Metformin Overcomes the Consequences of NKX3.1 Loss to Suppress Prostate Cancer Progression.

BACKGROUND: The antidiabetic drug metformin has known anticancer effects related to its antioxidant activity; however, its clinical benefit for prostate cancer (PCa) has thus far been inconclusive. Here, we investigate whether the efficacy of metformin in PCa is related to the expression status of NKX3.1, a prostate-specific homeobox gene that functions in mitochondria to protect the prostate from aberrant oxidative stress. OBJECTIVE: To investigate the relationship of NKX3.1 expression and metformin efficacy in PCa. DESIGN, SETTING, AND PARTICIPANTS: Functional studies were performed in vivo and in vitro in genetically engineered mouse models and human LNCaP cells, and organotypic cultures having normal or reduced/absent levels of NKX3.1. Correlative studies were performed using two independent retrospective tissue microarray cohorts of radical prostatectomies and a retrospective cohort of prostate biopsies from patients on active surveillance. INTERVENTION: Metformin was administered before or after the induction of oxidative stress by treatment with paraquat. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Functional endpoints included analyses of histopathology, tumorigenicity, and mitochondrial function. Correlative endpoints include Kaplan-Meier curves and Cox proportional hazard regression models. RESULTS AND LIMITATIONS: Metformin reversed the adverse consequences of NKX3.1 deficiency following oxidative stress in vivo and in vitro, as evident by reduced tumorigenicity and restored mitochondrial function. Patients with low NKX3.1 expression showed a significant clinical benefit from taking metformin. CONCLUSIONS: Metformin can overcome the adverse consequences of NKX3.1 loss for PCa progression by protecting against oxidative stress and promoting normal mitochondrial function. These functional activities and clinical correlates were observed only with low NKX3.1 expression. Thus, the clinical benefit of metformin in PCa may depend on the status of NKX3.1 expression. PATIENT SUMMARY: Prostate cancer patients with low NKX3.1 are likely to benefit most from metformin treatment to delay disease progression in a precision interception paradigm.

Survival and oncologic outcomes of complete transurethral resection of bladder tumor prior to neoadjuvant chemotherapy for muscle-invasive bladder cancer.

OBJECTIVES: Prior studies have shown that pathologic complete response at radical cystectomy, a significant prognostic factor, can be attributed to both neoadjuvant chemotherapy (NAC) and high-quality transurethral resections (TURBT) prior to NAC. It remains unclear whether the visual completeness of TURBT prior to NAC plays an important role in subsequent outcomes. We sought to assess the association of completeness of TURBT prior to NAC with response and survival outcomes. METHODS AND MATERIALS: We retrospectively reviewed all patients with clinically localized muscle-invasive bladder cancer at our institution who received NAC from 2000 to 2017. Complete TURBT was defined as resection of all visible tumor in entirety, resection to normal-appearing muscle, and/or repeat pre-NAC TURBT revealing cT0. Patients who were restaged as cT0 after NAC and refused cystectomy were placed on an active surveillance/delayed intervention (ASDI) protocol. The primary endpoints were overall and cancer-specific survival. The secondary endpoints were recurrence-free and muscle-invasive recurrence-free survival. RESULTS: Of 93 patients, 62 (67%) underwent complete TURBT prior to chemotherapy. Compared to patients with incomplete TURBT, those with complete TURBT had lower rates of variant histology (13% vs. 32%) and hydronephrosis (15% vs. 39%). Also, 36% of patients with incomplete TURBT had ≥cT3 disease prior to NAC, compared to none in the complete TURBT cohort. Patients with complete TURBT were more likely to defer RC and pursue ASDI (61% vs. 32%). Those with complete TURBT had lower rates of pT2 or higher disease at cystectomy (48% vs. 75%), with a lower rate of N+ disease trending towards significance (17% vs. 37%). Patients with complete TURBT had higher 5-year overall (77% vs. 46%, P = 0.003) and cancer-specific (85% vs. 50%, P = 0.001) survival. On Cox regression analysis, complete TURBT was significantly associated with superior cancer-specific, recurrence-free, and muscle-invasive recurrence-free survival. CONCLUSIONS: A complete TURBT prior to NAC is associated with improved survival and oncologic outcomes in this cohort with muscle-invasive bladder cancer. The extent to which complete TURBT simply represents a proxy for less aggressive disease or is actually a beneficial therapeutic intervention which improves response to chemotherapy is difficult to define retrospectively.

