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Objective: To investigate the relationship of preoperative prostate size, urinary retention, positive urine culture, and histopathological evidence of prostatitis or incidental prostate cancer on baseline and 3-month nadir prostate-specific antigen (PSA) value after Holmium laser enucleation of prostate (HoLEP)., Patients and Methods: Data from 90 patients who underwent a HoLEP by En-bloc technique were analyzed. PSA values at baseline and at 3-month follow-up, preoperative urinary retention and urine culture status, weight of resected tissue, and histopathological evidence of prostatitis or prostate cancer were recorded. We performed univariable and multivariable gamma-regression analyses to determine the impact of the aforementioned perioperative variables on preoperative PSA, 3-month postoperative PSA, and change in PSA., Results: Serum PSA reduced significantly at 3 months from 6.3 ± 5.9 ng/mL to 0.6 ± 0.6 ng/mL. On both univariable and multivariable analysis, 3-month nadir level was independent of all preoperative factors examined, except preoperative urinary retention status. Although patients with smaller prostate (resected tissue weight <40 g) had less percentile reduction in PSA when compared with those with larger prostate (resected tissue weight >80 g) (77.67% vs 89.06%; P  < .001), patients from both these groups noted a similar PSA nadir level after 3 months (0.54 vs 0.56 ng/dL). The drop in PSA level after HoLEP remained stable up to 1-year follow-up., Conclusions: PSA nadir 3 months after HoLEP remains relatively consistent across patients, regardless of preoperative prostate size, PSA value, urine culture status, and histopathological evidence of prostatitis or incidental prostate cancer., Competing Interests: The authors declare no competing financial interests., (© 2021 The Authors. BJUI Compass published by John Wiley & Sons Ltd on behalf of BJU International Company.)

Background: The challenge of managing non-muscle-invasive bladder cancer (NMIBC) is its high recurrence rate. Clinical investigations have begun to explore the role of androgen suppression as an adjunct to bladder cancer (BC) treatment., Objective: To examine the effect of androgen suppression therapy (AST) on recurrence and progression rate of risk-stratified NMIBC., Design, Setting, and Participants: Male patients with NMIBC were identified retrospectively from a US institutional database between 2001 and 2017. AST included 5α-reductase inhibitor, gonadotropin-releasing hormone agonist, and antiandrogen. Patients who were exposed to AST prior to documented recurrence/progression were included in the treatment arm. BC was risk stratified to investigate the differential response to AST., Outcome Measurements and Statistical Analysis: Hazard ratios (HRs) for NMIBC recurrence and progression were estimated using Cox proportional hazards multivariate regression models with stepwise method. Recurrence-free survival (RFS) and progression-free survival (PFS) were compared between groups with and without AST., Results and Limitations: We identified a total of 274 males with a median follow-up period of 3.1 yr (interquartile range [IQR] 1.5-5.2). Thirty-six patients were exposed to AST with a median duration of 1.7 yr (IQR 0.7-2.6). AST was associated with a lower risk of recurrence (HR 0.53, 95% confidence interval 0.30-0.88) as well as improved RFS (p =  0.014). However, no significant reduction of progression or improvement of PFS (p =  0.23) was found with AST. After risk stratification, all five patients who progressed in the AST cohort had high-risk disease on initial transurethral resection (TUR), whereas no patients with low/intermediate-risk disease progressed on AST. Limitations of the study include nonstandardized initiation of AST in relation to initial TUR, lack of androgen level quantification, and small sample size in the treatment arm., Conclusions: In this retrospective, single-institution study, AST was associated with a lower risk of recurrence in NMIBC. No significant association between AST and progression was found. Further investigation is warranted to define the role of AST as an adjunctive therapy for NMIBC., Patient Summary: Non-muscle-invasive bladder cancer is a highly recurrent disease that often requires patients to undergo repeated surgical treatments. This single-institution report suggests that medical suppression of androgen may be a potential preventive therapy to reduce recurrence in certain patients., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: To assess the outcomes through systematic review and meta-analysis of multi-parametric magnetic resonance imaging (mpMRI) of the prostate in biopsy naïve men., Methods: Systemic review and meta-analysis was performed to assess the performance of mpMRI on prostate cancer (PCa) detection at the time of biopsy. We used standard methods for performing a meta-analysis evaluating a diagnostic test and reported the pooled sensitivity and specificity, and the positive and negative likelihood ratios (LR) for mpMRI in the detection of any and clinically significant prostate cancer (csPCa)., Results: A total of 10 studies comprising 2486 patients were analyzed. Overall, if biopsies would have been performed only in men with an mpMRI suspicious for malignancy between 7.4% and 58.5% of the biopsies could have been avoided, but 2.3%-36% of any PCa and 0%-30.8% of csPCa would have been missed. The sensitivity, specificity, positive LR, and negative LR of mpMRI for any PCa detection were 0.86 (95% confidence interval [CI], 0.78-0.91), 0.67 (95% CI, 0.40-0.86), 2.6 (95% CI, 1.2-5.5), and 0.2 (95% CI, 0.12-0.32), respectively. The AUC for any PCa detection was 0.84 (95% CI, 0.75-0.90). The pooled sensitivity, specificity, positive LR, and negative LR of mpMRI for csPCa detection was 0.94 (95% CI, 0.83-0.98), 0.54 (95% CI, 0.42-0.65), 2 (95% CI, 1.5-2.7), and 0.1 (95% CI, 0.02-0.35), respectively. The AUC for csPCa detection was 0.94 (95% CI, 0.65-1)., Conclusion: This study provides summary estimates indicating that mpMRI can accurately detect prostate cancer and help avoid unnecessary biopsies in this population., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: We report short-term outcomes of focal high intensity focused ultrasound use for primary treatment of localized prostate cancer., Materials and Methods: Single-center prospectively collected data on patients with prostate cancer who underwent primary focal high intensity focused ultrasound from January 2016 to July 2018 were included. All patients underwent a 12-core biopsy with magnetic resonance imaging-ultrasound fusion biopsy depending on the presence of targetable lesions. Any Grade Group was allowed, however only patients with localized disease were included. The primary outcome was oncologic control, defined as negative followup in-field biopsy of treated cancer. Prostate specific antigen, Sexual Health Inventory for Men, International Prostate Symptom Score and Expanded Prostate Cancer Index Composite domain scores were assessed 3-monthly till 12 months. Biopsy was performed at 6 or 12 months for high or low/intermediate risk cancer, respectively., Results: Fifty-two patients with minimum followup of 12 months were included in the study. The majority of patients (67%) had cancer Grade Group 2 or greater. Fifteen patients (28.8%) underwent complete transurethral prostate resection/holmium laser enucleation of prostate procedure for debulking large prostates to avoid postoperative urinary retention. Among 30 (58%) patients who underwent followup biopsies, 25 (83%) had negative in-field biopsy results and 4 (13%) had de-novo positive out-of-field biopsy. Only 5 major complications (all grade III) in 4 patients were noted. Urinary symptoms returned to near baseline questionnaire scores within 3-6 months. Sexual function returned to baseline at 12 months., Conclusions: Focal high intensity focused ultrasound is a safe and effective treatment for patients with localized clinically significant prostate cancer with acceptable short-term oncologic and functional outcomes. The complications are minimal and patient selection is essential. Short-term oncologic outcomes are promising but longer followup is required to establish long-term oncologic outcomes.

Purpose: We evaluated health related quality of life following robotic and open radical cystectomy as a treatment for bladder cancer., Materials and Methods: Using the Randomized Open versus Robotic Cystectomy (RAZOR) trial population we assessed health related quality of life by using the Functional Assessment of Cancer Therapy (FACT)-Vanderbilt Cystectomy Index and the Short Form 8 Health Survey (SF-8) at baseline, 3 and 6 months postoperatively. The primary objective was to assess the impact of surgical approach on health related quality of life. As an exploratory analysis we assessed the impact of urinary diversion type on health related quality of life., Results: Analyses were performed in subsets of the per-protocol population of 302 patients. There was no statistically significant difference between the mean scores by surgical approach at any time point for any FACT-Vanderbilt Cystectomy Index subscale or composite score (p >0.05). The emotional well-being score increased over time in both surgical arms. Patients in the open arm showed significantly better SF-8 sores in the physical and mental summary scores at 6 months compared to baseline (p <0.05). Continent diversion (versus noncontinent) was associated with worse FACT-bladder-cystectomy score at 3 (p <0.01) but not at 6 months, and the SF-8 physical component was better in continent-diversion patients at 6 months (p=0.019)., Conclusions: Our data suggests lack of significant differences in the health related quality of life in robotic and open cystectomies. As robotic procedures become more widespread it is important to discuss this finding during counseling.

