OBJECTIVES:To determine the diagnostic performance of ex vivo fluorescence confocal microscopy (FCM) for prostate cancer detection in magnetic resonance imaging (MRI)-targeted biopsy specimens using final histopathology as the reference standard, and to quantify workflow component times relevant to same-day implementation. PATIENTS AND METHODS:In this single-centre prospective observational study, men undergoing MRI-targeted transperineal prostate biopsy were enrolled. Targeted biopsy cores were imaged ex vivo using a Histolog® FCM scanner (SamanTree Medical SA, Lausanne, Switzerland) after rapid acridine orange immersion and prior to routine histopathological processing. Two board-certified genitourinary pathologists independently reviewed FCM images in a blinded fashion and classified each specimen as positive or negative for prostate cancer and clinically significant cancer (CSC), defined as International Society of Urological Pathology Grade Group (GG) ≥2. Diagnostic performance was calculated against final histopathology. Workflow feasibility was assessed by measuring specimen preparation, scanning, and interpretation times. Interobserver agreement and exploratory discordance analyses were performed. RESULTS:A total of 50 MRI-targeted biopsy specimens from 44 patients were analysed, of which 33 (66%) contained prostate cancer and 17 (52%) met criteria for CSC. For cancer detection, Reader 1 achieved 87.9% sensitivity and 94.1% specificity, and Reader 2 achieved 97.0% sensitivity and 76.5% specificity, with overall accuracy of 90% for both readers. Interobserver agreement for cancer detection was 88% (κ = 0.74), and for CSC was 86% (κ = 0.61). Mean specimen preparation and interpretation times were ~2 min each, with standardised scanning time of 50 s, enabling complete FCM assessment in <5 min per target. Discordance was concentrated in GG 2 disease and Prostate Imaging-Reporting and Data System (PI-RADS) 3 targets, while higher-grade cancers and PI-RADS 5 lesions were uniformly concordant. CONCLUSION:Ex vivo FCM provides rapid, accurate, and reproducible assessment of MRI-targeted prostate biopsy specimens for cancer detection within clinically feasible timeframes. These findings support FCM as a same-day diagnostic adjunct and justify prospective trials evaluating real-time implementation during targeted biopsy.

OBJECTIVES:Positive surgical margins (PSMs) after robot-assisted radical prostatectomy (RARP) increase the risk of prostate cancer recurrence, often requiring salvage treatments that may compromise functional recovery. Intraoperative frozen section can detect PSM but is not feasible as a routine approach in most settings. Ex vivo fluorescence confocal microscopy (FCM) provides a rapid, real-time alternative, though evidence remains limited and knowledge gaps persist. This international Delphi consensus aimed to define expert recommendations on the clinical application of and workflow and research priorities for the safe integration of FCM during RARP. MATERIAL AND METHODS:A modified Delphi process was conducted following the RAND/UCLA Appropriateness Method and reported according to the ACCORD checklist. In total, 32 international experts in urology and pathology participated in a hybrid consensus meeting after structured literature review and preparatory online sessions. Forty-four evidence-based multiple-choice items across patient selection, image acquisition, and surgical management domains were developed and anonymously voted on via a secure online platform. Consensus was predefined as ≥80% agreement among respondents. RESULTS:Consensus was achieved for 24 of 44 items (55%). Key agreements included a risk-adapted use of FCM (97%), its role as an adjunct to magnetic resonance imaging for nerve-sparing decisions (87%), adoption of en-face imaging as the preferred FCM technique (82%), and a maximum reporting time of 30 min (85%). The panel endorsed formal certification for image interpretation (83%), standardized reporting of positive margin length (82%), and feasibility of remote intra-institutional reporting (84%). Larger (>3 mm) PSM in high-risk cases warranted complete neurovascular bundle resection (96%). CONCLUSIONS:This consensus provides a structured framework for the intraoperative use of FCM during RARP, defining its indications, workflow standards, and training requirements. Future multicentre studies are needed to assess its oncological and functional impact and to establish standardized implementation pathways.

