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.

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.

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.

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.

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.

ΔNp63 expression is a protective factor of progression in clinical high grade T1 bladder cancer.

PURPOSE: Several risk factors have been claimed to predict the progression of clinically high grade T1 bladder tumors. However, these factors are not specific enough to define which patients should be treated immediately with radical cystectomy. Therefore, it is critical to identify molecular markers that can help provide individualized, risk stratified decision making. Our main goal was to evaluate the role of total p63, p53 and ΔNp63 expression in cases of clinically high grade T1 bladder cancer progression. MATERIALS AND METHODS: Total p63, p53 and ΔNp63 expression was analyzed by immunohistochemistry in 134 clinically high grade T1 tumors. We assessed clinical progression to muscle invasive disease or radical cystectomy as a patient outcome end point. Survival analysis was done for recurrence-free, progression-free, disease specific and overall survival. RESULTS: A total of 132 patients (98.5%) underwent repeat transurethral resection. Cases of early progression (less than 3 months) were excluded from study to avoid under staging. Of the tumors 90 (67.2%) showed ΔNp63 expression loss. During a median followup of 62.1 months 19 patients (14.2%) progressed to muscle invasive disease. The progression rate was 21.1% in patients with tumors characterized by ΔNp63 loss but no progression was observed in those with tumors with ΔNp63 expression (p <0.001). There was no difference in the number of patients who underwent repeat transurethral resection, had associated carcinoma in situ, showed lymphovascular invasion or received followup intravesical bacillus Calmette-Guérin courses. CONCLUSIONS: ΔNp63 expression is a favorable prognostic factor in clinically high grade T1 bladder cancer. This marker identifies patients at low risk for progression who could benefit from conservative therapy with transurethral bladder tumor resection and bacillus Calmette-Guérin, avoiding over treatment with immediate radical cystectomy.

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.

Phase II trial of intravesical nanoparticle albumin bound paclitaxel for the treatment of nonmuscle invasive urothelial carcinoma of the bladder after bacillus Calmette-Guérin treatment failure.

PURPOSE: Response rates to current second line intravesical therapies for recurrent nonmuscle invasive bladder cancer range between 10% and 30%. Nanoparticle albumin bound (nab-)paclitaxel has increased solubility and lower toxicity compared to other taxanes. Results of the phase I intravesical trial of this compound demonstrated minimal toxicity during dose escalation. We now report the results of a phase II trial to assess efficacy. MATERIALS AND METHODS: This study was an investigator initiated, single center, single arm, phase II trial investigating the use of nab-paclitaxel in patients with recurrent Tis, T1 and Ta urothelial carcinoma in whom at least 1 prior regimen of intravesical bacillus Calmette-Guérin failed. Patients received 500 mg/100 ml nab-paclitaxel administered in 6 weekly intravesical instillations. Efficacy was evaluated with cystoscopy, biopsy, cytology and imaging. If complete response was achieved, patients were treated with full dose monthly maintenance treatments for 6 months. RESULTS: A total of 28 patients were enrolled in the study. Of these patients 10 (35.7%) exhibited a complete response after initial treatment. At 1 year all of these responses remained durable after maintenance therapy. At a mean followup of 21 months (range 5 to 47) 19 of 28 (67.8%) patients retained their bladders without progression or distant metastases. A single patient had progression to muscle invasive disease at radical cystectomy. Treatment related adverse events were noted in 9 of 28 (32.1%) patients and were limited to grade 1 or 2. CONCLUSIONS: Intravesical nab-paclitaxel has minimal toxicity and a 35.7% response rate in patients with nonmuscle invasive bladder cancer and previous bacillus Calmette-Guérin failure. Complete response remained durable at 1 year followup in this heavily pretreated patient population.

Metastatic epidural spinal cord compression among elderly patients with advanced prostate cancer.

