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Recent reports show a correlation between renal tumor radiographic characteristics and pathologic features. We hypothesize that a more central location within the relatively hypoxic renal medulla might confer a more aggressive tumor phenotype. To test this, radiographic tumor characteristics were compared with tumor grade and histology.We retrospectively reviewed renal masses 4 cm in diameter that underwent resection between 2008 and 2013. Tumor location was recorded using standard R.E.N.A.L. Nephrometry Score. Multivariate logistic regression was performed to compare independent anatomic features with incidence of malignancy and high nuclear grade.A total of 334 renal tumors had information available for analysis. Univariate analysis showed that increasing endophycity and proximity to the collecting system (4 mm) were predictors of malignancy and high-grade features. In multivariate analysis, proximity to the collecting system 4 mm remained the as the only anatomical variable predictive of malignancy (odds ratio [OR], 3.58; 95% confidence interval [CI], 1.06-12.05; P = .04) and high nuclear grade (OR, 2.81; 95% CI, 1.44-5.51; P = .003).Malignancy and high tumor grade occur with much greater frequency when tumors are located deep in the kidney, in close proximity to the collecting system and renal sinus. Ninety-six percent of small renal masses in this region were cancers and nearly half were Fuhrman Grade 3 or 4, suggesting that these small centrally located tumors should be targeted for early intervention.

Objective To improve risk stratification for recurrence prognostication in patients with localised clear cell renal cell carcinoma (ccRCC). Patients and Methods In all, 367 patients with non-metastatic ccRCC were included. The cohort was divided into a training and validation set. Using tissue microarrays, immunostaining was performed for 24 biomarkers representative of key pathways in ccRCC. Using Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression, we identified several markers that were used to construct a risk classifier for risk of disease recurrence. Results The median (interquartile range) follow-up was 63.5 (24.0–85.3) months. Five out of 24 markers were selected by LASSO Cox regression for the risk classifier: N-cadherin, E-cadherin, Ki67, cyclin D1 and phosphorylated eukaryotic initiation factor 4E binding protein-1 (p-4EBP1). Patients were classified as either low, intermediate or high risk of disease recurrence by tertiles of risk score. The 5-year recurrence-free survival (RFS) was 93.8%, 87.7% and 70% for patients with low-, intermediate- and high-risk scores, respectively (P < 0.001). Patients with a high marker score had worse RFS on multivariate analysis adjusted for age, gender, race and the Mayo Clinic Stage, Size, Grade, and Necrosis (SSIGN) score (hazard ratio 3.66, 95% confidence interval 1.58–8.49, P = 0.003 for high vs low marker score in the overall cohort). The five-marker classifier increased the concordance index of the clinical model in both the training and validation sets. Conclusion We developed a five-marker-based prognostic tool that can effectively classify patients with ccRCC according to risk of disease recurrence after surgery. This tool, if prospectively validated, could provide individualised risk estimation for patients with ccRCC.

To assess the potential biologic impact of tumor location on oncological outcomes for patients with upper tract urothelial carcinoma (UTUC), we used prospectively collected molecular signatures of high-grade UTUC. Immunohistochemical staining for p21, p27, p53, cyclin E, and Ki-67 was prospectively performed on 96 UTUC specimens of patients with non-metastatic high-grade UTUC treated with extirpative surgery. Patients were grouped according to primary tumor location (pelvicalyceal vs. ureteral) where primary tumor was defined as the highest tumor stage and diameter. Primary outcome was assessment of differences in marker expression between groups. Secondary outcome was difference in survival according to marker status. Pelvicalyceal and ureteral tumors were found in 52.1 and 47.9 %, respectively, and 42.7 % of patients had non-organ-confined disease. Over a median follow-up of 22.0 months, 31.2 and 20.8 % of patients experienced disease recurrence and died of UTUC, respectively. The total number of altered markers stained for was 0–2 in 67.7 and 3–5 in 32.3 % of patients. The number of altered markers and alteration status of markers were not significantly different between patients with primary pelvicalyceal versus ureteral tumors when stratified by tumor stage and nodal status. There were no significant differences in survival outcomes between both groups when stratified by number of altered markers (0–2 and 3–5). The prospective assessment of selected cell cycle and proliferative markers suggests no molecular difference between UTUC of the pelvicalyceal system and that of the ureter. Our study is limited by its size and definition of location.

Suprahepatic inferior vena caval tumor thrombus in renal cell carcinoma cases has historically portended a poor prognosis. With advances in perioperative treatment of patients with high level thrombus contemporary outcomes are hypothesized to be improved. We evaluated long-term oncologic outcomes of contemporary surgical treatment of patients with renal cell carcinoma in whom level III-IV inferior vena caval thrombus was managed at high volume centers.We examined clinical and pathological data on patients with renal cell carcinoma and level III-IV thrombus treated with surgery from January 2000 to June 2013 at 4 tertiary referral centers. Survival outcomes and associated prognostic variables were assessed by Kaplan-Meier and multivariate Cox regression analyses.We identified 166 patients, including 69 with level III and 97 with level IV thrombus. Median postoperative followup was 27.8 months. Patients with no evidence of nodal or distant metastasis (pN0/X, M0) had 5-year 49.0% cancer specific survival and 42.2% overall survival. There was no difference in survival based on tumor thrombus level or pathological tumor stage. Variables associated with an increased risk of death from kidney cancer on multivariate analysis were regional nodal metastases (HR 3.94, p0.0001), systemic metastases (HR 2.39, p = 0.01), tumor grade 4 (HR 2.25, p = 0.02), histological tissue necrosis (HR 3.11, p = 0.004) and increased preoperative serum alkaline phosphatase (HR 2.30, p = 0.006).Contemporary surgical management achieves almost 50% 5-year survival in patients without metastasis who have renal cell carcinoma thrombus above the hepatic veins. Factors associated with increased mortality included nodal/distant metastases, advanced grade, histological necrosis and increased preoperative serum alkaline phosphatase. These findings support an aggressive surgical approach to the treatment of patients with renal cell carcinoma who have advanced tumor thrombus.

