Citations

Abstract Purpose: Knowledge of prognostic factors and long-term survival in patients with diffuse hemispheric glioma, H3 G34–mutant (DHG, H3 G34), remains limited in this tumor with a poor prognosis. Experimental Design: This retrospective, multi-institutional study investigated prognostic variables for patients with DHG, H3 G34, and their association with progression-free survival (PFS) and overall survival (OS). Uni- and multivariable Cox proportional hazard models were applied with multiple imputed datasets. Results: A total of 153 patients (142 G34R, 9 G34V, 2 via DNA methylation) were included. The median age at diagnosis was 17 years (range, 2–45). Initial gross/near total resection (GTR/NTR) was achieved in 43% of patients. Radiation was given in 91% (85% focal irradiation), and initial chemotherapy was given in 87% [70% temozolomide-based (TMZ), 25% TMZ/lomustine, 5% non-TMZ]. Median OS was 24 months [interquartile range (IQR), 22–28] with a median PFS of 14 months (IQR, 12–19). Twelve patients (8%) were found to be long-term survivors (≥5 years). Exploratory multivariable analysis showed that adjuvant radiotherapy [HR, 0.076; 95% confidence interval (CI), 0.033–0.17] and achieving GTR/NTR compared with < NTR (HR, 0.51; 95% CI, 0.33–0.78) were associated with improved PFS. Multivariable analysis showed improved OS with increasing age at diagnosis (HR, 0.70; 95% CI, 0.57–0.87), initial radiotherapy (HR, 0.38; 95% CI, 0.15–0.96), and initial GTR/NTR compared with < NTR (HR, 0.60; 95% CI, 0.37–0.97). Conclusions: This cohort highlights prognostic factors for patients with DHG, H3 G34, and describes relapse patterns and therapy approaches. Clinical trials and prospective registries are needed to improve outcomes.

Abstract Rare Mendelian disorders affect 300-400 million people globally. Although genetic testing has become widely adopted, gene-specific evidence for tailored variant interpretation remains scattered across resources. We present Gene Portals, a framework for gene-centered multimodal knowledge bases that co-localize expert-harmonized clinical data, functional assays, population variation, structural annotations and gene-specific ACMG/AMP specifications within a single resource. A modular interface integrates this unified evidence with VCEP-refined ACMG specifications to enable automated gene-specific variant classification, infer molecular mechanisms, and support cross-gene analyses. We demonstrate the framework’s utility across five Gene portals spanning eleven neurodevelopmental disorder-associated genes, integrating data from 4,423 individuals with 2,838 unique variants, 36,149 ClinVar submissions, and 1,044 expert-curated molecular readouts. By organizing evidence that is otherwise dispersed across multiple sources into a unified, queryable framework, the SCN, GRIN, CACNA1A, SATB2 and SLC6A1 Gene Portals became widely used community resources and provide an extensible template for standardized rare-disease variant interpretation and mechanism-aware discovery.

Rationale: Neuromuscular blocking agents (NMBAs) show potential benefits on mortality and other complications of acute respiratory distress syndrome (ARDS) in adult patients. Evidence-based decisions and processes ensure appropriate use of neuromuscular blockade in adult patients with ARDS. Objectives: The objective of these guidelines was to develop evidence-based recommendations for the administration of NMBAs in critically ill adult patients with ARDS. Design: The American College of Critical Care Medicine Board convened a 21-member multidisciplinary panel of experts in critical care medicine, nursing, respiratory therapy, pharmacology, surgery, neurology, and anesthesiology. The panel included two expert methodologists specialized in developing evidence-based recommendations in alignment with the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. Conflict-of-interest policies were strictly followed during all phases of guidelines development including task force selection and voting. Methods: The panel members identified and formulated five Population, Intervention, Comparison, and Outcome questions. We conducted a systematic review for each question to identify the best available evidence, statistically analyzed the evidence, and assessed the certainty of the evidence using the GRADE methodology. We used the GRADE evidence-to-decision framework to formulate the recommendations. Results: The panel generated two conditional recommendations. One recommendation is to use NMBAs in adults with ARDS with Pa o 2 /F io 2 less than 150. For the other recommendations, there was equipoise in the recommendation for and against using titratable vs. fixed-dose NMBA dosing, a monitoring-based strategy for assessing depth of sedation and analgesia in adults with ARDS before initiating or while receiving neuromuscular blockade, and administration of NMBAs for patients who are proned, due to overall lack of evidence in critically ill patients and due to considerations of patient safety and experience concerns. Conclusions: These guidelines provide additional perspectives on the use of NMBA in patients with ARDS, recognizing that institutional and patient-specific considerations must help to guide the decision-making process.

