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Abstract Background Biological sex and endocrine signaling influence cancer biology, immune response, and therapeutic outcomes. Recent evidence suggests that testosterone signaling may exert brain-context-dependent protective effects in glioblastoma through the hypothalamic-pituitary-adrenal axis, reduced glucocorticoid-mediated immune suppression, and altered tumor-immune interactions. We assessed whether testosterone replacement therapy (TRT) exposure was associated with survival in solid tumor central nervous system (CNS) metastases and glioblastoma (GBM, IDH-wildtype, WHO grade 4), settings in which post-diagnosis survival and TRT timing can be clinically defined. Methods We performed a retrospective Mayo Clinic cohort study of adult patients with molecularly confirmed glioblastoma and solid tumor CNS metastases confirmed from neuroimaging reports using large language model-assisted adjudication. TRT exposure was defined by testosterone-specific prescription evidence within prespecified peri-diagnostic windows. Overall survival was evaluated using propensity score-matched Cox models, 24-month administratively censored Cox models, time-dependent Cox sensitivity analyses, and 24-month restricted mean survival time. Results In the pooled solid tumor CNS metastasis cohort, TRT exposure was associated with improved overall survival after propensity score matching (HR 0.80, 95% CI 0.65–0.98, p=0.029) and a 3.22-month improvement in 24-month restricted mean survival time. In glioblastoma, TRT exposure was similarly associated with improved overall survival after propensity score matching (HR 0.56, 95% CI 0.38–0.82, p=0.003) and a 5.81-month improvement in 24-month restricted mean survival time. Conclusions TRT exposure was associated with improved survival in CNS metastases and glioblastoma. These hypothesis-generating findings support prospective studies incorporating TRT timing, hormone levels, corticosteroid exposure, immune correlates, and tumor-specific stratification. Key points TRT exposure is associated with improved survival in aggressive brain tumors. Survival associations persist after propensity score matching. Prospective studies should define TRT timing, hormone levels, and immune effects. Importance of Study This study evaluates testosterone replacement therapy (TRT) in aggressive intracranial tumors with clinically interpretable survival timelines. Building on recent evidence that androgen signaling may have protective brain-specific effects in glioblastoma, we extend this question to CNS metastases. In a multi-site Mayo Clinic cohort, TRT exposure was associated with improved survival in CNS metastases and glioblastoma, supporting androgen biology as an underrecognized factor in neuro-oncology outcomes. These findings provide rationale for prospective clinical trials incorporating TRT timing, hormone levels, corticosteroid exposure, immune profiling, and tumor-specific stratification.

Abstract Introduction Postoperative radiotherapy is an adjuvant therapy for brain metastases(BrMs) that improves local recurrence(LR). The radiosensitivity index(RSI) is a 10-gene index of pan-cancer molecular radiosensitivity previously validated for predicting radiotherapy response in clinical datasets. In this external validation study, we evaluate RSI as a predictor of local recurrence(LR) after radiotherapy in resected BrM. Methods Patients from University Health Network Toronto(UHN) and McGill University who had a resected BrM and subsequently underwent whole brain radiation(WBRT) or stereotactic radiosurgery(SRS). RSI was calculated using a ranked linear regression model from the weighted expression of 10 radiosensitivity genes, with higher values corresponding to radioresistance. Radiophenotype was determined using a previously validated RSI cutoff of < 0.375 to identify radiosensitive tumors. LR was defined as recurrence in the resection cavity and overall survival(OS) was measured from time of BrM diagnosis. Results 106 BrM patients were included, comprising 29 breast, 37 GI, 33 lung, and 7 melanoma primary sources. Mean age at surgery was 59.2 years, 31.1%(n = 33) were male, 67.9%(n = 72) had WBRT, 23.6%(n = 25) had a subtotal resection, and 30.2%(n = 32) had postoperative chemotherapy. Overall, 34.0%(n = 36) patients had LR. Patients with breast BrMs had median RSI 0.70(IQR:0.55-0.75, 10.3% radiosensitive) with 48.3% LR(n = 14); gastrointestinal BrMs had median RSI 0.43(IQR: 0.35-0.46, 29.7% radiosensitive) and 24.3% LR(n = 9); lung BrMs had median RSI of 0.67(IQR:0.66-0.71, 9% radiosensitive) and 33.3% LR(n = 11); melanoma BrMs had median RSI of 0.72(IQR:0.53-0.92, 0% radiosensitive) and 28.6% LR(n = 2). After adjusting for demographics, primary organ, radiotherapy, resection extent, among others, RSI did not predict LR(p = 0.56) or OS(p = 0.61). Discussion RSI did not predict either LR or OS in patients with surgically resected BrMs status post radiotherapy, further establishing the need for improved predictive scores in this population.