Purpose: We applied nonmuscle invasive bladder cancer AUA (American Urological Association)/SUO (Society of Urologic Oncology) guidelines for risk stratification and analyzed predictors of recurrence and progression., Materials and Methods: We retrospectively reviewed the records of 398 patients with nonmuscle invasive bladder cancer treated between 2001 and 2017. Descriptive statistics were used to compare AUA/SUO risk groups. Predictors of recurrence and progression were determined by multivariable regression. Kaplan-Meier analysis was done, a Cox proportional hazards regression model was created and time dependent AUCs were calculated to determine progression-free and recurrence-free survival by risk group., Results: Median followup was 37 months (95% CI 35-42). Of the patients 92% underwent bacillus Calmette-Guérin induction and 46% received at least 1 course of maintenance treatment. Of the patients 11.5% were at low, 32.5% were at intermediate and 55.8% were at high risk. In patients at low, intermediate and high risk the 5-year progression-free survival rate was 93%, 74% and 54%, and the 5-year recurrence-free survival rate was 43%, 33% and 23%, respectively. Kaplan-Meier analysis was done to stratify high grade Ta 3 cm or less tumor recurrence-free and progression-free survival in the intermediate vs the high risk group. Relative to low risk, classification as intermediate and as high risk was an independent predictor of progression (HR 9.7, 95% CI 2.23-42.0, p <0.01, and HR 36, 95% CI 8.16-159, p <0.001, respectively). Recurrence was more likely in patients at high risk than in those at low risk (HR 2.03, 95% CI 1.11-3.71, p=0.022). For recurrence and progression the 1-year AUC was 0.60 (95% CI 0.546-0.656) and 0.68 (95% CI 0.622-0.732), respectively., Conclusions: The AUA/SUO nonmuscle invasive bladder cancer risk classification system appropriately stratifies patients based on the likelihood of recurrence and progression. It should be used at diagnosis to counsel patients and guide therapy.

Objective: To study if prostatic ductal adenocarcinoma (PDA) controlled by Grade Group (GG), PSA, and tumor volume (TV) is an independent predictor of adverse radical prostatectomy (RP) outcomes., Materials: One-hundred and twenty-eight PDA and 1141 acinar continuous RPs were studied. Each tumor nodule (TN) was individually graded, staged, and its TV measured. Univariate analysis (UVA) identified features associated with lymph node metastasis (LN+), extraprostatic extension (EPE), positive surgical margins (SM+), and seminal vesicle invasion (SV+). We then assessed PDA effect on RP outcomes in a multivariate analysis (MVA)., Results: In 127 cases PDA was present in 1 TN and no TN was pure PDA. One-hundred and twenty-three cases had PDA in TNs with highest grade, stage, and TV. Patients with PDA were older (65 vs 63 years, P < 0.001), had higher GG (P < 0.001), and LN+ (6.3% vs 2.7%, P = 0.049). Controlling these variables by GG eliminated statistical significance. Overall, there were 3249 separate TNs (129 PDA and 3120 acinar). In UVA, PDA predicted EPE (92/124 vs 517/3045), SV+ (28/1129 vs 116/3,120), and SM+ (51/129 vs 296/3120), all P < 0.001. In MVA, PDA lost its effect on EPE (OR = 0.88, P = 0.64), SM+ (OR = 0.86, P = 0.5), and SV+ (OR = 0.99, P = 0.98)., Conclusion: Controlled for grade and TV, PDA was not an independent predictor of adverse RP outcomes, but former 2 were. Hence, higher GG and TV associated with PDA TNs may be predictive of adverse RP outcomes rather than PDA by itself. These conclusions may be used in preoperative risk stratification and definitive therapy planning when PDA is identified on needle biopsy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: The RAZOR (Randomized Open versus Robotic Cystectomy) trial revealed noninferior 2-year progression-free survival for robotic radical cystectomy. This update was performed with extended followup for 3 years to determine potential differences between the approaches. We also report 3-year overall survival and sought to identify factors predicting recurrence, and progression-free and overall survival., Materials and Methods: We analyzed the per protocol population of 302 patients from the RAZOR study. Cumulative recurrence was estimated using nonbladder cancer death as the competing risk event and the Gray test was applied to assess significance in differences. Progression-free survival and overall survival were estimated by the Kaplan-Meier method and compared with the log rank test. Predictors of outcomes were determined by Cox proportional hazard analysis., Results: Estimated progression-free survival at 36 months was 68.4% (95% CI 60.1-75.3) and 65.4% (95% CI 56.8-72.7) in the robotic and open groups, respectively (p=0.600). At 36 months overall survival was 73.9% (95% CI 65.5-80.5) and 68.5% (95% CI 59.8-75.7) in the robotic and open groups, respectively (p=0.334). There was no significant difference in the cumulative incidence rates of recurrence (p=0.802). Patient age greater than 70 years, poor performance status and major complications were significant predictors of 36-month progression-free survival. Stage and positive margins were significant predictors of recurrence, and progression-free and overall survival. Surgical approach was not a significant predictor of any outcome., Conclusions: This analysis showed no difference in recurrence, 3-year progression-free survival or 3-year overall survival for robotic vs open radical cystectomy. It provides important prospective data on the oncologic efficacy of robotic radical cystectomy and high level data for patient counseling.

Background: We investigated the relationship between timing of adjuvant chemotherapy on overall survival following radical cystectomy., Methods: We retrospectively reviewed the National Cancer Data Base for patients with newly diagnosed pT2-T4, N0, M0 urothelial cell carcinoma who received no treatment prior to radical cystectomy. Patients who received no adjuvant chemotherapy or who received adjuvant chemotherapy more than 45 days after radical cystectomy were propensity matched to patients receiving adjuvant chemotherapy within 45 days of radical cystectomy. Selection bias was assessed by comparing the length of stay, readmission rate, and surgical approach between groups. Median survival was calculated using Kaplan-Meier analysis. Adjusted hazard ratios and 95% confidence intervals were calculated from a multivariable Cox regression model to examine factors affecting overall survival., Results: From 2004 to 2014, 284 patients with muscle-invasive bladder cancer met inclusion criteria. Patients receiving chemotherapy within 45 days had the best 5-year overall survival (47.0%, 95%CI: 40.6%-53.2%) compared to those receiving chemotherapy after 45 days (37.5%, 95%CI: 31.4%-43.7%). Chemotherapy after 45 days and no adjuvant chemotherapy were significant predictors of worse overall survival compared to chemotherapy within 45 days (1.27, 1.02-1.59, P = 0.033 and 1.41, 1.12-1.78, P = 0.003). Receiving no adjuvant chemotherapy was not significantly different than chemotherapy after 45 days (1.11, 0.89-1.38, P = 0.348). Significant predictors of poorer overall survival were female sex (1.37, 1.04-1.81, P = 0.028), Medicare (1.37, 1.06-1.76, P = 0.016), pT3 stage (1.79, 1.35-2.38, P < 0.001), and pT4 stage (3.00, 2.20-4.01, P < 0.001). Significantly more patients with length of stay ≤7 days following RC received chemotherapy within 45 days (53.2%) compared to those who received adjuvant chemotherapy after 45 days after RC (44.0%) or no adjuvant chemotherapy (43.0%; P = 0.0369)., Conclusions: Initiation of adjuvant chemotherapy within 45 days of radical cystectomy for patients with pT2-4 bladder cancer was associated with an overall survival benefit compared to patients who received adjuvant chemotherapy after 45 days or no adjuvant chemotherapy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Contemporary randomized controlled trials exploring adjuvant chemotherapy (AC) for bladder cancer (BCa) have yielded inconsistent results due to premature termination and/or poor patient accrual., Objective: To compare efficacy of AC vs. observation after radical cystectomy stratified by disease stage in a propensity-matched cohort., Design, Setting, and Participants: We performed a retrospective study that included patients who underwent radical cystectomy for any pT, N0-1, M0 BCa from the National Cancer Data Base (2004-2014). Patients who underwent AC were 1:1 propensity matched with patients who received observation only., Outcome Measurements and Statistical Analysis: Overall survival was assessed with multivariable Cox regression models where adjusted hazard ratios (aHR) and 95% confidence intervals (95% CI) were calculated., Results and Limitations: After coarsened exact 1:1 propensity matching, 3,066 patients (AC 1,533; observation 1,533) were included in the analysis. There were no significant differences in patient-, facility-, or tumor-level characteristics among cohorts. Compared with patients who underwent observation, recipients of AC had improved overall survival (aHR 0.67; 95% CI 0.61-0.74). Patients with pT2-4, pN1 disease significantly benefited from AC. Among the pN0 cohort, improved survival from AC was observed only in stages pT3 (aHR 0.67; 95% CI 0.55-0.83) and pT4 (aHR 0.70; 95% CI 0.50-0.98)., Conclusions: AC was associated with improved survival in locally advanced (pT3-4, pN0) and regionally advanced (pT2-4, pN1) chemotherapy-naive BCa., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: We assessed the impact of open or minimally-invasive partial cystectomy on surgical margin status in a nationwide hospital-based cohort., Materials and Methods: Patients who underwent partial cystectomy from 2010 to 2014 were identified in the National Cancer Data Base. The primary outcome was surgical margin status. A multivariable logistic regression model was fitted to identify patient, hospital, and surgical factors associated with positive surgical margins (PSMs)., Results: Partial cystectomy was performed in 1,118 patients via open (n = 715, 64%), laparoscopic (n = 209, 19%), and robotic (n = 194, 17%) approaches. Overall, 220 (19.7%) patients had PSMs. The PSM rate by surgical approach was 19.6% for open, 18.2% for laparoscopic, and 21.6% for robotic (P = 0.678). Compared to open partial cystectomy, the laparoscopic (aOR 1.06, 95%CI 0.70-1.60, P = 0.782), and robotic (aOR 1.28, 95%CI 0.85-1.91, P = 0.235) approaches were not significantly different in terms of PSM rate. There were higher odds of PSMs in non-Hispanic blacks (aOR 1.93, 95%CI 1.09-3.39, P = 0.023) compared to non-Hispanic whites, and in patients with muscle invasive bladder cancer (aOR 3.28, 95%CI 2.00-5.37, P < 0.001) or tumor size ≥ 3 cm (aOR 1.67, 95%CI 1.21-2.30, P = 0.002). Tumors in a dome/urachal location had lower odds of a PSM compared to tumors in a nondome/urachal location (aOR 0.67, 95%CI 0.47-0.94, P = 0.022)., Conclusions: Our results suggest that partial cystectomy using a laparoscopic or robotic-assisted approach is not associated with an increased risk of PSMs compared to open partial cystectomy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: To assess the secondary sequence rule in The Prostate Imaging Reporting Data System (PI-RADS) version 2 by comparing the detection of Grade group 1+ (GG1+) and 2+ (GG2+) cancers in PI-RADS 3, an upgraded PI-RADS 4, and true (non-upgraded) PI-RADS 4 targets., Materials and Methods: We analyzed a total of 589 lesions scored as PI-RADS 3 or 4 obtained from 434 men who underwent mpMRI-US fusion biopsy from September 2015 to November 2017 for evaluation of GG1+ and GG2+ prostate cancer. PI-RADS 4 lesions were differentiated into those that were 'upgraded' to PI-RADS 4 based on the secondary sequence and those that were 'true' PI-RADS 4 based on the dominant sequence., Results: The odds of detecting a GG2+ cancer was significantly higher for an upgraded 4 (peripheral zone (PZ): OR 5.06, 95%CI 2.04-12.54, p < 0.001, transitional zone (TZ): OR 3.08, 95%CI 1.04-9.08, p = 0.042) and true 4 (PZ: OR 5.82, 95%CI 3.10-10.94, p < 0.0001, TZ: OR 2.43, 95%CI 1.14-5.18, p = 0.022) lesions compared to PI-RADS 3 lesions. Additionally, we found no difference in the odds of detecting a GG2+ prostate cancer between a true PI-RADS 4 (OR 1.15, 95%CI 0.49-2.71 p = 0.746) and upgraded 4 (referent) in the PZ. Similar non-significance was noted between true 4 (OR 0.79, 95%CI 0.26-2.38 p = 0.674) and upgraded 4 lesions in the TZ for detection of GG2+ cancers., Conclusions: Upgraded PI-RADS 4 and true 4 targets have a higher odds of detecting GG1+ and GG2+ compared to PI-RADS 3 in the PZ and TZ. Our findings validate the revised scoring system for PI-RADS.

