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Objective To assess the effect of Moses™ 2.0 (Lumenis Be Ltd., Yokneam Illit, Israel; Boston Scientific, Marlborough, MA, USA) for lithotripsy of renal stones of 8–20 mm in diameter on operative time, surgeon workload, and retropulsion. Subjects/Patients and Methods In our multicentre, randomised, double‐blind clinical trial, patients were randomised 1:1 to standard or Moses 2.0 laser lithotripsy and stratified by stone size. Patients and surgeons were blinded to laser modality. Primary outcomes were total operative time as well as surgeon workload assessed by the National Aeronautics and Space Administration‐Task Load Index (NASA‐TLX). Secondary outcomes were stone retropulsion evaluated by blinded video review and postoperative clinical outcomes. Linear regression modelling was used for analysis. Results A total of 153 patients (79 Standard, 74 Moses 2.0) with similar clinical, stone, and operative characteristics were evaluated. There was no significant difference in operative times between the Standard and Moses 2.0 groups ( P = 0.73). Moses 2.0 was associated with lower effort, frustration, mental, physical, and temporal workload, as well as higher rated overall performance compared to the standard laser. Video review demonstrated no difference in rates of retropulsion ( P = 0.13). Complication rates (Standard: 13%; Moses 2.0: 10%) and stone‐free rates (Standard: 51%; Moses: 2.0 55%) were comparable. Conclusion Our study evaluated the impact of Moses 2.0 technology on high‐powered renal stone dusting, constituting the largest double‐blind trial of its kind to date. There was insufficient evidence to suggest any difference in operative times or clinical outcomes when using Moses 2.0 compared to standard laser lithotripsy. Moses 2.0 was associated with reduced surgeon workload, which has implicit impact on surgeon wellness.

Background: Several breast cancer (BC) risk prediction models have been developed to provide personal risk assessments. Though individually validated, their performance has not been systematically evaluated across a wide range of populations or ages. Methods: We harmonized individual-level baseline questionnaire data and incident BC diagnoses from 21 cohorts from North America, Europe, and Australia participating in the Breast Cancer Risk Prediction Project. Five-year absolute risk of invasive BC was estimated for five established risk prediction models using classical risk factors only. Discrimination was evaluated by area under the curve (AUC). Calibration was assessed using average and risk-decile specific expected to observed (E/O) ratios. Performance metrics were meta-analyzed across cohorts and models. Metaregression tested associations between cohort characteristics and performance metrics. Results: This analysis included 1,595,977 women aged 20-75 years, enrolled in studies between 1976-2015, with 19,062 (1.2%) invasive BC cases ascertained within 5 years from exposure assessment. Age-adjusted AUCs were similar across models and cohorts (pooled AUCs by model: 0.57-0.58), while E/O ratios varied substantially (pooled E/O ratios by model: 0.83-1.25). Overestimation was common among predicted high-risk individuals (>3%). No appreciable differences in model performance by cohort age, birth year, race, and variable missingness emerged. Calibration improved after assigning race-specific incidence rates. Conclusion: Existing BC risk prediction models provided similar risk discrimination across multiple cohorts, although there was overestimation of risk for high-risk individuals. Performance variation across cohorts was not driven by specific characteristics, which supports development of a unified risk model for diverse populations that leverages appropriate incidence rates.

