Treatment of Non-Metastatic Muscle-Invasive Bladder Cancer: AUA/ASCO/SUO GUIDELINE (2017; Amended 2020, 2024).

PURPOSE: Although representing approximately 25% of patients diagnosed with bladder cancer, muscle-invasive bladder cancer (MIBC) carries a significant risk of death that has not significantly changed in decades. Increasingly, clinicians and patients recognize the importance of multidisciplinary collaborative efforts that take into account survival and quality of life concerns. This guideline provides a risk-stratified, clinical framework for the management of muscle-invasive urothelial bladder cancer. METHODOLOGY/METHODS: In 2024, the MIBC guideline was updated through the AUA amendment process in which newly published literature is reviewed and integrated into previously published guidelines in an effort to maintain currency. The amendment allowed for the incorporation of additional literature released since the previous 2020 amendment. The updated search gathered literature from May 2020 to November 2023. This review identified 3739 abstracts, of which 46 met inclusion criteria.When sufficient evidence existed, the body of evidence was assigned a strength rating of A (high), B (moderate), or C (low) for support of Strong, Moderate, or Conditional Recommendations. In the absence of sufficient evidence, additional information is provided as Clinical Principles and Expert Opinions. RESULTS: Updates were made regarding neoadjuvant/adjuvant chemotherapy, radical cystectomy, pelvic lymphadenectomy, multi-modal bladder preserving therapy, and future directions. Further revisions were made to the methodology and reference sections as appropriate. CONCLUSIONS: This guideline seeks to improve clinicians' ability to evaluate and treat patients with MIBC based on currently available evidence. Future studies will be essential to further support or refine these statements to improve patient care.

Incidence and management of prostatic urethra recurrence in a cohort of 21 patients who received BCG induction for non-muscle invasive bladder cancer.

PURPOSE: To describe the incidence and management of patients who develop a prostatic urethral (PU) urothelial carcinoma recurrence after Bacillus Calmette-Guerin (BCG) induction for non-muscle invasive bladder cancer (NMIBC). MATERIALS AND METHODS: We performed a retrospective cohort study of all patients who received BCG induction at our institution from 1996 to 2021 (N = 642) for NMIBC. All patients with pathologically confirmed PU involvement following BCG induction with no known PU involvement pre-BCG were included. We describe the presentation, management, and outcomes for PU recurrence. RESULTS: Among the 642 patients, 21 (3.3%) patients had a PU recurrence after BCG induction. 8 (38%) patients received >2 cycles of BCG induction prior to the recurrence. Median time from induction to PU recurrence was 21 months and 12 (57.1%) patients had concurrent bladder recurrence. At the time of their PU recurrence, 14/21 (67%) of patients were deemed BCG Unresponsive. Nearly all (18/21) were high grade, and 10 were stage Tis, 7 Ta, and 3 T1, and 1 T2. 19/21 (90%) patients received bladder sparing treatment: 6 with TURBT and BCG, 6 with TURBT and intravesical chemotherapy, 5 with TURBT only, and 2 did not receive immediate treatment of their PU recurrence due to advanced stage of disease. 2/21 (9.5%) received a radical cystectomy for initial treatment of the post-BCG PU recurrence, of which all were >pT2. Median follow-up time from BCG induction to the patient's last visit was 64.5 months. Following treatment of PU recurrence, 15/18 patients had another recurrence at a median of 5 months: about 47% of recurrences were bladder only and 14% recurred only in the PU as well. About 1 patient received a RC after the second recurrence and was pT2. CONCLUSION: Patients with PU recurrences following intravesical BCG have a high-risk disease phenotype with a significant risk of recurrence. Conservative management may be appropriate for well-selected patients who do not desire a cystoprostatectomy.

Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer: AUA/SUO Guideline: 2024 Amendment.

