Natural History and Genomic Landscape of Chemotherapy-Resistant Muscle-Invasive Bladder Cancer.

PURPOSE: Patients with residual invasive bladder cancer after neoadjuvant chemotherapy (NAC) and radical cystectomy have a poor prognosis. Data on adjuvant therapy for these patients are conflicting. We sought to evaluate the natural history and genomic landscape of chemotherapy-resistant bladder cancer to inform patient management and clinical trials. METHODS: Data were collected on patients with clinically localized muscle-invasive urothelial bladder cancer treated with NAC and cystectomy at our institution between May 15, 2001, and August 15, 2019, and completed four cycles of gemcitabine and cisplatin NAC, excluding those treated with adjuvant therapies. Survival was estimated using the Kaplan-Meier method, and multivariable Cox proportional hazards models were used to identify predictors of recurrence-free survival (RFS). Genomic alterations were identified in targeted exome sequencing (Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets) data from post-NAC specimens from a subset of patients. RESULTS: Lymphovascular invasion (LVI) was the strongest predictor of RFS (hazard ratio, 2.15 [95% CI, 1.37 to 3.39]) on multivariable analysis. Patients with ypT2N0 disease without LVI had a significantly prolonged RFS compared with those with LVI (70% RFS at 5 years). Lymph node yield did not affect RFS. Among patients with sequencing data (n = 101), chemotherapy-resistant tumors had fewer alterations in DNA damage response genes compared with tumors from a publicly available chemotherapy-naïve cohort (15% v 29%; P = .021). Alterations in CDKN2A/B were associated with shorter RFS. PIK3CA alterations were associated with LVI. Potentially actionable alterations were identified in more than 75% of tumors. CONCLUSION: Although chemotherapy-resistant bladder cancer generally portends a poor prognosis, patients with organ-confined disease without LVI may be candidates for close observation without adjuvant therapy. The genomic landscape of chemotherapy-resistant tumors is similar to chemotherapy-naïve tumors. Therapeutic opportunities exist for targeted therapies as adjuvant treatment in chemotherapy-resistant disease.

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.

Response to 2 Induction Courses of Bacillus Calmette-Guèrin Therapy Among Patients With High-Risk Non-Muscle-Invasive Bladder Cancer: 5-year Follow-Up of a Phase 2 Clinical Trial.

Importance: With the ongoing bacillus Calmette-Guèrin (BCG) shortage, alternate therapeutic options for patients with high-risk non-muscle-invasive bladder cancer (NMIBC) are needed. Objective: To report the 5-year outcomes of a cohort from a prospective phase 2 trial of patients with high-risk NMIBC who underwent 12 instillations of induction BCG without maintenance. Design, Setting, and Participants: Between November 2015 and June 2018, patients at Memorial Sloan Kettering Cancer Center with primary or recurrent NMIBC (high-grade Ta, T1 tumors, with or without carcinoma in situ) were prospectively enrolled to receive 2 induction courses (12 intravesical instillations) of BCG without maintenance therapy. The analysis itself took place on July 28, 2023. Main Outcomes and Measures: Recurrence-free survival (RFS) and cancer-specific survival (CSS) was assessed by landmark analysis at 7.5 months. Recurrence was defined as pathologic high-grade disease. Results: Among 81 patients (65 men [84%] and 12 women [16%] with a median [IQR] age of 72 [64-77] years) who consented to participate in the study, 75 remained evaluable for long-term follow-up analysis. Twenty-one patients experienced high-grade recurrence, yielding a 5-year RFS rate of 69% (95% CI, 58%-81%), with a median (IQR) follow-up of 4.4 (3.8-5.3) years for patients without recurrence. Three patients died of bladder cancer, corresponding to a CSS rate of 97% (95% CI, 93%-100%) with a median (IQR) follow-up of 4.9 (4.2-5.7) years for survivors. Using 2 induction courses reduced the amount of BCG per patient from 27 vials to 12 vials. Conclusion and Relevance: Twelve induction instillations of BCG without maintenance for patients with high-risk NMIBC reduced the number of vials needed per patient while providing acceptable oncologic outcomes. Given the ongoing BCG shortage, this modified regimen may provide a suitable alternative in this setting.