Background: Partial nephrectomy is widely used for surgical management of small renal masses. Use of robotic (RPN) versus open partial nephrectomy (OPN) among various populations is not well characterized., Objective: To analyze trends in utilization of RPN and disparities that may be associated with this procedure for management of cT1 renal masses in the USA., Design, Setting, and Participants: Patients who underwent RPN or OPN for clinical stage T1N0M0 renal masses in the USA from 2010 to 2013 were identified in the National Cancer Data Base. A total of 23 154 patients fulfilled the inclusion criteria., Outcome Measurements and Statistical Analysis: Univariable and multivariable logistic regression analyses were performed to evaluate differences in receiving RPN or OPN across various patient groups., Results and Limitations: Utilization of RPN increased from 41% in 2010 to 63% in 2013. Black patients (adjusted odds ratio [aOR] 0.91, 95% confidence interval [CI] 0.84-0.98) and Hispanic patients (aOR 0.85, 95% CI 0.77-0.95) were less likely to undergo RPN. RPN was less likely to be performed in rural counties (aOR 0.80, 95% CI 0.66-0.98) and in patients with no insurance (aOR 0.52, 95% CI 0.44-0.61) or patients covered by Medicaid (aOR 0.81, 95% CI 0.73-0.90). There was no significant difference in RPN utilization between academic and non-academic facilities. Patients with higher clinical stage (aOR 0.58, 95% CI 0.55-0.62) and comorbidities (aOR 0.79, 95% CI 0.71-0.88) were also less likely to undergo RPN., Conclusions: Utilization of RPN has continued to increase over time; however, there are significant disparities in its utilization according to race and socioeconomic status. Black and Hispanic patients and patients in rural communities and with limited insurance were more likely to be treated with OPN instead of RPN., Patient Summary: The use of robotic surgery in partial nephrectomy for management of small renal masses has increased over time. We found a significant disparity across different racial and socioeconomic groups in use of robotic partial nephrectomy compared to open surgery. Patients living in rural areas, with limited insurance, and multiple medical comorbidities were more likely to undergo open than robotic partial nephrectomy., (Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Emerging evidence has shown that both prostatic basal and luminal cells are able to initiate oncogenic transformation. However, despite the diversity of tumor-initiating cells, most prostate cancer cells express the androgen receptor (AR) and depend on androgens for their growth and expansion, implicating an essential role of androgen signaling in prostate tumorigenesis. Prostatic basal cells express p63 and are able to differentiate into luminal, neuroendocrine, and basal cells. Here, we directly assessed the essential role of androgen signaling in prostatic p63-expressing cell initiated oncogenic transformation and tumor formation. Using novel and relevant mouse models, we demonstrated that, with stabilized β-catenin expression, prostatic p63-expressing cells possess the ability to initiate oncogenic transformation and, in the presence of androgens, they further transdifferentiate into luminal-like tumor cells and develop adenocarcinomas. Castration prior to activating stabilized β-catenin sensitizes p63-expressing cells and increases their sensitivity to androgens, resulting in aggressive and fast growing tumor phenotypes. These findings are consistent with what have been observed in human prostate cancers, demonstrating an essential role for androgen signaling in prostate cancer initiation and progression. This study also provides fresh insight into developing new therapeutic strategies for better treating prostate cancer patients.

Most prostate cancer cases remain indolent for long periods of time, but metastatic progression quickly worsens the prognosis and leads to mortality. However, little is known about what promotes the metastasis of prostate cancer and there is a lack of effective prognostic indicators, making it immensely difficult to manage options for treatment or surveillance. Arginyltransferase 1 (Ate1) is the enzyme mediating post-translational protein arginylation, which has recently been identified as a master regulator affecting many cancer-relevant pathways including stress response, cell cycle checkpoints, and cell migration/adhesion. However, the precise role of Ate1 in cancer remains unknown. In this study, we found the occurrence of metastasis of prostate cancer is inversely correlated with the levels of Ate1 protein and mRNA in the primary tumor. We also found that metastatic prostate cancer cell lines have a reduced level of Ate1 protein compared to non-metastatic cell lines, and that a depletion of Ate1 drives prostate cancer cells towards more aggressive pro-metastatic phenotypes without affecting proliferation rates. Furthermore, we demonstrated that a reduction of Ate1 can result from chronic stress, and that shRNA-reduced Ate1 increases cellular resistance to stress, and drives spontaneous and stress-induced genomic mutations. Finally, by using a prostate orthotropic xenograft mouse model, we found that a reduction of Ate1 was sufficient to enhance the metastatic phenotypes of prostate cancer cell line PC-3 in vivo. Our study revealed a novel role of Ate1 in suppressing prostate cancer metastasis, which has a profound significance for establishing metastatic indicators for prostate cancer, and for finding potential treatments to prevent its metastasis.

The tumor suppressor p16Ink4a, encoded by the INK4a gene, is an inhibitor of cyclin D-dependent kinases 4 and 6, CDK4 and CDK6. This inhibition prevents the phosphorylation of the retinoblastoma protein (pRb), resulting in cellular senescence through inhibition of E2F-mediated transcription of S phase genes required for cell proliferation. The p16Ink4a plays an important role in tumor suppression, whereby its deletion, mutation, or epigenetic silencing is a frequently observed genetic alteration in prostate cancer. To assess its roles and related molecular mechanisms in prostate cancer initiation and progression, we generated a mouse model with conditional deletion of p16Ink4a in prostatic luminal epithelium. The mice underwent oncogenic transformation and developed prostatic intraepithelial neoplasia (PIN) from eight months of age, but failed to develop prostatic tumors. Given the prevalence of aberrant androgen signaling pathways in prostate cancer initiation and progression, we then generated R26hARL/wt:p16L/L: PB-Cre4 compound mice, in which conditional expression of the human AR transgene and deletion of p16Ink4a co-occur in prostatic luminal epithelial cells. While R26hARL/wt:PB-Cre4 mice showed no visible pathological changes, R26hARL/wt:p16L/L: PB-Cre4 compound mice displayed an early onset of high-grade PIN (HGPIN), prostatic carcinoma, and metastatic lesions. Strikingly, we observed tumors resembling human sarcomatoid carcinoma with intermixed focal regions of signet ring cell carcinoma (SRCC) in the prostates of the compound mice. Further characterization of these tumors showed they were of luminal epithelial cell origin, and featured characteristics of epithelial to mesenchymal transition (EMT) with enhanced proliferative and invasive capabilities. Our results not only implicate a biological role for AR expression and p16Ink4a deletion in the pathogenesis of prostatic SRCC, but also provide a new and unique genetically engineered mouse (GEM) model for investigating the molecular mechanisms for SRCC development., Competing Interests: The authors have declared that no competing interests exist.

