To evaluate the association between a vessel size index (VSI
MRI
) derived from dynamic susceptibility contrast (DSC) perfusion imaging using a custom spin-and-gradient echo echoplanar imaging (SAGE-EPI) sequence and quantitative estimates of vessel morphometry based on immunohistochemistry from image-guided biopsy samples. The current study evaluated both relative cerebral blood volume (rCBV) and VSI
MRI
in eleven patients with high-grade glioma (7 WHO grade III and 4 WHO grade IV). Following 26 MRI-guided glioma biopsies in these 11 patients, we evaluated tissue morphometry, including vessel density and average radius, using an automated procedure based on the endothelial cell marker CD31 to highlight tumor vasculature. Measures of rCBV and VSI
MRI
were then compared to histological measures. We demonstrate good agreement between VSI measured by MRI and histology; VSI
MRI
= 13.67 μm and VSI
Histology
= 12.60 μm, with slight overestimation of VSI
MRI
in grade III patients compared to histology. rCBV showed a moderate but significant correlation with vessel density (r = 0.42, p = 0.03), and a correlation was also observed between VSI
MRI
and VSI
Histology
(r = 0.49, p = 0.01). The current study supports the hypothesis that vessel size measures using MRI accurately reflect vessel caliber within high-grade gliomas, while traditional measures of rCBV are correlated with vessel density and not vessel caliber.
Purpose
Anti-VEGF therapies remain controversial in the treatment of recurrent glioblastoma (GBM). In the current study we demonstrate that recurrent GBM patients with a specific diffusion MR imaging signature have an overall survival (OS) advantage when treated with cediranib, bevacizumab, cabozantinib, or aflibercept monotherapy at first or second recurrence. These findings were validated using a separate trial comparing bevacizumab with lomustine.
Experimental Design
Patients with recurrent GBM and diffusion MRI from the monotherapy arms of 5 separate Phase II clinical trials were included: 1) cediranib (NCT00035656); 2) bevacizumab (BRAIN Trial, AVF3708g; NCT00345163); 3) cabozantinib (XL184-201; NCT00704288); 4) aflibercept (VEGF Trap; NCT00369590); and 5) bevacizumab or lomustine (BELOB; NTR1929). Apparent diffusion coefficient (ADC) histogram analysis was performed prior to therapy to estimate “ADCL”, the mean of the lower ADC distribution. Pre-treatment ADCL, enhancing volume, and clinical variables were tested as independent prognostic factors for OS.
Results
The coefficient of variance (COV) in double baseline ADCL measurements was 2.5% and did not significantly differ (P=0.4537). An ADCL threshold of 1.24 um2/ms produced the largest OS differences between patients (HR~0.5) and patients with an ADCL>1.24 um2/ms had close to double the OS in all anti-VEGF therapeutic scenarios tested. Training and validation data confirmed baseline ADCL was an independent predictive biomarker for OS in anti-VEGF therapies, but not lomustine, after accounting for age and baseline enhancing tumor volume.
Conclusions
Pre-treatment diffusion MRI is a predictive imaging biomarker for OS in patients with recurrent GBM treated with anti-VEGF monotherapy at first or second relapse.
The CEST-SAGE-EPI technique provides simultaneous pH-sensitive and oxygen-sensitive image contrasts for evaluation of the brain tumor microenvironment. Advantages include fast whole-brain acquisition, in-line B correction, and simultaneous estimation of CEST effects, R , R2*, and R2' at 3 T.
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