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.

Differential NEUROD1, ASCL1, and POU2F3 Expression Defines Molecular Subsets of Bladder Small Cell/Neuroendocrine Carcinoma with Prognostic Implications.

Small cell carcinomas (SMC) of the lung are now molecularly classified based on the expression of transcriptional regulators (NEUROD1, ASCL1, POU2F3, YAP1) and DLL3, which has emerged as an investigational therapeutic target. PLCG2 has been shown to identify a distinct subpopulation of lung SMC with stem cell-like and pro-metastasis features and poor prognosis. We analyzed the expression of these novel neuroendocrine markers and their association with traditional neuroendocrine markers and patient outcomes in a cohort of bladder neuroendocrine carcinoma (NEC) consisting of 103 SMC and 19 large cell neuroendocrine carcinomas (LCNEC) assembled in tissue microarrays. Co-expression patterns were assessed and integrated with detailed clinical annotation including overall (OS) and recurrence free survival (RFS) and response to neoadjuvant/adjuvant chemotherapy. We identified five distinct molecular subtypes in bladder SMC based on expression of ASCL1, NEUROD1 and POU2F3: ASCL1+/NEUROD1- (n=33; 34%), ASCL1-/NEUROD1+ (n=21; 21%), ASCL1+/NEUROD1+ (n=17; 17%), POU2F3+ (n=22, 22%), and ASCL1-/NEUROD1-/POU2F3- (n=5, 5%). POU2F3+ tumors were mutually exclusive with those expressing ASCL1 and NEUROD1 and exhibited lower expression of traditional neuroendocrine markers. PLCG2 expression was noted in 33 tumors (32%) and was highly correlated with POU2F3 expression (p < 0.001). DLL3 expression was high in both SMC (n=72, 82%) and LCNEC (n=11, 85%). YAP1 expression was enriched in non- neuroendocrine components and negatively correlated with all neuroendocrine markers. In patients without metastatic disease who underwent radical cystectomy, PLCG2+ or POU2F3+ tumors had shorter RFS and OS (p<0.05), but their expression was not associated with metastasis status or response to neoadjuvant/adjuvant chemotherapy. In conclusion, NEC of the bladder can be divided into distinct molecular subtypes based on the expression of ASCL1, NEUROD1 and POU2F3. POU2F3 expressing tumors represent an ASCL1/NEUROD1-negative subset of bladder NEC characterized by lower expression of traditional neuroendocrine markers. Marker expression patterns were similar in SMC and LCNEC. Expression of PLCG2 and POU2F3 was associated with shorter recurrence-free and overall survival. DLL3 was expressed at high levels in both SMC and LCNEC of the bladder, nominating it as a potential therapeutic target.

An approach for normalization and quality control for NanoString RNA expression data.

The NanoString RNA counting assay for formalin-fixed paraffin embedded samples is unique in its sensitivity, technical reproducibility and robustness for analysis of clinical and archival samples. While commercial normalization methods are provided by NanoString, they are not optimal for all settings, particularly when samples exhibit strong technical or biological variation or where housekeeping genes have variable performance across the cohort. Here, we develop and evaluate a more comprehensive normalization procedure for NanoString data with steps for quality control, selection of housekeeping targets, normalization and iterative data visualization and biological validation. The approach was evaluated using a large cohort ($N=\kern0.5em 1649$) from the Carolina Breast Cancer Study, two cohorts of moderate sample size ($N=359$ and$130$) and a small published dataset ($N=12$). The iterative process developed here eliminates technical variation (e.g. from different study phases or sites) more reliably than the three other methods, including NanoString's commercial package, without diminishing biological variation, especially in long-term longitudinal multiphase or multisite cohorts. We also find that probe sets validated for nCounter, such as the PAM50 gene signature, are impervious to batch issues. This work emphasizes that systematic quality control, normalization and visualization of NanoString nCounter data are an imperative component of study design that influences results in downstream analyses.

Final Results of a Phase I Trial of WST-11 (TOOKAD Soluble) Vascular-targeted Photodynamic Therapy for Upper Tract Urothelial Carcinoma.