PURPOSE: The purpose of this American Urological Association (AUA)/Society of Urologic Oncology (SUO) guideline amendment is to provide a useful reference on the effective evidence-based treatment strategies for non-muscle invasive bladder cancer (NMIBC). MATERIALS AND METHODS: In 2023, the NMIBC guideline was updated through the AUA amendment process in which newly published literature is reviewed and integrated into previously published guidelines in an effort to maintain currency. The amendment allowed for the incorporation of additional literature released since the previous 2020 amendment. The updated search gathered literature from July 2019 to May 2023. This review identified 1918 abstracts, of which 75 met inclusion criteria.When sufficient evidence existed, the body of evidence was assigned a strength rating of A (high), B (moderate), or C (low) in support of Strong, Moderate, or Conditional Recommendations. In the absence of sufficient evidence, additional information is provided as Clinical Principles and Expert Opinions. RESULTS: Updates were made to statements on variant histologies, urine markers after diagnosis of bladder cancer, intravesical therapy, BCG maintenance, enhanced cystoscopy, and future directions. Further revisions were made to the methodology and reference sections as appropriate. CONCLUSIONS: This guideline seeks to improve clinicians' ability to evaluate and treat patients with NMIBC based on currently available evidence. Future studies will be essential to further support or refine these statements to improve patient care.

Noninvasive Papillary Urothelial Carcinoma of the Bladder: An Institutional Experience Focusing on Tumors With Borderline Features.

CONTEXT.­: Noninvasive papillary urothelial carcinomas (PUCs) comprise most urinary bladder tumors. Distinction between low-grade (LG-PUC) and high-grade (HG-PUC) PUCs is pivotal for determining prognosis and subsequent treatment. OBJECTIVE.­: To investigate the histologic characteristics of tumors with borderline features between LG-PUC and HG-PUC, focusing on the risk of recurrence and progression. DESIGN.­: We reviewed the clinicopathologic parameters of noninvasive PUC. Tumors with borderline features were subcategorized as follows: tumors that look like LG-PUC but have occasional pleomorphic nuclei (1-BORD-NUP) or elevated mitotic count (2-BORD-MIT), and tumors with side-by-side distinct LG-PUC and less than 50% HG-PUC (3-BORD-MIXED). Recurrence-free, total progression-free, and specific invasion-free survival curves were derived from the Kaplan-Meier method, and Cox regression analysis was performed. RESULTS.­: A total of 138 patients with noninvasive PUC were included, with the following distribution: LG-PUC (n = 52; 38%), HG-PUC (n = 34; 25%), BORD-NUP (n = 21; 15%), BORD-MIT (n = 14; 10%), and BORD-MIXED (n = 17; 12%). Median (interquartile range) follow-up was 44.2 months (29.9-73.1 months). Invasion-free survival was different between the 5 groups (P = .004), and pairwise comparison showed that HG-PUC had a worse prognosis compared with LG-PUC (P ≤ .001). On univariate Cox analysis, HG-PUC and BORD-NUP were 10.5 times (95% CI, 2.3-48.3; P = .003) and 5.9 times (95% CI, 1.1-31.9; P = .04) more likely to invade, respectively, when compared to LG-PUC. CONCLUSIONS.­: Our findings confirm a continuous spectrum of histologic changes in PUC. Approximately a third of noninvasive PUCs show borderline features between LG-PUC and HG-PUC. Compared with LG-PUC, BORD-NUP and HG-PUC were more likely to invade on follow-up. BORD-MIXED tumors did not statistically behave differently from LG-PUC.

Metformin Overcomes the Consequences of NKX3.1 Loss to Suppress Prostate Cancer Progression.