Bladder Preservation for Patients With Bladder Paragangliomas: Case Series and Review of the Literature.

Bladder paragangliomas are rare tumors, with no prospective studies or guidelines on the management of this disease. We present a case series of 6 patients managed with bladder preservation over a median follow-up period of 124 months. We also present a review of the recent literature on bladder paragangliomas. We aim to provide a timely synthesis of the recent evidence on bladder paragangliomas as changing paradigms necessitate individualized treatment.

Tumor Evolution and Drug Response in Patient-Derived Organoid Models of Bladder Cancer.

Bladder cancer is the fifth most prevalent cancer in the U.S., yet is understudied, and few laboratory models exist that reflect the biology of the human disease. Here, we describe a biobank of patient-derived organoid lines that recapitulates the histopathological and molecular diversity of human bladder cancer. Organoid lines can be established efficiently from patient biopsies acquired before and after disease recurrence and are interconvertible with orthotopic xenografts. Notably, organoid lines often retain parental tumor heterogeneity and exhibit a spectrum of genomic changes that are consistent with tumor evolution in culture. Analyses of drug response using bladder tumor organoids show partial correlations with mutational profiles, as well as changes associated with treatment resistance, and specific responses can be validated using xenografts in vivo. Our studies indicate that patient-derived bladder tumor organoids represent a faithful model system for studying tumor evolution and treatment response in the context of precision cancer medicine.

Role of Genetic Testing for Inherited Prostate Cancer Risk: Philadelphia Prostate Cancer Consensus Conference 2017.

Purpose Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-driven working framework for comprehensive genetic evaluation of inherited PCA in the multigene testing era addressing genetic counseling, testing, and genetically informed management. Methods An expert consensus conference was convened including key stakeholders to address genetic counseling and testing, PCA screening, and management informed by evidence review. Results Consensus was strong that patients should engage in shared decision making for genetic testing. There was strong consensus to test HOXB13 for suspected hereditary PCA, BRCA1/2 for suspected hereditary breast and ovarian cancer, and DNA mismatch repair genes for suspected Lynch syndrome. There was strong consensus to factor BRCA2 mutations into PCA screening discussions. BRCA2 achieved moderate consensus for factoring into early-stage management discussion, with stronger consensus in high-risk/advanced and metastatic setting. Agreement was moderate to test all men with metastatic castration-resistant PCA, regardless of family history, with stronger agreement to test BRCA1/2 and moderate agreement to test ATM to inform prognosis and targeted therapy. Conclusion To our knowledge, this is the first comprehensive, multidisciplinary consensus statement to address a genetic evaluation framework for inherited PCA in the multigene testing era. Future research should focus on developing a working definition of familial PCA for clinical genetic testing, expanding understanding of genetic contribution to aggressive PCA, exploring clinical use of genetic testing for PCA management, genetic testing of African American males, and addressing the value framework of genetic evaluation and testing men at risk for PCA-a clinically heterogeneous disease.

Oncologic Outcomes of Definitive Treatments for Low- and Intermediate-Risk Prostate Cancer After a Period of Active Surveillance.

BACKGROUND: To compare oncologic outcomes of different definitive treatment (DT) modalities in a cohort of patients with prostate cancer (PCa) after active surveillance (AS). METHODS: We identified 237 patients with National Comprehensive Cancer Network (NCCN) low- and intermediate-risk prostate cancer diagnosed from 1990 to 2012 who did not undergo immediate DT within 12 months of diagnosis (ie, AS patients as well as watchful waiting and those refusing DT). Charts were examined for clinical/pathologic data and type of DT: surgery (RP), radiation including brachytherapy (XRT), cryotherapy, and androgen deprivation therapy monotherapy (ADT). The impact of DT on oncologic outcomes of biochemical recurrence (BCR), metastasis, disease-specific (DSS), and overall survival (OS) was examined with the Cox proportional hazards model, along with the Kaplan-Meier method and log-rank test. RESULTS: After median time on AS of 63.4 months, 40% of patients underwent DT: 47% XRT, 28% RP, 14% ADT, and 11% cryotherapy. On multivariable analysis, the use of XRT predicted higher BCR (hazard ratio [HR] 6.1, P = .001) and worse overall mortality (HR 2.1, P = .03) compared with other treatments, controlling for age, Charlson Comorbidity Index (CCI), stage, Gleason score, and NCCN risk category. Median follow-up was 71.7 months. On Kaplan-Meier analysis, 10-year OS was superior for RP versus XRT among patients with prostatic specific antigen (PSA) velocity >2.0 ng/mL/y. CONCLUSIONS: Low- and intermediate-risk patients with PCa who progress to DT after AS may be inadequately treated with radiation therapy compared with other DT modalities, especially when pretreatment PSA velocity is > 2 ng/mL/y.

