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ABSTRACT Background Most genomic studies of adult-type diffuse gliomas have focused on predominantly European ancestry populations, limiting the generalizability of molecular classifications and precision medicine approaches. We assembled a multi-institutional glioma cohort of diverse patients to investigate how germline ancestry, molecular subtypes, and mutational processes shape tumor biology and clinical outcomes. Methods We analyzed 1,102 adults with WHO 2021–classified diffuse gliomas (IDH-mutant, 1p/19q-codeleted oligodendroglioma; IDH-mutant astrocytoma; IDH-wildtype glioma) from seven U.S. institutions. Whole-exome sequencing (WES) of FFPE tumors identified somatic alterations and COSMIC SBS v3.2 mutational signatures. Genetic ancestry was estimated from WES using 1000 Genomes reference populations. Overall survival was assessed using Kaplan–Meier and multivariable models. Results The cohort included 66.9% European (EUR), 21.1% Admixed American/Hispanic (AMR), 10.3% Admixed African (AFR), and 1.6% Asian (AS) ancestry. Survival followed expected molecular hierarchy (median overall survival: oligodendroglioma 15.7 years, astrocytoma 10.6 years, IDH-wildtype glioma 1.9 years). Within oligodendroglioma, AMR patients showed improved survival versus EUR (HR 0.67, 95% CI 0.48–0.94; p=0.011), with similar trends across subtypes. Somatic profiling confirmed canonical subtype-defining alterations and revealed higher ATRX alterations in AFR and AMR IDH-wildtype tumors compared with EUR. ATRX alterations were associated with improved survival only in AFR (p=0.003). Mutational signature analysis identified subtype-specific signatures, including therapy-associated signatures. Chemotherapy-related signatures were more frequent in EUR and AMR than in AFR. Conclusions This ancestrally diverse glioma cohort confirms established molecular classifications and identifies ancestry-associated differences in survival, somatic alterations, and mutational processes, indicating the critical need for broad representation to inform precision neuro-oncology. Key Points A multi-institutional glioma cohort validates subtype and survival patterns across ancestries. Therapy-associated mutational signatures differ by ancestry, suggesting distinct treatment-related mutational processes. Admixed American patients show improved survival, particularly in oligodendroglioma. Importance of the Study Most genomic studies of adult-type diffuse glioma have focused on populations of predominantly European ancestry which limits the ability to examine variation in tumor biology and clinical outcomes across populations. In this study, we assembled one of the largest ancestrally diverse cohorts of molecularly characterized adult diffuse gliomas, integrating germline ancestry inference with tumor whole-exome sequencing and mutational signature analysis. We confirm that established molecular classifications and survival hierarchies remain robust across ancestry groups. However, we also identified ancestry-associated differences in survival within specific tumor subtypes, higher ATRX alteration frequencies in African American and admixed American patients with IDH-wildtype tumors, and variation in therapy-associated mutational signatures across ancestry groups. These findings highlight the importance of incorporating population differences into genomic studies of glioma and provide a resource for future multi-ancestry investigations of glioma risk, tumor evolution, and treatment response, ultimately supporting more inclusive precision neuro-oncology.

Abstract Objective Invasive presurgical evaluation plays a key role in pediatric epilepsy surgery, particularly in magnetic resonance imaging (MRI)‐negative cases, by guiding resective, disconnective, or ablative procedures. This International League Against Epilepsy (ILAE) Pediatric Epilepsy Surgery Taskforce study provides an updated global overview of current invasive evaluation practices. Methods Group‐level data were collected from 61 epilepsy surgery programs (49 pediatric‐only) in 29 countries across six continents. Included were children and adolescents who underwent presurgical evaluation and epilepsy surgery in 2023. The study was designed to enable comparison with the similar ILAE survey conducted in 2004. Results A total of 2427 patients were included. Invasive evaluations were performed in 21.1% of cases, most frequently in North America (33.7%, higher than Europe: 18.0%, p = .003). Among invasive cases, 32.3% had no detectable MRI abnormalities. The main indication for invasive evaluation was seizure onset localization (88.1%), followed by motor or sensory mapping (17.2%) and language mapping (14.2%). Stereoelectroencephalography (SEEG) was the predominant technique (19.8% overall, 93.6% of invasive cases), more common in North America (30.0%, p = .021) and less common in South America (7.4%, p < .001). Subdural electrodes were used in only 3.2% of invasive cases, and combined depth and subdural approaches in 3.2%. SEEG‐guided radiofrequency thermocoagulation (RF‐TC) was performed in 40.9% of SEEG cases, most commonly in Asia (63.8%). In 16.2% of invasive evaluations, patients did not proceed to resection, disconnection, or ablation, with the highest rate in Europe (28.5%). Significance This global survey provides the first broad overview of invasive evaluation practices in pediatric epilepsy surgery across participating centers worldwide. It highlights the widespread adoption of SEEG, declining use of subdural electrodes, and increasing application of SEEG‐guided RF‐TC. The high proportion of MRI‐negative cases and the considerable proportion of patients not proceeding to resection, disconnection, or ablation underscore the complexity of contemporary surgical candidates and the need for further refinement of selection strategies.

