Zadeh, G Z

Abstract Background Approximately 12,000 adolescents and young adults (ages 15-39, AYAs) are diagnosed with a primary central nervous system (CNS) tumor each year. DNA methylation profiling has transformed CNS tumor classification by refining diagnostic accuracy and identifying biologically distinct subtypes, but its application has not been systematically evaluated in the AYA population. In this study, we examined the spectrum of CNS tumor types across age groups, with a focus on the AYA population. Methods We assembled a large dataset of CNS tumor samples with age annotations and methylation profiles matching with high confidence to a CNS tumor type using the NCI/Bethesda classifier. Prevalence of tumor type, methylation class and DNA copy number aberrations were compared across age strata (pediatric, AYA and adult). Results The cohort of 21,099 CNS tumors included 5139 tumors from AYAs (24%), which showed a mixed pattern, with tumors typical of childhood (e.g. medulloblastoma) as well as those common in older adults (e.g. glioblastoma). Several tumor types were specifically enriched in the AYA, including IDH-mutant astrocytoma, pleomorphic xanthoastrocytoma, posterior fossa group B ependymoma, and diffuse hemispheric glioma, H3 G34-mutant, among others. Distinct methylation subclasses of multiple tumor types were observed in the AYA, and patterns of genomic aberrations showed age-specific distributions. Conclusion Large-scale methylation profiling revealed unique classification patterns of CNS tumors in AYAs, with specific tumor types, subclasses, and genomic alterations enriched in this population. These data may serve as a valuable reference resource for better understanding the spectrum of CNS tumors affecting AYA patients.

Abstract Background Preparing tumor board patient summaries is time intensive. Large-language-model based systems may automate summarization but require real-world evaluation prior to clinical use. We performed an exploratory retrospective evaluation of the Microsoft Healthcare Agent Orchestrator (HAO), deployed in a Mayo Clinic–controlled staged environment, to generate tumor board–style patient summaries from retrospective Electronic Health Record (EHR) notes. Methods HAO generated summaries for breast, hepatobiliary, and neuro-oncology tumor board cases using up to the most recent 1,000 clinical notes. Clinician reviewers evaluated outputs via REDCap surveys across perceived factuality, completeness, clarity/conciseness, temporal cohesion, comparative performance, safety, and clinical utility (0–4 Likert scale). Reviewers were permitted to query the HAO chat interface to address missing details. Automated factuality was assessed using TBFact (bidirectional entailment), reporting precision and recall against available reference summaries. Results Among 57 survey responses from 5 different physicians, mean scores exceeded 2.8 across domains, with medians of 3 for most axes. In an exploratory comparison, oncology fellows required less time to review HAO-generated summaries than to manually generate patient summaries (mean difference 13.57 minutes per patient, p<0.001), although this difference may be influenced by prior familiarity with the same cases; 96% of survey responses indicated that HAO would save time. TBFact evaluations showed higher recall than precision across domains, consistent with broad capture of reference content alongside additional content that was not present in gold-standard summaries. Attribution was viewed favorably but showed issues with primary-source specificity and link reliability. Conclusions In a controlled Mayo environment, HAO demonstrated moderate performance and was associated with reduced review time for tumor board preparation. These findings are promising but preliminary and do not establish clinical safety, noninferiority to manual review, or readiness for routine clinical use. Limitations, including verbosity, specialty-specific content gaps, and inconsistent attribution, highlight the need for iterative refinement and further evaluation. Graphical Abstract Created using ChatGPT

e20700 Background: Leptomeningeal metastases (LM) are a particularly challenging complication of EGFR-mutant non–small cell lung cancer (NSCLC) and are often associated with rapid neurologic decline. Intrathecal (IT) chemotherapy is frequently used in this setting, but its efficacy and safety have not been well defined. We conducted a systematic review and meta-analysis to assess neurologic response and treatment-related toxicity associated with IT chemotherapy in EGFR-mutant NSCLC with LM. Methods: We performed a PRISMA-guided search of MEDLINE, EMBASE, Cochrane CENTRAL, and targeted grey literature to identify prospective and retrospective studies reporting outcomes of IT chemotherapy in EGFR-mutant NSCLC with LM. Quantitative analyses were restricted to studies with extractable endpoints. Neurologic response and grade ≥3 toxicity were pooled using random-effects generalized linear mixed models with logit transformation. Heterogeneity was assessed using I² and τ². Prespecified sensitivity analyses examined neurologic response by route of administration (lumbar puncture vs Ommaya reservoir), concomitant EGFR-TKI use, and study design or era. Results: Four studies comprising 76 patients reported extractable neurologic response data. The pooled neurologic response rate was 81.9% (95% CI, 64.0%–92.0%), with moderate heterogeneity (I² = 63.4%, p = 0.04). Grade ≥3 toxicity was reported in three studies (n = 59), with a pooled incidence of 11.8% (95% CI, 3.2%–34.9%) and substantial heterogeneity (I² = 71.3%, p = 0.03). Myelosuppression was the most frequently reported severe adverse event, and no consistent signal of severe neurologic toxicity was identified. Exploratory sensitivity analysis suggested higher neurologic response in LP-treated cohorts compared with mixed LP/Ommaya cohorts; however, this finding was driven by a single small study and is likely influenced by limited sample size and selection bias and should be considered hypothesis-generating only. Neurologic response was otherwise consistent across study designs and eras. Stratification by concomitant EGFR-TKI use was limited by incomplete reporting. Median overall survival was variably reported and ranged from approximately 7 to 12 months. Conclusions: In EGFR-mutant NSCLC with leptomeningeal metastases, IT chemotherapy is associated with a high pooled neurologic response and relatively uncommon severe toxicity, although heterogeneity across studies remains substantial. The observed neurologic benefit appears consistent across study designs and is more likely related to underlying EGFR-sensitive disease biology than to a definitive effect of route of administration. These findings support further prospective evaluation of IT chemotherapy as part of multimodal treatment strategies in this high-risk population.

