INTRODUCTION:Despite increased risk of adverse events and overdose associated with sustained-release opioids, evidence is lacking to support the short-term use of a low-dose, sustained-release opioid for acute pain control in a monitored setting. Both immediate-release and sustained-release opioids are used clinically in postoperative analgesia. We hypothesized that short-term use of low-dose, sustained-release hydromorphone combined with immediate-release hydromorphone as required would facilitate earlier ambulation after major urologic surgeries compared to immediate-release opioids alone. METHODS:Following ethics approval and patient consent, patients undergoing elective open abdominal urologic surgeries were randomized into two groups: sustained-release hydromorphone on a regular basis for two days, with immediate-release hydromorphone available on an as-required basis; or immediate-release hydromorphone on an as-required basis only. The primary outcome measure was the time to get up and walk three steps. RESULTS:A total of 66 participants were included in the data analysis. There was no statistically significant difference in the time to first mobilization, opioid consumption, or pain scores at any time point between the two groups. There were trends toward more nausea on postoperative days 1, 2, and 3, as well as more severe loss of sleep the first night after surgery in the immediate-release group, although the differences did not reach statistical significance. CONCLUSIONS:Our study showed that patients receiving short-term, low-dose, sustained-release hydromorphone immediately postoperatively did not mobilize sooner compared to those only receiving immediate-release hydromorphone. There was no difference in the pain score or opioid consumption.

Prostate cancer is among the most prevalent malignancies in men and a leading cause of cancer mortality worldwide. While localized prostate cancer is often curable, progression to metastatic and castration-resistant disease either in lymph nodes or bone/bone marrow remains the major cause of death. Understanding the genomic events that drive metastasis—particularly in treatment-naïve patients—is critical to improving early detection and individualized therapy. Bulk tumor sequencing has revealed key mutational signatures but cannot resolve the cellular heterogeneity and clonal dynamics underlying metastatic spread. Single-cell genomic approaches now enable high-resolution dissection of tumor evolution, uncovering the diversity of cancer clones across disease sites. We performed whole-genome and whole-exome sequencing on single cancer cells from a treatment-naïve patient with metastatic prostate cancer, isolating cells from the primary tumor, circulating tumor cells (CTCs), disseminated tumor cells (DTCs) in bone marrow, and metastatic bone lesions. Copy number aberrations (CNAs) and single-nucleotide variants (SNVs) were characterized to define genomic heterogeneity and infer clonal relationships. Frequent monoallelic losses in tumor suppressors (PTEN, TP53, FOXO4, STAG2) and gains in oncogenes (MTOR, RAF1, HRAS) and an angiogenic growth factor (VEGFB), were observed. Metastatic cells displayed fewer genomic alterations than CTCs or DTCs. While this observation is consistent with the hypothesis that metastatic competence may be associated with relative genomic stability, normal cell contamination of the metastatic biopsy cannot be excluded, and this interpretation should be considered preliminary. Clonal evolution analysis revealed a complex branching pattern consistent with multidirectional dissemination, suggesting bidirectional seeding between the primary tumor, circulation, and metastatic sites as one possible model of spread, though alternative explanations including phylogenetic reconstruction artefacts cannot be excluded from a single-patient study. This study provides a single-cell genomic map of metastatic prostate cancer from a treatment-naïve patient, highlighting the coexistence of diverse subclones across disease sites and supporting a multidirectional model of cancer spread.These findings raise the hypothesis that metastatic progression can emerge from multiple subclones with distinct CNA and SNV profiles. Single-cell genomic profiling of untreated tumors represents a promising approach to reconstruct clonal evolution and inform precision therapies targeting early metastatic lineages, though validation in larger patient cohorts will be required. Not applicable.

