Automated delineation of putative non-contrast-enhancing tumor in glioblastoma: Prognostic insights

BACKGROUND: Precise delineation of non-contrast-enhancing tumor (nCET) in glioblastoma (GB) is critical for maximal safe resection, yet routine imaging cannot reliably separate infiltrative tumor from vasogenic edema. The aim of this study was to develop and validate an automated method to identify peritumoral subregions compatible with nCET and assess its prognostic value. METHODS: Pre-operative T2-weighted and FLAIR MRI from 940 patients with newly diagnosed GB in four multicenter cohorts were analyzed. A deep-learning model segmented enhancing tumor, edema and necrosis; a non-local, spatially varying finite mixture model was applied to identify edema subregions characterized by relatively lower FLAIR hyperintensity, hypothesized to reflect nCET-related tissue. The ratio of these subregions to total edema volume defined the T2/FLAIR Heterogeneity Index (TFHI). Associations between TFHI and overall survival (OS) were examined with Kaplan-Meier curves and multivariable Cox regression. RESULTS: Higher TFHI values stratified patients with shorter OS. In the NCT03439332, TFHI above the optimal threshold was associated with a twofold increased hazard of death (hazard ratio [HR] 2.07, 95 % confidence interval 1.33-3.21; P = .0013) and a reduction in median survival of 98 days. Significant, though smaller, prognostic effects were confirmed in GLIOCAT & BraTS (HR= 1.37; P = .047), OUS (HR = 1.37; P = .0032) and pooled analysis (HR= 1.26; P = .0008). TFHI remained an independent predictor after adjustment for age, extent of resection and MGMT methylation. CONCLUSIONS: We present a reproducible, server-hosted tool for automated identification of imaging-defined, putative nCET-related peritumoral subregions and TFHI biomarker extraction that enables independent prognostic stratification. This approach provides a quantitative framework for studying peritumoral heterogeneity in GB.