Faculty Bibliography

Introduction: There have been no randomized controlled trials (RCTs) evaluating the clinical or economic benefit of mitomycin C intravesical therapy vs. radical cystectomy in patients with high-risk non-muscle invasive bladder cancer (NMIBC). We used the Archimedes computational model to simulate RCT comparing radical cystectomy versus intravesical mitomycin C (MMC) therapy to evaluate the clinical and economic outcomes for BCG-refractory NMIBC as well demonstrate the utility of computer based models to simulate a clinical trial. Methods: The Archimedes model was developed to generate a virtual population using the Surveillance Epidemiology and End Results database, other clinical trials, and expert opinions. Patients selected were diagnosed with NMIBC (<cT2 disease) who recurred or progressed despite BCG therapy and were randomized to 1) immediate radical cystectomy vs. 2) MMC induction intravesical therapy. Clinical (progression, overall survival, and disease specific survival) and economic outcomes were reported. Results: A total of 1300 virtual patients were evaluation. Progression to MIBC in the MMC treatment arm was 30% over the lifetime. Disease specific death at 5 years was 1.6% and 8.7% for the immediate cystectomy and MMC treatment arms respectively; while, overall death was 17.8% and 23.8% at 5 years. Over a 5-year period the average cost of immediate cystectomy was $64,675 vs $68,517 in the MMC arm. Conclusion: Immediate radical cystectomy after BCG failure for NMIBC has improved survival and is more cost-effective when compared to those undergoing MMC. Simulation of clinical trials using computational models similar to the Archimedes model can overcome shortcomings of real-world clinical trials and may prove useful in the face of current medical cost-conscious era.

OBJECTIVE:To examine the outcomes of endoscopic procedures for bladder neck contracture (BNC) in the orthotopic neobladder (ONB) after radical cystectomy focusing on success rates for patients who require multiple treatments. MATERIALS AND METHODS/METHODS:Patients who underwent treatment for cystoscopically confirmed BNC in an ONB from 2007 to 2014 were studied. Treatment information included procedure type, use of adjuvant clean intermittent catheterization (CIC), and follow-up procedures. Procedures followed by additional interventions were categorized as failures. Success was defined as no additional surgical procedure with at least 1 year of follow-up. Procedures were classified by a number of prior endoscopic treatments. RESULTS:Seventy-one patients underwent 155 individual endoscopic procedures (146 urethrotomy, 3 dilation, and 6 transurethral resection of bladder neck). All patients were male without prior radiation. Median follow-up after initial endoscopic treatment was 26.8 months (interquartile range: 16.6-51.7), and time to recurrence was 3.5 months (1.6-6.3). Success was experienced for 50 of 136 individual procedures (37%) after excluding 19 procedures for inadequate follow-up. Success rates remained 25%-43% even after multiple prior interventions. Adjuvant CIC was associated with a higher success rate (14/24 or 58%) compared to procedures without CIC (36/112 or 32%, P = .02). Successful outcomes were seen in 50 of 71 patients (73%) with 2 patients requiring ONB removal. CONCLUSION/CONCLUSIONS:Individual endoscopic treatments of BNC in the ONB were met with 37% success. The rate did not decrease with subsequent procedures. Adjuvant CIC improved the outcomes. Overall, a successful outcome was achieved for most patients, but the majority required more than one procedure.

INTRODUCTION/BACKGROUND:Transurethral resection of bladder tumor (TURBT) is the gold standard initial diagnostic intervention for bladder cancer and provides diagnostic, therapeutic and prognostic benefit in non-muscle-invasive bladder cancer (NMIBC). However, TURBT alone is inadequate for optimal management of NMIBC, as patients will experience recurrence or progression depending on tumor characteristics. Adjuvant intravesical therapy with either immunotherapy or chemotherapy has been shown to reduce recurrence and/or progression in appropriately selected patients through immunostimulation or direct cell ablation. AREAS COVERED/METHODS:This review will discuss risk stratification of patients with NMIBC and role of intravesical therapies in reducing recurrence and progression of disease in these patients. A Medline search was performed to identify the best available evidence available from various systematic reviews, meta-analyses, and clinical trials on various immunotherapy and chemotherapy agents. In addition, the main aspects of drug pharmacology (mechanism of action, dosing and administration) and side effects will be reviewed. EXPERT OPINION/CONCLUSIONS:The selection of the appropriate intravesical agent for NMIBC is complex and is dependent on risk stratification and intravesical agent toxicity. Intravesical induction and maintenance immunotherapy with Bacillus Calmette-Guerin (BCG) is the preferred and most effective agent for patients with high-risk NMIBC (carcinoma in situ and high-grade disease) and reduces both recurrence and progression.