Importance Patients undergoing cardiac surgery with cardiopulmonary bypass often require platelet transfusions for bleeding. Platelets are routinely stored at room temperature (20-24 °C) for up to 5 to 7 days; however, cold storage (1-6 °C) may allow for increased storage duration without loss of hemostatic function. Objective To determine the maximum cold-storage duration, up to 21 days, for which cold-stored platelets (CSPs) are noninferior or superior in hemostatic efficacy to room-temperature platelets (RTPs) when transfused in actively bleeding patients undergoing cardiac surgery with cardiopulmonary bypass. Design, Setting, and Participants A phase 3, multicenter, randomized, partially blinded, adaptive, noninferiority, storage duration–ranging trial conducted in pediatric and adult patients undergoing cardiac surgery with planned cardiopulmonary bypass at 27 sites in the US and Australia from December 2021 to March 2025. Statistical analysis was conducted from September 9 to October 3, 2025. Intervention Patients were randomized 2:1 to receive CSPs with a maximum of 21 days of storage vs RTPs with a maximum of 7 days of storage. Main Outcomes and Measures The primary outcome was a hemostatic efficacy score with values ranging from 1 to 5 and higher values indicating greater bleeding. The noninferiority margin was 1 point. The success criterion was met if at least 1 cold-storage duration of 7 days or more had a posterior probability of noninferiority of at least 97.5%. The secondary outcome was 24-hour chest tube output. Results Of the 1000 patients who underwent platelet transfusion, 989 were included in the primary analysis (650 CSPs and 339 RTPs). The cohort had a mean (SD) age of 42.1 (30.1) years and 67.8% were male. CSPs were noninferior to RTPs for the primary outcome, with a probability of greater than 99.9% for all cold-storage durations. Pooled across storage durations, CSPs had a mean difference from RTPs of 0.09 (95% credible interval, −0.06 to 0.23). Median (IQR) chest tube output at 24 hours (8.9 mL/kg [5.2-15.4] for CSPs vs 8.4 mL/kg [5.5-15.9] for RTPs; difference in medians, 0.4 [95% CI, −1.0 to 1.5]) was not statistically different between study groups. In a post hoc analysis, as all storage durations were noninferior, considering the CSPs as a single group, the hemostatic efficacy score was similar between both groups: mean (SD) of 3.08 (1.15) CSPs vs 2.99 (1.10) RTPs. There were no differences in venous or arterial thrombotic events, transfusion-associated adverse events, acute respiratory distress syndrome, kidney failure, septic shock, and mortality between the study groups, except for increased reexploration rates in the CSP group. Conclusions and Relevance For patients undergoing cardiac surgery, CSPs stored up to 21 days are noninferior to RTPs for the control of active surgical bleeding. Use of CSPs may allow for increased availability of platelets by reducing wastage and shortages and may allow for incorporation of platelets into inventory at locations where platelets cannot be maintained due to the 5- to 7-day shelf life of RTPs. Trial Registration ClinicalTrials.gov Identifier: NCT04834414

Abstract Background Breast cancer is etiologically heterogeneous, but which risk factors differ in their associations across tumor subtypes remains unclear. We conducted a large, pooled analysis to evaluate independent, dose-response associations between breast cancer risk factors and quantitative tumor features. Methods Analyses of 15,731 invasive breast cancers from 24 studies evaluated associations (p-trend) between reproductive and hormonal factors, body mass index (BMI), alcohol, smoking, and family history in relation to quantitative immunohistochemistry measures on tissue microarrays (ER, PR, HER2, KI67, TP53) and tumor grade. Analyses in a subset of 10 population-based studies estimated subtype-specific odds ratios (ORs) comparing cases to controls. A Bayesian False Discovery Probability (BFDP) <0.2 was used to identify associations with strong statistical evidence. Results Nulliparity and later age at menopause were associated with higher ER-positivity (p-trend=0.021 and 0.001, respectively), with corresponding OR[ER+] (95% CI) = 1.49 (1.16-1.90) for nulliparous vs. parous and 1.07 (1.03-1.11) per 5 years. Current combined menopausal hormone therapy (MHT) use was associated with lower grade (p-trend<0.001), with OR [grade1] = 3.37 (2.69-4.21) for current vs. never users. Higher BMI was associated with lower ER-positivity and higher grade in premenopausal women (p-trend<0.001 and <0.001), with OR[ER+] = 0.80 (0.74-0.87) and OR[grade1] = 0.75 (0.63-0.88) per 5 units, and with higher PR-positivity and higher grade in postmenopausal women (p-trend<0.001 and <0.001), with OR[PR+] = 1.08 (1.03-1.14) and OR[grade 3] = 1.10 (1.04-1.17) per 5 units. Conclusion This pooled analysis of 15,731 cases showed that nulliparity, age at menopause, MHT, and BMI have independent, dose-response associations with ER, PR, and grade, clarifying patterns of etiologic heterogeneity. Associations with HER2, KI67 and TP53, or other risk factors did not meet our threshold for strong evidence.

