TROP2 Expression Across Molecular Subtypes of Urothelial Carcinoma and Enfortumab Vedotin-resistant Cells.

Sacituzumab govitecan (SG) is an antibody-drug conjugate (ADC) targeting TROP2, which has recently been approved for treatment-refractory metastatic urothelial cancer (UC). However, the variability of TROP2 expression across different bladder cancer (BC) subtypes, as well as after enfortumab vedotin (EV) exposure, remains unknown. Using gene expression data from four clinical cohorts with >1400 patient samples of muscle-invasive BC and a BC tissue microarray, we found that TROP2 mRNA and protein are highly expressed across basal, luminal, and stroma-rich subtypes, but depleted in the neuroendocrine subtype. In addition, TROP2 mRNA levels are correlated with NECTIN4 mRNA but are more highly expressed than NECTIN4 mRNA in patient cohorts and BC cell lines. Moreover, CRISPR/Cas9-mediated knockdown of TROP2 demonstrates that its expression is one factor governing SG sensitivity. After prolonged EV exposure, cells can downregulate NECTIN4, leading to EV resistance, but retain TROP2 expression and remain sensitive to SG, suggesting nonoverlapping resistance mechanisms to these ADCs. While our findings warrant further validation, they have significant implications for biomarker development, patient selection, and treatment sequencing in the clinic as well as clinical trial design and stratification for metastatic BC patients. PATIENT SUMMARY: In this report, we investigated the expression levels of the drug target TROP2 across different molecular subtypes of bladder cancer in multiple patient cohorts and cell lines. We found high levels of TROP2 in most subtypes except in the neuroendocrine subtype. Overall, TROP2 gene expression is higher than NECTIN4 gene expression, and cells resistant to enfortumab vedotin (EV), a NECTIN4-targeting antibody-drug conjugate, remain sensitive to sacituzumab govitecan (SG). Our findings suggest that SG may be effective across most bladder cancer subtypes, including the bladder cancers previously treated with EV.

Heterogeneity in NECTIN4 Expression Across Molecular Subtypes of Urothelial Cancer Mediates Sensitivity to Enfortumab Vedotin.

PURPOSE: Enfortumab vedotin (EV) is an antibody-drug conjugate (ADC) targeting NECTIN4 (encoded by the PVRL4/NECTIN4 gene) approved for treatment-refractory metastatic urothelial cancer. Factors that mediate sensitivity or resistance to EV are unknown. In this study, we sought to (i) examine heterogeneity of NECTIN4 gene expression across molecular subtypes of bladder cancer and (ii) determine whether NECTIN4 expression mediates EV sensitivity or resistance. EXPERIMENTAL DESIGN: Molecular subtyping and NECTIN4 expression data from seven muscle-invasive bladder cancer clinical cohorts (n = 1,915 total specimens) were used to assess NECTIN4 expression across molecular subtypes. The outcome of the transcriptomic analysis was relative NECTIN4 expression in the consensus molecular subtypes of bladder cancer. Expression of NECTIN4 was validated in bladder cancer cell lines. NECTIN4 was stably overexpressed or knocked down in basal and luminal bladder cancer cell lines and EV drug sensitivity assays were performed, as measured by cell proliferation and clonogenic assays. RESULTS: NECTIN4 expression is heterogenous across molecular subtypes of bladder cancer and significantly enriched in luminal subtypes. NECTIN4 expression is positively correlated with luminal markers GATA3, FOXA1, and PPARG across all cohorts. NECTIN4 expression is both necessary and sufficient for EV sensitivity in luminal and basal subtypes of urothelial bladder cancer cells. Downregulation of NECTIN4 leads to EV resistance. CONCLUSIONS: Sensitivity to EV is mediated by expression of NECTIN4, which is enriched in luminal subtypes of bladder cancer. These findings may have implications for biomarker development, patient selection, and the inclusion of molecular subtyping in ongoing and future EV clinical trials.See related commentary by Teo and Rosenberg, p. 4950.

TERT promoter mutations and other prognostic factors in patients with advanced urothelial carcinoma treated with an immune checkpoint inhibitor.