The role of tissue engineering in the cystectomy population rests on the principle of sparing healthy intestinal tissue while replacing diseased bladder. Over the last 25 years advances in cell biology and material science have improved the quality and durability of bladder replacement in animals. The neo-urinary conduit ([NUC]-Tengion) employs autologous fat smooth muscle cells which are seeded onto synthetic, biodegradable scaffolds. This seeded construct is then implanted in the patient and purportedly regenerates native urinary tissue to serve as a passive channel connecting the ureters to the skin surface. Preclinical animal studies as well as the first phase I human trial implanting the NUC are reviewed. While the ultimate goal of creating a durable, effective, tissue-engineered conduit is still in its infancy, important technical and experimental strides have been made.

OBJECTIVES/OBJECTIVE:To assess the effect of the length of the ureter resected and other clinical variables on ureterointestinal anastomotic (UIA) stricture rate following radical cystectomy and ileal segment urinary diversion. METHODS AND MATERIALS/METHODS:We identified 519 consecutive patients who underwent cystectomy and ileal conduit or ileal orthotopic neobladder diversion from January 2007 to August 2012. The length of the ureter resected was defined as the length of the ureter in the cystectomy specimen plus the length of the distal ureter submitted for pathologic analysis. The primary end point was the risk of UIA stricture formation, assessed by Cox proportional hazards analysis. RESULTS:A total of 463 patients met the inclusion criteria with complete data. Median follow-up was 459 days (interquartile range [IQR]: 211-927). Median time to stricture formation was 235 (IQR: 134-352) and 232 days (IQR: 132-351) on the right and the left ureter, respectively. Overall stricture rate per ureter was 5.9% on the right vs. 10.0% on the left (P = 0.03). There was no difference in demographic, operative, or perioperative variables between patients with and without UIA strictures. On multivariate analysis adjusted for age, sex, anastomosis technique (running vs. interrupted), and length of ureter resected, only a Clavien complication≥III (hazard ratio = 2.11, 1.01-4.40) and urine leak (hazard ratio = 3.37, 1.08-10.46) significantly predicted for left- and right-sided stricture formation, respectively. The length of the ureter resected did not predict UIA stricture formation on either side. CONCLUSIONS:The etiology of benign UIA strictures following ileal urinary diversion is likely multifactorial. Our data suggest that a complicated postoperative course and urine leak are risk factors for UIA stricture formation. The length of the distal ureter resected did not significantly affect stricture rate.

Left ventricular assist device (LVAD) is an option for the surgical management of severe heart failure, and radical cystectomy remains the standard of care for muscle-invasive bladder cancer. Given a complicated population in terms of comorbidities and management for patients with an LVAD, there is little experience with major urologic procedures, which require balancing the benefits of surgery with considerable perioperative risks. We report our experience performing the first radical cystectomy with ileal conduit in a patient with an LVAD and muscle-invasive bladder cancer.