Emerging evidence has shown that the hepatocyte growth factor (HGF) and its receptor, MET proto-oncogene, receptor tyrosine kinase (MET), promote cell proliferation, motility, morphogenesis, and angiogenesis. Whereas up-regulation of MET expression has been observed in aggressive and metastatic prostate cancer, a clear understanding of MET function in prostate tumorigenesis remains elusive. Here, we developed a conditional Met transgenic mouse strain, H11 Met/ + :PB-Cre4 , to mimic human prostate cancer cells with increased MET expression in the prostatic luminal epithelium. We found that these mice develop prostatic intraepithelial neoplasia after HGF administration. To further assess the biological role of MET in prostate cancer progression, we bred H11 Met/ + /Pten LoxP/LoxP :PBCre4 compound mice, in which transgenic Met expression and deletion of the tumor suppressor gene Pten occurred simultaneously only in prostatic epithelial cells. These compound mice exhibited accelerated prostate tumor formation and invasion as well as increased metastasis compared with Pten LoxP/LoxP :PB-Cre4 mice. Moreover, prostatic sarcomatoid carcinomas and lesions resembling the epithelial-to-mesenchymal transition developed in tumor lesions of the compound mice. RNA-Seq and qRT-PCR analyses revealed a robust enrichment of known tumor progression and metastasis-promoting genes in samples isolated from H11 Met/ + /Pten LoxP/LoxP :PB-Cre4 compound mice compared with those from Pten LoxP/LoxP :PB-Cre4 littermate controls. HGF-induced cell proliferation and migration also increased in mouse embryonic fibroblasts (MEFs) from animals with both Met transgene expression and Pten deletion compared with Pten- null MEFs. The results from these newly developed mouse models indicate a role for MET in hastening tumorigenesis and metastasis when combined with the loss of tumor suppressors., (© 2018 Mi et al.)

Background: Non-Hispanic Black (NHB) men are at an increased risk for aggressive prostate cancer (PCa), making active surveillance (AS) potentially less optimal in this population. This concern has not been explored in other minority populations-specifically, Hispanic/Latino men. We recently found that Mexican-American men demonstrate an increased risk of PCa-specific mortality, and we hypothesized that they may also be at risk for an adverse outcome on AS., Methods: Using the Surveillance, Epidemiology, and End Results (SEER) program, we extracted a population-based cohort of men diagnosed from 2004 to 2013 with localized or regional PCa, who had ≤2 cores of only Grade Group (GG) 1 cancer, and underwent radical prostatectomy (RP) with available biopsy and surgical pathology results. We measured discovery of high-risk PCa at RP and collected socioeconomic status (SES) data across different racial/ethnic groups. We defined aggressive tumors as either an upgrade to GG 3 or higher (GG3+) cancer or non-organ-confined disease (≥pT3a or N1). Univariate and multivariate logistic regression models were developed to assess the association between racial/ethnic categories and the previously mentioned adverse oncologic outcomes both with and without adjusting for SES factors., Results: NHB and Mexican-American men were significantly more likely to have aggressive PCa, following RP. In multivariable logistic regression adjusting for SES factors and relative to non-Hispanic White (NHW) men, Mexican-American men had at increased odds of upgrading to GG3+ (OR 1.67; 95% CI [1.00-2.90]). NHB men were more likely to have non-organ-confined disease (OR 1.34; 95% CI [1.06-1.69]), while Mexican-American men had a similar risk to NHW men., Conclusion: Among individuals with low-risk PCa and eligible for AS, Mexican-American and NHB men are at an increased risk of harboring more aggressive disease at RP. This novel finding among Mexican-Americans deserves further evaluation.

Objective: To determine whether a specific lymph node yield (LNY) affects overall survival (OS) in patients with penile cancer., Materials and Methods: Using the National Cancer Database, we identified 364 men diagnosed with pSCC who underwent ILND between 2004 and 2013. Men diagnosed on autopsy or at the time of death, patients with preoperative chemotherapy or radiotherapy, M+ and N3 disease, or with less than 3-month of follow-up were excluded. Kaplan-Meier analysis was used to compare Overall Survival (OS). A multivariable Cox regression model was developed to assess predictors of OS., Results: The median number of LN retrieved was 16 (IQR: 9-23). There was no significant difference in race, stage, grade for men with LNY ≤15 vs. >15. However, men with LNY ≤15 were significantly older than those with LNY >15 (65 vs. 59 years, p<0.001). On multivariable analysis, radical surgery, age, N+ disease, and LNY ≤15 were independent predictors of worse OS. Patients with LNY ≤15 showed significantly worse 5-year OS versus those with LNY >15 (49% vs. 67%, p=0.008). Nodal density (ND) ≥12.5% was also associated with decreased 5-year OS versus ND <12.5% (31% vs. 70%, p<0.0001)., Conclusions: LNY following ILND for pSCC appears to be an independent predictor of OS. A total LNY of >15 following ILND may have a beneficial impact on OS and serve as the threshold for defining an adequate ILND., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Amyloid bodies (A-bodies) are inducible membrane-less nuclear compartments composed of heterogeneous proteins that adopt an amyloid-like state. A-bodies are seeded by noncoding RNA derived from stimuli-specific loci of the rDNA intergenic spacer (rIGSRNA). This raises the question of how rIGSRNA recruits a large population of diverse proteins to confer A-body identity. Here, we show that long low-complexity dinucleotide repeats operate as the architectural determinants of rIGSRNA. On stimulus, clusters of rIGSRNA with simple cytosine/uracil (CU) or adenosine/guanine (AG) repeats spanning hundreds of nucleotides accumulate in the nucleolar area. The low-complexity sequences facilitate charge-based interactions with short cationic peptides to produce multiple nucleolar liquid-like foci. Local concentration of proteins with fibrillation propensity in these nucleolar foci induces the formation of an amyloidogenic liquid phase that seeds A-bodies. These results demonstrate the physiological importance of low-complexity RNA and repetitive regions of the genome often dismissed as "junk" DNA., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: To evaluate the performance of mpMRI and the 4Kscore test together for the detection of significant prostate cancer. Material and methods We selected a consecutive series of men who were referred for evaluation of prostate cancer at an academic institution and underwent mpMRI and the 4Kscore test. The primary outcome was the presence of Gleason 7 or higher cancer on biopsy of the prostate. We used logistic regression and Decision Curve Analysis to report the discrimination and clinical utility of using mpMRI and the 4Kscore test for prostate cancer detection. We modeled the probability of harboring a Gleason 7 or higher prostate cancer based on the 4Kscore test and mpMRI findings. Finally, we examined various combinations and sequences of mpMRI and the 4Kscore test and assessed the impact on biopsies avoided and cancers missed., Results: Among 300 men who underwent a 4Kscore test and mpMRI, 149 (49%) underwent a biopsy. Among those, 73 (49%) had cancer, and 49 (33%) had Gleason 7 cancer. The area under the curve (AUC) for using the 4Kscore test and mpMRI together 0.82 (0.75-0.89) was superior to using the 4Kscore 0.70 (0.62-0.79) or mpMRI 0.74 (0.66-0.81) individually (p = 0.001). Similarly, decision analysis revealed the highest net benefit was achieved using both tests., Conclusions: The 4Kscore test and mpMRI results provide independent, but complementary, information that enhances the prediction of higher-grade prostate cancer and improves patient's selection for a prostate biopsy. Prospective trials are required to confirm these findings., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Minimally invasive nephroureterectomy (MINU) and open nephroureterectomy (ONU) have similar oncological outcomes for treatment of upper tract urothelial carcinoma (UTUC). We investigated perioperative outcomes and predictors of complications associated with MINU and ONU., Material and Methods: Using the National Surgical Quality Improvement Program (NSQIP) database, 912 patients were identified that underwent radical nephroureterectomy for UTUC between 2005 and 2013. Logistic regression and contingency table methods used preoperative covariates to predict rates of major (Clavien-Dindo grade ≥ 3) and 16 common perioperative complications. Additional comparisons between treatment groups were performed using unpaired t-tests, Wilcoxon rank-sum tests, or Fisher's Exact tests. P values were adjusted to maintain an experiment-wise p < 0.05., Results: A total of 625 (69%) and 287 (31%) patients underwent MINU and ONU, respectively. ONU was associated with a higher rate of major complications (OR: 2.5, CI: 1.2-5.1, p < 0.03). The incidence of pulmonary embolism (bias adjusted OR: 24, CI: 1.3-441, p < 0.003), postoperative pneumonia (OR: 4.9, CI: 1.7-16, p < 0.0016), and transfusion (OR: 2.7, CI: 1.8-4.0, p < 0.0001) was higher for ONU compared to MINU. There were no significant differences in the incidence of other complications. MINU took longer on average (median 223 versus 213 mins, p < 0.02). Time to discharge was longer for ONU (median 5 versus 4 days, p < 0.0001). No other covariates were independent predictors of major complications regardless of surgical approach., Conclusions: Occurrence of major complications were higher for ONU compared to MINU. These data suggest that MINU is an acceptable surgical option with lower morbidity compared to ONU for the management of UTUC.