Abstract This prognostic study created optimized ensembles of calibrated random forest models to predict clinically significant prostate cancer (csPCa, grade group ≥2 PCa) using total prostate-specific antigen (PSA), free PSA, negative biopsy status, and age, with or without DRE and MRI data. Observational data were aggregated from cohorts in six organizations in Canada, the USA, and Czechia. Prostate biopsies were performed between 2009 and 2024. Risk models (ClarityDX Prostate + DRE, ClarityDX Prostate + MRI, and ClarityDX Prostate + MRI + DRE) were derived (training cohorts n = 1626 to 2191) and validated (validation cohorts n = 378 to 1318) from different clinical sites. The models had ROC AUC values ≥ 0.80. Adding DRE improved the ROC AUC to 0.82 while models using MRI features had ROC AUC values of 0.87 (without DRE) and 0.88 (with DRE) in the validation cohort. These four ClarityDX Prostate models offer high accuracy in predicting csPCa in individuals in variable clinical settings.

This study evaluated outcomes, prognostic factors, and treatment patterns in 135 cases of advanced neuroendocrine prostate cancer (NEPC). NEPC was associated with poor survival, especially in the metastatic setting, with anemia and elevated neutrophil-lymphocyte ratio associated with worse outcomes. This study highlighted underdiagnosis of NEPC and rapid progression with high drop-off rates between lines of treatment in advanced disease. Background: Neuroendocrine prostate cancer (NEPC) encompasses pure NEPC and tumors with mixed adenocarcinoma and neuroendocrine histology. While NEPC is thought to confer a poor prognosis, outcome data are sparse, making risk stratification and treatment decisions difficult for clinicians. Methods: This retrospective study identified patients with morphological and/or immunohistochemical NEPC features on pathological review of high-grade prostate cancer cases. Median overall survival (OS) was calculated by stage and castration sensitivity. Prognostic factors were assessed via multivariate analysis. OS and progression-free survival on first-line metastatic systemic treatment were also evaluated. Results: Of 135 NEPC cases, 25.9% had NEPC documented in the original pathological report. Mixed pathology was found in 91.9% of cases. Median OS from NEPC diagnosis was 59.2, 42.3, 14.3, 17.6 and 9.6 months for localized, nonmetastatic castration-sensitive, nonmetastatic castration-resistant, metastatic castration-sensitive and metastatic castration-resistant prostate cancer, respectively. Anemia (hazard ratio [HR]: 1.66; 95% CI1.05-2.16; P = . 031) and elevated neutrophil-lymphocyte ratio (NLR) (HR: 1.51; 95% CI1.01-2.52; P = . 045), were associated with increased risk of death on multivariate analysis. 67 patients received first-line metastatic treatment beyond androgen deprivation, with a median progression-free survival of 5.2 months and OS of 15 months. Of these, 50.7% received more than 1 line of systemic treatment. Conclusion: We observed underdiagnosis of NEPC in pathology specimens. NEPC is associated with poorer prognosis than would be expected in pure adenocarcinoma populations, with rapid progression on first-line metastatic treatment and sharp drop-off between subsequent treatment lines. Anemia and elevated NLR were associated with poor survival.

INTRODUCTION:In patients undergoing radical cystectomy, ileal conduit (IC) urinary diversions are more frequently carried out than orthotopic neo-bladder reconstructions (ONB). Patients selected for IC likely have more comorbidities, advanced disease, and older age, with many being poor candidates for ONB; ONB often ends up being selected by younger and healthier patients. Differences in complications experienced by IC and ONB patients may be due to differences between patients or urinary diversions. To guide patient counseling and care, we aimed to assess 90-day complications and mortality for patients undergoing either procedure in a large, contemporary, Canadian cohort. METHODS:Patient information was obtained from the Canadian Bladder Cancer Information System (CBCIS), encompassing 14 academic Canadian centers. Patients who underwent radical cystectomy between February 2015 and September 2023 were included. Ninety-day complications were analyzed according to the Clavien-Dindo severity scale. Perioperative parameters and 90-day mortality were compared between IC and ONB diversion. We used rank-sum and Chi-squared exact tests as exploratory statistic. Unconditional logistic regression was used to evaluate the association between IC and ONB complications. RESULTS:Of 2161 patients, 1799 (83%) received an IC and 362 (16%) an ONB. Patients were followed for a median of 235 days (interquartile range [IQR] 486). The median age was 69 years (IQR 14). The age-adjusted Charlson comorbidity index (aCCI) was significantly higher in the IC group (median [IQR] 5 [2] vs. 4 [2], p<0.001). The 90-day complication rate was 46% and the 90-day mortality rate was 4.3% for the entire cohort. On multivariable logistic regression, the risk of overall complications was significantly higher in the ONB than in the IC group (odds ratio 2.2, 95% confidence interval 1.7-2.8, p<0.001). Ninety-day mortality was 4.9% in the IC group and 0.82% in the ONB group. CONCLUSIONS:In this multi-institutional cohort, patients with ONB had higher odds of perioperative complications; however, there was no difference in higher-severity complications between diversions.