PURPOSE: Vascular-targeted photodynamic therapy with the intravascular photosensitizing agent padeliporfin (WST-11/TOOKAD-Soluble) has demonstrated therapeutic efficacy as an ablative treatment for localized cancer with potential adaptation for endoscopic management of upper tract urothelial carcinoma. This Phase I trial (NCT03617003) evaluated the safety of vascular-targeted photodynamic therapy with WST-11 in upper tract urothelial carcinoma. MATERIALS AND METHODS: Nineteen patients underwent up to 2 endoscopic vascular-targeted photodynamic therapy treatments, with follow-up for up to 6 months. Patients who had residual or recurrent upper tract urothelial carcinoma (any grade/size) failing prior endoscopic treatment or unable or unwilling to undergo surgical resection were eligible for inclusion. The primary endpoint was to identify the maximally tolerated dose of laser light fluence. A dose escalation model was employed, with increasing light fluence (100-200 mW/cm) using a modified continual reassessment method. The secondary endpoint was treatment efficacy, defined by absence of visible tumor and negative urine cytology 30 days posttreatment. RESULTS: Fourteen (74%) patients received the maximally tolerated dose of 200 mW/cm, 2 (11%) of whom experienced a dose-limiting toxicity. The initial 30-day treatment response rate was 94% (50% complete, 44% partial). Eight patients underwent a second treatment, with a final observed 68% complete response rate. Leading toxicities were flank pain (79%) and hematuria (84%), which were transient. No ureteral strictures associated with treatment were identified during follow-up. CONCLUSIONS: Vascular-targeted photodynamic therapy with WST-11 has an acceptable safety profile with strong potential as an effective, kidney-sparing endoscopic management option for upper tract urothelial carcinoma. The recently initiated multicenter Phase 3 ENLIGHTED trial (NCT04620239) is expected to provide further evidence on this therapy.

Association of Biochemically Verified Post-Diagnosis Smoking and Nonmuscle-Invasive Bladder Cancer Recurrence Risk.

PURPOSE: Our goal was to determine the association between biochemically verified post-diagnosis smoking exposure and nonmuscle-invasive bladder cancer (NMIBC) recurrence risk. MATERIALS AND METHODS: We conducted a prospective study of 354 NMIBC patients with a smoking history undergoing care between 2015 and 2018. Patients contributed at least 2 biospecimens during followup which were tested for cotinine to determine biochemically verified post-diagnosis smoking exposure (yes/no). Our primary endpoint was time to first recurrence after study start date. We examined whether post-diagnosis smoking exposure was associated with recurrence risk in multivariable Cox proportional hazards models that accounted for demographics, clinicopathological variables, time since diagnosis and pack-years. RESULTS: Patients were predominantly White, male and had a median age of 68 years. Most patients had Ta disease (62%) and tumors of high grade (68%). Intravesical bacillus Calmette-Guérin was given to 63% of the cohort. Patients were followed for a median of 3.6 years since study start. Post-diagnosis smoking exposure was detected in 22% of patients, and 38.7% (137) of patients experienced a recurrence during followup. In multivariable models, only bacillus Calmette-Guérin treatment and prior recurrence rate were significantly associated with recurrence. There was no association between post-diagnosis smoking exposure and recurrence risk (HR: 0.73, 95% CI: 0.45-1.20). CONCLUSIONS: In a cohort of patients with predominantly high risk NMIBC, post-diagnosis smoking exposure was not associated with NMIBC recurrence. However, smoking cessation support remains a critical component of cancer care given that the benefits of quitting extend far beyond NMIBC recurrence.

Pathological and oncological outcomes in patients with sarcomatoid differentiation undergoing cystectomy.