BACKGROUND: Immune checkpoint inhibitors (ICI) can achieve durable responses in a subset of patients with locally advanced or metastatic urothelial carcinoma (aUC). The use of tumor genomic profiling in clinical practice may help suggest biomarkers to identify patients most likely to benefit from ICI. METHODS: We undertook a retrospective analysis of patients treated with an ICI for aUC at a large academic medical center. Patient clinical and histopathological variables were collected. Responses to treatment were assessed for all patients with at least one post-baseline scan or clear evidence of clinical progression following treatment start. Genomic profiling information was also collected for patients when available. Associations between patient clinical/genomic characteristics and objective response were assessed by logistic regression; associations between the characteristics and progression-free survival (PFS) and overall survival (OS) were examined by Cox regression. Multivariable analyses were performed to identify independent prognostic factors. RESULTS: We identified 119 aUC patients treated with an ICI from December 2014 to January 2020. Genomic profiling was available for 78 patients. Overall response rate to ICI was 29%, and median OS (mOS) was 13.4 months. Favorable performance status at the start of therapy was associated with improved OS (HR 0.46, p=0.025) after accounting for other covariates. Similarly, the presence of a TERT promoter mutation was an independent predictor of improved PFS (HR 0.38, p=0.012) and OS (HR 0.32, p=0.037) among patients who had genomic profiling available. Patients with both a favorable performance status and a TERT promoter mutation had a particularly good prognosis with mOS of 21.1 months as compared with 7.5 months in all other patients (p=0.03). CONCLUSIONS: The presence of a TERT promoter mutation was an independent predictor of improved OS in a cohort of aUC patients treated with an ICI who had genomic data available. Most of the clinical and laboratory variables previously shown to be prognostic in aUC patients treated with chemotherapy did not have prognostic value among patients treated with an ICI. Genomic profiling may provide important prognostic information and affect clinical decision making in this patient population. Validation of these findings in prospective patient cohorts is needed.

Patient-reported Health Status, Comorbidity Burden, and Prostate Cancer Treatment.

OBJECTIVE: To determine whether patient-reported health status, more so than comorbidity, influences treatment in men with localized prostate cancer. METHODS: Using Surveillance, Epidemiology, and End Results data linked with Medicare claims and CAHPS surveys, we identified men aged 65-84 diagnosed with localized prostate cancer from 2004 to 2013 and ascertained their National Cancer Institute (NCI) comorbidity score and patient-reported health status. Adjusting for demographics and cancer risk, we examined the relationship between these measures and treatment for the overall cohort, low-risk men aged 65-74, intermediate/high-risk men aged 65-74, and men aged 75-84. RESULTS: Among 2724 men, 43.0% rated their overall health as Excellent/Very Good, while 62.7% had a comorbidity score of 0. Beyond age and cancer risk, patient-reported health status was significantly associated with treatment. Compared to men reporting Excellent/Very Good health, men in Poor/Fair health less often received treatment (odds ratio [OR] 0.71, 95% confidence interval [CI] 0.56-0.90). Younger men with intermediate/high-risk cancer in Good (OR 0.60, 95% CI 0.41-0.88) or Fair/Poor (OR 0.49, 95% CI 0.30-0.79) health less often underwent prostatectomy vs radiation compared to men in Excellent/Very Good health. In contrast, men with NCI comorbidity score of 1 more often received treatment (OR 1.37, 95% CI 1.11-1.70) compared to men with NCI comorbidity score of 0. CONCLUSION: Patient-reported health status drives treatment for prostate cancer in an appropriate direction whereas comorbidity has an inconsistent relationship. Greater understanding of this interplay between subjective and empiric assessments may facilitate more shared decision-making in prostate cancer care.

Liposomal Bupivacaine Decreases Postoperative Length of Stay and Opioid Use in Patients Undergoing Radical Cystectomy.