We determined the association of the proliferation marker Ki-67 with pathological parameters and oncologic outcomes in patients with high grade upper tract urothelial carcinoma.Immunohistochemical staining for Ki-67 was done prospectively in 101 consecutive patients undergoing radical nephroureterectomy/ureterectomy for high grade upper tract urothelial carcinoma. Data were compared based on Ki-67 status (normal vs over expressed). Survival was assessed by the Kaplan-Meier method. Cox regression analysis was done to identify independent predictors of time dependent outcomes.Median patient age was 70.0 years and median followup was 22.0 months (range 1 to 77). Overall, 30.2% of the population experienced recurrence and 24.8% died of upper tract urothelial carcinoma. Organ confined disease (T2 or less and lymph node negative), lymphovascular invasion and sessile architecture were present in 56.3%, 33.3% and 20.8% of patients, respectively. Ki-67 was over expressed in 73.3% of patients and associated with adverse pathological features. Patients with over expressed Ki-67 had significantly worse recurrence-free survival (43.2 vs 69.0 months, p = 0.006) and cancer specific survival (48.9 vs 68.9 months, p = 0.031) than patients with normal Ki-67. Patients with nonmetastatic disease similarly had worse recurrence-free survival (40.7 vs 71.8 months, p = 0.003) and cancer specific survival (41 months vs not attained, p = 0.008) for over expressed vs normal Ki-67. After adjusting for the effects of organ vs nonorgan confined disease Ki-67 over expression was an independent predictor of recurrence-free survival in the total cohort (HR 4.3, p = 0.05) and in patients with nonmetastatic disease (HR 8.5, p = 0.038).Ki-67 over expression was associated with adverse pathological features in cases of upper tract urothelial carcinoma. It was also an independent predictor of recurrence-free survival in patients with high grade upper tract urothelial carcinoma.

Purpose: Patients with atypical cytology and equivocal or negative cystoscopy pose a challenge due to uncertainty about the presence of cancer. We determined the cost-effectiveness of using fluorescence in situ hybridization assays to determine the need for biopsy in patients with atypical cytology and equivocal or negative cystoscopy.Materials and Methods: Data from 2 large prospective studies evaluating the usefulness of fluorescence in situ hybridization in the setting of atypical cytology to detect urothelial carcinoma were combined. The data were used to calculate sensitivity and specificity for the UroVysion® fluorescence in situ hybridization assay in various clinical scenarios. Cost data were obtained from our institution and Medicare reimbursement rates. Evaluations with or without bladder biopsy and with or without upper tract evaluation were considered.Results: The study included 263 patients with atypical cytology and equivocal (62) or negative (201) cystoscopy. In patients with equivocal cyst...

Objective To validate the impact of Ki67 expression on oncological outcomes of patients treated for clinically localized clear-cell renal cell carcinoma (ccRCC). Patients and Methods Immunohistochemistry for Ki67 was performed on tissue microarray constructs of patients treated with radical or partial nephrectomy for clinically localized (M0) ccRCC and Ki67 expression >10% was considered abnormal. Clinical and pathological data elements were entered into an institutional review board-approved database. The Kaplan–Meier method and Cox regression models were used to analyse disease-free survival (DFS) and cancer-specific survival (CSS) probabilities. Results Of 401 patients, 59.6% were males. The median (range) age was 58 (17–85) years, follow-up was 22 (0–150) months and time to death was 27 (0–150) months. A total of 20.2% of patients had advanced stage (pT3–T4) and 31% had advanced grade (3–4) disease. Abnormal expression of Ki67 was seen in 6.5% of our cohort and was associated with adverse pathological features (P < 0.05). Patients with high expression of Ki67 were found to have 5-year DFS and CSS rates of 67 and 84%, respectively, vs 87 and 95%, respectively, in those with normal expression (P < 0.001 and P < 0.05, respectively). In multivariable analyses, adjusting for stage and grade, abnormal Ki67 expression was an independent predictor of DFS (hazard ratio [HR] 3.77, P = 0.011, 95% confidence interval [CI] 1.35–10.52), but not of CSS (HR 3.51 P = 0.137, 95% CI 0.671–18.35). Conclusions Our findings support the role of Ki67 as a powerful independent predictor of inferior oncological outcomes in patients with ccRCC. Further prospective studies are needed to determine the clinical applicability of these findings.

Objective To compare oncologic outcomes in an international cohort of patients who underwent either partial ureterectomy (PU) or radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). Methods A subgroup of patients from the UTUC Collaboration with operation classified as PU or RNU was used (n = 835). Clinicopathologic outcomes were evaluated. Survival was assessed using the Kaplan-Meier method. Cox regression addressed recurrence-free survival (RFS) and cancer-specific survival (CSS). Results Median age and follow-up were 69 years (range 32-97 years) and 34 months (range 1-246 months), respectively. Relapse occurred in 28.5% of patients (19.6% local, 8.9% systemic). At analysis, 180 patients (21.6%) died of UTUC. Eighty-one patients (9.7%) underwent PU and 754 (90.3%) underwent RNU. High tumor grade (77.3% vs 55.6%, P T1, 41.7% vs 30.9%, P

Use of metallic stents (Resonance) has been reported in the literature to be effective in relieving extrinsic obstruction in adults. Successful patency rates have been reported to be around 83.3%. The use of Resonance stents in children has not been reported. We present our experience with these stents in addressing extrinsic ureteral obstruction in the pediatric population.We identified two patients who underwent placement of Resonance stents for extrinsic compression at the Children's Hospital of the University of Pittsburgh Medical Center. The first patient is a 12-year-old girl with a solitary left kidney who had a diagnosis of pelvic rhabdomyosarcoma; she was treated with surgery followed by adjuvant chemoradiation. Two years post-treatment, worsening renal function secondary to ureteral strictures developed. The second patient is a 14-year-old girl with a history of Gardner syndrome. Recurrent desmoid tumors developed in her pelvis and retroperitoneum that led to right ureteral obstruction, necessitating a nephrostomy tube.Both patients underwent successful technical placement of a Resonance stent. The time to failure for patient 1 was 3 months and for patient 2, 3 weeks. The first patient presented to the emergency department 3 months poststent in renal failure with a creatinine level of 13.7 mg/dL. This necessitated nephrostomy tube placement and hemodialysis. Ultimately, she needed an ileal ureter to preserve renal function. She is off hemodialysis and has a creatinine level of 2.2 mg/dL.The second patient, recurrent episodes of pyelonephritis, worsening hydronephrosis, and flank pain developed with just the Resonance stent in place. It was elected to remove the Resonance stent and replace the nephrostomy tube. She needed extensive ureterolysis, a right subtotal ureterectomy with a right to left ureteroureterostomy.We did not find the use of these stents to be effective in children. The time to failure was significantly shorter in children than those reported in the literature for adults.

