Citations

e14017 Background: The role of stereotactic radiosurgery (SRS) is well established in the setting of one to four brain metastases (BM), offering effective control with reduced neurocognitive toxicity compared with whole-brain radiotherapy (WBRT). However, for patients with five or more BM, the optimal radiation strategy remains uncertain, and comparative outcome data are limited. We performed a systematic review and meta-analysis to compare overall survival (OS) between SRS and WBRT in patients with ≥ 5 BM. Methods: A systematic review was conducted to identify comparative studies of SRS versus WBRT in patients with ≥5 brain metastases. Retrospective and prospective studies reporting median OS with available cohort sizes were included. Comparative survival was summarized using pooled ratios of median survival within a random-effects meta-analytic framework. Results: Five comparative studies were included, comprising 226 patients treated with SRS and 261 treated with WBRT, including both retrospective and prospective cohorts. Sample-size–weighted summary (with reported medians) showed median OS was 8.1 months with SRS and 7.7 months with WBRT. Pooled analysis demonstrated no significant difference in OS between treatment strategies (ratio of median survival, 1.03; 95% CI, 0.73–1.46; p = 0.81). Conclusions: Among patients with ≥5 BM, SRS and WBRT were associated with comparable OS. These data suggest that OS alone may not guide treatment choice in this population, emphasizing the importance of careful patient selection. As focal therapies are increasingly incorporated into clinical practice for patients with higher intracranial disease burden, prospective, multi-institutional randomized clinical trials are needed to better define optimal management strategies. Summary of included studies reporting median overall survival (OS). Study Study Design SRS (n) WBRT (n) Median OS in SRS cohort (months) Median OS in WBRT cohort (months) Kim et al., 2009 Retrospective 29 39 5.6 7.2 Mizuno et al., 2019 Retrospective 24 20 7.3 7 .2 Li et al., 2020 Prospective, randomized 35 34 7.8 8.9 Bodensohn et al., 2023 Prospective, non-randomized 40 70 10.4 6.5 Aizer et al., 2025 Prospective, randomized 98 98 8.3 8.5

e14016 Background: Postoperative stereotactic radiosurgery (SRS) is utilized following resection of brain metastases (BM), however use is limited by target delineation uncertainty and an increased risk of leptomeningeal disease (LMD). Preoperative SRS allows for precise targeting and is being increasingly utilized in treatment paradigms of resectable BM. Reported outcomes across studies are promising and there are several phase 3 trials which are underway. Therefore, we pooled multiple studies and conducted a meta-analysis to estimate 1-year local control (LC), LMD incidence, and overall survival (OS) following single-fraction preoperative SRS for resectable BM. Methods: We systematically searched PubMed, Embase, and Scopus to identify studies of single-fraction preoperative SRS for resectable BM. For each cohort, data for 1-year LC, 1-year LMD, and 1-year OS, along with corresponding sample sizes, were extracted. A proportion-based meta-analysis was performed to derive pooled estimates and 95% confidence intervals (CIs), with between-study heterogeneity quantified using I². Results: Ten studies published between 2016 and 2025, including both prospective trials and retrospective cohorts, met the inclusion criteria. There were 617 patients treated with single-fraction preoperative SRS. The median age was 60.8 years (range 58-65 years), and the median prescribed dose was 15.8 Gy (range 14.5-17.0 Gy). The pooled 1-year LC rate was 81.9% (95% CI, 76.9-85.9; I² = 43.4%). The pooled 1-year incidence of LMD was 4.6% (95% CI, 2.8-7.4; I² = 0%), and the pooled 1-year OS rate was 60.2% (95% CI, 55.5-64.8; I² = 0%). Sensitivity analyses showed stable pooled estimates, with no single study driving the results. Conclusions: Single-fraction preoperative SRS is associated with low rates of LMD and acceptable LC and OS. In the context of historically reported postoperative SRS outcomes, these results suggest that preoperative SRS represents a promising strategy in selected patients. Randomized trials are needed to define the comparative role and optimal patient selection for preoperative SRS, with ongoing studies (NCT05341739, NCT03741673) expected to clarify its role in the management of resectable BM. Study characteristics and reported outcomes of single-fraction preoperative SRS for BM. Study Study design Number of patients Median age (years) Median dose (Gy) 1-year LTC (%) 1-year LMD (%) 1 year OS (%) Agarwal, 2024 Trial 47 59 NR NR 4.8 NR Higazy, 2025 Trial 35 61 17 82 2.86 NR Li, 2022 Retrospective 24 64 NR 87.6 NR NR Mallela, 2024 Retrospective 26 64.5 NR 77.2 NR NR Murphy, 2024 Trial 35 63 NR 76.6 NR 59 Patel, 2018 Retrospective 12 57.5 NR 49.1 10 74.1 Patel, 2016 Retrospective 66 58.2 14.5 84.1 3.2 NR Prabhu, 2025 Retrospective 124 NR 17 87.2 1.7 64.5 Prabhu, 2025 Retrospective 183 NR 15 86.4 7.3 58.1 Prabhu, 2020 Retrospective 65 NR NR 77.1 4.2 56.3

