This study demonstrates a correlation between the mean intra-operative USD and post-implant day 0 CTD values only for V(200). Significant variation in D(90), V(150), and V(200) values existed for individual patients between USD and CTD. These results suggest that real-time intra-operative USD does not serve as a surrogate for post-operative CTD, and that post-operative CTD is still necessary.

Jacobs, B. L., C. T. Lee, et al. (2010). "Bladder Cancer in 2010: How Far have We Come?" CA Cancer J Clin 60(4): 244-272.

Bladder cancer is the fourth most common cancer and ranks eighth as a cause of death from cancer among men in the United States. Although guidelines assist in treatment, the art of managing bladder cancer, such as the decision to use neoadjuvant chemotherapy and the timing of cystectomy, is still variable. Bladder cancer has a propensity to recur, and with recurrence, a significant number of cases progress, which makes the early detection of high-risk patients imperative. Advances in detection, surveillance, and treatment of bladder cancer are reviewed in this article. CA Cancer J Clin 2010. (c) 2010 American Cancer Society, Inc.

Jacobs, B. L. and J. K. Maranchie (2007). "Embolization with Tornado coils to control bleeding from an arterioureteral fistula." Can J Urol 14(6): 3770-3772.

Arterioureteral fistulae are rare, but potentially life-threatening causes of bleeding. We present a case of an 82 year-old woman with refractory, transfusion-dependent bleeding from an arterial fistula to her right ureteral stump, following right radical nephrectomy for advanced renal cell carcinoma. Cystoscopy with retrograde ureteral stump embolization using Tornado (Cook Medical, Bloomington, Indiana, USA) coils plus a slurry of thrombin-soaked Gelfoam (Pfizer Inc., New York, New York, USA) was performed, which led to prompt resolution of the patient's hematuria requiring no further hospitalizations or transfusions. Retrograde insertion of coils and injection of thrombin-soaked Gelfoam can be a minimally invasive, safe, and durable alternative for controlling hemorrhage from an arterioureteral fistula to a ureteral stump.

Jacobs, B. L., D. J. Matoka, et al. (2009). "Renal insufficiency secondary to delayed presentation of a retained foreign body." Can J Urol 16(3): 4697-4700.

We present the first report to our knowledge of progressive renal failure secondary to a retained intravesical foreign body. The urologic management of intravesical foreign bodies is challenging and is often complicated by a delay in presentation. Introduction into the bladder may be through a variety of means, including self insertion such as in this case. Extraction should be tailored according to the nature of the foreign body and should minimize bladder and urethral trauma. We report an unusual case of a 10 year delay in presentation after the insertion of two large intravesical foreign bodies manifesting as progressive renal failure and worsening lower urinary tract symptoms.

Jacobs, B. L., M. C. Smaldone, et al. (2008). "Conservative management of synchronous bilateral blunt renal injuries." Can J Urol 15(3): 4115-4117.

The kidney is the most commonly injured urologic organ, with most injuries occurring unilaterally. We report a rare case of synchronous bilateral renal hematomas in an 87 year old restrained driver involved in a motor vehicle accident and briefly review the management of renal trauma, including the indications for operative intervention. This case demonstrates that in select cases bilateral renal injuries can be managed conservatively.

Jacobs, B. L., M. C. Smaldone, et al. (2008). "Effect of skin-to-stone distance on shockwave lithotripsy success." J Endourol 22(8): 1623-1627.

PURPOSE: We evaluated the effect of increased body habitus on stone-free rates after shockwave lithotripsy (SWL), determined by three reproducible skin-to-stone distances (SSDs) on CT. PATIENTS AND METHODS: We retrospectively reviewed the records of 85 patients with preoperative CT scans available on Stentor Radiology Imaging who underwent SWL with the unmodified Dornier HM3 lithotripter from 2002 to 2007. SSDs were measured at the following angles: 0 degrees (vertical), 30 degrees, and 90 degrees (horizontal). Successful therapy was defined as stone free (residual fragments <2 mm) on follow-up imaging. Data were analyzed using descriptive statistics, Student t test, and the Fisher exact test. RESULTS: Four hundred and eighty patients underwent SWL at our institution from 2002 to 2007; 85 patients (50.6% men, mean age 50.8 +/- 15.7 years, mean body mass index [BMI] 28.8 +/- 6.6 kg/m2) had preoperative CT scans available for review. On follow-up imaging (142.7 +/- 217.2 days), 49.4% of patients were stone free. Mean SSDs (vertical, 30 degrees, horizontal) in patients who were stone-free v those with residual stone were 104.3 +/- 26.2 mm v 102.6 +/- 29.9 mm (P = 0.79), 103.9 +/- 28.2 mm v 101.0 +/- 31.5 mm (P = 0.66), and 106.6 +/- 25.3 mm v 107.1 +/- 29.3 mm (P = 0.94), respectively. CONCLUSIONS: Multiple variables have been shown to be associated with SWL success. In our sample of patients with preoperative CT scans, SSD was found to have no effect on SWL success.

Jacobs, B. L., M. C. Smaldone, et al. (2010). "Increased nerve growth factor in neurogenic overactive bladder and interstitial cystitis patients." Can J Urol 17(1): 4989-4994.

OBJECTIVES: Studies have suggested that pathology of the lower urinary tract can be detected by following changes in urinary proteins. We evaluated urine nerve growth factor (NGF) levels from patients with a variety of urologic conditions to examine NGF's role as a future biomarker. MATERIALS AND METHODS: Urine samples were obtained from 72 patients with normal non-diseased urinary tracts (n = 13), neurogenic overactive bladder (NOAB) (n = 13), idiopathic overactive bladder (OAB) (n = 17), interstitial cystitis/painful bladder syndrome (IC/PBS) (n = 8), prostate cancer (n = 7), history of prostate cancer status post robot-assisted laparoscopic prostatectomy (RALP) (n = 6), active bladder cancer (n = 4), and nephrolithiasis (n = 4). Urinary NGF levels were measured by enzyme linked immunosorbent assay (ELISA) using the Emax ImmunoAssay System (Promega, Madison, WI, USA); each NGF level was normalized to the patient's urine creatinine (Cr) level. The Bonferroni correction was used to adjust for multiple comparisons. RESULTS: Urinary NGF/Cr levels were significantly elevated in patients with NOAB (23.02 pg/mg (0-293), p = 0.004) and IC/PBS (31.24 pg/mg (0-291), p = 0.006); and approached significance in patients with nephrolithiasis (19.46 pg/mg (0-85), p = 0.06) compared to controls (0.00 pg/mg (0-12). CONCLUSIONS: Urinary NGF levels were significantly elevated in patients with NOAB and IC/PBS. Future studies are needed to further examine the significance of urinary NGF levels in the pathogenesis of a variety of urologic diseases and whether NGF could be used as a diagnostic or prognostic marker for specific urologic diseases.

Jain, A. K., D. A. Bloom, et al. (2005). "Nuclear import and export signals in control of Nrf2." J Biol Chem 280(32): 29158-29168.

Nrf2 binds to the antioxidant response element and regulates expression and antioxidant induction of a battery of chemopreventive genes. In this study, we have identified nuclear import and export signals of Nrf2 and show that the nuclear import and export of Nrf2 is regulated by antioxidants. We demonstrate that Nrf2 contains a bipartite nuclear localization signal (NLS) and a leucine-rich nuclear export signal, which regulate Nrf2 shuttling in and out of the nucleus. Immunofluorescence and immunoblot analysis revealed that Nrf2 accumulates in the nucleus within 15 min of antioxidant treatment and is exported out of nucleus by 8 h after treatment. Nrf2 mutant lacking the NLS failed to enter the nucleus and displayed diminished expression and induction of the downstream NAD(P)H:quinone oxidoreductase 1 gene. The Nrf2 NLS sequence, when fused to green fluorescence protein, resulted in the nuclear accumulation of green fluorescence protein, indicating that this signal sequence was sufficient to direct nuclear localization of Nrf2. A nuclear export signal (NES) was characterized in the C terminus of Nrf2, the deletion of which caused Nrf2 to accumulate predominantly in the nucleus. The Nrf2 NES was sensitive to leptomycin B and could function as an independent export signal when fused to a heterologous protein. Further studies demonstrate that NES-mediated nuclear export of Nrf2 is required for degradation of Nrf2 in the cytosol. These results led to the conclusion that Nrf2 localization between cytosol and nucleus is controlled by both nuclear import and export of Nrf2, and the overall distribution of Nrf2 is probably the result from a balance between these two processes. Antioxidants change this balance in favor of nuclear accumulation of Nrf2, leading to activation of chemopreventive proteins. Once this is achieved, Nrf2 exits the nucleus for binding to INrf2 and degradation.

Javidan, J. and D. P. Wood (2003). "Clinical interpretation of the prostate biopsy." Urol Oncol 21(2): 141-144.

Pathologic evaluation of the prostate biopsy provides the clinician with a wealth of information. Identifying needle biopsy parameters predictive of pathological stage and tumor volume at radical prostatectomy has become a major focus in the field of prostate pathology. From a review of the literature, the following factors are strongly predictive of extraprostatic disease; tumor involvement of greater than 25%, greater than two positive cores, cancer involvement greater than 3 mm, and perineural invasion. Such information could prove useful in patient counseling and identifying high-risk patients who may be good candidates for adjuvant therapy trials.

Jensen, S. L., D. P. Wood, Jr., et al. (1996). "Increased levels of nm23 H1/nucleoside diphosphate kinase A mRNA associated with adenocarcinoma of the prostate." World J Urol 14 Suppl 1: S21-25.

Overexpression of the nm23H1 gene has been associated with the suppression of metastasis in several solid tumors. However, in colorectal carcinoma and neuroblastoma, increased levels of nm23 H1 nucleoside diphosphate kinase A (NDPKA) mRNA are associated with tumorigenesis. To determine the role of nm23 H1/NDPKA in the prostate, normal and/or malignant tissue samples from 29 consecutive patients were studied. Levels of nm23 H1/NDPKA mRNA and nm23 H1/NDPKA mRNA protein were determined in tissue from 18 and 27 patients, respectively. In all, 16 of the 18 tumor samples expressed increased levels of nm23 H1/NDPKA mRNA as compared with those measured in normal tissue. The level of nm23 H1/NDPKA mRNA was > 10-fold higher in a metastatic lymph node than in normal prostate tissue. All cancer specimens and areas of prostatic intraepithelial neoplasia showed immunoreactivity with the nm23 H1/NDPKA antibody; however, normal prostatic tissue was unreactive. These findings suggest that overexpression of the nm23 H1/NDPKA gene occurs frequently in adeno-carcinomas of the prostate and may be an early event in prostate cancer tumorigenesis.

Jerde, T. J., W. S. Mellon, et al. (2004). "Suppression of 15-hydroxyprostaglandin dehydrogenase messenger RNA concentration, protein expression, and enzymatic activity during human ureteral obstruction." J Pharmacol Exp Ther 309(1): 398-403.

Prostanoids produce significant effects in the ureter, particularly in response to obstruction. Ureteral obstruction is associated with increased prostanoid synthesis via cyclooxygenase induction; however, prostaglandin degradation mediated by 15-hydroxyprostaglandin dehydrogenase (PGDH) has not been evaluated in the ureter. The purpose of this study was to determine whether PGDH steady-state mRNA, protein, and enzyme activity are altered in the human ureter during obstruction. Human ureteral segments from patients undergoing donor nephrectomy (normal segments) or ureteral stricture repair (obstructed segments) were obtained with proper informed consent. We evaluated PGDH steady-state mRNA relative to ribosomal protein S26 reference gene by reverse transcription-polymerase chain reaction and Vistra Green fluoroimaging. We determined PGDH protein content relative to glyceraldehyde-3-phosphate dehydrogenase by immunoblotting and PGDH localization by immunohistochemistry. PGDH enzymatic activity was determined by measurement of conversion of 15-hydroxy- to 15-keto-prostaglandin using thin layer chromatography separation. We found that PGDH mRNA and protein were decreased 4- to 6-fold, and enzyme activity was decreased >3-fold in obstructed human ureter relative to normal controls. PGDH was localized to the urothelial cells, with little or no expression in smooth muscle. Our results indicate that PGDH mRNA, protein, and enzyme activity are suppressed in the human ureter during obstruction. Increased concentrations of prostanoids subsequent to ureteral obstruction seem to be due to decreased degradation as well as increased synthesis. Modulation of prostanoid degradation may have therapeutic relevance in obstructive disorders of the ureter.

Jimenez, R. E., E. Gheiler, et al. (2000). "Grading the invasive component of urothelial carcinoma of the bladder and its relationship with progression-free survival." Am J Surg Pathol 24(7): 980-987.

Although grading is valuable prognostically in pTa and pT1 papillary urothelial carcinoma, it is unclear whether it provides any prognostic information when applied to the invasive component in muscle-invasive carcinoma. The authors analyzed 93 cases of muscle-invasive urothelial carcinoma of the bladder treated with radical cystectomy for which follow-up information was available. Each case was graded using the Malmstrom grading system for urothelial carcinoma, applied to the invasive component. Pathologic stage, lymph node status, and histologic invasion pattern were also recorded and correlated with progression-free survival. Thirty-four cases (37%) were pT2, 40 (43%) were pT3, and 19 (20%) were pT4. Of the 77 patients who had a lymph node dissection at the time of cystectomy, 34 (44%) had metastatic carcinoma to one or more lymph nodes. The median survival for pT2, pT3, and pT4 stages was 85, 24, and 29 months, respectively (p = 0.0001). Lymph node-negative and lymph node-positive patients had a median survival of 63 and 23 months, respectively (p = 0.0001). Fifteen patients (16%) were graded as 2b and 78 patients (84%) were graded as 3. Median survival of patients graded as 2b was 34 months compared with 31 months for patients graded as 3 (p value not significant). Three invasive patterns were recognized: nodular (n = 13, 14%), trabecular (n = 39, 42%), and infiltrative (n = 41, 44%). The presence of any infiltrative pattern in the tumor was associated with a median survival of 29 months, compared with 85 months in tumors without an infiltrative pattern (p = 0.06). Pathologic T stage and lymph node status remain the most powerful predictors of progression in muscle-invasive urothelial carcinoma. In this group of patients histologic grade, as defined by the Malmstrom system and as applied to the invasive component, provided no additional prognostic information. An infiltrative growth pattern may be associated with a more dismal prognosis.

Jimenez, R. E., M. Hussain, et al. (2001). "Her-2/neu overexpression in muscle-invasive urothelial carcinoma of the bladder: prognostic significance and comparative analysis in primary and metastatic tumors." Clin Cancer Res 7(8): 2440-2447.

PURPOSE: The prognostic significance of Her-2/neu overexpression in muscle-invasive urothelial carcinoma of the bladder is largely unknown. Accurate determination of Her-2/neu overexpression may have therapeutic importance. EXPERIMENTAL DESIGN: Eighty consecutive cases of muscle-invasive urothelial carcinoma of the bladder treated by radical cystectomy with available follow-up were analyzed. In each case, one representative section was stained with anti-Her-2/neu. Staining was graded as 1 = faint/equivocal, 2 = moderate, and 3 = strong and was considered positive if > or =2. In those cases with a metastasis, the stain was also performed in the metastatic tumor. Results were correlated with survival. RESULTS: Twenty-two (28%) cases were considered Her-2/neu-positive in the primary tumor, and 17 of 32 (53%) were considered Her-2/neu-positive in the lymph node metastasis. Median survival for Her-2/neu-positive primary tumors was 33 months, compared with 50 months for Her-2/neu-negative cases (P = 0.46). Similarly, Her-2/neu overexpression in the lymph node metastasis did not predict survival. Sixty metastatic urothelial carcinomas were further studied by comparing Her-2/neu expression in the primary tumor with that of the lymph node and/or distant metastasis. Forty-five percent of Her-2/neu-negative primary tumors had a Her-2/neu-positive lymph node metastasis, whereas only one case (8%) of Her-2/neu-positive primary tumors was Her-2/neu-negative in the lymph node metastasis (P = 0.009). Similarly, 67% of Her-2/neu-negative primary tumors had a Her-2/neu-positive distant metastasis, whereas no Her-2/neu-positive primary tumor was negative in the metastasis (P = 0.429). CONCLUSIONS: Her-2/neu overexpression in primary or metastatic tumor did not predict survival in this cohort of muscle-invasive tumors. Overexpression in the primary tumors consistently predicts overexpression in a distant or regional metastasis. However, some Her-2/neu-negative primary tumors may show overexpression in their corresponding metastasis. Her-2/neu analysis in a metastasis may be necessary to accurately determine Her-2/neu status in metastatic bladder urothelial carcinoma.

Johnson, E. K., S. Daignault, et al. (2008). "Patterns of hematuria referral to urologists: does a gender disparity exist?" Urology 72(3): 498-502; discussion 502-493.

OBJECTIVES: To examine the referral patterns of hematuria within a nonprofit healthcare organization to determine the factors that influence referral. Hematuria continues to be an important sign of urologic disease, including urothelial malignancy. An increasing awareness of gender differences in tumor stage at bladder cancer presentation has led to speculation about delayed referral and diagnosis in women. However, little is known about the referral patterns of hematuria and whether gender differences exist. METHODS: The insurance records were examined from 926 consecutive adult health plan participants (559 men and 367 women) with newly diagnosed hematuria from 1998 to 2002. The patterns of urologic referral were evaluated. A Cox multivariate regression model was used to examine the relationship between urologic referral and the relevant variables. RESULTS: Overall, 263 men (47%) and 102 women (28%) were referred for urologic evaluation of hematuria, with a median follow-up of 27 and 26 months, respectively. Referral was initiated by the primary care physician in 80% of the cohort. Increased urologic referral was associated with advancing age, repeated hematuria, provider type, and male gender. The adjusted hazard ratio of male referral was 1.65 (95% confidence interval 1.31-2.08) compared with female referral. CONCLUSIONS: Primary care physicians practicing in a managed care setting are less likely to refer women for a urologic evaluation of new or first recurrent episodes of hematuria than to refer men in all patient age categories, except for 40-49 years. This apparent gender disparity could result in unequal access of specialty evaluation and could potentially delay the diagnosis of important urologic conditions.

Johnson, E. K. and D. P. Wood, Jr. (2010). "Converting from open to robotic prostatectomy: key concepts." Urol Oncol 28(1): 77-80.

Robotic-assisted laparoscopic prostatectomy (RALP) is rapidly becoming the surgical procedure of choice for treating localized prostate cancer. Although a learning curve does exist, RALP can readily be adopted by surgeons with minimal training in laparoscopy. Monitoring short- and long-term patient outcomes is the key to the individual surgeon improving this procedure for his/her patients. Although both open radical prostatectomy (ORP) and RALP can provide excellent patient outcomes, recent trends indicate that demand for RALP will continue to increase, and it is in the interest of the open surgeon to adopt this technique and aim to continuously improve patient outcomes after RALP.

Johnson, J., R. Gosnell, et al. (1979). "New arterial cannulation techniques in cadaver kidney preservation." Urology 14(4): 370-372.

Johnson, R. M. and E. J. McGuire (1981). "Urogenital complications of anterior approaches to the lumbar spine." Clin Orthop Relat Res(154): 114-118.

The superior hypogastric plexus of the sympathetic nervous system is the only major innervation of the urogenital system which is normally at risk in anterior exposures of the lower lumbar spine. When this is injured, one can expect to see disturbances of urogenital function with retrograde ejaculation or sterility in males. Failure of penile erection is not anticipated unless the patient has, in addition, advanced peripheral vascular disease. The superior hypogastric plexus may be spared by careful dissection about the iliac arteries and lumbosacral junction or by approaching the spine laterally through a retroperitoneal exposure.

