Figure S3. Male predominance across cohorts in NFH cohort.

Background:Glioblastoma is the most common and aggressive central nervous system malignancy with poor prognosis. Tumor-treating fields (TTFields), approved in China in May 2020, represents a significant advancement in GBM treatment. Leveraging the extensive real-world data accumulated in the Chinese Medical Information and Big Data Association (CHMIA) database, this study aims to assess clinical outcomes of Chinese patients with glioblastoma on TTFields therapy. Methods:This ambispective, observational study assessed post-marketing safety (data cut-off: November 15, 2021) and effectiveness (data cut-off: May 18, 2024) of TTFields in Chinese patients with newly diagnosed glioblastoma (ndGBM) and recurrent glioblastoma (rGBM). Safety outcomes included incidence and severity of skin adverse events (AEs); effectiveness was measured by overall survival (OS) and landmark OS rates. Results:Of 648 patients screened for this study, 315 were eligible and enrolled for analysis (ndGBM: n = 210; rGBM: n = 105). In the ndGBM cohort, the median OS was 19.9 months (95% CI: 13.4-24.8), with a 12-month OS rate of 63.5% (95% CI: 54.8-71.0). In the rGBM cohort, the median OS was 8.1 months (95% CI: 5.3-9.8), and 3-month and 6-month OS rates were 80.2% (95% CI: 70.4-87.1) and 58.7% (95% CI: 47.0-68.7), respectively. Most treatment-emergent AEs (TEAEs), including skin TEAEs, were mild to moderate (Grade 1-2). Conclusions:This study provided the largest real-world dataset to-date on TTFields in Chinese patients with glioblastoma. These patients showed survival outcomes similar to those in prior pivotal studies, without new safety concerns identified, supporting its use in Chinese glioblastoma population.

Figure S2. Bimodal age distribution of 900 primary glioma patients (NFH cohort).

This guideline was developed under the auspices of the Pediatric Neurosurgery Group of the Neurosurgery Branch of the Chinese Medical Association, the Neuro-oncology Expert Committee of the Chinese Society of Clinical Oncology, and the Neuro-oncology Professional Committee of the China Anti-Cancer Association. Craniopharyngioma is the most common tumor in the sellar turcica region among children, with the majority being adamantinomatous craniopharyngioma (ACP) and a smaller proportion being papillary craniopharyngioma (PCP). Management of craniopharyngioma involves not only tumor control but also the treatment of tumor-related hypothalamic dysfunction and pituitary endocrine disorders. To standardize the diagnosis and management of pediatric craniopharyngioma, this guideline incorporates evidence from 398 literature references. It provides recommendations on diagnostic evaluation, surgical strategies, radiotherapy principles, prognostic assessment, follow-up and long-term management, and targeted therapy. This guideline is intended to serve as a reference for healthcare professionals engaged in pediatric neuro-oncology. Recommendations were developed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, taking into account the quality of evidence, clinical applicability, and expert consensus. Key recommendations are supported by explanatory rationale. The guideline were reviewed and approved by 35 multidisciplinary experts and 6 external reviewers, followed by formal voting on each recommendation. For areas lacking high-quality evidences, future well-designed clinical trials are recommended to validate and update these recommendations.

Figure S7. Kaplan-Meier survival curves demonstrate superior survival outcomes for adult-type diffuse gliomas compared to pediatric-type diffuse gliomas throughout the disease course in the AYA patients.

Figure S11. Comparative analysis of genomics testing data demonstrated distinct genomic alteration frequencies in pediatric-type versus adult-type gliomas.