5054 Background: Rucaparib significantly improved radiographic progression-free survival (rPFS) versus physician’s choice of docetaxel or an androgen-receptor pathway inhibitor (ARPI) (abiraterone or enzalutamide) in men with BRCA mutations who were chemotherapy-naïve in the mCRPC setting and had received one prior ARPI in the phase 3 TRITON3 trial (NCT02975934). This post-hoc analysis evaluated whether the timing of prior ARPI therapy impacted the efficacy of rucaparib. Methods: Patients were randomized 2:1 to rucaparib (600 mg BID) or physician’s choice of docetaxel or ARPI, after progression on 1 prior second-generation ARPI in any setting. The primary endpoint was rPFS. Outcomes were analyzed according to whether patients received the prior ARPI in the metastatic castration sensitive (mCSPC) or castration resistant (mCRPC) setting. Data cutoff was August 25, 2022. Results: Of the 302 BRCA1/2 patients, 68 received prior ARPI in the mCSPC setting (42 rucaparib; 26 physician’s choice) and 234 in the mCRPC setting (159 rucaparib; 75 physician’s choice). Baseline characteristics were generally similar. Prior treatments in the mCSPC and mCRPC groups, respectively, included abiraterone (73.5% vs 53.0%), enzalutamide (29.4% vs 48.3%), and docetaxel (17.6% vs 24.8%). Median rPFS favored rucaparib over physician’s choice in both groups (mCSPC: 13.6 vs 8.2 months; HR 0.60 [95% CI, 0.32–1.15]; mCRPC: 11.2 vs 5.8 months; HR 0.43 [95% CI, 0.30–0.61]). Median OS was similar between treatments in both settings (mCSPC: 23.2 vs 21.7 months; HR 0.81 [95% CI, 0.47–1.41]; mCRPC: 23.2 vs 21.0 months; HR 0.91 [95% CI, 0.66–1.25]). Treatment-related adverse events occurred at comparable rates (89.6% vs 86.1%). Conclusions: Rucaparib demonstrated efficacy in patients with BRCA-mutated mCRPC, regardless of whether prior ARPI was administered in the mCSPC or mCRPC setting. Clinical trial information: NCT02975934 .