OBJECTIVE: To analyze differences in length of stay, opioid use, and other perioperative outcomes in patients undergoing radical cystectomy with urinary diversion who received either liposomal bupivacaine (LB) or epidural analgesia. METHODS: This was a single center, retrospective cohort study of patients undergoing open radical cystectomy with urinary diversion from 2015-2019 in the early recovery after surgery (ERAS) pathway. Patients received either LB or epidural catheter analgesia for post-operative pain control. LB was injected at the time of fascial closure to provide up to 72 hours of local analgesia. The primary outcome was post-operative length of stay. Secondary outcomes were post-operative opioid use, time to solid food, time to ambulation, and direct hospitalization costs. Multivariable Cox proportional hazards regression was used to determine associations between analgesia type and discharge. RESULTS: LB use was independently associated with shorter post-operative length of stay compared to epidural use (median (IQR) 4.9 days (3.9-5.8) vs 5.9 days (4.9-7.9), P<.001), less total opioid use (mean 188.3 vs 612.2 OME, P <.001), earlier diet advancement (mean 1.6 vs 2.4 days, P <.001), and decreased overall direct costs ($23,188 vs $29,628, P <.001). 45% of patients who received LB were opioid-free after surgery, none in the epidural group. On multivariable Cox proportional hazards regression modeling, LB use was independently associated with earlier discharge (HR 2.1, IQR 1.0-4.5). CONCLUSION: Use of LB in open radical cystectomy is associated with reduced LOS, less opioid exposure, and earlier diet advancement.

Rapid Utilization of Telehealth in a Comprehensive Cancer Center as a Response to COVID-19: Cross-Sectional Analysis.

BACKGROUND: The emergence of the coronavirus disease (COVID-19) pandemic in March 2020 created unprecedented challenges in the provision of scheduled ambulatory cancer care. As a result, there has been a renewed focus on video-based telehealth consultations as a means to continue ambulatory care. OBJECTIVE: The aim of this study is to analyze the change in video visit volume at the University of California, San Francisco (UCSF) Comprehensive Cancer Center in response to COVID-19 and compare patient demographics and appointment data from January 1, 2020, and in the 11 weeks after the transition to video visits. METHODS: Patient demographics and appointment data (dates, visit types, and departments) were extracted from the electronic health record reporting database. Video visits were performed using a HIPAA (Health Insurance Portability and Accountability Act)-compliant video conferencing platform with a pre-existing workflow. RESULTS: In 17 departments and divisions at the UCSF Cancer Center, 2284 video visits were performed in the 11 weeks before COVID-19 changes were implemented (mean 208, SD 75 per week) and 12,946 video visits were performed in the 11-week post-COVID-19 period (mean 1177, SD 120 per week). The proportion of video visits increased from 7%-18% to 54%-72%, between the pre- and post-COVID-19 periods without any disparity based on race/ethnicity, primary language, or payor. CONCLUSIONS: In a remarkably brief period of time, we rapidly scaled the utilization of telehealth in response to COVID-19 and maintained access to complex oncologic care at a time of social distancing.

Effect of COVID-19 on Urology Residency Training: A Nationwide Survey of Program Directors by the Society of Academic Urologists.

PURPOSE: Coronavirus disease (COVID-19) has profoundly impacted residency training and education. To date, there has not been any broad assessment of urological surgery residency changes and concerns during the COVID-19 pandemic. MATERIALS AND METHODS: The Society of Academic Urologists distributed a questionnaire to urology residency program directors on March 30, 2020 exploring residency program changes related to the COVID-19 pandemic. Descriptive statistics are presented. A qualitative analysis of free response questions was undertaken. A post hoc analysis of differences related to local COVID-19 incidence is described. RESULTS: The survey was distributed to 144 residency programs with 65 responses for a 45% response rate. Reserve staffing had started in 80% of programs. Patient contact time had decreased significantly from 4.7 to 2.1 days per week (p <0.001). Redeployment was reported by 26% of programs. Sixty percent of programs reported concern that residents will not meet case minimums due to COVID-19. Wellness activities centered on increased communication. All programs had begun to use videoconferencing and the majority planned to continue. Programs in states with a higher incidence of COVID-19 were more likely to report resident redeployment (48% vs 11%, p=0.002) and exposure to COVID-19 positive patients (70% vs 40%, p=0.03), and were less likely to report concerns regarding exposure (78% vs 97%, p=0.02) and personal protective equipment availability (62% vs 89%, p=0.02). CONCLUSIONS: As of April 1, 2020 the COVID-19 pandemic had resulted in significant changes in urology residency programs. These findings inform a rapidly changing landscape and aid in the development of best practices.

Pilot Study of [18F] Fluorodeoxyglucose Positron Emission Tomography (FDG-PET)/Magnetic Resonance Imaging (MRI) for Staging of Muscle-invasive Bladder Cancer (MIBC).

