Revealing the Infiltration: Prognostic Value of Automated Segmentation of Non-Contrast-Enhancing Tumor in Glioblastoma

BackgroundPrecise 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 nCET and assess its prognostic value. MethodsPre-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 then isolated edema subregions containing nCET. The ratio of nCET to total edema volume--the Diffuse Infiltration Index (DII)--was calculated. Associations between DII and overall survival (OS) were examined with Kaplan-Meier curves and multivariable Cox regression. ResultsThe algorithm distinguished nCET from vasogenic edema in 97.5 % of patients, showing a mean signal-intensity gap > 5 %. Higher DII is able to stratify patients with shorter OS. In the NCT03439332 cohort, DII above the optimal threshold doubled the hazard of death (hazard ratio 2.09, 95 % confidence interval 1.34-3.25; p = 0.0012) and reduced median survival by 122 days. Significant, though smaller, effects were confirmed in GLIOCAT & BraTS (hazard ratio 1.31; p = 0.022), OUS (hazard ratio 1.28; p = 0.007) and in pooled analysis (hazard ratio 1.28; p = 0.0003). DII remained an independent predictor after adjustment for age, extent of resection and MGMT methylation. ConclusionsWe present a reproducible, server-hosted tool for automated nCET delineation and DII biomarker extraction that enables robust, independent prognostic stratification. It promises to guide supramaximal surgical planning and personalized neuro-oncology research and care. Key Points- KP1: Robust automated MRI tool segments non-contrast-enhancing (nCET) glioblastoma. - KP2: Introduced and validated the Diffuse Infiltration Index with prognostic value. - KP3: nCET mapping enables RANO supramaximal resection for personalized surgery. Importance of the StudyThis study underscores the clinical importance of accurately delineating non-contrast-enhancing tumor (nCET) regions in glioblastoma (GB) using standard MRI. Despite their lack of contrast enhancement, nCET areas often harbor infiltrative tumor cells critical for disease progression and recurrence. By integrating deep learning segmentation with a non-local finite mixture model, we developed a reproducible, automated methodology for nCET delineation and introduced the Diffuse Infiltration Index (DII), a novel imaging biomarker. Higher DII values were independently associated with reduced overall survival across large, heterogeneous cohorts. These findings highlight the prognostic relevance of imaging-defined infiltration patterns and support the use of nCET segmentation in clinical decision-making. Importantly, this methodology aligns with and operationalizes recent RANO criteria on supramaximal resection, offering a practical, image-based tool to improve surgical planning. In doing so, our work advances efforts toward more personalized neuro-oncological care, potentially improving outcomes while minimizing functional compromise.