Supplementary Figure S4. Immunohistochemistry for Ki-67 protein expression in representative prostate tumors of the placebo (PBO) group and the BroccoMax (BMAX) group.

INTRODUCTION:Black patients with muscle-invasive bladder cancer have higher mortality compared with White patients. This study evaluated the association of treatment type on overall and bladder cancer-specific survival across these racial groups. PATIENTS AND METHODS:We identified patients diagnosed with nonmetastatic urothelial muscle-invasive bladder cancer from 2008 to 2017 using the Surveillance, Epidemiology and End Results (SEER)-Medicare Database. Black and White patients treated with cystectomy or trimodal therapy were included. Cox proportional hazards regression was used to examine the association of race and treatment type on overall survival, adjusting for tumor stage, age at diagnosis, sex, and comorbidity score. Fine-Gray competing risks regression was used to examine bladder cancer-specific survival with adjustment for the same covariates. RESULTS:Among 2119 patients, race was not significantly associated with all-cause mortality after adjusting for treatment type (ie, cystectomy or trimodal therapy), sex, age at diagnosis, and comorbidity score (P = .12). However, among patients who underwent cystectomy, Black patients had a significantly higher hazard of bladder cancer-specific death compared with White patients (P < .01). This difference in cancer-specific survival was not observed in patients who underwent trimodal therapy. CONCLUSION:Black patients treated with cystectomy, but not trimodal therapy, have a higher hazard of bladder cancer-specific death, even after adjusting for patient factors and tumor stage. This difference was not observed for overall survival.

INTRODUCTION:Non-clear cell renal cell carcinoma (nccRCC) comprises heterogeneous cancers historically managed using evidence extrapolated from clear cell RCC. Current guidelines support histology-guided treatment, but real-world adoption of systemic strategies and cytoreductive nephrectomy remains incompletely characterized. We assessed temporal trends in systemic treatment and cytoreductive surgery and identified predictors of treatment allocation in metastatic nccRCC. METHODS:We used the National Cancer Database to identify adults diagnosed with metastatic nccRCC from 2016 to 2022. Patients were classified as receiving targeted therapy (TT) only, immunotherapy (IO) only, IO + TT, or no documented systemic therapy. Temporal trends were assessed using annual treatment proportions and estimated annual percentage change (EAPC). Multivariable logistic regression evaluated predictors of systemic treatment allocation and receipt of cytoreductive surgery. RESULTS:Among 3677 patients, 30.9% received TT only, 19.3% IO only, 13.7% IO + TT, and 36.1% had no documented systemic therapy. Among treated patients, TT use decreased over time (EAPC -23.46%, 95% CI -25.80 to -21.05; P < .001), whereas IO only (EAPC +32.26%, 95% CI +6.21 to +64.71; P = .022) and IO + TT (EAPC +30.70%, 95% CI +25.00 to +36.66; P < .001) increased. Cytoreductive surgery declined (EAPC -8.89%, 95% CI -12.04 to 5.64; P = .001). Later year of diagnosis was associated with IO-based treatment, with differential use across histologic subtypes. CONCLUSIONS:Between 2016 and 2022, treatment patterns for metastatic nccRCC in the US shifted from TT toward IO-based regimens, while cytoreductive surgery declined, reflecting evolving real-world management of this heterogeneous disease.

OBJECTIVE:To examine the impact of private equity (PE) acquisition on the volume of common outpatient urologic procedures. METHODS:PE acquisitions of urology practices in 2016 and 2018 were identified through use of financial databases cataloguing both public and private transactions. Yearly office visit and procedure volume by provider were extracted from the publicly available Medicare Physician & Other Practitioners by Provider and Service database from 2013 to 2022. We chose the most commonly billed procedures and visits for analysis: cystoscopy, post-void residual (PVR), prostate biopsy, complex cystometrogram (CMG), complex uroflow, extracorporeal shock-wave lithotripsy, ureteroscopy, 30- and 45-minute new patient visits, and 15-, 25-, and 40-minute follow-up patient visits. We used comparative interrupted time series analysis to analyze yearly procedure and visit volumes before and after the acquisition. RESULTS:We identified 199 and 196 physicians acquired by PE and not acquired, respectively. The volumes of complex CMG increased at the time of acquisition in 2018 by 10.2 per physician-year, more than the control physicians. For some procedures (cystoscopy, PVR, prostate biopsy, complex CMG, complex uroflow), the post-acquisition trends in volume were different for those acquired in 2018 compared to the control groups. The number of new patient and follow-up office visits were largely unaffected by PE acquisition in 2016 and 2018. CONCLUSION:We observed variability in procedure volumes after PE acquisition, depending on the procedure type. The full impact of the changing ownership model in urology is yet to be determined.