INTRODUCTION: Computed tomography (CT) has limited diagnostic accuracy for staging of muscle-invasive bladder cancer (MIBC). [18F] Fluorodeoxyglucose positron emission tomography (FDG-PET)/magnetic resonance imaging (MRI) is a novel imaging modality incorporating functional imaging with improved soft tissue characterization. This pilot study evaluated the use of preoperative FDG-PET/MRI for staging of MIBC. PATIENTS AND METHODS: Twenty-one patients with MIBC with planned radical cystectomy were enrolled. Two teams of radiologists reviewed FDG-PET/MRI scans to determine: (1) presence of primary bladder tumor; and (2) lymph node involvement and distant metastases. FDG-PET/MRI was compared with cystectomy pathology and computed tomography (CT). RESULTS: Eighteen patients were included in the final analysis, most (72.2%) of whom received neoadjuvant chemotherapy. Final pathology revealed 10 (56%) patients with muscle invasion and only 3 (17%) patients with lymph node involvement. Clustered analysis of FDG-PET/MRI radiology team reads revealed a sensitivity of 0.80 and a specificity of 0.56 for detection of the primary tumor with a sensitivity of 0 and a specificity of 1.00 for detection of lymph node involvement when compared with cystectomy pathology. CT imaging demonstrated similar rates in evaluation of the primary tumor (sensitivity, 0.91; specificity, 0.43) and lymph node involvement (sensitivity, 0; specificity, 0.93) when compared with pathology. CONCLUSIONS: This pilot single-institution experience of FDG-PET/MRI for preoperative staging of MIBC performed similar to CT for the detection of the primary tumor; however, the determination of lymph node status was limited by few patients with true pathologic lymph node involvement. Further studies are needed to evaluate the potential role for FDG-PET/MRI in the staging of MIBC.

Correlation of Relative Value Units With Surgical Complexity and Physician Workload in Urology.

OBJECTIVE: To define the relationship between urology relative value units (RVUs) and measures of surgical complexity and physician workload. Secondary objectives include: (1) identifying procedures with outlying RVU values for their measures of surgical complexity and workload; and (2) calculating projected RVU values for these procedures. METHODS: We obtained surgical case data for 71 urology current procedural terminology (CPT) codes from the 2017 American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database. Pearson correlation coefficients were calculated to measure the association between mean total work RVU and operative time, length of hospital stay, serious adverse events, readmissions, and mortality. We developed a multivariable regression model to predict mean total work RVU from these measures. Studentized residuals were used to identify outlying CPT codes for both bivariable and multivariable regression models, and empirically derived RVU values from complexity and work effort metrics were estimated. RESULTS: We analyzed 71 urology CPT codes encompassing 55,068 cases. RVUs correlated well with median length of hospital stay (R = 0.81), median operative time (R = 0.92), serious adverse events (R = 0.83), and readmissions (R = 0.74). RVUs were poorly correlated with mortality (R = 0.34). Outlying procedures identified using the multivariable model were retroperitoneal lymph node dissection (projected +21.09 RVUs), laparoscopic ureteroneocystotomy (projected -12.34 RVUs), and cystectomy with bilateral pelvic lymphadenectomy (projected +9.37 RVUs). CONCLUSION: Urology work RVUs correlate more with operative time than other measures of surgical complexity and physician workload. There exist several significant outlying procedures for various work measures. Incorporating objective work data may improve RVU assignments in the future.

Predictors of Recurrence, and Progression-Free and Overall Survival following Open versus Robotic Radical Cystectomy: Analysis from the RAZOR Trial with a 3-Year Followup.