OBJECTIVE: To evaluate whether urothelial carcinoma (UC) with sarcomatoid differentiation is associated with a lower pathological response rate to neoadjuvant chemotherapy (NAC) and worse oncological outcomes compared to UC without variant histology among patients undergoing radical cystectomy. PATIENTS AND METHODS: Patients with UC undergoing cystectomy from 1995 to 2018 at the Memorial Sloan Kettering Cancer Centre were identified. Patients with sarcomatoid differentiation at transurethral resection (TUR) or cystectomy, and patients without variant histology were selected. Downstaging from ≥cT2 to ≤pT1N0 defined partial response and pT0N0 defined complete response. Recurrence-free, cancer-specific and overall survival were modelled. RESULTS: We identified 131 patients with sarcomatoid differentiation and 1722 patients without variant histology, of whom 25 with sarcomatoid histology on biopsy and 313 without variant histology received NAC. Those with sarcomatoid differentiation presented with higher consensus tumour stage (94% ≥T2 vs 62%; P < 0.001) and were, therefore, more likely to receive NAC (29% vs 18%; P = 0.003). We found no evidence to support a difference in partial (24% vs 31%) or complete (20% vs 24%) response between patients with sarcomatoid histology and those with pure UC at TUR (P = 0.6). Among patients with sarcomatoid differentiation, 5-year recurrence-free survival was 55% (95% confidence interval [CI] 41-74) among patients receiving NAC and 40% (95% CI 31-52) among patients undergoing cystectomy alone (P = 0.1). Adjusting for stage, nodal involvement, margin status and receipt of NAC, sarcomatoid differentiation was associated with worse recurrence-free (hazard ratio [HR] 1.82, 95% CI 1.39-2.39), disease-specific (HR 1.66, 95% CI 1.23-2.22), and overall survival (HR 1.37, 95% CI 1.06-1.78). CONCLUSIONS: Sarcomatoid differentiation was associated with higher stage at presentation and independently associated with worse survival. Given similar pathological response rates if sarcomatoid differentiation is detected at initial resection, and greater survival among patients receiving NAC, treatment with NAC appears warranted. Other drivers of the poor outcomes of this histology must be investigated.

Natural history, response to systemic therapy, and genomic landscape of plasmacytoid urothelial carcinoma.

BACKGROUND: Plasmacytoid urothelial carcinoma (PUC) is a rare, aggressive histologic variant of urothelial cancer characterised by a diffuse growth pattern and CDH1 mutation. We studied the efficacy of preoperative platinum-based chemotherapy in nonmetastatic PUC and immune checkpoint inhibitors (ICIs) in advanced PUC. METHODS: Cases of nonmetastatic PUC and advanced PUC treated with ICIs at our institution were identified. Outcomes were compared to those of a published cohort of patients with urothelial carcinoma not otherwise specified. RESULTS: We identified 81 patients with nonmetastatic PUC. Of the patients with localised disease who underwent neoadjuvant chemotherapy, pathologic complete response and downstaging rates were 12 and 21%, respectively. Pathologic downstaging was not associated with significant improvement in clinical outcomes. Up to 18% of localised disease and 28% of locally advanced cases had unresectable disease at the time of surgery. ICI-treated advanced PUC (N = 21) had progression-free and overall survival of 4.5 and 10.5 months, respectively, and a 38% response rate. FGFR3 and DNA damage response gene alterations were observed in 3 and 15% of cases, respectively. CONCLUSIONS: PUC is associated with high disease burden and poor chemosensitivity. Increased awareness and recognition of this disease variant will allow for new treatment strategies.

Examining the Accuracy of Self-Reported Smoking-Related Exposure among Recently Diagnosed Nonmuscle Invasive Bladder Cancer Patients.