Johnson, T. R., K. Pituch, et al. (2007). "Why and how a Department of Obstetrics and Gynecology stopped doing routine newborn male circumcision." Obstet Gynecol 109(3): 750-752.

In 2004, the Department of Obstetrics and Gynecology at the University of Michigan decided to stop offering routine circumcision for specialty and disciplinary, logistic, and educational reasons. The Pediatric Hospitalist Service assumed responsibility for the procedures and the educational process with resultant patient and staff satisfaction, educational, logistical and economic benefits.

Johnston, W. K., 3rd, B. K. Hollenbeck, et al. (2005). "Comparison of neuromuscular injuries to the surgeon during hand-assisted and standard laparoscopic urologic surgery." J Endourol 19(3): 377-381.

BACKGROUND AND PURPOSE: Hand-assisted procedures have assumed a greater role in the practice of many laparoscopists. We surveyed major laparoscopy program directors to compare the incidence and location of neuromuscular injury to the surgeon during hand-assisted laparoscopic (HAL) and standard laparoscopic (SL) surgery. MATERIALS AND METHODS: A questionnaire on neuromuscular injuries was e-mailed to 42 laparoscopic program directors. Respondents were instructed to report only injuries or pain associated with laparoscopic surgery when they were the primary responsible surgeon and not during open or endoscopic procedures. RESULTS: Surveys were returned from 23 attending laparoscopic surgeons and 2 laparoscopic fellows. Surgeons reported an average of 3.9 HAL and 6.3 SL cases per month as the primary surgeon. The HAL was completed with the GelPort, LapDisk, Omniport, or a combination of devices 55%, 22%, 5%, and 14%, respectively, of the time. Comparing HAL with SL, there was significantly more hand/wrist, forearm, and shoulder pain/injuries associated with HAL (P < 0.004). There was significantly more neck pain associated with SL than HAL (P < 0.003), but no significant difference in lower-back pain (P = 0.40). Comparing the two most commonly used hand-assist devices (GelPort and LapDisk), the LapDisk demonstrated significantly more hand/wrist pain or injury (P = 0.001). CONCLUSION: Hand-assisted laparoscopy is associated with more frequent neuromuscular strain to the upper extremity than SL, but SL surgeons experience more neck pain or injury. Surgeon discomfort is also dependent on the type of hand-assist device. The long-term consequences of physical strain on the laparoscopic surgeon are unknown currently, but measures to minimize neuromuscular strain should be considered.

Johnston, W. K., 3rd, K. M. Kelel, et al. (2006). "Acute integrity of closure for partial nephrectomy: comparison of 7 agents in a hypertensive porcine model." J Urol 175(6): 2307-2311.

PURPOSE: We assessed the acute effectiveness of closure after partial nephrectomy of 7 techniques in a large hypertensive porcine model using shallow and deep resections to approximate clinical situations. MATERIALS AND METHODS: Open surgical partial nephrectomy with hilar clamping was performed in pigs weighing 150 to 200 lbs, including small-a quarter length and a quarter width of kidney, medium-a third length and a third width of kidney, and into the renal sinus and up to the collecting system, and large-lower pole heminephrectomy at the renal sinus. Seven agents were compared after a single application, namely thrombin/collagen granules, polyethylene glycol hydrogel, fibrin glue, thrombin/gelatin granules, cyanoacrylate glue, fibrin glue/gelatin sponge and sutured bolster. Failure and success were determined by the presence or absence of bleeding, respectively, after unclamping and by an increase in SBP to 100 and then to 200 mm Hg with dopamine infusion. RESULTS: Of 70 partial nephrectomies the success rates were 33% and 14% for thrombin/collagen granules, and 67% and 0% for polyethylene glycol hydrogel in small and medium resections; 100%, 71% and 0% for fibrin glue, and 100%, 86% and 0% for thrombin/gelatin granules in small, medium and large resections; and 67% and 80% for cyanoacrylate glue, 100% and 20% for fibrin glue/gelatin sponge, and 100% for sutured bolster in medium and large resections, respectively. Of the kidneys that did not bleed at an SBP of 100 mm Hg 31% bled at 200 mm Hg. CONCLUSIONS: There is considerable variability among agents. Most were effective for small resections and some worked for medium resections but for large resections only sutured bolster was consistently effective. SBP also appears to be an important factor. These results bear on the selection of techniques during laparoscopic partial nephrectomy.

Johnston, W. K., 3rd, J. S. Montgomery, et al. (2005). "Fibrin glue v sutured bolster: lessons learned during 100 laparoscopic partial nephrectomies." J Urol 174(1): 47-52.

PURPOSE: Laparoscopic partial nephrectomy (LPN) is performed with marked technical variations. We defined the limits of sutureless LPN and determined which closure technique is best in a particular situation. MATERIALS AND METHODS: During 100 consecutive LPNs fibrin glue products were used for closure in the first 75 (group 1) and sutured bolsters were applied when the collecting system (CS) or renal sinus was entered in the final 25 (group 2). RESULTS: In groups 1 and 2 hand assisted laparoscopy was used in 72% vs 40% of cases and hilar clamping was used in 27% vs 92%, respectively. Mean tumor size was 25 vs 26 mm, tumor depth was 11 vs 13 mm, distance to the renal sinus was 9 vs 5 mm, operating room time was 185 vs 210 minutes, estimated blood loss was 398 vs 247 cc and hospital stay was 2.9 vs 2.6 days in groups 1 and 2, respectively. Overall postoperative hemorrhage and urine leakage occurred in 9% and 2% of patients, respectively. Tumors associated with postoperative hemorrhage/leakage tended to be larger (35 vs 24 mm, p = 0.007) and closer to the renal sinus (0.5 vs 8.2 mm, p = 0.02). Postoperative hemorrhage or urine leakage occurred in 41% of the 17 patients in group 1 with CS or renal sinus entry but in only 2 of the 58 (3.4%) without entry (p <0.0001). In group 2 hemorrhage/leakage occurred in 11% of the 18 patients with CS or renal sinus entry (vs same subset in group 1, p = 0.04). CONCLUSIONS: LPN with closure using fibrin glue products provides adequate hemostasis when the CS or renal sinus is not entered. When the CS or renal sinus is entered, a sutured bolster is recommended.

Johnston, W. K., 3rd, J. S. Montgomery, et al. (2005). "Retroperitoneoscopic radical and partial nephrectomy in the patient with cirrhosis." J Urol 173(4): 1094-1097.

PURPOSE: In patients with cirrhosis and a renal mass options may be limited by medical disease and the surgical difficulties associated with portal hypertension. We describe a retrospective review of patients with cirrhosis with renal masses who underwent radical or partial nephrectomy through a retroperitoneoscopic approach. MATERIALS AND METHODS: Ten consecutive patients, including 4 men and 6 women, with cirrhosis, of whom 2 had undergone liver transplantation, underwent radical (7) or partial (3) nephrectomy for a total of 5 right and 5 left renal neoplasms via the retroperitoneoscopic approach at our institution from March 2002 to February 2004. Recovery data were prospectively obtained and other information was gathered retrospectively from the medical record. RESULTS: Average patient age was 58 years and average American Society of Anesthesiology score was 2.8. Average renal tumor size for radical and partial nephrectomy was 4.6 (range 2.9 to 7) and 1.8 cm (range 1.3 to 2.3), respectively. Operative time was 140 to 315 minutes (median 172) and estimated blood loss was 100 to 5,000 ml (median 225). One patient required open conversion due to hemorrhage from left portosystemic venous communications. Mean postoperative hospitalization was 1.5 days (range 1 to 6). CONCLUSIONS: Although retroperitoneoscopic surgery avoids many surgical dangers associated with portal hypertension and it is our preferred approach to renal surgery in patients with cirrhosis, significant portosystemic venous communications exist in the retroperitoneum, especially on the left side, and they still lead to substantial blood loss in some patients.

Joseph, M. A., S. D. Harlow, et al. (2003). "Risk factors for lower urinary tract symptoms in a population-based sample of African-American men." Am J Epidemiol 157(10): 906-914.

Previous epidemiologic studies evaluating risk factors for lower urinary tract symptoms (LUTS) have focused on White populations. Between September 1996 and January 1998, in a population-based sample of African-American men aged 40-79 years in Flint, Michigan, the authors assessed the role of putative sociodemographic, lifestyle, and medical history risk factors in moderate to severe LUTS, including the subcategories of obstructive and irritative symptoms. After the exclusion of men with prostate cancer or prior prostate surgery and men who were taking alpha-blockers for urinary tract symptoms, 708 participants provided responses to a structured interviewer-administered questionnaire. After multivariable adjustment, current and former smokers were at increased risk of moderate to severe LUTS, including obstructive symptoms. Heavy alcohol consumption and a history of hypertension or diabetes were positively associated with LUTS, and high income (>/=$30,000) was inversely associated with LUTS and with obstructive and irritative symptoms. A history of heart disease was positively associated with LUTS and with irritative symptoms. To the authors' knowledge, this was the first population-based study undertaken in African-American men to evaluate putative risk factors for moderate to severe LUTS, including subcategories of obstructive and irritative urinary symptoms. These results describe associations with specific lifestyle and medical history risk factors.

Joseph, M. A., J. T. Wei, et al. (2002). "Relationship of serum sex-steroid hormones and prostate volume in African American men." Prostate 53(4): 322-329.

BACKGROUND: Previous epidemiologic investigations of the associations of sex-steroid hormones and benign prostatic hyperplasia (BPH) have focused on predominately white populations. The objective of this study was to evaluate potential associations of body mass index (BMI), cigarette smoking, use of alcohol, and endogenous sex-steroid hormones with prostate volume in a population-based sample of African American (AA) men, ages 40-79 yr. METHODS: A total of 369 AA men without clinical evidence of prostate cancer were identified in the Flint Men's Health Study by using a population-based sampling procedure. All subjects underwent a complete urologic evaluation that included prostate volume determination by transrectal ultrasonography and serum assays for androgens and estrogens. RESULTS: After age adjustment, BMI (weight (kg)/height (m)2) was positively correlated with increasing levels of androstanediol glucuronide (AG), estradiol (E2), estrone sulfate (E1S), and the ratios of E2:total testosterone (TT) and E2:free testosterone (FT); however, increasing BMI was negatively correlated with androstenedione (AD), FT, TT, and sex hormone-binding globulin (SHBG). Multivariable regression models demonstrated that prostate volume increased with age (P < 0.001) and BMI (P = 0.02) and decreased with increasing levels of SHBG (P = 0.01). Larger prostatic volumes were also marginally associated with increasing levels of TT (P = 0.058). CONCLUSION: Circulating serum levels of SHBG and endogenous sex-steroid hormones are correlated with prostate volume and potentially impact the natural history of BPH. However, longitudinal studies are needed to demonstrate the temporal relationships of hormones and growth factors in the pathogenesis of BPH in AA men.

Joshi, D. P., R. B. Shah, et al. (2002). "Isolated recurrent renal cell carcinoma metastatic to the bladder." J Natl Med Assoc 94(10): 912-914.

Jung, Y., Y. Shiozawa, et al. (2009). "Expression of PGK1 by prostate cancer cells induces bone formation." Mol Cancer Res 7(10): 1595-1604.

Prostate cancer (PCa) is one of the solid tumors that metastasize to the bone. Once there, the phenotype of the bone lesions is dependent upon the balance between osteoblastogenesis and osteoclastogenesis. We previously reported that overexpression of phosphoglycerate kinase 1 (PGK1) in PCa cell lines enhanced bone formation at the metastatic site in vivo. Here, the role of PGK1 in the bone formation was further explored. We show that PCa-derived PGK1 induces osteoblastic differentiation of bone marrow stromal cells. We also found that PGK1 secreted by PCa inhibits osteoclastogenesis. Finally, the expression levels of the bone-specific markers in PCa cells were higher in cells overexpressing PGK1 than controls. Together, these data suggest that PGK1 secreted by PCa regulates bone formation at the metastatic site by increasing osteoblastic activity, decreasing osteoclastic function, and expressing an osteoblastic phenotype by PCa cells.

Kacergius, T., Y. Deng, et al. (2003). "Influenza virus and gamma interferon synergistically increase nitric oxide production in RAW 264.7 and AMJ2-C11 macrophages." Acta Medica Lituanica 10: 174-184.

Kaplan, J. R., R. S. Sung, et al. (2009). "Bilateral native nephrectomy: Before or after renal transplantation?" UroToday International Journal 2(1).

Kaplan, J. R. and J. S. Wolf, Jr. (2009). "Efficacy and survival associated with cystoscopy and clot evacuation for radiation or cyclophosphamide induced hemorrhagic cystitis." J Urol 181(2): 641-646.

PURPOSE: We assessed the outcome of patients with hemorrhagic cystitis severe enough to require cystoscopy and clot evacuation. MATERIALS AND METHODS: We retrospectively evaluated the records of 33 patients with cyclophosphamide or radiation induced hemorrhagic cystitis treated with cystoscopy. RESULTS: Mean followup of living patients was 76 months. Of 33 patients 20 (61%) had resolution of hematuria after single cystoscopy unrelated to hemorrhagic cystitis etiology. Only 4 of 11 patients (36%) had resolution after 2 or more cystoscopies, and all were in the radiation induced hemorrhagic cystitis group (4 of 6, 67%) with none in the cyclophosphamide induced hemorrhagic cystitis group (0 of 5, p = 0.02). Hematuria was refractory to cystoscopy in 9 patients and ileal conduits were created in 4. Kaplan-Meier overall survival at 1, 2 and 5 years was 58%, 51% and 43%, respectively, with survival tending to be worse in patients who received cyclophosphamide for bone marrow transplantation induction. Of the 18 deaths 3 were due to complications of hemorrhagic cystitis, 13 were due to the disease underlying the hemorrhagic cystitis and 2 were unrelated. CONCLUSIONS: The response of hemorrhagic cystitis to single cystoscopy and clot evacuation is reasonable but response to subsequent cystoscopy (unless the hemorrhagic cystitis is radiation induced) is less likely, so alternate interventions should be considered if hematuria does not resolve after initial cystoscopy. Patients with hemorrhagic cystitis requiring cystoscopy have a poor prognosis even if hematuria resolves, although most deaths are related to the disease underlying the hemorrhagic cystitis rather than its direct result.

Kaplinsky, R., S. Greenfield, et al. (1996). "Expanded followup of intravesical oxybutynin chloride use in children with neurogenic bladder." J Urol 156(2 Pt 2): 753-756.

PURPOSE: We evaluated the long-term results of intravesical oxybutynin chloride use in children with neurogenic bladders who could not tolerate or whose conditions were refractory to oral therapy. MATERIALS AND METHODS: We reviewed our experience with 28 children (myelomeningocele in 27 and imperforate anus in 1) who presented with urinary incontinence and/or elevated bladder pressures refractory to intermittent catheterization and oral anticholinergic medication. Intravesical oxybutynin was administered to each child by instillation of 5 mg. crushed oxybutynin chloride in 10 cc sterile saline 2 times daily during catheterization. RESULTS: Seven patients (25%) could not tolerate intravesical oxybutynin secondary to anticholinergic side effects. The remaining 21 children have been followed on intravesical oxybutynin for a mean of 35 months (range 3 to 67). Of these 21 children 12 (57%) became completely dry day and night, 5 (24%) achieved daytime continence between catheterizations and 4 (19%) remained clinically unchanged with 2 in diapers. On urodynamics these 21 patients had increased bladder capacity of up to 1,150% (mean 237%, p < 0.0001) and decreased mean maximum filling pressures of -31% (p = 0.002). CONCLUSIONS: Although a number of patients continued to have anticholinergic side effects, a majority had significant improvement in urodynamic parameters and continence. The response appears to be durable, and it spares many of these children from undergoing bladder augmentation.

Karam, J. A., V. Margulis, et al. (2008). "Carcinoma in situ of the upper urinary tract treated with radical nephroureterectomy--results from a multicenter study." Eur Urol 54(4): 961-963.

Karlsson, E. K., I. Baranowska, et al. (2007). "Efficient mapping of mendelian traits in dogs through genome-wide association." Nat Genet 39(11): 1321-1328.

With several hundred genetic diseases and an advantageous genome structure, dogs are ideal for mapping genes that cause disease. Here we report the development of a genotyping array with approximately 27,000 SNPs and show that genome-wide association mapping of mendelian traits in dog breeds can be achieved with only approximately 20 dogs. Specifically, we map two traits with mendelian inheritance: the major white spotting (S) locus and the hair ridge in Rhodesian ridgebacks. For both traits, we map the loci to discrete regions of <1 Mb. Fine-mapping of the S locus in two breeds refines the localization to a region of approximately 100 kb contained within the pigmentation-related gene MITF. Complete sequencing of the white and solid haplotypes identifies candidate regulatory mutations in the melanocyte-specific promoter of MITF. Our results show that genome-wide association mapping within dog breeds, followed by fine-mapping across multiple breeds, will be highly efficient and generally applicable to trait mapping, providing insights into canine and human health.

Kasina, S., P. A. Scherle, et al. (2009). "ADAM-mediated amphiregulin shedding and EGFR transactivation." Cell Prolif 42(6): 799-812.

INTRODUCTION: The ectodomain shedding of epidermal growth factor receptor (EGFR) ligands, such as amphiregulin (AREG), by ADAMs (A Disintegrin And Metalloproteases) can be stimulated by G protein-coupled receptor (GPCR) agonists. Interactions between the CXCR4 GPCR and the CXCL12 chemokine have been shown to mediate gene transcription and cellular proliferation in non-transformed and transformed prostate epithelial cells, as well as motility/invasiveness in transformed cells. OBJECTIVES: In this report, we investigated the ability of CXCL12 to stimulate amphiregulin ectodomain shedding in non-transformed and transformed prostate epithelial cells that respond proliferatively to sub-nanomolar levels of CXCL12 and amphiregulin. MATERIALS AND METHODS: Non-transformed N15C6 and transformed PC3 prostate epithelial cells were assessed for amphiregulin shedding, ADAM activation, Src phosphorylation and EGFR activation using ELISA, immunoblot, and immunoprecipitation techniques, and for proliferation using cell counting after stimulation with CXCL12 or vehicle. RESULTS: The results of these studies identify CXCL12 as a novel inducer of amphiregulin ectodomain shedding and show that both basal and CXCL12-mediated amphiregulin shedding are ADAM10- and Src kinase-dependent in non-transformed N15C6 cells. In contrast, amphiregulin shedding is not amplified subsequent to stimulation with exogenous CXCL12, and is not reduced subsequent to metalloprotease- or Src kinase-inhibition, in highly aggressive PC3 prostate cancer cells. These data also show that CXCL12-mediated cellular proliferation requires EGFR transactivation in a Src- and ADAM-dependent manner in non-transformed prostate epithelial cells. However, these same mechanisms are dysfunctional in highly transformed prostate cancer cells, which secrete amphiregulin in an autocrine manner that cannot be repressed through metalloprotease- or Src kinase inhibition. CONCLUSION: These findings show that non-transformed and transformed prostate epithelial cells may employ different mechanisms to activate EGFR ligands and thereby utilize the EGFR axis to promote cellular proliferation.

Kato, K., A. J. Wein, et al. (1990). "Short term functional effects of bladder outlet obstruction in the cat." J Urol 143(5): 1020-1025.

