Abstract Background- Cystoscopy is standard of care in evaluating patients with gross hematuria for bladder cancer with hematuria being the primary sign of bladder cancer. Oncuria-Detect, a liquid biopsy to detect de novo bladder cancer from a single voided urine sample demonstrated favorable performance. Methods- To investigate whether Oncuria-Detect, a multiplex immunoassay that detects a urothelial cancer associated diagnostic signature composed of 10 proteins in voided urine could improve detection of urothelial cancer while evaluating participants with gross hematuria. From September 2016 through July 2025, 9 academic, private practice, and hospital facilities in the US and Japan prospectively enrolled 450 participants with gross hematuria into this urothelial cancer evaluation study. Diagnosis of urothelial cancer was based on cystoscopy (or ureteroscopy) with biopsy, which is accepted as the reference standard. Prior to the cystoscopic/ureteroscopic evaluation, participants provided a urine sample for analysis of Oncuria-Detect and BladderChek (analyzed in a blinded manner) as well as urine cytology. The performance of Oncuria-Detect was compared with BladderChek and urine cytology as an aid to detect de novo urothelial cancer with cystoscopy/ureteroscopy and histological evaluation. Results- Urothelial cancer was diagnosed in 97 participants (4 of whom had upper tract urothelial carcinoma and 93 with urothelial carcinoma of the bladder). The Oncuria-Detect assay was positive in 80 of 97 participants with cancer resulting in a sensitivity of 82.6% (95% CI, 74.9%-89.6%) with a specificity of 33.3% (95% CI, 28.7%-38.7%) and 88.4% adjusted negative predictive value (NPV) (95% CI, 83.8%-93.0%). BladderChek results were positive in 16 of 97 participants resulting in a sensitivity, 16.4% (95% CI, 10.0%-23.5%) with a specificity of 99.2% (95% CI, 98.0%-100.0%) and 82.6% adjusted NPV (95% CI, 81.5%-83.7%), whereas cytology test results were positive in 35 of 97 participants with a noted sensitivity of 35.7% (95% CI, 26.5%-46.1%) at a specificity of 99.7% (95% CI, 99.1%-100.0%) and 86.1% adjusted NPV (95% CI 84.4-88.1). Oncuria-Detect sensitivity remained high for low-grade 81.7% (95% CI, 67.2%-94.7%) vs. high grade 82.7% (95% CI, 74.2%-90.9%) and NMIBC 82.9% (95% CI, 74.4%-90.8%) vs. MIBC 79.8% (95% CI, 61.3%-94.7%). Conclusions- In this large prospective trial, Oncuria-Detect, had a substantially superior sensitivity compared to both BladderChek and urinary cytology in detecting de novo urothelial cancers, allowing it to effectively rule out approximately 30% of individuals presenting for gross hematuria evaluation. Citation Format: Sunao Tanaka, Yair Lotan, Makito Miyake, Edward M. Messing, Arnold I. Chin, Menghan Liu, Ian Pagano, Toru Sakatani, Yingye Zheng, Zhen Zhang, Charles Joel Rosser, Hideki Furuya. Detection of bladder cancer in patients with gross hematuria using Oncuria-Detect, a urine-based multiplex immunoassay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6513.

Abstract Background- Microscopic hematuria occurs in up to 10% of the general population and initiates costly evaluation to ensure no bladder cancer exists. Oncuria-Detect is a 10-plex immunoassay that detects de novo bladder cancer by generating a protein biomarker signature from a single voided urine sample. This report details the interim analysis of our prospective study that compares the diagnostic performance of the multiplex Oncuria-Detect assay to that of the single-analyte (i.e., NMP22) BladderChek urine assay and urine cytology for identifying bladder cancer in patients with microscopic hematuria. Methods- From September 2018 through July 2025, 9 medical facilities in the US and Japan prospectively enrolled 292 eligible patients (∼30%) of the proposed 900 patients with microscopic hematuria into this study. The bladder cancer diagnostic reference standard was cystoscopy with biopsy. Pre-cystoscopy, patients provided a urine sample for analysis by Oncuria-Detect and BladderChek (analyzed in a blinded manner) as well as urine cytology. Results- Bladder cancer was diagnosed in 22 patients (7.5%). The Oncuria-Detect assay had the following performance characteristics 82.0% sensitivity, 37.8% specificity, 97.5% adjusted negative predictive value (NPV) compared to BladderChek (9.3% sensitivity, 99.6% specificity, 95.4% adjusted NPV) and cytology (44.8% sensitivity, 99.3% specificity, 97.2% adjusted NPV). Oncuria-Detect displayed better sensitivity than BladderChek and cytology for identifying early- and late-stage cancer. Conclusions- In this interim analysis of an international prospective trial, Oncuria-Detect performed favorably in the non-invasive evaluation of bladder cancer presence in patients presenting with microscopic hematuria. Citation Format: Sunao Tanaka, Yair Lotan, Makito Miyake, Edward M. Messing, Arnold I. Chin, Menghan Liu, Ian Pagano, Yingye Zheng, Charles Joel Rosser, Zhen Zhang, Hideki Furuya. Detection of bladder cancer in patients with microscopic hematuria using Oncuria-Detect, interim analysis of an international prospective study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6514.