Importance Current risk prediction guidelines for hypertrophic cardiomyopathy predict only sudden cardiac death and are imperfect, leading to avoidable deaths and unnecessary implantable cardioverter defibrillators. Objective To combine prospectively collected clinical history, imaging, genetic, and biomarker data to improve risk prediction of adverse events in hypertrophic cardiomyopathy. Design, Setting, and Participants A total of 2750 patients with hypertrophic cardiomyopathy were prospectively enrolled in the registry-based study from 44 sites in North America and Europe with expertise in hypertrophic cardiomyopathy and cardiac magnetic resonance (CMR) imaging. Participants were enrolled from April 1, 2014, to April 7, 2017. Exposures Patients underwent a health history questionnaire, blood sampling for biomarkers and genotyping, and contrast-enhanced CMR. Patients were followed up yearly by telephone and through records review regarding event documentation. Main Outcomes and Measures The predefined composite adjudicated primary end point was time to first event for hypertrophic cardiomyopathy–related deaths; nonfatal sustained ventricular arrhythmias (VAs) requiring cardioversion or defibrillation; and left ventricular (LV) assist device implant or heart transplant. A secondary end point was a composite of sudden cardiac death and nonfatal VA events. The elastic-net method identified the most important predictors. Cox proportional hazards regression assessed associations with time to the first end point. Results Of the 2750 prospectively enrolled patients, 2698 (98%) had analyzable data after 9 were excluded because they had hypertrophic cardiomyopathy phenocopies and 43 withdrew. Of these remaining patients, 1919 (71%) were male, mean age was 50 years (SD, 11 years), and 423 (16%) were from underrepresented racial and minority groups. The mean follow-up was 6.9 years (SD, 2.1 years). The primary event model in 104 patients included LV scar as a percentage of LV mass by late gadolinium enhancement (LGE%; hazard ratio [HR], 1.86; 95% CI, 1.58-2.20; P < .001), LV mass index (HR, 1.09; 95% CI, 1.01-1.17; P = .03), LV end-systolic volume index (HR, 1.28; 95% CI, 1.12-1.46; P < .001 ), all per 10-unit increase, history of heart failure at study entry (HR, 2.89; 95% CI, 1.75-4.77; P < .001), and log N-terminal pro–B-type natriuretic peptide (NT-proBNP; HR, 1.41; 95% CI, 1.17-1.70; P < .001) level per log unit, (C index for all, 0.77). An LGE percentage of the LV mass of 9% or higher substantially increased the primary composite event rate ( P = .001). The secondary sudden cardiac death and VA risk factor model (in 69 patients) included LGE%, LV mass index, LV ejection fraction, and log(NT-proBNP) (C index, 0.76). Conclusions and Relevance These results provide prospective evidence for incorporating cardiac magnetic resonance and NT-proBNP in the evaluation of patients with hypertrophic cardiomyopathy. Trial Registration ClinicalTrials.gov Identifier: NCT01915615

BACKGROUND: Hemorrhagic risk in dural arteriovenous fistulas (dAVFs) is largely determined by venous anatomy, but the contribution of systemic cardiovascular factors and their medical therapy remains poorly defined. This study examined associations between cardiovascular risk factors and antithrombotic use and hemorrhagic presentation, angiographic obliteration, and early functional outcomes after treatment. METHODS: We analyzed 1350 adults with intracranial dAVFs from the international Consortium for Dural Arteriovenous Fistula Outcomes Research registry, which retrospectively accrued cases across 14 centers in 4 countries between 1990 and 2017. Demographics, cardiovascular comorbidities, antithrombotic use, angioarchitectural features, treatment strategies, and follow-up outcomes were collected from prospectively maintained databases. Primary end points were hemorrhagic presentation, angiographic obliteration, and 90-day functional status after treatment. Univariable and multivariable logistic regressions were performed with model-specific adjustments. RESULTS: Hemorrhage occurred in 375 patients (27.8%) and was most strongly associated with high-grade dAVF classification and male sex; antithrombotic therapy was associated with lower odds of hemorrhagic presentation. Other cardiovascular risk factors showed no independent relationship with bleeding. Angiographic obliteration was achieved in 621 of 845 patients (73.5%). Hemorrhagic onset, high dAVF grade, and surgical treatment were independently associated with angiographic obliteration, whereas smoking and embolization demonstrated only nonsignificant trends after adjustment. At 90 days, 934 patients (88.9%) were functionally independent. Baseline modified Rankin Scale score was the strongest factor associated with 90-day functional outcome, while neither cardiovascular comorbidities nor treatment modality independently influenced functional status. CONCLUSIONS: In this large multicenter dAVF cohort, hemorrhagic presentation was most strongly associated with venous angioarchitecture. Male sex and antithrombotic therapy were also independently associated with hemorrhagic presentation. Angiographic obliteration was common, particularly among surgically treated lesions, and 90-day functional outcome was most strongly associated with baseline functional status.