BACKGROUND: A recent randomized trial demonstrated that for metastatic epidural spinal cord compression (MESCC), a complication of advanced prostate cancer, surgical decompression may be more effective than external beam radiation therapy (RT). We investigated predictors of MESCC, its treatment, and its impact on hospital length of stay for patients with advanced prostate cancer. METHODS: We used the SEER-Medicare database to identify patients >65 years with stage IV (n = 14,800) prostate cancer. We used polytomous logistic regression to compare those with and without MESCC and those hospitalized for treatment with surgical decompression and/or RT. RESULTS: MESCC developed in 711 (5 %) of patients, among whom 359 (50 %) received RT and 107 (15 %) underwent surgery ± RT. Median survival was 10 months. MESCC was more likely among patients who were black (OR 1.75, 95 %CI 1.39-2.19 vs. white) and had high-grade tumors (OR 3.01, 95 %CI 1.14-7.94), and less likely in those younger; with prior hormonal therapy (OR 0.73, 95 %CI 0.62-0.86); or with osteoporosis (OR 0.63, 95 %CI 0.47-0.83). Older patients were less likely to undergo either RT or surgery, as were those with ≥1 comorbidity. Patients with high-grade tumors were more likely to undergo RT (OR 1.92, 95 %CI 1.25-2.96). Those who underwent RT or surgery spent an additional 11 and 29 days, respectively, hospitalized. CONCLUSIONS: We found that black men with metastatic prostate cancer are more likely to develop MESCC than whites. RT was more commonly utilized for treatment than surgery, but the elderly and those with comorbidities were unlikely to receive either treatment.

The role of pelvic lymphadenectomy in non-muscle invasive bladder cancer.

INTRODUCTION: We evaluated whether the extent of lymphadenectomy at the time of radical cystectomy for non-muscle invasive bladder cancer (NMIBC) impacts recurrence free survival. MATERIALS AND METHODS: We conducted an IRB approved retrospective analysis of patients with clinical NMIBC who underwent radical cystectomy from 1990-2010. Patients were stratified based on extent of lymph node dissection using total lymph node yield as a surrogate indicator of lymph node dissection extent, with cut off analyses performed at 0, 8, 10, and 20 nodes removed. Analyses of recurrence free survival (RFS) were performed using log-rank analysis and multivariate Cox regression. RESULTS: One hundred and ninety-six patients with NMIBC met the inclusion criteria for this study, with no differences in RFS detected in those who had ≥ 10 nodes compared to < 10 nodes removed (p = 0.63). Upon multivariate analysis, ≥ 10 nodes removed (HR 1.00; p = 0.99) was not significantly associated with decreased RFS, while high grade tumor (HR 3.22; p = 0.05) and positive margin status (HR 3.87; p = 0.04) were. The median number of nodes removed was 8 (range 0-45), with no difference in RFS using this as a cut off point (p = 0.19). The removal of ≥ 20 nodes did not predict worse survival compared to < 20 nodes removed (p = 0.07). CONCLUSIONS: Although the extent of lymphadenectomy has been associated with improved survival in patients undergoing radical cystectomy for muscle invasive bladder cancer, we were unable to detect an impact of lymph node dissection extent on RFS in patients with NMIBC. This finding emphasizes that when determining extent of lymph node dissection in radical cystectomy, one size does not fit all.

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.

Long-term survival outcomes with intravesical docetaxel for recurrent nonmuscle invasive bladder cancer after previous bacillus Calmette-Guérin therapy.