Upper tract urothelial cancer (UTUC) accounts for roughly 5 % of all urothelial cancers. At presentation, 30 % of patients demonstrate invasive and/or locally advanced disease, 30-40 % have regional lymph node involvement, and 20 % harbor metastatic disease. Systemic recurrence and progression rates after surgery for patients with advanced disease range between 45-60 %. Five-year cancer specific survival rates for pT2 and pT3 tumors are 73 % and 40 %, respectively. Median survival for patients with pT4 disease is approximately 6 months. Nonetheless, there is a lack of improvement in the rates of systemic recurrence and progression in patients with advanced UTUC. Extrapolating evidence obtained from experience with multi-modal therapy of patients with urothelial bladder cancer, additional improvements in oncological outcomes for patients with UTUC can be achieved through integration of effective systemic chemotherapy with local tumor control. We provide an overview of the rationale and utilization strategies of peri-operative systemic chemotherapy in patients with UTUC.

Upper tract urothelial cancers (UTUC) are uncommon and the information guiding their management used to be driven from small single center studies. Multi-center international collaborations should provide clinicians with best management practices as well as prognostic factors guiding treatment decisions and outcomes. We reviewed literature from the largest multicenter collaborations for radical nephroureterctomy (RNU) performed for management of UTUC. Our review included over 50 recent manuscripts from 2009-2012 that were published from multi-center UTUC collaboration groups. Our review aims to determine of the prognostic factors predicting oncological outcomes after RNU and to provide insights about possible maximization of cure with utilization of multimodal treatment approaches. Application of approaches comprising RNU including lymphadenectomy and systemic chemotherapy; particularly in neoadjuvant settings; might have implications on improvement of oncological outcomes in high risk patients.

We evaluated percutaneous access for percutaneous nephrolithotomy (PCNL) that was obtained by interventional radiologists or urologists at a single academic institution and compared access outcomes and complications.The records of 233 patients who underwent PCNL at the University of Pittsburgh Medical Center between 2000 and 2008 were retrospectively reviewed. Patients were stratified according to percutaneous access by urologists (group 1) or a group of interventional radiologists (group 2) in 195 and 38 patients, respectively. Radiologist-acquired access was performed for collecting system decompression in 33.3% of patients in group 2. A predicted access difficulty score was calculated using demographic, stone, and operative variables. Percutaneous access complications and stone-free rates were compared between groups.Mean patient age was 53 ± 16 years (51% male, range 19-90 y) and 58 ± 17 years (62% male, range 25-95 y) in groups 1 and 2, respectively. Use of multiple access tracts (4.3% vs 5.4%; P = 0.54), mean stone diameter (3.5 ± 1.8 cm vs 3.6 ± 1.9 cm; P = 0.97), and percentage of supracostal tracts (36% vs 35%; P = 0.63) were comparable between groups. Mean access difficulty parameters were comparable between groups. The percentage of staghorn calculi (39% vs 30%; P = 0.28) and number of obese (body mass index30) patients (30% vs 38%; P = 0.34) were also comparable between groups 1 and 2. The complication rate was the same in the two groups (14.3% vs 13.5%; P = 0.52). The overall stone-free rate was significantly greater in the urology access group (99% vs 92.1%; P = 0.033) on univariate analysis. Radiologist-obtained access could not be used in 36.8% of patients, necessitating additional access tract placement at the time of surgery.Urologist-obtained access is safe and effective for PCNL. Access obtained by radiologists for decompression of infected or obstructed systems often is not adequate for PCNL. Despite similar stone complexity and access difficulty, urologist-obtained access was associated with a statistically significant improvement in overall stone-free rate.

In the 1980s, the advent of shock wave lithotripsy (SWL) revolutionized pediatric stone management and is currently the procedure of choice in treating most upper tract calculi < 1.5 cm in children. However, with miniaturization of instruments and refinement of surgical technique the management of pediatric stone disease has undergone a dramatic evolution over the past twenty years. In a growing number of centers, ureteroscopy (URS) is now being performed in cases that previously would have been treated with SWL or percutaneous nephrolithotomy (PCNL). PCNL has replaced open surgical techniques for the treatment of large stone burdens> 2 cm with efficacy and complication rates similar to the adult population. Recent results of retrospective reviews of large single institution series demonstrate stone free and complication rates with URS comparable to PCNL and SWL but concerns remain with these techniques regarding renal development and damage to the pediatric urinary tract. Randomized controlled trials comparing the efficacy of SWL and URS for upper tract stone burden are needed to reach consensus regarding the most effective primary treatment modality in children. This report provides a comprehensive review of the literature evaluating the indications, techniques, complications, and efficacy of endourologic stone management in children.

OBJECTIVES Urinary retention after urethral catheter removal is a well-established complication of radical prostatectomy (RP). Its effect on subsequent urethral stricture formation has not been established. The objective of this study was to evaluate the association between post-RP early urinary retention (EUR) and subsequent symptomatic urethral stricture formation. METHODS A total of 1289 patients who underwent RP from January 1998 to November 2004 at our tertiary medical center were included in a prospective database project. EUR was defined as that which occurred 7 days or earlier after urethral catheter removal and was identified by retrospective chart review. Multivariate logistic regression models were constructed to evaluate the association between EUR and symptomatic urethral stricture formation. RESULTS Of the 1289 patients, 44 (3.4%) experienced EUR, and 16 of these patients (36.4%) developed symptomatic urethral strictures. The stricture rate for patients without EUR was 9.0% (112 of 1245). Compared with the patients without EUR, the patients with EUR had a greater rate of bladder neck contracture (94% versus 68%, P = 0.04) and exhibited a significantly decreased time to stricture formation (1.6 months versus 3.0 months, P = 0.002). After adjusting for patient age, clinical stage, surgeon, and Gleason score, the odds of developing a symptomatic urethral stricture were 4.7 times greater in the patients with EUR (95% confidence interval 2.3 to 9.6). CONCLUSIONS The results of this study have shown that patients with EUR after RP are at a significantly greater risk of developing symptomatic urethral strictures, tend to form bladder neck contractures instead of more distal strictures, and to form strictures sooner after surgery. EUR might be a previously unrecognized risk factor for the development of post-RP urethral stricture.