Experimental bladder outlet obstruction in cats was produced by surgical placement of a silastic cuff around the urethra. Two sizes of cuff were used to produce either moderate or severe obstruction. The following is a summary of the short-term effects on bladder function. Obstruction induced a significant increase in the in vivo voiding pressure, in proportion to severity of the obstruction. There were no significant differences between control and obstructed cats in bladder mass, response of the isolated whole bladder to field stimulation or bethanechol, response of isolated bladder strips to field stimulation, bethanechol and ATP, or muscarinic receptor density in the bladder body. Although there were no differences in bladder mass between control and obstructed bladders, the hydroxyproline concentration of the severely obstructed bladders was significantly reduced. Creatine phosphate concentration was also significantly reduced in obstructed bladders. Although all whole cat bladder preparations displayed spontaneous contractile activity during in vitro cystometry, the obstructed bladders had a greater amplitude and frequency of spontaneous contractions with a lower volume threshold. In addition, the obstructed bladders had a greater tetrodotoxin-resistant contractile response to field stimulation. These results suggest that the obstructed cat bladder can compensate for increased outlet resistance without induction of bladder hypertrophy or significant functional changes, as seen in both rat and rabbit.

Katske, F. A., D. A. Bloom, et al. (1981). "Renal malakoplakia: acute onset of renal failure due to bilateral upper tract involvement." Urology 17(1): 88-90.

A case of malakoplakia-induced acute renal failure is presented. In the twenty months following diagnosis the patient remains anuric. Malakoplakia involving the upper urinary tract is not self-limiting and should be considered in the differential diagnosis of acute renal failure.

Katz, M. D., M. F. Serrano, et al. (2010). "Percent microscopic tumor necrosis and survival after curative surgery for renal cell carcinoma." J Urol 183(3): 909-914.

PURPOSE: Tumor necrosis is a potential marker of recurrence and survival after surgery for renal cell carcinoma. We determined whether a correlation exists between the amount (not just the presence/absence) of tumor necrosis, and metastasis-free, disease specific and overall survival after surgery for renal cell carcinoma. MATERIALS AND METHODS: We identified 841 consecutive patients who underwent partial or radical nephrectomy from 1989 to 2004 for renal cell cancer. Specimens were re-reviewed by a single pathologist (MFS). The tumor necrosis percent was none in 586 cases, less than 50% in 198 and 50% or greater in 55. Grade, stage, subtype, size, gender and age were also analyzed. Variables at p <0.05 on univariate analysis were incorporated into a Cox proportional hazards multivariate model. Metastasis-free, disease specific and overall survival was described using the Kaplan-Meier method and compared with the log rank test. RESULTS: Tumor necrosis was found in 253 specimens (30%). Univariate analysis revealed that the percent and presence of tumor necrosis correlated with metastasis-free, disease specific and overall survival. On multivariate analysis tumor necrosis presence/absence did not remain an independent predictor of disease specific (p = 0.7), metastasis-free (p = 0.7) or overall (p = 0.2) survival. Greater than 50% tumor necrosis was no longer a statistically significant predictor of metastasis-free survival (p = 0.45) but remained significant for disease specific (p = 0.02) and overall (p = 0.01) survival. CONCLUSIONS: The presence of 50% or greater tumor necrosis correlates with worse disease specific and overall survival but not metastasis-free survival in patients with renal cell carcinoma. Results support the inclusion of percent tumor necrosis over the presence/absence of tumor necrosis in the risk assessment of patients who undergo surgical treatment for renal cell carcinoma.

Katz, M. D., M. F. Serrano, et al. (2009). "The role of lymphovascular space invasion in renal cell carcinoma as a prognostic marker of survival after curative resection." Urol Oncol.

OBJECTIVES: Lymphovascular invasion (LVI) correlates with adverse outcomes in numerous malignancies. However, its role in predicting outcomes in RCC is unclear. Herein, we evaluated what effect LVI had on metastasis free survival (MFS), disease-specific survival (DSS), and overall survival (OS) in patients with RCC treated with surgical excision. METHODS: Eight hundred forty-one consecutive patients who underwent partial or radical nephrectomy from 1989 to 2004 were identified. Pathologic and gross features examined were LVI, subtype, Fuhrman grade, stage, and size. Age and gender were also analyzed. Slides were re-reviewed by a single pathologist (MS). Variables with P < 0.1 on univariate analysis were incorporated in a Cox proportional hazards multivariate model. MFS, DSS, and OS were described for patients with and without LVI using the Kaplan-Meier method, and compared with the log-rank test. RESULTS: LVI was seen on H and E stained slides in 91 patients (11%); 120 (14%) developed metastatic disease, 91 (11%) died of RCC, and 306 (36%) died during a median follow-up of 61 months. While on univariate analysis, LVI was strongly associated with decreased MFS, DSS, and OS (P < 0.0001), on multivariate analysis, LVI was no longer statistically significant for MFS, DSS, and OS with a HR of 0.976 (95% CI: 0.583-1.63; P = 0.93), 0.96 (95% CI: 0.542-1.69; P = 0.88), and 1.24 (95% CI: 0.869-1.77; P = 0.24). CONCLUSIONS: We found LVI to be associated with worse MFS, DSS, and OS on univariate analysis, but not on multivariate analysis for patients with nonmetastatic RCC. In contrast to previously reported studies, LVI may not be an independent prognostic variable in patients with localized RCC.

Katz, S. M., M. Liebert, et al. (1982). "Nonmajor histocompatibility complex genes in allograft rejection." Curr Surg 39(6): 414-417.

Katz, S. M., M. Liebert, et al. (1983). "The relative roles of MHC and non-MHC genes in heart and skin allograft survival." Transplantation 36(1): 96-101.

Although the role of the major histocompatibility complex (MHC) of the rat (RT1) in graft rejection has been established, the role of non-RT1 genes is not well understood. To investigate the influence of MHC and non-MHC genes in graft rejection, various combinations of congenic and inbred strains of rats were used as donors and recipients of skin grafts and perfused abdominal heart grafts. In addition, hemagglutinating and cytotoxic antibody responses were evaluated to assess loci that were serologically active in transplantation. Our results demonstrate that: (1) RT1 antigens are the most important determinant in heart and skin rejection; (2) antigens controlled by non-MHC genes also play a major role in rejection because they cause disparate heart grafts to be rejected by day 18 and skin grafts by day 26; (3) RT2 cell antigens alone do not cause graft rejection; and (4) allogeneic differences at the RT1, RT2, RT3, and RT6 loci elicit an antibody response in heart transplantation.

Kauffman, H. M., M. A. McBride, et al. (1997). "United Network for Organ Sharing Donor Data Update, 1988-1995." Transplantation Proceedings 29(1-2): 122-124.

Kauffman, H. M., M. A. McBride, et al. (1997). "Trends in organ donation, recovery and disposition: UNOS data for 1988-1996." Transplantation Proceedings 29(8): 3303-3304.

Kauffman, H. M., M. A. McBride, et al. (1999). "Determinants of waiting time for heart transplants in the United States. [erratum appears in J Heart Lung Transplant 1999 Jul;18(7):733.]." Journal of Heart & Lung Transplantation 18(5): 414-419.

BACKGROUND: Reports have been published on factors affecting the variations in waiting times for kidney and liver transplant candidates who have been registered on the United Network for Organ Sharing's waiting list. This study reports on determinants of waiting time differences that occur in the eleven UNOS regions for heart transplant candidates. METHODS: Retrospective analysis of 11,345 primary heart waiting-list registrations and 15,868 cadaveric donors, from whom 7,043 hearts were recovered and transplanted for the years 1994-96. Because estimated populations in the eleven UNOS regions vary from 10.8 to 43.2 million, analyses utilized Registrations/million population and Transplants/million population to obtain an R/T ratio. The relationship of the R/T ratio to the median waiting time was then examined for different demographic variables. RESULTS: The numbers of new heart candidate registrations, heart transplants performed, and waiting list deaths have undergone little change from 1991 through 1996. National median waiting times varied by basic demographic variables such as ABO blood type, race, age group, and UNOS medical urgency status. In the eleven UNOS regions, registrations per million ranged from 11.5 to 33.0 and transplants per million from 5.3 to 10.7. Registration/Transplant ratios correlated with median waiting times for urgency Status 1 and 2 as well as for blood group O recipients. Correlation with blood type AB recipients was less consistent, in part, due to the small number of AB recipients. CONCLUSIONS: There are wide variations in the number of heart transplant candidate registrations and in the number of heart transplants performed in the eleven UNOS regions. The registration to transplantation ratio correlated with median waiting times in these regions. Factors possibly contributing to the observed variations were examined. <14>

Kaufman, A. M., M. L. Ritchey, et al. (1996). "Decreased bladder compliance in patients with myelomeningocele treated with radiological observation." J Urol 156(6): 2031-2033.

PURPOSE: Recently others advocated frequent radiological surveillance to detect upper urinary tract deterioration in children with neurogenic bladder secondary to spina bifida. We reviewed the consequences of such expectant management on bladder compliance and urinary continence. MATERIALS AND METHODS: We retrospectively reviewed the records of 214 children presenting to our spina bifida clinic in a 13-year period. Follow-up is available for 95 girls and 86 boys. Imaging studies of the kidneys were repeated at 6 to 12-month intervals. Urodynamics were performed when upper urinary tracts deteriorated or in incontinent school age children. RESULTS: On radiographic study there was evidence of upper urinary tract deterioration in 79 children, including hydronephrosis in 34, hydronephrosis and vesicoureteral reflux in 19, and reflux only in 26. Follow up studies performed after clean intermittent catheterization and pharmacological therapy were instituted revealed resolution or improvement of upper tract deterioration in 52 patients (69%), while bladder compliance improved in only 42%. Surgical intervention was required in 34 children, despite improvement of upper tract changes in many of these patients on follow up radiographic studies. CONCLUSIONS: Although radiological surveillance of patients with myelomeningocele allows recognition of upper tract changes, the effects of elevated outlet resistance on bladder compliance are not as readily reversible as the initial radiographic findings. The incidence of enterocystoplasty exceeds that reported for patients treated prospectively based on urodynamic findings, which should be considered in the treatment of these children.

Kaufman, J. M., E. J. McGuire, et al. (1974). "Viscus perforation: unusual complication of ureteroneocystostomy." Urology 4(6): 728-730.

Kawachi, M. H., R. R. Bahnson, et al. (2010). "NCCN clinical practice guidelines in oncology: prostate cancer early detection." J Natl Compr Canc Netw 8(2): 240-262.

Kawachi, M. H., R. R. Bahnson, et al. (2007). "Prostate cancer early detection. Clinical practice guidelines in oncology." J Natl Compr Canc Netw 5(7): 714-736.

Keller, E. T. (1990). "Elevated trypsin-like immunoreactivity in a dog with exocrine pancreatic insufficiency and chronic pancreatitis." J Am Vet Med Assoc 196: 623-626.

Keller, E. T. (1990). "Gene therapy for the dog." Veterinary Cancer Society Newsletter 18(1): 10-11.

Keller, E. T. (1990). "Testing for exocrine pancreatic insufficiency in cats." J Am Vet Med Assoc 197(9): 1112-1113, 1116.

Keller, E. T. (1992). "Immune-mediated disease as a risk factor for canine lymphoma." Cancer 70(9): 2334-2337.

BACKGROUND: Autoimmune diseases and neoplasia have been associated as occurring simultaneously in individuals. This study evaluated the association between the simultaneous occurrence of canine lymphoma and various immune-mediated diseases. METHODS: The Veterinary Medical Data Program, a national disease data registry for veterinary schools, was examined. The following immune-mediated disease categories were evaluated: lupus disorders, pemphigus disorders, autoimmune polyarthritis, immune-mediated hemolytic anemia, and immune-mediated thrombocytopenia. Odds ratios with 99% confidence intervals were calculated for the occurrence of lymphoma and each of the immune-mediated disorder categories. RESULTS: Only dogs with immune-mediated thrombocytopenia had a statistically significantly increased odds ratio (5.61; 99% confidence interval, 4.16-7.57) for the occurrence of lymphoma versus the general population. This association still was observed for immune-mediated thrombocytopenia when stratified by age, sex, and neutering status. CONCLUSION: Dogs with immune-mediated thrombocytopenia had a greater occurrence of lymphoma than dogs without immune-mediated thrombocytopenia.

Keller, E. T. (1997). "Of mice and women." Trends Endocrinol Metab 8: 327-328.

Keller, E. T. (2002). "Overview of metastasis and metastases." J Musculoskelet Neuronal Interact 2(6): 567-569.

Keller, E. T. (2002). "The role of osteoclastic activity in prostate cancer skeletal metastases." Drugs Today (Barc) 38(2): 91-102.

Metastasis of prostate cancer to bone is a common complication of progressive prostate cancer. Skeletal metastases are often associated with severe pain and thus demand therapeutic interventions. Although often characterized as osteoblastic, prostate cancer skeletal metastases usually have an underlying osteoclastic component. Advances in osteoclast biology and pathophysiology have led toward defining putative therapeutic targets to attack tumor-induced osteolysis. Several factors have been found to be important in tumor-induced promotion of osteoclast activity. One key factor is the protein receptor activator of nuclear factor-kappa B ligand (RANKL), which is required to induce osteoclastogenesis. RANKL is produced by prostate cancer bone metastases, enabling these metastases to induce osteolysis through osteoclast activation. Another factor, osteoprotegerin, is a soluble decoy receptor for RANKL and inhibits RANKL-induced osteoclastogenesis. Osteoprotegerin has been shown in murine models to inhibit tumor-induced osteolysis. In addition to RANKL, parathyroid hormone-related protein and interleukin-6 are produced by prostate cancer cells and can promote osteoclastogenesis. Finally, matrix metalloproteinases (MMPs) are secreted by prostate cancer cells and promote osteolysis primarily through degradation of the nonmineralized bone matrix. MMP inhibitors have been shown to diminish tumor establishment in bone in murine models. Thus, many factors derived from prostate cancer metastases can promote osteolysis, and these factors may serve as therapeutic targets. The importance of osteoclasts in the establishment and progression of skeletal metastases has led to clinical evaluation of therapeutic agents to target them for slowing metastatic progression. Bisphosphonates are a class of compounds that decrease osteoclast life span by promoting their apoptosis. The bisphosphonate pamidronate has proven clinical efficacy for relieving bone pain associated with breast cancer metastases and has a promising outlook for prostate cancer metastases. Another bisphosphonate, zoledronic acid, appears to directly target prostate cancer cells in addition to diminishing osteoclast activity at the metastatic site. In addition to bisphosphonates, other novel therapies based on studies that delineate mechanisms of skeletal metastases establishment and progression will be developed in the near future.

Keller, E. T. (2004). "Metastasis suppressor genes: a role for raf kinase inhibitor protein (RKIP)." Anticancer Drugs 15(7): 663-669.

The metastatic cascade is a complicated process that involves many steps from gain of the metastatic phenotype in the primary tumor cells through establishment of macroscopic tumor at the distant target organ. A group of genes, termed metastasis suppressor genes (MSG), encode for proteins that inhibit various steps of the metastatic cascade. Accordingly, loss of MSG promotes the metastatic phenotype. Although several MSG have been identified, the mechanisms through which they enhance metastasis are not clearly defined. Gene array analysis of a low metastatic LNCaP prostate cancer cell line compared to its highly metastatic derivative C4-2B prostate cancer cell line revealed decreased expression of raf kinase inhibitor protein (RKIP) in the C4-2B cell line. RKIP blocks the activation of several signaling pathways including MEK, G-proteins and NFkappaB. Immunohistochemical analysis of prostate cancer primary tumors and metastases revealed that RKIP protein expression was decreased in metastases. Restoration of RKIP expression in the C4-2B cell line diminished metastasis in a murine model. These results demonstrate that RKIP is a MSG. Loss of RKIP enhanced both angiogenesis and vascular invasion, and protected against apoptosis. These findings suggest that targeting the RKIP pathway may diminish the metastatic cascade. However, challenges exist as to the best method to target RKIP expression. Restoration of RKIP expression in all cancer cells in vivo is challenging. A plausible strategy is to use small molecules that target proteins in signaling pathways that are dysregulated due to loss of RKIP.

Keller, E. T. (2004). "Signal Transduction Pathways as Therapeutic Targets. 25-28 January 2004, Luxembourg." IDrugs 7(3): 217-222.

The Signal Transduction Pathways as Therapeutic Targets meeting was attended by approximately 400 participants from a wide spectrum of backgrounds, including basic scientists, pharmaceutical scientists and postdoctoral fellows from many fields. The overall focus of the meeting was on the role that signal transduction plays in biology and pathophysiology and the design of compounds that can modulate these pathways. This report describes several signaling pathways that are potential targets for inflammation and cancer, including those that involve the following signaling molecules: Jun N-terminal kinase, cyclin-dependent kinases, hypoxia-inducible factor, p21-activated kinases, MEK kinase 1, phosphoinositide 3-kinases, myc, p53, Smad, hedgehog, nuclear factor-kB and G protein. This report also describes various compounds as potential anti-inflammatory or anticancer agents.

Keller, E. T., N. C. Binkley, et al. (2000). "Ovariectomy does not induce osteopenia through interleukin-6 in rhesus monkeys (Macaca mulatta)." Bone 26(1): 55-62.

To characterize the role of interleukin-6 (IL-6) in estrogen (E2)-depletion bone loss, we utilized a nonhuman primate model of human skeletal physiology. Adult female rhesus monkeys were sham-operated (S; n = 5), ovariectomized (ovx; n = 10), or ovx followed by E2 replacement (ovx + E2; n = 10) and evaluated for the indicated parameters at 0, 3, 6, and 9 months post-ovx. Lumbar spine bone mineral density (BMD) decreased by 3 months and continued to decline through 9 months in the ovx, but not in the ovx + E2 or S groups. Middle and distal radius BMD was decreased at 9 months in the ovx, but not in the ovx + E2 or S groups. The S group had marked fluctuations in bone remodeling parameters, and cytokine levels in S animals were consistent with menstrual cycling, and therefore only those values in the ovx and ovx + E2 groups are reported. Serum osteocalcin and skeletal-specific alkaline phosphatase were elevated in the ovx group compared with the ovx + E2 group. There was no difference in serum or bone marrow plasma IL-6 levels between the ovx and ovx + E2 groups. Similarly, there was no difference in basal or phorbol ester-stimulated IL-6 levels of peripheral blood mononuclear cell or bone marrow cell culture supernatants between groups. There was no difference in serum or bone marrow soluble IL-6 receptor between groups. However, the bone marrow plasma soluble IL-6 receptor levels were transiently increased from baseline at 3 months in the ovx but not in the ovx + E2 group. In summary, there was no bone loss in the ovx + E2 group, although the serum and bone marrow IL-6 levels were similar to those of the ovx group. These data suggest that modulation of IL-6 is not the key mechanism through which estrogen deprivation mediates bone loss in rhesus monkeys.

Keller, E. T. and J. Brown (2004). "Prostate cancer bone metastases promote both osteolytic and osteoblastic activity." J Cell Biochem 91(4): 718-729.

Advanced prostate cancer is frequently accompanied by the development of metastasis to bone. In the past, prostate cancer bone metastases were characterized as being osteoblastic (i.e., increasing bone density) based on radiographs. However, emerging evidence suggests that development of prostate cancer bone metastases requires osteoclastic activity in addition to osteoblastic activity. The complexities of how prostate tumor cells influence bone remodeling are just beginning to be elucidated. Prostate cancer cells produce a variety of pro-osteoblastic factors that promote bone mineralization. For example, both bone morphogenetic proteins and endothelin-1 have well recognized pro-osteoblastic activities and are produced by prostate cancer cells. In addition to factors that enhance bone mineralization prostate cancer cells produced factors that promote osteoclast activity. Perhaps the most critical pro-osteoclastogenic factor produced by prostate cancer cells is receptor activator of NFkappaB ligand (RANKL), which has been shown to be required for the development of osteoclasts. Blocking RANKL results in inhibiting prostate cancer-induced osteoclastogenesis and inhibits development and progression of prostate tumor growth in bone. These findings suggest that targeting osteoclast activity may be of therapeutic benefit. However, it remains to be defined how prostate cancer cells synchronize the combination of osteoclastic and osteoblastic activity. We propose that as the bone microenvironment is changed by the developing cancer, this in turn influences the prostate cancer cells' balance between pro-osteoclastic and pro-osteoblastic activity. Accordingly, the determination of how the prostate cancer cells and bone microenvironment crosstalk are important to elucidate how prostate cancer cells modulate bone remodeling.

