This study indicates that an SI increase in the DN and GP on T1-weighted images is caused by serial application of the linear GBCA gadopentetate dimeglumine but not by the macrocyclic GBCA gadoterate meglumine. Clinical implications of this observation remain unclear.

Purpose To evaluate whether radiomic feature-based magnetic resonance (MR) imaging signatures allow prediction of survival and stratification of patients with newly diagnosed glioblastoma with improved accuracy compared with that of established clinical and radiologic risk models. Materials and Methods Retrospective evaluation of data was approved by the local ethics committee and informed consent was waived. A total of 119 patients (allocated in a 2:1 ratio to a discovery [n = 79] or validation [n = 40] set) with newly diagnosed glioblastoma were subjected to radiomic feature extraction (12 190 features extracted, including first-order, volume, shape, and texture features) from the multiparametric (contrast material-enhanced T1-weighted and fluid-attenuated inversion-recovery imaging sequences) and multiregional (contrast-enhanced and unenhanced) tumor volumes. Radiomic features of patients in the discovery set were subjected to a supervised principal component (SPC) analysis to predict progression-free survival (PFS) and overall survival (OS) and were validated in the validation set. The performance of a Cox proportional hazards model with the SPC analysis predictor was assessed with C index and integrated Brier scores (IBS, lower scores indicating higher accuracy) and compared with Cox models based on clinical (age and Karnofsky performance score) and radiologic (Gaussian normalized relative cerebral blood volume and apparent diffusion coefficient) parameters. Results SPC analysis allowed stratification based on 11 features of patients in the discovery set into a low- or high-risk group for PFS (hazard ratio [HR], 2.43; P = .002) and OS (HR, 4.33; P < .001), and the results were validated successfully in the validation set for PFS (HR, 2.28; P = .032) and OS (HR, 3.45; P = .004). The performance of the SPC analysis (OS: IBS, 0.149; C index, 0.654; PFS: IBS, 0.138; C index, 0.611) was higher compared with that of the radiologic (OS: IBS, 0.175; C index, 0.603; PFS: IBS, 0.149; C index, 0.554) and clinical risk models (OS: IBS, 0.161, C index, 0.640; PFS: IBS, 0.139; C index, 0.599). The performance of the SPC analysis model was further improved when combined with clinical data (OS: IBS, 0.142; C index, 0.696; PFS: IBS, 0.132; C index, 0.637). Conclusion An 11-feature radiomic signature that allows prediction of survival and stratification of patients with newly diagnosed glioblastoma was identified, and improved performance compared with that of established clinical and radiologic risk models was demonstrated. (©) RSNA, 2016 Online supplemental material is available for this article.

Purpose To evaluate the association of multiparametric and multiregional magnetic resonance (MR) imaging features with key molecular characteristics in patients with newly diagnosed glioblastoma. Materials and Methods Retrospective data evaluation was approved by the local ethics committee, and the requirement to obtain informed consent was waived. Preoperative MR imaging features were correlated with key molecular characteristics within a single-institution cohort of 152 patients with newly diagnosed glioblastoma. Preoperative MR imaging features (n = 31) included multiparametric (anatomic and diffusion-, perfusion-, and susceptibility-weighted images) and multiregional (contrast-enhancing regions and hyperintense regions at nonenhanced fluid-attenuated inversion recovery imaging) information with histogram quantification of tumor volumes, volume ratios, apparent diffusion coefficients, cerebral blood flow, cerebral blood volume, and intratumoral susceptibility signals. Molecular characteristics determined included global DNA methylation subgroups (eg, mesenchymal, RTK I "PGFRA," RTK II "classic"), MGMT promoter methylation status, and hallmark copy number variations (EGFR, PDGFRA, MDM4, and CDK4 amplification; PTEN, CDKN2A, NF1, and RB1 loss). Univariate analyses (voxel-lesion symptom mapping for tumor location, Wilcoxon test for all other MR imaging features) and machine learning models were applied to study the strength of association and discriminative value of MR imaging features for predicting underlying molecular characteristics. Results There was no tumor location predilection for any of the assessed molecular parameters (permutation-adjusted P > .05). Univariate imaging parameter associations were noted for EGFR amplification and CDKN2A loss, with both demonstrating increased Gaussian-normalized relative cerebral blood volume and Gaussian-normalized relative cerebral blood flow values (area under the receiver operating characteristics curve: 63%-69%, false discovery rate-adjusted P < .05). Subjecting all MR imaging features to machine learning-based classification enabled prediction of EGFR amplification status and the RTK II glioblastoma subgroup with a moderate, yet significantly greater, accuracy (63% for EGFR [P < .01], 61% for RTK II [P = .01]) than prediction by chance; prediction accuracy for all other molecular parameters was not significant. Conclusion The authors found associations between established MR imaging features and molecular characteristics, although not of sufficient strength to enable generation of machine learning classification models for reliable and clinically meaningful prediction of molecular characteristics in patients with glioblastoma. RSNA, 2016 Online supplemental material is available for this article.