PURPOSE: Cigarette smoking is a risk factor for developing nonmuscle invasive bladder cancer, and continued smoking exposure after diagnosis may increase the likelihood of adverse clinical outcomes. We compare self-reported vs biochemically verified nicotine exposure to determine the accuracy of self-report among recently diagnosed nonmuscle invasive bladder cancer patients. MATERIALS AND METHODS: This cross-sectional analysis consisted of 517 nonmuscle invasive bladder cancer patients who contributed a urine or saliva specimen the same day as self-reporting their smoking, use of e-cigarettes, nicotine replacement therapy and whether they lived with a smoker. Cotinine, the primary metabolite of nicotine, was used as an objective biomarker of recent nicotine exposure. RESULTS: The prevalence of high, low and no cotinine exposure was 13%, 54% and 33%, respectively. Overall, 7.3% of patients (38/517) reported being a current cigarette smoker, while 13% (65/517) had cotinine levels consistent with active smoking exposure. Of these 65 patients 27 denied current smoking, resulting in a sensitivity of self-reported current smoking of 58%. After considering other sources of nicotine exposure such as e-cigarettes, cigars, nicotine replacement therapy and living with a smoker, the sensitivity was higher, at 82%. Nearly all patients with low cotinine denied any smoking-related exposure. CONCLUSIONS: Our findings suggest either biochemical verification with cotinine or additional questions about other sources of nicotine are needed to accurately identify nonmuscle invasive bladder cancer patients who have smoking-related exposures. Accurate classification of active and passive smoking exposure is essential to allow clinicians to advise cessation and help researchers estimate the association between post-diagnosis smoking-related exposure and nonmuscle invasive bladder cancer recurrence risk.

Genomic landscape of inverted urothelial papilloma and urothelial papilloma of the bladder.

Inverted urothelial papilloma (IUP) and urothelial papilloma (UP) are rare urothelial neoplasms that typically follow a benign clinical course. Oncogenic mutations in FGFR3, HRAS, and the TERT promoter have been reported in these entities but no comprehensive molecular analysis has been performed. We sought to characterize the genomic landscape of IUP and UP using whole-exome and targeted next-generation sequencing. In IUP, 10 of 11 tumors harbored oncogenic hotspot mutations in HRAS and the remaining tumor had an oncogenic KRAS mutation. None of the IUP tumors harbored TERT promoter or FGFR3 mutations. In UP, 8 of 11 tumors had oncogenic KRAS mutations and two had oncogenic HRAS mutations. One UP tumor had oncogenic mutations in FGFR3, PIK3CA, and the TERT promoter, and arose in a patient with recurrent non-invasive papillary urothelial carcinomas. In contrast to urothelial carcinoma, the APOBEC mutational signature was not present in any IUP and UP tumors, and oncogenic alterations in chromatin remodeling genes were uncommon in both IUP and UP. The current study suggests that IUP and UP are driven primarily by RAS pathway activation and lack the more common genomic features of urothelial cancers. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Clinical Outcomes in Patients with Panurothelial Carcinoma Treated with Radical Nephroureterectomy Following Cystectomy for Metachronous Recurrence.

PURPOSE: We report pathological, functional and oncologic outcomes in patients treated with radical nephroureterectomy following radical cystectomy. MATERIALS AND METHODS: We identified patients who underwent radical cystectomy and then radical nephroureterectomy for metachronous urothelial recurrence at our institution between January 1995 and December 2014. Univariable Cox regression was used to assess the association between overall survival and age, grade, stage, lymph node metastasis and radiographic findings. RESULTS: Of the 3,173 patients treated with radical cystectomy 64 underwent subsequent radical nephroureterectomy for metachronous urothelial recurrence. Median age at radical cystectomy was 66 years (IQR 61-74). In the 64 patients who underwent radical nephroureterectomy median time from radical cystectomy to radical nephroureterectomy was 2.7 years (IQR 1.4-4.6). Among 37 patients who underwent ureteroscopy prior to radical nephroureterectomy 29 (78%) had a positive biopsy. Radical nephroureterectomy pathology findings revealed locally advanced disease (pT3/pT4) in 39% of cases and positive node status in 11% compared with locally advanced disease in 17% and positive node status in 6% on radical cystectomy pathology findings. The post-radical nephroureterectomy estimated glomerular filtration rate was less than 60 and less than 30 ml/minute/1.73 m2 in 96% and 40% of patients, respectively. Median overall survival after radical nephroureterectomy was 3.1 years (95% CI 2.4-4.3). Only lymph node involvement at radical nephroureterectomy was significantly associated with worse overall mortality (HR 2.73, 95% CI 1.04-7.15, p = 0.041). CONCLUSIONS: The prognosis is poor in patients with panurothelial carcinoma treated with nephroureterectomy following cystectomy with locally advanced disease in a large proportion. Renal function after these procedures diminished and almost all patients were ineligible for cisplatin based chemotherapy.