BACKGROUND: The antidiabetic drug metformin has known anticancer effects related to its antioxidant activity; however, its clinical benefit for prostate cancer (PCa) has thus far been inconclusive. Here, we investigate whether the efficacy of metformin in PCa is related to the expression status of NKX3.1, a prostate-specific homeobox gene that functions in mitochondria to protect the prostate from aberrant oxidative stress. OBJECTIVE: To investigate the relationship of NKX3.1 expression and metformin efficacy in PCa. DESIGN, SETTING, AND PARTICIPANTS: Functional studies were performed in vivo and in vitro in genetically engineered mouse models and human LNCaP cells, and organotypic cultures having normal or reduced/absent levels of NKX3.1. Correlative studies were performed using two independent retrospective tissue microarray cohorts of radical prostatectomies and a retrospective cohort of prostate biopsies from patients on active surveillance. INTERVENTION: Metformin was administered before or after the induction of oxidative stress by treatment with paraquat. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Functional endpoints included analyses of histopathology, tumorigenicity, and mitochondrial function. Correlative endpoints include Kaplan-Meier curves and Cox proportional hazard regression models. RESULTS AND LIMITATIONS: Metformin reversed the adverse consequences of NKX3.1 deficiency following oxidative stress in vivo and in vitro, as evident by reduced tumorigenicity and restored mitochondrial function. Patients with low NKX3.1 expression showed a significant clinical benefit from taking metformin. CONCLUSIONS: Metformin can overcome the adverse consequences of NKX3.1 loss for PCa progression by protecting against oxidative stress and promoting normal mitochondrial function. These functional activities and clinical correlates were observed only with low NKX3.1 expression. Thus, the clinical benefit of metformin in PCa may depend on the status of NKX3.1 expression. PATIENT SUMMARY: Prostate cancer patients with low NKX3.1 are likely to benefit most from metformin treatment to delay disease progression in a precision interception paradigm.

The Utility of Renal Mass Biopsy in Shared Decision-Making for Renal Mass Treatment.

OBJECTIVE: To evaluate the utility of renal mass biopsy (RMB) in shared decision-making for renal mass treatment. Underutilization of RMB for patients with renal masses is due in part to physicians believing that results have limited clinical utility. MATERIALS AND METHODS: This was a prospective study of all patients referred for RMB from October 2019 to October 2021. Patients and physicians completed pre- and post-RMB questionnaires. Questionnaires assessed both parties' perceived utility of RMB and the impact of biopsy results on treatment preference using Likert scales. RESULTS: We enrolled 22 patients with a mean age of 66years (SD 14.5) and mean renal tumor size 3.1 cm (SD 1.4). Five were lost to follow-up (three pre-RMB, two post-RMB). Pre-RMB, 100% of patients believed that a biopsy would help them choose a treatment and 45% were unsure of their treatment preferences. After RMB, 92% perceived their biopsy results as useful and only 9% were unsure of treatment preference. Overall, 100% of patients were glad they had a biopsy. Results led patients and physicians to change their treatment preference in 57% and 40% of cases, respectively. Patients and physicians disagreed about treatment in 81% of cases prior to biopsy, but in only 25% of cases after biopsy. CONCLUSION: Discordance between patient and physician treatment preference for renal masses is higher in the absence of RMB data. Select patients are willing to undergo RMB and RMB data can increase patient confidence and comfort in a shared decision-making approach for renal mass treatment.

Survival outcomes in patients with muscle invasive bladder cancer undergoing radical vs. partial cystectomy.

PURPOSE: While radical cystectomy (RC) is the standard of care for muscle invasive bladder cancer (MIBC), partial cystectomy (PC) is an effective alternative in select patients. We sought to examine differences in survival for RC and PC in a hospital-based registry. MATERIAL AND METHODS: We identified patients diagnosed with cT2-4 bladder cancer who underwent RC or PC from 2003 to 2015 in the National Cancer Database (NCDB). Using inverse probability treatment weighting (IPTW) to control for known confounders, we compared the primary outcome of overall survival (OS) in patients who underwent RC vs. PC. Kaplan-Meier survival analysis, univariable and multivariable Cox proportional hazards modeling were used. We performed a secondary survival analysis for a subcohort of patients with cT2, cN0, tumor size ≤5 cm, and no concurrent carcinoma in situ (CIS), who may be optimal candidates for PC. RESULTS: A total of 22,534 patients met inclusion criteria, of which 6.9% (1,457) underwent PC. RC had longer median OS than PC (67.8 vs. 54.1 months) and on Cox regression analysis (HR 0.88, 95% CI, 0.80-0.95, P = 0.002). However, in our subcohort, there was no difference in OS between RC and PC (HR 1.02, 95% CI, 0.9-1.2, P = 0.74). PC was associated with increased time from surgery to any systemic therapy or death in the subcohort. CONCLUSIONS: Among patients with clinically organ-confined MIBC, PC appears to afford similar survival outcomes to RC in a large national data set. The safety and tolerability of PC may warrant consideration in highly selected patients.

A Transcriptome-Based Precision Oncology Platform for Patient-Therapy Alignment in a Diverse Set of Treatment-Resistant Malignancies.