PURPOSE:Active surveillance (AS) is a standard management strategy for low-risk prostate cancer (PCa), but a significant proportion of patients ultimately experience disease progression. Metformin, a commonly prescribed antidiabetic agent, has demonstrated antitumor activity in preclinical studies and observational data, prompting investigation into its potential to delay PCa progression. PATIENTS AND METHODS:The Metformin Active Surveillance Trial (MAST) was a multicenter, randomized, double-blind, placebo-controlled phase III trial evaluating the efficacy of metformin in men with low-risk, localized PCa managed with AS. Eligible participants were randomly assigned 1:1 to receive either metformin (850 mg twice daily) or placebo and were followed for up to 36 months. The primary end point was time to progression, defined as therapeutic and/or pathologic progression. Progression-free survival (PFS) was assessed using Kaplan-Meier analysis and Cox proportional hazards models. RESULTS:A total of 408 patients were randomly assigned (205 metformin, 203 placebo). After a median follow-up of 36 months, 144 participants experienced progression (70 metformin, 74 placebo), with no significant difference in PFS (hazard ratio [HR], 1.09 [95% CI, 0.79 to 1.52]; P = .59). Negative biopsy rates at 36 months were 41.0% (metformin) versus 31.1% (placebo; P = .181). In prespecified subgroup analysis, metformin was associated with increased pathologic progression among obese patients (BMI ≥ 30; HR, 2.36 [95% CI, 1.21 to 4.59]; P = .0092). CONCLUSION:Metformin did not reduce progression in men with low-risk PCa on AS. The observed adverse effect in obese patients merits further investigation.

Objectives: Perioperative blood transfusion (PBT) has been associated with worse survival after radical cystectomy (RC) in patients with muscle-invasive bladder cancer (MIBC). Here, we evaluated the association between PBT and survival after RC that was preceded by neoadjuvant chemotherapy (NAC). Methods: A retrospective analysis was performed on 949 patients with cT2-4aN0M0 bladder cancer who received NAC prior to RC between 2000 and 2013 at 19 centers. Kaplan–Meier estimates of overall survival (OS) were made. Presumed risk factors for OS were analyzed using Cox regression analysis. PBT was defined by the administration of any packed red blood cells during surgery or during the post-operative hospital stay. Results: A transfusion was given to 608 patients (64%). Transfused patients were more likely to have adverse clinical and pathologic parameters, including clinical stage and performance status. Transfused patients had worse OS (p = 0.01). On multivariable Cox regression, PBT was found to be independently associated with worse OS (HR 1.53 (95% CI 1.13–2.08), p = 0.007). Conclusions: PBT is common after NAC and RC, which may be linked, in part, to the anemia induced by NAC. PBT was associated with several adverse risk factors that correlate with poor outcomes after NAC and RC, and it was an independent predictor of adverse OS on multivariable analysis. Further study should determine if measures to avoid blood loss can reduce the need for PBT and thereby improve patient outcomes.