Sepsis remains a leading cause of death in intensive care, and effective therapies that restore host adaptation are limited. The hypothalamus is a central hub that coordinates endocrine and immune homeostasis, yet how defined hypothalamic microcircuits are engaged in sepsis induced neuroimmune dysregulation is poorly understood. Within the hypothalamus, the arcuate nucleus lies adjacent to the fenestrated median eminence, placing microglia close to circulating inflammatory cues, but how these cells respond during systemic inflammation remains unclear. Polymicrobial sepsis was induced in mice by cecal ligation and puncture (CLP). Arcuate microglial responses were evaluated by immunofluorescence, confocal and electron microscopy, acute slice live imaging, and transcriptomic profiling of the mediobasal hypothalamus using Smart-seq2 of sorted microglia and 10× single-nucleus RNA sequencing (snRNA-seq) with bioinformatic analyses. Microglia were depleted using a Tmem119 driven diphtheria toxin strategy. AgRP neuronal activity was assessed by c-Fos staining, whole-cell patch clamp recordings, and synaptic analysis. AgRP neurons were manipulated by chemogenetics. Sepsis outcomes were assessed by survival, clinical scores, systemic cytokines, endocrine hormones, and open field behavior. ARHGAP24 function was tested by lentiviral knockdown in LPS stimulated BV2 microglia, and Rac1 and Cdc42 signaling was pharmacologically modulated in vitro and via third ventricle delivery in vivo. CLP rapidly activated arcuate microglia and this activation persisted, accompanied by cytoskeletal remodeling and increased motility. AgRP neurons underwent sustained hyperexcitability after CLP, showing increased firing at both 1 day and 7 days with stage specific electrophysiological remodeling. Microglial depletion reduced AgRP activation, worsened sepsis severity, blunted corticosterone release, impaired inflammatory resolution, and compromised open field performance. Chemogenetic manipulation indicated that AgRP activity tracked sepsis outcomes independent of feeding behavior. snRNA-seq of the mediobasal hypothalamus revealed enhanced microglia-AgRP communication after CLP and identified Arhgap24 as a microglial state associated regulator induced along the activation trajectory. Arhgap24 knockdown enhanced microglial protrusive remodeling and amplified LPS induced cytokine responses. Pharmacological inhibition of Rac1 and Cdc42 using AZA1 restrained microglial remodeling and improved sepsis outcomes, whereas pathway activation using CN02 exacerbated these responses. Arcuate microglia act as central neuroimmune sensors that couple systemic inflammation to sustained functional remodeling of AgRP neurons, thereby linking sepsis to endocrine and behavioral adaptation. ARHGAP24 restrains Rac1/Cdc42 dependent cytoskeletal remodeling in microglia, maintains an adaptive microglial state, and shapes sepsis outcomes.

Microplastic compounds (MPCs), pervasive environmental pollutants, are increasingly implicated in human health risks. However, their neurotoxic mechanisms remain poorly understood. This study aims to investigate how MPCs contribute to neurodegenerative diseases, focusing on Alzheimer's (AD) and Parkinson's (PD) diseases as critical models. Using computational toxicology approaches, we screened 12 types of MPCs via SwissADME, identifying four representative MPCs with significant blood-brain barrier permeability and neurotoxic potential. Network toxicology (SwissTargetPrediction, ChEMBL) and protein interaction analysis (STRING, Cytoscape) revealed MPC-related AD/PD targets, including MAPK8 and SLC6A3, which were further validated through molecular docking (AutoDock). Key pathways-neuronal apoptosis and G protein-coupled receptor (GPCR) signaling-were disrupted by MPCs interactions, as evidenced by Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses. Notably, MPCs exhibited strong binding affinities to MAPK8 and SLC6A3, implicating these targets in neurodegeneration. Our findings establish a novel mechanistic link between environmental MPCs exposure and AD/PD pathogenesis, highlighting apoptosis dysregulation and GPCR signaling interference as central pathways. This work provides critical insights for policymakers and clinicians, underscoring the urgency of regulating MPCs to mitigate neurodegenerative risks and informing targeted therapeutic strategies.

Figure S5. Kaplan-Meier analysis demonstrated significantly superior prognosis in AYA glioma patients compared to adult glioma patients (age ≥40 years) within the NFH cohort.