PURPOSE: The RAZOR (Randomized Open versus Robotic Cystectomy) trial revealed noninferior 2-year progression-free survival for robotic radical cystectomy. This update was performed with extended followup for 3 years to determine potential differences between the approaches. We also report 3-year overall survival and sought to identify factors predicting recurrence, and progression-free and overall survival. MATERIALS AND METHODS: We analyzed the per protocol population of 302 patients from the RAZOR study. Cumulative recurrence was estimated using nonbladder cancer death as the competing risk event and the Gray test was applied to assess significance in differences. Progression-free survival and overall survival were estimated by the Kaplan-Meier method and compared with the log rank test. Predictors of outcomes were determined by Cox proportional hazard analysis. RESULTS: Estimated progression-free survival at 36 months was 68.4% (95% CI 60.1-75.3) and 65.4% (95% CI 56.8-72.7) in the robotic and open groups, respectively (p=0.600). At 36 months overall survival was 73.9% (95% CI 65.5-80.5) and 68.5% (95% CI 59.8-75.7) in the robotic and open groups, respectively (p=0.334). There was no significant difference in the cumulative incidence rates of recurrence (p=0.802). Patient age greater than 70 years, poor performance status and major complications were significant predictors of 36-month progression-free survival. Stage and positive margins were significant predictors of recurrence, and progression-free and overall survival. Surgical approach was not a significant predictor of any outcome. CONCLUSIONS: This analysis showed no difference in recurrence, 3-year progression-free survival or 3-year overall survival for robotic vs open radical cystectomy. It provides important prospective data on the oncologic efficacy of robotic radical cystectomy and high level data for patient counseling.

Association of an organ transplant-based approach with a dramatic reduction in postoperative complications following radical nephrectomy and tumor thrombectomy in renal cell carcinoma.

OBJECTIVES: Our aim was to determine whether using an organ transplant-based(TB) approach reduces postoperative complications(PCs) following radical nephrectomy(RN) and tumor thrombectomy(TT) in renal cell carcinoma(RCC) patients with level II-IV thrombi. METHODS: A total of 390(292 non-TB/98 TB) IRCC-VT Consortium patients who received no preoperative embolization/IVC filter were included. Stepwise linear/logistic regression analyses were performed to determine significant multivariable predictors of intraoperative estimated blood loss(IEBL), number blood transfusions received, and overall/major PC development within 30days following surgery. Propensity to receive the TB approach was controlled. RESULTS: The TB approach was clearly superior in limiting IEBL, blood transfusions, and PC development, even after controlling for other significant prognosticators/propensity score(P < .000001 in each case). Median IEBL for non-TB/TB approaches was 1000 cc/300 cc and 1500 cc/500 cc for tumor thrombus Level II-III patients, respectively, with no notable differences for Level IV patients(2000 cc each). In comparing PC outcomes between non-TB/TB patients with a non-Right-Atrium Cranial Limit, the observed percentage developing a: i) PC was 65.8%(133/202) vs. 4.3%(3/69) for ECOG Performance Status(ECOG-PS) 0-1, and 84.8%(28/33) vs. 25.0%(4/16) for ECOG-PS 2-4, and ii) major PC was 16.8%(34/202) vs. 1.4%(1/69) for ECOG-PS 0-1, and 27.3%(9/33) vs. 12.5%(2/16) for ECOG-PS 2-4. Major study limitation was the fact that all TB patients were treated by a single, experienced, high volume surgeon from one center (non-TB patients were treated by various surgeons at 13 other centers). CONCLUSIONS: Despite this major study limitation, the observed dramatic differences in PC outcomes suggest that the TB approach offers a major breakthrough in limiting operative morbidity in RCC patients receiving RN and TT.

Robot-assisted radical cystectomy versus open radical cystectomy in patients with bladder cancer (RAZOR): an open-label, randomised, phase 3, non-inferiority trial.