Background: To assess pathological correlations and temporal trends of Angiopoietin-2 (ANGPT2), vascular endothelial growth factor (VEGF) and M2 Pyruvate kinase (TuM2PK), markers of tumor vascular development and metabolism, in patients with renal cell carcinoma (RCC). Methods: We prospectively collected plasma samples from 89 patients who underwent surgical/ablative therapy for RCC and 38 patients with benign disease (nephrolithiasis, hematuria without apparent neoplastic origin, or renal cysts). In RCC patients, marker levels were compared between at least 1 preoperative and 1 postoperative time point generally 3 weeks after surgery. Marker temporal trends were assessed using the Wilcoxon sign-rank test. Plasma VEGF, ANGPT2, and TuM2PK levels were determined by ELISA and tested for association with pathological variables. Results: Median age was comparable between groups. 83/89 (93%) of the cohort underwent surgical extirpation. 82% of the tumors were organ confined (T ≤2, N0). Only ANGPT2 exhibited significantly elevated preoperative levels in patients with RCC compared to benign disease (p= 0.046). Elevated preoperative levels of ANGPT2 and TuM2PK significantly correlated with increased tumor size and advanced grade (p< 0.05). Chromophobe RCC exhibited higher levels of ANGPT2 compared to other histologies (p < 0.05). A decline in marker level after surgery was not observed, likely due to the timing of the analyses. Conclusion: Our results suggest that ANGPT2 is a marker of RCC. Additionally, ANGPT2 and TuM2PK significantly correlated with several adverse pathological features. Further studies are needed to determine clinical applicability.

Objective: Surgical resection for renal cell carcinoma (RCC) with suprahepatic inferior vena cava tumor thrombus is associated with significant morbidity, yet there are currently no tools for preoperative prognostic evaluation. Our goal was to develop a preoperative multivariable model for prediction of survival and risk of major complications in patients with suprahepatic thrombi. Methods: We identified patients who underwent surgery for RCC with suprahepatic tumor thrombus extension from 2000 to 2013 at 4 tertiary centers. A Cox proportional hazard model was used for analysis of overall survival (OS) and logistic regression was used for major complications within 90 days of surgery (Clavien Z3A). Nomograms were internally calibrated by bootstrap resampling method. Results: A total of 49 patients with level III thrombus and 83 patients with level IV thrombus were identified. During median follow-up of 24.5 months, 80 patients (60.6%) died and 46 patients (34.8%) experienced major complication. Independent prognostic factors for OS included distant metastases at presentation (hazard ratio 1⁄4 2.52, P 1⁄4 0.002) and Eastern Cooperative Oncology Group (ECOG) performance status (hazard ratio 1⁄4 1.84, P o 0.0001). Variables associated with increased risk of major complications on univariate analysis included preoperative systemic symptoms, level IV thrombus, and elevated preoperative alkaline phosphatase and aspartate transaminase levels; however, only systemic symptoms (odds ratio 1⁄4 8.45, P o 0.0001) was an independent prognostic factor. Preoperative nomograms achieved a concordance index of 0.72 for OS and 0.83 for major complications. Conclusions: We have developed and internally validated multivariable preoperative models for the prediction of survival and major complications in patients with RCC who have a suprahepatic inferior vena cava thrombus. If externally validated, these tools may aid in patient selection for surgical intervention. r 2015 Elsevier Inc. All rights reserved.

Surgical resection for renal cell carcinoma (RCC) with suprahepatic inferior vena cava tumor thrombus is associated with significant morbidity, yet there are currently no tools for preoperative prognostic evaluation. Our goal was to develop a preoperative multivariable model for prediction of survival and risk of major complications in patients with suprahepatic thrombi.We identified patients who underwent surgery for RCC with suprahepatic tumor thrombus extension from 2000 to 2013 at 4 tertiary centers. A Cox proportional hazard model was used for analysis of overall survival (OS) and logistic regression was used for major complications within 90 days of surgery (Clavien ≥ 3A). Nomograms were internally calibrated by bootstrap resampling method.A total of 49 patients with level III thrombus and 83 patients with level IV thrombus were identified. During median follow-up of 24.5 months, 80 patients (60.6%) died and 46 patients (34.8%) experienced major complication. Independent prognostic factors for OS included distant metastases at presentation (hazard ratio = 2.52, P = 0.002) and Eastern Cooperative Oncology Group (ECOG) performance status (hazard ratio = 1.84, P0.0001). Variables associated with increased risk of major complications on univariate analysis included preoperative systemic symptoms, level IV thrombus, and elevated preoperative alkaline phosphatase and aspartate transaminase levels; however, only systemic symptoms (odds ratio = 8.45, P0.0001) was an independent prognostic factor. Preoperative nomograms achieved a concordance index of 0.72 for OS and 0.83 for major complications.We have developed and internally validated multivariable preoperative models for the prediction of survival and major complications in patients with RCC who have a suprahepatic inferior vena cava thrombus. If externally validated, these tools may aid in patient selection for surgical intervention.

Obesity adversely affects surgical procedures and outcomes. We used a validated health related quality of life measure to examine the effects of obesity on disease specific health related quality of life before and following radical retropubic prostatectomy.From June 2000 to April 2003, 575 consecutive patients with prostate cancer were approached to participate in a prospective, health related quality of life study. Health related quality of life was assessed before surgery, and 1, 4, 12, 24 and 36 months postoperatively. Repeated measures mixed models were constructed to determine the independent effects of body mass index on health related quality of life.Of 472 consenting subjects 376 (80%) completed a baseline and at least 1 followup survey. Higher body mass index was associated with worse preoperative hormonal/vitality function (p = 0.0009) and bother (p = 0.02), and delayed recovery of bowel function (p = 0.01) and bother (p = 0.01) health related quality of life. There were no measurable differences postoperatively in hormonal/vitality, urinary or sexual health related quality of life associated with higher body mass index. Increased body mass index was associated with prostate specific antigen recurrence (p = 0.05) and adjuvant treatment (p = 0.02). Adjuvant treatment was independently associated with worse bowel function (p = 0.01) and bother (p = 0.01) health related quality of life in obese patients. At 24 months bowel health related quality of life in obese patients no longer significantly differed from that in nonobese patients.Obesity is associated with worse preoperative hormonal/vitality health related quality of life, slower recovery of bowel function and bother health related quality of life after radical retropubic prostatectomy, and prostate specific antigen recurrence. Impaired health related quality of life recovery in obese patients is influenced by disease recurrence and resultant adjuvant therapies. Despite these findings obese patients should not be dissuaded from considering prostatectomy as definitive treatment for localized prostate cancer.

