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Volumetric Analysis of Contrast Enhancement in Patients With Newly Diagnosed Glioblastomas. BACKGROUND AND OBJECTIVES: The results of chemotherapy trials in patients with newly diagnosed glioblastoma during the past 30 years have been disappointing largely because the blood-brain barrier is extremely effective at restricting drug entry into the brain. This study was designed to estimate the proportion of the tumor volume in patients with newly diagnosed glioblastomas that have sufficient blood-brain barrier disruption to allow the penetration of gadolinium which is where chemotherapy most likely penetrates. METHODS: Preoperative MRI scans were analyzed from 50 consecutive patients with histologically confirmed newly diagnosed glioblastoma and requisite imaging at a single tertiary-care institution in 2022. Tumor segmentation was performed automatically using the HD-GLIO tool. Nonoverlapping volumes were extracted for the T2/fluid-attenuated inversion-recovery hyperintense, contrast-enhancing, and necrotic segments. RESULTS: Patients had a median age of 64.5 years (range 35-85), 62% were male, and the median daily dexamethasone dose at the time of the preoperative MRI was 10 mg (range 0-40). Median volumes of each segment were the following: T2/fluid-attenuated inversion-recovery hyperintense = 54.2 cm3 (IQR: 24.5-92.4), contrast enhancing = 17.2 cm3 (IQR: 3.3-33.5), and necrosis = 4.6 cm3 (IQR: 0.1-15.2). Analysis revealed that only 19% of the preoperative tumor volume was contrast enhancing (IQR: 7.1-29), 74% was T2/fluid-attenuated inversion-recovery hyperintense only (IQR: 56.5-92.5), and 7% was necrotic (IQR: 0.4-12.4). CONCLUSION: This study demonstrates that the gadolinium permeable volume in preoperative patients with glioblastoma makes up only 19% of the total tumor volume. As most cytotoxic and targeted agents are much less likely than gadolinium to cross the blood-brain barrier, it is likely that >80% of the tumor will have very limited exposure to systemically administered drugs. These findings suggest that meaningful improvements in the survival of these patients will require focusing on strategies to improve the delivery of therapeutic concentrations of systemically administered drugs to the large nonenhancing regions of this cancer.