The Impact of Blue Light Cystoscopy on the Diagnosis and Treatment of Bladder Cancer.

Photodynamic diagnostic technique with blue light cystoscopy (BLC) takes advantage of the preferential uptake and accumulation of protoporphyrins in neoplastic tissue which emit a red fluorescence when illuminated with blue light (360-450 nm wavelengths). This allows enhanced visualization of small papillary tumors and flat carcinoma in situ lesions that might have been missed on white light cystoscopy (WLC). There is compelling evidence that the ability of BLC to detect these additional tumors translates into improved recurrence rates compared to WLC. However, the impact of BLC with regard to progression rates and in patients who are managed with intravesical therapy is not yet known. Further work is required to optimize the integration of BLC into clinical practice, but the future for BLC appears promising.

Neoadjuvant Treatment of High-Risk, Clinically Localized Prostate Cancer Prior to Radical Prostatectomy.

Multimodal strategies combining local and systemic therapy offer the greatest chance of cure for many with men with high-risk prostate cancer who may harbor occult metastatic disease. However, no systemic therapy combined with radical prostatectomy has proven beneficial. This was in part due to a lack of effective systemic agents; however, there have been several advancements in the metastatic and castrate-resistant prostate cancer that might prove beneficial if given earlier in the natural history of the disease. For example, novel hormonal agents have recently been approved for castration-resistant prostate cancer with some early phase II neoadjuvant showing promise. Additionally, combination therapy with docetaxel-based chemohormonal has demonstrated a profound survival benefit in metastatic hormone-naïve patients and might have a role in eliminating pre-existing ADT-resistant tumor cells in the neoadjuvant setting. The Cancer and Leukemia Group B (CALGB)/Alliance 90203 trial has finished accrual and should answer the question as to whether neoadjuvant docetaxel-based chemohormonal therapy provides an advantage over prostatectomy alone. There are also several promising targeted agents and immunotherapies under investigation in phase I/II trials with the potential to provide benefit in the neoadjuvant setting.

Histology of Testicular Biopsies Obtained for Experimental Fertility Preservation Protocol in Boys with Cancer.

PURPOSE: Cryopreservation of testicular tissue with subsequent reimplantation after therapy has the potential to preserve fertility for prepubertal boys with cancer. We present the histology and feasibility of testicular tissue procurement for this novel approach. MATERIALS AND METHODS: We performed a prospective cohort study of boys at significant risk for treatment associated gonadotoxicity who were eligible for an experimental research protocol between 2008 and 2011. Open testicular biopsy was performed while the patients were anesthetized for another treatment related procedure. Half of the specimen was reserved for cryopreservation, while the other half was used for research purposes. Semithin sections of the biopsy specimens were evaluated for histological features and compared to age adjusted reference values. RESULTS: A total of 34 boys underwent biopsy between March 2008 and October 2011. Of the patients 29 had solid tumors and 5 underwent hematopoietic stem cell transplantation for benign disease. A total of 27 patients had adequate tissue for histological analysis. Median patient age was 8.7 years (IQR 2.2 to 11.5). All children had either normal (81.5% of patients) or increased (18.5%) numbers of germ cells per tubule for their age. However, 5 of 26 patients (19%) older than 6 months had no evidence of adult dark spermatogonia and 9 of 16 (56%) older than 6 years had no evidence of primary spermatocytes on biopsy, which would be expected based on age norms. These findings are suggestive of abnormal germ cell maturation. CONCLUSIONS: The preliminary histological findings of abnormal spermatogenesis maturation in the testes of prepubertal boys with cancer warrants further investigation.