Preoperative Antibiotics Before Bladder Biopsy: Are They Necessary?

OBJECTIVE: To compare postoperative infectious outcomes of bladder biopsies performed in the office without antibiotic prophylaxis vs those done with preoperative antibiotic prophylaxis in the operating room (OR). MATERIALS AND METHODS: Our institutional review board-approved database was retrospectively reviewed for patients who underwent bladder biopsy in the office or in the OR between July 2014 and August 2015. All patients with bladder biopsies performed in the OR and none in the office received preoperative antibiotic prophylaxis. Patient characteristics and post-procedural outcomes including bacteriuria, urinary tract infection (UTI), and febrile UTI were recorded. The rates of these outcomes were compared between the 2 groups using the chi-square test. Patients were excluded from analysis if they experienced a UTI or were prescribed antibiotics within 30 days before their procedure. RESULTS: In all, 216 biopsies were identified (106 in the office and 110 in the OR). No difference was noted in the rate of UTI (0.94% vs 0.91%, P = .98), or febrile UTI (0% vs 0.91%, P = .33) between those undergoing bladder biopsy in the office and those in the OR. There was no difference in the incidence of new urinary symptoms (2.8% vs 5.5%, P = .33) or post-procedural bacteriuria (3.8% vs 3.6%, P = .96). CONCLUSION: Since the introduction of the mandated use of antibiotics for routine procedures such as bladder biopsy, antibiotic use has markedly increased. Our data suggest that the preoperative antibiotic prophylaxis that is recommended may not confer benefit to select patients. At a time when antibiotic stewardship is of utmost importance, guidelines regarding its use should be reconsidered.

A Prospective Randomized Trial of the Effects of Early Enteral Feeding After Radical Cystectomy.

OBJECTIVE: To investigate the role of early feeding on recovery after radical cystectomy and urinary diversion. Enhanced recovery protocols have helped to standardize postoperative recovery. This is the first study to directly review the impact of early feeding on recovery in a randomized multi-institutional protocol. METHODS: From 2011 to 2014, patients at 2 large hospitals were randomized after radical cystectomy to receive access to liquids and then a regular diet on postoperative days 1 and 2 or conventional care with introduction of a liquid diet after return of bowel activity, typically days 3-5. Early ambulation, use of metoclopramide, and no nasogastric tube were standard for all patients. The study was powered to detect a 50% decrease in 90-day complication rate with secondary end points of length of stay, time to bowel activity, and time to diet tolerance. The study was terminated early due to slow accrual (102 of 328). RESULTS: Overall complications for the early vs standard groups were similar (34 vs 31, P = .86). Immediate inpatient and postdischarge complication rates were also similar (P = .63 and P = .44). Length of stay was not different (8.74 days vs 9.69 days, P = .43). Rates of ileus (27% vs 41%, P = .21) and return of bowel function (4.67 days vs 4.09 days, P = .62) were the same in arms. CONCLUSION: Although this prospective randomized study did not meet the accrual target, early introduction of diet was well tolerated and did not show a negative or positive difference in any outcomes. Enhanced recovery protocols standardize postoperative care and early feeding is a well-tolerated addition.

Urine Exosomes for Non-Invasive Assessment of Gene Expression and Mutations of Prostate Cancer.