Bladder cancer (BC) patients face high rates of disease recurrence, partially driven by the cancer field effect. This effect is mediated in part by the release of pro-tumorigenic cargos in membrane-enclosed extracellular vesicles (EVs), but the specific underlying mechanisms remain poorly understood. Protein disulfide isomerase (PDIA1) catalyze disulfide bond formation and can help mitigate endoplasmic reticulum (ER) stress, potentially supporting tumor survival. Here, BC cells were found to exhibit better survival under ER stress when PDIA1 was downregulated. These cells maintained homeostatic PDIA1 levels through the EV-mediated release of PDIA1. Chronic exposure of urothelial cells to these PDIA1-enriched BCEVs induced oxidative stress and DNA damage, ultimately leading to the malignant transformation of recipient cells. The EV-transformed cells exhibited DNA damage patterns potentially attributable to oxidative damage, and PDIA1 was found to be a key tumorigenic cargo within EVs. Tissue microarray analyses of BC recurrence confirmed a significant correlation between tumor recurrence and the levels of both PDIA1 and ER stress. Together, these data suggest that cancer cells selectively sort oxidized PDIA1 into EVs for removal, and these EVs can, in turn, induce oxidative stress in recipient urothelial cells, predisposing them to malignant transformation and thereby increasing the risk of recurrence.

596 Background: The American Cancer Society estimates 14,390 deaths from kidney cancer in 2024 Chromophobe renal cell carcinoma (chRCC) is the third most common subtype of kidney cancer, and 5-10% of patients with chRCC develop metastatic disease. Being able to prognosticate which tumors are aggressive vs. indolent is a significant unmet need. Methods: All partial and radical nephrectomies performed at our institution between 2012-2018 were queried. Cases stage pT1a-pT3a N0M0 at the time of surgery with a minimum of three-year follow up were included. Cases were evaluated for recurrence after surgery. chRCC tissue microarrays (TMA) were constructed from formalin-fixed paraffin-embedded surgical specimens with five 2 mm cores obtained from each tumor. Biomarker choice was hypothesis driven based on publicly available TCGA data. Immunohistochemistry (IHC) was performed for each antibody (Ab) of interest per protocol, with appropriate positive and negative controls. A blinded genitourinary pathologist reviewed the slides and designated an average Immunoreactive Score for all 5 punches for each Ab. Log rank test was used to compare expression levels of recurrent disease to non-recurrent disease based on high and low biomarker expression. Survival analysis for 0-3 positive markers was performed using Log-rank test. Results: Forty-six patients were included in the TMA. Six had recurrent disease: two developed metastasis and four had local recurrences. Two recurrences were from pT1a primaries, two were from pT1b primaries, and two were from pT3a primaries. One metastasis developed from a pT1b primary and one from a pT3a primary. Median length of follow up was 70.5 months, median age at surgery was 54.5 years, median time to recurrence was 32 months, and median mass size was 4.1 cm. High expression of glucose transporter 1 (GLUT1; hazard ratio (HR) = 33.6, p = 0.02) and Claudin-7 (HR = 6.1, p = 0.02) and low expression of platelet derived growth factor receptor (PDGFR; HR = 7.9, p = 0.005) relative to the median was associated with metastatic disease. Recurrences also tended to have high expression of cluster of differentiation 10 (CD10). When markers were combined as a panel, having two to three positive markers was associated with decreased recurrence free survival (RFS) on univariate analysis. Median RFS was 23 months vs. 92 months for three vs. two positive markers, respectively (p < 0.0001). Conclusions: High expression of GLUT1, important in glycolysis, and the epithelial mesenchymal transitional markers CD10 and Claudin-7 and low PDGFR is a protein expression signature that may signal chRCC capable of recurrent or metastatic disease. This provides post-translational insight to proteins that may be important for chRCC invasion and metastasis. Biomarker analysis using IHC is readily and widely available for use. External validation in a larger cohort is currently underway.

