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The association of overall survival (OS) with tumor burden, including contrast enhanced (CE) volume on CE T1-weighted images, fluid-attenuated inversion recovery (FLAIR) hyperintense volume, and 3, 4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (FDOPA) hypermetabolic volume, in isocitrate dehydrogenase (IDH) wild-type gliomas remains unclear. This study aimed to assess the association between biological tumor burden in pre- and post-operative status and OS in IDH wild-type gliomas, and evaluated which volume was the best predictor of OS. Thirty-four patients with treatment-naive IDH wild-type gliomas (WHO grade II 6, III 15, IV 13) were retrospectively included. Three pre-operative tumor regions of interest (ROIs) were segmented based on the CE, FLAIR hyperintense, and FDOPA hypermetabolic regions. Resected ROIs were segmented from the post-operative images. Residual CE, FLAIR hyperintense, and FDOPA hypermetabolic ROIs were created by subtracting resected ROIs from pre-operative ROIs. Cox regression analysis was conducted to investigate the association of OS with the volume of each ROI, and Akaike information criterion was used to assess the fitness. Residual CE volume had a significant association with OS [hazard ratio (HR) = 1.26, p = 0.039], but this effect disappeared when controlling for tumor grade. Residual FDOPA hypermetabolic volume best fit the regression model and was significantly associated with OS (HR = 1.18, p = 0.008), even when controlling for tumor grade. FLAIR hyperintense volume showed no significant association with OS. Residual FDOPA hypermetabolic burden predicted OS for IDH wild-type gliomas, regardless of the tumor grade. Furthermore, removing hypermetabolic and CE regions may improve the prognosis.

Although tumor localization and 3,4-dihydroxy-6-18F-fluoro-l-phenylalanine (FDOPA) uptake may have an association, preferential tumor localization in relation to FDOPA uptake is yet to be investigated in lower-grade gliomas (LGGs). This study aimed to identify differences in the frequency of tumor localization between FDOPA hypometabolic and hypermetabolic LGGs using a probabilistic radiographic atlas. Fifty-one patients with newly diagnosed LGG (WHO grade II, 29; III, 22; isocitrate dehydrogenase wild-type, 21; mutant 1p19q non-codeleted,16; mutant codeleted, 14) who underwent FDOPA positron emission tomography (PET) were retrospectively selected. Semiautomated tumor segmentation on FLAIR was performed. Patients with LGGs were separated into two groups (FDOPA hypometabolic and hypermetabolic LGGs) according to the normalized maximum standardized uptake value of FDOPA PET (a threshold of the uptake in the striatum) within the segmented regions. Spatial normalization procedures to build a 3D MRI-based atlas using each segmented region were validated by an analysis of differential involvement statistical mapping. Superimposition of regions of interest showed a high number of hypometabolic LGGs localized in the frontal lobe, while a high number of hypermetabolic LGGs was localized in the insula, putamen, and temporal lobe. The statistical mapping revealed that hypometabolic LGGs occurred more frequently in the superior frontal gyrus (close to the supplementary motor area), while hypermetabolic LGGs occurred more frequently in the insula. Radiographic atlases revealed preferential frontal lobe localization for FDOPA hypometabolic LGGs, which may be associated with relatively early detection.

To develop a robust amine chemical exchange saturation transfer (CEST) physical phantom, validate the temporal stability, and create a supporting software for automatic image processing and quality assurance. The phantom was designed as an assembled laser-cut acrylic rack and 18 vials of phantom solutions, prepared with different pHs, glycine concentrations, and gadolinium concentrations. We evaluated glycine concentrations using ultraviolet absorbance for 70 days and measured the pH, relaxation rates, and CEST contrast for 94 days after preparation. We used Spearman’s correlation to determine if glycine degraded over time. Linear regression and Bland–Altman analysis were performed between baseline and follow-up measurements of pH and MRI properties. No degradation of glycine was observed (p > 0.05). The pH and MRI measurements stayed stable for 3 months and showed high consistency across time points (R2 = 1.00 for pH, R1, R2, and CEST contrast), which was further validated by the Bland–Altman plots. Examples of automatically generated reports are provided. We designed a physical phantom for amine CEST-MRI, which is easy to assemble and transfer, holds 18 different solutions, and has excellent short-term chemical and MRI stability. We believe this robust phantom will facilitate the development of novel sequences and cross-scanners validations.

IntroductionThere is growing evidence that the subventricular zone (SVZ) plays a key role in glioblastoma (GBM) tumorigenesis. However, little is known regarding how the SVZ, which is a harbor for adult neural stem cells, may be influenced by chemoradiation. The current diffusion-weighted imaging (DWI) study explored ipsilateral and contralateral alterations in the anterior SVZ in GBM patients with posterior enhancing lesions following chemoradiation.MethodsForty GBM patients with tumor involvement in the posterior SVZ (mean age = 57 ± 10; left-hemisphere N = 25; right-hemisphere N = 15) were evaluated using DWI before and after chemoradiation. Regions-of-interest were drawn on the ipsilesional and contralesional anterior SVZ on apparent diffusion coefficient (ADC) maps for both timepoints. ADC histogram analysis was performed by modeling a bimodal, double Gaussian distribution to obtain ADCL, defined as the mean of the lower Gaussian distribution.ResultsThe ipsilesional SVZ had lower ADCL values compared to the contralesional SVZ before treatment (mean difference = 0.025 μm2/ms; P = 0.007). Following chemoradiation, these changes were no longer observed (mean difference = 0.0025 μm2/ms; P > 0.5), as ADCL values of the ipsilesional SVZ increased (mean difference = 0.026 μm2/ms; P = 0.037). An increase in ipsilesional ADCL was associated with shorter progression-free (P = 0.0119) and overall survival (P = 0.0265).ConclusionsThese preliminary observations suggest baseline asymmetry as well as asymmetric changes in the SVZ proximal (ipsilesional) to the tumor with respect to contralesional SVZ regions may be present in GBM, potentially implicating this region in tumorigenesis and/or treatment resistance.