The pliability of cancer cells to mutate into several different phenotypes in an attempt to find one that will survive and colonize at the metastatic site is a tremendous "hurdle" to overcome in designing novel cancer therapeutics. New targets of therapy are essential if we are to effectively overcome the evasiveness of cancer. The interaction between the tumor cell and the surrounding microenvironment creates a vicious cycle that perpetuates disease survival and progression. The future of cancer therapy resides in the ability to focus on the recruited and exploited relationships of the cancer cell with the host environment. These therapies target cancer cell growth early and interrupt the vicious cycle that is created by the tumor cells interacting with bone components by inhibiting osteoclasts, osteoblasts, stromal cells, and endothelial cells. They alter the bone microenvironment, creating a hostile "soil" that prevents the "seed" from developing into bone metastases and represent a potential new platform for the development of prostate cancer therapeutics.

Prostate cancer continues to be the second leading cause of cancer related mortality in men within the United States. Despite a consistent decline in prostate cancer mortality over the past two decades, the prognosis for men with metastatic prostate cancer remains poor with no curative therapies. In this article, we review the recently approved and emerging therapeutics for patients with castrate resistant prostate cancer.An advanced search was conducted on the clinicaltrials.gov database, using search terms "metastatic prostate cancer", and limiting results to phase II-IV clinical trials. Clinically relevant emerging therapeutics were selected and a Medline search for supporting documents was performed. An emphasis was placed on newly approved and promising new therapeutics.A total of four Food and Drug Administration approved medications and eight investigational agents were chosen for review. The background and role of these therapeutics in the treatment of prostate cancer treatment is discussed.The past few years have yielded a near exponential increase in treatments for metastatic prostate cancer, many of which have a unique mechanism of action. The estimated median survival for patients with metastatic prostate cancer remains dynamic as we begin to integrate these therapeutics into clinical practice and determine the optimal sequence and timing of treatment.

Objective: To prospectively evaluate the feasibility of obtaining a reliable histochemical assessment of cell cycle biomarkers from endoscopic biopsy specimens of patients with upper tract urothelial cancer. Methods: Overall, 17 patients were identified who had an available biopsy as well as those who underwent subsequent radical nephroureterectomy (RNU) or segmental ureterectomy (SU) for clinically localized high-grade upper tract urothelial cancer of the renal pelvis or ureter. Of those 17 patients, 15 (88%) had sufficient tissue to undergo immunohistochemical staining. Biopsies were obtained using various endoscopic techniques. Tumor characteristics were recorded and prospectively evaluated for immunohistochemical expression of 5 biomarkers: p21, p27, p53, cyclin E, and Ki67/pRb. Unfavorable prognostic score (PS) was defined as 42 altered markers. Results: The median age of the patients was 68 years (range: 53–82 y) with 87% being males. Of the 15 specimens, 9 (60%) tumors were organ confined (T r 2 and N0), and all were high grade. Of the 15 patients, 4 (27%), 7 (46.6%), 3 (20%), and 1 (6.7%) individuals had 1, 2, 3, and 5 markers altered on biopsy marker profiling, respectively, with Ki67 being the most frequent alteration (13/15; 87.7%). An overall concordance rate of 60% (9/15) was seen between biopsy and RNU/SU PS. Those patients with favorable biopsy biomarker PS were less likely to display adverse pathological features, with organ-confined disease in 7/11 (63.6%) patients and 9/11 (81.8%) being free of carcinoma in situ in the final specimen. Additionally, 10/11 (91%) had no evidence of necrosis and 7/11 (64%) had no evidence of lymphovascular invasion on final pathologic evaluation. Conclusions: Preliminary results suggest that obtaining interpretable biomarker profile of ureteroscopic biopsy specimens is feasible. Tumor heterogeneity and limited biopsy material may account for the discordance between biopsy and RNU/SU specimens. Meaningful biopsy biomarker profiling could serve as a powerful tool for individualizing treatment regimens and augmenting current predictive variables. Further studies are needed to evaluate clinical applicability. r 2014 Elsevier Inc. All rights reserved.

10.8 mos (range: 0.7-37.8). The median primary renal mass size was 8.3cm with 5.9cm sized necrosis. Among the three different times of CT scans, higher correlation of first CT with prognosis of progression (OR 5.843, p1⁄40.022) was found than the others. The tumor size reduction with necrotic size increasing (0.72cm, HR 2.505, CI 1.348-4.655; p1⁄40.004) at initial CT after 1st or 2nd cycle of TT, enhancing HU changes after TTS compared to baseline CT (HR 0.967, CI 0.938-0.996; p1⁄40.025), and RCC histology (HR 0.004 CI 0.000-0.597, p1⁄40.031) were significantly related to the prognosis of survival in patients with mRCC in multivariate analysis (p

Objective To evaluate the prognostic value of altered mammalian target of rapamycin (mTOR) pathway biomarkers in upper tract urothelial carcinoma (UTUC). Materials and Methods We performed a multi-institutional review of clinical and pathologic information on patients receiving extirpative surgery for UTUC from 1990 to 2008. Immunohistochemistry for phosphorylated-S6, mTOR, phosphorylated-mTOR, PI3K, phosphorylated-4EBP1, phosphorylated-AKT, PTEN, HIF-1a, raptor, and cyclin D was performed on tissue microarrays from radical nephroureterectomy (RNU) specimens. Prognostic markers were identified and the significance of altered markers was assessed with the Kaplan-Meier analysis and the Cox regression analysis. Results Six hundred twenty patients were included. Over a median follow-up of 27.3 months, 24.6% of patients recurred and 21.8% died of UTUC. On multivariate analysis, PI3K (odds ratio, 1.28; P = .001) and cyclin D (odds ratio, 3.45; P = .05) were significant predictors of clinical outcomes. Cumulative marker score was defined as low risk (no altered markers or 1 altered marker) or high risk (cyclin D and PI3K altered). Patients with high-risk marker score had a significantly higher proportion of high-grade disease (91% vs 71%; P

Androgen deprivation therapy is the mainstay treatment for patients with prostate cancer who are not candidates for definitive treatment, are diagnosed with advanced disease on initial presentation or progress after primary treatment. Patients who stop responding to androgen deprivation therapy develop castration resistant prostate cancer (CRPC). Emerging drugs undergoing clinical evaluation and drugs that have recently received FDA approval for the treatment of CRPC are reviewed.As the natural history and signaling pathways of prostate cancer are better understood, new treatments and targeted therapies will be developed. The FDA recently approved 5 medications that increase survival in patients with CRPC. Additional medications and drug classes are being explored that may eventually lead to new treatment options. Articles were identified using a PubMed database search.Recent FDA medication approvals and the development of emerging treatments are promising for the future of patients with prostate cancer. The addition of new medications challenges physicians to identify the optimal sequence and/or combination in which newer and older medications should be administered. Physicians treating patients with prostate cancer have a growing responsibility to keep pace with these new medications so that they may counsel and treat patients appropriately.