We performed a clinical trial in patients with non-muscle-invasive (NMI) urothelial cancer randomized (2:1) to the EGFR tyrosine kinase inhibitor erlotinib or placebo (either orally once weekly × 3 doses prior to scheduled surgery) to assess for a difference in EGFR phosphorylation in tumor-adjacent normal urothelium <24 hours post-study dose and tolerance of weekly erlotinib therapy. Thirty-seven volunteers (6 female/31 male; mean age 70; 35 White/2 non-White) with confirmed or suspected NMI urothelial cancer were enrolled into either erlotinib (n = 24; 900 mg-13, 600 mg-11) or placebo (n = 13). IHC assessment of phosphorylated and total EGFR in tumor-adjacent normal urothelium (20 erlotinib and 9 placebo subjects) or tumor (21 erlotinib and 11 placebo subjects) at study end showed no significant difference between those receiving erlotinib or placebo. This was also true for other assessed tissue biomarkers (phosphorylated ERK, ERK, E-cadherin, p53, and Ki67). Adverse events were more common, in a dose-related fashion, in participants receiving erlotinib, e.g., 38% experienced grade 1 with rare grade 2 diarrhea and skin toxicity versus 8% in placebo. Clinically insignificant but statistically significant (P = 0.001) elevations in serum total bilirubin and creatinine were observed in participants receiving erlotinib. Serum erlotinib and metabolite concentrations (OSI-420) confirmed compliance in all subjects receiving erlotinib and did not significantly differ between the 600 and 900 mg doses. Despite compelling preclinical and clinical data for targeted EGFR inhibition in bladder cancer prevention, these data do not support the use of weekly erlotinib therapy to prevent progression of NMI bladder cancer. Prevention Relevance: We evaluated the potential of erlotinib in preventing cancer by performing a randomized, double-blind, placebo-controlled trial of weekly erlotinib therapy in participants undergoing surgical removal of suspected noninvasive bladder neoplasia. Weekly erlotinib therapy was tolerated with common grade 1 to 2 toxicities but without evidence of beneficial effect upon urothelial tissue. See related Spotlight, p. 7.

Table S3 shows bivariate associations of patient, cancer, and treatment factors with hematuria

Deciding whether to perform pelvic lymph node dissection at the time of prostate cancer surgery could be assisted by using prostate-specific membrane antigen-PET imaging. In favourable intermediate-risk prostate cancer, this imaging technique could be used to identify patients who could forego pelvic lymph node dissection.

BACKGROUND:Late bladder toxicity is a concern for patients receiving prostate cancer radiotherapy and negatively affects survivors. Few risk factors are known beyond the radiation dose and volume of bladder exposed. A polygenic risk score (PRS) could identify susceptible patients. METHODS:A PRS was built using genome-wide association results from the Radiogenomics Consortium (N = 3,988) and then tested in the prospective REQUITE and URWCI studies (N = 2,034). The primary outcome was time to patient-reported gross [grade ≥2, (≥G2)] hematuria, analyzed using Cox proportional hazards regression. Secondary outcomes were ≥G2 urinary retention and frequency. The PRS was externally validated for clinically diagnosed irradiation cystitis in the UK Biobank (N = 8,430). A gene-burden test evaluated rare coding variants. RESULTS:A 115-variant PRS was associated with a significantly increased risk of ≥G2 hematuria [hazard ratio (HR) per SD = 1.22; P = 0.009] as well as urinary retention (HR per SD = 1.18; P = 0.016) and frequency (HR per SD = 1.14; P = 0.036). When binarized, men in the upper decile (PRShigh) had a >2-fold increased risk of hematuria after adjusting for clinical risk factors [HR = 2.12; P = 0.002; Harrel's concordance index = 0.71 (95% confidence interval, 0.65-0.76)]. A similar effect size was seen in the UK Biobank for clinically diagnosed irradiation cystitis [odds ratio (OR) = 2.15; P = 0.026]. The burden test identified BOD1L1 as a putative novel radiosensitivity gene. CONCLUSIONS:This PRS identifies susceptible patients and could guide the selection of those needing reoptimized treatment plans that spare the bladder beyond currently recommended constraints. IMPACT:PRS-guided treatment planning in radiation oncology could lower the incidence of clinically relevant bladder toxicity and reduce the impact of this outcome on prostate cancer survivors.