PurposeTo correlate histopathologic findings from biopsy specimens with their corresponding location within enhancing areas, non-enhancing areas and necrotic areas on contrast enhanced T1-weighted MRI scans (cT1).Materials and MethodsIn 37 patients with newly diagnosed glioblastoma who underwent stereotactic biopsy, we obtained a correlation of 561 1mm3 biopsy specimens with their corresponding position on the intraoperative cT1 image at 1.5 Tesla. Biopsy points were categorized as enhancing (CE), non-enhancing (NE) or necrotic (NEC) on cT1 and tissue samples were categorized as “viable tumor cells”, “blood” or “necrotic tissue (with or without cellular component)”. Cell counting was done semi-automatically.ResultsNE had the highest content of tissue categorized as viable tumor cells (89% vs. 60% in CE and 30% NEC, respectively). Besides, the average cell density for NE (3764 ± 2893 cells/mm2) was comparable to CE (3506 ± 3116 cells/mm2), while NEC had a lower cell density with 2713 ± 3239 cells/mm2. If necrotic parts and bleeds were excluded, cell density in biopsies categorized as “viable tumor tissue” decreased from the center of the tumor (NEC, 5804 ± 3480 cells/mm2) to CE (4495 ± 3209 cells/mm2) and NE (4130 ± 2817 cells/mm2).DiscussionThe appearance of a glioblastoma on a cT1 image (circular enhancement, central necrosis, peritumoral edema) does not correspond to its diffuse histopathological composition. Cell density is elevated in both CE and NE parts. Hence, our study suggests that NE contains considerable amounts of infiltrative tumor with a high cellularity which might be considered in resection planning.

ObjectiveTo explore the correlation between Nuclear Overhauser Enhancement (NOE)-mediated signals and tumor cellularity in glioblastoma utilizing the apparent diffusion coefficient (ADC) and cell density from histologic specimens. NOE is one type of chemical exchange saturation transfer (CEST) that originates from mobile macromolecules such as proteins and might be associated with tumor cellularity via altered protein synthesis in proliferating cells.Patients and MethodsFor 15 patients with newly diagnosed glioblastoma, NOE-mediated CEST-contrast was acquired at 7 Tesla (asymmetric magnetization transfer ratio (MTRasym) at 3.3ppm, B1 = 0.7 μT). Contrast enhanced T1 (CE-T1), T2 and diffusion-weighted MRI (DWI) were acquired at 3 Tesla and coregistered. The T2 edema and the CE-T1 tumor were segmented. ADC and MTRasym values within both regions of interest were correlated voxelwise yielding the correlation coefficient rSpearman (rSp). In three patients who underwent stereotactic biopsy, cell density of 12 specimens per patient was correlated with corresponding MTRasym and ADC values of the biopsy site.ResultsEight of 15 patients showed a weak or moderate positive correlation of MTRasym and ADC within the T2 edema (0.16≤rSp≤0.53, p<0.05). Seven correlations were statistically insignificant (p>0.05, n = 4) or yielded rSp≈0 (p<0.05, n = 3). No trend towards a correlation between MTRasym and ADC was found in CE-T1 tumor (-0.310.05, n = 6). The biopsy-analysis within CE-T1 tumor revealed a strong positive correlation between tumor cellularity and MTRasym values in two of the three patients (rSp patient3 = 0.69 and rSp patient15 = 0.87, p<0.05), while the correlation of ADC and cellularity was heterogeneous (rSp patient3 = 0.545 (p = 0.067), rSp patient4 = -0.021 (p = 0.948), rSp patient15 = -0.755 (p = 0.005)).DiscussionNOE-imaging is a new contrast promising insight into pathophysiologic processes in glioblastoma regarding cell density and protein content, setting itself apart from DWI. Future studies might be based on the assumption that NOE-mediated CEST visualizes cellularity more accurately than ADC, especially in the CE-T1 tumor region.