BACKGROUND: Radical cystectomy is the surgical standard for invasive bladder cancer. Robot-assisted cystectomy has been proposed to provide similar oncological outcomes with lower morbidity. We aimed to compare progression-free survival in patients with bladder cancer treated with open cystectomy and robot-assisted cystectomy. METHODS: The RAZOR study is a randomised, open-label, non-inferiority, phase 3 trial done in 15 medical centres in the USA. Eligible participants (aged ≥18 years) had biopsy-proven clinical stage T1-T4, N0-N1, M0 bladder cancer or refractory carcinoma in situ. Individuals who had previously had open abdominal or pelvic surgery, or who had any pre-existing health conditions that would preclude safe initiation or maintenance of pneumoperitoneum were excluded. Patients were centrally assigned (1:1) via a web-based system, with block randomisation by institution, stratified by type of urinary diversion, clinical T stage, and Eastern Cooperative Oncology Group performance status, to receive robot-assisted radical cystectomy or open radical cystectomy with extracorporeal urinary diversion. Treatment allocation was only masked from pathologists. The primary endpoint was 2-year progression-free survival, with non-inferiority established if the lower bound of the one-sided 97·5% CI for the treatment difference (robotic cystectomy minus open cystectomy) was greater than -15 percentage points. The primary analysis was done in the per-protocol population. Safety was assessed in the same population. This trial is registered with ClinicalTrials.gov, number NCT01157676. FINDINGS: Between July 1, 2011, and Nov 18, 2014, 350 participants were randomly assigned to treatment. The intended treatment was robotic cystectomy in 176 patients and open cystectomy in 174 patients. 17 (10%) of 176 patients in the robotic cystectomy group did not have surgery and nine (5%) patients had a different surgery to that they were assigned. 21 (12%) of 174 patients in the open cystectomy group did not have surgery and one (1%) patient had robotic cystectomy instead of open cystectomy. Thus, 302 patients (150 in the robotic cystectomy group and 152 in the open cystectomy group) were included in the per-protocol analysis set. 2-year progression-free survival was 72·3% (95% CI 64·3 to 78·8) in the robotic cystectomy group and 71·6% (95% CI 63·6 to 78·2) in the open cystectomy group (difference 0·7%, 95% CI -9·6% to 10·9%; pnon-inferiority=0·001), indicating non-inferiority of robotic cystectomy. Adverse events occurred in 101 (67%) of 150 patients in the robotic cystectomy group and 105 (69%) of 152 patients in the open cystectomy group. The most common adverse events were urinary tract infection (53 [35%] in the robotic cystectomy group vs 39 [26%] in the open cystectomy group) and postoperative ileus (33 [22%] in the robotic cystectomy group vs 31 [20%] in the open cystectomy group). INTERPRETATION: In patients with bladder cancer, robotic cystectomy was non-inferior to open cystectomy for 2-year progression-free survival. Increased adoption of robotic surgery in clinical practice should lead to future randomised trials to assess the true value of this surgical approach in patients with other cancer types. FUNDING: National Institutes of Health National Cancer Institute.

Optimal Trial Design for Studying Urinary Markers in Bladder Cancer: A Collaborative Review.

CONTEXT: Urine-based tumor markers are not routinely used in the diagnosis and surveillance of bladder cancer. The main limitation of urinary markers has been a lack of clarity regarding clinical benefit. OBJECTIVE: To review the indications for urinary marker use, barriers to marker utilization, and clinical trial designs for markers available for detection (hematuria populations) and surveillance (bladder cancer populations). The study aim was to facilitate an optimal trial design that could change clinical practice. EVIDENCE ACQUISITION: A PubMed search was conducted on February 17, 2018, using the MeSH search terms "Urinary Bladder Neoplasms" [Mesh] AND "Biomarkers" [Mesh] AND "Urine" [Mesh] yielded 127 articles, of which only two also fulfilled the search term "Randomized Controlled Trial" [Publication Type]. Neither of these two articles examined clinical outcomes for patients but rather focused on the performance characteristics of the urinary marker. For the search terms "Hematuria" [Mesh] AND "Randomized Controlled Trial" [Publication Type] AND "Urinary Bladder Neoplasms" [Mesh] yielded 12 articles, none of which used randomization with the outcome of interest being a clinical endpoint. EVIDENCE SYNTHESIS: Several potential designs for urinary marker trials were developed for detection and surveillance of bladder cancer. A marker-based approach compared to usual care for evaluation of hematuria in a primary care setting could reduce unnecessary cystoscopy in patients with low risk and expedite care in patients with higher risk. For bladder cancer surveillance, marker-based approaches could reduce cystoscopy for patients with low-grade disease and potentially improve detection for patients with high risk. CONCLUSIONS: Urinary markers are not currently routinely used owing to the absence of level 1 evidence supporting incorporation of urinary markers into protocols for detection or surveillance of bladder cancer. This review provides practical designs for studies that could demonstrate superiority of marker-based approaches over current clinical care. The sample sizes required for these studies are no greater than many of those accrued for previous urinary marker studies, but the proposed trial concepts require planning and a willingness to risk failure of the marker to demonstrate the desired benefits. PATIENT SUMMARY: In this review we discuss current limitations in the use of urinary markers for detection and surveillance of bladder cancer. We identify potential studies that could demonstrate a clinical benefit of the use of markers in improving detection of bladder cancer by reducing evaluation of patients unlikely to have cancer or expediting identification of cancer. For surveillance, a marker trial could improve identification of bladder cancer or reduce cystoscopy in patients with low risk.