PURPOSE: Docetaxel is a safe agent for intravesical therapy. Adding monthly maintenance treatments can extend response durability. We report our cumulative experience with intravesical docetaxel in a larger cohort with extended followup. MATERIALS AND METHODS: A total of 54 patients received salvage intravesical docetaxel for bacillus Calmette-Guérin refractory nonmuscle invasive bladder cancer between 2003 and 2012, including 18 treated during the original phase I trial. All patients received 6 weekly instillations of intravesical docetaxel. After the phase I trial, those with a complete response to induction treatment were offered single dose monthly maintenance treatments for a total of up to 12 months of docetaxel therapy. Recurrence was defined as positive biopsy or urine cytology. Recurrence-free, disease specific and overall survival was determined by Kaplan-Meier analysis. RESULTS: Median followup was 39.1 months. Of the 54 patients 32 (59%) had a complete initial response after induction therapy, including 18 who received additional monthly maintenance treatments. Median time to recurrence in initial responders treated with vs without docetaxel maintenance was 39.3 vs 19.0 months. One and 3-year recurrence-free survival rates for the entire cohort were 40% and 25%, respectively. Of the 54 patients 17 (24%) underwent radical cystectomy at a median of 24 months of followup. Five-year disease specific and overall survival rates were 85% and 71%, respectively. CONCLUSIONS: Intravesical docetaxel appears to be a promising agent with significant efficacy and durability for bacillus Calmette-Guérin refractory nonmuscle invasive bladder cancer. Adding maintenance treatments may increase the duration of recurrence-free survival.

Pathological outcome and biochemical recurrence-free survival after radical prostatectomy in African-American, Afro-Caribbean (Jamaican) and Caucasian-American men: an international comparison.

OBJECTIVE: To compare pathological and biochemical outcomes of radical prostatectomy (RP) among African-American (AA), Afro-Caribbean (AC; Jamaican) and Caucasian-American (CA) men using an international cohort of patients who underwent RP in the USA and Jamaica. MATERIALS AND METHODS: A retrospective review was performed of men who underwent RP for clinically organ-confined (OC) prostate cancer between 2000 and 2011 at Columbia University Medical Center (New York, USA) and the University Hospital of the West Indies (Kingston, Jamaica) between 2000 and 2007. Men who had received neoadjuvant or adjuvant (within 3 months) therapy were excluded. Clinicopathological variables were compared among the three groups, focusing on age, stage, PSA level, Gleason sum (GS) and margin status. Multivariate analysis was performed to determine the predictors of biochemical recurrence (BCR; PSA >0.2 ng/mL), and Kaplan-Meier analysis was performed to determine BCR-free survival rates in AA, AC and CA men. RESULTS: A total of 483 men underwent RP for clinically OC disease (CM, n = 309, AA, n = 93 and AC, n = 81). The mean patient age was 59 years, with AA men being younger than CA men (58 vs 60 years, P< 0.05). The mean (range) follow-up was 49 (13-133) months with no significant difference among the groups. The men in the AC cohort had a higher mean PSA level than AA and CA men (8.8 vs 6.2 and 5.0 ng/mL, respectively, P< 0.05) and more clinical GS ≥7 (44%) tumours than AA (8%) and CA men (0%; P< 0.01). On multivariate analysis, controlling for stage, grade, PSA level and margins, AA and AC race were independent predictors of BCR. AA and AC men had significantly lower 5-year BCR-free survival (76 and 74%, respectively) than CA men (98% [P < 0.001]). CONCLUSIONS: This international comparison of clinicopathological outcomes in AA, AC and CA men undergoing RP shows that AA and AC men present similarly with more aggressive disease features than CA men and have lower 5-year BCR-free survival. Both AA and AC race are significant predictors of BCR, independently of stage, grade, PSA level and margin status. Further research is needed to elucidate and correct the mechanisms behind the observed difference in outcome among these populations.

Racial disparities in the use of palliative therapy for ureteral obstruction among elderly patients with advanced prostate cancer.