Changes in the Perioperative Management and Outcomes of Patients With Upper Tract Urothelial Carcinoma Undergoing Radical Nephroureterectomy at Memorial Sloan Kettering Cancer Center: Over 20 Years of Experience.

INTRODUCTION: We evaluated surgical trends, perioperative management evolution, and oncologic outcomes in patients who underwent radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) at a tertiary cancer center over a 24-year period. METHODS: Between 1995 and 2018, we evaluated 743 consecutive patients with UTUC who underwent RNU. Generalized additive models were used to estimate the associations between date of surgery and continuous outcomes using a linear model, dichotomous outcomes using a logit link, categorical outcomes using multinomial models, and 2- and 5-year survival outcomes using Cox proportional hazards models. RESULTS: Over the study period, preoperative diagnostic endoscopic biopsies increased from 10% to 66%, along with the proportion of patients who underwent RNU for high-grade disease from 55% to 91%. The rate of open RNU declined from 100% to 56% with a rise in minimally invasive approaches. Median lymph node yield increased with more retroperitoneal lymph node dissections performed. Neoadjuvant chemotherapy utilization increased with a contemporary utilization rate of 32%, coinciding with an increase in pT0 rate from 2% to 8%. Cancer-specific survival probabilities improved over the study period, while metastasis-free and overall survival remained stable. CONCLUSIONS: We found several changes in treatment patterns and outcomes for patients with UTUC over the past 2 decades. How individual alterations in management factors, such as patient selection, perioperative chemotherapy, lymphadenectomy, and salvage therapies, impact patient outcomes is challenging in the setting of multiple overlapping practice changes for this rare disease and warrants further investigation.

Multicenter Phase II Clinical Trial of Gemcitabine and Cisplatin as Neoadjuvant Chemotherapy for Patients With High-Grade Upper Tract Urothelial Carcinoma.

PURPOSE: Neoadjuvant chemotherapy (NAC) has proven survival benefits for patients with invasive urothelial carcinoma of the bladder, yet its role for upper tract urothelial carcinoma (UTUC) remains undefined. We conducted a multicenter, single-arm, phase II trial of NAC with gemcitabine and split-dose cisplatin (GC) for patients with high-risk UTUC before extirpative surgery to evaluate response, survival, and tolerability. METHODS: Eligible patients with defined criteria for high-risk localized UTUC received four cycles of split-dose GC before surgical resection and lymph node dissection. The primary study end point was rate of pathologic response (defined as < ypT2N0). Secondary end points included progression-free survival (PFS), overall survival (OS), and safety and tolerability. RESULTS: Among 57 patients evaluated, 36 (63%) demonstrated pathologic response (95% CI, 49 to 76). A complete pathologic response (ypT0N0) was noted in 11 patients (19%). Fifty-one patients (89%) tolerated at least three complete cycles of split-dose GC, 27 patients (47%) tolerated four complete cycles, and all patients proceeded to surgery. With a median follow up of 3.1 years, 2- and 5-year PFS rates were 89% (95% CI, 81 to 98) and 72% (95% CI, 59 to 87), while 2- and 5-year OS rates were 93% (95% CI, 86 to 100) and 79% (95% CI, 67 to 94), respectively. Pathologic complete and partial responses were associated with improved PFS and OS compared with nonresponders (≥ ypT2N any; 2-year PFS 100% and 95% v 76%, P < .001; 2-year OS 100% and 100% v 80%, P < .001). CONCLUSION: NAC with split-dose GC for high-risk UTUC is a well-tolerated, effective therapy demonstrating evidence of pathologic response that is associated with favorable survival outcomes. Given that these survival outcomes are superior to historical series, these data support the use of NAC as a standard of care for high-risk UTUC, and split-dose GC is a viable option for NAC.

Long-term Outcomes of Local and Metastatic Small Cell Carcinoma of the Urinary Bladder and Genomic Analysis of Patients Treated With Neoadjuvant Chemotherapy.