Objective To evaluate patient preferences for intermediate-risk prostate cancer treatment and determine how these preferences vary across demographic groups using a discrete choice experiment. Methods We recruited patients with intermediate-risk prostate cancer from a single-center urology clinic. In this survey, we included 8 attributes with 3-4 levels each to capture the full spectrum of prostate cancer treatment outcomes. We estimated patient preferences using a conditional logit model. We conducted a latent class analysis to identify patient subgroups with distinct choice behavior patterns. We used a multivariable linear probability model to assess the association between patient demographic characteristics and latent class membership. Results A total of 88 patients completed the survey. In our primary analysis, patients had a significant preference towards avoiding bowel symptoms, erectile dysfunction, use of a catheter, or frequent trips to the facility. Bowel symptoms were considered the most important of all attributes, while urinary symptoms did not significantly influence patients’ choices. Patients placed a low weight on facing prolonged travel times or undergoing a major surgery. Latent class analysis revealed 2 groups based on survey response patterns: (1) patients averse to surgery and catheter and (2) patients averse to erectile and bowel symptoms. Older patients and racial and ethnic minorities were more likely to be members of the surgery and catheter-focused class. Conclusion Overall, patients appear to prioritize avoiding bowel and sexual side effects after prostate cancer treatment. However, a subset of older patients may have strong preferences against surgery or the prolonged use of a catheter.

Serum albumin is a well-established surrogate marker of nutritional and systemic health. Among patients with renal cell carcinoma (RCC), hypoalbuminemia is associated with increased mortality; however, its correlation with hospital length of stay (LOS) and readmission remains poorly characterized. This study aims to evaluate the association between preoperative hypoalbuminemia, LOS, and 90-day readmission in patients undergoing nephrectomy. We reviewed a prospectively maintained RCC database at our institution for patients undergoing nephrectomy between 2000 and 2025. Inclusion criteria were age 18 or older and nonmetastatic RCC (T1–3N0M0). Multivariable logistic and negative binomial regression models were used to assess predictors of prolonged LOS (≥7 days) and 90-day readmission. Albumin was evaluated as both a continuous and categorical variable (<3.5 vs ≥3.5 g/dL). Among 1774 patients, 14.8% had hypoalbuminemia (<3.5 g/dL), 12.9% experienced prolonged LOS, and 10.1% were readmitted within 90 days. On linear regression, lower serum albumin was significantly associated with longer LOS (B = −1.67 days per g/dL, P < 0.001). On multivariable analysis, hypoalbuminemia was independently associated with increased odds of prolonged LOS (OR 1.65, 95%CI 1.13-2.42, P = .01) and readmission (OR 1.61, 95%CI 1.06-2.44, P = .03). Similar results were noted on multivariable negative binomial regression. Preoperative hypoalbuminemia is independently associated with prolonged hospitalization and increased risk of 90-day readmission in patients undergoing nephrectomy for nonmetastatic RCC. Serum albumin may serve as a valuable risk stratification tool. Nutritional optimization and integration of albumin-based assessments into perioperative protocols may improve recovery trajectories.

OBJECTIVE:To understand patterns in private equity (PE) acquisition of urology practices based on the Social Vulnerability Index (SVI), a composite, area-level measurement reflecting the following themes: socioeconomic status, household characteristics, racial & ethnic minority status, and housing & transportation type. METHODS:We identified PE-owned urology practices by cross-referencing multiple sources. We linked the SVI for census tracts with and surrounding a PE practice (census places). We used multilevel, multivariable logistic regression to predict the probability of PE acquisition for a census tract within a census place based on SVI and its separate themes, adjusted for urban/non-urban designation and physician office density. RESULTS:We identified 349 census tracts containing at least 1 PE practice and 11,868 census tracts in the same census places with no PE practices. There was no statistically significant association between the composite SVI measurement and PE acquisition (False Discovery Rate (FDR)-adjusted P=.390). In exploratory analysis, we found that census tracts with lower socioeconomic status and more racial and ethnic minorities were associated with a significantly lower probability of PE acquisition, although only to a small degree (FDR-adjusted P=.003 and P=.002, respectively). CONCLUSION:Composite social vulnerability index was not associated with PE acquisition of urology practices.

