Standard management for recurrent low-grade non-muscle-invasive bladder cancer (LG-NMIBC) often involves a substantial treatment burden, which is not justified by the relatively indolent course of the disease, prompting a need for de-intensification strategies. Active surveillance (AS) is an alternative approach aimed at reducing overtreatment in selected patients. However, the broader adoption of AS is hindered by a lack of standardized protocols for patient selection, monitoring and intervention. To address this gap, we conducted an international, two-round Delphi consensus among 51 bladder cancer experts to establish foundational statements for the use of AS. Consensus was achieved on 20 statements, providing clear recommendations for terminology; inclusion and exclusion criteria; follow-up monitoring; and exit criteria. This Delphi consensus provides the first expert-driven framework to standardize the clinical application of AS for LG-NMIBC. These statements could guide current clinical practice and unify the design of future trials.

BACKGROUND:Although intermediate clinical endpoints (ICEs) may expedite completion of randomized controlled trials (RCTs) evaluating perioperative systemic treatments for localized muscle-invasive bladder cancer (MIBC), no validated surrogate for overall survival (OS) has been established. We aimed to assess the surrogacy of pathologic complete response (pCR), pathologic objective response (pOR), and disease-free survival (DFS) for OS. PATIENTS AND METHODS:We analyzed 4,828 patients with MIBC (cT2-T4N0M0) who underwent radical cystectomy (RC) with or without neoadjuvant chemotherapy (NAC) across 29 European centers (2001-2024). The inverse probability of treatment weighting (IPTW) approach was used to adjust for confounding between NAC and RC-only groups. Surrogacy was evaluated using: (1) adapted Prentice criteria to test whether each ICE remained a significant predictor of OS while the treatment effect disappeared in IPTW-adjusted multivariable Cox models; (2) the proportion of treatment effect explained (PTE); and (3) an emulated 2-stage meta-analytic framework to estimate the pseudo-trial-level R2 between treatment effects on each ICE and OS across 1,000 replicates of 5 random clusters. The surrogate threshold effect (STE) was calculated for ICEs demonstrating strong surrogacy (R2≥0.7). RESULTS:Overall, 1,288 (26.7%) patients received NAC followed by RC and 3,540 (73.3%) underwent RC alone. In IPTW-adjusted Cox regression analyses including NAC and each ICE separately, pCR (hazard ratio [HR], 0.32; 95% CI, 0.24-0.41; P<.001), pOR (HR, 0.26; 95% CI, 0.21-0.31; P<.001), and DFS (HR, 5.17; 95% CI, 4.56-5.86; P<.001) were independent predictors of OS. The PTE was 0.42 (95% CI, 0.22-0.54), 0.48 (95% CI, 0.24-0.58), and 0.84 (95% CI, 0.66-0.96) for pCR, pOR, and DFS, respectively. At the pseudo-trial level, the R2 was 0.22 (95% CI, 0.20-0.25), 0.33 (95% CI, 0.31-0.36), and 0.83 (95% CI, 0.81-0.84) for the correlation between treatment effects on pCR, pOR, and DFS and OS, respectively. The STE was 0.82 (95% CI, 0.81-0.84) for DFS. CONCLUSIONS:We observed uncertainty regarding the surrogacy of pCR and pOR in patients undergoing RC with or without NAC for localized MIBC. Only DFS consistently mediated the treatment effect on OS, supporting its use as a surrogate for RCT dimensioning when a recurrence or death risk reduction of ≥18% is expected.