Objective To examine the potential errors of a general large language model (LLM) (ie, Claude 3.5 Sonnet) on data extraction from randomised controlled trials (RCTs). Design and setting An empirical study comparing Claude 3.5 Sonnet extractions against a human-performed verification dataset. The extraction tasks for Claude 3.5 Sonnet were based solely on original RCT portable document format (PDF) files. For PDFs that could not be directly extracted by Claude 3.5 Sonnet, optical character recognition was employed to convert them into text format before extraction. Participants A random sample of 664 trials was selected from a well-established trial bank and a final data pool was established based on rigorous manual cross-checking as a reference standard. Data sources PubMed, EMBASE, Scopus, Web of Science (all databases) and the Cochrane Central Register of Controlled Trials (CENTRAL) up to February 2023. Eligibility criteria for selecting studies RCTs on children involving medication and adverse events. Main outcome measures Claude 3.5 Sonnet was applied to extract the basic information (eg, trial design, population information and source of funding) and adverse outcomes (ie, name of adverse events, number of events). Claude 3.5 Sonnet outputs were compared against the final data pool and all errors were recorded. Results are presented as error rates and with 95% CI, estimated using a generalised linear mixed model. Results For the 664 trials, a total of 23 069 data cells were extracted via Claude 3.5 Sonnet, with 10 624 for basic information and 12 445 for adverse outcomes. The overall error rate for data extraction was 6.6% (95% CI 5.4% to 8.2%), with 5.7% (95% CI 5.2% to 6.1%) in basic information and 7.6% (95% CI 4.9% to 11.8%) in adverse outcomes. When stratified the 1542 total errors by error types, misallocation (assigning data to incorrect fields; 57.1%, 881/1542) and missed or omitted data (incomplete extraction of available data; 23.2%, 357/1542) accounted for the two most frequent errors, with misallocation occurring more in basic information (53.3%, 470/881), while missed or omitted data occurred more in adverse outcomes (96.1%, 343/357). Post hoc analysis examining the association between trial reporting quality (assessed using Consolidated Standards of Reporting Trials (CONSORT) 2025 and LLM data extraction error rates indicated that higher CONSORT adherence was associated with lower extraction error rates. Conclusions The data extraction error of Claude was relatively low, but it alerts LLM applications in evidence synthesis. Detailed checking for LLM outputs should be the primary consideration for evidence synthesisers.

BACKGROUND: The metabolic mechanisms underlying right ventricular (RV) dysfunction are poorly understood, particularly outside of group 1 pulmonary hypertension (PH). We aimed to identify metabolites and pathways associated with RV systolic function and explored whether associations differed by pulmonary vascular resistance, PH group 1 status, and sex. METHODS: We analyzed data from the multicenter PVDOMICS (Pulmonary Vascular Disease Phenomics) cohort. RV systolic function metrics included fractional area change (echo), global longitudinal strain (echo), and ejection fraction (cardiac magnetic resonance). We used linear regression adjusted for age, sex, body mass index, and PH group to assess associations between metabolites and RV function. Pathway enrichment analyses were used to identify pathways significantly associated with RV function. Interaction terms were assessed to determine whether metabolite associations were modified by pulmonary vascular resistance, group 1 PH status, or sex. Least absolute shrinkage and selection operator regression was used to develop metabolite-based scores for RV function, and prognostic performance was assessed. RESULTS: There were 979 participants with plasma metabolomics and RV function data. Linear regression identified 170 metabolites that were significantly associated with all 3 RV metrics. Androgenic steroid, gamma-glutamyl amino acid, polyamine, vitamin A, fatty acid, and sterol pathways are most strongly associated with RV systolic function. Two metabolites interacted with group 1 PH status, and 6 interacted with pulmonary vascular resistance. Four androgenic steroids are associated more strongly with RV systolic function in women compared with men. Metabolite-based scores were prognostically equivalent to RV systolic function metrics and less accurate than REVEAL Lite 2 scores. CONCLUSIONS: We provide a blueprint of metabolites and metabolic pathways associated with RV systolic function across the spectrum of PH. Novel links to vitamin A and glutathione metabolites were observed. We detected few metabolites that associated with RV systolic function differentially by group 1 PH status or degree of pulmonary vascular resistance elevation. Androgenic steroids may associate more strongly with RV systolic function in women compared with men.