INTRODUCTION: Small cell carcinoma of the bladder (SCCB) is a rare variant of bladder cancer with poor outcomes. We evaluated long-term outcomes of nonmetastatic (M0) and metastatic (M1) SCCB and correlated pathologic response with genomic alterations of patients treated with neoadjuvant chemotherapy (NAC). PATIENTS AND METHODS: Clinical history and pathology samples from SCCB patients diagnosed at our institution were reviewed. RESULTS: One hundred and ninety-nine SCCB patients were identified. (M0: 147 [74%]; M1: 52 [26%]). Among M0 patients, 108 underwent radical cystectomy (RC) (NAC: 71; RC only: 23; adjuvant chemotherapy: 14); 14 received chemoradiotherapy; the rest received chemotherapy alone or no cancer-directed therapy. RC-only patients had a median follow-up of 9.1 years, and median disease-free survival (DFS) and overall survival (OS) were 1.1 and 1.2 years, respectively. NAC patients had pathologic response (

Clinical and Genomic Characterization of Bladder Carcinomas With Glandular Phenotype.

PURPOSE: To compare oncologic outcomes and genomic alteration profiles in patients with bladder and urachal adenocarcinoma, urothelial carcinoma (UC) with glandular differentiation, and UC, not otherwise specified (NOS) undergoing surgical resection, with emphasis on response to systemic therapy. METHODS: We identified patients with bladder cancer with glandular variants who underwent surgical resection at Memorial Sloan Kettering from 1995 to 2018 (surgical cohort) and/or patients who had tumor sequencing using a targeted next-generation sequencing platform (genomics cohort). Pathologic complete and partial response rates to neoadjuvant chemotherapy (NAC) and recurrence-free and cancer-specific survival were measured. Alteration frequencies between histologic subtypes were compared. RESULTS: Thirty-seven patients with bladder adenocarcinoma, 46 with urachal adenocarcinoma, 84 with UC with glandular differentiation, and 1,049 with UC, NOS comprised the surgical cohort. Despite more advanced disease in patients with bladder and urachal adenocarcinoma, no significant differences in recurrence or cancer-specific survival by histology were observed after adjusting for stage. In patients with UC with glandular differentiation, NAC resulted in partial (≤ pT1N0) and complete (pT0N0) responses in 28% and 17%, respectively. Bladder and urachal adenocarcinoma genomic profiles resembled colorectal adenocarcinoma with frequent TP53, KRAS, and PIK3CA alterations while the genomic profile of UC with glandular differentiation more closely resembled UC, NOS. Limitations include retrospective nature of analysis and small numbers of nonurothelial histology specimens. CONCLUSION: The genomic profile of bladder adenocarcinomas resembled colorectal adenocarcinomas, whereas UC with glandular differentiation more closely resembled UC, NOS. Differences in outcomes among patients with glandular bladder cancer variants undergoing surgical resection were largely driven by differences in stage. Cisplatin-based NAC demonstrated activity in UC with glandular differentiation, suggesting NAC should be considered for this histologic variant.

Feasibility of a geriatric comanagement (GERICO) pilot program for patients 75 and older undergoing radical cystectomy.

BACKGROUND: Retrospective studies have shown the beneficial impact of geriatric comanagement (GERICO) on perioperative outcomes of older adults with cancer. We prospectively assessed the feasibility of perioperative GERICO for older adults with bladder cancer undergoing radical cystectomy. METHODS: We conducted a pilot study wherein all patients 75 years and older undergoing radical cystectomy between October 2019 and November 2020 were referred to the Geriatric Service preoperatively. Feasibility was defined according to the percentage of patients who received preoperative evaluation by the Geriatrics Service, who were followed for more than 80% of their inpatient days and who had their surgery rescheduled for logistical reasons. Urology advanced practice provider (APP) satisfaction with the program was measured via an 11-item survey. RESULTS: Sixty-six eligible patients underwent radical cystectomy in the stated time frame; 59 (89%; 95% confidence interval [CI], 79-97%) were referred to the Geriatric Service for evaluation. The median age of patients who had geriatric comanagement was 79 years; 40 (68%) were male. Forty-one patients (69%) were visited on at least 80% of the days in which they were not in the intensive care unit. No surgeries were rescheduled for logistical reasons. Nine of the 12 urology APPs (75%) responded to the survey; all nine "somewhat" or "strongly" agreed with statements indicating satisfaction with the program. CONCLUSION: Despite the challenges of the COVID-19 pandemic, we showed that perioperative GERICO is feasible. Fully powered prospective randomized controlled trials should be conducted to assess GERICO's impact on perioperative outcomes of older adults with cancer.