323 Background: A positive family history is a well-established risk factor for prostate cancer (PCa), making the identification of individuals with inherited susceptibility particularly relevant. The detection of germline pathogenic variants (PVs) in DNA-repair genes (DRGs) further supports the implementation of targeted screening strategies. The present study aimed to investigate the performance and adherence of a personalized screening protocol designed for this high-risk population, integrating both the Prostate Health Index (PHI) and multiparametric magnetic resonance imaging (mpMRI). Methods: This ongoing prospective study, supported by AIRC-(ID-IG-25027-V1.3), is based on the concept of a dedicated PCa screening protocol. It was conducted at a tertiary referral center in collaboration with multiple departments. The study enrolled men aged 35–69 years carrying documented PVs in DRGs who provided informed consent to participate in the screening program. Probands were classified into two groups: (1) male relatives of women harboring DRG PVs associated with breast or ovarian cancer, and (2) male relatives of men with DRG PVs diagnosed with high-grade PCa (ISUP grade group >2). Participants underwent annual assessments including PSA testing, PHI measurement, DRE, and mpMRI, according to individual risk stratification (PHI <20, 20–40, >40). Results: Between 2021 and 2025, a total of 129 patients were enrolled, with a median age of 52 years (IQR 47–64). Among them, 118 belonged to the group 1 and 11 to the group 2. The most prevalent PVs was BRCA2 (56.0%), followed by BRCA1 (21.6%), ATM (3.4%), PMS2 (2.6%), MSH2 (2.6%), MLH1 (2.6%), PALB2 (2.6%), and MSH6 (1.7%). Screening compliance was high: 95% of participants completed the T1 visit, 86% completed T2, 90% completed T3, and 100% completed T4. Among patients with PHI values between 20 and 40, 85% underwent mpMRI. Three of these showed a positive mpMRI and proceeded to biopsy, which was negative two cases and positive in one. An additional 3 patients underwent biopsy due to clinical suspicion, all yielding negative results. Among those with PHI >40, 75.5% underwent mpMRI followed by biopsy according to protocol, all of which were negative for prostate cancer. At the fourth year of follow-up, the screening program detected its first case of PCa: a BRCA2 carrier with a PVs, whose biopsy confirmed ISUP 4 PCa. The patient has been scheduled for surgery. Conclusions: The screening program detected the first case of PCa in a 57-year-old man. Despite this finding, the overall incidence of PCa in our cohort remains notably lower than reported in international studies, including the IMPACT trial. This unexpected result may suggest the presence of a population-specific protective factor, a phenomenon we refer to as the “Italian paradox.” Nevertheless, given the limited sample size and short follow-up, this observation should be interpreted cautiously.

Xpert Bladder Cancer (BC) is an mRNA-based urine assay for diagnosis and surveillance of urothelial carcinoma. Although previous meta-analyses have examined Xpert, none has evaluated its accuracy in both BC detection and non-muscle-invasive bladder cancer (NMIBC) surveillance, while also exploring its potential role in guiding repeat transurethral resection (re-TURBT) and in the diagnostic evaluation of upper tract urothelial carcinoma (UTUC). We systematically assessed the diagnostic accuracy of Xpert in all these clinical settings, integrating grade-specific analysis and formal evidence-certainty assessment. PubMed/MEDLINE, Embase, Scopus, Web of Science, and the Cochrane Library were searched to January 2026 (PROSPERO: CRD420251184275). Sensitivity and specificity were pooled using bivariate random-effects models; PPV and NPV using univariate models. Grade-specific sensitivity was pooled across 13 studies with tumour-grade-stratified data. Evidence certainty was assessed using GRADE-DTA. Publication bias was evaluated with Deeks' funnel plots. Twenty-six studies (8613 patients) were included. For Detection (k = 8, where k denotes the number of cohorts pooled), pooled sensitivity was 0.83 (95% CI 0.73-0.90) and specificity 0.77 (0.65-0.86); NPV was 0.96. For Monitor (k = 15), sensitivity was 0.71 (0.63-0.77) and specificity 0.78 (0.70-0.85); NPV was 0.91. Grade-specific pooling showed high-grade (HG) sensitivity of 0.89 (0.83-0.93) in Detection and 0.80 (0.71-0.87) in Monitor, versus 0.60 for low-grade (LG) in both settings; heterogeneity was not statistically significant for HG estimates. Re-TURBT (k = 2) and UTUC (k = 2) were exploratory, with encouraging NPV but limited by sparse events. Evidence certainty was low for sensitivity/NPV and very low for specificity/PPV. No publication bias was detected. Xpert demonstrates high sensitivity and NPV, particularly for HG disease, supporting its role as an adjunctive rule-out tool. Grade-adapted interpretation is warranted. Prospective validation with standardised grade-specific reporting is needed.

