Faculty Bibliography

Mutagenic processes leave distinct signatures in cancer genomes. The mutational signatures attributed to APOBEC3 cytidine deaminases are pervasive in human cancers. However, data linking individual APOBEC3 proteins to cancer mutagenesis in vivo are limited. Here, we showed that transgenic expression of human APOBEC3G promotes mutagenesis, genomic instability, and kataegis, leading to shorter survival in a murine bladder cancer model. Acting as mutagenic fuel, APOBEC3G increased the clonal diversity of bladder cancer, driving divergent cancer evolution. Characterization of the single base substitution signature induced by APOBEC3G in vivo established the induction of a mutational signature distinct from those caused by APOBEC3A and APOBEC3B. Analysis of thousands of human cancers revealed the contribution of APOBEC3G to the mutational profiles of multiple cancer types, including bladder cancer. Overall, this study dissects the mutagenic impact of APOBEC3G on the bladder cancer genome, identifying it contributes to genomic instability, tumor mutational burden, copy-number loss events, and clonal diversity.

OBJECTIVE:To determine if there is an association between patient race and physician time spent with the patient during outpatient urology consultations. METHODS:We identified all adult urology new outpatient visits in the National Ambulatory Medical Care Survey dataset for 2012-2016. Patient race was dichotomized as White or non-White. Our primary outcome was time spent during the visit between the patient and urologist. Using population-level weighting, we compared differences in mean time spent during visits with White and non-White patients. Mixed-effects linear regression was used to adjust for confounding factors and to account for clustering among individual physicians. Secondary outcomes included number of services provided and if ancillary providers were seen. RESULTS:Over the 5 year period, 1668 raw visits met criteria and were used to estimate 21million new outpatient urology visits nationwide. 80% of all visits were with White patients. Mean physician time spent among visits with white patients was 23.9 minutes and 24.4 minutes for non-White patients. There was no difference in number of services provided but visits with non-white patients were less likely to include an ancillary provider. After adjustment, there was no significant difference in mean time spent with the urologist among visits with White and non-White patients (difference 0.9 minutes, 95% CI: -0.6-2.4). There were also no differences in adjusted mean time spent among return visits or new visits for hematuria, urologic cancers, or BPH. CONCLUSION/CONCLUSIONS:We found no statistically significant difference in time spent with a urologist during outpatient office consultations between White and non-White patients.

INTRODUCTION AND HYPOTHESIS/OBJECTIVE:To evaluate whether the studies contributing to the national treatment guidelines on pelvic organ prolapse adequately represent the racial and/or ethnic makeup of the American population. METHODS:This analysis examines the racial and ethnic makeup of all primary study cohorts contributing to the American College of Obstetricians and Gynecologists/American Urogynecologic Society Practice Bulletin No. 214 on pelvic organ prolapse. References were excluded if they lacked a primary patient population or were from outside the US. Mean proportional representation of racial/ethnic groups was compared to the 2018 United States Census data on race/ethnicity. The representation quotient was also calculated to evaluate for relative representation of each group. Descriptive statistics were used. RESULTS:Of the 110 references, 53 primary studies were included in the final analysis with 30 studies reporting on race/ethnicity. On average, 82% (SD = 15%) of study populations were White, while Blacks, Hispanics, and Asians represented 67% (SD = 7%), 4% (SD = 8%), and < 1% (SD = 1%), respectively, differing significantly from the 2018 US Census (p < 0.01.) The representation quotients for White women was 1.36, demonstrating a 36% overrepresentation, while Black, Hispanic, and Asian women were underrepresented among studies of all evidence levels, with representative quotients of 0.50, 0.23, and 0.09, respectively. CONCLUSIONS:Our study demonstrates a significant underrepresentation of non-White populations in primary cohorts of studies contributing to the ACOG/AUGS Practice Bulletin No. 214 on POP. This analysis reinforces that more efforts are required to include and report on racial and ethnically diverse cohorts to better serve all patients.

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.

OBJECTIVE:To elucidate potential biomarkers or mechanistic principles involved with the gut microbiota and its impact on prostate cancer pathogenesis. MATERIALS AND METHODS/METHODS:We performed a prospective case-control pilot study evaluating the gut microbiome of 20 men with either benign prostatic conditions (n = 8) or intermediate or high risk clinically localized prostate cancer (Gleason ≥4 + 3 cN0M0) (n = 12) undergoing care at tertiary referral center from September 1, 2015 to March 1, 2016. Key exclusion criteria included recent antibiotic use, significant gastrointestinal disorders, hormonal or systemic therapy for prostate cancer. Computational genomics analysis was performed on collected stool samples using MetaPhlAn2 and HUMAnN2 platforms. Linear discriminant analysis effect size method was used to support high-dimensional class comparisons to find biologically relevant features. Kruskal-Wallis sum-rank test was used to detect features with significant differential abundance with respect to class, with biological consistency investigated using a set of pairwise tests among subclasses using the Wilcoxon rank-sum test, both to an α ≤0.05. RESULTS:Higher relative abundance of Bacteriodes massiliensis was seen in prostate cancer cases compared to controls. Faecalibacterium prausnitzii and Eubacterium rectalie had higher relative abundance among controls. Biologically significant differences were also found in relative gene, pathway, and enzyme abundance. CONCLUSION/CONCLUSIONS:Biologically significant differences exist in the gut microbial composition of men with prostate cancer compared to benign controls. These differences may play a role in the pathobiology of prostate cancer, and warrant further exploration.

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.

OBJECTIVE:To evaluate whether there is a correlation between publicized health ranking systems and surgical outcomes after radical cystectomy (RC) in New York State (NYS). MATERIALS AND METHODS/METHODS:Using the Statewide Planning and Research Cooperative System, data were collected in an aggregated fashion per hospital for the 20 hospitals with the highest RC volume in NYS from 2009 to 2012. Hospital characteristics were obtained from the publicly available sources such as the Centers for Medicare and Medicaid Services. Publicized ranking systems evaluated included the US News & World Health Report for Urology ranking (USHR), Healthgrades (HG) score, and Consumer Reports (CR) safety ranking. Outcomes measured included mortality, readmissions, and causes of readmissions. RESULTS:CR safety scores were inversely associated with overall death at 90 days after surgery (R = -0.527, P = .030), number of readmissions (R = -0.608, P = .030), and readmissions because of surgical complications (R = -0.523, P = .031) on a Pearson correlation test. On Kendall rank tau test, USHR and HG were not associated with any outcome of interest, although the scores correlated with increasing RC volume. CONCLUSION/CONCLUSIONS:In our analysis of 20 hospitals with the highest RC volume in NYS, USHR and HG scores were not strongly associated with any clinical outcome after RC. CR performed well in comparison with USHR and HG. Nevertheless, better metrics are needed to compare hospitals and to incorporate curative rates for morbid surgeries.