PURPOSE: The analysis of exosome/microvesicle (extracellular vesicles (EVs)) and the RNA packaged within them (exoRNA) has the potential to provide a non-invasive platform to detect and monitor disease related gene expression potentially in lieu of more invasive procedures such as biopsy. However, few studies have tested the diagnostic potential of EV analysis in humans. EXPERIMENTAL DESIGN: The ability of EV analysis to accurately reflect prostate tissue mRNA expression was examined by comparing urinary EV TMPRSS2:ERG exoRNA from pre-radical prostatectomy (RP) patients versus corresponding RP tissue in 21 patients. To examine the differential expression of TMPRSS2:ERG across patient groups a random urine sample was taken without prostate massage from a cohort of 207 men including prostate biopsy negative (Bx Neg, n = 39), prostate biopsy positive (Bx Pos, n = 47), post-radical prostatectomy (post-RP, n = 37), un-biopsied healthy age-matched men (No Bx, n = 44), and young male controls (Cont, n = 40). The use of EVs was also examined as a potential platform to non-invasively differentiate Bx Pos versus Bx Neg patients via the detection of known prostate cancer genes TMPRSS2:ERG, BIRC5, ERG, PCA3 and TMPRSS2. RESULTS: In this technical pilot study urinary EVs had a sensitivity: 81% (13/16), specificity: 80% (4/5) and an overall accuracy: 81% (17/21) for non-invasive detection of TMPRSS2:ERG versus RP tissue. The rate of TMPRSS2:ERG exoRNA detection was found to increase with age and the expression level correlated with Bx Pos status. Receiver operator characteristic analyses demonstrated that various cancer-related genes could differentiate Bx Pos from Bx Neg patients using exoRNA isolated from urinary EVs: BIRC5 (AUC 0.674 (CI:0.560-0.788), ERG (AUC 0.785 (CI:0.680-0.890), PCA3 (AUC 0.681 (CI:0.567-0.795), TMPRSS2:ERG (AUC 0.744 (CI:0.600-0.888), and TMPRSS2 (AUC 0.637 (CI:0.519-0.754). CONCLUSION: This pilot study suggests that urinary EVs have the potential to be used as a platform to non-invasively differentiate patients with prostate cancer with very good accuracy. Larger studies are needed to confirm the potential for clinical utility.

The Timing of Radical Cystectomy for bacillus Calmette-Guérin Failure: Comparison of Outcomes and Risk Factors for Prognosis.

PURPOSE: We compared the pathological and survival outcomes of patients who underwent radical cystectomy soon after bacillus Calmette-Guérin failure with those of patients who received additional salvage intravesical chemotherapy before cystectomy for nonmuscle invasive bladder cancer. We also identified predictors of prognosis in the entire cohort. MATERIALS AND METHODS: We retrospectively analyzed the records of 117 patients who underwent radical cystectomy for recurrent nonmuscle invasive bladder cancer at our institution from 1990 to 2012. The cohort was divided into group 1 of 61 patients treated only with bacillus Calmette-Guérin with or without interferon-α and group 2 of 56 who received at least 1 additional salvage intravesical chemotherapy after bacillus Calmette-Guérin. RESULTS: Final pathology and survival outcomes did not differ significantly between the groups. Five-year overall and cancer specific survival was similar in groups 1 and 2 at 80% and 85%, respectively, at approximately equivalent followups. Median bladder retention was 1.7 years longer in group 2 (p <0.001). On multivariate Cox regression analysis delayed cystectomy in group 2 did not convey a significant hazard for all cause mortality after cystectomy (HR 1.08, p = 0.808). Only up-staging to cT1 (HR 1.88, p = 0.045), lymph node invasion (HR 2.58, p = 0.023) and prostatic urethra involvement (HR 1.95, p = 0.029) achieved significance. CONCLUSIONS: With appropriate selection for salvage intravesical chemotherapy patients who elect bladder sparing treatment instead of earlier radical cystectomy after bacillus Calmette-Guérin fails do not sacrifice positive pathological or oncologic outcomes while retaining bladder function for a significantly longer duration.

Partial Cystectomy for Primary Bladder Tumors in Contemporary Patients with Diverse Tumor Locations.