Predicting in vivo response to antineoplastics remains an elusive challenge. We performed a first-of-kind evaluation of two transcriptome-based precision cancer medicine methodologies to predict tumor sensitivity to a comprehensive repertoire of clinically relevant oncology drugs, whose mechanism of action we experimentally assessed in cognate cell lines. We enrolled patients with histologically distinct, poor-prognosis malignancies who had progressed on multiple therapies, and developed low-passage, patient-derived xenograft models that were used to validate 35 patient-specific drug predictions. Both OncoTarget, which identifies high-affinity inhibitors of individual master regulator (MR) proteins, and OncoTreat, which identifies drugs that invert the transcriptional activity of hyperconnected MR modules, produced highly significant 30-day disease control rates (68% and 91%, respectively). Moreover, of 18 OncoTreat-predicted drugs, 15 induced the predicted MR-module activity inversion in vivo. Predicted drugs significantly outperformed antineoplastic drugs selected as unpredicted controls, suggesting these methods may substantively complement existing precision cancer medicine approaches, as also illustrated by a case study. SIGNIFICANCE: Complementary precision cancer medicine paradigms are needed to broaden the clinical benefit realized through genetic profiling and immunotherapy. In this first-in-class application, we introduce two transcriptome-based tumor-agnostic systems biology tools to predict drug response in vivo. OncoTarget and OncoTreat are scalable for the design of basket and umbrella clinical trials. This article is highlighted in the In This Issue feature, p. 1275.

Evaluation of Growth Rates for Small Renal Masses in Elderly Patients Undergoing Active Surveillance.

Background: As the adoption of active surveillance (AS) for small renal masses (SRMs) grows, the number of elderly patients enrolled for a prolonged period of time will increase. However, our understanding of comparative growth rates (GRs) in aging patients with SRMs remains poor. Objective: To examine whether particular age cutoffs are associated with an increased GR for patients undergoing AS for SRMs. Design setting and participants: We identified all patients with SRMs enrolled in the multi-institutional, prospective Delayed Intervention and Surveillance for Small Renal Masses (DISSRM) registry since 2009 who elected for AS. Outcome measurements and statistical analysis: Two definitions of GR were examined: GR from the initial image (GRi) and GR from the prior image (GRp). Image measurements were dichotomized based on patient age at the time of imaging. Multiple age cutoffs were examined: 65, 70, 75, and 80 yr. Mixed-effect linear regression examined the associations between age and GR, with controlling to account for multiple measurements from the same individual. Results and limitations: We examined 2542 measurements from 571 patients. The median age at enrollment was 70.9 yr (interquartile range [IQR] 63.2-77.4) with a median tumor diameter of 1.8 cm (IQR 1.4-2.5). As a continuous variable, age was not associated with GRi (-0.0001 cm/yr, 95% confidence interval [CI] -0.007 to 0.007, p = 0.97) or GRp (0.008 cm/yr, 95% CI -0.004 to 0.020, p = 0.17) after adjustment. The only age thresholds associated with an increased GR were 65 yr for GRi and 70 yr for GRp. Limitations include the one-dimensional nature of the measurements used. Conclusions: Increased age for patients on AS for SRMs is not associated with increased GRs. Patient summary: We examined whether patients undergoing active surveillance (AS) exhibited accelerated growth of their small renal masses (SRMs) after a certain age. No demonstrable change was seen, suggesting that AS is a safe and durable management option for aging patients with SRMs.

A Phase 1 Trial of Durvalumab in Combination with Bacillus Calmette-Guerin (BCG) or External Beam Radiation Therapy in Patients with BCG-unresponsive Non-muscle-Invasive Bladder Cancer: The Hoosier Cancer Research Network GU16-243 ADAPT-BLADDER Study.