Keller, E. T. and J. M. Brown (2003). "Osteoprotegerin (OPG), receptor activator of NFκB ligand (RANKL) and RANK in cancer metastasis." Research Advances in Cancer 3: 81-93.

Keller, E. T., J. K. Burkholder, et al. (1996). "In vivo particle-mediated cytokine gene transfer into canine oral mucosa and epidermis." Cancer Gene Ther 3(3): 186-191.

Cytokines can stimulate immune effector cells present within the oral mucosa and epidermis to respond to vaccination or to combat cancer. However, intravenous cytokine delivery is often inefficient and frequently accompanied by systemic toxicity. The goal of this study was to evaluate dogs as a large animal model for gene therapy of cancer because they develop spontaneous oral and epidermal tumors. In this report, we demonstrate that particle-mediated gene transfer of beta-galactosidase, luciferase, interleukin-2, interleukin-6, and granulocyte-macrophage colony stimulating factor (GM-CSF) complementary DNA (cDNA) into the oral mucosa and epidermis of healthy dogs resulted in effective, localized, transgenic protein expression. Additionally, the epidermal sites transfected with GM-CSF developed a profound inflammatory reaction characterized by neutrophilic infiltration. Clinical pathology analyses were unremarkable. These results demonstrate that in vivo particle-mediated gene transfer of canine oral mucosa and epidermis with cytokine cDNA can result in production of biologically active transgenic cytokines with minimal toxicity. These findings have applications to cancer immunotherapy using a gene gun approach.

Keller, E. T., C. Chang, et al. (1996). "Inhibition of NFkappaB activity through maintenance of IkappaBalpha levels contributes to dihydrotestosterone-mediated repression of the interleukin-6 promoter." J Biol Chem 271(42): 26267-26275.

Androgens repress expression of many genes, yet the mechanism of this activity has remained elusive. The cytokine, interleukin-6, is active in a variety of biological systems, and its expression is repressed by androgens. Accordingly we dissected the mechanism of androgen's ability to inhibit interleukin-6 expression at the molecular level. In a series of co-transfection assays, we found that 5alpha-dihydrotestosterone, through the androgen receptor, repressed activation of the interleukin-6 promoter, in part, by inhibiting NFkappaB activity. It did not appear that 5alpha-dihydrotestosterone inhibited NFkappaB by activating the androgen receptor to compete for the NFkappaB response element as we could not detect androgen receptor binding to the IL-6 promoter by DNase I footprinting assay. However, by electrophoretic mobility shift assay we found that 5alpha-dihydrotestosterone repressed formation of NFkappaB middle dotNFkappaB response element complex formation. In LNCaP prostate carcinoma cells, 5alpha-dihydrotestosterone achieved this effect through maintenance of IkappaBalpha protein levels in the face of phorbol ester, a stimulus that results in IkappaBalpha degradation. Finally, we confirmed that IkappaBalpha inhibits NFkappaB-mediated activation of the interleukin-6 promoter. These data suggest that maintenance of IkappaBalpha levels may represent the first identified mechanism for androgen-mediated repression of a natural androgen-regulated gene.

Keller, E. T., J. Dai, et al. (2007). "New trends in the treatment of bone metastasis." J Cell Biochem 102(5): 1095-1102.

Bone metastasis is often the penultimate harbinger of death for many cancer patients. Bone metastases are often associated with fractures and severe pain resulting in decreased quality of life. Accordingly, effective therapies to inhibit the development or progression of bone metastases will have important clinical benefits. To achieve this goal understanding the mechanisms through which bone metastases develop and progress may provide targets to inhibit the metastases. In the past few years, there have been advances in both understanding the mechanisms through which bone metastases develop and how they impact bone remodeling. Additionally, gains in promising clinical strategies to target bone metastases have been developed. In this prospectus, we will discuss some of these advances.

Keller, E. T. and W. B. Ershler (1995). "Effect of IL-6 receptor antisense oligodeoxynucleotide on in vitro proliferation of myeloma cells." J Immunol 154(8): 4091-4098.

IL-6 stimulates proliferation of various tumors, including lymphoma and myeloma; thus, inhibiting IL-6 may decrease the growth of these tumors. Accordingly, we examined the effect of IL-6 and IL-6R antisense phosphorothioated oligodeoxynucleotides (ODNs) on proliferation of IL-6 responsive (U266) and nonresponsive (RPMI 8226) myeloma cell lines. Cells were grown in the presence or absence of IL-6, with added antisense to either IL-6 or IL-6R. Cells were evaluated for proliferation ([3H]thymidine uptake) and steady state levels of both IL-6 and IL-6R mRNA by competitive PCR (C-PCR). Proliferation of U266 cells was decreased markedly by IL-6 antisense ODN in the absence of IL-6, but not in its presence. In contrast, IL-6R antisense ODN inhibited proliferation of U266 cells in both the presence and absence of IL-6. As anticipated, neither IL-6 nor IL-6R antisense ODN had an effect on RPMI 8226 proliferation. C-PCR demonstrated a marked and specific decrease of IL-6 and IL-6R mRNA in cells exposed to IL-6 ODN and IL-6R ODN, respectively. These results suggest that IL-6R antisense ODN may be a more effective inhibitor of IL-6-stimulated cells than IL-6 antisense in a therapeutic setting.

Keller, E. T., W. B. Ershler, et al. (1996). "The androgen receptor: a mediator of diverse responses." Front Biosci 1: d59-71.

Androgens mediate a number of diverse responses through the androgen receptor, a 110 kD ligand-activated nuclear receptor. Androgen receptor expression, which is found in a variety of tissues, changes throughout development, aging, and malignant transformation. The androgen receptor can be activated by two ligands, testosterone and dihydrotestosterone, which bind to the androgen receptor with different affinities. This difference in binding affinity results in different levels of activation of the androgen receptor by the two ligands. The androgen receptor acts as a transcriptional modifier of a variety of genes by binding to an androgen response element. The ability to confer androgen specific actions by the androgen response element may depend on other cell-specific transcription factors and cis-acting DNA elements in close proximity to it. Testosterone and dihydrotestosterone appear to act upon an identical nuclear receptor. However, in certain instances, they mediate different physiologic responses. For example, dihydrotestosterone, but not testosterone, is capable of mediating full sexual development of the male external genitalia. In some cases, the androgen receptor may induce opposite physiologic responses in similar tissue types depending on their location. For example, in male pattern baldness, activated androgen receptors may suppress the growth of distinct hair follicle populations through initiating stromal-epithelial actions, whereas other hair follicles continue to proliferate. In other cases, altered androgen receptor activity due to its mutation or altered expression may lead to pathology such as recurrence of prostate cancer due to development of androgen independence allowing tumor cell proliferation under androgen deprivation.

Keller, E. T. and Z. Fu (2004). "Defining RKIP as a protein that regulates prostate cancer metastasis." Urology Rev 2: 72-80.

Keller, E. T., Z. Fu, et al. (2004). "The role of Raf kinase inhibitor protein (RKIP) in health and disease." Biochem Pharmacol 68(6): 1049-1053.

Raf kinase inhibitor protein (RKIP) is a member of the phosphatidylethanolamine-binding protein (PEBP) family. RKIP plays a pivotal modulatory role in several protein kinase signaling cascades. RKIP binds inhibits Raf-1-mediated phosphorylation of MEK through binding to Raf-1. Protein kinase C (PKC) phosphorylates RKIP, resulting in release of Raf-1 and activation of MEK and ERK. The phosphorylated RKIP binds to and inhibits G-protein-coupled receptor kinase, resulting in sustained G-protein signaling. The regulatory role that RKIP has in cell signaling is reflected in its role in physiology and pathophysiology. RKIP is involved in neural development, cardiac function and spermatogenesis and appears to have serine protease activity. In addition to its roles in physiology, dysregulated RKIP expression has the potential to contribute to pathophysiological processes including Alzheimer's disease and diabetic nephropathy. RKIP has been shown to fit the criteria of being a metastasis suppressor gene, including having decreased expression in prostate cancer metastases and restoring RKIP expression in a prostate cancer cell line diminishes metastasis in a murine model. Clearly, RKIP has multiple molecular and cellular functions. In this review, RKIP's molecular roles in intracellular signaling, its physiological functions and its role in disease are described.

Keller, E. T., Z. Fu, et al. (2005). "The biology of a prostate cancer metastasis suppressor protein: Raf kinase inhibitor protein." J Cell Biochem 94(2): 273-278.

Raf kinase inhibitor protein (RKIP) was originally identified as a protein that bound membrane phospholipids and was named phosphatidylethanolamine binding protein-2 (PEBP-2). RKIP was than identified as a protein that bound Raf and blocked its ability to phosphorylate MEK, thus earning its new name of RKIP. Subsequent to identification of its role in the Raf:MEK pathway, RKIP has been demonstrated to regulate several other signaling pathways including G-protein signaling and NF-kappaB signaling. Its involvement in several signaling pathways has engendered RKIP to contribute to several physiological processes including membrane biosynthesis, spermatogenesis, neural development, and apoptosis. RKIP is expressed in many tissues including brain, lung, and liver and thus, dysregulation of RKIP expression or function has potential to contribute to pathophysiology in these tissues. Loss of RKIP expression in prostate cancer cells confers a metastatic phenotype on them. Additionally, restoration of RKIP expression in a metastatic prostate cancer cell line does not effect primary tumor growth, but it does inhibit prostate cancer metastasis. These parameters identify RKIP as a metastasis suppressor gene. In this review, the biology and pathophysiology of RKIP is described.

Keller, E. T., Z. Fu, et al. (2004). "Raf kinase inhibitor protein: a prostate cancer metastasis suppressor gene." Cancer Lett 207(2): 131-137.

Defining the mechanisms that confer metastatic ability on cancer cells is an important goal towards prevention of metastasis. A gene array screen between a non-metastatic prostate cancer cell and its metastatic derivative line revealed decreased expression of Raf kinase inhibitor protein (RKIP) in the metastatic cell line. This finding is consistent with the possibility that loss of RKIP is associated with metastasis. RKIP is expressed in many tissues including brain, lung, and liver. RKIP blocks Raf-induced phosphorylation of MEK. In addition to its modulation of Raf signaling, RKIP modulates both G-protein signaling and NF-kappaB activity. The impact that RKIP has on multiple signaling pathways grants it the ability to play a role in several cellular functions including membrane biosynthesis, spermatogenesis, and neural signaling. Novel cellular functions for RKIP continue to be identified, several of which contribute to cancer biology. For example, RKIP promotes apoptosis of cancer cells, which suggests that loss of RKIP in cancer will protect cancer cells against cell death. Additionally, restoration of RKIP expression ina metastatic prostate cancer cell line does not effect primary tumor growth, but it does inhibit prostate cancer metastasis. These parameters identify RKIP as a metastasis suppressor gene, which suggest that it or proteins it interacts with are putative molecular targets to control metastasis. These findings are supported by the observation that RKIP expression is decreased in metastases of prostate cancer patients, compared to normal prostate or the primary prostate tumor. In this review, RKIP biology and its role in cancer will be described.

Keller, E. T., C. Hall, et al. (2004). "Biomarkers of growth, differentiation, and metastasis of prostate epithelium." J Clin Lig Assay 27(2): 133-136.

Keller, E. T., E. G. MacEwen, et al. (1993). "Evaluation of prognostic factors and sequential combination chemotherapy with doxorubicin for canine lymphoma." J Vet Intern Med 7(5): 289-295.

Fifty-five dogs with lymphoma were treated using a doxorubicin-based sequential combination chemotherapy protocol. Complete response, partial response, and no response were seen in 46, 4, and 5 dogs, respectively. The overall median remission duration and survival times were 36 and 51 weeks, respectively. Age, sex, weight, World Health Organization stage, World Health Organization substage (i.e., a = not ill, b = ill), serum calcium concentration, blood urea nitrogen concentration, breed and protocol alteration secondary to toxicity were evaluated for prognostic significance. Univariate analysis of prognostic factors identified sex, World Health Organization substage, and serum calcium as statistically significant (P < or = .05) variables for both survival and remission duration. Upon multivariate analysis, only substage (P = .036) was a significant prognostic factor for remission duration, whereas, both substage (P = .006) and sex (P = .005) were significant prognostic factors for survival.

Keller, E. T. and B. R. Madewell (1992). "Locations and types of neoplasms in immature dogs: 69 cases (1964-1989)." J Am Vet Med Assoc 200(10): 1530-1532.

Sites, histologic types, and frequencies of neoplasms in immature dogs (less than or equal to 6 months old) were evaluated from data collected over 25 years. The frequencies of neoplasms in immature dogs were compared with those of mature dogs (greater than 6 months old). Of 69 immature dogs with neoplasms, 5 had 2 primary neoplasms each, resulting in a total of 74 neoplasms. The 3 most common sites for neoplasia, in decreasing order, were the hematopoietic system, brain, and skin. Immature dogs were 10.9 times more likely to have a neoplasm located in the brain, compared with mature dogs. Immature dogs also were 3.3 times more likely to have a neoplasm associated with the hematopoietic system, compared with mature dogs.

Keller, E. T. and J. M. Murtha (2004). "The use of mature zebrafish (Danio rerio) as a model for human aging and disease." Comp Biochem Physiol C Toxicol Pharmacol 138(3): 335-341.

Zebrafish (Danio rerio) have been extensively utilized for understanding mechanisms of development. These studies have led to a wealth of resources including genetic tools, informational databases, and husbandry methods. In spite of all these resources, zebrafish have been underutilized for exploring pathophysiology of disease and the aging process. Zebrafish offer several advantages over mammalian models for these studies, including the ability to perform saturation mutagenesis and the capability to contain thousands of animals in a small space. In this review, we will discuss the use of mature zebrafish as an animal model and provide specific examples to support this novel use of zebrafish. Examples include demonstrating that clinical pathology can be performed in mature zebrafish and that age-associated changes in heat shock response can be observed in zebrafish. These highlights demonstrate the utility of zebrafish as a model for disease and aging.

Keller, E. T., T. D. Pugh, et al. (1996). "Evaluation of ovariectomy and dehydro-epiandrosterone sulfate administration on interleukin-6 levels and B16 melanoma growth in mice." Age 19: 75-81.

Keller, E. T., D. R. Rowley, et al. (2007). "Eleventh Prouts Neck Meeting on Prostate Cancer: emerging strategies in prostate cancer therapy." Cancer Res 67(20): 9613-9615.

Keller, E. T. and D. M. Vail (1992). "Intrapleural administration of cisplatin (DDP) for treatment of pleural neoplasia." J Vet Intern Med 6(3): 198-199.

Keller, E. T., J. Wanagat, et al. (1996). "Molecular and cellular biology of interleukin-6 and its receptor." Front Biosci 1: d340-357.

Interleukin-6 (IL-6) is a member of the family of cytokines collectively termed "the interleukin-6 type cytokines." Among its many functions, IL-6 plays an active role in immunology, bone metabolism, reproduction, arthritis, neoplasia, and aging. IL-6 expression is regulated by a variety of factors, including steroidal hormones, at both the transcriptional and post-transcriptional levels. IL-6 achieves its effects through the ligand-specific IL-6 receptor (IL-6R). Unlike most other cytokine receptors, the IL-6R is active in both membrane bound and soluble forms. Defining mechanisms to control IL-6 or IL-6R expression may prove useful for therapy of the many clinical disorders in IL-6 plays a role.

Keller, E. T. and Z. Yao (2002). "Applications of high-throughput methods to cancer metastases." J Musculoskelet Neuronal Interact 2(6): 575-578.

Keller, E. T., J. Zhang, et al. (2001). "Prostate carcinoma skeletal metastases: cross-talk between tumor and bone." Cancer Metastasis Rev 20(3-4): 333-349.

The majority of men with progressive prostate cancer develop metastases with the skeleton being the most prevalent metastatic site. Unlike many other tumors that metastasize to bone and form osteolytic lesions, prostate carcinomas form osteoblastic lesions. However, histological evaluation of these lesions reveals the presence of underlying osteoclastic activity. These lesions are painful, resulting in diminished quality of life of the patient. There is emerging evidence that prostate carcinomas establish and thrive in the skeleton due to cross-talk between the bone microenvironment and tumor cells. Bone provides chemotactic factors, adhesion factors, and growth factors that allow the prostate carcinoma cells to target and proliferate in the skeleton. The prostate carcinoma cells reciprocate through production of osteoblastic and osteolytic factors that modulate bone remodeling. The prostate carcinoma-induced osteolysis promotes release of the many growth factors within the bone extracellular matrix thus further enhancing the progression of the metastases. This review focuses on the interaction between the bone and the prostate carcinoma cells that allow for development and progression of prostate carcinoma skeletal metastases.

Keller, E. T., J. Zhang, et al. (1997). "Ethanol activates the interleukin-6 promoter in a human bone marrow stromal cell line." J Gerontol A Biol Sci Med Sci 52(6): B311-317.

Chronic ethanol consumption is associated with the development of osteoporosis. The pro-inflammatory cytokine interleukin-6 (IL-6) plays a role in the development of osteoporosis through stimulation of osteoclastic activity. We hypothesized that ethanol promotes osteoporosis, in part, by increasing IL-6 production in the bone microenvironment. Accordingly, we evaluated ethanol's effect on IL-6 production in the Saka human bone marrow stromal cell line and in the HOBIT human osteoblast-like cell line. We found that ethanol increased IL-6 protein levels in the culture supernatants from Saka, but not HOBIT, cells. In addition, we observed that ethanol increased steady-state IL-6 mRNA levels and activated an IL-6 promoter-driven reporter vector in Saka cells. We conclude that ethanol stimulates IL-6 expression in the Saka bone marrow stromal cell line by enhancing transcriptional activity of the IL-6 gene. Our findings support the contention that ethanol may contribute to the pathogenesis of osteoporosis, in part, by increasing IL-6 expression in the bone microenvironment.

Keller, E. T., J. Zhang, et al. (2001). "The impact of chronic estrogen deprivation on immunologic parameters in the ovariectomized rhesus monkey (Macaca mulatta) model of menopause." J Reprod Immunol 50(1): 41-55.

A large clinical literature suggests that estradiol (E(2)) plays a critical role in immune function. To further explore the relationship between E(2) and immune function, we examined a variety of immunological parameters in a rhesus monkey model of menopause and hormone replacement therapy. Rhesus monkeys (Age, 13.7+/-2.6 years) were ovariectomized and received either sham (n=10) or estradiol (n=10) replacement implants. Nine months post-ovariectomy, a variety of immunologic parameters were measured. E(2)-deprivation reduced natural killer cell activity and increased serum soluble gp130 levels. There was a trend for an increased proportion of CD8(+) (P=0.12) and HLA-DR(+)CD3(+) cells (P=0.15) and decreased proportion of eosinophils (P=0.11) in the E(2)-deprived monkeys. There was no difference in leukocyte distribution, CD28, CD56, CD4, CD8/CD45, colony forming units-granulocyte/monocytes formation, peripheral blood mononuclear cell apoptotic rate, or serum TNF, TNF-R1, TNF-R2, IL-6, soluble IL-6R, and IL-1 between the groups. These data demonstrate that E(2)-deprivation affects several aspects of immune function. These findings may have implications for menopause-associated changes of immune function that occur in women.