Abstract Context Osteoanabolic therapy for osteoporosis should be followed by antiresorptive treatment (“consolidation”) to preserve bone mass. Although osteoanabolic therapy is increasingly endorsed for primary fracture prevention, real-world implementation of consolidation remains unknown. Objective To assess patterns and predictors of timely consolidation after osteoanabolic therapy for primary fracture prevention. Methods We conducted a retrospective cohort study using US commercial, Medicare Advantage, and traditional Medicare claims data. Adults aged ≥50 years who initiated romosozumab, teriparatide, or abaloparatide between 2011 and 2022 were included. The primary outcome was timely consolidation, defined as initiation of an antiresorptive medication within 3 months after osteoanabolic therapy. Secondary outcomes included delayed consolidation (initiation >3 months after completion), osteoanabolic restart following a treatment gap, and no consolidation therapy. We further distinguished participants who completed the full osteoanabolic course, defined as ≥12 months for romosozumab and ≥18 months for teriparatide or abaloparatide. Multivariable logistic regression models were used to identify predictors of consolidation patterns. Results Among 15 389 patients (mean age 70.6 years; 89% women; 85% White), 30% completed osteoanabolic therapy (median, 12.9 months for romosozumab; 23.4 months for teriparatide/abaloparatide). Overall, 25% had timely consolidation, 24% delayed consolidation, 12% restarted osteoanabolics, and 40% had no consolidation; only 12% completed therapy with timely consolidation. Timely consolidation was more likely with endocrinology (OR 1.31; 95% CI, 1.17-1.48) or rheumatology (OR 1.45; 1.30-1.62) vs primary care, and less likely among patients aged 50-64 years (OR 0.67; 0.58-0.77) vs 65-74, those enrolled in Medicare Advantage (OR 0.85; 0.74-0.98) vs traditional Medicare, or those recently hospitalized (OR 0.88; 0.80-0.97). Odds increased over time (OR 4.27; 3.63-5.05 for 2021 vs 2011 starts). Conclusion Only 1 in 4 patients received timely consolidation therapy after osteoanabolic treatment, and 1 in 8 completed the full sequence. Strategies to improve consolidation in primary fracture prevention are needed.