BACKGROUND: Novel treatments and trial designs remain a high priority for bacillus Calmette-Guerin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) patients. OBJECTIVE: To evaluate the safety and preliminary efficacy of anti-PD-L1 directed therapy with durvalumab (D), durvalumab plus BCG (D + BCG), and durvalumab plus external beam radiation therapy (D + EBRT). DESIGN, SETTING, AND PARTICIPANTS: A multicenter phase 1 trial was conducted at community and academic sites. INTERVENTION: Patients received 1120 mg of D intravenously every 3 wk for eight cycles. D + BCG patients also received full-dose intravesical BCG weekly for 6 wk with BCG maintenance recommended. D + EBRT patients received concurrent EBRT (6 Gy × 3 in cycle 1 only). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Post-treatment cystoscopy and urine cytology were performed at 3 and 6 -mo, with bladder biopsies required at the 6-mo evaluation. The recommended phase 2 dose (RP2D) for each regimen was the primary endpoint. Secondary endpoints included toxicity profiles and complete response (CR) rates. RESULTS AND LIMITATIONS: Twenty-eight patients were treated in the D (n = 3), D + BCG (n = 13), and D + EBRT (n = 12) cohorts. Full-dose D, full-dose BCG, and 6 Gy fractions × 3 were determined as the RP2Ds. One patient (4%) experienced a grade 3 dose limiting toxicity event of autoimmune hepatitis. The 3-mo CR occurred in 64% of all patients and in 33%, 85%, and 50% within the D, D + BCG, and D + EBRT cohorts, respectively. Twelve-month CRs were achieved in 46% of all patients and in 73% of D + BCG and 33% of D + EBRT patients. CONCLUSIONS: D combined with intravesical BCG or EBRT proved feasible and safe in BCG-unresponsive NMIBC patients. Encouraging preliminary efficacy justifies further study of combination therapy approaches. PATIENT SUMMARY: Durvalumab combination therapy can be safely administered to non-muscle-invasive bladder cancer patients with the goal of increasing durable response rates.

Preliminary efficacy of [90Y]DOTA-biotin-avidin radiotherapy against non-muscle invasive bladder cancer.

PURPOSE: Bladder cancer represents 3% of all new cancer diagnoses per year. We propose intravesical radionuclide therapy using the ß-emitter 90Y linked to DOTA-biotin-avidin ([90Y]DBA) to deliver short-range radiation against non-muscle invasive bladder cancer (NMIBC). MATERIAL AND METHODS: Image-guided biodistribution of intravesical DBA was investigated in an animal model by radiolabeling DBA with the 68Ga and dynamic microPET imaging following intravesical infusion of [68Ga]DBA for up to 4 h and post-necropsy γ-counting of organs. The antitumor activity of [90Y]DBA was investigated using an orthotopic MB49 murine bladder cancer model. Mice were injected with luciferase-expressing MB49 cells and treated via intravesical administration with 9.2 MBq of [90Y]DBA or unlabeled DBA 3 days after the tumor implantation. Bioluminescence imaging was conducted after tumor implantation to monitor the bladder tumor growth. In addition, we investigated the effects of [90Y]DBA radiation on urothelial histology with immunohistochemistry analysis of bladder morphology. RESULTS: Our results demonstrated that DBA is contained in the bladder for up to 4 h after intravesical infusion. A single dose of [90Y]DBA radiation treatment significantly reduced growth of MB49 bladder carcinoma. Attaching 90Y-DOTA-biotin to avidin prevents its re-absorption into the blood and distribution throughout the rest of the body. Furthermore, immunohistochemistry demonstrated that [90Y]DBA radiation treatment did not cause short-term damage to urothelium at day 10, which appeared similar to the normal urothelium of healthy mice. CONCLUSION: Our data demonstrates the potential of intravesical [90Y]DBA as a treatment for non-muscle invasive bladder cancer.

Partial cystectomy: Review of a single center experience from 2004 to 2019.

PURPOSE: Partial cystectomy (PC) is a bladder sparing option to treat bladder cancer in a carefully selected group of patients. We sought to analyze outcomes of partial cystectomy (PC) in a contemporary cohort of patients at a single institution. MATERIAL AND METHODS: Records were reviewed for 43 patients with a primary urothelial carcinoma (UC) who had a partial cystectomy with curative intent at Columbia University Medical Center from 2004 to 2019. Endpoints of interest were noninvasive recurrence (defined as any recurrent nonmuscle invasive disease), advanced recurrence (defined as a muscle invasive recurrence or metastasis), and death. We used unadjusted Cox proportional hazards regressions and log rank tests to estimate the association between clinical characteristics and endpoints of interest. RESULTS: Among 43 patients with bladder cancer treated with partial cystectomy, median patient age was 73 years (interquartile range 67-77.5) and 86% were male. Twenty-three percent of patients received preoperative neoadjuvant chemotherapy (NAC) and 49% of patients were given perioperative intravesical chemotherapy at the time of PC. Pathologic stage was

Press Ganey Ratings in Urology: Who is at Risk of Bias?