Keller, J. M., J. F. Escara-Wilke, et al. (2008). "Heat stress-induced heat shock protein 70 expression is dependent on ERK activation in zebrafish (Danio rerio) cells." Comp Biochem Physiol A Mol Integr Physiol 150(3): 307-314.

Heat shock response is a common event that occurs in many species. Despite its evolutionary conservation, comparative studies of heat shock response have been largely unexplored. In mammals, heat shock response decreases with age through unclear mechanisms. Understanding how the age-related decline in heat shock response occurs may provide information to understanding the biology of aging. We have previously shown that heat shock response similarly declines with age in zebrafish. However, signaling pathways that regulate the heat shock response in zebrafish are unknown. In mammals there is evidence that mitogen-activated protein kinases (MAPKs) of the ERK family alter Hsp70 transcription, serving as a potential regulator of the heat shock response. We explored if heat stress-induced Hsp70 expression is altered by activation of ERK in the zebrafish Pac2 fibroblast cell line as occurs in mammalian cells. Heat stress induced both Hsp70 mRNA expression and phosphorylation of both ERK1 and ERK2 (ERK1/2) in Pac2 cells. ERK inhibitors PD98059 and U0126 blocked both heat stress-induced and plated-derived growth factor (PDGF)-induced ERK1/2 phosphorylation, and also diminished heat-induced Hsp70 expression. Pac2 cell viability was not affected by either the ERK inhibitors or heat stress. These results demonstrate that induction of Hsp70 in response to heat stress is dependent on ERK activation in Pac2 cells. This suggests that the heat shock response in zebrafish utilizes a similar signaling pathway to that of mammals and that zebrafish are a good model for comparative studies of heat shock response.

Kennelly, M. J., D. A. Bloom, et al. (1995). "Outcome analysis of bilateral Cohen cross-trigonal ureteroneocystostomy." Urology 46(3): 393-395.

OBJECTIVES. The perioperative and long-term outcomes of children with vesicoureteral reflux (VUR) treated by cross-trigonal ureteroneocystostomy were ascertained. METHODS. One hundred ten consecutive children with VUR who underwent bilateral cross-trigonal ureteroneocystostomy were studied retrospectively. Nineteen children with neurovesical dysfunction or megaureters requiring tapered reimplants were excluded. Outcome parameters of the remaining 91 children consisted of operative time, length of hospitalization, days of Foley catheter drainage perioperative complications, correction of reflux, subsequent morbidity, and parental satisfaction. RESULTS. Of 182 renal units, 11 (6%) had grade 0 VUR, 18 (10%) had grade I, 43 (24%) had grade II, 59 (32%) had grade III, 36 (20%) had grade IV, and 15 (8%) had grade V reflux. The mean operative and hospitalization times were 180 minutes and 5.6 days, respectively. No postoperative complications occurred. Three children were lost to follow-up, and the remaining 88 children had an extended mean follow-up in excess of 3 years. Voiding cystourethrogram documented a 98.3% (173 of 176 renal units) success rate. Sixteen children (18%) experienced nonfebrile clinically symptomatic cystitis episodes and 3 children (3%) experienced one febrile episode each. Telephone parental survey of overall surgical experience revealed a 94% very satisfied, 2% satisfied, and 3% dissatisified rate. CONCLUSIONS. Cross-trigonal ureteroneocystostomy is a safe and effective technique that is virtually complication free and has high parental satisfaction. The results of this study provide a baseline for comparison of non-operative treatment of reflux as well as laparoscopic and endoscopic techniques.

Kennelly, M. J., E. A. Gormley, et al. (1994). "Early clinical experience with adult bladder auto-augmentation." J Urol 152(2 Pt 1): 303-306.

Five patients 18 to 73 years old underwent auto-augmentation for a small capacity, poorly compliant bladder. The mean operative time and hospital stay were 106 minutes and 6 days, respectively. No postoperative complications occurred. Followup ranged from 12 to 82 weeks. Bladder capacity increased from 75 to 310 cc or 40 to 310%. Compliance also improved in all patients. Three patients had reflux preoperatively, which resolved in 1 and improved in 2. Of 4 patients who were incontinent preoperatively 3 became continent postoperatively and extended the interval between catheterizations. Upper tract function has remained stable. No patient required enterocystoplasty to control bladder pressures.

Kent, E., H. Sandler, et al. (2004). "Combined-modality therapy with gemcitabine and radiotherapy as a bladder preservation strategy: results of a phase I trial." J Clin Oncol 22(13): 2540-2545.

PURPOSE: We conducted a phase I trial of gemcitabine given twice weekly with concurrent radiotherapy in patients with muscle-invasive bladder cancer. PATIENTS AND METHODS: Eligible patients underwent maximal transurethral resection of their bladder tumors followed by twice-weekly infusion of gemcitabine with 2 Gy/d concurrent radiotherapy to the bladder, for a total of 60 Gy over 6 weeks. The starting dose of gemcitabine was 10 mg/m(2) with subsequent dose levels of 20, 27, 30, and 33 mg/m(2). The primary end point was the determination of the maximum-tolerated dose (MTD) of twice weekly gemcitabine with concurrent radiotherapy. Secondary end points included assessment of toxicity associated with combined-modality therapy and initial assessment of the rate of bladder preservation. RESULTS: Twenty-four patients were enrolled and 23 were assessable for toxicity and response. No significant toxicity was demonstrated at the 10 or 20 mg/m(2) twice-weekly doses. Dose-limiting toxicity (DLT) occurred in two of three patients treated at 33 mg/m(2). Intermediate dose levels of 27 and 30 mg/m(2) were then evaluated. The MTD of gemcitabine was 27 mg/m(2). The DLT was systemic, manifested as an elevation in liver function tests, malaise, and edema. Fifteen of 23 patients (65%) are alive with bladders intact and no evidence of recurrent disease at a median follow-up of 43 months. CONCLUSION: Twice-weekly gemcitabine with concurrent radiotherapy at 2 Gy/d to a total dose of 60 Gy is well-tolerated. The MTD of gemcitabine is 27 mg/m(2). There is a high rate of bladder preservation in this selected group of patients.

Key, D., J. Wan, et al. (1990). "Urinary tract reconstruction: Applied urodynamics." Neurouro Urodyn 9: 509-519.

Key, D. W., D. A. Bloom, et al. (1992). "Low-dose DDAVP in nocturnal enuresis." Clin Pediatr (Phila) 31(5): 299-301.

A five-year experience with the vasopressin analogue desmopressin acetate (DDAVP) for nocturnal enuresis is described in 59 children. The initial starting dose of 5 micrograms at bedtime is lower than that reported in other series. Eighty-one percent of patients required 10 micrograms or less to achieve improvement or resolution of bedwetting.

Khaira, H., D. McLean, et al. (2005). "Spermatogonial stem cell isolation, storage, and transplantation." J Androl 26(4): 442-450.

Khaira, H. S., J. F. Platt, et al. (2003). "Helical computed tomography for identification of crossing vessels in ureteropelvic junction obstruction-comparison with operative findings." Urology 62(1): 35-39.

OBJECTIVES: To evaluate the use of contrast-enhanced helical computed tomography (HCT) scanning with three-dimensional reconstructions as a possible identifier of crossing vessels in ureteropelvic junction (UPJ) obstruction. Endoscopic treatment of UPJ obstruction has a success rate that approaches 90%. These results drop to 40% in the presence of crossing vessels. Unrecognized crossing vessels can also result in significant hemorrhage during endopyelotomy. The presence of crossing vessels is, for many, an indication for open or laparoscopic UPJ repair. Therefore, accurate preoperative imaging is crucial for appropriate treatment planning. METHODS: Our study population consisted of 18 patients evaluated and treated for UPJ obstruction at the University of Michigan Health System. These patients underwent routine contrast-enhanced preoperative HCT scanning before UPJ repair. A prior history of failed endoscopic treatment, patient preference, and HCT findings of crossing vessels were indications for open or laparoscopic repair. The imaging findings were compared with open findings during laparoscopic or open pyeloplasty. RESULTS: An HCT finding of the presence of crossing vessels was a significant positive predictor, with a value of 100%. The sensitivity in this population was 91% and the specificity was 100%. No difference was noted between the detection of arterial or venous crossing vessels. The positive predictive value was 100%, and the negative predictive value was 88%. CONCLUSIONS: HCT is an accurate predictor of the presence of crossing vessels in UPJ obstruction. Because crossing vessels may have a profound impact on treatment outcome, HCT can serve as an effective, noninvasive, preoperative screening tool.

Khaira, H. S., R. B. Shah, et al. (2005). "Laparoscopic and open surgical nephrectomy for xanthogranulomatous pyelonephritis." J Endourol 19(7): 813-817.

BACKGROUND AND PURPOSE: Xanthogranulomatous pyelonephritis (XGP) is a severe, chronic renal-parenchymal infection. Nephrectomy is the treatment of choice. Because of the renal and perirenal inflammatory changes that commonly accompany XGP, the laparoscopic approach is difficult. We compared our experience with laparoscopic and open surgical nephrectomy for XGP. PATIENTS AND METHODS: A retrospective chart review of all adult nephrectomy specimens with the pathologic diagnosis of XGP between January 1997 and May 2003 was performed. Preoperative presentation, operative details, and postoperative recovery and complications were included in the data collection. RESULTS: Three patients approached laparoscopically and eight patients approached with open surgery were found to have XGP on pathologic analysis. The disease was suspected preoperatively in all patients. Among the laparoscopically treated patients, there was 1 (33%) who suffered major complications; this was the only patient who required conversion to open surgery. Among the open-surgical group, there were 2 (22%) major and 3 (33%) minor complications. Postoperative hospitalization was longer in the open-surgical group (mean 13.7 v 4.7 days), and when the case of open conversion was excluded, narcotic use was less in the laparoscopy group. CONCLUSIONS: The treatment of some XGP cases with laparoscopic nephrectomy is a possible, albeit challenging, option. The incidences of intraoperative and postoperative complications were roughly equivalent in the laparoscopic and open-surgery patients in our study. If completed, laparoscopy appears to be associated with decreased postoperative morbidity. However, this may represent selection bias, and larger, prospective studies may better define the suspected benefit.

Khaira, H. S. and J. S. Wolf, Jr. (2004). "Intraoperative local anesthesia decreases postoperative parenteral opioid requirements for transperitoneal laparoscopic renal and adrenal surgery: a randomized, double-blind, placebo controlled investigation." J Urol 172(4 Pt 1): 1422-1426.

PURPOSE: To determine if local anesthesia decreases discomfort following laparoscopic upper retroperitoneal surgery, we performed a randomized, double-blind, placebo controlled study in which the port sites and hand assist incision were infiltrated with bupivacaine or placebo prior to surgery. MATERIALS AND METHODS: A total of 72 patients undergoing transperitoneal laparoscopic renal or adrenal surgery were randomly assigned to the treatment (0.5% bupivacaine) or placebo (0.9% normal saline) arm. Port and hand assist port sites were infiltrated at the outset of the procedure. Postoperative pain and opioid use were measured at consistent intervals. RESULTS: A total of 37 individuals were treated with placebo (standard laparoscopy [SL] in 15 and hand assisted laparoscopy [HALS] in 22) and 35 were treated with bupivacaine (SL in 16 and HALS in 19). Mean parenteral morphine equivalents use for the placebo vs bupivacaine groups were 29.6 vs 20.0 mg at 12 hours, 50.2 vs 34.5 mg at 24 hours and 57.1 vs 36.6 mg for the total hospital stay (all p <0.05). Parenteral opioid use was decreased in the bupivacaine group in the SL and HALS subgroups with a significant effect at 12 hours in the latter subgroup. On multivariate ANOVA bupivacaine use but not SL vs HALS was associated with decreased parenteral opioid use at all time points (p <0.05). CONCLUSIONS: At the outset of transperitoneal laparoscopic urological surgery in the upper retroperitoneum, port site and other incision infiltration with long acting local anesthesia decreases postoperative parenteral opioid requirements compared with placebo controls. The effect was seen with SL and HALS and it was greater than any effect of SL vs HALS.

Kiefer, J. A., R. L. Vessella, et al. (2004). "The effect of osteoprotegerin administration on the intra-tibial growth of the osteoblastic LuCaP 23.1 prostate cancer xenograft." Clin Exp Metastasis 21(5): 381-387.

Osteoprotegerin (OPG) plays a central role in controlling bone resorption. Exogenous administration of OPG has been shown to be effective in preventing osteolysis and limiting the growth of osteolytic metastasis. The objective of this study was to investigate the effects of OPG on osteoblastic prostate cancer (CaP) metastases in an animal model. LuCaP 23.1 cells were injected intra-tibially and Fc-OPG (6.0 mg/kg) was administered subcutaneously three times a week starting either 24 hours prior to cell injection (prevention regimen) or at 4 weeks post-injection (treatment regimen). Changes in bone mineral density at the tumor site were determined by dual x-ray absorptiometry. Tumor growth was monitored by evaluating serum prostate specific antigen (PSA). Fc-OPG did not inhibit establishment of osteoblastic bone lesions of LuCaP 23.1, but it decreased growth of the tumor cells, as determined by decreases in serum PSA levels of 73.0 +/- 44.3% (P < 0.001) and 78.3 +/- 25.3% (P < 0.001) under the treatment and prevention regimens, respectively, compared to the untreated tumor-bearing animals. Administration of Fc-OPG decreased the proliferative index by 35.0% (P = 0.1838) in the treatment group, and 75.2% (P = 0.0358) in the prevention group. The results of this study suggest a potential role for OPG in the treatment of established osteoblastic CaP bone metastases.

Kielb, S., R. L. Dunn, et al. (2001). "Assessment of early continence recovery after radical prostatectomy: patient reported symptoms and impairment." J Urol 166(3): 958-961.

PURPOSE: Patients considering radical prostatectomy often inquire as to when they can expect to regain urinary continence. However, there is a paucity of patient self-reported data regarding the recovery of continence during the initial 3 months after surgery. Our objectives were to assess urinary continence changes early in the postoperative period and determine which of 2 commonly used definitions of continence more closely relate to patient reported urinary impairment. MATERIALS AND METHODS: A prospective study of 90 men with clinically localized prostate cancer who selected radical prostatectomy as primary therapy was conducted. Repeated measures of urinary continence as defined by 1) total urinary control, 2) the use of 1 or 0 pads daily, and 3) small or no problem with urinary function were obtained with a brief survey preoperatively and postoperatively. RESULTS: At 56 days after removal of urethral catheters, the actuarial rates of urinary continence recovery based on definitions 1 to 3 were 43%, 84% and 82%, respectively. The use of definition 2 for continence resulted in a 1.9 times higher actuarial rate for continence recovery when compared to definition 1 at 56 days (p <0.001). However, strong agreement was observed between definitions 2 and 3 (kappa = 0.69). CONCLUSIONS: Urinary control is recovered in a significant proportion of men who undergo radical prostatectomy during the initial 3 months. Continence rates will vary significantly based on the use of alternative definitions. The clinical practice of asking patients how many pads daily they use may be valid, as it corresponds well to the impairment they have.

Kielb, S., R. L. Dunn, et al. (2001). "Assessment of early continence recovery after radical prostatectomy: patient reported symptoms and impairment. [see comments.]." Journal of Urology 166(3): 958-961.

PURPOSE: Patients considering radical prostatectomy often inquire as to when they can expect to regain urinary continence. However, there is a paucity of patient self-reported data regarding the recovery of continence during the initial 3 months after surgery. Our objectives were to assess urinary continence changes early in the postoperative period and determine which of 2 commonly used definitions of continence more closely relate to patient reported urinary impairment. MATERIALS AND METHODS: A prospective study of 90 men with clinically localized prostate cancer who selected radical prostatectomy as primary therapy was conducted. Repeated measures of urinary continence as defined by 1) total urinary control, 2) the use of 1 or 0 pads daily, and 3) small or no problem with urinary function were obtained with a brief survey preoperatively and postoperatively. RESULTS: At 56 days after removal of urethral catheters, the actuarial rates of urinary continence recovery based on definitions 1 to 3 were 43%, 84% and 82%, respectively. The use of definition 2 for continence resulted in a 1.9 times higher actuarial rate for continence recovery when compared to definition 1 at 56 days (p <0.001). However, strong agreement was observed between definitions 2 and 3 (kappa = 0.69). CONCLUSIONS: Urinary control is recovered in a significant proportion of men who undergo radical prostatectomy during the initial 3 months. Continence rates will vary significantly based on the use of alternative definitions. The clinical practice of asking patients how many pads daily they use may be valid, as it corresponds well to the impairment they have. <27>

Kielb, S., H. P. Koo, et al. (2000). "Nephrolithiasis associated with the ketogenic diet." J Urol 164(2): 464-466.

PURPOSE: The ketogenic diet has been used for treating seizure disorders for more than 70 years. Nephrolithiasis is a known complication of this diet with a reported stone rate as high as 10% but there is sparse literature detailing the nature and treatment of these stones. We report on 4 children with nephrolithiasis on this diet. MATERIALS AND METHODS: We describe stone treatment and analysis as well as metabolic and urine abnormalities in 4 children with nephrolithiasis on the ketogenic diet who presented to our institution. RESULTS: All patients were treated with shock wave lithotripsy, fluid liberalization and oral citrate. One child was ultimately withdrawn from the diet due to persistent stone formation. Analysis revealed 3 calcium and 1 ammonium urate stones. Three patients had hypercalciuria, 2 elevated urinary uric acid and 1 hypocitruria. Serum studies revealed acidosis in 3 cases. CONCLUSIONS: The ketogenic diet induces several metabolic abnormalities that increase the propensity for stone formation. Urologists should be aware of this potential complication. Fluid liberalization and bicitrate are recommended as prophylaxis.

Kielb, S. J. and J. Q. Clemens (2005). "Comprehensive urodynamics evaluation of 146 men with incontinence after radical prostatectomy." Urology 66(2): 392-396.

OBJECTIVES: To assess the filling, storage, and voiding urodynamic parameters in a large group of men with urinary incontinence after radical prostatectomy. METHODS: We reviewed the videourodynamics testing results for 146 consecutive men referred for urinary incontinence after radical prostatectomy. RESULTS: The mean patient age was 69.0 years (range 48 to 85), and the mean interval since radical prostatectomy was 4 years (range 4 months to 19 years). All but four tests were performed more than 12 months postoperatively. Stress urinary incontinence (SUI) was demonstrated in 139 men (95%), with a mean abdominal leak point pressure of 59 cm H2O. A statistically significant correlation was found between the leak point pressure and static urethral pressure profilometry measurements (r = 0.46, P < 0.0001). The mean urethral pressure profilometry measurements in those with SUI were significantly lower than in those without (46.6 versus 69 cm H2O, P = 0.001). A total of 34 patients had diminished compliance or detrusor instability, but this was the sole finding in only 3. A hypocontractile detrusor response was seen in 49 patients, and 35 of these augmented voiding by abdominal straining. Patients with previous radiotherapy (n = 24) were more likely to have bladder outlet obstruction; the other parameters were similar to those in patients without radiotherapy. CONCLUSIONS: Incontinence after radical prostatectomy is caused by intrinsic sphincter deficiency in the vast majority of patients. Urethral pressure profilometry measurements correlated with the severity of SUI, as measured by abdominal leak point pressure. Bladder outlet obstruction may coexist with SUI in a significant portion of patients. During voiding, a hypocontractile detrusor response may be seen, but the clinical significance of this finding is unclear.