Objective: To determine if recently found disparities in prostate cancer-specific mortality (PCSM) among Mexican and Puerto Rican men remained true in patients undergoing radical prostatectomy (RP), where the true grade and extent of cancer are known and can be accounted for., Materials and Methods: Men diagnosed with localized-regional prostate cancer who had undergone RP as primary treatment were identified (N = 180,794). Patients were divided into the following racial and ethnic groups: non-Hispanic white (NHW) (n = 135,358), non-Hispanic black (NHB) (n = 21,882), Hispanic or Latino (n = 15,559), and Asian American or Pacific Islander (n = 7995). Hispanic or Latino men were further categorized into the following subgroups: Mexican (n = 3323) and South or Central American, excluding Brazilian (n = 1296), Puerto Rican (n = 409), and Cuban (n = 218). A multivariable analysis was conducted using competing risk regression in the prediction of PCSM., Results: This analysis revealed hidden disparities in surgical outcomes for prostate cancer. In the multivariable analysis, Hispanic or Latino men (hazard ratio [HR] = 0.88, P = .207) did not show a significant difference in PCSM compared with NHW men. When breaking Hispanic or Latino men into their country of origin or ancestry, Puerto Rican men were found to have significantly worse PCSM than NHW men (HR = 2.55, P = .004) and NHB men (HR = 2.33, P = .016)., Conclusion: Our findings reveal higher rates of PCSM for Puerto Rican men after RP than for both NHW and NHB men. At a minimum, these findings need further validation and should be considered in the screening and management of these men., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Radical cystectomy is the surgical standard for invasive bladder cancer. Robot-assisted cystectomy has been proposed to provide similar oncological outcomes with lower morbidity. We aimed to compare progression-free survival in patients with bladder cancer treated with open cystectomy and robot-assisted cystectomy., Methods: The RAZOR study is a randomised, open-label, non-inferiority, phase 3 trial done in 15 medical centres in the USA. Eligible participants (aged ≥18 years) had biopsy-proven clinical stage T1-T4, N0-N1, M0 bladder cancer or refractory carcinoma in situ. Individuals who had previously had open abdominal or pelvic surgery, or who had any pre-existing health conditions that would preclude safe initiation or maintenance of pneumoperitoneum were excluded. Patients were centrally assigned (1:1) via a web-based system, with block randomisation by institution, stratified by type of urinary diversion, clinical T stage, and Eastern Cooperative Oncology Group performance status, to receive robot-assisted radical cystectomy or open radical cystectomy with extracorporeal urinary diversion. Treatment allocation was only masked from pathologists. The primary endpoint was 2-year progression-free survival, with non-inferiority established if the lower bound of the one-sided 97·5% CI for the treatment difference (robotic cystectomy minus open cystectomy) was greater than -15 percentage points. The primary analysis was done in the per-protocol population. Safety was assessed in the same population. This trial is registered with ClinicalTrials.gov, number NCT01157676., Findings: Between July 1, 2011, and Nov 18, 2014, 350 participants were randomly assigned to treatment. The intended treatment was robotic cystectomy in 176 patients and open cystectomy in 174 patients. 17 (10%) of 176 patients in the robotic cystectomy group did not have surgery and nine (5%) patients had a different surgery to that they were assigned. 21 (12%) of 174 patients in the open cystectomy group did not have surgery and one (1%) patient had robotic cystectomy instead of open cystectomy. Thus, 302 patients (150 in the robotic cystectomy group and 152 in the open cystectomy group) were included in the per-protocol analysis set. 2-year progression-free survival was 72·3% (95% CI 64·3 to 78·8) in the robotic cystectomy group and 71·6% (95% CI 63·6 to 78·2) in the open cystectomy group (difference 0·7%, 95% CI -9·6% to 10·9%; p non-inferiority =0·001), indicating non-inferiority of robotic cystectomy. Adverse events occurred in 101 (67%) of 150 patients in the robotic cystectomy group and 105 (69%) of 152 patients in the open cystectomy group. The most common adverse events were urinary tract infection (53 [35%] in the robotic cystectomy group vs 39 [26%] in the open cystectomy group) and postoperative ileus (33 [22%] in the robotic cystectomy group vs 31 [20%] in the open cystectomy group)., Interpretation: In patients with bladder cancer, robotic cystectomy was non-inferior to open cystectomy for 2-year progression-free survival. Increased adoption of robotic surgery in clinical practice should lead to future randomised trials to assess the true value of this surgical approach in patients with other cancer types., Funding: National Institutes of Health National Cancer Institute., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: To compare survival outcome between chemoradiation therapy (CRT) and radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC)., Patients and Methods: We conducted a retrospective analysis of patients with MIBC (≥cT2, N0, M0) in the National Cancer Database (2004-2013). CRT was defined as a radiation dose of ≥40 Gy and chemotherapy within 90 days of radiation. Descriptive statistics were used to compare groups. RC and CRT patients were propensity matched. Kaplan-Meier analysis was used to compare overall survival (OS). Multivariable Cox regression was used to determine predictors of survival., Results: In all, 8 379 (6 606 RC and 1 773 CRT) patients met the inclusion criteria and 1 683 patients in each group were propensity matched. On multivariable extended Cox analysis, significant predictors of decreased OS were age, Charlson-Deyo Comorbidity score of 1, Charlson-Deyo Comorbidity score of 2, stage cT3-4, and urothelial histology. CRT was associated with decreased mortality at year 1 (hazard ratio [HR] 0.84, 95% confidence interval [CI] 0.74-0.96; P = 0.01), but at 2 years (HR 1.4, 95% CI 1.2-1.6; P < 0.001) and 3 years onward (HR 1.5, 95% CI 1.2-1.8; P < 0.001) CRT was associated with increased mortality. The 5-year OS was greater for RC than for CRT (38% vs 30%, P = 0.004)., Conclusions: Initially after treatment for MIBC the risk of mortality is lower with CRT compared to RC. However, at ≥2 years after treatment the mortality risk favours RC. Patients who are suitable surgical candidates, with a low risk of morbidity, may be better served by RC., (© 2018 The Authors BJU International © 2018 BJU International Published by John Wiley & Sons Ltd.)

Objective: To determine whether there is a survival difference for African-American men (AAM) versus Caucasian American men (CM) with penile squamous cell carcinoma (pSCC), particularly in locally advanced and metastatic cases where disease mortality is highest., Patients and Methods: Using the Florida Cancer Data System, we identified men with pSCC from 2005 to 2013. We compared age, follow-up, stage, race, and treatment type between AAM and CM. We performed Kaplan-Meier analysis for overall survival (OS) between AAM and CM for all stages, and for those with locally advanced and metastatic disease. A multivariable model was developed to determine significant predictors of OS., Results: In all, 653 men (94 AAM and 559 CM) had pSCC and 198 (30%) had locally advanced and/or metastatic disease. A higher proportion of AAM had locally advanced and/or metastatic disease compared to CM (38 [40%] vs 160 [29%], P = 0.03). The median (interquartile range) follow-up for the entire cohort was 12.6 (5.4-32.0) months. For all stages, AAM had a significantly lower median OS compared to CM (26 vs 36 months, P = 0.03). For locally advanced and metastatic disease, there was a consistent trend toward disparity in median OS between AAM and CM (17 vs 22 months, P = 0.06). After adjusting for age, stage, grade, and treatment type, AAM with pSCC had a greater likelihood of death compared to CM (hazard ratio 1.64, P = 0.014)., Conclusions: AAM have worse OS compared to CM with pSCC and this may partly be due to advanced stage at presentation. Treatment disparity may also contribute to lessened survival in AAM, but we were unable to demonstrate a significant difference in treatment utilisation between the groups., (© 2018 The Authors BJU International © 2018 BJU International Published by John Wiley & Sons Ltd.)