Neoadjuvant Atezolizumab With Gemcitabine and Cisplatin in Patients With Muscle-Invasive Bladder Cancer: A Multicenter, Single-Arm, Phase II Trial.

PURPOSE: Neoadjuvant gemcitabine and cisplatin (GC) followed by radical cystectomy (RC) is standard for patients with muscle-invasive bladder cancer (MIBC). On the basis of the activity of atezolizumab (A) in metastatic BC, we tested neoadjuvant GC plus A for MIBC. METHODS: Eligible patients with MIBC (cT2-T4aN0M0) received a dose of A, followed 2 weeks later by GC plus A every 21 days for four cycles followed 3 weeks later by a dose of A before RC. The primary end point was non-muscle-invasive downstaging to < pT2N0. RESULTS: Of 44 enrolled patients, 39 were evaluable. The primary end point was met, with 27 of 39 patients (69%) < pT2N0, including 16 (41%) pT0N0. No patient with < pT2N0 relapsed and four (11%) with ≥ pT2N0 relapsed with a median follow-up of 16.5 months (range: 7.0-33.7 months). One patient refused RC and two developed metastatic disease before RC; all were considered nonresponders. The most common grade 3-4 adverse event (AE) was neutropenia (n = 16; 36%). Grade 3 immune-related AEs occurred in five (11%) patients with two (5%) requiring systemic steroids. The median time from last dose of chemotherapy to surgery was 7.8 weeks (range: 5.1-17 weeks), and no patient failed to undergo RC because of AEs. Four of 39 (10%) patients had programmed death-ligand 1 (PD-L1)-positive tumors and were all < pT2N0. Of the patients with PD-L1 low or negative tumors, 23 of 34 (68%) achieved < pT2N0 and 11 of 34 (32%) were ≥ pT2N0 (P = .3 for association between PD-L1 and < pT2N0). CONCLUSION: Neoadjuvant GC plus A is a promising regimen for MIBC and warrants further study. Patients with < pT2N0 experienced improved relapse-free survival. The PD-L1 positivity rate was low compared with published data, which limits conclusions regarding PD-L1 as a predictive biomarker.

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.

Prospective Phase II Study to Evaluate Response to Two Induction Courses (12 intravesical instillations) of BCG Therapy for High-risk Non-muscle-invasive Bladder Cancer.

OBJECTIVE: To test whether 2 sequential BCG-induction courses improve the response of high-risk non-muscle invasive bladder cancer. Achieving a complete response (CR) to BCG is critical to disease-free survival. Patients with preexisting BCG-specific immunity owing to prior exposure to BCG have longer disease-free survival than BCG-naïve patients likely due to heterologous immunity from the initial priming of the immune system. We evaluated this hypothesis in a phase II prospective clinical trial. METHODS: From 2015 to 2018, we recruited patients with primary or recurrent NMIBC (high-grade Ta, T1 tumors, with or without CIS) to receive 2-induction courses (12 intra-vesical instillations) of BCG. The primary aim of the study was CR rate 6 months after start of the first BCG induction. CR was defined as no tumor at cystoscopy or TURB biopsy. No maintenance BCG was given. We targeted at least 75 evaluable patients, and a CR of 80% or better was deemed significant. RESULTS: Eighty-one patients agreed to participate. Five withdrew before starting BCG, leaving 76 evaluable patients. Sixty-three patients (83%) completed the 12 instillations on schedule. Of these, 62 patients (91%) had a CR at 6 months. None of the patients had tumor progression. Serious adverse event was seen in 1 patient (1%). Recurrence-free survival at 2 years after complete response was 85% (95% CI 77%, 95%). CONCLUSION: The high response rate in patients with high-risk non-muscle-invasive bladder cancer justifies 2 BCG induction cycles in current practice.