INTRODUCTION: Partial cystectomy use has historically been limited by stringent selection criteria. We compared outcomes following partial cystectomy at our institution with those in other contemporary series. Also, we specifically characterized outcomes in patients with tumors in bladder locations traditionally considered unamenable to partial cystectomy. METHODS: Patients who underwent partial cystectomy for primary bladder cancer from 1990 to 2012 were identified from our database. Clinical and pathological data were reviewed. Survival analyses were performed using Kaplan-Meier methods. Cox regression was done to identify factors associated with survival and recurrence. RESULTS: A total of 55 patients were included in analysis. Five-year overall, disease specific and recurrence-free survival was 70.3%, 77.0% and 39.4%, respectively. When controlling for clinical and pathological covariates, lymphovascular invasion predicted decreased recurrence-free survival (HR 10.6, p = 0.025). Perioperative morbidity and mortality rates were 4% and 5%, respectively. In 8 patients (15%) trigone tumors required ureteral reimplantation. Two of the 8 patients (25%) experienced complications, including hydronephrosis and bladder neck contracture, which were treated conservatively. Cancer recurred in 2 of the 8 patients (25%) and both were treated successfully. None of the 8 patients died of bladder cancer. CONCLUSIONS: Patients treated with partial cystectomy for primary bladder cancer had satisfactory cancer control and favorable perioperative morbidity consistent with other contemporary reports. Patients with tumors in the bladder trigone, historically considered poor candidates for partial cystectomy, also had good oncologic outcomes without significant complications related to reimplantation. Our data further support partial cystectomy in select patients with bladder cancer.

Prospective Correlation between Likelihood of Favorable Pathology on the 17-Gene Genomic Prostate Score and Actual Pathological Outcomes at Radical Prostatectomy.

INTRODUCTION: We evaluate the Genomic Prostate Score in a prospective clinical setting and determine the cutoff point for likelihood of favorable pathology, below which definitive treatment should be advised. METHODS: Pathological data were recorded for men who had the Genomic Prostate Score performed and who ultimately underwent radical prostatectomy. Inclusion criteria were newly diagnosed prostate cancer, and NCCN classification as very low, low and low volume intermediate risk. Adverse pathology was defined as any pT3 stage and primary Gleason grade of 4 or any pattern 5. ROC analysis was used to determine the optimal cutoff point of likelihood of favorable pathology for each NCCN risk group. RESULTS: A total of 95 patients were enrolled and 50 patients (53%) underwent radical prostatectomy. Adverse pathology was found in 21 patients (42%), grouped as very low risk 0%, low risk 32.4% and low volume intermediate risk 71.4%. Among those with low risk disease, ROC analysis determined that a likelihood of favorable pathology cutoff of 76% or greater performed the best, correctly classifying 91.2% of patients with a sensitivity of 95.7%, specificity of 81.8% and AUC 0.95. For intermediate risk patients the optimal likelihood of favorable pathology cutoff was 68% or greater, with 92.3% correct, sensitivity 75%, specificity 100% and AUC 0.95. CONCLUSIONS: NCCN low risk patients had the most meaningful information provided by the Genomic Prostate Score. Men with low risk disease with a likelihood of favorable pathology threshold greater than 75% are at very low risk for adverse pathology, whereas those with a likelihood of favorable pathology of 75% or less are at high risk. This likelihood of favorable pathology threshold is greater than 69% for men with low volume intermediate risk disease. These results should help clinicians use Genomic Prostate Score information when making decisions regarding active surveillance or intervention for prostate cancer.

Predictors of biochemical recurrence in pT3b prostate cancer after radical prostatectomy without adjuvant radiotherapy.

BACKGROUND: Men with pathologic evidence of seminal vesicle invasion (SVI) at radical prostatectomy (RP) have higher rates of biochemical recurrence (BCR) and mortality. Adjuvant radiotherapy (XRT) has been shown to increase freedom from BCR, but its impact on overall survival is controversial and it may represent overtreatment for some. The present study, therefore, sought to identify men with SVI at higher risk for BCR after RP in the absence of adjuvant XRT. METHODS: We identified 180 patients in our institutional database who underwent RP from 1990 to 2011 who had pT3bN0-1 disease. The Kaplan-Meier method was used to estimate freedom from BCR for the overall cohort and substratified by Gleason score, PSA, surgical margin status, and lymph node positivity. Cox Proportional Hazards models were used to determine demographic and histopathological factors predictive of BCR. Time-dependent ROC curve analysis was conducted to assess the ability of the UCSF-CAPRA score to predict BCR. RESULTS: Median age was 64 years, and 52.8% of patients were preoperative D'Amico high risk. At RP, 41.4% had a positive surgical margin (PSM), and 12.2% had positive lymph nodes (LN). The most common sites of PSM were the peripheral zone (56.8%) and the apex (32.4%). Positive bladder neck margin (HR = 7.01, P = 0.035) and PSA 10-20 versus ≤10 (HR = 1.63, P = 0.047) predicted higher BCR in multivariable analyses. Median follow-up was 26 months, and 2-, 3-, and 5-year BCR-free rates were 56.1%, 49.0%, and 39.5%. Log rank tests showed that freedom from BCR was significantly less for Gleason 9-10, PSA >20, PSM, and N1 patients. The area under curve (AUC) for CAPRA in predicting BCR was 0.713 at 2 years, 0.692 at 3 years, and 0.641 at 5 years. Increasing CAPRA score was associated with an increased risk of BCR (HR = 1.33, P < 0.001). CONCLUSIONS: pT3b prostate cancer is a heterogeneous disease commonly associated with several high-risk features. Stratifying men with SVI by prognostic features (i.e., Gleason, PSA, node status, surgical margin status) and using these features to augment the CAPRA score will improve identification of those at higher risk for BCR that should be strongly considered for adjuvant XRT.