Single instillation of mitomycin C plus bacillus Calmette-Guérin (BCG) versus BCG alone in high grade non-muscle invasive bladder cancer.

INTRODUCTION: This study sought to determine if the addition of perioperative mitomycin C (MMC) to treatment with bacillus Calmette-Guérin (BCG) after transurethral resection (TURBT) is superior to TURBT plus BCG alone in high grade non-muscle invasive bladder cancer (NMIBC). MATERIALS AND METHODS: Data for 719 patients diagnosed with NMIBC at the University of Pennsylvania Health System between 1977 and 2009 was reviewed retrospectively. Of these patients, 120 had high grade disease and were treated with either BCG alone or with a single instillation of 40 mg of MMC perioperatively in addition to BCG and were thus included in our study. The primary endpoints of this study included recurrence-free survival, overall and disease-free survival as assessed via Kaplan-Meier analysis. RESULTS: Of the 120 patients identified who received treatment for high grade NMIBC, 97 were treated with BCG alone and 23 received a single instillation of perioperative MMC in addition to BCG. There were no statistically significant differences noted in demographic or pathologic variables. Patients were followed for a median of 4.5 years and a maximum of 21.8 years, with no differences demonstrated in recurrence-free survival (p = 0.75), overall survival (p = 0.93) or disease-free survival (p = 0.76). Both lack of lymphovascular invasion and BCG maintenance therapy reached significance as independent predictors of recurrence-free survival (p = 0.19 and p = 0.28). CONCLUSIONS: While our study indicates that perioperative MMC likely offers little benefit in regards to recurrence or survival in high grade NMIBC, at this point in time, a larger scale, randomized, controlled trial is needed to adequately address this question.

Simplification of the Fuhrman grading system for renal cell carcinoma.

INTRODUCTION: The Fuhrman grading system (FGS) is the most widely utilized pathological classification and predictor of renal cell carcinoma (RCC) prognosis. The aim of this study was to test the prognostic ability of a simplified two-tier FGS. MATERIALS AND METHODS: We reviewed the data of 509 patients with clear cell RCC who underwent radical or partial nephrectomy between January 1994 and April 2007. The conventional four-tier (I, II, III, IV) FGS was compared to a simplified two-tier FGS in which grades I and II were combined (low grade) and grades III and IV were combined (high grade). Cancer-specific survival (CSS) was calculated for each patient. Univariate and multivariate analyses were used in combination with area under the curve (AUC) of receiver operating characteristic curves to compare prognostic accuracies between grading schemes. RESULTS: Median follow up was 81.6 months. Using the conventional FGS, the 5 year CSS for Fuhrman grades I, II, III, and IV were 74.1%, 76.0%, 57.3%, and 40.7%, respectively (p < 0.001). Using the simplified two-tier FGS, the 5 year CSS for low grade and high grade were 75.5% and 54.7%, respectively (p < 0.001). Both FGSs achieved independent predictor status in multivariate analyses. Prognostic accuracy of multivariate models between the two FGSs had nearly identical AUCs, with a c-statistic of 0.769 and 0.716 for the two-tier and conventional systems, respectively. CONCLUSIONS: Our findings indicate that the simplified FGS performs similarly to the conventional system. The use of this simplified system may promote greater continuity of pathological interpretation as well as provide a more simplified approach for clinician utilization.

Factors influencing the length of stay after radical cystectomy: implications for cancer care and perioperative management.