You have accessJournal of UrologyBladder Cancer: Invasive VI (MP77)1 May 2024MP77-13 DOWNSTAGING OF PRIMARY VS. SECONDARY MUSCLE INVASIVE BLADDER CANCER AFTER CYSTECTOMY AND ITS ASSOCIATION WITH SURVIVAL Jessica E. Caterini, Wassim Kassouf, Rodney H. Breau, Adrian Fairey, Ramana-Kumar Agnihotram, Nimira Alimohamed, Jasmir G. Nayak, Jean-Baptiste Lattouf, Michele Lodde, Ricardo Rendon, Peter Black, Girish S. Kulkarni, Peter Chung, and D. Robert Siemens Jessica E. CateriniJessica E. Caterini , Wassim KassoufWassim Kassouf , Rodney H. BreauRodney H. Breau , Adrian FaireyAdrian Fairey , Ramana-Kumar AgnihotramRamana-Kumar Agnihotram , Nimira AlimohamedNimira Alimohamed , Jasmir G. NayakJasmir G. Nayak , Jean-Baptiste LattoufJean-Baptiste Lattouf , Michele LoddeMichele Lodde , Ricardo RendonRicardo Rendon , Peter BlackPeter Black , Girish S. KulkarniGirish S. Kulkarni , Peter ChungPeter Chung , and D. Robert SiemensD. Robert Siemens View All Author Informationhttps://doi.org/10.1097/01.JU.0001009404.49693.12.13AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Although previous studies have suggested that patients who progress to muscle-invasive bladder cancer (secondary MIBC) after previous treatment for non-invasive disease have worse outcomes than those that present de novo (primary MIBC), recent studies have been conflicting. Further, there is emerging evidence that secondary MIBC may be more resistant to peri-operative chemotherapy. This study aimed to assess differences in downstaging and association with survival outcomes in patients with primary MIBC compared to secondary MIBC in a retrospective cohort from tertiary care centres. METHODS: This retrospective multicentre study utilized the Canadian Bladder Cancer Information System (CBCIS) database, which includes patient, tumor, and treatment data from 14 centres in Canada. The main outcome from downstaging at cystectomy defined as

The current prostate cancer (PCa) screen test, prostate-specific antigen (PSA), has a high sensitivity for PCa but low specificity for high-risk, clinically significant PCa (csPCa), resulting in overdiagnosis and overtreatment of non-csPCa. Early identification of csPCa while avoiding unnecessary biopsies in men with non-csPCa is challenging. We built an optimized machine learning platform (ClarityDX) and showed its utility in generating models predicting csPCa. Integrating the ClarityDX platform with blood-based biomarkers for clinically significant PCa and clinical biomarker data from a 3448-patient cohort, we developed a test to stratify patients’ risk of csPCa; called ClarityDX Prostate. When predicting high risk cancer in the validation cohort, ClarityDX Prostate showed 95% sensitivity, 35% specificity, 54% positive predictive value, and 91% negative predictive value, at a ≥ 25% threshold. Using ClarityDX Prostate at this threshold could avoid up to 35% of unnecessary prostate biopsies. ClarityDX Prostate showed higher accuracy for predicting the risk of csPCa than PSA alone and the tested model-based risk calculators. Using this test as a reflex test in men with elevated PSA levels may help patients and their healthcare providers decide if a prostate biopsy is necessary.

e17105 Background: In patients suspected of prostate cancer, the decision to perform a biopsy hinges on available clinical data. Magnetic resonance imaging (MRI) and digital rectal exam (DRE) data are informative but may not be available. We created accurate models for clinically significant prostate cancer (csPCa), flexible to MRI and DRE data availability. Methods: Optimized ensembles of calibrated random forest models predicting csPCa (Grade Group ≥2) used total PSA, free PSA, prior negative biopsy status, and age, with or without DRE and MRI data (prostate volume and PI-RADS score). Risk models were derived (training cohorts n=1257 to 2191) and validated (validation cohorts n=317 to 1257) from different clinical sites. Models were evaluated by the area under the receiver operating characteristic curve (ROC AUC), sensitivity, specificity, positive predictive value, and negative predictive value, using thresholds providing ~ 95% sensitivity. Feature importance was determined by SHAP analysis. Results: All models had an AUC of at least 0.80, showing that predicting csPCa can be accurate without MRI or DRE data. Including MRI data significantly increased the AUC in the validation cohort (ClarityDX Prostate 0.80 vs ClarityDX Prostate +MRI 0.87). DRE had moderate value for models without MRI data (ClarityDX Prostate 0.80 vs ClarityDX Prostate +DRE 0.82) and minor value with MRI data (ClarityDX Prostate +MRI vs ClarityDX Prostate +DRE+MRI; AUC 0.87 vs 0.87; specificity 45% vs 47%, Table). Mean absolute SHAP values were highest for PI-RADS and prostate volume. Conclusions: These optimized risk models provide high accuracy for predicting csPCa in various clinical settings. Including MRI data greatly increases model accuracy, while DRE has a smaller effect on model accuracy. [Table: see text]