Figure S8. Within pediatric-type diffuse gliomas (n = 79), patients harboring BRAF mutations demonstrated significantly superior survival outcomes compared to those with H3.3 mutations.

Table S1. Patient characteristics for NFH cohort. Table S2. Results of univariate and multivariate Cox regression analysis on OS.

PURPOSE:Gliomas represent the second most common malignancy and leading cause of cancer death in adolescents and young adults (AYA; ages 15-39 years), yet their molecular landscape remains incompletely characterized. This study aims to characterize the molecular landscape of primary gliomas in AYAs by integrating multi-omics data. EXPERIMENTAL DESIGN:We recruited a cohort of patients with histopathologically diagnosed primary gliomas. The data encompassed clinical, imaging, histopathologic, genomic testing, and survival outcome data. The correlations of clinicopathologic features, molecular characteristics, and anatomic heterogeneity with prognosis were evaluated. RESULTS:Adult-type gliomas (66.2%) predominated, but pediatric-type gliomas constituted 23.6%, exhibiting distinct clinicopathologic profiles: pediatric-type tumors harbored frequent H3.3 (51.9%), TP53 (35.1%), and BRAF mutations (22.8%), whereas adult-type showed isocitrate dehydrogenase (IDH, 72.5%) and TP53 alterations (48.6%). IDH and H3.3/BRAF mutations were mutually exclusive. Anatomically, midline involvement (18.3%) correlated with younger age (≤25 years, P = 0.019), frontal gliomas were predominantly IDH mutations (58.3%), and midline tumors were enriched H3.3 K27M mutations (52.5%). Survival analysis revealed that H3.3 K27M-mutant high-grade gliomas had the poorest prognosis (median survival: 16 months), whereas BRAF-driven low-grade gliomas showed favorable outcomes. Pediatric-type molecular alterations are enriched in AYA gliomas. IDH wild-type tumors require sequencing to detect pediatric-type drivers (e.g., H3.3/BRAF mutations). CONCLUSIONS:The treatment strategies for AYA gliomas should be determined by molecular classification rather than age-based stratification. Adult-type and pediatric-type gliomas exhibit distinct biological and driver profiles. AYA gliomas exhibit significant molecular-anatomic heterogeneity, with specific anatomic regions demonstrating enrichment of molecular signatures.

ObjectiveTo obtain perioperative cerebral blood flow measurements and assess the role of intraoperative blood flow evaluation in predicting postoperative complications.MethodsWe conducted a retrospective analysis of 102 cases of extracranial-intracranial (EC-IC) bypass surgery performed for flow augmentation in patients with moyamoya disease. The study monitored blood flow in the donor artery, graft vessels, and recipient artery at various stages. We measured superficial temporal artery (STA) flow during the perioperative period using a transit time ultrasonic flowmeter and Doppler ultrasound for real-time monitoring. A modified MBC scale was developed to evaluate the vascular network of the middle cerebral artery (MCA). STA flow measurements and the modified MBC scale were analyzed for their correlation with the incidence of cerebral hyperperfusion syndrome (CHS).ResultsA total of 102 hemispheres underwent revascularization through EC-IC bypass, comprising 69 direct bypass cases and 33 combined bypass cases. We observed fluctuations in donor vascular flow during the perioperative period. The STA flow increased post-anastomosis, stabilizing at an elevated level thereafter. Specifically, the STA in situ flow measured 7.06 ± 3.30 mL/min, while the STA-Cut flow was 59.75 ± 37.49 mL/min. The flow following STA anastomosis was 36.07 ± 22.59 mL/min. Prior to the anastomosis of the bonnet aponeurosis and skin, STA flow was recorded at 35.14 ± 22.93 mL/min. Postoperative STA flow on day one was 111.91 ± 62.06 mL/min, and on day seven it was 104.47 ± 64.93 mL/min. Notably, 12.74% of patients developed CHS. Logistic regression analysis indicated that the occurrence of CHS was significantly correlated with STA-Cut flow, suggesting that lower flow rates are associated with a higher likelihood of CHS. Additionally, surgical approach and the MBC scale were also related to the incidence of CHS.ConclusionThe transit time flow (TTF) measurements indicate that the superficial temporal artery (STA) transitions from a low-flow vessel in situ to a medium- to high-flow graft vessel immediately after anastomosis. The variability in flow within the graft vessel plays a significant role in the occurrence of postoperative hyperperfusion syndrome.