Epithelial-to-mesenchymal transition is thought to have a crucial role in cancer progression and metastatic egress. We evaluated the association of β-catenin, an important mediator of epithelial-to-mesenchymal transition, with pathological parameters and oncologic outcomes in patients with clear cell renal cell carcinoma.Immunohistochemical staining was performed for β-catenin on tissue microarrays of patients with nonmetastatic clear cell renal cell carcinoma. Membranous and cytoplasmic expression patterns were assessed separately. β-Catenin was considered dysregulated if membranous as well as cytoplasmic expression was abnormal. Groups were compared based on normal vs dysregulated β-catenin. Survival probabilities were assessed by the Kaplan-Meier method. Cox proportional hazard models were used to identify predictors of oncologic outcomes.Included in the study were 406 patients with a median followup of 58 months. Of the patients 52 (12.8%) and 25 (6.2%) experienced recurrence and died of clear cell renal cell carcinoma, respectively. β-Catenin was dysregulated in 70 patients (17.2%). Dysregulation was uniformly associated with adverse pathological features, including advanced T stage, larger tumor diameter, nodal positivity, higher Fuhrman grade, tumor thrombus, sarcomatoid features, necrosis and lymphovascular invasion (each p0.001). Patients with dysregulated β-catenin had inferior recurrence-free and cancer specific survival (each p0.001). On multivariate analysis adjusting for tumor stage, nodal status and grade dysregulation was an independent predictor of recurrence-free and cancer specific survival (HR 2.2, 95% CI 1.2-3.9, p=0.008 and HR 2.4, 95% CI 1.1-5.6, p=0.044, respectively).Dysregulation of β-catenin may be an important phenomenon in clear cell renal cell carcinoma carcinogenesis. These findings support further study of β-catenin, and systematic assessment of β-catenin and epithelial-to-mesenchymal transition in clear cell renal cell carcinoma.

To validate the impact of Ki67 expression on oncological outcomes of patients treated for clinically localized clear-cell renal cell carcinoma (ccRCC).Immunohistochemistry for Ki67 was performed on tissue microarray constructs of patients treated with radical or partial nephrectomy for clinically localized (M0) ccRCC and Ki67 expression10% was considered abnormal. Clinical and pathological data elements were entered into an institutional review board-approved database. The Kaplan-Meier method and Cox regression models were used to analyse disease-free survival (DFS) and cancer-specific survival (CSS) probabilities.Of 401 patients, 59.6% were males. The median (range) age was 58 (17-85) years, follow-up was 22 (0-150) months and time to death was 27 (0-150) months. A total of 20.2% of patients had advanced stage (pT3-T4) and 31% had advanced grade (3-4) disease. Abnormal expression of Ki67 was seen in 6.5% of our cohort and was associated with adverse pathological features (P0.05). Patients with high expression of Ki67 were found to have 5-year DFS and CSS rates of 67 and 84%, respectively, vs 87 and 95%, respectively, in those with normal expression (P0.001 and P0.05, respectively). In multivariable analyses, adjusting for stage and grade, abnormal Ki67 expression was an independent predictor of DFS (hazard ratio [HR] 3.77, P = 0.011, 95% confidence interval [CI] 1.35-10.52), but not of CSS (HR 3.51 P = 0.137, 95% CI 0.671-18.35).Our findings support the role of Ki67 as a powerful independent predictor of inferior oncological outcomes in patients with ccRCC. Further prospective studies are needed to determine the clinical applicability of these findings.

Cell cycle regulatory molecules are implicated in various stages of carcinogenesis. In this proof of principle study we systematically evaluate the association of aberrant expression of cell cycle regulators and proliferative markers and their effect on oncologic outcomes of patients with clear cell renal carcinoma.Immunohistochemistry for Cyclin D, Cyclin E, p16, p21, p27, p53, p57 and Ki67 was performed on tissue microarray constructs of 452 patients treated with extirpative therapy for clear cell renal cell carcinoma between 1997 and 2010. Clinical and pathological data elements were collected. A prognostic marker score was defined as unfavorable if more than 4 biomarkers were altered. The relationship between marker score and pathological features and oncologic outcomes was evaluated.Median age was 57 years (range 17 to 85) and median followup was 24 months (range 6 to 150). An unfavorable marker score was found in 55 (12.2%) patients and was associated with adverse pathological features. A significant correlation between unfavorable marker score and disease-free survival (HR 26.62, 95% CI 43.38-100.04, p=0.000) and with cancer specific survival (HR 8.15, 95% CI 74.42-101.56, p=0.004) was demonstrated on Kaplan-Meier survival analysis. On multivariate analysis an unfavorable marker score was an independent predictor of disease-free survival (HR 2.63, 95% CI 1.08-6.38, p=0.033).The cumulative number of aberrantly expressed cell cycle and proliferative biomarkers correlates with aggressive pathological features and inferior oncologic outcomes in patients with clear cell renal cell carcinoma. Our findings indicate that interrogation of cell cycle and proliferative markers is feasible, and further prospective pathway based exploration of biomarkers is needed.

We report the case of a 60-year-old male who presented withleft-sided back pain 1 month after an uncomplicated ureteroscopyand stone-basketing for left 6-mm mid-pole and 4-mm lower polestones.

Purpose To assess if a panel of cell-cycle markers could improve the discrimination of European Organization for Research and Treatment of Cancer (EORTC) and Spanish Urological Club for Oncological Treatment (CUETO) models in predicting recurrence and progression of high-grade non–muscle-invasive bladder cancer (NMIBC). Materials and methods Between January 2007 and January 2012, every patient with high-grade NMIBC treated with transurethral resection of bladder underwent immunohistochemical staining for 5 biomarkers (p21, p27, p53, KI-67, and cyclin E1). We excluded patients who had muscle-insvasive disease, underwent early cystectomy, and those with incomplete follow-up. Kaplan-Meier curves assessed recurrence and progression-free survival. Univariate and multivariate Cox regression analysis assessed the predictive ability of markers after correcting for EORTC or CUETO risk scores. Harrel concordance index assessed for discrimination. Results There were 131 patients with a median follow-up of 31.1 months. Stage was Ta (50%), T1 (44%), and Tis (8%). For 95 patients this was the primary tumor. Intravesical therapy was used in 76% of cases of which 45% had maintenance. Recurrence-free survival rates at 6, 12, and 24 months were 68.9%, 52.1%, and 33.2%, respectively, whereas progression-free survival rate at 6, 12, and 24 months were 93.8%, 88%, and 84.3%, respectively. No differences in survival based on number of altered markers were noted. Biomarker status was neither a significant predictor of recurrence nor progression. Marker alterations marginally improved discrimination of EORTC and CUETO models, which were confirmed to be mediocre. Conclusions Markers were not significant predictors of recurrence nor progression in patients with high-grade NMIBC and their addition to prediction models is of little benefit.