OBJECTIVE: To evaluate effect of patient and physician demographics on Press Ganey (PG) survey ratings for urologists. METHODS: PG surveys (02/2020-08/2021) for urologists at a single tertiary care center were analyzed. Univariate and multivariate logistic regression models were used to assess the relationship between patient and physician-level covariates and the primary outcome of a "topbox" Overall Doctor Rating (topbox-ODR) score of 9 or 10 of 10. RESULTS: A total of 4155 surveys of 20 attending urologists (8 female (F)) across 7 subspecialties, were assessed. Mean ODR score for F physicians was 9.2 (SD 1.7) compared to 9.5 (SD 1.3) for males (M), P < .001. Univariate regression demonstrated that F patients are less likely (OR 0.27, P < .001) to give topbox-ODRs than M patients, and F physicians are 58% less likely (OR 0.42, P = .01) to receive topbox-ODRs than M physicians. Oncologists are more likely to receive topbox-ODRs (OR 3.3, P = .009) than all other subspecialists. Multivariate regression demonstrated that M patients are more likely to give M physicians top-box-ODRs (OR 0.32, P = .02), while F patients are less likely to give topbox-ODRs to physicians of both genders (M: OR 0.24, P < .001; F: 0.21, P < .001). Physicians in practice for >10 years are 66% less likely to receive topbox-ODRs (OR 0.33, P = .002). CONCLUSION: Urologists who care for F patients are at risk of being affected by bias in PG physician ratings. M physicians who care for M patients appear to be at the least risk; while F physicians who care for F patients appear to be at the highest risk.

Intravesical Therapy Compared to Radical Cystectomy Among Patients With Non-Muscle Invasive Bladder Cancer Requiring Additional Treatment After Induction BCG.

BACKGROUND: Many patients with recurrent high-risk non-muscle invasive bladder cancer after intravesical bacillus calmette-guerin (BCG) face a difficult decision between radical cystectomy (RC) or salvage intravesical therapy (IVT). We sought to determine if there is a difference in overall survival RC and IVT after previous treatment with BCG. METHODS: We performed a retrospective cohort study of patients with Ta, T1, and Tis bladder cancer treated with induction BCG in the SEER-Medicare dataset from 2000 to 2015. We used a proportional hazards regression model to compare differences in survival between patients having RC and IVT. We adjusted for confounding using a propensity score and stratified our analysis according to timing of treatment and stage at diagnosis. RESULTS: We identified 3940 patients who received either IVT (79%) or RC (21%) following induction BCG. Among patients treated within 12 months of BCG, there was no significant difference in survival between RC and IVT (HR 0.92, 95% CI 0.81-1.04) and 17% of patients having early IVT ultimately required RC. Among patients treated at least 12 months after BCG, RC was associated with worse survival than IVT (HR 1.19, 95% CI 1.06-1.35) and 10% of patients having late IVT ultimately required RC. CONCLUSION: Among patients with bladder cancer who required additional treatments after induction BCG, we did not observe a difference in overall survival between IVT and RC within 12 months of starting BCG. While RC remains the gold-standard for high risk recurrent NMIBC after BCG, bladder preservation with IVT may be appropriate for well-selected patients.

The effect of tumor grade heterogeneity on recurrence in non-muscle invasive bladder cancer.