PurposeThe objective of the current study was to explore the efficacy of using pH-weighted amine CEST-EPI as a potential non-invasive imaging biomarker for treatment response and/or failure in recurrent GBM patients treated with bevacizumab.MethodA total of 11 patients with recurrent GBM treated with bevacizumab were included in this prospective study. CEST-EPI, perfusion MRI, and standardized anatomic MRI were obtained in patients before and after bevacizumab administration. CEST-EPI measures of magnetization transfer ratio asymmetry (MTRasym) at 3ppm were used for pH-weighted imaging contrast. Multiple measures were examined for their association with progression-free survival (PFS).ResultTumor acidity, measured with MTRasym at 3ppm, was significantly reduced in both contrast enhancing and non-enhancing tumor after bevacizumab (p = 0.0002 and p

Previous data suggest that apparent diffusion coefficient (ADC) imaging phenotypes predict survival response to anti-VEGF monotherapy in glioblastoma. However, the mechanism by which imaging may predict clinical response is unknown. We hypothesize that decorin (DCN), a proteoglycan implicated in the modulation of the extracellular microenvironment and sequestration of pro-angiogenic signaling, may connect ADC phenotypes to survival benefit to anti-VEGF therapy. Patients undergoing resection for glioblastoma as well as patients included in The Cancer Genome Atlas (TCGA) and IVY Glioblastoma Atlas Project (IVY GAP) databases had pre-operative imaging analyzed to calculate pre-operative ADCL values, the average ADC in the lower distribution using a double Gaussian mixed model. ADCL values were correlated to available RNA expression from these databases as well as from RNA sequencing from patient derived mouse orthotopic xenograft samples. Targeted biopsies were selected based on ADC values and prospectively collected during resection. Surgical specimens were used to evaluate for DCN RNA and protein expression by ADC value. The IVY Glioblastoma Atlas Project Database was used to evaluate DCN localization and relationship with VEGF pathway via in situ hybridization maps and RNA sequencing data. In a cohort of 35 patients with pre-operative ADC imaging and surgical specimens, DCN RNA expression levels were significantly larger in high ADCL tumors (41.6 vs. 1.5; P = 0.0081). In a cohort of 17 patients with prospectively targeted biopsies there was a positive linear correlation between ADCL levels and DCN protein expression between tumors (Pearson R2 = 0.3977; P = 0.0066) and when evaluating different targets within the same tumor (Pearson R2 = 0.3068; P = 0.0139). In situ hybridization data localized DCN expression to areas of microvascular proliferation and immunohistochemical studies localized DCN protein expression to the tunica adventitia of blood vessels within the tumor. DCN expression positively correlated with VEGFR1 & 2 expression and localized to similar areas of tumor. Increased ADCL on diffusion MR imaging is associated with high DCN expression as well as increased survival with anti-VEGF therapy in glioblastoma. DCN may play an important role linking the imaging features on diffusion MR and anti-VEGF treatment efficacy. DCN may serve as a target for further investigation and modulation of anti-angiogenic therapy in GBM.

Co-deletion of 1p/19q is a hallmark of oligodendroglioma and predicts better survival. However, little is understood about its metabolic characteristics. In this study, we aimed to explore the extracellular acidity of WHO grade II and III gliomas associated with 1p/19q co-deletion. We included 76 glioma patients who received amine chemical exchange saturation transfer (CEST) imaging at 3 T. Magnetic transfer ratio asymmetry (MTRasym) at 3.0 ppm was used as the pH-sensitive CEST biomarker, with higher MTRasym indicating lower pH. To control for the confounder factors, T2 relaxometry and l-6-18F-fluoro-3,4-dihydroxyphenylalnine (18F-FDOPA) PET data were collected in a subset of patients. We found a significantly lower MTRasym in 1p/19q co-deleted gliomas (co-deleted, 1.17% ± 0.32%; non-co-deleted, 1.72% ± 0.41%, P = 1.13 × 10−7), while FDOPA (P = 0.92) and T2 (P = 0.61) were not significantly affected. Receiver operating characteristic analysis confirmed that MTRasym could discriminate co-deletion status with an area under the curve of 0.85. In analysis of covariance, 1p/19q co-deletion status was the only significant contributor to the variability in MTRasym when controlling for age and FDOPA (P = 2.91 × 10−3) or T2 (P = 8.03 × 10−6). In conclusion, 1p/19q co-deleted gliomas were less acidic, which may be related to better prognosis. Amine CEST-MRI may serve as a non-invasive biomarker for identifying 1p/19q co-deletion status.