Impact of lymph node dissection at the time of radical nephrectomy with tumor thrombectomy on oncological outcomes: Results from the International Renal Cell Carcinoma-Venous Thrombus Consortium (IRCC-VTC).

OBJECTIVES: To study the effect of lymph node dissection (LND) at the time of nephrectomy and tumor thrombectomy on oncological outcomes in patients with renal cell carcinoma (RCC) and tumor thrombus. PATIENTS AND METHODS: The records of 1,978 patients with RCC and tumor thrombus who underwent radical nephrectomy and tumor thrombectomy from 1985 to 2014 at 24 centers were analyzed. None of the patients had distant metastases. Extent and pathologic results of LND were compared with respect to cancer-specific survival (CSS). Multivariable Cox regression models were used to quantify the effect of multiple covariates. RESULTS: LND was performed in 1,026 patients. In multivariable analysis, the presence of LN metastasis, the number of positive LNs, and LN density were independently associated with cancer-specific mortality (CSM). Clinical node-negative (cN-) disease was documented in 573 patients, 447 of them underwent LND with 43 cN- patients (9.6%) revealing positive LNs at pathology. LN positive cN- patients showed significantly better CSS when compared to LN positive cN+ patients. In multivariable analysis, positive cN status in LN positive patients was a significant predictor of CSM (HR, 2.923; P = 0.015). CONCLUSIONS: The number of positive nodes harvested during LND and LN density was strong prognostic indicators of CSS, while number of removed LNs did not have a significant effect on CSS. The rate of pN1 patients among clinically node-negative patients was relatively high, and LND in these patients suggested a survival benefit. However, only a randomized trial can determine the absolute benefit of LND in this setting.

Contemporary survival trends in penile cancer: Results from the National Cancer Database.

OBJECTIVE: To investigate contemporary survival trends in penile cancer. METHODS: The National Cancer Database was queried for men with penile cancer diagnosed between 1998 and 2009. Patient, tumor, treatment, and facility characteristics were obtained. Overall survival (OS) was analyzed using the Kaplan-Meier method and multivariable Cox proportional hazards regression model for all cases and stratified by stage. RESULTS: A total of 8,122 cases of penile cancer were reported from 1998 to 2009 in the National Cancer Database. Complete staging, survival, and covariate data were available for 5,043 cases. The estimated crude 5-year OS for the entire cohort was 61.0%. For all patients, no significant differences in crude 5-year OS were detected between 2006 to 2009 and 2002 to 2005 compared to 1998 to 2001. On multivariable analysis, OS did not significantly differ across all eras. Regional lymph node dissection was associated with improved OS (hazard ratio [HR] = 0.777, P ≤ 0.0001). In patients who underwent lymph node dissection, dissection of ≥8 nodes significantly improved survival (HR = 0.672; P = 0.0011). Additional modeling stratified by stage revealed that OS for stage II cancers increased significantly in 2006 to 2009 compared to 1998 to 2001 (HR = 0.714; P = 0.0034). CONCLUSIONS: Survival in penile cancer has remained unchanged as a whole and for each stage, except for stage II disease. An improved survival trend was detected in stage II penile cancer. Performing a lymph node dissection, especially extensive dissections, may benefit long-term survival.

Functional Outcomes Following Radical Cystectomy in Women with Bladder Cancer: A Systematic Review.