Purpose : To report the effects of a 12-week high-intensity interval training (HIIT) program on cardiometabolic biomarkers in prostate cancer (PCa) patients on active surveillance (AS) from the Exercise During Active Surveillance for Prostate Cancer (ERASE) Trial. Methods : Fifty-two men with PCa on AS were randomized to either an exercise (HIIT; n=26) or usual care (UC; n=26) group. The HIIT intervention consisted of progressive, supervised, aerobic HIIT at an intensity of 85 to 95% VO 2peak for 28 to 40 minutes per session performed three times/week for 12 weeks. Blood samples were collected at baseline and post-intervention to analyze cardiometabolic biomarkers. Analysis of covariance was used to examine between-group mean differences. Results : Blood data were obtained from 49/52 (94%) participants at postintervention. Participants were aged 63.4±7.1 years and 40% were obese. The HIIT group attended 96% of the planned exercise sessions. No significant between-group changes in weight were observed after the intervention. Compared to UC, HIIT significantly improved total cholesterol (-0.40 mmol/L; 95% confidence interval[CI], -0.70 to -0.10; p =0.011), non-high-density lipoprotein-c (-0.35 mmol/L; 95% CI, -0.60 to -0.11; p =0.006), insulin (-13.6 pmol/L; 95% CI, -25.3 to -1.8; p =0.025), insulin-like growth factor (IGF)-1 (-15.0 ng/mL; 95% CI, -29.9 to -0.1; p =0.048), and IGF binding protein (IGFBP)-3 (152.3 ng/mL; 95% CI, 12.6 to 292.1; p =0.033). No significant differences were observed for fasting glucose, HbA1c, other lipid markers, IGFBP-1, adiponectin, and leptin. Conclusions : The ERASE Trial showed that a 12-week aerobic HIIT program improved several cardiometabolic biomarkers in PCa patients on AS that may contribute to cardiovascular health benefits and potentially influence the signaling pathways in the progression of prostate cancer. Further research is needed to explore the effects of exercise on cardiometabolic markers in men with PCa on AS and determine if these effects are associated with improved long-term clinical outcomes.

LBA5002 Background: Active Surveillance (AS) involves vigilant monitoring of selected prostate cancer (PCa) patients, with radical treatment initiation upon significant disease progression. AS eligibility varies, generally including low-risk PCa men. Metformin, a widely-used oral hypoglycemic agent, is known for its excellent tolerability and efficacy in diabetes management. Extensive preclinical data suggested that metformin may slow PCa progression. The purpose of this study is to examine the effect of metformin on the rates of progression among men with low-risk localized PCa on AS. Methods: A randomized double blind placebo controlled trial was carried out in 14 centres across Canada.Eligible patients had biopsy-proven, low-risk, localized PCa diagnosed within the past 6 months, with a Gleason score of <6 observed in ≤1/3 of the total cores, less than 50% positivity in any one core, a PSA level of ≤10 ng/ml, and a clinical stage between T1c-T2a. Additionally, they chose active surveillance as their primary treatment. Subjects that met eligibility criteria were randomly assigned (1:1) to receive metformin 850 mg BID or placebo for 3 years. All patients underwent repeat prostate biopsy at 18 and 36 months. The primary endpoint indicated was time to progression, defined as the earliest occurrence of primary PCa therapy (e.g., prostatectomy, radiation, hormonal therapy) or pathological progression (>1/3 of total cores involved, at least 50% of any one core involved, or Gleason pattern 4 or higher). Results: In our cohort of 407 patients, 204 were administered metformin, and 203 received a placebo. The median age of the overall cohort was 63 years. Out of the total 407 patients, 141 experienced disease progression. There was no statistically significant difference in progression-free survival (PFS) observed between patients treated with metformin and those receiving placebo (p=0.63). Conclusions: Despite tantalizing preclinical and epidemiological data, metformin consumption does not alter rates of progression among men with low risk PCa on AS. Clinical trial information: NCT01864096 .