This retrospective study uses data from the National Cancer Database to examine patterns and temporal trends in use of focal therapy for prostate cancer in US cancer centers; characterize inappropriate use in low-, high-, or very–high-risk disease; and describe intermediate-risk use.

Fatty acid synthesis pathway is a valid target for prevention of prostate cancer. However, a clinical grade inhibitor of fatty acid synthesis is still lacking. This bench-to-bedside study was undertaken to determine the feasibility of fatty acid synthesis inhibition using broccoli constituent sulforaphane (SFN) and its clinical grade formulation BroccoMax® (BMAX). Oral administration of SFN to Hi-Myc mice resulted in inhibition of prostate adenocarcinoma burden by about 61% that was accompanied by a significant decrease in prostate tumor levels of c-Myc and PCNA proteins and increased apoptosis. Expression of acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FASN) were lower by about 46% and 31%, respectively, in the prostate tumor of SFN-treated mice when compared to that of control mice (P < 0.001). Plasma levels of total free fatty acids (TFFA), cholesterol, and total phospholipids were decreased significantly following SFN treatment. In a double-blind clinical trial, patients with histologically confirmed prostate cancer were randomized to the BMAX group (n= 19) or placebo group (n= 22). Patients were treated with 4 capsules BMAX or 4 capsules of matching placebo orally two times daily after breakfast and dinner for 4 weeks. Prostate tumor expression of c-Myc, ACC1, FASN, and Ki-67 proteins were significantly lower in the BMAX arm when compared to PBO group. However, serum or prostate tumor level of acetyl-CoA or TFFA was not decreased by BMAX treatment. A longer duration treatment with BMAX in early-stage prostate cancer patients may be necessary to lower circulating or prostate tumor level of TFFA.

BACKGROUND:Benign prostatic hyperplasia (BPH) is the most common disease in aging males. BPH growth is androgen-dependent, and it appears that androgens preferentially stimulate the growth of BPH as compared to normal prostate. The mechanism of preferential androgen stimulation of BPH growth is not clear. Our previous studies suggest that primary BPH stromal cells, but not the paired normal adjacent prostate (NAP) stromal cells from the same patients, could stimulate prostatic epithelial cell proliferation in 3D co-culture. However, whether androgen regulation of prostatic stromal cells is altered in BPH nodules is not clear. METHODS:Paired BPH and NAP primary stromal cells were prepared from the same patients. Early passage paired BPH and NAP primary cells were treated with androgens and/or antiandrogens for RNA-seq analysis. RNA-seq data were analyzed using principal component analysis (PCA) and functional enrichment analysis. Conditioned medium of the paired BPH and NAP primary cells in the presence or absence of androgens were used in three-dimensional (3D) culture of benign prostatic epithelial cells. RESULTS:RNA-seq data analysis suggests that androgen-induced gene expression in BPH primary stromal cells is heightened compared to paired NAP stromal cells. AR activation in BPH stromal cells appears to enhance cellular motility, vascular and extracellular matrix remodeling, and paracrine signaling, while simultaneously modulating cell cycle and metabolic processes. Compared to regular BPH stromal conditioned medium, conditioned medium of androgen-stimulated BPH stromal cells further enhanced prostatic epithelial cell proliferation in 3D culture. In contrast, medium of NAP stromal cell culture conditioned in the presence of androgen had no significant effect on prostatic epithelial cell proliferation in 3D culture. CONCLUSIONS:Our findings suggest that androgen stimulation of prostatic epithelial cell growth via paracrine prostatic stromal signaling is enhanced in BPH and is associated with heightened androgen-responsiveness of BPH stromal cells.

Prevention is desirable to reduce suffering and death from prostate cancer. However, a clinical-grade intervention for the prevention of this malignancy is still lacking. This study was undertaken to determine the feasibility of prostate cancer prevention by broccoli constituent sulforaphane (SFN) because epidemiological studies have suggested an inverse association between intake of broccoli and the risk of prostate cancer. Oral administration of 1 mg SFN/mouse (three times/week) to 5-week-old male Hi-Myc transgenic mice for 5 weeks decreased the incidence of prostatic adenocarcinoma in situ by about 54% without causing weight loss or any other side effects. Existing literature strongly implicates fatty acid synthesis in prostate cancer progression. Therefore, we determined the effect of SFN treatment on fatty acid synthesis. Prostate cancer prevention by SFN in Hi-Myc mice was accompanied by a decrease in: (a) the uptake of 11C-acetate in the prostate of live mice; (b) plasma levels of fatty acid synthesis intermediates acetyl-CoA and malonyl-CoA; (c) circulating levels of total free fatty acids (TFFA); (d) downregulation of fatty acid synthesis enzyme proteins acetyl-CoA carboxylase 1 and fatty acid synthase; and (e) plasma levels of interkeukin-10 and interleukin-12. Because prostate cancer in Hi-Myc mice is driven by Myc, we determined the effect of overexpression of c-Myc in 22Rv1 cells on TFFA level. Overexpression of c-Myc conferred partial protection against TFFA suppression by SFN treatment. In summary, this study reveals that SFN administration prevents prostate cancer development in Hi-Myc mice by suppressing fatty acid synthesis.