Purpose: To analyze the impact of urinary diversion type following radical cystectomy (RC) on readmission and short-term mortality rates., Methods: Patients who underwent RC for bladder cancer in the National Cancer Data Base were grouped based on the type of urinary diversion performed: non-continent [ileal conduit (IC)] or two continent techniques [continent pouch (CP) and orthotopic neobladder (NB)]. We used propensity score matching and multivariable logistic regression models to compare 30-day readmission and 30- and 90-day mortality between the different types of urinary diversion., Results: Among 11,933 patients who underwent RC, we identified 10,197 (85.5%) IC, 1044 (8.7%) CP, and 692 (5.8%) NB. Patients who received IC were significantly older and had more comorbidities (p < 0.0001). Continent diversions were more likely to be performed at an academic center (p < 0.0001). Surgery performed at a non-academic center was an independent predictor of 30-day readmission (OR 1.19, p = 0.010) and 30-day mortality (OR 1.27, p = 0.043). Patients undergoing NB had an increased likelihood of being readmitted (OR 1.41, p = 0.010). There was no significant difference in short-term mortality between groups., Conclusions: Patients undergoing NB had marginally increased rates of readmission compared to IC. Surgery performed at a non-academic center was associated with higher readmission and 30-day mortality. Similar short-term mortality rates were observed among the different types of urinary diversion.

Introduction: To investigate the impact of perioperative factors on overall survival among patients with histologic variants of bladder cancer treated with radical cystectomy., Materials and Methods: The National Cancer Data Base was utilized to identify patients diagnosed with muscle-invasive bladder cancer (cT2-4, N0, M0) from 2004-2013. Variant histology bladder cancers (non-mucinous adenocarcinoma, mucinous/signet ring adenocarcinoma, micropapillary urothelial carcinoma, small cell carcinoma, and squamous cell carcinoma) were compared to urothelial carcinoma with respect to overall survival. Adjusted hazard ratios (aHR) and 95% confidence intervals (95% CI) were calculated from a multivariable Cox regression model to examine factors affecting overall survival, T upstaging, N upstaging, and positive surgical margins. Median survival was calculated using Kaplan-Meier analysis., Results: A total of 5,856 patients were included in this study. Significant predictors of worse overall survival included: African-American ancestry (aHR = 1.24, 95%CI: 1.03-1.48, p = 0.021), age (1.03, 1.02-1.03, p < 0.001), comorbidity (1.30, 1.20-1.40, p < 0.001), cT3 stage (1.41, 1.26-1.57, p < 0.001), and cT4 stage (1.59, 1.38-1.84, p < 0.001). Small cell carcinoma (2.10, 1.44-3.06, p < 0.001) and non-mucinous adenocarcinoma (1.59, 1.15-2.20, p = 0.005) were significant predictors of worse overall survival compared to urothelial carcinoma. Small cell carcinoma had the worst 5 year overall survival (15.5%, 95% CI: 5.2%-30.9%) compared to urothelial carcinoma (48.7%, 95% CI: 47.2%-50.2%). Micropapillary urothelial carcinoma was a significant predictor of increased progression to node positivity and positive margin status after radical cystectomy compared to urothelial carcinoma (6.01, 3.11-11.63, p < 0.001; 4.38, 2.05-9.38; p < 0.001)., Conclusions: Among bladder cancer patients with equal treatment and staging, small cell carcinoma and non-mucinous adenocarcinoma variant histologies were predictive of worse overall survival compared to urothelial carcinoma. Patient demographics such as African-American ancestry and age were also predictive of worse overall survival among variant histology bladder cancer and urothelial carcinoma.

Objectives: To evaluate the impact of adding magnetic resonance imaging-ultrasound (MRI-US) fusion biopsy cores to standard 12-core biopsy in selecting men for active surveillance (AS)., Materials and Methods: Among men undergoing a fusion biopsy for evaluation of prostate cancer, we selected men who were eligible for at least 1 of 7 different AS criteria based on the standard biopsy alone. We assessed each patient's eligibility for each AS criterion with and without the inclusion of fusion biopsy cores. The primary end point was the proportion of men who were initially eligible for AS but became ineligible after addition of the fusion biopsy cores., Results: A total of 100 men were eligible for at least 1 AS criterion. After addition of fusion biopsy cores, the proportion of men who became ineligible for AS varied from 10.3% to 40.7%. Criteria that incorporated an absolute maximum number of cores positive had the highest rates of ineligibility. Using a percentage of cores positive helped to reduce the number of patients who would have been excluded. Combining the targeted biopsy cores into one, or taking the single core with the highest grade or volume did not appear to reduce the proportion of men who became ineligible., Conclusions: The addition of fusion biopsy to standard 12-core biopsy significantly increased the number of men who became ineligible for AS. Using the percent of cores positive, instead of an absolute number, allowed fewer exclusions. AS criteria may need to be updated to prevent the unnecessary exclusion of men due to an oversampling of low-risk disease., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: To review oncological and functional outcomes for partial nephrectomy in the setting of T2 tumors., Materials and Methods: We performed a comprehensive literature review on partial nephrectomy for T2 tumors, focusing on major primary series reporting oncological and functional outcomes, as well as complication rates in the last 10 years., Results: Recent series have reported comparable oncological outcomes between partial nephrectomy and radical nephrectomy for ≥ T2 tumors. However, most of these studies are retrospective in design with small sample sizes. With regard to functional outcomes, partial nephrectomy outperforms radical nephrectomy. However, outcomes are dependent on the amount of residual renal parenchyma left after partial nephrectomy for larger tumors. Partial nephrectomy is associated with an increased rate of complications when compared to radical nephrectomy, but in experienced hands this increase tends to remain at an acceptable level. There are few studies that have investigated the role of minimally invasive surgery (MIS) in the setting of T2 tumors. Although MIS techniques may be underutilized for management of T2 tumors, it is a feasible approach in highly selected patients., Conclusions: Partial nephrectomy has emerged as an acceptable alternative for surgical management of T2 renal tumors over the last decade. Nephron-sparing surgery demonstrates similar oncological outcomes compared to radical nephrectomy and can be considered even for larger tumors in carefully selected patients whenever feasible.

The amyloid state of protein organization is typically associated with debilitating human neuropathies and is seldom observed in physiology. Here, we uncover a systemic program that leverages the amyloidogenic propensity of proteins to regulate cell adaptation to stressors. On stimulus, cells assemble the amyloid bodies (A-bodies), nuclear foci containing heterogeneous proteins with amyloid-like biophysical properties. A discrete peptidic sequence, termed the amyloid-converting motif (ACM), is capable of targeting proteins to the A-bodies by interacting with ribosomal intergenic noncoding RNA (rIGSRNA). The pathological β-amyloid peptide, involved in Alzheimer's disease, displays ACM-like activity and undergoes stimuli-mediated amyloidogenesis in vivo. Upon signal termination, elements of the heat-shock chaperone pathway disaggregate the A-bodies. Physiological amyloidogenesis enables cells to store large quantities of proteins and enter a dormant state in response to stressors. We suggest that cells have evolved a post-translational pathway that rapidly and reversibly converts native-fold proteins to an amyloid-like solid phase., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Radical prostatectomy (RP) outcomes have been studied in White and Black non-Hispanic men qualifying for Epstein active surveillance criteria (EASC). Herein, we first analyzed such outcomes in White Hispanic men. We studied 70 men with nonpalpable Gleason score 3+3=6 (Grade Group [GG] 1) prostate cancer (PCa) with ≤2 positive cores on biopsy who underwent RP. In 18 men, prostate-specific antigen (PSA) density (PSAD) was >0.15 ng/mL/g. Three of these had insignificant and 15 had significant PCa. The remaining 52 men qualified for EASC. One patient had no PCa identified at RP. Nineteen (37%) had significant PCa defined by volume (n=7), grade (n=7), and volume and grade (n=5). Nine cases were 3+4=7 (GG 2) (5/9 [56%] with pattern 4 <5%), 2 were 3+5=8 (GG 4), and 1 was 4+5=9 (GG 5). Patients with significant PCa more commonly had anterior dominant disease (11/19, 58%) versus patients with insignificant cancer (7/33, 21%) (P=0.01). In 12 cases with higher grade at RP, the dominant tumor nodule was anterior in 6 (50%) and posterior in 6 (median volumes: 1.1 vs. 0.17 cm, respectively; P=0.01). PSA correlated poorly with tumor volume (r=0.28, P=0.049). Gland weight significantly correlated with PSA (r=0.54, P<0.001). While PSAD and PSA mass density correlated with tumor volume, only PSA mass density distinguished cases with significant disease (median, 0.008 vs. 0.012 μg/g; P=0.03). In summary, a PSAD threshold of 0.15 works well in predicting significant tumor volume in Hispanic men. EASC appear to perform better in White Hispanic men than previously reported outcomes for Black non-Hispanic and worse than in White non-Hispanic men. Significant disease is often Gleason score 3+3=6 (GG 1) PCa >0.5 cm. Significant PCa is either a larger-volume anterior disease that may be detected by multiparametric magnetic resonance imaging-targeted biopsy or anterior sampling of the prostate or higher-grade smaller-volume posterior disease that in most cases should not pose immediate harm and may be detected by repeat template biopsies.