OBJECTIVES: Palliative issues are an important but understudied issue for patients with advanced cancer. Ureteral obstruction is a complication of advanced prostate cancer, usually relieved with placement of retrograde ureteral stent (RUS) or percutaneous nephrostomy (PCN) to palliate symptoms associated with obstructive uropathy and/or renal failure. We investigated predictors of receipt of RUS and PCN and their association with survival for older advanced prostate cancer patients. METHODS: Using the Surveillance, Epidemiology, and End Results-Medicare database, we identified patients aged 65 or older with stage IV (n = 10,848) or recurrent (n = 7,872) prostate cancer. We used multivariable analysis to compare those with ureteral obstruction treated with RUS or PCN to those not treated and to analyze the association between RUS, PCN, and survival. RESULTS: Sixteen percent (n = 2,958) of the sample developed ureteral obstruction. Compared to no treatment, African Americans were more likely to undergo placement of PCN [odds ratio 1.48, 95 % confidence intervals (CI) 1.03-2.13] than Whites, but equally likely to receive a stent. Subjects of >80 years were less likely to undergo RUS (ages 80-84, 0.41, 95 % CI 0.27-0.63; ages ≥85, 0.30, 95 % CI 0.16-0.54) compared to patients 65-69 years. Subjects who received a PCN were 55 % more likely to die than those who were untreated. There was no difference in survival among those receiving RUS vs untreated. Nine percent of subjects received RUS or PCN within 30 days of dying. CONCLUSIONS: This is the first population-based study to demonstrate a racial disparity in the palliative treatment of advanced prostate cancer. Reasons for disparate care need to be determined so that interventions may be developed.

Experience with newer intravesical chemotherapy for high-risk non-muscle-invasive bladder cancer.

The definitive treatment for patients with high-risk non-muscle-invasive bladder cancer (NMIBC) who fail to respond to intravesical bacillus Calmette-Guérin (BCG) is cystectomy. However, many patients who experience recurrence after BCG are either poor operative candidates or refuse surgery due to the long-term impact on their quality of life. In the last decade, there has been an increased interest in alternative intravesical therapies, and several novel chemotherapeutics have emerged as promising agents for high-risk NMIBC patients unable or unwilling to undergo cystectomy. Additionally, extended treatment regimens with combined induction and maintenance therapy have been investigated, and may increase the durability of response to these new agents, as has been shown for conventional intravesical therapy.

Dysregulation of circulating microRNAs and prediction of aggressive prostate cancer.

BACKGROUND: It is becoming increasingly evident that microRNAs (miRNAs) are associated with the development and progression of prostate cancer (PCa). METHODS: We examined the hypothesis that plasma miRNA levels can differentiate patients by aggressiveness in 82 PCa patients. Taqman based quantitative RT-PCR assays were performed to measure copy number of target miRNAs. RESULTS: miR-20a was significantly overexpressed in plasma from patients with stage 3 tumors compared to stage 2 or below (P = 0.03). The expression levels for miR-20a and miR-21 were significantly increased in patients with high risk CAPRA scores (16,623 and 1,595 copies, respectively). Significantly increased miR-21 and miR-145 expression were observed for patients with intermediate or high risk D'Amico scores compared to patients with low risk scores (P = 0.047 and 0.011, respectively). The relapse rates for CAPRA scores ranged from 1.9% for low risk to 9.5% for intermediate risk and to 22.2% for high risk patients (P = 0.023). For D'Amico scores, the relapse rates ranged from 0.0% for low risk to 7.4% for intermediate risk and 17.6% for high risk patients (P = 0.039). Expression of miR-21 and miR-221 significantly differentiated patients with intermediate risk from those with low risk CAPRA scores (AUC = 0.801, P = 0.002). Four miRNAs (miR-20a, miR-21, miR-145, and miR-221) could also distinguish high versus low risk in PCa patients by D'Amico score with an AUC of 0.824. CONCLUSIONS: These preliminary data suggest that altered plasma miRNAs may be useful predictors to distinguish PCa patients with varied aggressiveness. Further larger studies to validate this promising finding are warranted.

A comparison of the outcomes of neoadjuvant and adjuvant chemotherapy for clinical T2-T4aN0-N2M0 bladder cancer.