Supplementary Figure S1. Immunohistochemistry for c-Myc protein expression in representative prostate tumors of the placebo (PBO) group and the BroccoMax (BMAX) group.

Purpose:Bladder cancer is associated with significant morbidity and mortality in the US, with 85,000 new cases and 17,400 deaths expected in 2025. Black patients are more likely than White patients to be diagnosed with bladder cancer at advanced stages, as are female patients compared with male patients. We examine whether differences in cancer diagnosis rates by race and sex can explain the observed variability using a simulation model and project outcomes of potential improvement in diagnosis. Methods:We developed a state transition model for bladder cancer to simulate four cohorts based on sex (males, females) and race (Blacks, Whites) from birth through various health states, including disease-free, preclinical stages (0a/0is - IV), clinical stages (0a/0is - IV), and death (bladder cancer or other cause death). Parameters related to disease onset, progression, and diagnosis were estimated by calibrating the model to race- and sex-specific incidence rates by age, and stage distribution at diagnosis for cases diagnosed between 2015 and 2019 in SEER 17 registry areas. We conducted a scenario analysis to examine the impact of differences in diagnosis rates on stage distribution and life expectancy, assuming that Black males (or females) and White females had diagnosis rates similar to those of White males. Results:The calibrated model attributes the differences in stage distribution to lower diagnosis rates in White females (hazard ratio, [HR] = 0.95, 95% credible interval [CI]: 0.92 - 0.96), Black males (0.80, 95% CI: 0.75 - 0.81) and Black females (0.56, 95% CI: 0.53 - 0.58), relative to White males. If diagnosis rates for all demographic groups were similar to White males, the expected life span of a 65-year-old bladder cancer patient would increase by 0.2 years for White females (from 13.8 to 13.9 years), 0.6 years for Black males (from 10.6 to 11.1 years), and 1.9 years for Black females (from 10.5 to 12.4 years). Conclusions:Differences in diagnosis rates of bladder cancer by race and sex explain the observed differences in stage distribution at diagnosis. Targeted interventions aimed at improving diagnosis rates have the potential to substantially improve survival for patients with bladder cancer.

INTRODUCTION AND OBJECTIVE:The onset of the COVID-19 pandemic in March of 2020 led to the delay of routine prostate cancer screening. While screening rates recovered after the first wave of the COVID-19 pandemic, the degree to which this recovery occurred in different populations remains unknown. We sought to determine the association of the COVID-19 pandemic with prostate cancer screening, particularly for traditionally underserved patients. METHODS:We performed a retrospective cohort study using electronic health records (EHR) data from the Optum de-identified Electronic Health Record dataset for all male patients between the ages of 55 to 69 eligible for prostate cancer screening from quarter 1 (Q1) of 2016 through Q2 of 2021. We studied trends in prostate cancer screening over time using adjusted generalized estimating equation (GEE) logit models to account for clustering of data within patients. RESULTS:A total of 7,361,765 patients were included. After adjusting for all selected patient demographics, the percentage of eligible patients with prostate cancer screening per quarter decreased from 2.2% in Q4 of 2019 to 1.3% in Q2 of 2020. There was a rebound in screening to 2.3% in Q3 of 2020 and a subsequent decline to 1.6% in Q2 of 2021. This trend was seen even after stratifying based on age, race, ethnicity, Census division of residence, and insurance status. CONCLUSIONS:Prostate cancer screening rates declined during the first and second waves of the COVID -19 pandemic across all demographic groups. This trend was unaffected by patient characteristics, such as age, race, insurance status, or Census division of residence.