INTRODUCTION: Although radical cystectomy (RC) is the gold standard treatment for muscle invasive bladder cancer it is associated with perioperative complications, readmissions, and a prolonged length of hospital stay (PLOS). We explored the perioperative factors associated with a PLOS after RC and subsequent long-term outcomes. MATERIAL AND METHODS: Consecutive patients with urothelial bladder cancer undergoing RC with curative intent at our institution were classified into two groups: LOS <12 days and PLOS ≥12 days. Clinicopathological variables were compared on univariate and multivariable analysis. Complications, re-admissions, adjuvant chemotherapy use, recurrence free survival (RFS), and overall survival (OS) were compared between the two groups. Competing risk analysis was performed for bladder cancer specific mortality (BCSM). RESULTS: 330 patients were included in the analysis (median LOS = 9 days [IQR = 8-11]) of which, 274 patients (83 %) had a LOS <12 days (median = 8 days [IQR = 7-10]) and 56 patients (17 %) had a PLOS ≥12 days (median = 16 days [IQR = 13-21.5]). Only female gender, older age, and perioperative complications were associated with a PLOS. 90 day readmission rates were similar (p = 0.75). No difference was seen for BCSM, RFS, or adjuvant chemotherapy usage between the two groups. However, OS was significantly worse for PLOS (median OS = 27.7 vs. 45.6 months [p = 0.046]; HR = 1.53 [95 % CI = 1.01-2.33]). CONCLUSION: Both female and elderly patients should receive preoperative counseling about their increased risk of a PLOS after RC. Patients who experience a PLOS are at greater risk for subsequent all-cause mortality. These patient groups may benefit from proactive interventions.

Does quantification of smoking history correlate with initial bladder tumor grade and stage?

The causal association between cigarette smoking and urothelial bladder cancer has been firmly established for several decades. However, the impact of smoking intensity on initial tumor aggressiveness is less established and is reviewed in this manuscript. Particular attention is given to the relation between smoking history with both muscle-invasive bladder cancer (MIBC) and non-muscle-invasive bladder cancer (NMIBC). This article also briefly reviews the epidemiologic evidence, smoking-associated carcinogenesis, and the limitations of quantifying smoking history. There is evidence to suggest that smokers have a three-fold increased risk of developing invasive bladder cancer compared to non-smokers, and smoking cessation can reduce this risk. Continued efforts should be made to raise awareness of bladder cancer in smokers and to advocate further for smoking cessation.

Implementation and Validation of an Automated, Longitudinal Robotic Surgical Evaluation and Feedback Program at a High-volume Center and Impact on Training.

Background: Surgical education lacks a standardized, proficiency-based approach to evaluation and feedback. Objective: To assess the implementation and reception (ie, feasibility) of an automated, standardized, longitudinal surgical skill assessment and feedback system, and identify baseline trainee (resident and fellow) characteristics associated with achieving proficiency in robotic surgery while learning robotic-assisted laparoscopic prostatectomy. Design setting and participants: A quality improvement study assessing a pilot of a surgical experience tracking program was conducted over 1 yr. Participants were six fellows, eight residents, and nine attending surgeons at a tertiary cancer center. Intervention: Trainees underwent baseline self-assessment. After each surgery, an evaluation was completed independently by the trainee and attending surgeons. Performance was rated on a five-point anchored Likert scale (trainees were considered "proficient" when attending surgeons' rating was ≥4). Technical skills were assessed using the Global Evaluative Assessment of Robotic Skills (GEARS) and Prostatectomy Assessment and Competency Evaluation (PACE). Outcome measurements and statistical analysis: Program success and utility were assessed by evaluating completion rates, evaluation completion times, and concordance rates between attending and trainee surgeons, and exit surveys. Baseline characteristics were assessed to determine associations with achieving proficiency. Results and limitations: Completion rates for trainees and attending surgeons were 72% and 77%, respectively. Fellows performed more steps/cases than residents (median [interquartile range]: 5 [3-7] and 3 [2-4], respectively; p < 0.01). Prior completion of robotics or laparoscopic skill courses and surgical experience measures were associated with achieving proficiency in multiple surgical steps and GEARS domains. Interclass correlation coefficients on individual components were 0.27-0.47 on GEARS domains. Conclusions: An automated surgical experience tracker with structured, longitudinal evaluation and feedback can be implemented with good participation and minimal participant time commitment, and can guide curricular development in a proficiency-based education program by identifying modifiable factors associated with proficiency, individualizing education, and identifying improvement areas within the education program. Patient summary: An automated, standardized, longitudinal surgical skill assessment and feedback system can be implemented successfully in surgical education settings and used to inform education plans and predict trainee proficiency.