BACKGROUND:This study aimed to evaluate whether pre-surgical tumor-informed circulating tumor DNA (ctDNA) predicts pathologic nodal status at radical cystectomy and its potential role in risk stratification for future biomarker-guided surgical strategies. METHODS:The study prospectively analyzed 40 patients with non-muscle-invasive and muscle-invasive bladder cancer who underwent radical cystectomy with pelvic lymph node dissection (LND) and pre-surgical tumor-informed ctDNA testing. Compared with pathologic nodal findings, ctDNA status was classified as positive or negative. Diagnostic performance metrics with 95 % confidence intervals (CIs) were calculated. To assess reproducibility, data from a published cohort meeting comparable inclusion criteria were integrated for pooled descriptive analysis. RESULTS:Of 40 patients, 27 (68 %) were ctDNA-negative and 13 (32 %) were ctDNA-positive before cystectomy. Pathologic nodal metastases were identified in seven patients (18 %). For nodal metastases, ctDNA demonstrated a sensitivity of 86 % (95 % CI, 49-97 %), a specificity of 79 % (95 % CI, 62-89 %), and negative predictive value of 96 % (95 % CI, 82-99 %). In pooled descriptive analysis including 149 patients, the negative predictive value remained high at 92 % (95 % CI, 84-97 %). A simulated ctDNA-guided omission strategy may have avoided LND for 27 patients (68 %), with one false-negative case (3.7 %) that subsequently had recurrence. CONCLUSION:Pre-surgical tumor-informed ctDNA showed high negative predictive value for nodal metastases at radical cystectomy. These findings supported prospective validation of ctDNA as a biomarker to identify patients at low risk of nodal metastases and inform future trials of biomarker-guided surgical strategies.

Objectives To evaluate whether a simplified risk model preserves the prognostic performance of the International Bladder Cancer Group (IBCG) five-factor risk stratification model in intermediate-risk (IR) non-muscle-invasive bladder cancer (NMIBC).Patients and Methods We performed a multicentre retrospective analysis of 2822 patients with IR NMIBC treated with transurethral resection of bladder tumour and intravesical therapy between 2005 and 2025. Multivariable Cox regression identified independent predictors of recurrence and progression. A simplified risk model was constructed using significant variables and compared with the full IBCG model using recurrence and progression rates, area under the curve analysis, and likelihood ratio testing.Results A total of 2822 patients with IR NMIBC were included. When classified using the full IBCG model, 1143 (41%) were in the IR-low, 1535 (54%) IR-intermediate, and 144 (5%) IR-high-risk groups. On multivariable analysis, only multifocality, early recurrence, and failure of intravesical therapy independently predicted oncological outcomes. Using these factors, patients were stratified as IR-low (no factors), IR-intermediate (one factor), or IR-high (two or more factors). Under the simplified model, 1535 (54%) patients were classified as IR-low, 906 (32%) as IR-intermediate, and 381 (14%) as IR-high. The 3-year recurrence and progression rates increased stepwise across simplified risk groups. Discriminative performance of the simplified model was comparable to the full model across all metrics, with no meaningful loss of discrimination.Conclusion Three variables captured the most prognostic signal in this cohort without loss of discrimination compared with the full model. This simplified model is an internally validated refinement, with planned external validation to confirm generalisability and to ensure that simplified thresholds do not alter the clinically important IR-high subgroup used in care and trials.

