Synaptogenesis-related neuron–glioma interactions are increasingly recognized in glioma, yet it remains unclear whether routine H&E morphology can capture these programs and improve prognostic stratification. We integrated H&E whole-slide images, transcriptomes, and clinical data from 434 TCGA gliomas. Deep learning and quantitative pathology yielded an integrated histomorphologic feature set of 2678 features. Synaptogenesis-related activity was quantified using ssGSEA for ninety-eight synaptogenesis-related genes. In the training cohort, Spearman analysis identified 149 correlated histomorphologic features, which were refined to thirty-five by elastic net regularization. Seventeen prognostic candidates were entered into the MIME1 framework, and the most parsimonious model, Enet[0.1], retained fourteen non-zero-coefficient features to define the synaptogenesis-associated histomorphologic signature and construct the pathology-derived risk score (PRS). Multi-omic analyses, Human Protein Atlas validation, and single-nucleus RNA-seq were used to investigate the hub gene and its cellular context. PRS robustly stratified survival in both training and validation cohorts and remained an independent prognostic factor after adjustment for age and 2021 WHO CNS grade. High-risk tumors showed increased stromal and immune scores and enrichment of immune, adhesion, and phagosome-related pathways. EFNB2 emerged as the hub gene and was enriched in glioblastoma, and EFNB2-positive malignant cells displayed prominent communication with neurons, including EFNB2-EPHB1 signaling. Exploratory re-analysis of the myeloid compartment further showed that glioblastoma was enriched for suppressive TAM-like states relative to astrocytoma grade 2, supporting a shift toward a more tumor-associated and potentially immunosuppressive microenvironment. Routine H&E histomorphology can capture synaptogenesis-related molecular programs in glioma. The resulting PRS provides clinically relevant prognostic stratification, while EFNB2-positive malignant cells may represent a candidate hub for neuron–tumor communication within a remodeled tumor ecosystem.

Objectives: The objective of this study is to explore the potential variations in metabolic activity across gliomas originating from distinct cortical regions, as assessed by O-(2-¹⁸F-fluoroethyl)-L-tyrosine positron emission tomography (¹⁸F-FET PET). Also, this study seeks to elucidate whether these metabolic disparities correlate with the molecular characteristics and clinical prognoses of the tumors. Specifically, this research aims to determine whether variations in ¹⁸F-FET PET uptake are indicative of underlying genetic or biochemical differences that could influence patients’ outcomes. Methods: The researchers retrospectively included 107 patients diagnosed with gliomas from neocortex and mesocortex, all of whom underwent hybrid PET/MR examinations, including ¹⁸F-FET PET and diffusion weighted imaging (DWI), prior to surgery. The mean and maximum tumor-to-background ratio (TBR) and apparent diffusion coefficient (ADC) values were calculated based on whole tumor volume segmentations. Comparisons of TBR, ADC values, and survival outcomes were performed to determine statistical differences between groups. Results: Among glioblastomas (GBMs, WHO grade 4) originating from the two cortical regions, there was a significant difference in the human Telomerase Reverse Transcriptase (TERT) promoter mutation rate, while no difference was observed in O⁶-Methylguanine-DNA Methyltransferase (MGMT) promoter methylation status. For WHO grade 3 gliomas, significant differences were found in the TERT promoter mutation rate and the proportion of 1p/19q co-deletion between the two cortical regions, whereas no difference was noted in MGMT methylation status. For WHO grade 2 gliomas, no molecular phenotypic differences were observed between the two cortical regions. In terms of survival, only GBMs originating from the mesocortex demonstrated significantly longer survival compared to those from the neocortex, while no statistically significant differences were found in survival for the other two groups. Conclusions: Gliomas originating from different cortical regions exhibit variations in metabolic activity, molecular phenotypes, and clinical outcomes.