Purpose: Recent studies suggest a potential application for digoxin in the prevention and/or treatment of prostate cancer. However, the effect of digoxin on androgen receptor (AR)-positive prostate tumor in vivo is not clear. This study is designed to determine if digoxin can inhibit AR-positive xenograft prostate tumors. Materials and Methods: Athymic male nude mice were utilized to establish subcutaneous C4-2 castration-resistant prostate tumors. The animals were castrated and then treated with daily intraperitoneal (i.p.) injection of digoxin at 2mg/kg along with vehicle controls for 7 consecutive days. Tumor growth was determined by measuring tumor volume changes, blood vessel density by immunostaining of CD31, and cell proliferation by BrdU labeling. The expression of HIF-1a in C4-2 tumors was measured by Western blot and real-time RT-PCR. Results: Digoxin inhibited blood vessel density about fourfold and down-regulated HIF-1a expression at both mRNA and protein levels. However, digoxin did not inhibit C4-2 tumor growth. Conclusions: Digoxin is a potent inhibitor of HIF-1a signaling pathway and blood vessel formation in C4-2 castration-resistant prostate tumors. Clin Trans Sci 2012; Volume #: 1–4

We compared laparoscopic and robotic pyeloplasty to identify factors associated with procedural efficacy.We conducted a retrospective multicenter trial incorporating 865 cases from 15 centers. We collected perioperative data including anatomical and procedural factors. Failure was defined subjectively as pain that was unchanged or worse per medical records after surgery. Radiographic failure was defined as unchanged or worsening drainage on renal scans or worsening hydronephrosis on computerized tomography. Bivariate analyses were performed on all outcomes and multivariate analysis was used to assess factors associated with decreased freedom from secondary procedures.Of the cases 759 (274 laparoscopic pyeloplasties with a mean followup of 15 months and 465 robotic pyeloplasties with a mean followup of 11 months, p0.001) had sufficient data. Laparoscopic pyeloplasty, previous endopyelotomy and intraoperative crossing vessels were associated with decreased freedom from secondary procedures on bivariate analysis, with a 2-year freedom from secondary procedures of 87% for laparoscopic pyeloplasty vs 95% for robotic pyeloplasty, 81% vs 93% for patients with vs without previous endopyelotomy and 88% vs 95% for patients with vs without intraoperative crossing vessels, respectively. However, on multivariate analysis only previous endopyelotomy (HR 4.35) and intraoperative crossing vessels (HR 2.73) significantly impacted freedom from secondary procedures.Laparoscopic and robotic pyeloplasty are highly effective in treating ureteropelvic junction obstruction. There was no difference in their abilities to render the patient free from secondary procedures on multivariate analysis. Previous endopyelotomy and intraoperative crossing vessels reduced freedom from secondary procedures.

Angiomyolipomas (AMLs) are benign tumours characterized byfat, smooth muscle and vascular components. Epithelioid AMLis a recognized variant of AML that is comprised of epithelioidsmooth muscle cells. We present a case of a 41-year-old male whopresented with light-headedness, dizziness, right-sided abdominalpain and, on subsequent computed tomography, was found tohave an enormous right kidney mass characteristic of an AML.The patient underwent preoperative selective arterial embolizationfollowed by a right radical nephrectomy. The pathology revealed a36-cm AML with focal epithelioid features. Although uncommon,AMLs can present as enormous retroperitoneal masses.

To review our experience with laparoscopic ureteropelvic junction (UPJ) release in the treatment of UPJ obstruction (UPJO) in adults.We retrospectively reviewed 44 consecutive patients who underwent laparoscopic treatment of UPJO at our institution between December 2000 and April 2008. Patient characteristics, perioperative data, intraoperative findings leading to a decision to perform UPJ release, and outcomes were recorded. Mean patient age was 47.4 years (range 20-60 years).UPJ release was performed as definitive treatment in 9 of 47 laparoscopic procedures for UPJO. The obstruction was right-sided in five and left-sided in four patients. Three (33%) patients were previously treated with either balloon dilation or endopyelotomy, or both. Intraoperative findings included (1) significant scarring, inflammation, or fibrosis, (2) adherent bands between a crossing vessel and the UPJ, or (3) obvious constricting periureteral bands. A crossing vessel was observed in seven patients (78%). Mean operative time, estimated blood loss, and length of stay were 370.1 +/- 76.9 minutes, 24.4 +/- 31.3 mL, and 1.4 +/- 0.5 days, respectively. At a mean follow-up of 25.1 +/- 17.3 months, a 78% overall success rate was achieved. UPJ release was most successful in the patients in the "significant scarring, inflammation, or fibrosis" category (100%).Although pyeloplasty remains the preferred treatment for UPJO, UPJ release can be successful in certain circumstances, particularly when significant scarring, inflammation, or fibrosis appears to be the primary etiology of the obstruction. Further investigation is warranted to help define the specific clinical situations in which UPJ release may be beneficial.

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.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.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.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.

Purpose To compare renal function outcomes in patients undergoing radical nephroureterectomy (RNU) or partial (distal) ureterectomy (PU) for upper tract urothelial carcinoma (UTUC). Methods Clinicopathologic data of patients undergoing RNU or PU for UTUC from 1998 to 2012 were compiled. Glomerular filtration rate was calculated preoperatively and postoperatively using the Modification of Diet in Renal Disease equation. We defined “event” as new-onset stage III chronic kidney disease (CKD) or worsening of CKD stage with preexisting CKD. Event-free survival was assessed with Kaplan-Meier methods. Cox regression analyses were performed to identify predictors of events. Results In total, 193 patients underwent RNU ( n = 143) or PU ( n = 50) over a median follow-up of 25.9 months. Overall, 15% of patients died of UTUC. High tumor grade (85.9% vs. 66.0%, P = 0.003) and locally advanced stage (>pT2, 37.8% vs. 18.0%, P = 0.014) were significantly more frequent in the RNU cohort. Stage III or higher CKD was present in 61% of RNU patients vs. 48% of PU patients ( P = 0.135) at baseline. Although total event rate was higher in the PU cohort (66% vs. 43.4%, P = 0.008), event rates within the first 3 months of surgery were similar between the groups ( P = 0.572). Adjuvant chemotherapy was the only predictor of events on Cox regression. Conclusions Rates of new-onset CKD or worsening of CKD stage were similar in patients treated with RNU and PU. Adjuvant chemotherapy may have a more significant effect on renal outcomes than surgical approach, warranting further investigation. Consideration should be given to preoperative chemotherapy, as adjuvant chemotherapy is limited by decreased renal function following surgery.