Association of patients' sex with treatment outcomes after intravesical bacillus Calmette-Guérin immunotherapy for T1G3/HG bladder cancer.

PURPOSE: To investigate the association of patients' sex with recurrence and disease progression in patients treated with intravesical bacillus Calmette-Guérin (BCG) for T1G3/HG urinary bladder cancer (UBC). MATERIALS AND METHODS: We analyzed the data of 2635 patients treated with adjuvant intravesical BCG for T1 UBC between 1984 and 2019. We accounted for missing data using multiple imputations and adjusted for covariate imbalance between males and females using inverse probability weighting (IPW). Crude and IPW-adjusted Cox regression analyses were used to estimate the hazard ratios (HR) with their 95% confidence intervals (CI) for the association of patients' sex with HG-recurrence and disease progression. RESULTS: A total of 2170 (82%) males and 465 (18%) females were available for analysis. Overall, 1090 (50%) males and 244 (52%) females experienced recurrence, and 391 (18%) males and 104 (22%) females experienced disease progression. On IPW-adjusted Cox regression analyses, female sex was associated with disease progression (HR 1.25, 95%CI 1.01-1.56, p = 0.04) but not with recurrence (HR 1.06, 95%CI 0.92-1.22, p = 0.41). A total of 1056 patients were treated with adequate BCG. In these patients, on IPW-adjusted Cox regression analyses, patients' sex was not associated with recurrence (HR 0.99, 95%CI 0.80-1.24, p = 0.96), HG-recurrence (HR 1.00, 95%CI 0.78-1.29, p = 0.99) or disease progression (HR 1.12, 95%CI 0.78-1.60, p = 0.55). CONCLUSION: Our analysis generates the hypothesis of a differential response to BCG between males and females if not adequately treated. Further studies should focus on sex-based differences in innate and adaptive immune system and their association with BCG response.

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.

Goal-directed versus Standard Fluid Therapy to Decrease Ileus after Open Radical Cystectomy: A Prospective Randomized Controlled Trial.

BACKGROUND: Postoperative ileus is a common complication of intraabdominal surgeries, including radical cystectomy with reported rates as high as 32%. Perioperative fluid administration has been associated with improvement in postoperative ileus rates, but it is difficult to generalize because earlier studies lacked standardized definitions of postoperative ileus and other relevant outcomes. The hypothesis was that targeted individualized perioperative fluid management would improve postoperative ileus in patients receiving radical cystectomy. METHODS: This is a parallel-arm, double-blinded, single-center randomized trial of goal-directed fluid therapy versus standard fluid therapy for patients undergoing open radical cystectomy. The primary outcome was postoperative ileus, and the secondary outcome was complications within 30 days post-surgery. Participants were at least 21 yr old, had a maximum body mass index of 45 kg/m and no active atrial fibrillation. The intervention in the goal-directed therapy arm combined preoperative and postoperative stroke volume optimization and intraoperative stroke volume variation minimization to guide fluid administration, using advanced hemodynamic monitoring. RESULTS: Between August 2014 and April 2018, 283 radical cystectomy patients (142 goal-directed fluid therapy and 141 standard fluid therapy) were included in the analysis. Postoperative ileus occurred in 25% (36 of 142) of patients in the goal-directed fluid therapy arm and 21% (30 of 141) of patients in the standard arm (difference in proportions, 4.1%; 95% CI, -5.8 to 13.9; P = 0.418). There was no difference in incidence of high-grade complications between the two arms (20 of 142 [14%] vs. 23 of 141 [16%]; difference in proportions, -2.2%; 95% CI, -10.6 to 6.1; P = 0.602), with the exception of acute kidney injury, which was more frequent in the goal-directed fluid therapy arm (56% [80 of 142] vs. 40% [56 of 141] in the standard arm; difference in proportions, 16.6%; 95% CI, 5.1 to 28.1; P = 0.005; P = 0.170 after adjustment for multiple testing). CONCLUSIONS: Goal-directed fluid therapy may not be an effective strategy for lowering the risk of postoperative ileus in patients undergoing open radical cystectomy.