Importance:Among cancer surgeries, patients requiring open radical cystectomy have the highest risk of red blood cell (RBC) transfusion. Prophylactic tranexamic acid (TXA) reduces blood loss during cardiac and orthopedic surgery, and it is possible that similar effects of TXA would be observed during radical cystectomy. Objective:To determine whether TXA, administered before incision and for the duration of radical cystectomy, reduced the number of RBC transfusions received by patients up to 30 days after surgery. Design, Setting, and Participants:The Tranexamic Acid During Cystectomy Trial (TACT) was a double-blind, placebo-controlled, randomized clinical trial with enrollment between June 2013 and January 2021. This multicenter trial was conducted in 10 academic centers. A consecutive sample of patients was eligible if the patients had a planned open radical cystectomy for the treatment of bladder cancer. Intervention:Before incision, patients in the intervention arm received a loading dose of intravenous TXA, 10 mg/kg, followed by a maintenance infusion of 5 mg/kg per hour for the duration of the surgery. In the control arm, patients received indistinguishable matching placebo. Main Outcomes and Measures:The primary outcome was receipt of RBC transfusion up to 30 days after surgery. Results:A total of 386 patients were assessed for eligibility, and 33 did not meet eligibility. Of 353 randomized patients (median [IQR] age, 69 [62-75] years; 263 male [74.5%]), 344 were included in the intention-to-treat analysis. RBC transfusion up to 30 days occurred in 64 of 173 patients (37.0%) in the TXA group and 64 of 171 patients (37.4%) in the placebo group (relative risk, 0.99; 95% CI, 0.83-1.18). There were no differences in secondary outcomes among the TXA group vs placebo group including mean (SD) number of RBC units transfused (0.9 [1.5] U vs 1.1 [1.8] U; P = .43), estimated blood loss (927 [733] mL vs 963 [624] mL; P = .52), intraoperative transfusion (28.3% [49 of 173] vs 24.0% [41 of 171]; P = .08), or venous thromboembolic events (3.5% [6 of 173] vs 2.9% [5 of 171]; P = .57). Non-transfusion-related adverse events were similar between groups. Conclusions and Relevance:Results of this randomized clinical trial reveal that TXA did not reduce blood transfusion in patients undergoing open radical cystectomy for bladder cancer. Based on this trial, routine use of TXA during open radical cystectomy is not recommended. Trial Registration:ClinicalTrials.gov Identifier: NCT01869413.