Background Meningiomas, among the most common primary intracranial tumors, present significant clinical challenges, particularly due to the propensity for recurrence in higher-grade variants and the paucity of effective non-surgical therapies.Lipid metabolism plays a critical role in tumor progression; however, the specific lipid dysregulation underlying meningioma biology remains incompletely understood. Methods In this study, meningioma tissues and patient-matched arachnoid membrane tissues were collected from 12 patients undergoing meningioma resection surgery. A comprehensive lipidomic analysis was performed on these tissues, and lipid metabolic differences between meningioma and arachnoid tissues were evaluated using multiple t-tests with appropriate correction for multiple comparisons. Results Our analyses revealed pronounced lipidomic remodeling in meningiomas, characterized by an overall increase in total lipid abundance compared with arachnoid tissues. Specifically, phospholipids such as phosphatidylcholine (PC), phosphatidylethanolamine (PE), and cardiolipin (CL) were significantly elevated, whereas phosphatidylinositol (PI) levels were reduced. Fatty acid composition also displayed distinct alterations, with decreased saturated fatty acids (SFAs) and increased polyunsaturated fatty acids (PUFAs). In addition, glycerophospholipids and sphingolipids, including sphingomyelin (SM) and ceramide (Cer), exhibited significant remodeling, reflecting profound metabolic reprogramming in meningiomas. Correlation analyses further suggested associations between specific lipid species (e.g., MePC and SM) and clinicopathological features such as tumor size and patient age. Conclusion These findings highlight the pivotal role of lipid metabolic reprogramming in meningioma pathogenesis and underscore the potential of lipidomic profiling to identify biologically relevant biomarkers and therapeutic targets through comparison with arachnoid tissue.

Figure S10. Co-occurrence mutation and mutual exclusiveness of driven genes in 206 AYA gliomas through WES analysis.

Background: High-grade gliomas, including isocitrate dehydrogenase (IDH)-mutant astrocytoma and IDH wild-type glioblastoma, have a poor prognosis and limited treatment options. The PTPRZ1-MET (ZM) fusion gene is a potential therapeutic target. This study evaluated vebreltinib, a highly selective, adenosine-triphosphate-competitive inhibitor of the mesenchymal-epithelial transition factor (MET), in patients with ZM-fusion-positive glioma. Methods: In this multicenter, open-label ZM FUsion GENe (FUGEN) trial, patients with previously treated astrocytoma, IDH-mutant, grade 4, or glioblastoma, IDH wild-type, harboring the ZM fusion were randomized in a 1:1 ratio to receive vebreltinib (300 mg orally twice daily) or control treatment (temozolomide or cisplatin plus etoposide) in 28-d cycles. The primary end point was overall survival (OS). Key secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety analyses. Results: Eighty-one patients (42 in the vebreltinib group and 39 in the control group) were included in the full analysis set. As of 2023 April 1, the median follow-up duration was 5.9 (range, 0.8 to 44.7) months in the vebreltinib group and 3.4 (range, 0.5 to 40.5) months in the control group. Median OS was significantly longer in the vebreltinib group than in the control group (6.3 months versus 3.4 months; hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.32 to 0.85; stratified log-rank P = 0.007). In the IDH-mutant subgroup, median OS was 7.7 months in the vebreltinib group and 3.3 months in the control group (HR, 0.48; 95% CI, 0.28 to 0.80; stratified log-rank P = 0.005). Among patients with a baseline tumor diameter of ≤3.0 cm, median OS was 32.5 months in the vebreltinib group versus 4.2 months in the control group (HR, 0.27; 95% CI, 0.07 to 1.06; stratified log-rank P = 0.046). Median PFS was also longer in the vebreltinib group (1.9 months versus 1.1 months; HR, 0.54; 95% CI, 0.33 to 0.88; stratified log-rank P = 0.012). The ORR was 9.5% with vebreltinib and 2.6% with control treatment. The incidence of grade ≥3 adverse events was comparable between groups, and no treatment-related deaths were reported. Conclusion: Vebreltinib significantly improved OS in patients with previously treated high-grade glioma harboring the ZM fusion, particularly in the subgroup with IDH-mutant astrocytoma, and the safety profile was manageable. Trial registration: This study was registered with the Chinese Drug Clinical Trial Registry (ChinaDrugTrials.org.cn) under the identifier, CTR20181664 (registration date: 2018 September 19).