Background Tumor-infiltrating lymphocytes (TILs) are established determinants of clinical outcomes in breast cancer. 1–6 While stromal TILs (sTILs) are commonly evaluated due to easier scoring and higher interobserver reproducibility, intraepithelial TILs may provide additional insights into anti-tumor immunity. 7 We aimed to comprehensively characterize immunotype-associated cellular landscapes in triple-negative breast cancer (TNBC) and identify features associated with clinical outcomes. Methods 212 TNBC tumors were classified into three immunotypes based on immune infiltrate location and density: immune desert (ID), immune excluded (IE), and immune inflamed (IN). 8 Single-cell spatial transcriptomics was performed on 75 tumors to define the cellular composition and functional states of the tumor microenvironment across immunotypes. Findings were validated and integrated with bulk RNA sequencing data and clinical outcome datasets from FinXX, CALGB-40603, I-SPY 2, and Real-World Clinico-Genomic Data (RWCGD) cohorts. Results Patients with IN tumors had significantly improved outcomes compared with ID tumors. Despite high sTILs, IE tumors showed poor outcomes similar to ID tumors. Single-cell spatial analysis revealed that ID and IE tumors exhibited reduced major histocompatibility complex I/II expression and fewer tumor-resident plasmacytoid dendritic cells (pDCs) compared with IN tumors, which were enriched for interferon-alpha (IFNα) and interferon-gamma (IFNγ) responses. High IFN response scores were associated with favorable outcomes across multiple therapy types in independent datasets. Deconvolution of RWCGD bulk RNA-seq data confirmed that pDC abundance correlated with improved outcomes specifically in hormone receptor–negative subtypes. Conclusions Our study highlights pDCs and IFN signaling as hallmarks of effective anti-tumor immunity in TNBC. Immunotype-based profiling underscores the limited prognostic value of sTILs alone in immune-excluded tumors and supports pDCs and IFN pathways as potential biomarkers for prognosis and therapeutic development in TNBC.

As machine learning (ML)-based decision support tools proliferate in clinical practice, understanding how clinicians integrate personalized ML predictions alongside randomized controlled trial (RCT) evidence is critical. We designed a web-based clinical decision support system (CDSS) presenting survival and adverse event data from a simulated RCT and ML model across 12 synthetic multiple myeloma scenarios. In a within-subjects study with 32 physicians, we evaluated how clinicians synthesize competing evidence sources to make treatment decisions. When ML and RCT outputs were concordant, physicians reported greater confidence than with RCT data alone. When results were discordant, most physicians shifted toward the ML-supported treatment, often before reviewing any information about model training or validation, suggesting a tendency toward automation bias rather than algorithm avoidance. Despite reporting higher perceived reliability after viewing model quality disclosures, physicians were largely unable to describe the validation procedures they had reviewed. Taken together, these findings reveal that clinicians may over-rely on ML recommendations even when equipped with tools designed to support critical appraisal. We discuss implications for CDSS design, clinician training, and the institutional safeguards needed before ML-based systems are deployed in high-stakes oncology settings.