CONTEXT: Gender-specific functional and health-related quality of life (HRQOL) outcomes following radical cystectomy (RC) for bladder cancer (BCa) remain unclear, with many studies excluding women from the study population. OBJECTIVE: To better characterize female-specific functional outcomes following RC and urinary diversion for BCa. EVIDENCE ACQUISITION: We performed a critical review of PubMed/Medline and Embase in August 2015 according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement. Outcomes of interest included urinary function (for orthotopic neobladder), sexual function, bowel function, and quality of life. Excluded were nonbladder malignancies, RCs performed for neurogenic bladder dysfunction, and patients with exposure to radiation therapy prior to surgery. Forty-five publications were selected for inclusion in this analysis. EVIDENCE SYNTHESIS: Included reports addressed urinary function (34 studies), sexual function (11 studies), and HRQOL (9 studies). All studies had a high risk of bias and ranged significantly in sample size, inclusion criteria, and follow-up time, precluding meaningful meta-analysis. Daytime incontinence approximated 20%, nighttime incontinence 20%, and hypercontinence 10-20%. Sexual function appeared to be better among those patients undergoing genitalia-sparing RC, but generally poor outcomes were noted among those undergoing routine RC. Only 40% of studies assessed sexual function using standardized instruments. HRQOL differences between diversion types appeared to be minimal, whereas comparisons with the general population revealed significant differences in emotional problems, role functioning, fatigue, and appetite. CONCLUSIONS: Functional outcomes among women undergoing RC for BCa are poorly studied with limitations regarding use of validated questionnaires, heterogeneous patient populations, and small sample sizes. Collaborative efforts will be needed to better define functional outcomes among this poorly studied patient population. PATIENT SUMMARY: We reviewed functional outcomes following cystectomy among women with bladder cancer. We found that urinary, sexual, and bowel function and quality of life are poorly studied among women, with function ranging significantly across studies.

The Expanding Role of Advanced Practice Providers in Urologic Procedural Care.

OBJECTIVE: To understand the role of Advanced Practice Providers (APPs) in urologic procedural care and its change over time. As the population ages and the urologic workforce struggles to meet patient access demands, the role of APPs in the provision of all aspects of urologic care is increasing. However, little is currently known about their role in procedural care. MATERIALS AND METHODS: Commonly performed urologic procedures were linked to Current Procedural Terminology (CPT) codes from 1994 to 2012. National Medicare Part B beneficiary claims frequency was identified using Physician Supplier Procedure Summary Master Files. Trends were studied for APPs, urologists, and all other providers nationally across numerous procedures spanning complexity, acuity, and technical skill set requirements. RESULTS: Between 1994 and 2012, annual Medicare claims for urologic procedures by APPs increased dramatically. Cystoscopy increased from 24 to 1820 (+7483%), transrectal prostate biopsy from 17 to 834 (+4806%), complex Foley catheter placement from 471 to 2929 (+522%), urodynamics testing from 41 to 9358 (+22,727%), and renal ultrasound from 18 to 4500 (+24,900%) CONCLUSION: We found dramatic growth in the provision of urologic procedural care by APPs over the past 2 decades. These data reinforce the known expansion of the APP role in urology and support the timeliness of ongoing collaborative multidisciplinary educational efforts to address unmet needs in education, training, and guideline formation to maximize access to urologic procedural services.

Comprehensive Molecular Characterization of Urachal Adenocarcinoma Reveals Commonalities With Colorectal Cancer, Including a Hypermutable Phenotype.

PURPOSE: Urachal adenocarcinoma is a rare type of primary bladder adenocarcinoma that comprises less than 1% of all bladder cancers. The low incidence of urachal adenocarcinomas does not allow for an evidence-based approach to therapy. Transcriptome profiling of urachal adenocarcinomas has not been previously reported. We hypothesized that an in-depth molecular understanding of urachal adenocarcinoma would uncover rational therapeutic strategies. PATIENTS AND METHODS: We performed targeted exon sequencing and global transcriptome profiling of 12 urachal tumors to generate a comprehensive molecular portrait of urachal adenocarcinoma. A single patient with an MSH6 mutation was treated with the anti-programmed death-ligand 1 antibody, atezolizumab. RESULTS: Urachal adenocarcinoma closely resembles colorectal cancer at the level of RNA expression, which extends previous observations that urachal tumors harbor genomic alterations that are found in colorectal adenocarcinoma. A subset of tumors was found to have alterations in genes that are associated with microsatellite instability (MSH2 and MSH6) and hypermutation (POLE). A patient with an MSH6 mutation was treated with immune checkpoint blockade, which resulted in stable disease. CONCLUSION: Because clinical trials are next to impossible for patients with rare tumors, precision oncology may be an important adjunct for treatment decisions. Our findings demonstrate that urachal adenocarcinomas molecularly resemble colorectal adenocarcinomas at the level of RNA expression, are the first report, to our knowledge, of MSH2 and MSH6 mutations in this disease, and support the consideration of immune checkpoint blockade as a rational therapeutic treatment of this exceedingly rare tumor.