Objective: The real-world efficacy, predictive biomarkers, and resistance mechanisms of Tumor Treating Fields (TTFields)-based triple therapy (combined with radiotherapy and temozolomide) in high-grade glioma (HGG) remain poorly defined. This study aimed to evaluate the survival benefit of triple therapy and identify genomic determinants of treatment response in the real-world cohort study. Methods: In this real-world cohort study, we included 118 patients with newly diagnosed HGG. All patients underwent comprehensive next‑generation sequencing of tumor tissue. A subset underwent integrated proteomic, phosphoproteomic and metabolomic profiling. The primary endpoint was overall survival (OS). Result: We found that triple therapy significantly prolonged median OS compared with standard therapy (25.8 vs 17.7 months; HR 0.55, 95% CI 0.35–0.88; P=0.0128). Multivariate analysis identified MGMT promoter methylation (HR 0.26, 95% CI 0.09–0.74; P=0.01), wild‑type PIK3CA (HR 6.30, 95% CI 1.39–14.44; P=0.01) and wild‑type EGFR (HR 2.89, 95% CI 1.04–8.04; P=0.04) as independent predictors of OS benefit. The TRS stratified patients into low‑risk (OS 27.5 months) and high‑risk (14.0 months) groups (HR 0.32, 95% CI 0.13–0.79; P=0.0015). In the CGGA cohort (n=54, no TTFields exposure), the TRS showed no prognostic association (HR 1.31, 95% CI 0.52–3.31; P=0.264). Multi-omics profiling revealed that TTFields-resistant tumors are characterized by coordinated upregulation of cell-cycle, DNA repair, and glycolytic pathways. Conclusions: TTFields within triple therapy confers a significant survival advantage in newly diagnosed HGG. The composite biomarker panel (MGMTp/ PIK3CA/EGFR) provides a framework for precision patient selection, and the identified molecular resistance axis offers targets for future combination strategies.

Figure S9. Kaplan-Meier analysis demonstrated statistically superior survival outcomes in GBM patients with supratentorial tumors compared to those with infratentorial tumors.

Figure S6. Proportion of cerebral hemisphere tumors across age group in AYA patients.

Glioblastoma is one of the most common primary malignant brain tumors, characterized by high aggressiveness and chemoresistance. Glioma stem like cells (GSCs) are recognized as critical drivers of tumor initiation, intratumoral heterogeneity, and treatment resistance. This protocol establishes a standardized 3D-tumor spheroid assay to functionally evaluate tumor cell stemness, providing a reproducible platform for investigating glioma malignant phenotypes and screening therapeutic strategies targeting GSCs. This streamlined 96 well assay reduces detection time and resource requirements compared to traditional multi round sphere forming workflows, thereby facilitating high throughput drug screening and detailed mechanistic studies of glioma biology in both research and preclinical settings.