Validation of a frailty index in patients undergoing curative surgery for urologic malignancy and comparison with other risk stratification tools.

OBJECTIVE: To retrospectively validate and compare a modified frailty index predicting adverse outcomes and other risk stratification tools among patients undergoing urologic oncological surgeries. MATERIALS AND METHODS: The American College of Surgeons National Surgical Quality Improvement Program was queried from 2005 to 2013 to identify patients undergoing cystectomy, prostatectomy, nephrectomy, and nephroureterectomy. Using the Canadian Study of Health and Aging Frailty Index, 11 variables were matched to the database; 4 were also added because of their relevance in oncology patients. The incidence of mortality, Clavien-Dindo IV complications, and adverse events were assessed with patients grouped according to their modified frailty index score. RESULTS: We identified 41,681 patients who were undergoing surgery for presumed urologic malignancy. Patients with a high frailty index score of >0.20 had a 3.70 odds of a Clavien-Dindo IV event (CI: 2.865-4.788, P<0.0005) and a 5.95 odds of 30-day mortality (CI: 3.72-9.51, P<0.0005) in comparison with nonfrail patients after adjusting for race, sex, age, smoking history, and procedure. Using C-statistics to compare the sensitivity and specificity of the predictive ability of different models per risk stratification tool and the Akaike information criteria to assess for the fit of the models with the data, the modified frailty index was comparable or superior to the Charlson comorbidity index but inferior to the American Society of Anesthesiologists Risk Class in predicting 30-day mortality or Clavien-Dindo IV events. When the modified frailty index was augmented with the American Society of Anesthesiologists Risk Class, the new index was superior in all aspects in comparison to other risk stratification tools. CONCLUSION: Existing risk stratification tools may be improved by incorporating variables in our 15-point modified frailty index as well as other factors such as walking speed, exhaustion, and sarcopenia to fully assess frailty. This is relevant in diseases such as kidney and prostate cancer, where surveillance and other nonsurgical interventions exist as alternatives to a potentially complicated surgery. In these scenarios, our modified frailty index augmented by the American Society of Anesthesiologists Risk Class may help inform which patients have increased surgical complications that may outweigh the benefit of surgery although this index needs prospective validation.

Predicting Renal Parenchymal Loss after Nephron Sparing Surgery.

PURPOSE: We analyze the relationship among various patient, operative and tumor characteristics to determine which factors correlate with renal parenchymal volume loss after nephron sparing surgery using a novel 3-dimensional volume assessment. MATERIALS AND METHODS: We conducted a retrospective review of an institutional database of patients who underwent nephron sparing surgery from 1992 to 2014 for a localized renal mass. Tumors were classified according to the R.E.N.A.L. nephrometry system. Using 3-dimensional reconstruction imaging software, preoperative and postoperative renal parenchymal volume was calculated for the ipsilateral and contralateral kidney. RESULTS: A total of 158 patients were analyzed. Mean patient age was 58.7 years and mean followup was 40.1 months. Mean preoperative tumor volume was 34.0 cc and mean tumor dimension was 3.4 cm. Mean R.E.N.A.L. nephrometry score was 6.2, with 60.1%, 34.2% and 5.7% of tumors classified as low, medium and high complexity, respectively. Mean change in renal parenchymal volume after nephron sparing surgery was -15.3% for the ipsilateral kidney and -6.8% for total kidney volume. On univariate analysis ischemia time, tumor size, R.E.N.A.L. nephrometry score, complexity grouping and the individual nephrometry components of tumor size, percent exophytic, anterior/posterior, depth and tumor proximity to the renal artery or vein were associated with greater renal parenchymal volume loss. On multivariate analysis only ischemia time, tumor size, posterior location and percent exophytic were independently associated with more renal parenchymal volume loss. CONCLUSIONS: Using precise 3-dimensional volumetric analysis we found that ischemia time, tumor size and endophytic/exophytic properties of a localized renal mass are the most important determinants of renal parenchymal volume loss.