PURPOSE/OBJECTIVE:Because of suboptimal outcomes in muscle-invasive bladder cancer even with multimodality therapy, determination of potential genetic drivers offers the possibility of improving therapeutic approaches and discovering novel prognostic indicators. EXPERIMENTAL DESIGN/METHODS:Using pTN staging, we case-matched 81 patients with resected ≥pT2 bladder cancers for whom perioperative chemotherapy use and disease recurrence status were known. Whole-exome sequencing was conducted in 43 cases to identify recurrent somatic mutations and targeted sequencing of 10 genes selected from the initial screening in an additional 38 cases was completed. Mutational profiles along with clinicopathologic information were correlated with recurrence-free survival (RFS) in the patients. RESULTS:We identified recurrent novel somatic mutations in the gene UNC5C (9.9%), in addition to TP53 (40.7%), KDM6A (21.0%), and TSC1 (12.3%). Patients who were carriers of somatic mutations in DNA repair genes (one or more of ATM, ERCC2, FANCD2, PALB2, BRCA1, or BRCA2) had a higher overall number of somatic mutations (P = 0.011). Importantly, after a median follow-up of 40.4 months, carriers of somatic mutations (n = 25) in any of these six DNA repair genes had significantly enhanced RFS compared with noncarriers [median, 32.4 vs. 14.8 months; hazard ratio of 0.46, 95% confidence interval (CI), 0.22-0.98; P = 0.0435], after adjustment for pathologic pTN staging and independent of adjuvant chemotherapy usage. CONCLUSION/CONCLUSIONS:Better prognostic outcomes of individuals carrying somatic mutations in DNA repair genes suggest these mutations as favorable prognostic events in muscle-invasive bladder cancer. Additional mechanistic investigation into the previously undiscovered role of UNC5C in bladder cancer is warranted.

Hexaminolevulinate (HAL) is a tumour photosensitizer that is used in combination with blue-light cystoscopy (BLC) as an adjunct to white-light cystoscopy (WLC) in the diagnosis and management of non-muscle-invasive bladder cancer (NMIBC). Since being licensed in Europe in 2005, HAL has been used in >200,000 procedures, with consistent evidence that it improves detection compared with WLC alone. Current data support an additional role in the reduction of recurrence of NMIBC. Since the approval of HAL by the FDA in 2010, experience of HAL-BLC in the USA continues to expand. To define areas of need and to identify the benefits of HAL-BLC in clinical practice, a focus group of expert urologists specializing in the management of patients with bladder cancer convened to review the clinical evidence, share their experiences and reach a consensus regarding the optimal use of HAL-BLC in the USA. The focus group concluded that HAL-BLC should be considered for initial assessment of NMIBC, surveillance for recurrent tumours, diagnosis in patients with positive urine cytology but negative WLC findings, and for tumour staging.

OBJECTIVE:To better define health-related quality of life (HRQOL) for patients undergoing radical cystectomy (RC) and urinary diversion. MATERIALS AND METHODS/METHODS:Patients undergoing RC and urinary diversion for urothelial carcinoma by 1 of 2 surgeons (G.D.S. or N.D.S.) had a HRQOL assessment at baseline and at follow-up using the validated, bladder cancer-specific Functional Assessment of Cancer Therapy-Vanderbilt Cystectomy Index questionnaire. The primary outcome was change in HRQOL between baseline and follow-up. RESULTS:From September 15, 2011, to July 23, 2012, 74 of 103 eligible patients were enrolled, and all but 1 completed the baseline Functional Assessment of Cancer Therapy-Vanderbilt Cystectomy Index leaving 73 patients in the study. Median age was 68 years (interquartile range, 60-74 years), 58 (78%) were Caucasian, 53 (73%) were ≥ cT2, 45 (62%) underwent incontinent diversion, and the mean age-adjusted Charlson Comorbidity Index score was 2.4 ± 1.8, with no significant differences among the 73 participants and 30 nonparticipants. The median time from surgery to response was 175 days (interquartile range, 102-232 days), and the response rate was 67%, with 9 deaths during follow-up. Baseline HRQOL scores did not significantly differ between respondents and nonrespondents or between those living vs deceased. Overall, RC-specific, physical, social, and functional HRQOL scores did not differ from baseline to follow-up, whereas emotional HRQOL scores were significantly improved (15.7 ± 5.8 vs 18.1 ± 3.9, P = .03). Overall or domain-specific HRQOL measures did not differ significantly between patients undergoing incontinent (n = 27) vs continent (n = 16) diversions. CONCLUSION/CONCLUSIONS:Overall, HRQOL scores did not statistically differ from baseline to the median 6-month follow-up for patients undergoing RC and urinary diversion for urothelial carcinoma. Patients undergoing continent vs incontinent urinary diversions had similar overall HRQOL scores at follow-up.