Kielb, S. J., N. L. Shah, et al. (2001). "Functional p53 mutation as a molecular determinant of paclitaxel and gemcitabine susceptibility in human bladder cancer. [see comments.]." Journal of Urology 166(2): 482-487.

PURPOSE: Paclitaxel and gemcitabine are promising new agents for treatment of human bladder cancer. We determine how the presence or absence of p53 function impacts the cytotoxic effects of these chemotherapeutic agents in human bladder cancer. MATERIALS AND METHODS: The J82 human bladder cancer (TCC) cell line was transfected with a temperature sensitive p53 (tsp53) mutant that functions as mutated p53 at 37C but functions as wild-type (normal) p53 at 32C. Susceptibility of these inducible p53 TCC cells to paclitaxel and gemcitabine induced cytotoxicity was evaluated and kill significance determined between sub-lethal and lethal doses. RESULTS: Significant paclitaxel dose dependent cytotoxicity was observed in J82 TCC cells lacking normal p53 and tsp53 transfected cells at 37C, which was the mutant p53 temperature in transfectants between maximal and minimal kill concentrations for either (p <0.001). Likewise, significant cytotoxicity was observed in parental J82 TCC at 32C (p <0.001), while restoration of p53 function in tsp53 transfected cells on shift to 32C abrogated significant dose dependent cytotoxicity. Gemcitabine caused significant cell death in the cell lines incubated at either temperature and, thus, was equally effective regardless of cellular p53 function (p <0.001, respectively). CONCLUSIONS: Paclitaxel requires functionally mutated p53 to induce cell death in human bladder cells, indicating that it may be more effective against TCC with p53 mutations than against TCC, which lacks p53 abnormalities, while gemcitabine is effective regardless of p53 function. These findings provide a rationale for selecting chemotherapy based on the p53 status of individual bladder cancers. <28>

Kielb, S. J., Z. L. Voeltz, et al. (2001). "Evaluation and management of traumatic posterior urethral disruption with flexible cystourethroscopy." Journal of Trauma-Injury Infection & Critical Care 50(1): 36-40.

BACKGROUND: We sought to consolidate evaluation and management of traumatic urethral disruption using cystourethroscopic evaluation without retrograde urethrogram or suprapubic cystostomy placement. METHODS: We review our experience with initial flexible cystourethroscopic evaluation of suspected urethral injury from blunt trauma with placement of a Council urethral catheter to provide primary endoscopic realignment of the urethra. RESULTS: Access into the bladder was achieved in 8 of 10 patients. After a mean follow-up of 18 months (range, 9-27 months) in the six living patients, only three have required treatment for urethral stricture--direct vision internal urethrotomy in two, and open perineal urethroplasty in one. Urinary continence has been achieved in five of six patients. CONCLUSION: Primary flexible cystourethroscopy with placement of a urethral catheter streamlines evaluation of traumatic posterior urethral injury. In the presence of partial disruption it provided stricture-free outcomes in three of three surviving patients. <10>

Kieran, K., T. L. Hall, et al. (2007). "Refining histotripsy: defining the parameter space for the creation of nonthermal lesions with high intensity, pulsed focused ultrasound of the in vitro kidney." J Urol 178(2): 672-676.

PURPOSE: Focused ultrasound therapy is a promising modality for noninvasive tissue ablation. However, the relative contributions of thermal and cavitational effects are poorly defined. We characterized the ultrasound parameters within which tissue ablation occurs by cavitational mechanisms without significant thermal effect. MATERIALS AND METHODS: In vitro porcine kidneys were submerged in degassed water. Tissue ablation was performed by delivering ultrasound (750 kHz and 20 microsecond pulses) of constant spatial peak energy dose (100 J/cm(2)) to adjacent foci in a 3 x 3 grid configuration. For each ablation different intensity (0.11 to 211 kW/cm(2)) and duty cycle (0.04% to 100%) parameters were selected. A thermocouple co-localized with the center of each grid continuously measured temperature. Following ablation each kidney was examined grossly and histologically. RESULTS: Ablated tissue lesions were classified into 4 discrete morphological categories, including blanched--firm, pale, desiccated tissue, disrupted--a cavity containing thin, isochromatic liquid, mixed--a cavity containing pale, thick liquid with minimal blanching and no grossly visible effect. Morphologically similar lesions clustered at separable regions of the ultrasound parameter space. The maximal temperature attained in disrupted lesions was similar to that attained when there was no effect (44.2C and 47.2C, respectively, p = 0.31), although it was significantly lower than the maximal temperatures for desiccated or mixed lesions (67.5C and 59.4C, each p <0.0001). CONCLUSIONS: In an in vitro model we defined the ultrasound parameter region within which purely cavitational ablation of tissue is possible with a negligible thermal component. Additional research is needed to optimize the parameters for in vivo cavitational tissue ablation, incorporating the influence of tissue perfusion.

Kieran, K., J. S. Montgomery, et al. (2007). "Comparison of intraoperative parameters and perioperative complications of retroperitoneal and transperitoneal approaches to laparoscopic partial nephrectomy: support for a retroperitoneal approach in selected patients." J Endourol 21(7): 754-759.

BACKGROUND AND PURPOSE: Retroperitoneal laparoscopy (RP) may have some intrinsic advantages over transperitoneal laparoscopy (TP) in certain patients undergoing partial nephrectomy. We reviewed our experience with RP and TP partial nephrectomy to identify differences in intraoperative and postoperative parameters. PATIENTS AND METHODS: The records of 72 patients (45 TP, 27 RP) undergoing laparoscopic partial nephrectomy without hand assistance between January 2003 and August 2005 were reviewed. The two groups were similar demographically; tumors were smaller in RP patients (2.1 v 2.7 cm; P = 0.03), and the RP approach was used more frequently on right kidneys (70.4% v 37.8%; P = 0.01). RESULTS: The operative time (mean 160 v 192 minutes; P = 0.008) and length of stay (LOS; median 1.0 days [range 1-10 days] v 2.0 days [range 1-64 days]; P = 0.001) were shorter in RP patients. Rates of collecting system entry (22% v 38%), positive-margin rate (0% v 6.7%; P = 0.29), and complications (19% v 22%; P = 0.77) were similar in RP and TP patients. Hemorrhage was the most common complication in both groups. Bowel-related complications occurred in three TP patients, but in no RP patients. Overall, the median estimated blood loss (EBL) was lower in RP patients (100 mL [range 25-3500 mL] v 225 mL [range 25-1900 mL]; P = 0.06). Among patients with complications, EBL was similar in both groups (median 325 mL [50-1500 mL] v 200 mL [50-3500 mL] for RP and TP; P = 0.86). CONCLUSIONS: The RP approach reduces operative time, LOS, and some types of complications without compromising the quality of tumor resection. Complications in the retroperitoneal space are not associated with higher EBL. Anatomic considerations and surgeon experience may improve outcomes.

Kieran, K., C. P. Nelson, et al. (2006). "Ureteroscopy for symptomatic hydrocalices: a case series." J Endourol 20(6): 413-417.

BACKGROUND: Hydrocalix is an uncommon condition that typically is treated with percutaneous dilation of the stenotic infundibulum. Ureteroscopy has the advantage of minimizing invasiveness. METHODS: We reviewed our experience with 12 retrograde ureteroscopies for hydrocalix in 10 patients. RESULTS: Access to the hydrocalix could not be achieved in one. Of the remaining 11, the original infundibulum was dilated in all but one, in whom neoinfundibulotomy was performed with a laser. The laser was used in eight cases, balloon dilation with cautery in two, and cautery alone in one. Of the seven hydrocalices bearing stones, four were rendered stone free. Immediate symptomatic success was achieved after 6 of the 11 evaluable procedures (one patient was lost to follow-up after a technically successful procedure). Of the five symptomatic failures, three went on to additional treatment (one ureteroscopy and two percutaneous), one elected against treatment despite recurrence of stenosis, and one had persistent pain owing to stones even though the hydrocalix was cured. Of the six symptomatic successes, three were without symptoms at a mean 25 months of follow-up, two have had recurrences necessitating additional treatment (both percutaneous) a mean of 51 months later, and one did not have adequate imaging follow-up. CONCLUSION: Ureteroscopy for hydrocalix achieved technical success in most patients, but relief of symptoms followed only about half of the procedures. A trial of ureteroscopy does not preclude subsequent success with a percutaneous approach. Ureteroscopy is a reasonable option for hydrocalix for patients who wish to avoid percutaneous surgery.

Kikuchi, E., V. Margulis, et al. (2009). "Lymphovascular invasion predicts clinical outcomes in patients with node-negative upper tract urothelial carcinoma." J Clin Oncol 27(4): 612-618.

PURPOSE: To assess the association of lymphovascular invasion (LVI) with cancer recurrence and survival in a large international series of patients treated with radical nephroureterectomy (RNU) for upper urinary tract urothelial carcinoma (UTUC). PATIENTS AND METHODS: Data were collected on 1,453 patients treated with RNU at 13 academic centers and combined into a relational database. Pathologic slides were rereviewed by genitourinary pathologists according to strict criteria. LVI was defined as presence of tumor cells within an endothelium-lined space. RESULTS: LVI was observed in 349 patients (24%). Proportion of LVI increased with advancing tumor stage, high tumor grade, presence of tumor necrosis, sessile tumor architecture, and presence of lymph node metastasis (all P < .001). LVI was an independent predictor of disease recurrence and survival (P < .001 for both). Addition of LVI to the base model (comprising pathologic stage, grade, and lymph node status) marginally improved its predictive accuracy for both disease recurrence and survival (1.1%, P = .03; and 1.7%, P < .001, respectively). In patients with negative lymph nodes and those in whom a lymphadenectomy was not performed (n = 1,313), addition of LVI to the base model improved the predictive accuracy of the base model for both disease recurrence and survival by 3% (P < .001 for both). In contrast, LVI was not associated with disease recurrence or survival in node-positive patients (n = 140). CONCLUSION: LVI was an independent predictor of clinical outcomes in nonmetastatic patients who underwent RNU for UTUC. Assessment of LVI may help identify patients who could benefit from multimodal therapy after RNU. After confirmation, LVI should be included in staging of UTUC.

Kim, C., L. N. McEwen, et al. (2008). "Stress urinary incontinence in women with a history of gestational diabetes mellitus." J Womens Health (Larchmt) 17(5): 783-792.

OBJECTIVE: Stress urinary incontinence may serve as a barrier to lifestyle modification among women at high risk for diabetes, but the prevalence of stress urinary incontinence among women with histories of gestational diabetes mellitus (hGDM) is unknown. The purpose of this study was to examine the prevalence of stress incontinence among women with hGDM and to examine its association with their current physical activity. METHODS: We surveyed women with hGDM within the past 5 years who were currently enrolled in a managed care plan (n = 228). In a cross-sectional analysis, self-reported weekly or more frequent stress incontinence was the primary independent variable and measures of physical activity and body mass index (BMI) were the outcomes of interest. We constructed multivariable models that adjusted for participant characteristics associated with the measure of incontinence or outcomes in bivariate analyses. RESULTS: Of the 228 women with hGDM, 49% reported weekly or more frequent incontinence during pregnancy, and 28% reported that incontinence affected their activities during pregnancy. Fifty percent reported weekly or more frequent incontinence after delivery, with 27% reporting interference of incontinence with activity. Less than a third of women reported optimal physical activity, and 42% were obese. After adjustment for characteristics associated with measures of activity and incontinence, there was minimal association between levels of activity and stress urinary incontinence; similarly, there was no association between BMI and measures of stress incontinence. CONCLUSIONS: Stress urinary incontinence is common among women with hGDM but does not appear to be associated with physical activity levels or BMI.

Kim, G., S. W. Huang, et al. (2007). "Indocyanine-green-embedded PEBBLEs as a contrast agent for photoacoustic imaging." J Biomed Opt 12(4).

Kim, H., W. D. Belville, et al. (1992). "Rapid injection cystometry and hydroxyproline content in the acutely over distended rabbit bladder." Neurouro Urodyn 11: 33.

Kim, J. H., S. M. Dhanasekaran, et al. (2007). "Integrative analysis of genomic aberrations associated with prostate cancer progression." Cancer Res 67(17): 8229-8239.

Integrative analysis of genomic aberrations in the context of trancriptomic alterations will lead to a more comprehensive perspective on prostate cancer progression. Genome-wide copy number changes were monitored using array comparative genomic hybridization of laser-capture microdissected prostate cancer samples spanning stages of prostate cancer progression, including precursor lesions, clinically localized disease, and metastatic disease. A total of 62 specific cell populations from 38 patients were profiled. Minimal common regions (MCR) of alterations were defined for each sample type, and metastatic samples displayed the most number of alterations. Clinically localized prostate cancer samples with high Gleason grade resembled metastatic samples with respect to the size of altered regions and number of affected genes. A total of 9 out of 13 MCRs in the putative precursor lesion, high-grade prostatic intraepithelial neoplasia (PIN), showed an overlap with prostate cancer cases (amplifications in 3q29, 5q31.3-q32, 6q27, and 8q24.3 and deletions in 6q22.31, 16p12.2, 17q21.2, and 17q21.31), whereas postatrophic hyperplasia (PAH) did not exhibit this overlap. Interestingly, prostate cancers that do not overexpress ETS family members (i.e., gene fusion-negative prostate cancers) harbor differential aberrations in 1q23, 6q16, 6q21, 10q23, and 10q24. Integrative analysis with matched mRNA profiles identified genetic alterations in several proposed candidate genes implicated in prostate cancer progression.

Kim, S. H., T. E. Carey, et al. (2000). "Characterization of AMC-HN-9, a cell line established from an undifferentiated carcinoma of the parotid gland: expression of alpha6beta4 with the absence of BP180 and 230." Acta Otolaryngol 120(5): 660-666.

We recently reported the development of a cell line, AMC-HN-9, established from an undifferentiated carcinoma (UDC) of the parotid gland. AMC-HN-9 consists mostly of spindle-shaped cells, has poor in vitro adhesiveness and an in vitro appearance that is different from that of other epithelial cell lines. To test the hypothesis that structural or functional abnormalities of the hemidesmosomes might contribute to the morphological appearance and biology of UDCs, we studied the expression of hemidesmosomal proteins in AMC-HN-9. Flow cytometry, indirect immunofluorescence, immunoprecipitation, reverse transcriptase-polymerase chain reaction, and cytogenetic analysis were used. AMC-HN-9 cells express the alpha6 and beta4 integrin subunits at nearly the same intensity as head and neck squamous cell carcinoma cell lines. However, AMC-HN-9 does not express BP180 and BP230, although there is no gross deletion of the loci of the BP180 and BP230 genes, suggesting that a more subtle mechanism has silenced these genes. In conclusion, the failure to express certain hemidesmosomal proteins is a likely explanation for the functional and morphologic characteristics of UDC cells both in vivo and in vitro.

Kim, S. P., Z. Sarmast, et al. (2008). "Long-term durability and functional outcomes among patients with artificial urinary sphincters: a 10-year retrospective review from the University of Michigan." J Urol 179(5): 1912-1916.

PURPOSE: The artificial urinary sphincter continues to be one of the most effective and commonly used surgical treatments for severe urinary incontinence. The long-term durability and functional outcome remains unclear. This study sought to report the artificial urinary sphincter complication rates, associated risk factors with complications, and long-term quality of life and durability. MATERIALS AND METHODS: This single institution study reports the outcomes of 124 consecutive index cases of artificial urinary sphincter from 1996 to 2006 for complications (infection, erosion, and mechanical failure). Bivariate statistics and multivariable logistic models were used to identify patient and artificial urinary sphincter characteristics associated with complications. Functional outcomes and long-term durability were assessed using a cross sectional analysis of a validated health related quality of life survey and a product limit estimates, respectively. RESULTS: Among the 124 male patients median followup was 6.8 years. The overall complication rate for patients undergoing an artificial urinary sphincter was 37.0%, with mechanical failure the most common cause (29), followed by erosion (10) and then infection (7). Significant differences between complications and specific patient and artificial urinary sphincter characteristics risk factors were not found. Functional outcomes appeared stable with similar mild-moderate urinary incontinence severity and 0 to 1 daily pad use at intervals of 0 to 4 years, 4 to 8 years and more than 8 years. Long-term durability was notable with 36% having complications (requiring surgical revision or removal) within 10 years and most events occurring within the first 48 months. CONCLUSIONS: Long-term durability and functional outcomes are achievable for the AMS 800, but there are appreciable complication rates for erosion, mechanical failure and infection in the first 48 months from implantation.

Kim, S. Y., N. J. Bachman, et al. (1997). "Beta 4 integrin transfection of UM-UC-2 (human bladder carcinoma) cells: stable expression of a spontaneous cytoplasmic truncation mutant with rapid loss of clones expressing intact beta 4." Cancer Res 57(1): 38-42.

The alpha 6 beta 4 integrin is a component of the hemidesmosome, the anchoring structure in the basal membrane of epithelial cells. alpha 6 beta 4 expression is frequently altered in neoplastic cells. It is sometimes lost and sometimes overexpressed, which suggests that disruption of normal function is involved in neoplastic transformation. To examine the effect of this integrin on the growth and behavior of malignant cells that have lost beta 4, we transfected a full-length beta 4 cDNA into the UM-UC-2 cell line that expresses alpha 6 but not beta 4. Although large numbers of clones were obtained when a control vector was used in the transfection, only 12 clones could be isolated that expressed beta 4. Of these, only two beta 4-positive clones, clones 8 and 11, persisted long enough for further study. Clone 8 cells initially expressed beta 4, but within 2 weeks, all positive cells were lost from the culture. Clone 11 persisted in culture and retained strong surface expression of alpha 6 beta 4. Biochemical analysis and Western blotting revealed that this clone contained a truncated form of beta 4 that had lost the distal cytoplasmic domain. We conclude that expression of wild-type beta 4 in UM-UC-2 inhibits cell growth, presumably by an integrin-mediated signaling pathway. Clone 11 escaped from normal signaling because the cytoplasmic domain, a region essential for basal polar localization, was lost. The alpha 6 beta 4 integrin appears to have tumor suppressor activity in epithelial tumors.

King, E. R., L. S. DeGiorgi, et al. (1969). "Irradiation as an immunosuppressive agent in organ transplantation." Radiology 93(2): 297-306.

Kiser, W. S., C. B. Hewitt, et al. (1971). "The surgical complications of renal transplantation." Surgical Clinics of North America 51(5): 1133-1140.

Kissberth, W. C., E. G. MacEwen, et al. (1995). "Response to liposome-encapsulated doxorubicin (TLC D-99) in a dog with myeloma." J Vet Intern Med 9: 425-428.

Kitagawa, Y., J. Dai, et al. (2005). "Vascular endothelial growth factor contributes to prostate cancer-mediated osteoblastic activity." Cancer Res 65(23): 10921-10929.