Abstract Background Breast cancer chemoprevention is underutilized among high-risk women. We examined whether decision support could increase informed decision making. Methods We conducted a cluster randomized controlled trial to evaluate the effect of a patient-facing decision aid (RealRisks) and provider tool (BNAV) compared with standard education on the number of women with high-risk breast lesions making informed choices. Questionnaires were administered at baseline and 6 and 12 months. The primary outcome was chemoprevention informed choice (defined as adequate knowledge and attitudes congruent with decision) at 6 months. Secondary endpoints included breast cancer risk perceptions, worry, chemoprevention knowledge, decision conflict, and chemoprevention decision. Results Across 31 randomized sites, we enrolled 210 providers, who were primarily breast health specialists. Of these, 24 sites (14 intervention, 10 control) enrolled 412 patients. Among 287 patients evaluable for the primary outcome, there were no statistically significant differences in informed choice between the intervention and control arms at 6 months (35% vs 27%, respectively; P = .20) and 12 months (37% vs 25%, respectively; P = .05). At 6 months, women in the intervention compared with control arm were more likely to have accurate breast cancer risk perceptions (31% vs 21%, respectively; P = .03) and adequate chemoprevention knowledge (33% vs 23%, respectively; P = .04). At 12 months, 52% of women in the control and 50% in the intervention arm self-reported initiating chemoprevention. Conclusion Decision support led to modest improvements in accurate risk perceptions and chemoprevention knowledge but not informed choice. Relatively high chemoprevention uptake was achieved among women with high-risk breast lesions managed mainly by breast health specialists. Trial Registration NCT04496739, https://clinicaltrials.gov/study/NCT04496739?cond=NCT04496739&viewType=Card&rank=1

Abstract Background Rare pediatric and young adult brain tumors pose major diagnostic and therapeutic challenges due to limited evidence and scattered expertise. The International Rare Brain Tumor Board was established to enable multidisciplinary case review, shared learning, and collaborative decision support. Methods Launched in February 2025, the Rare Brain Tumor Board is a monthly collaborative initiative led by Children’s National Hospital and the National Institutes of Health (NIH). Close partnership with the European Pediatric Rare CNS Tumor Board enhances transatlantic exchange and alignment of diagnostic and treatment recommendations. De-identified cases are presented with clinical history, neuroimaging, histopathology, and molecular profiling, including DNA methylation classification, available for the majority of cases. Sessions are structured to support integrated diagnosis and evidence-informed management recommendations through multidisciplinary discussion (neuropathology, neuroradiology, neurosurgery, radiation oncology, and pediatric as well as adult neuro-oncology). Findings Since its inception, 12 sessions have been held averaging 138 participants per session, reviewing a total of 32 cases (mean 3 cases/session; range 1–4) from 7 different countries and 3 different continents. Entities reviewed include DICER1-intracranial sarcoma (n = 5), astroblastoma (n = 4), FOXR2-activated neuroblastoma (n = 4), CNS tumors with BCOR internal tandem duplication (n = 3) and, BCOR-fused tumors (n = 3), CIC-rearranged-sarcoma (n = 3), intracranial mesenchymal tumor FET::CREB fusion positive (n = 3), MN1::PATZ1 fusion tumors (n = 2), undifferentiated sarcoma (n = 2), PLAG1-fusion tumor (n = 1), medullomyoblastoma (n = 1), and EZHIP-altered diffuse midline glioma (DMG) (n = 1). Multidisciplinary review has supported diagnostic clarification, strengthened familiarity with ultra-rare entities, and informed real-world treatment discussions in settings where prospective data are limited. Discussions have also increased awareness of rare brain tumor registries and opportunities for systematic case capture. Conclusion An international multidisciplinary rare brain tumor board is a feasible, scalable model to advance integrated diagnosis and collaborative management of ultra-rare pediatric and young adult brain tumors, while building a shared knowledge base across institutions.