INTRODUCTION:Bilateral renal masses (BRMs) are classically linked to inherited familial syndromes, often associated with distinct histologies. Current guidelines recommend genetic counseling for all patients with BRMs; however, the utility of genetic testing in patients with BRMs with apparently sporadic etiology remains unclear. Our objective was to characterize histologic pairings between the index/contralateral renal masses and evaluate the value of genetic testing across histologic subgroups. METHODS:We reviewed 527 patients surgically treated for BRMs (2002-2024), and 414 had no evidence of familial etiology. Histologic concordance between the index (first operated) and contralateral renal masses were assessed. Adherence with genetic testing and outcomes were compared across histologic groupings. RESULTS:Histologic concordance between the index/contralateral masses was observed in most patients: 78% for clear cell, 70% for papillary, and 74% for oncocytic neoplasms. Overall, only 88 patients (21%) were referred for genetic counseling and germline genetic testing was performed in 53 (13%). Pathogenic variants were only observed in 4 patients, including 1 hereditary papillary renal carcinoma, 2 Birt-Hogg-Dubé, and 1 tuberous sclerosis. No pathogenic variants were observed in the bilateral clear cell group. CONCLUSIONS:Among patients with BRMs with apparently sporadic etiology, strong concordance between bilateral histologies was observed. Although guidelines recommend genetic counseling for all patients with BRMs, our findings suggest that testing was underutilized and diagnostic yield was low, particularly for high-risk mutations (eg, von Hippel-Lindau or fumarate hydratase-deficient renal cell carcinoma). These findings suggest that genetic testing for patients with BRMs could be considered selectively, prioritizing patients with extrarenal manifestations, family history, young age, or pathology suspicious for hereditary etiology.

INTRODUCTION:Current risk stratification after radical prostatectomy (RP) relies on Grade Group (GG) and genomics, which may not fully capture metastatic potential. Unfavorable histology (UH), defined by adverse architectural patterns such as large cribriform carcinoma and intraductal carcinoma, has emerged as a strong predictor. We evaluated whether integrating genomic and other clinicopathologic variables improves prediction beyond quantitative UH burden. METHODS:We analyzed 418 men from an event-enriched RP cohort (1987-2004) with centralized pathology review, Genomic Prostate Score (GPS), and long-term follow-up. We recorded the percentage of tumor with UH (UH%), cribriform size, GG, stage, margin status, prostate-specific antigen, and GPS. Multivariable Cox models and a sequential modeling framework evaluated independent associations and incremental predictive performance for metastasis at 15 years. RESULTS:During median 15.5-year follow-up, 102 men (24%) developed metastases, all within UH-positive tumors. UH ≥10% was strongly associated with metastasis (hazard ratios [HR] 50.95, 95% confidence intervals [CI] 10.4-249). GPS (HR 1.03 per unit, 95% CI 1.01-1.05) and cribriform size (HR 1.0007 per μm, 95% CI 1.0003-1.0010) were independently associated but added only modest discrimination. UH% alone achieved high 15-year discrimination (c-index ∼0.85); inclusion of GPS and cribriform size increased this to 0.901. Limitations include retrospective design and single-institution pathology review. CONCLUSION:UH% is the dominant determinant of metastatic risk after RP, offering greater prognostic discrimination than GG, stage, and other clinicopathologic variables. Genomic classifiers and cribriform size provide secondary refinement but do not materially alter risk once UH burden is established. These findings support pathology-anchored risk models.

Background and objective:Upper tract urothelial carcinoma (UTUC) shows lower urinary tract recurrence after nephroureterectomy, with rates of 22-47%. We aimed to evaluate recurrence patterns and survival outcomes in UTUC patients with divergent differentiation and histologic subtypes (DDHSs) compared with pure urothelial carcinoma (UC), with a focus on differentiating urothelial versus extraurothelial recurrences. Methods:A retrospective review was conducted of 398 patients who underwent nephroureterectomy for UTUC at a single center (2014-2024). Clinical, pathologic, and treatment data were collected. Patients were stratified by histology (pure UC vs DDHSs). The primary outcomes include urothelial (U-RFS) and extraurothelial (EU-RFS) recurrence-free survival. Multivariable Cox proportional hazards regression was used to evaluate the predictors of recurrence-free survival. A Kaplan-Meier analysis was used to estimate recurrence-free and overall survival. Key findings and limitations:Among 398 patients, 14% had DDHSs. Patients with DDHSs received adjuvant therapy more frequently (33% vs 13%) and presented with more advanced pathologic stage and nodal involvement at nephroureterectomy than those with pure UC. Overall recurrence rates were similar between groups. The Kaplan-Meier analysis demonstrated significantly worse EU-RFS in patients with DDHSs (p < 0.001), while U-RFS did not differ. On a multivariable Cox analysis, DDHSs (hazard ratio [HR] 3.18, p = 0.01) and advanced pathologic T stage (HR 4.64, p = 0.047) were independently associated with extraurothelial recurrence. Overall survival was similar between groups. Conclusions and clinical implications:Patients with DDHS UTUC exhibit higher rates of extraurothelial recurrence despite similar rates of urothelial recurrence. These findings underscore the need for intensified surveillance and early systemic therapy consideration in DDHS UTUC patients. Patient summary:We studied patients with upper tract urothelial cancer who had different tumor types. We found that patients with these specific rare tumor types were more likely to have cancer spread outside the urinary tract. These patients may benefit from closer follow-up and additional treatment after surgery.