INTRODUCTION:Despite strong evidence supporting its effectiveness, single, immediate instillation of intravesical chemotherapy (SI-IVC) following transurethral resection of bladder tumor (TURBT) remains vastly underutilized in managing low- and intermediate-risk non - non-muscle-invasive bladder cancer (NMIBC). This review addresses the gap between evidence and practice in adopting this cost-effective, recurrence-reducing intervention and offers potential solutions through an implementation science approach. AREAS COVERED:We examined the clinical benefits of SI-IVC based on landmark trials and meta-analyses across various agents, including mitomycin and gemcitabine. A targeted literature review was conducted using PubMed and major urology guidelines to identify studies assessing efficacy, utilization rates, and barriers to implementation. Particular focus is given to logistical and systems-based challenges limiting real-world application, including issues with drug availability, perioperative workflow, and post-resection coordination. We also discuss strategies informed by an implementation science framework, including planning and system engagement, executing interventions, and evaluating their impact within hospital systems. EXPERT OPINION:Incorporating SI-IVC into routine practice requires pragmatic, system-level changes that address logistical barriers rather than clinical hesitancy. With institutional support and streamlined protocols, SI-IVC can be more consistently delivered, however, local adaptation and fine-tuning remain essential, as healthcare systems and available personnel vary across institutions.

5089 Background: Older men with prostate cancer who have aging-related conditions are at high risk for adverse events (AEs) from ADT. 5-ARI inhibit the conversion of testosterone to dihydrotesterone and could be synergistic with Enz. In this phase II study, we evaluated Enz and Dutasteride (Dut) or Finasteride (Fin) in lieu of ADT for older men with CSPC who are at risk of AEs from ADT. Methods: Eligible patients were ≥65 years (y); deemed “not fit” by geriatric assessment (GA) or at high risk for side effects from ADT as determined by the treating physician; had metastatic (M1) or non-metastatic (M0) CSPC with a PSA doubling time ≤9 months and testosterone >50ng/dl. Enz 160 mg daily and Dut 0.5mg daily or Fin 5mg daily were administered until disease progression per Prostate Cancer Clinical Trials Working Group 2 guidelines. The primary study endpoint is PSA progression free survival (PFS). Key secondary endpoints include time to PSA nadir, absolute PSA nadir and evaluation of safety and toxicity of study treatments per CTCAE V4.0. Results: 43 men enrolled in the study. At study entry, subjects had the following baseline characteristics: median age was 78 y (range 66-94); 93% had ECOG 0-1; 63% had M1 CSPC with 30% of them having high volume disease per CHAARTED criteria; 23% had Gleason ≥ 8 CSPC; median PSA was 11.4 ng/ml (2-145), and median testosterone level was 342 ng/dl (56-639). Baseline GA at study entry showed that 18.6% had Instrumental Activity of Daily Living impairment; 9.8% had recent falls; 52.4% had Short Physical Performance Battery impairment; 40.5% had Older American Resources and Services (OARS) physical health and 31% had OARS medical social support impairments; 11.6% had Geriatric Depression Scale impairments; 65.9% had either Blessed Orientation-Memory-Concentration or Montreal Cognitive Assessment impairments; and 34.9% had Vulnerable Elders Survey-13 impairments. At a median follow-up of 5.9 y, 23 pts (53%) remained on study treatment and the median PSA PFS has not been reached for the entire group. The median time to PSA nadir was 8.1 months, with median PSA nadir at 0.02 ng/ml (range 0-2.75) and 98% having ≥90% PSA decline. The five most common any grade AE was fatigue (88%), gynecomastia (72%), hot flashes (42%), hypertension (40%), and falls (37%). No subject had treatment-related Grade 4 or 5 AEs. Four (9.3%) subjects withdrew treatment, 21% held treatments and 30.2% reduced dose of treatment due to AEs. Conclusions: The combination treatment with Enz and Dut/Fin appears to have clinical efficacy for older patients with CSPC who are at high risk for AEs from ADT. Clinical trial information: NCT02213107 .