Objective To prospectively evaluate the feasibility of obtaining a reliable histochemical assessment of cell cycle biomarkers from endoscopic biopsy specimens of patients with upper tract urothelial cancer. Methods Overall, 17 patients were identified who had an available biopsy as well as those who underwent subsequent radical nephroureterectomy (RNU) or segmental ureterectomy (SU) for clinically localized high-grade upper tract urothelial cancer of the renal pelvis or ureter. Of those 17 patients, 15 (88%) had sufficient tissue to undergo immunohistochemical staining. Biopsies were obtained using various endoscopic techniques. Tumor characteristics were recorded and prospectively evaluated for immunohistochemical expression of 5 biomarkers: p21, p27, p53, cyclin E, and Ki67/pRb. Unfavorable prognostic score (PS) was defined as>2 altered markers. Results The median age of the patients was 68 years (range: 53–82 y) with 87% being males. Of the 15 specimens, 9 (60%) tumors were organ confined (T≤2 and N0), and all were high grade. Of the 15 patients, 4 (27%), 7 (46.6%), 3 (20%), and 1 (6.7%) individuals had 1, 2, 3, and 5 markers altered on biopsy marker profiling, respectively, with Ki67 being the most frequent alteration (13/15; 87.7%). An overall concordance rate of 60% (9/15) was seen between biopsy and RNU/SU PS. Those patients with favorable biopsy biomarker PS were less likely to display adverse pathological features, with organ-confined disease in 7/11 (63.6%) patients and 9/11 (81.8%) being free of carcinoma in situ in the final specimen. Additionally, 10/11 (91%) had no evidence of necrosis and 7/11 (64%) had no evidence of lymphovascular invasion on final pathologic evaluation. Conclusions Preliminary results suggest that obtaining interpretable biomarker profile of ureteroscopic biopsy specimens is feasible. Tumor heterogeneity and limited biopsy material may account for the discordance between biopsy and RNU/SU specimens. Meaningful biopsy biomarker profiling could serve as a powerful tool for individualizing treatment regimens and augmenting current predictive variables. Further studies are needed to evaluate clinical applicability.

525 Background: There have been multiple reports implicating the role of hydronephrosis (HN) as a predictor of outcome in patients diagnosed with upper tract urothelial carcinoma (UTUC). However, this was done in mixed populations (low-/high-grade) and degree of HN (DOH) was not taken into account. We evaluated the impact of severity of hydronephrosis on systemic and bladder relapse in patients with UTUC. Methods: We retrospectively reviewed the records of 141 patients with localized UTUC that underwent extirpative surgery. Preoperative imaging was used to evaluate ipsilateral DOH. We analyzed the association between DOH (none/mild vs. moderate/severe), pathological findings and oncological outcomes in high-grade vs. low-grade patients. Bladder recurrence was assessed separately from local or systemic (L/S) recurrence. Results: High-grade UTUC was present in 80% of patients, 35% had muscle-invasive disease (≥pT2), and 29% had non-organ-confined disease. At a median follow-up of 34 months (range, 1-149), 35% of patients experienced intravesical recurrence, 20% developed L/S recurrence, and 17% died of UTUC. No difference in outcomes was seen between patients without HN and mild HN. DOH was none/mild in 55% and moderate/severe in 45% of cases. In patients with high-grade UTUC, moderate/severe HN was associated with advanced pathologic stage (p

323 Background: Alterations in the MTOR and HIF pathways may have prognostic significance in bladder carcinoma. We evaluated the predictive value of altered MTOR-pathway biomarkers in upper tract urothelial carcinoma (UTUC). Methods: Multi-institutional review of clinicopathological data on patients receiving extirpative surgery for UTUC from 1990-2008. Immunohistochemistry for phosphorylated-S6, mTOR, phosphorylated-mTOR, PI3K, p4E-BP, phosphorylated-AKT, PTEN, HIF-1a, Raptor and Cyclin D was performed on tissue microarrays from radical nephroureterectomy specimens. Predictive markers were identified by regression analyses. Significance of altered markers was assessed with Kaplan-Meier and Cox regression analysis. Results: 620 patients with a mean age of 69 years were included. 37% of patients had non-organ confined (T3/T4 and/or N+) disease. 74% of patients had high-grade disease and 22% had LVI on final pathology. Over a median follow-up of 27.3 months, 24.6% of patients recurred and 21.8% died of UTUC. On multivariable analysis, PI3K (OR 1.28, p=0.001) and Cyclin D (OR 3.45, p=0.05) were significant predictors of clinical outcomes. Cumulative marker-score was defined as low-risk (zero/one altered marker) or high-risk (Cyclin D AND PI3K altered). Patients with high-risk marker-score had a significantly higher proportion of high-grade disease (91% vs. 71%, p

493 Background: Epithelial to mesenchymal transition (EMT) is thought to play a crucial role in cancer progression and development of metastasis. Thus, we evaluated dysregulation of beta-catenin as a part of EMT and its clinical implications in patients with clear cell renal cell carcinoma (ccRCC). Methods: Immunohistochemical staining was performed for beta-catenin on tissue microarrays of patients with ccRCC. Membranous and cytoplasmatic beta-catenin expression patterns were assessed separately. Beta-catenin was considered normal if none or only one component was abnormal and was considered dysregulated if both components were abnormal. Differences in pathological characteristics between both groups were investigated. Differences in recurrence-free survival (RFS) and cancer-specific survival (CSS) were assessed with the Kaplan-Meier method. Uni- and multivariate Cox proportional hazard models were used to assess independent predictors of oncological outcomes. Results: 406 patients with a median follow-up of 58 months were included. Overall, 52 (12.8%) and 25 (6.2%) patients recurred and died of ccRCC. Beta-catenin was dysregulated in 70 (17.2%) patients. Dysregulation of beta-catenin was significantly associated with adverse pathologic features, such as higher T-stage, nodal positivity, higher grade, presence of tumor thrombus, sarcomatoid features, necrosis and LVI (all p