Trends in Management and Outcomes among Patients with Urothelial Carcinoma Undergoing Radical Cystectomy from 1995 to 2015: The Memorial Sloan Kettering Experience.

PURPOSE: We evaluated trends in oncologic characteristics and outcomes as well as perioperative management among patients undergoing radical cystectomy at Memorial Sloan Kettering from 1995 to 2015. MATERIALS AND METHODS: We retrospectively reviewed our institutional database to analyze changes in disease recurrence probability, cancer specific and all cause mortality, incidence of muscle invasive bladder cancer, use of perioperative chemotherapy, rate of positive soft tissue surgical margins and lymph node yield. RESULTS: In 2,740 patients with nonmetastatic urothelial carcinoma undergoing radical cystectomy from 1995 to 2015 the 5-year probability of disease recurrence decreased from a peak of 42% in 1997 to 34% in 2013 (p=0.045), while the 5-year probability of cancer specific mortality likewise declined from 36% in 1997 to 24% in 2013 (p=0.009). The incidence of nonmuscle invasive disease before radical cystectomy did not change, comprising 30% to 35% of patients across the study period. Use of neoadjuvant chemotherapy rose significantly as 57% of patients with muscle invasive bladder cancer from 2010 to 2015 received it. We observed a corresponding rise in complete pathological response (pT0) at radical cystectomy, as well as decreasing positive soft tissue surgical margins (10% to 2.5%) and rising lymph node yield (7 to 24) from 1995 to 2015. CONCLUSIONS: During a 21-year period outcomes after radical cystectomy at our institution improved significantly, as the probability of recurrence and cancer specific mortality decreased. Increasing use of neoadjuvant chemotherapy, rising pT0 rates, decreased positive soft tissue surgical margins and increasing lymph node yields likely contributed, suggesting that optimized surgical and perioperative care led to improved cancer outcomes in patients undergoing radical cystectomy.

Late Recurrences Following Radical Cystectomy Have Distinct Prognostic and Management Considerations.

PURPOSE: Disease recurrence after radical cystectomy generally occurs within 2 years and has a poor prognosis. Less well defined are the outcomes in patients who experience a late recurrence (more than 3 years after radical cystectomy). We report our institutional experience with late recurrences and describe the relationships between time to recurrence, management strategies and survival. MATERIALS AND METHODS: The study cohort comprised 2,315 patients who underwent radical cystectomy for urothelial carcinoma at our center between 2000 and 2014, of whom 617 had a recurrence. Median followup for survivors was 2.6 years after recurrence (IQR 0.95-4.5). For the study we considered disease recurrence as recurrences outside the urinary tract. We compared baseline characteristics and post-recurrence management between those with recurrence 3 or less and more than 3 years after radical cystectomy. RESULTS: A total of 58 patients with late recurrence had significantly lower consensus T stage and lower frequency of nodal involvement. The average 1-year bladder cancer death rate from the time of recurrence declined from 66% to 50% to 33% for patients with recurrence times of 6 months, 2 years, and 5 years after radical cystectomy, respectively. For patients who survived at least 1 year after recurrence, the estimated survival at 5 years after recurrence was 45% for those with late recurrence and 21% for patients who had an early recurrence. Local consolidative therapy (metastasectomy or radiation) was more common in patients with late recurrence (19% vs 3.6%, p <0.0001). Cancer specific survival in early recurring cases was significantly worse than in late recurring cases in the subset receiving local consolidation (p=0.02). CONCLUSIONS: The prolonged lifespan of patients experiencing a late recurrence after radical cystectomy can be leveraged to individualize management. There is strong rationale for investigating the role of metastasectomy in the management of late recurrences.

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.