Abstract Germline variants in DDX41 are the most frequent genetic predisposition to adult hematologic malignancies. The most common variants are truncating, implicating loss of function in the pathogenesis. However, non-truncating variants account for 30-40% of cases, and their impact on essential DDX41 functions remains unknown. We utilized a genetic complementation assay to assess the functionality of 10 recurrent germline non-truncating variants of DDX41. All variants restored viability to Ddx41 -deficient hematopoietic progenitor cells at exogenous expression levels. In contrast, the hotspot mutant p.R525H, which is somatically acquired at disease onset in >50% of patients, failed to restore viability. CRISPR-based modeling in cell lines and mice revealed heterogeneity: some variants were non-functional at endogenous expression levels whereas others maintained complete functionality, supporting normal cell proliferation and even lifelong hematopoiesis in a homozygous setting. Notably, co-expression of p.R525H with some variants caused impaired hematopoietic progenitor cell viability, indicating a dominant-negative effect of p.R525H. In contrast, other variants, all classified as variants of unknown significance, were unaffected by the presence of p.R525H. A screen of 100 disease-associated variants confirmed that many non-truncating germline variants are susceptible to p.R525H-mediated dominant-negative effects, whereas wild-type DDX41 is not. These findings indicate that DDX41 variant curation is complicated by variable effects on functionality and variant-specific interactions with somatically-acquired DDX41 mutations. The dominant-negative effect of p.R525H provides a mechanistic basis for the conclusion of recent patient cohort analyses that co-occurrence with a somatic hotspot mutation is a reliable indicator of DDX41-driven disease in carriers of non-truncating variants.

Abstract Epilepsy affects more than 50 million individuals globally and has a substantial genetic component that remains to be completely understood. Traditional studies have focused on severe, early onset cases enrolled through clinical or research settings. Recent biobank‐based approaches, leveraging large‐scale population datasets, offer opportunities to explore genetic associations in broader epilepsy phenotypes, including milder, later onset forms. We analyzed data from more than 750 000 individuals across the UK Biobank, All of Us, and Massachusetts General Brigham Biobank, including 20 026 individuals with epilepsy. Rare coding variant burden testing revealed a significant association with LGI1 , a known epilepsy gene. Among the other top 10 associated genes, seven had prior evidence linking them to epilepsy ( GABRG2 , ATP1A3 ), neurological disorders with comorbid seizures ( HTRA2 , KRIT1 , STAG1 ), possible involvement in seizure phenotypes ( ADAM23 ), or roles in neuronal function ( PDCD4 ). Thus, we provide the first statistical evidence for ADAM23 as a candidate gene for epilepsy, based on the suggestive association signal combined with prior biological evidence from both animal (canine and murine) and one recent human epilepsy case study, potentially contributing to human epilepsy through its direct interaction with LGI1 . Phenome‐wide analyses highlighted the pleiotropic effects of epilepsy genes, with LGI1 and ADAM23 predominantly associated with epilepsy, whereas other genes such as KRIT1 , TSC1 , and TSC2 exhibited broader systemic involvement. Our study shows the potential of population‐scale genomic data and suggests that integrating these datasets with deep phenotyping will uncover more novel insights into epilepsy genetics in the future.

7532 Background: BsAbs are highly effective, off-the-shelf T-cell engagers recently approved for relapsed/refractory multiple myeloma (MM) but remain underutilized in real-world settings. In partnership with the Florida Society of Clinical Oncology (FLASCO), a statewide initiative was launched to expand BsAb access through peer-led regional discussions focused on operational barriers, care transitions, and therapy management strategies. This study assessed the real-world impact of these interventions on BsAb utilization in FL. Methods: Multidisciplinary discussion forums were held in 4 FL metropolitan areas (Jan-Apr 2024). We conducted single and controlled interrupted time series (ITS) analyses using IQVIA eLAAD claims data (Apr 2023 - Sep 2025) including adult patients with a diagnosis of MM, evidence of claim activity, and provider state information. Fifth line or later (5L+) status was estimated as 3.3% of MM prevalence (Nikolaou et al.) BsAb utilization (% of MM 5L+ patients receiving a BsAb) was evaluated using segmented regression to estimate pre- and post-intervention trends, excluding the intervention period. We reported BsAb utilization by comparing FL with all other states, between community versus academic settings, and assessing the number of sites administering BsAb. Results: Before the intervention, BsAb utilization among MM 5L+ patients in FL rose from 8.2% (Apr 2023) to 11.2% (Dec 2023) (0.3 pp/mo; p=0.23), compared with a rise from 6.7% to 16.3% (1.3 pp/mo; p<0.0001) across all other states over the same time period. Post-intervention, BsAb utilization in FL increased from 22.8% (May 2024) to 35.9% (Sep 2025), reflecting a 7.0% immediate increase and 0.8 pp/mo sustained growth, exceeding the post-intervention trend observed across all other states (23.5% to 30.3%; 0.5 pp/mo). Overall, although pre-intervention BsAb utilization in FL was lower than all other states, FL demonstrated a 1.2 pp/month higher post-intervention utilization trend (p<0.001; Table). Post-intervention, FL community sites showed a 0.13 pp/mo higher BsAb utilization trend than academic sites, and the number of community sites administrating BsAb increased from 5 to 9, with no change among academic sites. Conclusions: This study suggests that the FLASCO-led, collaborative model increased BsAb utilization in FL community oncology sites and offers a framework for broader community adoption across other states. Parameter estimates from ITS model(s). FL (%) p-value Other US States (%) p-value Difference CITS:FL - Other US States (%) p-value Intercept (Apr 2023) 8.6 <.0001 7.7 <.0001 0.9 0.52 Monthly change pre-intervention 0.3 0.23 1.3 <.0001 -0.9 0.002 (Apr - Dec 2023) Immediate change post-intervention 7 0.01 0.2 0.87 6.8 0.01 (May 2024) Monthly change post-intervention 0.8 <.0001 0.5 <.0001 1.2 0.0003 (May 2024 – Sep 2025)