Delay from biopsy to radical prostatectomy influences the rate of adverse pathologic outcomes.

BACKGROUND: We sought to determine maximum wait times between biopsy diagnosis and surgery for localized prostate cancer, beyond which the rate of adverse pathologic outcomes is increased. METHODS: We retrospectively reviewed 4,610 patients undergoing radical prostatectomy between 1990 and 2011. Patients were stratified by biopsy Gleason score and PSA value. For each stratification, χ2 analysis was used to determine the smallest 15-day multiple of surgical delay (e.g., 15, 30, 45…180 days) for which adverse pathologic outcomes were significantly more likely after the time interval than before. Adverse outcomes were defined as positive surgical margins, upgrading from biopsy, upstaging, seminal vesicle invasion, or positive lymph nodes. RESULTS: Two thousand two hundred twelve patients met inclusion criteria. Median delay was 64 days (mean 76, SD 47). One thousand six hundred seventy-five (75.7%), 537 (24.3%), and 60 (2.7%) patients had delays of <=90, >90, and >180 days, respectively. Twenty-six percent were upgraded on final pathology and 23% were upstaged. The positive surgical margin rate was 24.2% and the positive lymph node rate was 1.1%. Significant increases in the proportion of adverse pathological outcomes were found beyond 75 days in the overall cohort (P = 0.03), 150 days for patients with Gleason <=6, and PSA 0-10 (P = 0.038), 60 days for patients with Gleason 7 and PSA >20 (P = 0.032), and 30 days for patients with Gleason 8-10 and PSA 11-20 (0.041). CONCLUSION: In low-risk disease, there is a considerable but not unlimited surgical delay which will not adversely impact the rate of adverse pathologic features found. In higher risk disease, this time period is considerably shorter.

Mixed low- and high-grade non-muscle-invasive bladder cancer: a histological subtype with favorable outcome.

OBJECTIVE: To determine whether heterogeneity of tumor grade affects the response to Bacillus Calmette-Guérin (BCG) treatment for patients with non-muscle-invasive bladder cancer (NMIBC). METHODS: Patients with Ta or T1 NMBIC receiving a 6-week induction course of intravesical BCG therapy after transurethral resection were divided according to the tumor grade. Clinical and pathological variables were compared. Advanced intervention-free survival (AIFS), defined as duration of freedom from advanced intervention (including non-BCG intravesical agents or cystectomy) or metastasis, was plotted using Kaplan-Meier methods. The effect of grade on survival duration was assessed by multivariate Cox proportional hazards modeling. RESULTS: One hundred and fifty-three patients were identified: 17 with mixed low- and high-grade (MG) and 136 with pure high-grade (PHG) NMIBC. Demographic and additional pathologic variables were comparable between groups (p > 0.05). Five-year AIFS was 88.2% for MG patients, compared to 48.5% for PHG patients (p = 0.030 by log-rank test). On multivariate analysis, PHG was an independent risk factor for worse AIFS (HR 4.4, 95% CI 1.1-18.4, p = 0.040). Among patients failing to respond to primary BCG induction, who underwent a secondary induction of BCG with interferon, MG patients had better response than PHG patients (100 vs. 26.3%, p = 0.035). CONCLUSIONS: Mixed low- and high-grade NMIBC exhibits a significantly better response profile to intravesical BCG therapy compared to PHG NMIBC. The implications of these results are that less aggressive treatment strategies for this unique cancer entity may be needed and that there is a benefit to the reporting of tumor heterogeneity in transurethral resection of bladder tumor specimens.