OBJECTIVE: To investigate the outcomes of mixed-grade non-muscle invasive bladder cancer (NMIBC) based on the degree of high-grade predominance. METHODS: We identified patients in our institutional database who had a transurethral resection of bladder tumor(s) for NMIBC. Tumors with mixed-grade features on pathology report were reanalyzed, assigned the percentage high-grade component, and stratified into ≤ 5% high-grade and > 5% high-grade groups. All others were classified as low-grade or high-grade NMIBC. Differences in recurrence-free survival were assessed by log-rank test. A multivariable Cox regression model was used to evaluate the impact of tumor grade on recurrence, controlling for tumor stage, size, multifocality, and intravesical therapy. RESULTS: Two hundred and twenty patients were followed for a median of 2 years; 127 (58%) had low-grade NMIBC, 66 (30%) had high-grade NMIBC, and 27 (12%) had mixed-grade NMIBC. Of the mixed-grade patients, 14 had a ≤ 5% high-grade component, and 13 had a > 5% high-grade component. Recurrence rates across all groups ranged from 42% to 79%. There was no significant difference in intravesical recurrence-free survival among the grade categories as assessed by log-rank test. On multivariable Cox regression analysis, grade category was not significantly associated with likelihood of recurrence. CONCLUSIONS: The prognosis of mixed-grade histology in NMIBC has not previously been well defined. Although grade category was not found to be an independent significant predictor of recurrence, the recurrence rate for mixed-grade tumors was quite high overall. Further studies are required to better understand appropriate risk stratification and treatment of mixed-grade NMIBC.

Promoting Organizational Change: A Urology Department-wide Wellness Program to Reduce Burnout.

INTRODUCTION: We developed a comprehensive wellness initiative to address burnout with specific interventions targeted at faculty, residents, nurses, administrators, coordinators, and other departmental personnel. METHODS: A department-wide wellness initiative was implemented in October 2020. General interventions included monthly holiday-themed lunches, weekly pizza lunches, employee recognition events, and initiation of a virtual networking board. Urology residents received financial education workshops, weekly lunches, peer support sessions, and exercise equipment. Faculty were offered personal wellness days to use at their discretion at no penalty to their calculated productivity. Administrative and clinical staff were given weekly lunches and professional development sessions. Pre- and post-intervention surveys included a validated single-item burnout instrument and the Stanford Professional Fulfillment Index. Outcomes were compared using Wilcoxon rank-sum tests and multivariable ordinal logistic regression. RESULTS: Among 96 department members, 66 (70%) and 53 (55%) participants completed the pre- and post-intervention surveys, respectively. Burnout scores were significantly improved after the wellness initiative (mean 2.06 vs 2.42, mean difference -0.36, P = .012). An improvement was also observed in the sense of community (mean 4.04 vs 3.36, mean difference 0.68, P < .001). Adjusting for role group and gender, completion of the curriculum was associated with decreased burnout (OR 0.44, P = .025), increased professional fulfillment (OR 2.05, P = .038), and increased sense of community (OR 3.97, P < .001). The highest-rated components were monthly gatherings (64%), sponsored lunches (58%), and employee of the month (53%). CONCLUSIONS: A department-wide wellness initiative with group-specific interventions can help reduce burnout and may improve professional fulfillment and workplace community.

Pparg signaling controls bladder cancer subtype and immune exclusion.

Pparg, a nuclear receptor, is downregulated in basal subtype bladder cancers that tend to be muscle invasive and amplified in luminal subtype bladder cancers that tend to be non-muscle invasive. Bladder cancers derive from the urothelium, one of the most quiescent epithelia in the body, which is composed of basal, intermediate, and superficial cells. We find that expression of an activated form of Pparg (VP16;Pparg) in basal progenitors induces formation of superficial cells in situ, that exit the cell cycle, and do not form tumors. Expression in basal progenitors that have been activated by mild injury however, results in luminal tumor formation. We find that these tumors are immune deserted, which may be linked to down-regulation of Nf-kb, a Pparg target. Interestingly, some luminal tumors begin to shift to basal subtype tumors with time, down-regulating Pparg and other luminal markers. Our findings have important implications for treatment and diagnosis of bladder cancer.

Novel Mouse Models of Bladder Cancer Identify a Prognostic Signature Associated with Risk of Disease Progression.