OBJECTIVES:To systematically identify, appraise and synthesise artificial intelligence (AI) and machine-learning (ML) models that predict treatment response and clinical outcomes after intravesical bacillus Calmette-Guérin (BCG) in non-muscle-invasive bladder cancer (NMIBC), a setting in which current risk calculators underperform, and identifying non-responders has become urgent as alternatives to BCG enter practice. METHODS:PubMed, EMBASE and Web of Science were searched through April 2026 following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines (International Prospective Register of Systematic Reviews [PROSPERO] number CRD420261376808). Studies developing or validating AI/ML models for BCG-associated outcomes with a quantitative performance metric were included. Risk of bias was assessed with the Prediction model Risk Of Bias ASsessment Tool (PROBAST). Evidence was synthesised along a clinically oriented framework: AI as a perceptual tool (extracting signal from histology or imaging) or integrative tool (re-weighting clinicopathological, molecular, or urinary variables). RESULTS:A total of 15 studies (>24 900 patients) were included: seven perceptual, eight integrative. By input data, six used digital pathology, two radiomics, two genomics/transcriptomics, four clinicopathological markers, and one urinary biomarkers. The digital-pathology Computational Histology Artificial Intelligence (CHAI) platform, validated across 12 international centres, stratified high-grade recurrence (hazard ratio [HR] 2.08), progression (HR 3.87) and BCG-unresponsive disease (HR 2.31), and was the only model providing a first signal of predictive value, demonstrating a significant BCG vs gemcitabine/docetaxel interaction (P = 0.029). Integrative models PROGRxN-BCa (concordance index [C-index] 0.79) and DeepSurv (C-index 0.881) outperformed standard calculators but with modest gains (ΔC-index 0.05-0.10). Only 40% of studies performed external validation, none prospectively; five were at high risk of bias. CONCLUSION:Perceptual AI, particularly digital pathology, has the highest external validation and provides the only biomarker with a first signal of predictive value for BCG vs alternatives, increasingly relevant in the context of the global BCG shortage. Integrative models such as PROGRxN-BCa and DeepSurv outperform standard calculators with incremental gains and are freely accessible. Prospective validation, systematic calibration reporting and treatment-by-biomarker interaction analyses, ideally embedded in trials such as the BRIDGE trial (ClinicalTrials.gov identifier: NCT05538663), remain priorities before clinical adoption.

BACKGROUND AND OBJECTIVE:Patients undergoing radical cystectomy (RC) for bladder cancer may present with synchronous or metachronous upper tract urothelial carcinoma (UTUC). These scenarios may differ in oncological outcomes and surgical complexity. This study sought to compare oncologic and perioperative outcomes in patients undergoing RC and radical nephroureterectomy (RNU) for synchronous or metachronous UTUC. METHODS:Data from 23 tertiary referral centers were retrospectively collected (2002-2024). Perioperative outcomes included length of stay (LOS) and complications (Clavien-Dindo classification). Disease-free survival (DFS), cancer-specific survival (CSS) and overall survival (OS) were estimated from RC using Kaplan-Meier and landmark analysis. Multivariable Cox regression modeling identified predictors of DFS and OS and explored the impact of RNU timing on oncological outcomes. KEY FINDINGS AND LIMITATIONS:Among 177 RC patients (n = 142 [80%] males), 106 (60%) underwent RNU subsequent to RC for metachronous UTUC. Concomitant RC and RNU led to longer LOS (10 vs. 7 days, P = 0.004), and statistically significant higher rate of major complications (Clavien-Dindo ≥ IIIa, 29.6% vs. 15.1%, P = 0.03). Metachronous disease showed better 60-month DFS (69.1% vs. 47.6%), CSS (80.3% vs. 66.4%) and OS (69.2% vs. 47.6%). Histological subtype at RNU independently predicted worse DFS (HR 2.64, P = 0.01) and OS (HR 3.22, P = 0.01), while metachronous presentation predicted better DFS (HR 0.36, P < 0.001) and OS (HR 0.53, P = 0.04). Limitations include the retrospective design and a relatively limited sample size. CONCLUSIONS AND CLINICAL IMPLICATIONS:Synchronous panurothelial disease at diagnosis requiring RC and RNU is related to worse perioperative and survival outcomes compared to metachronous disease. Our results highlight the need for dedicated studies to define individualized treatment and surveillance strategies for this challenging patient population.