LBA630 Background: Enfortumab vedotin (EV) + pembrolizumab (pembro) is the established first-line standard of care for locally advanced/metastatic urothelial carcinoma and represents a novel neoadjuvant and adjuvant treatment strategy for patients with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-based chemotherapy. The randomized phase 3 KEYNOTE-B15/EV-304 study (NCT04700124) evaluates neoadjuvant and adjuvant EV + pembro followed by radical cystectomy plus pelvic lymph node dissection (RC + PLND) vs neoadjuvant chemotherapy followed by RC + PLND in participants (pts) with MIBC who are eligible for cisplatin-based therapy. Methods: Pts with clinical stage T2-T4aN0M0 or T1-T4aN1M0 MIBC (confirmed by central pathology and central imaging assessment) who were eligible for cisplatin-based chemotherapy and RC + PLND were randomized 1:1 to receive either 4 cycles neoadjuvant EV 1.25 mg/kg IV on days 1 and 8 + pembro 200 mg IV on day 1 Q3W, followed by RC + PLND, and adjuvant 5 cycles EV + 13 cycles pembro (EV + pembro arm) vs 4 cycles neoadjuvant gemcitabine 1000 mg/m 2 on days 1 and 8 + cisplatin 70 mg/m 2 on day 1 Q3W, followed by RC + PLND (cis + gem arm). The primary endpoint was event-free survival (EFS) by blinded independent central review. Key secondary endpoints were pathological complete response (pCR) rate by blinded central pathological review and overall survival (OS). Safety was a secondary endpoint; AEs of special interest were based on distinct prespecified lists for each drug. Results: A total of 405 and 403 pts were randomized to EV + pembro and cis + gem, respectively. Median time from randomization to the data cutoff date of October 27, 2025 was 33.6 months (range, 22.5–53.6). Baseline characteristics were generally balanced between groups. EV + pembro significantly improved EFS (median NR vs 48.5 mo; 24-mo estimated EFS rate 79.4% vs 66.2%; HR 0.53, 95% CI 0.41–0.70; 1-sided P <.0001), OS (median NR vs NR; 24-mo estimated OS rate 86.9% vs 81.3%; HR 0.65, 95% CI 0.48–0.89; 1-sided P =.0029), and pCR rate (55.8% vs 32.5%; estimated difference 23.4%, 95% CI 16.7–29.8; 1-sided P <.0001) vs cis + gem. Grade ≥3 treatment-emergent AEs occurred in 75.7% of pts with EV + pembro and 67.2% with cis + gem. Most common grade ≥3 drug-related AE of special interest for EV was skin reactions (14.1%); most common grade ≥3 AE of special interest for pembro was severe skin reactions (13.9%). Conclusions: Neoadjuvant and adjuvant EV + pembro significantly improved EFS, OS, and pCR rate compared with neoadjuvant gem + cis in pts with MIBC who were eligible for cisplatin-based chemotherapy. The safety profile of EV + pembro was consistent with prior experience with the combination. These results support EV + pembro as an effective perioperative treatment option in this setting. Clinical trial information: NCT04700124 .

776 Background: There continues to be a significant unmet need for safe, effective, and bladder sparing treatment options for patients with non-muscle invasive bladder cancer (NMIBC). TARA-002 is a lyophilized biological preparation for intravesical instillation containing inactivated cells of Streptococcus pyogenes (Group A, type 3) Su strain. TARA-002 rapidly enters cancer cells, activating TLR2 and NOD2 to trigger innate immunity, inflammation, and potential immunogenic cell death. ADVANCED-2 (NCT05951179) is an ongoing Phase 2, open-label study to evaluate the safety and efficacy of intravesical TARA-002 in adults ≥ 18 years with high-grade (HG)-NMIBC CIS (± Ta/T1). Preliminary results showed promising complete response (CR) rates and durable responses in patients with HG NMIBC treated with TARA-002 (Jayram et al. AUA 2025). This abstract presents pooled safety data of TARA-002 from the BCG-naïve cohort and BCG-unresponsive cohort of the ADVANCED-2 study. Methods: The ADVANCED-2 study includes 2 cohorts of BCG-naïve (Cohort A) and BCG-unresponsive (Cohort B) participants. Key exclusion criteria include penicillin allergy; history of ≥ T2 bladder cancer, nodal, or metastatic disease; and concomitant prostatic or upper tract urothelial involvement. Each participant is treated with TARA-002 to receive induction (6 weekly doses), reinduction (if persistent disease at 3 months), and maintenance (through 24 months). Response is assessed every 3 months for 2 years. Long-term follow-up is conducted up to 60 months. Safety is monitored throughout the study. Results: As of 07-October-2025, 60 participants (median age: 74; range: 45 to 92), have been enrolled and exposed to TARA-002: 31 BCG-naïve (Cohort A) and 29 BCG-unresponsive (Cohort B). In both cohorts, 18/60 (30.0 %) participants reported drug-related treatment emergent adverse events (TEAEs). Related TEAEs were Grade 1 (18/60; 30.0%) and Grade 2 (3/60; 5.0%), with no reported Grade 3-5 related TEAEs. Commonly reported related TEAEs (≥ 5%) included bladder spasm (10.0%), dysuria (13.3%), fatigue (6.7%), and micturition urgency (6.7%). Most TEAEs were mild and transient. In both cohorts, 10/60 (16.7%) experienced serious AEs (SAEs); 4/60 (6.7%) were Grade 2 and 9/60 (15.0%) were Grade 3. No participants experienced drug-related SAEs or drug-related TEAEs leading to withdrawal or death. Conclusions: TARA-002 monotherapy was well tolerated, thus demonstrating a favorable tolerability profile to date for the treatment of BCG-naïve and BCG-unresponsive HG NMIBC with CIS (±Ta/T1). TARA-002 has a promising safety profile as a bladder-sparing treatment in HG NMIBC across BCG exposure status. Updated safety data will be provided based on evaluable time points at the time of the presentation. Clinical trial information: NCT05951179 .