Prostate cancer frequently metastasizes to bone resulting in the formation of osteoblastic metastases through unknown mechanisms. Vascular endothelial growth factor (VEGF) has been shown recently to promote osteoblast activity. Accordingly, we tested if VEGF contributes to the ability of prostate cancer to induce osteoblast activity. PC-3, LNCaP, and C4-2B prostate cancer cell lines expressed both VEGF-165 and VEGF-189 mRNA isoforms and VEGF protein. Prostate cancer cells expressed the mRNA for VEGF receptor (VEGFR) neuropilin-1 but not the VEGFRs Flt-1 or KDR. In contrast, mouse pre-osteoblastic cells (MC3T3-E1) expressed Flt-1 and neuropilin-1 mRNA but not KDR. PTK787, a VEGFR tyrosine kinase inhibitor, inhibited the proliferation of human microvascular endothelial cells but not prostate cancer proliferation in vitro. C4-2B conditioned medium induced osteoblast differentiation as measured by production of alkaline phosphatase and osteocalcin and mineralization of MC3T3-E1. PTK787 blocked the C4-2B conditioned medium-induced osteoblastic activity. VEGF directly induced alkaline phosphatase and osteocalcin but not mineralization of MC3T3-E1. These results suggest that VEGF induces initial differentiation of osteoblasts but requires other factors, present in C4-2B, to induce mineralization. To determine if VEGF influences the ability of prostate cancer to develop osteoblastic lesions, we injected C4-2B cells into the tibia of mice and, after the tumors grew for 6 weeks, administered PTK787 for 4 weeks. PTK787 decreased both intratibial tumor burden and C4-2B-induced osteoblastic activity as measured by bone mineral density and serum osteocalcin. These results show that VEGF contributes to prostate cancer-induced osteoblastic activity in vivo.

Klein, D. H., W. K. Graham, et al. (1996). "Streamlining the donor organ placement process: use of portable computers in the field." Transplantation Proceedings 28(1): 217-218.

Klein, E. A., J. E. Montie, et al. (1986). "Jejunal conduit urinary diversion." Journal of Urology 135(2): 244-246.

The clinical course of 14 patients undergoing jejunal conduit urinary diversion between 1971 and 1985 is reviewed. Indications for use of jejunum rather than ileum or colon for diversion included radiation changes of the ileum, concurrent colonic neoplasms or injury, concerns about collateral blood supply of the colon and multiple adhesions. There were 2 operative deaths. Followup in the remaining 12 patients was 1 to 116 months (mean 34 months). All of the patients had satisfactory postoperative renal function. Eight patients (67 per cent) experienced a total of 13 complications. Only 3 patients (25 per cent) suffered the electrolyte imbalance characteristic of jejunal conduit syndrome, representing the only complication directly attributable to the use of jejunum. The jejunal conduit is a viable alternative form of urinary diversion in patients in whom the use of other intestinal segments is undesirable because of previous irradiation, surgery or concurrent disease processes. Although jejunal conduits carry an increased risk of electrolyte imbalance, the use of short jejunal loops and prophylactic oral electrolyte replacement therapy can minimize the occurrence of this complication. <180>

Klein, E. A., J. E. Montie, et al. (1989). "Stomal complications of intestinal conduit urinary diversion." Cleveland Clinic Journal of Medicine 56(1): 48-52.

Intestinal conduits of the ileum, colon, or jejunum were used for urinary diversion in 319 patients at The Cleveland Clinic Foundation between 1970 and 1981 due to pelvic malignancy , primary bladder cancer, or benign conditions. End stomas were constructed in 65% and Turnbull loop stomas in 35%. Follow-up ranged from one to 152 months (median, 35 months). The mean number of days between appliance changes was 5.7 (range, 2-10). The overall complication rate was 8.5%. Stomal revisions were required in 5%. There were no significant differences in the mean number of days between appliance changes, type or number of complications, or rate of revision between end and loop stomas or between the various intestinal segments used for diversion. The presence or absence of previous irradiation and the indication for diversion were independent of complications. Stomas constructed from any segment of the intestinal tract in end or loop fashion yielded equivalent long-term function and complication rates. Stomal complications can be minimized and the time between appliance changes maximized by careful attention to all phases of stomal construction and care. <158>

Klein, E. A., D. P. Wood, et al. (1986). "Retained straight catheter: complication of clean intermittent catheterization." J Urol 135(4): 780-781.

Clean intermittent catheterization is a simple and widely used technique with relatively few complications. A child on intermittent catheterization recently was treated for a retained straight catheter. Removal of the catheter was accomplished by urethral dilation. Proper technique of catheter insertion can prevent this complication.

Kliger, A. S., F. O. Finkelstein, et al. (1976). "The antecubital fossa fistula." Clin Nephrol 5(5): 229-231.

We have reviewed our experience with 19 proximal forearm arteriovenous fistulas used in chronic hemodialysis. Thirteen functioned adequately, and of these 10 were complicated by dislodge needles during dialysis, arm edema or hematomas. Although 3 patients developed symptoms of arterial steal, none required ligation of the fistula. This experience suggests that antecubital fossa fistulas might best be used as a second line angioaccess when distal forearm fistulas have been unsuccessful or are impossible to contruct.

Knapp, P. M., Jr., J. W. Konnak, et al. (1987). "Urodynamic evaluation of ileal conduit function." J Urol 137(5): 929-932.

Bilateral hydroureteronephrosis following ileal conduit urinary diversion is not uncommon. It may be owing to ureteroileal stenosis, stomal stenosis or a poorly compliant ileal conduit. The standard evaluation of stoma size, conduit residual urine and a loopogram often fail to allow determination of the cause of ureteral dilatation. In addition to these standard tests, we have used conduit urodynamics to study conduit function with a triple lumen urodynamic catheter to measure simultaneously conduit pressure proximal and distal to the fascia during filling under fluoroscopy. In 4 control patients with normal upper tracts who were studied with this technique conduit leak point pressures ranged from 5 to 20 cm. water pressure. Six patients with bilateral hydroureteronephrosis were studied to evaluate conduit function. We found abnormalities in 5 patients, including functional stomal stenosis in 2, an atonic loop in 1, segmental obstruction in 1 and a high pressure noncompliant distal segment in 1.

Knezevic-Cuca, J., K. B. Stansberry, et al. (2000). "Neurotrophic role of interleukin-6 and soluble interleukin-6 receptors in N1E-115 neuroblastoma cells." J Neuroimmunol 102(1): 8-16.

Interleukin 6 (IL-6) plays a role in physiological and pathophysiological processes in neuronal cells. We studied whether IL-6 plays a role in neuroblastoma cells in culture. These studies demonstrate that N1E-115 cells constitutively express IL-6 but not IL-6R. Exogenous IL-6 stimulated neuronal proliferation in a dose-dependent manner. Under serum-free conditions soluble IL-6 receptors (sIL-6R) alone or in combination with IL-6 exerted significant proliferative effects, while IL-6 alone failed to promote cell proliferation. Neutralizing anti-IL-6 antibody caused a 30-40% reduction in IL-6 mediated proliferation. Our results suggest the importance of IL-6/sIL-6R for proliferation and survival of N1E-115 adrenergic neuroblastoma cells.

Knoester, P. A., M. Leonard, et al. (2007). "Fertility issues for men with newly diagnosed prostate cancer." Urology 69(1): 123-125.

OBJECTIVES: With the increased use of prostate-specific antigen screening, younger men are being diagnosed with prostate cancer. A subset of these men is still interested in potentially having children after cancer treatment. To our knowledge, the topic of future fertility in patients with newly diagnosed prostate cancer has not previously been reported. METHODS: The charts of 8 patients with prostate cancer who were interested in future fertility before treatment were retrospectively reviewed. Preceding definitive treatment, the men underwent fertility counseling and were counseled to preserve semen before treatment. RESULTS: All 8 patients decided to have their semen stored using cryopreservation before their operation. After undergoing radical prostatectomy, one of the patients and his wife underwent successful intrauterine insemination and bore a child. CONCLUSIONS: A subset of men, regardless of age, diagnosed with prostate cancer will be interested in preserving their fertility for the future. Fertility options and potential counseling should be part of the routine pretreatment appointments in men undergoing treatment of prostate cancer.

Konnak, J. W. and D. A. Ohl (1989). "Microsurgical penile revascularization using the central corporeal penile artery." J Urol 142(2 Pt 1): 305-308.

We treated 9 patients with vasculogenic impotence by penile revascularization using a microsurgical anastomosis between the inferior epigastric artery and the central corporeal penile artery. Diagnostic evaluation included penile brachial indexes and pelvic arteriograms, which were abnormal in all 9 patients. Revascularization was technically possible in 7 of 9 patients; 2 had inadequate central arteries. The penile brachial index initially was improved in all 7 patients, although 1 had an early occlusion at 2 months and 1 had a late occlusion at 4 years. Potency was improved initially in 6 of the 9 patients, with longer term improvement in 5 of 9 followed 1 to 8 years. Two patients remain potent currently. The advantages of this technique are a reasonably high technical success rate in selected patients, with improved initial potency in more than half. The disadvantages include technical difficulty, lack of clear-cut selection criteria and unknown long-term results.

Koo, H. P. and D. A. Bloom (1999). "Lower ureteral reconstruction." Urol Clin North Am 26(1): 167-173, x.

Lower ureteral reconstruction is commonly performed in instances of congenital anomalies and ureteral injury. Keys to a successful outcome are an understanding of ureteral anatomy, familiarity with the principles of tissue handling, and the knowledge of various techniques of repair. This article presents some important and useful reconstructive techniques that can be considered in the management of patients with congenital anomaly or lower ureteral injury.

Koo, H. P., T. E. Bunchman, et al. (1999). "Renal transplantation in children with severe lower urinary tract dysfunction." J Urol 161(1): 240-245.

PURPOSE: Renal transplantation in children with end stage renal disease due to congenital urological malformations has traditionally been associated with a poor outcome compared to transplantation in those with a normal urinary tract. In addition, the optimal urological treatment for such children remains unclear. To address these issues, we retrospectively reviewed our experience with renal transplantation in this population. MATERIALS AND METHODS: Between 1986 and 1998, 12 boys and 6 girls a mean age of 8.4 years with a severe dysfunctional lower urinary tract underwent a total of 15 living related and 6 cadaveric renal transplantations. Urological anomalies included posterior urethral valves in 8 cases, urogenital sinus anomalies in 4, the prune-belly syndrome in 2, and complete bladder duplication, ureterocele, lipomeningocele and the VATER syndrome in 1 each. In 11 children (61%) bladder augmentation or continent urinary diversion was performed, 2 (11%) have an intestinal conduit and 5 (28%) have a transplant into the native bladder. RESULTS: In this group patient and overall allograft survival was 100 and 81%, respectively. These values were the same in all children who underwent renal transplantation at our center during this era. In the 17 children with a functioning transplant mean serum creatinine was 1.4 mg./dl. Technical complications occurred in 4 patients (22%), including transplant ureteral obstruction in 2 as well as intestinal conduit stomal stenosis and Mitrofanoff stomal incontinence. CONCLUSIONS: Renal transplantation may be successfully performed in children with end stage renal disease due to severe lower urinary tract dysfunction. Bladder reconstruction, which may be required in the majority of these cases, appears to be safe when performed before or after the transplant. A multidisciplinary team approach to surgery is advantageous.

Kotsis, S. V., S. L. Spencer, et al. (2002). "Early onset prostate cancer: predictors of clinical grade." J Urol 167(4): 1659-1663.

PURPOSE: Prostate cancer is typically a disease of elderly men and, therefore, it has not been well characterized in those affected at a young age. With the advent of serum prostate specific antigen testing, we are able to detect prostate cancer in young men even in the absence of symptoms. We studied a large group of early onset prostate cancer cases to illustrate the clinical presentation of men with early onset prostate cancer and to determine the effect of family history on Gleason grade as a reflection of prognosis. MATERIALS AND METHODS: All study participants were enrolled in the University of Michigan Prostate Cancer Genetics Project. Enrollment criterion of the Prostate Cancer Genetics Project includes a diagnosis of prostate cancer at age 55 years or younger. Descriptive statistics and logistic regression were used to characterize early onset prostate cancer and assess the associated prognostic factors. RESULTS: The study group was comprised of 257 men with prostate cancer diagnosed at age 55 years or younger. Median age at diagnosis was 51 years (range 34 to 55) and almost half of the participants reported a negative family history of prostate cancer. In logistic regression analysis having an affected father, an affected first-degree relative or an affected relative of any relation was each a statistically significant predictor of well differentiated (Gleason 6 or less) compared to moderately and poorly differentiated prostate cancer (Gleason 7-10) after adjusting for confounding variables. Men with an affected relative were nearly twice as likely to have well differentiated prostate cancer compared to men without affected relatives. CONCLUSIONS: Family history appears to predict the development of well differentiated tumors independently. In our study men with no family history of prostate cancer had higher grade tumors, which are associated with a more serious prognosis. Future studies of early onset prostate cancer should be directed toward identifying additional risk factors that may be relevant for men without a family history of the disease.

Kraklau, D. M. and D. A. Bloom (1998). "The cystometrogram at 70 years." J Urol 160(2): 316-319.

PURPOSE: The origin and the development of the cystometrogram are described. MATERIALS AND METHODS: We reviewed and analyzed the published literature on cystometrography. RESULTS: The cystometrogram originated in the latter half of the nineteenth century, an age of intense clinimetric investigation. Early investigators studied fundamental aspects of bladder function with meticulous techniques using relatively crude equipment. The first clinical cystometer was designed by Dalton K. Rose in 1927. He was followed by Nesbit, McLellan, Muschat and Munro, who brought the cystometrogram to its current key role in modern urology. CONCLUSIONS: Numerous investigators have advanced the knowledge of bladder function using the cystometrogram, a key urological tool.

Kraklau, D. M. and J. S. Wolf, Jr. (1999). "Review of antibiotic prophylaxis recommendations for office-based urologic procedures." Tech Urol 5(3): 123-128.

Prophylactic antibiotic recommendations for urologic procedures are not well established. Any assessment of the need for antibiotics entails thorough cost-benefit analysis. The subject of this article is an evaluation of the role of antimicrobial prophylaxis for outpatient office-based diagnostic procedures, including diagnostic flexible cystoscopy, transrectal ultrasound biopsy, and urodynamics. Relevant studies were identified using MEDLINE database searches and review of selected bibliographies. Studies of infections after transrectal ultrasound and biopsy suggest that periprocedure antibiotics are indicated, but that the exact course and timing have not been defined. Most evidence suggests that outpatient cystoscopy is associated with minimal infectious risk and that the routine administration of oral antibiotics is not indicated. Support in the literature for the use of prophylactic antibiotics at the time of urodynamic evaluation is equivocal. The current prophylactic regimens at the University of Michigan are presented as recommendations, but optimization of antimicrobial prophylaxis will require multicenter studies with large numbers of patients.

Kryczek, I., S. Wei, et al. (2007). "Stromal-derived factor (SDF-1/CXCL12) and human tumor pathogenesis." Am J Physiol Cell Physiol 292(3): C987-C995.

Kryczek, I., S. Wei, et al. (2007). "Cutting edge: opposite effects of IL-1 and IL-2 on the regulation of IL-17+ T cell pool IL-1 subverts IL-2-mediated suppression." J Immunol 179(3): 1423-1426.

In this report, we show that IL-17(+)CD4(+) and IL-17(+)CD8(+) T cells are largely found in lung and digestive mucosa compartments in normal mice. Endogenous and exogenous IL-1 dramatically contribute to IL-17(+) T cell differentiation mediated by TGFbeta and IL-6. IL-1 is capable of stimulating IL-17(+) T cell differentiation in the absence of IL-6. Furthermore, although IL-2 reduces IL-17(+) T cell differentiation, IL-1 completely disables this effect. Mechanistically, IL-1 and IL-2 play opposite roles in regulating the expression of several molecules regulating Th17 cell differentiation, including the orphan nuclear receptor ROR gamma t, the IL-1 receptor, and the IL-23 receptor. IL-1 subverts the effects of IL-2 on the expression of these gene transcripts. Altogether, our work demonstrates that IL-6 is important but not indispensable for IL-17(+) T cell differentiation and that IL-1 plays a predominant role in promoting IL-17(+) T cell induction. Thus, the IL-17(+) T cell pool may be controlled by the local cytokine profile in the microenvironment.

Kucuk, O., F. H. Sarkar, et al. (2002). "Effects of lycopene supplementation in patients with localized prostate cancer." Exp Biol Med (Maywood) 227(10): 881-885.

Epidemiological studies have shown an inverse association between dietary intake of lycopene and prostate cancer risk. We conducted a clinical trial to investigate the biological and clinical effects of lycopene supplementation in patients with localized prostate cancer. Twenty-six men with newly diagnosed prostate cancer were randomly assigned to receive a tomato oleoresin extract containing 30 mg of lycopene (n = 15) or no supplementation (n = 11) for 3 weeks before radical prostatectomy. Biomarkers of cell proliferation and apoptosis were assessed by Western blot analysis in benign and cancerous prostate tissues. Oxidative stress was assessed by measuring the peripheral blood lymphocyte DNA oxidation product 5-hydroxymethyl-deoxyuridine (5-OH-mdU). Usual dietary intake of nutrients was assessed by a food frequency questionnaire at baseline. Prostatectomy specimens were evaluated for pathologic stage, Gleason score, volume of cancer, and extent of high-grade prostatic intraepithelial neoplasia. Plasma levels of lycopene, insulin-like growth factor-1, insulin-like growth factor binding protein-3, and prostate-specific antigen were measured at baseline and after 3 weeks of supplementation or observation. After intervention, subjects in the intervention group had smaller tumors (80% vs 45%, less than 4 ml), less involvement of surgical margins and/or extra-prostatic tissues with cancer (73% vs 18%, organ-confined disease), and less diffuse involvement of the prostate by high-grade prostatic intraepithelial neoplasia (33% vs 0%, focal involvement) compared with subjects in the control group. Mean plasma prostate-specific antigen levels were lower in the intervention group compared with the control group. This pilot study suggests that lycopene may have beneficial effects in prostate cancer. Larger clinical trials are warranted to investigate the potential preventive and/or therapeutic role of lycopene in prostate cancer.

Kucuk, O., F. H. Sarkar, et al. (2001). "Phase II randomized clinical trial of lycopene supplementation before radical prostatectomy." Cancer Epidemiol Biomarkers Prev 10(8): 861-868.

An inverse association has been observed between dietary intake of lycopene and the risk of prostate cancer. We investigated the effects of lycopene supplementation in patients with prostate cancer. Twenty-six men with newly diagnosed, clinically localized (14 T(1) and 12 T(2)) prostate cancer were randomly assigned to receive 15 mg of lycopene (n = 15) twice daily or no supplementation (n = 11) for 3 weeks before radical prostatectomy. Biomarkers of differentiation and apoptosis were assessed by Western blot analysis on benign and malignant parts of the prostate gland. Prostatectomy specimens were entirely embedded, step-sectioned, and evaluated for pathological stage, Gleason score, volume of cancer, and extent of high-grade prostatic intraepithelial neoplasia. Plasma levels of lycopene, insulin-like growth factor-1 (IGF-1), IGF binding protein-3, and prostate-specific antigen were measured at baseline and after 3 weeks of supplementation or observation. Eleven (73%) subjects in the intervention group and two (18%) subjects in the control group had no involvement of surgical margins and/or extra-prostatic tissues with cancer (P = 0.02). Twelve (84%) subjects in the lycopene group and five (45%) subjects in the control group had tumors <4 ml in size (P = 0.22). Diffuse involvement of the prostate by high-grade prostatic intraepithelial neoplasia was present in 10 (67%) subjects in the intervention group and in 11 (100%) subjects in the control group (P = 0.05). Plasma prostate-specific antigen levels decreased by 18% in the intervention group, whereas they increased by 14% in the control group (P = 0.25). Expression of connexin 43 in cancerous prostate tissue was 0.63 +/- 0.19 absorbance in the lycopene group compared with 0.25 +/- 0.08 in the control group (P = 0.13). Expression of bcl-2 and bax did not differ significantly between the two study groups. IGF-1 levels decreased in both groups (P = 0.0002 and P = 0.0003, respectively). The results suggest that lycopene supplementation may decrease the growth of prostate cancer. However, no firm conclusions can be drawn at this time because of the small sample size.