To study the progression of bladder cancer from non-muscle-invasive to muscle-invasive disease, we have developed a novel toolkit that uses complementary approaches to achieve gene recombination in specific cell populations in the bladder urothelium in vivo, thereby allowing us to generate a new series of genetically engineered mouse models (GEMM) of bladder cancer. One method is based on the delivery of adenoviruses that express Cre recombinase in selected cell types in the urothelium, and a second uses transgenic drivers in which activation of inducible Cre alleles can be limited to the bladder urothelium by intravesicular delivery of tamoxifen. Using both approaches, targeted deletion of the Pten and p53 tumor suppressor genes specifically in basal urothelial cells gave rise to muscle-invasive bladder tumors. Furthermore, preinvasive lesions arising in basal cells displayed upregulation of molecular pathways related to bladder tumorigenesis, including proinflammatory pathways. Cross-species analyses comparing a mouse gene signature of early bladder cancer with a human signature of bladder cancer progression identified a conserved 28-gene signature of early bladder cancer that is associated with poor prognosis for human bladder cancer and that outperforms comparable gene signatures. These findings demonstrate the relevance of these GEMMs for studying the biology of human bladder cancer and introduce a prognostic gene signature that may help to stratify patients at risk for progression to potentially lethal muscle-invasive disease. SIGNIFICANCE: Analyses of bladder cancer progression in a new series of genetically engineered mouse models has identified a gene signature of poor prognosis in human bladder cancer.

Telemedicine in management of genitourinary malignancies: Patient and physician perspectives.

PURPOSE: The rapid expansion of telemedicine has presented a challenge for the care of patients with genitourinary malignancies. We sought to assess patient and physician perspectives on the use of telemedicine for genitourinary cancer care. METHODS: We conducted a prospective cross-sectional study of patients who had telemedicine visits with urology, medical oncology, or radiation oncology for management of genitourinary malignancies from July-August 2020. Patients and physicians each received a questionnaire regarding the telemedicine experience. Responses were scored on a 5-point Likert scale. The primary outcomes of the study were patient and physician satisfaction. RESULTS: Of the 115 patients who enrolled, we received 96 patient responses and 46 physician responses. Overall, 77% of patients and 70% of physicians reported being "extremely satisfied" with the telemedicine encounter. Satisfaction was high among all components of the encounter including patient-physician communication, counseling, shared decision making, time spent, timeliness and efficiency, and convenience. Additionally, 78% of patients and 85% of physicians "strongly agreed" that they were able to discuss sensitive topics about cancer care as well as they could at an in-person visit. Nine telemedicine visits (9%) encountered technological barriers. Technological barriers were associated with lower overall satisfaction scores among both patients and physicians (p ≤ 0.01). CONCLUSION: We observed high levels of patient and physician satisfaction for telemedicine visits for management of genitourinary malignancies. Technological barriers were encountered by 9% of patients and were associated with decreased satisfaction.

NKX3.1 Localization to Mitochondria Suppresses Prostate Cancer Initiation.

Mitochondria provide the first line of defense against the tumor-promoting effects of oxidative stress. Here we show that the prostate-specific homeoprotein NKX3.1 suppresses prostate cancer initiation by protecting mitochondria from oxidative stress. Integrating analyses of genetically engineered mouse models, human prostate cancer cells, and human prostate cancer organotypic cultures, we find that, in response to oxidative stress, NKX3.1 is imported to mitochondria via the chaperone protein HSPA9, where it regulates transcription of mitochondrial-encoded electron transport chain (ETC) genes, thereby restoring oxidative phosphorylation and preventing cancer initiation. Germline polymorphisms of NKX3.1 associated with increased cancer risk fail to protect from oxidative stress or suppress tumorigenicity. Low expression levels of NKX3.1 combined with low expression of mitochondrial ETC genes are associated with adverse clinical outcome, whereas high levels of mitochondrial NKX3.1 protein are associated with favorable outcome. This work reveals an extranuclear role for NKX3.1 in suppression of prostate cancer by protecting mitochondrial function. SIGNIFICANCE: Our findings uncover a nonnuclear function for NKX3.1 that is a key mechanism for suppression of prostate cancer. Analyses of the expression levels and subcellular localization of NKX3.1 in patients at risk of cancer progression may improve risk assessment in a precision prevention paradigm, particularly for men undergoing active surveillance.See related commentary by Finch and Baena, p. 2132.This article is highlighted in the In This Issue feature, p. 2113.