Abstract Background Outpatient antibiotic stewardship programs (ASP) are recommended by the CDC and Joint Commission. We analyzed the impact of annual, focused syndrome-specific ASP interventions on trends in long-duration antibiotic prescribing (LDAP). Methods This was a retrospective, observational, multicenter cohort study from November 2020 through June 2025. All ambulatory encounters generating systemic antibiotic prescriptions within the healthcare enterprise were screened. Hospitalizations, emergency department visits, and infectious diseases encounters were excluded. Encounters generating ≥1 systemic antibiotic with >7 days duration were categorized as long-duration. Targeted departments (primary and urgent care) received direct intervention (eg, education, peer-comparison reporting, data tracking). LDAP was modeled over time by month and compared by diagnosis group (ASP-priority diagnoses vs nonpriority) and provider specialty department (ASP-targeted vs nontargeted) using linear regression models. Results Of 642 579 encounters included, 42.2% were long duration. LDAP in ASP-targeted departments dropped from 46.8% to 34.8% (difference −12 percentage points [pp]), whereas nontargeted departments dropped from 45.5% to 39.1% (difference −6.4 pp). The estimated annual LDAP decrease was 3.4 pp in targeted versus 2.4 pp in nontargeted departments (difference 1.0 pp, P = .009). Within targeted departments, significant LDAP decreases were seen both in priority and nonpriority diagnoses, whereas nontargeted departments showed no change in LDAP in priority diagnoses. In a sensitivity analysis of nonpriority diagnoses, ASP-targeted departments had a larger estimated annual decrease in LDAP versus nontargeted (difference 1.4 pp, P < .001). Conclusions Annual syndrome-specific ASP interventions correlated with improvements in LDAP, including outside of priority syndromes in targeted departments. LDAP is a viable metric for evaluating ambulatory ASPs.

ABSTRACT Sodium glucose co‐transporter 2 inhibitors (SGLT2i) and glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) are nephroprotective and their use is recommended for adults with chronic kidney disease (CKD). The role of SGLT2i and GLP‐1 RAs in patients with acute kidney injury (AKI) is unknown. This systematic review aimed to estimate the effect of SGLT2i or GLP‐1 RAs on clinical outcomes in AKI. We systematically searched Embase, MEDLINE, Scopus, Web of Science Core Collection, and clinical trials registries for observational studies and clinical trials from database inception to July 3, 2025. Included studies evaluated adults (≥ 18 years) with AKI during a hospitalization and compared patients subsequently exposed to either SGLT2i or GLP‐1 RAs to a non‐exposed control group. Random effects meta‐analyses were performed. Six studies related to SGLT2i (five observational, one randomized trial) and one related to GLP‐1 RAs (one observational) met eligibility criteria ( N = 432,048 patients). SGLT2i/GLP‐1 RA exposure was associated with lower odds of major adverse kidney events (MAKE) (OR 0.63, 95% CI 0.46–0.86) and all‐cause mortality [odds ratio (OR) 0.36, 95% confidence interval (CI) 0.21–0.62] compared to controls. The odds for kidney replacement therapy were lower with SGLT2i therapy in the three studies where it was evaluated (OR 0.61, 95% CI 0.40–0.93). Sensitivity analyses restricted to SGLT2i data were consistent with the overall findings [MAKE OR 0.63 (95% CI 0.42–0.95); Mortality OR 0.34 (95% CI 0.18, 0.65)]. Exposure to SGLT2i or GLP‐1 RAs after AKI, examined primarily in observational studies, was associated with improved clinical outcomes. These findings are promising and warrant evaluation in randomized clinical trials.