BACKGROUND: Despite evidence supporting perioperative chemotherapy, few randomized studies compare neoadjuvant and adjuvant chemotherapy for bladder cancer. Consequently, the standard of care regarding the timing of chemotherapy for locally advanced bladder cancer remains controversial. We compared patient outcomes following neoadjuvant or adjuvant systemic chemotherapy for cT2-T4aN0-N2M0 bladder cancer. METHODS: In a retrospective review of a single institutional database from 1988 through 2009, we identified patients receiving neoadjuvant or adjuvant multiagent platinum-based systemic chemotherapy for locally advanced bladder cancer. Survival analysis was performed comparing disease-specific survival (DSS) and overall survival (OS). RESULTS: A total of 146 patients received systemic perioperative chemotherapy (73 neoadjuvant, 73 adjuvant). Of these, 84% (122/146) received cisplatin-based chemotherapy compared with carboplatin-based chemotherapy (24/146, 16.4%). Most patients receiving cisplatin-based chemotherapy were treated with methotrexate/vinblastine/adriamycin/cisplatin (79/122, 64.8%), whereas the remaining patients received gemcitabine/cisplatin (GC) (43/122, 35.2%). In multivariable analysis, there was no significant difference in DSS (P = .46) or OS (P = .76) between neoadjuvant or adjuvant chemotherapy groups. There was statistically significant improvement in DSS when patients received neoadjuvant GC rather than adjuvant GC (P = .049, hazard ratio, 10.6; 95% confidence interval, 1.01-112.2). CONCLUSION: In this study, there was no statistically significant difference in OS and DSS between patients receiving neoadjuvant versus adjuvant systemic platinum-based chemotherapy for locally advanced bladder cancer. In addition, there was no significant difference between neoadjuvant and adjuvant cisplatin- or carboplatin-based chemotherapy. Chemotherapy sequence relative to surgery appeared less important than whether or not a patient actually received perioperative chemotherapy.

Routine transition zone biopsy during active surveillance for prostate cancer rarely provides unique evidence of disease progression.

PURPOSE: Routine sampling of the transition zone during prostate biopsy has become increasingly common. Although approximately 10% of prostate cancers originate in the transition zone, the benefit of transition zone biopsies may be limited. We evaluated the usefulness of transition zone biopsy in patients with prostate cancer enrolled in active surveillance. MATERIALS AND METHODS: Patients on active surveillance followed at our institution between 1993 and 2011 were identified in the urological oncology database. All surveillance biopsies were stratified by transition and peripheral zone pathology results. The usefulness of transition zone biopsy was assessed by whether transition zone specific cancer characteristics, eg volume and grade, changed disease management recommendations. RESULTS: A single surgeon performed a total of 244 prostate biopsies in 92 men. Each patient underwent initial positive prostate biopsy and at least 1 active surveillance prostate biopsy. Mean age was 69 years. A mean of 2.7 biopsies were done per patient. Nine patients (10%) had positive transition zone cores on initial positive prostate biopsy, of whom 3 had transition zone unique cancers. One of these patients showed transition zone disease progression on active surveillance prostate biopsy, which led to up staging and exclusion from active surveillance. A total of 16 patients (17%) had positive transition zone cores on active surveillance prostate biopsy, of whom 13 had a negative transition zone on initial positive prostate biopsy. Transition and peripheral zone Gleason scores were identical in 9 of these patients and the transition zone score was lower in 4. Thus, transition zone pathology did not result in up staging or disease management alterations in any patient with new transition zone pathology. CONCLUSIONS: Up staging due to transition zone specific pathology is exceedingly rare. Transition zone biopsy in patients on active surveillance should be limited to those with transition zone involvement on initial positive prostate biopsy only.

Effect of delaying surgery on radical prostatectomy outcomes: a contemporary analysis.