321 Background: Family history represents a significant risk factor for prostate cancer (PCa), emphasizing its genetic basis. Early identification of germline pathogenic variants (PVs) in DNA repair genes (DRGs) is crucial for timely PCa diagnosis, prognosis, and for informing at-risk relatives. Conversely, the presence of variants of uncertain significance (VUS) has been associated with worse clinical outcomes. This study aimed to assess how the presence of germline PVs and VUS affect clinical and pathological outcomes in a monocentric cohort of patients who underwent robot-assisted laparoscopic prostatectomy (RALP) for PCa. Methods: This prospective study, supported by AIRC - Fondazione AIRC per la Ricerca sul Cancro (registered and emended with the number ID-IG-25027-V1.3), was conducted at a tertiary referral center in collaboration with the Departments of Oncology, Urology, Pathology, Radiology, and Medical Genetics. A total of 179 men aged 58–70 years who underwent RALP for localized PCa were screened for germline PVs and VUS in DRGs prior to surgery. Patients were enrolled if they had an ISUP grade ≥3 at biopsy and/or a confirmed PCa diagnosis at ≤50 years of age. Individuals harboring a VUS or PVs were compared to those with negative genetic results. Results: Of the 179 patients screened between 2021 and 2024, 163 shared the results of genetic testing. Median age at surgery did not differ between groups (65 years, IQR 59–70). Among them, 114 (69.9%) tested negative, while 39 (29.4%) and 9 (5%) carried a VUS or PVs in DRGs, respectively. The most frequent VUS involved ATM (22.2%), CHEK2 (15.6%), BRCA2 (13.3%), ATR (6.7%), NBN (6.7%), RAD51D (6.7%), and MSH6 (4.4%). The nine PVs identified were: BRCA2, PALB2 + NBN, PALB2 + BRCA2, BRCA1 PALB2, CHEK2 + PMS2, CHEK2, and ATM . A family history of cancer was reported in 50% of VUS/PV carriers compared to 34.6% of non-carriers. High-grade PCa (ISUP >3) was found in 46.3% of carriers versus 38.0% of non-carriers. A pathological stage ≥pT3a occurred in 53.6% of carriers versus 45.1% of non-carriers, while nodal involvement (pN1) was more frequent among carriers (21.4% vs 12.6%). Biochemical recurrence (BCR) occurred in 36.8% of carriers versus 30.4% of non-carriers. Conclusions: This study provides valuable insight into the role of germline VUS, by the first, and PVs in DRGs among PCa patients, suggesting that such variants may confer a less favorable disease course. Although differences did not reach statistical significance, carriers tended to present with higher-grade and more advanced disease at final pathology. Genetic screening for PCa may therefore aid not only in early detection among high-risk individuals but also in guiding clinical management and follow-up strategies.

Background:Lower urinary tract symptoms (LUTS) and pain are clinically relevant problems after transurethral resection (TURBT) of nonmuscle-invasive bladder cancer. Although intravesical instillation of hyaluronic acid has already been proven to be a valid treatment for storage LUTS and pain in patients with inflammatory bladder syndrome, its efficacy in patients who undergo TURBT is unknown. This study aimed to present the results of a prospective, randomized, controlled, clinical pilot study on the safety and clinical performance of HydealCyst (Fidia Farmaceutici S.p.A., Italy), a device formulated to provide progressive, long-lasting intravesical release of hyaluronic acid. Materials and methods:Adults diagnosed with nonmuscle-invasive bladder cancer and scheduled for TURBT were included and underwent 4 visits up to 25 days after TURBT. Of the 47 patients who completed the investigation, 25 participants received 2 postoperative intravesical instillations with HydealCyst. The efficacy of HydealCyst on storage LUTS, pain, urinary symptoms, and patients' quality of life was evaluated using validated questionnaires. Results:Although the overall LUTS were similar in the 2 experimental groups, lower micturition frequency and fewer daytime micturitions were observed in patients treated with HydealCyst. These patients also showed a significant reduction in pain (p = 0.03) 3 days after catheter removal and better quality of life at the end of the study. The device was well tolerated, with no treatment-emergent adverse events of severe intensity. Conclusion:The results from this pilot study indicate a clinically meaningful improvement of symptoms after 2 instillations of HydealCyst, supporting this intervention as a potentially effective treatment for LUTS and pain after TURBT.

This prospective imaging trial was designed to compare [68Ga]PSMA-11 PET/CT with multiparametric MRI (mpMRI) in parallel in men with suspicion of prostate cancer (PCa) after at least one previous negative biopsy (ClinicalTrials.gov: NCT05297162; GR-2018-12366240). Between April 2022 and June 2025, we enrolled 130 patients who met the inclusion criteria and completed protocol investigations. Target lesions were defined based on PI-RADS v2.1 for mpMRI and PRIMARY Score, SUVmax and SUVratio for [68Ga]PSMA-11 PET/CT. Findings were statistically correlated with pathology results. Subsequently, we developed a nomogram to predict clinically significant PCa (csPCa), defined as International Society of Urological Pathology [ISUP] grade ≥ 2, using Boruta’s algorithm for variable selection. Median age in our cohort was 65.5 years (range, 50.5–82.2) and median PSA 9.7 ng/ml (range, 4–35). According to pathology, 20 patients (15.4