Background: Rural patients often experience barriers accessing high-quality surgical care. The Pennsylvania Rural Health Model (PARHM) aimed to improve rural health through all-payer hospital global budgets and transformation plans, which may influence hospitals' incentives and capacity to provide various surgical services, including cancer surgery.Objectives: Examine the association between PARHM and patterns of cancer surgery overall, by timing of entry into PARHM, and by cancer type.Research Design: Stacked difference-in-differences (DID) models including hospital service area (HSA)-level propensity score weights, comparing patients living in HSAs with hospitals participating in PARHM to those in HSAs with eligible nonparticipating hospitals.Subjects: Patients in eligible HSAs who had surgery between 2016 and 2023 for one of 11 cancers with evidence of surgical volume-outcome relationships.Measures: Surgery at a high-volume, Commission on Cancer (CoC) accredited, or National Cancer Institute (NCI)-designated hospital, and travel distance to the surgical hospital.Results: The sample included 22,728 cancer surgeries for patients across 60 HSAs. Pooled estimates indicate no statistically significant differential changes in outcomes. In HSAs served by the 2019 cohort of PARHM hospitals (smaller and more remote facilities), PARHM was associated with a differential increase in surgery at CoC hospitals (DID estimate: 8.7 percentage points, 95% CI: 1.5- 16.0). We observed differential increases in surgery at CoC hospitals for colon and rectal cancers, and decreases in surgery at CoC and high-volume hospitals for liver cancer and at NCI centers for bladder cancer.Conclusion: PARHM had limited overall effects on surgical cancer care, with some variation across hospitals and cancer types.

Background:Bladder cancer imposes substantial clinical and economic burden, yet key natural-history quantities that determine the potential effectiveness of screening-such as the size of the screen-detectable preclinical reservoir and the preclinical sojourn time-are largely unobservable. The Cancer Intervention and Surveillance Modeling Network (CISNET) uses standardized stress tests to compare independently developed microsimulation models and to clarify how differences in model structure translate into differences in intervention impact. The Maximum Clinical Incidence Reduction (MCLIR) framework estimates the maximum achievable reduction in clinically detected incidence following a one-time, perfect screening intervention, while Realistic Clinical Incidence Reduction (RCLIR) relaxes the perfect-test and/or perfect-treatment assumptions. Methods:We applied the CISNET MCLIR/RCLIR protocol to three independently developed bladder cancer microsimulation models (COBRAS, Kystis, and SCOUT), each calibrated to common U.S. epidemiologic targets. We simulated a U.S. birth cohort born in 1950 and compared: (1) no-screening baseline; (2) one-time perfect screening with universally curative treatment (MCLIR) at ages 60, 65, 70, and 75; and (3) one-time realistic screening with cystoscopy sensitivity of 80% and perfect treatment (RCLIR-1) or usual-care treatment effectiveness (RCLIR-2). Outcomes included age-specific clinical incidence and incidence-reduction curves relative to baseline, as well as cumulative reductions over follow-up. Results:Across models, median ages at first lesion emergence, clinical diagnosis, and onset of muscle-invasive disease were similar, but preclinical sojourn time differed meaningfully: COBRAS produced the shortest median sojourn time (2.1 years) compared with Kystis (3.3 years) and SCOUT (3.1 years). Under MCLIR, all models predicted an immediate drop in clinical incidence followed by attenuation toward zero as new lesions emerged after the screening age. Peak MCLIR at age 65 among White men ranged from 20% (COBRAS) to 21% (Kystis) and 32% (SCOUT), with reductions dissipating within ∼8 years in COBRAS and persisting ∼10 years in Kystis and SCOUT. In COBRAS and Kystis, incidence reductions later became negative, consistent with rebound emergence of new lesions among individuals whose first lesions were removed by screening. Under RCLIR-1, peak reductions were smaller and varied substantially across models (13%, 4%, and 37% for COBRAS, Kystis, and SCOUT, respectively). RCLIR-2 further reduced gains and produced more gradual decay, reflecting incomplete prevention under usual-care treatment. Across models, most residual post-screening incidence was attributable to new lesion emergence rather than missed detection or incomplete treatment. Conclusions:In a standardized CISNET stress test, three bladder cancer microsimulation models imply a relatively short detectable preclinical phase, placing a modest upper bound on the effectiveness of one-time screening in the general population. Differences in MCLIR/RCLIR magnitude and persistence are explained by differences in implied sojourn time and detectable reservoir size. These findings motivate evaluation of risk-targeted and repeated early-detection strategies and highlight key empirical priorities for improving inference on bladder cancer natural history.

Supplementary Table S1: Representativeness of Study Participants