9568 Background: Stage IIB/C cutaneous melanoma is associated with high recurrence risk, however stratification of risk in relation to time after surgery has not been comprehensively evaluated. We evaluated recurrence-free survival (RFS) at key time points, stratified by clinicopathologic factors, to identify patients (pts) at higher recurrence risk and personalize postoperative surveillance strategies. Methods: In this multi-institutional, international retrospective cohort study from the Sentinel Lymph Node Working Group database, we included pts with pathologic T3b/T4a/T4b and N0 disease who underwent surgical resection and sentinel node biopsy from 1994-2025. The type of first recurrence (local, regional, distant) was characterized based on time category (0-12, 12-24, 24-60, and 60+ months after surgery). Restricted mean survival time (RMST) analysis was used to measure the average survival time up to a specified time point (6-, 12-, 24-, and 60-months after surgery), and associations of clinicopathologic variables (age, sex, Breslow thickness, ulceration and lymphovascular invasion [LVI]) with RFS. Results: We included 2514 stage IIB/C pts from 19 sites in 4 countries, with a median follow-up of 53 (stage IIB) and 49 (stage IIC) months. 675 (27%) pts experienced a recurrence (92 [14%] local, 238 [35%] regional and 345 [51%] distant), and 400 (59%) recurrences occurred within 24 months. The proportion of distant recurrences as the first recurrence increased significantly with time, comprising 39%, 50%, 62%, and 59% of recurrences in the 0-12, 12-24, 24-60, and 60+ month time categories respectively (χ 2 p<0.001). No significant differences were observed for the included clinicopathologic variables for 6-month RMST estimates. At 12 months, RMST estimates for thickness ≥4 mm (11.2 vs 11.6 months for thickness 2-3.99 mm, p<0.001) and presence of LVI (10.7 vs 11.4 months, p=0.009) were significantly different. 24-month RMST estimates differed for male sex (20.7 vs 21.5 months vs females, p=0.002), thickness ≥4 mm (20.5 vs 21.9 months, p<0.001), and presence of LVI (19.0 vs 21.1 months, p<0.001). Lastly, 60-month RMST estimates differed for male sex (42.0 vs 45.2 months, p=0.001), thickness ≥4 mm (41.5 vs 46.2 months, p<0.001), LVI (36.0 vs 43.7 months, p<0.001), and age >65 years (41.5 vs 46.4 for age <42, p=0.022). Conclusions: In this real-world, multi-center analysis of pathologic stage IIB/C melanoma pts, recurrence patterns varied based on time after surgery. Breslow thickness, LVI, male sex, and age were significantly associated with earlier recurrence at different time intervals on RMST analysis. Additionally, given that >50% of first recurrences 12+ months after surgery were distant, active surveillance for distant relapses may be warranted.

9524 Background: Unresectable melanoma in-transit metastases (ITM) can pose a significant clinical challenge. Our recently published data comparing first-line treatments for ITM, isolated limb infusion or perfusion (ILI/ILP), immune checkpoint inhibitors (ICI) and intralesional talimogene laherparepvec (TVEC), found superior outcomes with TVEC. However, TVEC was used more often in patients with lower disease burden and earlier stage (IIIB vs. IIIC/D). Therefore, we sought to better investigate these differences with a propensity score-matched (PSM) analysis. Methods: A multi-institutional, international IRB- approved retrospective analysis was conducted for unresectable melanoma ITM from 2016-2022. PSM analysis comparing first-line ILI/ILP, ICI, and TVEC for was performed. Patients were matched for stage, number of ITM, anatomical site, CLND status, gender and age. Kaplan-Meier curves (OS, PFS, DMFS) and Cumulative incidence function (MSS) were used to visualize time-to-event outcomes in the PSM cohort, though both methods do not account for the matched structure. Results: 274 patients were identified, 120 female/154 male; 96 treated with ILI/ILP, 111 with ICI, and 67 with TVEC. Median follow-up was 40 months (range, 1-80). PSM was performed and identified 36 TVEC–ICI pairs and 27 TVEC–ILI pairs. These were combined resulting in a final cohort of 108 observations (45 TVEC, 36 ICI and 27 ILI). The groups were well balanced. No statistical difference was found for metastasis-free survival (DMFS), progression-free survival (PFS), melanoma-specific survival (MSS), and overall survival (OS) between treatment modalities. TVEC was associated with significant improvement in local PFS (median was 2.2 years (y) for ILI/ILP, 1.5y for ICI and not reached for TVEC, p=0.048). While not statistically significant, a clinical benefit was seen in PFS being longer for TVEC (2.1y for TVEC vs. 1.2y for ILI/ILP and 1.1y for ICI; p=0.2) and OS (not reached vs 2.9y for ILI/ILP and 5.2y for ICI; p=0.2). On mixed effect Cox regression proportional hazard model using the matched data set, there were no significant differences in any of the survival and recurrence outcomes. Conclusions: When patients are propensity-matched, there were no significant differences in first-line treatment modalities for unresectable melanoma ITM. Treatment with TVEC did result in clinically meaningful improved overall and local PFS and OS. This supports that selection of ITM therapy should incorporate an individualized approach, incorporating disease distribution, stage, burden, treatment side effects and patient priorities.