UNLABELLED: Study Type - Therapy (case series). Level of Evidence 4. What's known on the subject? and What does the study add? For patients electing surgical treatment, the question of the effect of surgical delay on clinical outcomes in prostate cancer is controversial. In this study we examined the effect of delay from diagnosis to surgery on outcomes in men with localized prostate cancer and found no association between time to surgery and risk of biochemical recurrence, even for patients with longer delays and high-risk disease. Men with localized prostate cancer can be reassured that reasonable delays in treatment will not influence disease outcomes. OBJECTIVE: • To examine the effect of time from last positive biopsy to surgery on clinical outcomes in men with localized prostate cancer undergoing radical prostatectomy (RP). PATIENTS AND METHODS: • We conducted a retrospective review of 2739 men who underwent RP between 1990 and 2009 at our institution. • Clinical and pathological features were compared between men undergoing RP ≤ 60, 61-90 and >90 days from the time of prostate biopsy. • A Cox proportional hazards model was used to analyse the association between clinical features and surgical delay with biochemical progression. Biochemical recurrence (BCR)-free rates were assessed using the Kaplan-Meier method. RESULTS: • Of the 1568 men meeting the inclusion criteria, 1098 (70%), 303 (19.3%) and 167 (10.7%) had a delay of ≤ 60, 61-90 and >90 days, respectively, between biopsy and RP. A delay of >60 days was not associated with adverse pathological findings at surgery. • The 5-year survival rate was similar among the three groups (78-85%, P= 0.11). • In a multivariate Cox model, men with higher PSA levels, clinical stages, Gleason sums, and those of African-American race were all at higher risk for developing BCR. • A delay to surgery of >60 days was not associated with worse biochemical outcomes in a univariate and multivariate model. CONCLUSIONS: • A delay of >60 days is not associated with adverse pathological outcomes in men with localized prostate cancer, nor does it correlate with worse BCR-free survival. • Patients can be assured that delaying treatment while considering therapeutic options will not adversely affect their outcomes.

Immediate radical cystectomy vs conservative management for high grade cT1 bladder cancer: is there a survival difference?

OBJECTIVE: To determine whether a survival difference exists between patients with high grade (HG) cT1 urothelial cell carcinoma (UCC) receiving immediate radical cystectomy (IRC) as opposed to those choosing bladder-sparing therapy. PATIENTS AND METHODS: Between January 1990 and August 2010, 349 patients were retrospectively identified with a diagnosis of HG cT1 UCC of the bladder. Patients were divided into two groups: those who underwent IRC and those treated with conservative management (CM), consisting of transurethral resection of the bladder tumour (TURBT) and intravesical therapy. IRC was defined as surgery within 90 days of HG cT1 diagnosis with no intervening transurethral resection (TUR) or intravesical therapy (IVT). Trends in patient selection and cancer-specific survival (CSS) were analyzed over consecutive decades. The primary outcome was to compare CSS among patients during consecutive decades whereby management paradigms shifted from IRC to CM. The secondary outcome was to examine whether patient selection changed over time for each respective intervention. RESULTS: One hundred and thirteen patients underwent IRC and 236 had CM. From 1990 to 1999, only 90 patients were diagnosed with HG cT1 disease, and a majority of patients (n= 54) underwent IRC. From 2000 to 2010, only 23% (59/259) of the patients with HG cT1 underwent IRC. Despite 42.3% more patients successfully maintaining their bladder in the long-term, no difference in 5 year bladder CSS was noted between decades (77% vs 80% consecutively, P= 0.566). A subset analysis of risk factors for bladder cancer progression/recurrence demonstrated more patients with lymphovascular invasion (LVI) on TUR underwent IRC in the current era (13/59 (22.0%) vs 13/200 (6.5%), P < 0.001). These findings remain to be validated in prospective work at other institutions. CONCLUSION: Conservative management strategies are a viable treatment option within a well selected subset of patients with HG cT1 UCC.