Purpose: The cell cycle progression test is a validated molecular assay that assesses prostate cancer specific disease progression and mortality risk when combined with clinicopathological parameters. We present the results from PROCEDE-1000, a large, prospective registry designed to evaluate the impact of the cell cycle progression test on shared treatment decision making for patients newly diagnosed with prostate cancer., Materials and Methods: Untreated patients with newly diagnosed prostate adenocarcinoma were enrolled in the study and the cell cycle progression test was performed on the initial prostate biopsy tissue. A set of 4 sequential surveys tracked changes relative to initial therapy recommendations (before cell cycle progression) based on clinicopathological parameters following physician review of the cell cycle progression test result, physician/patient review of the cell cycle progression test results and a minimum of 3 months of clinical followup (actual treatment)., Results: Of the 1,596 patients enrolled in this registry 1,206 were eligible for analysis. There was a significant reduction in the treatment burden recorded at each successive evaluation (p <0.0001), with the mean number of treatments per patient decreasing from 1.72 before the cell cycle progression test to 1.16 in actual followup. The cell cycle progression test caused a change in actual treatment in 47.8% of patients. Of these changes 72.1% were reductions and 26.9% were increases in treatment. For each clinical risk category there was a significant change in treatment modality (intervention vs nonintervention) before vs after cell cycle progression testing (p=0.0002)., Conclusions: The cell cycle progression test has a significant impact in assisting physicians and patients reach personalized treatment decisions., (Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Protein concentrations evolve under greater evolutionary constraint than mRNA levels. Translation efficiency of mRNA represents the chief determinant of basal protein concentrations. This raises a fundamental question of how mRNA and protein levels are coordinated in dynamic systems responding to physiological stimuli. This report examines the contributions of mRNA abundance and translation efficiency to protein output in cells responding to oxygen stimulus. We show that changes in translation efficiencies, and not mRNA levels, represent the major mechanism governing cellular responses to [O2] perturbations. Two distinct cap-dependent protein synthesis machineries select mRNAs for translation: the normoxic eIF4F and the hypoxic eIF4F(H). O2-dependent remodeling of translation efficiencies enables cells to produce adaptive translatomes from preexisting mRNA pools. Differences in mRNA expression observed under different [O2] are likely neutral, given that they occur during evolution. We propose that mRNAs contain translation efficiency determinants for their triage by the translation apparatus on [O2] stimulus., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Emerging evidence has demonstrated the critical roles for both androgen and Wnt pathways in prostate tumorigenesis. A recent integrative genomic analysis of human prostate cancers (PCas) has revealed a unique enrichment of androgen and Wnt signaling in early-onset PCas, implying their clinical significance in the disease. Additionally, interaction between the androgen receptor (AR) and β-catenin has long been detected in PCa cells. However, the consequence of this interaction in prostate tumorigenesis is still unknown. Because mutations in adenomatous polyposis coli, β-catenin and other components of the destruction complex are generally rare in PCas, other mechanisms of aberrant Wnt signaling activation have been speculated. To address these critical questions, we developed Ctnnb1(L(ex3)/+)/R26hAR(L/+):PB-Cre4 mice, in which transgenic AR and stabilized β-catenin are co-expressed in prostatic epithelial cells. We observed accelerated tumor development, aggressive tumor invasion and a decreased survival rate in Ctnnb1(L(ex3)/+)/R26hAR(L/+):PB-Cre4 compound mice compared with age-matched Ctnnb1(L(ex3)/+):PB-Cre4 littermate controls, which only have stabilized β-catenin expression in the prostate. Castration of the above transgenic mice resulted in significant tumor regression, implying an essential role of androgen signaling in tumor growth and maintenance. Implantation of the prostatic epithelial cells isolated from the transgenic mice regenerated prostate intraepithelial neoplasias and prostatic adenocarcinoma lesions. Microarray analyses of transcriptional profiles showed more robust enrichment of known tumor- and metastasis-promoting genes: Spp1, Egr1, c-Myc, Sp5, and Sp6 genes, in samples isolated from Ctnnb1(L(ex3)/+)/R26hAR(L/+):PB-Cre4 compound mice than those from Ctnnb1(L(ex3)/+):PB-Cre4 and R26hAR(L/+):PB-Cre4 littermate controls. Together, these data demonstrate a confounding role of androgen signaling in β-catenin-initiated oncogenic transformation in prostate tumorigenesis.

Bladder cancer represents a significant human tumor burden, accounting for about 7.7% and 2.4% of all cancer cases in males and females, respectively. While men have a higher risk of developing bladder cancer, women tend to present at a later stage of disease and with more aggressive tumors. Previous studies have suggested a promotional role of androgen signaling in enhancing bladder cancer development. To directly assess the role of androgens in bladder tumorigenesis, we have developed a novel transgenic mouse strain, R26hARLoxP/+:Upk3aGCE/+, in which the human AR transgene is conditionally expressed in bladder urothelium. Intriguingly, both male and female R26hARLoxP/+:Upk3aGCE/+ mice display a higher incidence of urothelial cell carcinoma (UCC) than the age and sex matched control littermates in response to the carcinogen, N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). We detect expression of the human AR transgene in CK5-positive and p63-positive basal cells in bladder urothelium. Further analyses of UCC tissues from R26hARLoxP/+:Upk3aGCE/+ mice showed that the majority of tumor cells are of urothelial basal cell origin. Positive immunostaining of transgenic AR protein was observed in the majority of tumor cells of the transgenic mice, providing a link between transgenic AR expression and oncogenic transformation. We observed an increase in Ki67 positive cells within the UCC lesions of transgenic AR mice. Manipulating endogenous androgen levels by castration and androgen supplementation directly affected bladder tumor development in male and female R26hARLoxP/+:Upk3aGCE/+ mice, respectively. Taken together, our data demonstrate for the first time that conditional activation of transgenic AR expression in bladder urothelium enhances carciongen-induced bladder tumor formation in mice. This new AR transgenic mouse line mimics certain features of human bladder cancer and can be used to study bladder tumorigenesis and for drug development.

Current use of testicular biomarkers for screening, diagnosis, and follow-up is reviewed in the context of potential clinical utility of these tests. This information will be of value to clinicians to determine patient suitability for certain treatments and will also assist in reviewing current literature regarding potential biomarkers that may be used for testicular cancer., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose. The surgical expertise to perform robotic partial nephrectomy is heavily dependent on technology. The Da Vinci Xi (XI) is the latest robotic surgical platform with significant advancements compared to its predecessor. We describe our operative technique and experience with the XI system for robotic partial nephrectomy (RPN). Materials and Methods. Patients with clinical T1 renal masses were offered RPN with the XI. We used laser targeting, autopositioning, and a novel "in-line" port placement to perform RPN. Results. 15 patients underwent RPN with the XI. There were no intraoperative complications and no operative conversions. Mean console time was 101.3 minutes (range 44-176 minutes). Mean ischemia time was 17.5 minutes and estimated blood loss was 120 mLs. 12 of 15 patients had renal cell carcinoma. Two patients had oncocytoma and one had benign cystic disease. All patients had negative surgical margins and pathologic T1 disease. Two postoperative complications were encountered, including one patient who developed a pseudoaneurysm and one readmitted for presumed urinary tract infection. Conclusions. RPN with the XI system can be safely performed. Combining our surgical technique with the technological advancements on the XI offers patients acceptable pathologic and perioperative outcomes.

The search continues for optimal markers that can be utilized to improve bladder cancer detection and to predict disease recurrence. Although no single marker has yet replaced the need to perform cystoscopy and urine cytology, many tests have been evaluated and are being developed. In the future, these promising markers may be incorporated into standard practice to address the challenge of screening in addition to long-term surveillance of patients who have or are at risk for developing bladder cancer.