Preclinical and clinical data suggest that androgen receptor signaling strongly contributes to bladder cancer development. The roles of the androgen receptor in bladder carcinogenesis have obvious implications for understanding the strong male sex bias in this disease and for potential therapeutic strategies as well. In this review, we summarize what is known about androgen receptor signaling in urothelial carcinoma as well as in tumor-infiltrating immune cells, reviewing preclinical and clinical data. We also highlight clinical trial efforts in this area.

You have accessJournal of UrologyKidney Cancer: Basic Research & Pathophysiology II (PD51)1 May 2024PD51-10 ESTROGEN RECEPTOR SIGNALS PROMOTE AUTOPHAGY AND M2 MACROPHAGE POLARIZATION IN THE TKI-RESISTANT RCC Shuyuan Yeh, Huiyang Xu, Yixi Hu, Guosheng Yang, Jean Joseph, and Edward M. Messing Shuyuan YehShuyuan Yeh , Huiyang XuHuiyang Xu , Yixi HuYixi Hu , Guosheng YangGuosheng Yang , Jean JosephJean Joseph , and Edward M. MessingEdward M. Messing View All Author Informationhttps://doi.org/10.1097/01.JU.0001009360.84490.42.10AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Early studies indicated that estrogen receptor β (ERβ) could influence the progression of clear cell renal cell carcinoma (ccRCC). Its potential functions on regulating macrophages within the tumor microenvironment and the impacts on the sensitivity of tyrosine kinase inhibitor (TKI) treatment remain to be further studied. METHODS: The human cell lines: 786-O, A498, THP-1 and mouse RAW 264.7 cells were used. Lentiviral plasmids were used to generate gene engineering viral particles. The qPCR and Western blot were applied to evaluate the gene expressions at RNA and protein levels, respectively. The trans-well co-cultures of RCC cells with human macrophages with high vs. low ER expression were used to determine the changes of TKI sensitivity of RCC cells. Protein-DNA binding complexes were detected by Chromatin immunoprecipitation (ChIP) assays. The human non-coding RNA promoter was cloned into pGL3 vector for Luciferase assays. Preclinical mouse RCC model was used to evaluate the anti-cancer effect of TKI plus non-coding RNA blockage in TKI-resistant RCC. RESULTS: Autophagy may serve to mitigate the limited availability of external nutrients and sustain tumor cell viability. Our results from multiple cell line studies revealed that infiltrating macrophages could increase the ERβ/Egr1-mediated autophagy to decrease the TKI treatment sensitivity of RCC cells. Furthermore, the increased ERβ in RCC cells could function via a positive feedback mechanism to induce M2 macrophage polarization with increasing ARG1 to further decrease the TKI (sunitinib or pazopanib) sensitivity of ccRCC. The up-regulated ERβ could then transcriptionally increase the miRNA expression to decrease PTEN expression in macrophages in the tumor microenvironment. Detailed mechanism studies reveal the involvement of altering no-coding RNA function to control pTEN/p-AKT signaling. CONCLUSIONS: Here we found that ERβ might function via increasing the autophagy and M2 macrophage polarization to decrease the RCC cell sensitivity to the TKI treatment. Preclinical studies using in vivo mouse models also prove that targeting this newly identified ARG1/ERβ/p-AKT signaling by blocking the non-coding RNA and/or anti-estrogen leads to increase the TKI sensitivity to better suppress RCC progression, which, if successful in future clinical trial, may help in the development of a novel therapy to better suppress the ccRCC progression. Source of Funding: The study was partially supported by the URMC Urology Research fund © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e1069 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Shuyuan Yeh More articles by this author Huiyang Xu More articles by this author Yixi Hu More articles by this author Guosheng Yang More articles by this author Jean Joseph More articles by this author Edward M. Messing More articles by this author Expand All Advertisement PDF downloadLoading ...