4157 Background: IDH1/2 mutations occur in ~25% of cholangiocarcinomas (CCAs). Preclinical studies suggest synergy between PARP inhibition and PD-L1 blockade. We previously conducted a phase II trial of olaparib plus durvalumab in advanced IDH -mutant CCA. We report matched baseline tissue and serial cell-free DNA (cfDNA)-based correlative analysis of pts samples. The primary objective was to develop a cfDNA methylome signature as a non-invasive biomarker. Methods: This single-arm, open-label phase II study (NCT03991832) enrolled patients with unresectable/metastatic IDH -mutant CCA and ≤2 prior lines of systemic therapy. Patients received olaparib 300 mg orally twice daily and durvalumab 1500 mg IV every 4 weeks. Blood samples were collected at baseline and monthly while on treatment for planned correlatives to examine R2HG, S2HG, and artemin levels using HPLC (High-Performance Liquid Chromatography). Cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq) was performed on pts cfDNA samples and case-matched IDH -wildtype pts. Formalin-fixed, paraffin-embedded blocks of baseline tumor biopsies were used for multispectral fluorescent IHC (FL-IHC) using a 6-marker panel composed of pan-cytokeratin, CD4, CD8, CD163, PD-L1, and CD68. Results: Ten patients were enrolled (median age 63.5 y; 50% female; 90% received prior platinum). Median treatment duration was 1.95 mo (range 1.8–13.5). No complete or partial responses were observed. DCR was 30% (3 patients with stable disease); one patient remained on therapy for 13.5 mo before progression. Median PFS was 1.97 mo (95% CI 1.73–3.93). HPLC from baseline plasma showed lower baseline artemin levels correlated with stable disease (p=0.038), while R2HG/S2HG ratios showed no association with outcome. FL-IHC showed enriched immune cell populations, specifically CD4 + T cells (p=0.0032) and a trend for CD68 + macrophages (p=0.062), in the tumor stroma compared with tumor core. 54 plasma samples (from 8 patients) were profiled with cfMeDIP-seq along with 8 IDH -wildtype controls. Using top 100 differentially methylated regions, the circulating tumour DNA methylome exhibited a highly specific signature, accurately discriminating IDH -mutant and IDH -wildtype CCA regardless of treatment status. The specific differentially methylated gene pathways between groups were comprehensively examined in both on-treatment and baseline plasma samples. Conclusions: Advanced IDH -mutant CCA harbors an immune-excluded phenotype, which may underlie primary resistance to immunotherapy. Plasma cfDNA methylome signature can accurately discriminate CCA with IDH mutations. Clinical trial information: NCT03991832 .

Abstract Background Meningiomas exhibit clinical heterogeneity. Radiotherapy (RT) remains the only adjuvant therapy, but tumor-control is variable, and biomarkers are limited. NRG/RTOG-0539 is the first prospective phase 2 trial to stratify meningioma patients for adjuvant RT based on clinical risk. Here, we apply modern molecular tools to this cohort and identify correlates of RT response. Methods Tumor tissue from 100 RTOG-0539 patients was profiled using DNA methylation arrays, RNA sequencing, and whole-exome sequencing. Recurrence scores, Molecular Groups, gene expression, and copy number alterations were compared across clinical groups and between RT responders and non-responders; non-response was defined as progression or death within 3 years. Results Modern grading criteria, including brain invasion, TERT mutation, CDKN2A/B deletion, and 1p/1q status, would reclassify 10% of tumors and alter treatment group assignment in 7%. Non-responders to RT exhibited more frequent 1p and 14q loss, and more copy number alterations. Transcriptomic and epigenetic profiling revealed immune-related signatures in responders and cell cycle–related pathways in non-responders, several of which overlapped with targets of vorinostat, a histone deacetylase inhibitor previously validated in aggressive meningioma models. The Proliferative Molecular Group was an independent predictor of post-RT recurrence in multivariable analysis, outperforming WHO grade. Conclusion Multi-omic analysis of the NRG/RTOG-0539 cohort shows that updated WHO grading criteria, incorporating molecular and cytogenetic features, improve risk stratification. However, molecular classification, particularly the Proliferative group, remains an independent and stronger predictor of RT response. These findings support integrating molecular biomarkers alongside modern grading frameworks to guide treatment and trial design in meningioma. Clinical Trial Information NCT00895622.