Background: Neoadjuvant radiotherapy (NART) for muscle-invasive bladder cancer (MIBC) is currently underused. However, the outcomes for MIBC have remained suboptimal. We investigated the relationship of NART to cause-specific mortality (CSM) and overall mortality (OM) among patients with a diagnosis of MIBC., Materials and Methods: The patients diagnosed with primary invasive urothelial carcinoma of the bladder from 1983 to 2008 with localized disease were included. Patients aged > 90 years, those diagnosed with T1 or T4 BC, and those with no information on tumor grade were excluded from the analysis. Kaplan-Meier, Cox regression, and competing risk methods were used in the analysis of OM and CSM., Results: A total of 5562 patients were included in the cohort (115 NART and 5447 surgery alone). On univariate analysis, NART significantly decreased the OM for patients with high-grade BC (hazard ratio [HR], 0.8), stage T2b (HR, 0.74), and stage T2b/T3 (HR, 0.74). CSM was also lower for those with stage T2b disease (HR, 0.63). Multivariable analysis revealed that NART was associated with a significant decrease in CSM (P = .043) and OM (P = .0462) for those with T2b. Likewise, an improvement was seen in OM (P = .0337) for patients with T2b/T3 who had received NART., Conclusion: NART was significantly associated with decreased CSM and OM in patients with clinical T2b/T3 BC and OM for patients with T2b/T3. These data suggest that NART could be beneficial in patients with T2b/T3 BC. In the modern era, the greatest utility would potentially be for patients with an incomplete response to neoadjuvant chemotherapy or as an adjunct to chemotherapy to improve the complete response rates., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: Robotic-assisted laparoscopic nephroureterectomy (RALNU) has been previously utilized for management of upper tract urothelial carcinoma. The da Vinci Xi surgical system was released in April of 2014. We describe our operative technique and early experience for RALNU using the da Vinci Xi system highlighting unique features of this surgical platform., Materials and Methods: A total of 10 patients with a diagnosis of upper tract urothelial carcinoma underwent RALNU using the da Vinci Xi system between April and November of 2014. A novel, oblique "in line" robotic trocar configuration was utilized to access the upper abdomen (nephrectomy portion) and pelvis (bladder cuff excision) without undocking. The port hopping feature of da Vinci Xi was utilized to facilitate optimal, multi-quadrant visualization during RALNU., Results: Robotic-assisted laparoscopic nephroureterectomy was successfully completed without open conversion in all 10 patients. Mean operative time was 184 min (range 140-300 min), mean estimated blood loss was 121 cc (range 60-300 cc), and mean hospital stay was 2.4 days. Final pathology demonstrated high grade urothelial carcinoma in all patients. Surgical margins were negative in all patients. No intra-operative complications were encountered. One patient developed a pulmonary embolus after being discharged. No patients required a blood transfusion. Mean patient follow-up was 130 days (range 15-210 days)., Conclusion: The use of da Vinci Xi with a novel, oblique "in line" port configuration and camera port hopping technique allows for an efficient and reproducible method for RALNU without the need for repositioning the patient or the robot during surgery.

Objectives: To investigate pathological and oncological outcomes of obese patients who underwent robot-assisted radical prostatectomy (RARP) compared with laparoscopic radical prostatectomy (LRP) or open retropubic radical prostatectomy (RRP) since limited comparative data exist with regard to oncological and survival outcomes., Methods: A total of 869 patients with body mass index ≥ 30 from two academic centers were identified. A total of 194 patients who underwent RARP were propensity score (PS) matched 1:1 to LRP or RRP cases. PS-matching variables included prostate-specific antigen (PSA), biopsy Gleason score, clinical stage, surgeon experience, and nerve-sparing technique. Predictors of positive surgical margins (PSMs) were analyzed using logistic regression. Predictors of recurrence-free survival (RFS) were analyzed within Cox regression models. Overall survival was compared with RFS using the log-rank test., Results: Pathologic Gleason scores <7, =7, and >7 were found in 24.2, 63.6, and 11.7 % of patients, respectively. There were no statistically significant differences related to pathologic stage or lymph node metastases between surgical techniques. PSM for pT2 disease were observed in 22.9, 17.4, and 19.3 % of patients undergoing RARP, LRP, and RRP, respectively (not significantly different). Preoperative PSA and clinical stage cT2 disease were independently associated with PSM. There were no significant differences in mean 3-year RFS for RARP, LRP, and RRP (87.4, 91.0, and 85.7 %). Biopsy Gleason score >7, PSM, and clinical stage two were independent predictors of decreased RFS., Conclusions: RARP demonstrates similar pathological and oncological results compared with LRP or RRP for obese patients.

The purpose of the RAZOR (randomized open vs robotic cystectomy) study is to compare open radical cystectomy (ORC) vs robot-assisted RC (RARC), pelvic lymph node dissection (PLND) and urinary diversion for oncological outcomes, complications and health-related quality of life (HRQL) measures with a primary endpoint of 2-year progression-free survival (PFS). RAZOR is a multi-institutional, randomized, non-inferior, phase III trial that will enrol at least 320 patients with T1-T4, N0-N1, M0 bladder cancer with ≈160 patients in both the RARC and ORC arms at 15 participating institutions. Data will be collected prospectively at each institution for cancer outcomes, complications of surgery and HRQL measures, and then submitted to trial data management services Cancer Research and Biostatistics (CRAB) for final analyses. To date, 306 patients have been randomized and accrual to the RAZOR trial is expected to conclude in 2014. In this study, we report the RAZOR trial experimental design, objectives, data safety, and monitoring, and accrual update. The RAZOR trial is a landmark study in urological oncology, randomizing T1-T4, N0-N1, M0 patients with bladder cancer to ORC vs RARC, PLND and urinary diversion. RAZOR is a multi-institutional, non-inferiority trial evaluating cancer outcomes, surgical complications and HRQL measures of ORC vs RARC with a primary endpoint of 2-year PFS. Full data from the RAZOR trial are not expected until 2016-2017., (© 2014 The Authors. BJU International © 2014 BJU International.)

Purpose: To compare oncologic outcomes between open radical cystectomy (ORC) and robotic-assisted radical cystectomy (RARC) using propensity score (PS) matching of preoperative variables., Methods: A group of 51 consecutive patients who underwent RARC between 2009 and 2012 were matched by propensity scoring with an equal number of patients who underwent ORC. Patient demographics, clinical staging, pathologic staging, pathologic grading, histology, positive margin status, lymph node yield, duration of hospital stay, and overall survival were examined., Results: PS-matched ORC and RARC cohorts demonstrated no significant differences with respect to preoperative variables, pathologic stage, grade, histology, metastasis at preoperative staging, and postoperative positive margin status. There were statistically significant differences in nodal status (66.7 % N0 for ORC vs. 80.4 % N0 for RARC, p = 0.039) and median lymph node yield (6 for ORC vs. 18 for RARC, p < 0.0001). No positive soft tissue margins were observed in the RARC group compared to 5.9 % in the ORC group (p = 0.332). There were no significant differences in mean duration of hospital stay or mean overall survival between ORC and RARC., Conclusion: ORC and RARC represent effective surgical approaches for the treatment of bladder cancer. Histopathologic outcomes for RARC compare favorably to ORC with respect to soft tissue margin rates and lymph node yield. These data suggest that RARC is an acceptable surgical approach for treatment of bladder cancer that can achieve outcomes that are equal or superior to those of ORC.

Purpose: Comparative data related to the use of open and minimally invasive surgical approaches for the treatment of high-risk prostate cancer (PCa) remain limited. We determined outcomes of open radical prostatectomy (RRP), laparoscopic RP (LRP), and robot-assisted RP (RARP) in matched cohorts of patients with high-risk prostate cancer., Materials and Methods: A total of 805 patients with high-risk PCa [prostate-specific antigen (PSA) >20 ng/mL, Gleason score ≥8, or clinical stage ≥cT2c] were identified. A total of 407 RRP cases were propensity score (PS) matched 1:1 to 398 LRP or RARP cases to yield 3 cohorts (RARP, LRP, and RRP) of 110 patients each for analysis. PS matching variables included the following: age, clinical stage, preoperative PSA, biopsy Gleason score, surgeon experience, and nerve-sparing technique. Overall survival (OS) and recurrence-free survival (RFS) were compared with log-rank test. RFS predictor analysis was calculated within Cox regression models., Results: Pathological Gleason scores <7, =7, and >7 were found in 3.3, 50.9, and 45.8 % of patients. There were no statistically significant differences for pathological stage and positive surgical margins between surgical techniques. Mean 3-year RFS was 41.4, 77.9, and 54.1 %, for RARP, LRP, and RRP, respectively (p < 0.0001 for RARP vs. LRP). There were no significant differences for mean estimated 3-year OS for patients treated with RARP, LRP, or RRP (95.4, 98.1, and 100 %)., Conclusions: RARP demonstrated similar oncologic outcomes compared to RRP and LRP in a PS-matched cohort of patients with high-risk prostate cancer.

Objective: To determine pathological and oncological outcomes of patients diagnosed with low-risk prostate cancer in two age cohorts who underwent radical prostatectomy (RP) and qualified for active surveillance (AS) according to Prostate Cancer Research International: Active Surveillance (PRIAS) criteria, as AS for low-risk prostate cancer represents an acceptable management strategy especially for older patients., Patients and Methods: In all, 320 patients aged ≥65 years who underwent RP and were eligible for AS according to PRIAS criteria were propensity score matched 1:1 to patients aged <65 years. Patient characteristics were compared with chi-square, Kruskal-Wallis, and one-way anova tests. Predictors of RP pathological upgrading or upstaging were analysed using logistic regression. Recurrence-free survival (RFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Predictors of RFS were analysed within Cox regression models., Results: Pathological upgrading and upstaging were significantly higher among older (≥65 years) vs younger (<65 years) patients (53.1% vs 44.1% and 12.2% vs 7.2%, respectively). Higher prostate-specific antigen levels and increasing age were independent predictors of upgrading among patients aged <65 years. There were no differences in RFS or OS between the two age groups. Positive surgical margin status was the only independent predictor of shorter RFS., Conclusions: Patients aged ≥65 years who are eligible for AS by PRIAS criteria have a higher risk of being upgraded and upstaged at RP than those aged <65 years. These findings should be taken into consideration when discussing treatment options for patients diagnosed with prostate cancer., (© 2013 The Authors. BJU International © 2013 BJU International.)