Kucuk, O. and D. P. Wood, Jr. (2002). "Re: Response of hormone refractory prostate cancer to lycopene." J Urol 167(2 Pt 1): 651.

Kuefer, R., K. C. Day, et al. (2006). "ADAM15 disintegrin is associated with aggressive prostate and breast cancer disease." Neoplasia 8(4): 319-329.

The aim of the current study was to evaluate the expression of ADAM15 disintegrin (ADAM15) in a broad spectrum of human tumors. The transcript for ADAM15 was found to be highly upregulated in a variety of tumor cDNA expression arrays. ADAM15 protein expression was examined in tissue microarrays (TMAs) consisting of 638 tissue cores. TMA analysis revealed that ADAM15 protein was significantly increased in multiple types of adenocarcinoma, specifically in prostate and breast cancer specimens. Statistical association was observed with disease progression within clinical parameters of predictive outcome for both prostate and breast cancers, pertaining to Gleason sum and angioinvasion, respectively. In this report, we also present data from a cDNA microarray of prostate cancer (PCa), where we compared transfected LNCaP cells that overexpress ADAM15 to vector control cells. In these experiments, we found that ADAM15 expression was associated with the induction of specific proteases and protease inhibitors, particularly tissue inhibitor of metalloproteinase 2, as validated in a separate PCa TMA. These results suggest that ADAM15 is generally overexpressed in adenocarcinoma and is highly associated with metastatic progression of prostate and breast cancers.

Kuefer, R., M. D. Hofer, et al. (2003). "The role of an 80 kDa fragment of E-cadherin in the metastatic progression of prostate cancer." Clin Cancer Res 9(17): 6447-6452.

PURPOSE: The purpose of this study was to evaluate an 80 kDa proteolytic fragment of E-cadherin as a potential biomarker for prostate cancer progression and to identify putative proteases that are responsible for the cleavage of E-cadherin. EXPERIMENTAL DESIGN: A wide spectrum of prostate cancer tissue and serum specimens representing different stages of prostate cancer was examined for the accumulation of the 80 kDa fragment of E-cadherin. Additionally, an expression array analysis was used to identify putative proteases that may have been involved in the cleavage of E-cadherin. RESULTS: A reproducible E-cadherin fragment was detected as a strong 80 kDa band in tissue samples. This fragment was detectable almost exclusively in metastatic sites. It was not visible in normal prostate tissue and was weak in 1 of 16 localized prostate cancers. The fragment is shed into the extracellular space and was detectable in patient serum in which the expression of the fragment showed a strong association with advanced prostate cancer. On the basis of cDNA expression analysis, several members of the metalloproteinase family could be identified as potentially responsible for the cleavage of the fragment from full-length E-cadherin. CONCLUSIONS: In this study, we present the first report of serum levels of the 80 kDa fragment of E-cadherin in prostate cancer patients. This fragment is exclusively seen in neoplastic prostate tissue and may represent a useful biomarker of prostate cancer disease progression. This study also demonstrates an association of increased levels of several metalloproteinases with metastatic prostate cancer and could provide a useful correlation between metalloproteinase expression/activity and E-cadherin cleavage and the metastatic progression of prostate cancer.

Kuefer, R., M. D. Hofer, et al. (2005). "Assessment of a fragment of e-cadherin as a serum biomarker with predictive value for prostate cancer." Br J Cancer 92(11): 2018-2023.

In prostate cancer, biomarkers may provide additional value above standard clinical and pathology parameters to predict outcome after specific therapy. The purpose of this study is to evaluate an 80 kDa fragment of the cell adhesion molecule e-cadherin as a serum biomarker. A broad spectrum of prostate cancer serum samples, representing different stages of prostate cancer disease, including benign prostatic hyperplasia (BPH), localised (Loc PCA) and metastatic prostate cancer (Met PCA), was examined for the cleaved product. There is a significant difference in the expression level of the 80 kDa fragment in the serum of healthy individuals vs patients with BPH and between BPH vs Loc PCA and Met PCA (P<0.001). Highest expression levels are observed in advanced metastatic disease. In the cohort of Loc PCA cases, there was no association between the 80 kDa serum concentration and clinical parameters. Interestingly, patients with an 80 kDa level of >7.9 microg l(-1) at the time of diagnosis have a 55-fold higher risk of biochemical failure after surgery compared to those with lower levels. This is the first report of the application of an 80 kDa fragment of e-cadherin as a serum biomarker in a broad spectrum of prostate cancer cases. At an optimised cutoff, high expression at the time of diagnosis is associated with a significantly increased risk of biochemical failure, potentially supporting its use for a tailored follow-up protocol for those patients.

Kulkarni, R., J. S. Wolf, Jr., et al. (2002). "Severe intrarenal fibrosis, infundibular stenosis, renal cysts, and persistent perilobar nephrogenic rests in a patient with Beckwith-Wiedemann syndrome 27 years after diffuse nephroblastomatosis and Wilms tumor: natural progression or a consequence of treatment?" J Pediatr Hematol Oncol 24(5): 389-393.

A27-year-old woman presented with back and abdominal pain. She was diagnosed in infancy with Beckwith-Wiedemann syndrome and bilateral multifocal perilobar nephrogenic rests that progressed to diffuse nephroblastomatosis with neoplastic nephroblastomatous rests at 14 months of age and subsequently to a right Wilms tumor at 5 years of age. Computed tomography of the abdomen during the current admission showed multiple obstructed calices. Ureteroscopic inspection of the left kidney revealed severe intrarenal scarring with multiple infundibular stenosis, hydrocalices, and nephrocalcinosis. Renal biopsy showed sclerotic glomeruli with calcification and scarring and persistent subcapsular nodular renal blastema. Electrocautery incision and balloon dilatation provided temporary pain relief. After discharge, the patient has had two or three episodes of recurrent pain associated with new areas of infundibular stenoses and renal cysts. Bilateral nephrectomy and renal transplantation is being considered for management of progressive disease and relief of intractable pain. The potential causes of progressive and severe intrarenal fibrosis, infundibular stenosis and nephrocalcinosis, and renal cysts in this patient may include abnormal renal development secondary to Beckwith-Wiedemann syndrome itself, radiation or chemotherapy damage, or a combination.

Kumar-Sinha, C., R. B. Shah, et al. (2004). "Elevated alpha-methylacyl-CoA racemase enzymatic activity in prostate cancer." Am J Pathol 164(3): 787-793.

Alpha-methylacyl-CoA racemase (AMACR) is a peroxisomal and mitochondrial enzyme involved in the beta-oxidation of branched fatty acids, shown to be elevated in prostate cancer by several recent studies. Sequence variants of AMACR have been linked to prostate cancer risk. Although mRNA transcript, protein, and sequence variants of AMACR have been studied in the context of prostate cancer, AMACR enzymatic activity has not been addressed. Here we present evidence that AMACR activity is consistently elevated in prostate cancer tissue specimens. This activity can be immunodepleted from prostate cancer tissue extracts. Furthermore, mock needle biopsy cores containing foci of prostate cancer exhibited increased AMACR enzymatic activity, correlating with both protein levels and histopathology. Taken together, our studies suggest that AMACR activity is increased in prostate cancer relative to benign epithelia and suggests that monitoring AMACR activity levels in prostate needle biopsies may have clinical applications.

Kunju, L. P., S. Daignault, et al. (2009). "Multiple prostate cancer cores with different Gleason grades submitted in the same specimen container without specific site designation: should each core be assigned an individual Gleason score?" Hum Pathol 40(4): 558-564.

To better represent the Gleason score of radical prostatectomy, the International Society of Urologic Pathologists Consensus Committee recommends assigning individual Gleason scores to prostate cancer cores submitted in separate containers and/or multiple cores in the same container with site identifiers. However, scenarios where multiple cores are submitted in the same container without site identifiers or labeled "left/right" are common. To assess this scenario, we analyzed 110 extended biopsies containing different Gleason scores with corresponding radical prostatectomy for clinically significant grade differences. Because cores are individually labeled and submitted at our institution, we simulated a scenario of multiple intact cores with different Gleason scores in the same container(s) by analyzing as if submitted in containers labeled "left/right." For each biopsy, a Global (all positive cores averaged as 1 long positive core), Worst, and Largest tumor volume Gleason score was determined and compared with grade of radical prostatectomy using kappa statistics. Biopsies containing core(s) with 3+4 and other core(s) 3+3 were excluded because in this situation, both Global and Worst Gleason score will be always 3+4. The following scenarios were considered clinically significant upgrading: biopsy Gleason score 6 / 3+4 to radical prostatectomy 4+3; biopsy 7 to radical prostatectomy 8-10; biopsy 7 to radical prostatectomy 7 with tertiary Gleason pattern 5. Overall, 51 cases met inclusion criteria. Biopsy Worst Gleason score had the best correlation with radical prostatectomy (kappa agreement of 0.37). Clinically significant upgrading at radical prostatectomy was least with Worst (4%) and highest with Global Gleason score (37%). Upgrading and downgrading were noted in 14% and 8%, respectively, of 59 cases containing core(s) with a Gleason score of 3+4 and other core(s) 3+3, suggesting that any amount of higher Gleason pattern should be recorded. When multiple intact cores are submitted in the same container without specific identifiers, individual cores with cancer should be graded and/or the Worst Gleason score should be recorded.

Kunju, L. P., C. T. Lee, et al. (2005). "Utility of cytokeratin 20 and Ki-67 as markers of urothelial dysplasia." Pathol Int 55(5): 248-254.

Reactive urothelial atypia (RUA) can be difficult to differentiate from dysplastic urothelium. The goal was to evaluate the efficacy of cytokeratin 20 (CK20), Ki-67 and E-cadherin (E-Cad) in this regard. Fifty carcinoma in situ (CIS) cases, 50 non-neoplastic urothelia (25 normal, 25 reactive urothelial atypia (RUA)) and 17 atypia of unknown significance (AUS) cases were evaluated. All cases were stained with monoclonal antibodies against Ki-67, CK20 and E-Cad. All (100%) normal urothelia showed normal staining patterns. In the CIS group, 86%, 82% and 20% of cases showed abnormal expression with CK20, Ki-67 and E-Cad, respectively. Both Ki-67 and CK20 were positive in 68% of cases. In the RUA group, 96%, 72% and 100% of cases showed normal expression patterns with CK20, Ki-67 and E-Cad, respectively. Of 28% RUA cases with increased Ki-67, none demonstrated abnormal CK20 or E-Cad expression. In the AUS group, 47% demonstrated abnormal CK20 and increased Ki-67 expression, suggestive of urothelial dysplasia/CIS, 29% were negative with both, suggestive of RUA, and the remaining 24% cases could not be resolved. In summary, abnormal CK20 is a useful adjunct to morphology for confirming dysplasia. Ki-67 by itself is a less reliable marker of dysplasia. E-Cad is not a useful marker in this setting.

Kunju, L. P., K. Wojno, et al. (2008). "Papillary renal cell carcinoma with oncocytic cells and nonoverlapping low grade nuclei: expanding the morphologic spectrum with emphasis on clinicopathologic, immunohistochemical and molecular features." Hum Pathol 39(1): 96-101.

Papillary renal cell carcinoma (PRCC), a morphologically and genetically distinct subtype of RCC, is morphologically separated into 2 subtypes, type 1 and 2, for prognostic purposes. Type 1 PRCC (single layer of small cells, scant pale cytoplasm) is more common and has a favorable prognosis compared with type 2 (pseudostratified high-grade nuclei, abundant eosinophilic/oncocytic cytoplasm). We report the clinicopathologic, immunohistochemical, and molecular data of 7 adult papillary tumors with morphological features distinct from type 1 or 2 PRCC. All tumors demonstrated predominant papillary architecture, lined by cells with oncocytic cytoplasm, and nonoverlapping low Fuhrman grade nuclei (1 or 2). Foamy macrophages were noted in 2 of 7 tumors. No case demonstrated necrosis or psammoma bodies. Most tumors (6/7) were small (mean size, 2.0 cm; range, 0.8-5.7 cm) and limited to the kidney. No tumor recurrence or metastasis was identified (median follow-up, 22 months). All tumors demonstrated trisomy for 7 and 17 by fluorescence in situ hybridization analysis and uniform CK 7, CD10, and alpha-methylacyl-coenzyme A racemase expression, characteristic of PRCC. These results suggest that these tumors are distinct from type 1 (owing to oncocytic cells) and type 2 (owing to low-grade nonstratified nuclei, low stage, and good outcome). Awareness of this favorable spectrum of PRCC is important to avoid its potential misinterpretation as an aggressive type 2 PRCC (owing to oncocytic cells) or rarely as an oncocytoma (owing to oncocytic cells and low-grade nuclei). Morphologic spectrum of these PRCCs emphasizes that the future prognostic model of PRCC may need to be based primarily on the nuclear characteristics, irrespective of the cytoplasmic features.

Kunju, L. P., L. You, et al. (2008). "Lymphovascular invasion of urothelial cancer in matched transurethral bladder tumor resection and radical cystectomy specimens." J Urol 180(5): 1928-1932; discussion 1932.

PURPOSE: Lymphovascular invasion is an independent predictor of nodal invasion and survival in patients undergoing radical cystectomy. When assessed in transurethral bladder tumor resection specimens, lymphovascular invasion could predict tumor behavior and guide treatment decisions. However, the reliability of assessing lymphovascular invasion in such specimens has not been systematically evaluated. We examined the agreement of lymphovascular invasion status in matched transurethral bladder tumor resection and cystectomy specimens. MATERIALS AND METHODS: A retrospective analysis was performed of patients undergoing transurethral bladder tumor resection within 6 weeks of cystectomy. Tumor stage and lymphovascular invasion status were assessed in transurethral bladder tumor resection specimens and compared to those in corresponding cystectomy specimens. Agreement of lymphovascular invasion status was determined using McNemar's test. RESULTS: A total of 75 patients were eligible for study. In transurethral bladder tumor resection specimens lymphovascular invasion was identified in 17 patients (23%), including 2 (8%) in the T1 and 15 (30%) in the T2 or greater groups. In matched cystectomy specimens lymphovascular invasion was identified in 30 patients (40%), including 9 (36%) in the T1 and 21 (42%) in the T2 or greater populations. A lack of lymphovascular invasion agreement was observed between transurethral bladder tumor resection and cystectomy specimens in the entire population and in patients with cT1 tumors (p = 0.009 and 0.02, respectively). However, good concordance was seen in patients with muscle invasive disease (p = 0.13). Nodal metastasis was observed in 7 of 17 patients (41%) with detectable lymphovascular invasion in the transurethral bladder tumor resection specimen. CONCLUSIONS: When lymphovascular invasion is identified in a transurethral bladder tumor resection sample, it will be present in the cystectomy sample in 65% of cases and associated with nodal metastasis in 41%. Lymphovascular invasion is a valuable histological tool in the evaluation of transurethral bladder tumor resection samples, particularly cT2 tumors, because there is significant agreement of lymphovascular invasion status at transurethral bladder tumor resection and at subsequent cystectomy.

Kunz, H. W., T. J. Gill, 3rd, et al. (1981). "Gene order in the major histocompatibility complex of the rat." Immunogenetics 13(5): 371-379.

The loci in the major histocompatibility complex (MHC) of the rat which code for class I and class II antigens--RT1.A and RT1.B, respectively--have previously been separated by laboratory-derived recombinants and by observations in inbred and wild rats. Closely linked to the MHC is the growth and reproduction complex (Grc) which contains genes influencing body size (dw3) and fertility (ft). These phenotypic markers were used in this study to orient the A and B loci of the MHC. Two recombinants were used for mapping. The BIL(R1) animal is a recombinant between the MHC and Grc, and it carries the haplotype RT1.AlBlGrc+. The r10 animal is an intra-MHC recombinant, and it has the haplotype RT1.AnB1Grc. These recombinants were characterized serologically, by mixed lymphocyte reactivity, by immune responsiveness to poly (Glu52Lys33Tyr15) and by the presence of the dw-3 gene. The data demonstrate that the gene order of the loci is: dw-3--RT1.B--RT1.A.

Kupelian, V., J. T. Wei, et al. (2006). "Prevalence of lower urinary tract symptoms and effect on quality of life in a racially and ethnically diverse random sample: the Boston Area Community Health (BACH) Survey." Arch Intern Med 166(21): 2381-2387.

BACKGROUND: Previous studies of lower urinary tract symptoms (LUTS) have focused on men, with few studies including minority populations. The Boston Area Community Health (BACH) Survey is designed to study the prevalence and impact of LUTS among both men and women in a racially, ethnically, and socioeconomically diverse population. METHODS: The BACH Survey used a stratified 2-stage cluster design to randomly sample 5506 adults aged 30 to 79 from the city of Boston, Mass (2301 men, 3205 women, 1770 blacks, 1877 Hispanics, and 1859 whites). Data were obtained using interviewer and self-administered questionnaires. The presence of LUTS was defined as an American Urological Association symptom index score of 8 or above. Quality of life was assessed using the Medical Outcomes Study 12-Item Short Form Survey (SF-12), and a measure of bother was based on the interference of urinary symptoms with various activities. Analyses were weighted to the Boston population using SUDAAN version 9.0 statistical software. RESULTS: The overall prevalence of LUTS was 18.7% and increased with age (10.5% at age 30-39 years to 25.5% at age 70-79 years) but did not differ by sex or race/ethnicity. Quality of life was significantly reduced among those with LUTS, as measured by the bother of symptoms and the SF-12 component scores. Prevalence of prescription medication use for urinary symptoms was low even among participants with LUTS, with more than 90% of participants reporting no medication use. CONCLUSIONS: In this population-based, racially and ethnically diverse random sample, LUTS were common among both men and women and increased substantially with age. Lower urinary tract symptoms had a negative impact on quality of life across age, sex, and race/ethnic groups.

Kurzman, I. D., E. G. MacEwen, et al. (1995). "Adjuvant therapy for osteosarcoma in dogs: results of randomized clinical trials using combined liposome-encapsulated muramyl tripeptide and cisplatin." Clin Cancer Res 1(12): 1595-1601.

Two randomized, double-blind clinical trials in dogs with spontaneous appendicular osteosarcoma treated with combination chemoimmunotherapy are reported. In both trials, dogs without overt metastasis underwent complete amputation of the affected limb. In trial 1, 40 dogs were treated with cisplatin chemotherapy [(CDDP), 70 mg/m2 i.v. every 28 days x 4]. Following CDDP, dogs without evidence of overt metastasis (n = 25) were randomized to receive liposome-encapsulated muramyl tripeptide phosphatidylethanolamine ](L-MTP-PE), 2 mg/m2 i.v.) or placebo liposomes (lipid equivalent) twice weekly for 8 weeks. Of 14 dogs in the placebo group, 13 (93%) died of metastasis; the median survival time was 9.8 months. Of 11 dogs in the L-MTP-PE group, 8 (73%) developed metastasis; the median survival time was 14.4 months, which was significantly longer than that of the placebo group (P < 0.01). In trial 2, 64 dogs received CDDP (70 mg/m2 i.v. every 21 days x 4) and were randomized to concurrently receive L-MTP-PE (2 mg/m2 i.v.) twice or once weekly, or placebo liposomes once weekly for 8 weeks. Median survival times were 10.3, 10.5, and 7.6 months, respectively. There were no significant differences among the three treatment groups in trial 2. Survival times for dogs receiving L-MTP-PE in trial 1 were significantly longer than those for dogs in trial 2 that received four doses of CDDP concurrently with twice weekly L-MTP-PE (P < 0. 04). The results of the first trial confirm our previous observation that L-MTP-PE has antimetastatic activity in dogs with osteosarcoma when given following amputation. The results of the