160 Background: To our knowledge, no tools are available to guide care in oligometastatic prostate cancer (omPC). Here, we leveraged individual patient-level data pooled from 8 randomized trials in the X-Met collaboration to construct CEREBRO, a tool for predicting patient-specific responses to various treatment scenarios. Methods: Patients with omPC from the STOMP, ORIOLE, SABR COMET, EXTEND continuous ADT, EXTEND intermittent ADT, ARTO, RADIOSA, and RAVENS trials were included. 6 patients (1%) with missing data were excluded. Treatment scenarios were defined as active surveillance (AS), metastasis-directed therapy (MDT), systemic therapy (ST), or MDT+ST. To account for varying baseline hazards, Weibull models were fit for overall survival (OS); progression-free survival (PFS); and castration-resistance free survival (CRFS) for patients with hormone-sensitive disease. Endpoint definitions were harmonized per X-Met framework. Results: Of 600 patients included (treatment scenarios: AS=50; MDT=153; ST=172; MDT+ST=225), 405 (67%) had hormone-sensitive omPC. With median follow-up of 38 months, median PFS, CRFS, and OS of all patients were 18, 70, and 84 months. In order of relative contribution, inputs for predicting outcomes were: treatment scenario, stage, prostate-specific antigen annotated by ADT status, metachronous vs synchronous presentation, imaging type, number of metastases, hormone sensitivity, and age. The model for each endpoint showed robust fit, calibration, superiority against the null model (per the likelihood ratio test), and risk stratification (Table). Median PFS times for model-defined low-, intermediate-, and high-risk strata were 46 months, 18 months, and 7 months ( p <0.0001). In addition, the PFS and OS models also showed strong discrimination via c index and a large interval of risk probabilities with additive clinical utility per decision-curve analysis (Table). A public webpage will be made available to facilitate prospective trial stratification, patient counseling for patient-specific outcome predictions for each potential treatment scenario, and forecasts comparing outcomes between treatment scenarios. Conclusions: CEREBRO is a high-performance tool, trained on robust prospective data from 8 randomized trials with routinely collected clinical variables, for predicting risk and treatment outcomes in omPC. Given the uncertainties in optimal timing of MDT and combination with ST, this tool has been built to facilitate current decision making. External validation is planned. Model summary. Endpoint C index (95% CI) Calibration Likelihood ratio p Risk strata p Net clinical utility observed between thresholds PFS 0.72 (0.70-0.75) 1.04 <0.0001 <0.0001 0.2-1.0 CRFS 0.63 (0.60-0.70) 1.01 0.02 0.004 0.2-0.5 OS 0.81 (0.76-0.86) 1.01 <0.0001 <0.0001 0.05-1.0