You have accessJournal of UrologyBladder Cancer: Non-invasive II (PD30)1 May 2024PD30-05 DEVELOPMENT AND EXTERNAL VALIDATION OF AN ARTIFICIAL INTELLIGENCE-BASED TOOL FOR PROGRESSION RISK ASSESSMENT IN NON-MUSCLE INVASIVE BLADDER CANCER (PROGRXN-BCA) Jethro C. C. Kwong, Zizo Al-Daqqaq, Yashan Chelliahpillai, Soomin Lee, Kellie Kim, Maximiliano Ringa, Amna Ali, Andrew Feifer, Marian S. Wettstein, Wassim Kassouf, Peter C. Black, Rodney H. Breau, Michele Lodde, Adrian Fairey, Jean-Baptiste Lattouf, Claudio Jeldres, Ricardo Rendon, Nimira Alimohamed, Peter Chung, Neil E. Fleshner, Antonio Finelli, Alexandre R. Zlotta, Alistair E. W. Johnson, and Girish S. Kulkarni Jethro C. C. KwongJethro C. C. Kwong , Zizo Al-DaqqaqZizo Al-Daqqaq , Yashan ChelliahpillaiYashan Chelliahpillai , Soomin LeeSoomin Lee , Kellie KimKellie Kim , Maximiliano RingaMaximiliano Ringa , Amna AliAmna Ali , Andrew FeiferAndrew Feifer , Marian S. WettsteinMarian S. Wettstein , Wassim KassoufWassim Kassouf , Peter C. BlackPeter C. Black , Rodney H. BreauRodney H. Breau , Michele LoddeMichele Lodde , Adrian FaireyAdrian Fairey , Jean-Baptiste LattoufJean-Baptiste Lattouf , Claudio JeldresClaudio Jeldres , Ricardo RendonRicardo Rendon , Nimira AlimohamedNimira Alimohamed , Peter ChungPeter Chung , Neil E. FleshnerNeil E. Fleshner , Antonio FinelliAntonio Finelli , Alexandre R. ZlottaAlexandre R. Zlotta , Alistair E. W. JohnsonAlistair E. W. Johnson , and Girish S. KulkarniGirish S. Kulkarni View All Author Informationhttps://doi.org/10.1097/01.JU.0001008848.77629.6f.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Current tools to predict progression risk in non-muscle invasive bladder cancer (NMIBC) perform poorly and do not completely reflect current practice. We aimed to develop and validate PROGRxN-BCa (PROGression Risk assessment in NMIBC) – an artificial intelligence tool to better predict progression. METHODS: PROGRxN-BCa, based on a gradient-boosted survival forest, was trained on NMIBC patients treated between 2005-2015 at one of three academic or community hospital networks: University Health Network, Sinai Health System, and Trillium Health Partners (n=2002). Internal validation was performed on patients treated between 2016-2022 at the same institutions (n=1321). External validation was performed on patients treated between 2012-2023 across 13 academic institutions affiliated with the Canadian Bladder Cancer Information System (n=3708). Primary outcome was time to progression, defined as development of muscle-invasive or metastatic disease. PROGRxN-BCa was compared to the European Association of Urology (EAU) risk calculator, the most widely used clinical prediction model for progression. RESULTS: During a median follow-up of 36 months (IQR 17-65), 1,006 out of 7,031 (14%) patients developed progression. PROGRxN-BCa achieved a c-index of 0.75-0.81, compared to 0.69-0.76 for the EAU risk calculator (p<0.001 for all cohorts). This performance benefit was consistent across clinically relevant subgroups, including age, sex, and tumor history. PROGRxN-BCa was well-calibrated for risks between 0-40%. At 5 and 10 years, PROGRxN-BCa demonstrated a higher net benefit (i.e. avoid unnecessary treatment escalation) compared to the EAU risk calculator for clinically relevant decision thresholds between 15-35%. When applied to intermediate risk patients (n=1555), PROGRxN-BCa identified 19% of patients with an observed average 5-year progression risk of 32% - revealing a subset of patients who may benefit from treatment intensification. Similarly, the model identified 32% of patients with an observed average 5-year progression risk of 2.5%. This approach outperformed sub-stratification based on intermediate risk factors. CONCLUSIONS: PROGRxN-BCa outperformed current tools in NMIBC prognostication in both academic and community settings, particularly in its ability to further sub-stratify intermediate risk patients. PROGRxN-BCa has the potential to further improve NMIBC risk stratification, inform clinical decision-making, and determine eligibility for clinical trials. Source of Funding: This project was supported by the MSH UHN AMO Innovation Fund, PSI Foundation Resident Research Grant, Data Sciences Institute Data Access Grant, CUASF-Bladder Cancer Canada Research Grant, and the University of Toronto Surgeon Scientist Training Program © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e626 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Jethro C. C. Kwong More articles by this author Zizo Al-Daqqaq More articles by this author Yashan Chelliahpillai More articles by this author Soomin Lee More articles by this author Kellie Kim More articles by this author Maximiliano Ringa More articles by this author Amna Ali More articles by this author Andrew Feifer More articles by this author Marian S. Wettstein More articles by this author Wassim Kassouf More articles by this author Peter C. Black More articles by this author Rodney H. Breau More articles by this author Michele Lodde More articles by this author Adrian Fairey More articles by this author Jean-Baptiste Lattouf More articles by this author Claudio Jeldres More articles by this author Ricardo Rendon More articles by this author Nimira Alimohamed More articles by this author Peter Chung More articles by this author Neil E. Fleshner More articles by this author Antonio Finelli More articles by this author Alexandre R. Zlotta More articles by this author Alistair E. W. 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