OBJECTIVE:To guide biopsy decision making via a predictive model for clinically significant prostate cancer (csPCa) in men with positive imaging (PI-RADS 3-5). We aim to elucidate the influence of zone on the predictive accuracy of PI-RADS v2.1, establish a threshold of quantified apparent diffusion coefficient (ADC) values suspicious for csPCa, and create a logistic-regression model, unique in its inclusion of lesion zone and quantified ADC. METHODS:Data were retrospectively collected from a single cancer center, with institutional review board review and exemption waiver, on a lesion-level retrospective analysis of prostate multiparametric magnetic resonance imaging (mpMRI) of N = 429 men, harboring N = 546 lesions. MRIs were read and reviewed by a fellowship-trained genitourinary/abdominal imaging radiologist. Pathologic analysis was conducted by a fellowship-trained genitourinary pathologist. All statistical analysis including predictive modeling were conducted by an expert biostatistician. RESULTS:On multivariate analysis, zone (PZ as compared to TZ) was a predictor of csPCa (OR 2.58, 95% CI 1.50-4.44, P<.0005). A 700 µm2/s ADC value cutoff in isolation had an AUC of 0.56, but our combined model, bolstered by clinical and imaging data, including zone and prostate-specific antigen density, yielded an AUC of 0.78, at an ADC value cutoff of 947 µm2/s. In application, simulated scenarios yielded probabilities between 16% and 82%, therefore above a biopsy omission threshold of 10% or less. CONCLUSION:Prostate zone and ADC value quantification each independently contribute to csPCa predictability, but no simulated use of the model yielded biopsy-omission thresholds for patients with MRI visible lesions.

PURPOSE:Fusion prostate biopsy of prostate imaging report and data system lesions has become an integral part of diagnosis of prostate cancer. Though the scoring system is slightly different between peripheral zone and transition zone located lesions, a score of 4 or 5, regardless of lesion location is associated with a high or very high chance of clinically significant prostate cancer. Our goal is to examine whether lesion location impacts detection of clinically significant prostate cancer, defined as International Society of Urological Pathology grade group ≥2. MATERIALS AND METHODS:Multi-institutional retrospective review of patients who underwent MRI fusion biopsy at 3 tertiary care medical centers between 2017 and 2022. Lesion level review was performed to compare targeted biopsy results for PI-RADS 4 and 5 lesions located in the transition zone and peripheral zone. Primary outcome of interest was detection of clinically significant prostate cancer. Multivariable logistic regression analyses were performed to assess for predictors of clinically significant prostate cancer detection. RESULTS AND CONCLUSIONS:Two thousand one hundred twenty eight lesions from 1,635 patients were included. On multivariate analysis, lesions located in the transition zone were independently associated with decreased detection of clinically significant prostate cancer (OR 0.55, P < 0.001). Similarly, detection of grade group 3 or higher prostate cancer was also lower for lesions in the transition zone (adjusted OR: 0.37; 95% CI: 0.26-0.54; P < 0.001). These differences have implications for further workup in patients with negative or low-grade pathology on MRI-TBx of PI-RADS 5 lesions and suggest a needs for reworking of the PI-RADS system.