7516 Background: With the growing use of anti-CD38 therapies in early multiple myeloma (MM) management, there is a need for data in patients previously exposed to anti-CD38 therapy to guide decision making. In the Phase 3 IRAKLIA trial (NCT05405166), patients with relapsed/refractory MM (RRMM) received the anti-CD38 monoclonal antibody isatuximab (Isa) subcutaneously (SC) delivered via an innovative on-body injector (OBI) or intravenously (IV), with pomalidomide and dexamethasone (Pd). In this post hoc analysis, we examined outcomes in IRAKLIA patients with vs without prior anti-CD38 exposure. Methods: RRMM patients ≥18 years with ≥1 prior line of therapy including lenalidomide and a proteasome inhibitor were randomized to receive Isa SC (n=263) or IV (n=268) weekly in Cycle 1, then every 2 weeks, with Pd. Patients with prior anti-CD38 exposure <9 months (mos) before randomization or intolerance to anti-CD38 were excluded. Refractory patients were defined as those who failed to achieve minimal response on treatment or had progression within 60 days after last dose. Patients receiving Isa SC or IV were pooled. Results: Overall, 67 patients (12.6%) had prior anti-CD38 exposure with a median washout period of 20.2 mos, of which 26 (38.8%) were anti-CD38 refractory. Baseline characteristics were largely consistent between patients with or without prior anti-CD38 exposure; the median follow-up for the overall population was 12 mos. Patients with prior anti-CD38 exposure had an overall response rate (ORR) of 52.2%, 12-mo progression-free survival (PFS) rate of 40.6%, and median PFS of 8.5 mos. In patients without prior exposure, an ORR of 73.5%, 12-mo PFS of 68.8%, and non-estimable (NE) median PFS were reported. Anti-CD38 non-refractory vs refractory patients had an ORR of 48.8% vs 57.7%, 12-mo PFS of 38.9% vs 42.2%, and median PFS of 9.0 vs 7.5 mos. Patients with a longer washout period (>median of 20.2 mos) had an ORR of 63.6%, 12-mo PFS of 61.8% and NE median PFS, whereas patients whose prior anti-CD38 therapy ended more recently (≤median of 20.2 mos) had an ORR of 41.2%, 12-mo PFS of 19.2%, and median PFS of 6.7 mos. The safety profile of Isa + Pd was similar in patients with vs without prior anti-CD38 exposure. Conclusions: Isa + Pd demonstrated clinical benefit across anti-CD38–naïve, anti-CD38–exposed, and anti-CD38–refractory patients. A washout period >median of 20.2 mos resulted in outcomes comparable to those in anti-CD38–naïve patients, and outcomes were consistent between anti-CD38–exposed and anti-CD38–refractory patients after a >9-mo washout period. Efficacy of Isa + Pd in patients with prior anti-CD38 exposure from the IRAKLIA trial presents an opportunity to address an unmet need in a difficult-to-treat patient population. Clinical trial information: NCT05405166 .