Antiantiogenic therapy with bevacizumab in recurrent glioblastoma is currently understood to both reduce microvascular density and to prune abnormal tumor microvessels. Microvascular pruning and the resulting vascular normalization are hypothesized to reduce tumor hypoxia and increase supply of systemic therapy to the tumor; however, the underlying pathophysiological changes and their timing after treatment initiation remain controversial. Here, we use a novel dynamic susceptibility contrast MRI-based method, which allows simultaneous assessment of tumor net oxygenation changes reflected by the tumor metabolic rate of oxygen and vascular normalization represented by the capillary transit time heterogeneity. We find that capillary transit time heterogeneity, and hence the oxygen extraction fraction combine with the tumoral blood flow (cerebral blood flow) in such a way that the overall tumor oxygenation appears to be worsened despite vascular normalization. Accordingly, hazards for both progression and death are found elevated in patients with a greater reduction of tumor metabolic rate of oxygen in response to bevacizumab and patients with higher intratumoral tumor metabolic rate of oxygen at baseline. This implies that tumors with a higher degree of angiogenesis prior to bevacizumab-treatment retain a higher level of angiogenesis during therapy despite a greater antiangiogenic effect of bevacizumab, hinting at evasive mechanisms limiting bevacizumab efficacy in that a reversal of their biological behavior and relative prognosis does not occur.

MRI parameters help to predict OS in a univariate Cox regression analysis, and increased rCBV is associated with shorter PFS in the multivariable model. In summary, however, our findings suggest that the relevance of MRI parameters is outperformed by clinical parameters in a multivariable analysis, which limits their prognostic value for survival prediction at the time of initial diagnosis.

Purpose To analyze if tumor vessels can be visualized, segmented and quantified in glioblastoma patients with time of flight (ToF) angiography at 7 Tesla and multiscale vessel enhancement filtering. Materials and Methods Twelve patients with newly diagnosed glioblastoma were examined with ToF angiography (TR = 15 ms, TE = 4.8 ms, flip angle = 15°, FOV = 160×210 mm2, voxel size: 0.31×0.31×0.40 mm3) on a whole-body 7 T MR system. A volume of interest (VOI) was placed within the border of the contrast enhancing part on T1-weighted images of the glioblastoma and a reference VOI was placed in the non-affected contralateral white matter. Automated segmentation and quantification of vessels within the two VOIs was achieved using multiscale vessel enhancement filtering in ImageJ. Results Tumor vessels were clearly visible in all patients. When comparing tumor and the reference VOI, total vessel surface (45.3±13.9 mm2 vs. 29.0±21.0 mm2 (p<0.035)) and number of branches (3.5±1.8 vs. 1.0±0.6 (p<0.001) per cubic centimeter were significantly higher, while mean vessel branch length was significantly lower (3.8±1.5 mm vs 7.2±2.8 mm (p<0.001)) in the tumor. Discussion ToF angiography at 7-Tesla MRI enables characterization and quantification of the internal vascular morphology of glioblastoma and may be used for the evaluation of therapy response within future studies.