5004 Background: Patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC) treated continuously with testosterone suppression (TS) plus an androgen receptor pathway inhibitor (ARPI) can experience cumulative toxicity. We conducted this single-arm phase 2 trial (NCT05241860) to test the hypothesis that pts who achieve favorable response to TS + ARPI can have prolonged treatment-free interval with testosterone recovery after treatment interruption (TI). Here we report on the primary endpoint. Methods: Eligible pts had mHSPC by conventional imaging with prostate-specific antigen (PSA) ≥ 5 ng/ml and testosterone ≥ 150 ng/dl prior to starting TS+ARPI, with PSA < 0.2 ng/ml and testosterone < 50 ng/dl at the time of enrollment after having received TS for 540-750 days and ARPI for ≥ 360 days. Prior local therapy, radiation to metastases and docetaxel were permitted. After enrollment, pts discontinued TS and ARPI and were followed with PSA and testosterone levels every 3 months (mo), CT/MRI and bone scan at least every 6 mo, and FACT-P questionnaire for patient-reported outcomes (PROs) every 6 mo. Treatment was resumed for PSA ≥ 5 ng/ml, radiographic change (progressive disease [PD] per RECIST 1.1 on CT/MRI or unconfirmed PD per PCWG3 on bone scan), or prostate cancer-related symptoms. The primary endpoint was proportion of men remaining treatment-free 18 mo after TI with eugonadal testosterone ( > 150 ng/dl). Target enrollment was 75 pts to differentiate 18-mo treatment-free rates of 0.30 (H 0 ) and 0.45 (H a ). Results: Of 79 pts enrolled between 07/2022 and 03/2024, 78 were eligible and underwent TI. Among these 78, median PSA prior to starting TS+ARPI was 19 (range 5-6759), 27 (35%) had high volume disease, 31 (40%) never received local therapy, and 55 (71%) did not receive radiation to metastases. By 18 mo after TI, 67% (52/78) recovered testosterone and 58% (45/78) remained treatment-free; 41% (32/78) remained treatment-free with testosterone recovery (80% CI 33.5-48.9%, one-sided p 0.0249). At median follow-up of 21.2 mo, 35% (27/78) resumed initial TS+ARPI after meeting re-initiation criteria (of whom 1 required treatment switch for PD 9 mo later); 5% (4/78) resumed prior to meeting criteria; 9% (7/78) pursued alternative therapy instead of resuming TS+ARPI per protocol; 5% (4/78) withdrew; 1 died of myocardial infarction prior to resuming treatment. 4 pts died, 1 of prostate cancer. Conclusions: The primary objective was achieved with 41% of favorable responders to TS+ARPI remaining treatment-free with testosterone recovery at 18 mo after TI. Analyses of biomarkers and PROs are in progress, and pts will be followed for long-term outcomes. Support: U10CA180821, U10CA180882, UG1CA189823, https://acknowledgments.alliancefound.org, Veracyte Inc. Clinical trial information: NCT05241860 .