Importance Elevated low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for cardiovascular disease, the leading cause of premature death worldwide. Assessing the LDL-C–related burden is critical for guiding prevention and treatment strategies. Objectives To estimate the global, regional, and national burden of ischemic heart disease and ischemic stroke attributable to elevated LDL-C (relative to 35-54 mg/dL) from 1990 to 2023 and to quantify the contributions of population growth, aging, risk-deleted burden, and exposure changes to burden trends. Design, Setting, and Population This comparative risk assessment, part of the Global Burden of Disease Study 2023, estimated population-level LDL-C exposure and associated health loss in 204 countries and territories. Mean LDL-C levels were estimated using spatiotemporal gaussian process regression based on 806 studies across 161 countries. Relative risks were derived from meta-analyses of 38 randomized clinical trials. Population-attributable fractions for deaths and disability-adjusted life-years (DALYs) were estimated by age and sex for adults aged 25 years or older from 1990 to 2023, with 95% uncertainty intervals. Exposure Population-level LDL-C concentrations. Main Outcomes and Measures Population-attributable fractions, counts, and rates (all ages and age standardized per 100 000) of LDL-C–attributable deaths and DALYs from ischemic heart disease and ischemic stroke, with uncertainty intervals. Results In 2023, elevated LDL-C accounted for 3.6 million deaths (95% uncertainty interval, 2.2-5.4 million; 6.0% of global mortality) and 90.7 million DALYs (95% uncertainty interval, 58.9-123.3 million; 3.2% of DALYs). Although global all-ages rates remained stable, age-standardized death and DALY rates decreased by 45.6% and 39.5%, respectively, since 1990. In 2023, age-standardized LDL-C–attributable DALY rates were highest in Eastern Europe and lowest in high-income Asia-Pacific. One-third of the global LDL-C burden occurred in India and China. Population growth and aging drove the increasing burden, with notable regional disparities in LDL-C exposure and risk-deleted DALY rates shifting toward middle-sociodemographic settings. Conclusions and Relevance Despite declining age-standardized rates, the absolute LDL-C burden has increased since 1990 due to demographic changes and has shifted toward middle-sociodemographic countries. Measurement and surveillance gaps persist. Strengthened prevention, diagnosis, and treatment access strategies are essential to mitigate the health burden of LDL-C.

Abstract Background Glioblastoma (GB) exhibits marked tumor microenvironmental heterogeneity, contributing to both therapy resistance and poor survival outcomes. Intercellular adhesion molecule 1 (ICAM1) is an inflammation-associated adhesion molecule implicated in immune-stromal interactions, but its clinical and biological significance in GB remains incompletely defined. Methods We performed ICAM1 immunohistochemistry, bulk RNA sequencing, DNA methylation analysis, single-nucleus RNA sequencing, and preoperative MRI-derived morphologic feature analysis across multi-institutional cohorts of treatment-naïve IDH-wildtype GB. Results High ICAM1 expression at both transcript and protein levels is associated with shorter overall survival, particularly within the mesenchymal transcriptional subtype. ICAM1 expression is inversely associated with promoter methylation. Single-nucleus RNA-sequencing analysis shows that ICAM1-high tumors are enriched for mesenchymal, hypoxia, stress-associated, and immunosuppressive myeloid programs, suggesting that ICAM1 reflects a multicompartment inflammatory tumor ecosystem. ICAM1 expression, tumor surface irregularity, and patient age are independently prognostic and minimally correlated, capturing complementary clinical, imaging, and molecular features of GB biology. When combined, our Clinical-Imaging-Molecular (CIM) framework refines outcome prediction across independent GB cohorts using routinely available clinical data, conventional imaging, and standard immunohistochemistry. Conclusions ICAM1 characterizes an immune-remodeled, stress-adapted GB ecosystem associated with poor clinical outcomes. Integrating patient age, surface irregularity, and ICAM1 expression yields a scalable and clinically accessible prognostic framework for GB, supporting tailored outcome prediction, particularly in low- and middle-resource settings without routine access to advanced molecular profiling.

Abstract Background Glioblastoma (GBM) is the most common malignant primary brain tumor and is associated with a poor prognosis. Repurposed posaconazole (PCZ) has demonstrated efficacy in vitro by targeting key metabolic pathways. The aim of this study was to determine the neuropharmacological profile of PCZ in patients with GBM through a Phase 0 first-in-human trial for this indication (NCT04825275). Methods We conducted an open-label, non-randomized, parallel-arm trial in participants with primary or recurrent GBM. Patients in the treatment arm received oral PCZ for 7-10 days presurgically to achieve steady-state concentrations. Microdialysis catheters were implanted to measure interstitial drug levels. Postoperative tissue and fluid samples were analyzed to evaluate PCZ pharmacokinetics (mass spectrometry) and pharmacodynamics, including vascular density, apoptosis, and metabolite concentrations (lactate and pyruvate) compared to controls. Results The trial was closed early due to slow accrual, enrolling 2 participants in the PCZ arm and three in the control arm. No drug-related safety issues were observed. Although PCZ was undetectable in microdialysate fluid, it accumulated in tumor tissue, with concentrations showing an association with CD31-measured endothelial content. PCZ-treated tumors exhibited trends toward lower BCL2 expression indicative of increased apoptosis, and significantly lower pyruvate levels in the tumor periphery compared to controls. Plasma lactate levels in treated patients normalized to control levels over 24 h. Conclusions Despite limited accrual, this trial provides the first clinical evidence that oral PCZ accumulates in human GBM tissue and shows preliminary signals of metabolic modulation. These findings provide biological rationale warranting further clinical investigation, potentially utilizing direct tissue sampling rather than microdialysis.

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.