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ObjectiveTo determine the feasibility and biologic correlations of dynamic susceptibility contrast (DSC), dynamic contrast enhanced (DCE), and quantitative maps derived from contrast leakage effects obtained simultaneously in gliomas using dynamic spin-and-gradient-echo echoplanar imaging (dynamic SAGE-EPI) during a single contrast injection.Materials and methodsThirty-eight patients with enhancing brain gliomas were prospectively imaged with dynamic SAGE-EPI, which was processed to compute traditional DSC metrics (normalized relative cerebral blood flow [nrCBV], percentage of signal recovery [PSR]), DCE metrics (volume transfer constant [Ktrans], extravascular compartment [ve]), and leakage effect metrics: ΔR2,ss* (reflecting T2*-leakage effects), ΔR1,ss (reflecting T1-leakage effects), and the transverse relaxivity at tracer equilibrium (TRATE, reflecting the balance between ΔR2,ss* and ΔR1,ss). These metrics were compared between patient subgroups (treatment-naïve [TN] vs recurrent [R]) and biological features (IDH status, Ki67 expression).ResultsIn IDH wild-type gliomas (IDHwt-i.e., glioblastomas), previous exposure to treatment determined lower TRATE (p = 0.002), as well as higher PSR (p = 0.006), Ktrans (p = 0.17), ΔR1,ss (p = 0.035), ve (p = 0.006), and ADC (p = 0.016). In IDH-mutant gliomas (IDHm), previous treatment determined higher Ktrans and ΔR1,ss (p = 0.026). In TN-gliomas, dynamic SAGE-EPI metrics tended to be influenced by IDH status (p ranging 0.09-0.14). TRATE values above 142 mM-1s-1 were exclusively seen in TN-IDHwt, and, in TN-gliomas, this cutoff had 89% sensitivity and 80% specificity as a predictor of Ki67 > 10%.ConclusionsDynamic SAGE-EPI enables simultaneous quantification of brain tumor perfusion and permeability, as well as mapping of novel metrics related to cytoarchitecture (TRATE) and blood-brain barrier disruption (ΔR1,ss), with a single contrast injection.Clinical relevance statementSimultaneous DSC and DCE analysis with dynamic SAGE-EPI reduces scanning time and contrast dose, respectively alleviating concerns about imaging protocol length and gadolinium adverse effects and accumulation, while providing novel leakage effect metrics reflecting blood-brain barrier disruption and tumor tissue cytoarchitecture.Key points• Traditionally, perfusion and permeability imaging for brain tumors requires two separate contrast injections and acquisitions. • Dynamic spin-and-gradient-echo echoplanar imaging enables simultaneous perfusion and permeability imaging. • Dynamic spin-and-gradient-echo echoplanar imaging provides new image contrasts reflecting blood-brain barrier disruption and cytoarchitecture characteristics.

BackgroundNon-enhancing (NE) infiltrating tumor cells beyond the contrast-enhancing (CE) bulk of tumor are potential propagators of recurrence after gross total resection of high-grade glioma.MethodsWe leveraged single-nucleus RNA sequencing on 15 specimens from recurrent high-grade gliomas (n = 5) to compare prospectively identified biopsy specimens acquired from CE and NE regions. Additionally, 24 CE and 22 NE biopsies had immunohistochemical staining to validate RNA findings.ResultsTumor cells in NE regions are enriched in neural progenitor cell-like cellular states, while CE regions are enriched in mesenchymal-like states. NE glioma cells have similar proportions of proliferative and putative glioma stem cells relative to CE regions, without significant differences in % Ki-67 staining. Tumor cells in NE regions exhibit upregulation of genes previously associated with lower grade gliomas. Our findings in recurrent GBM paralleled some of the findings in a re-analysis of a dataset from primary GBM. Cell-, gene-, and pathway-level analyses of the tumor microenvironment in the NE region reveal relative downregulation of tumor-mediated neovascularization and cell-mediated immune response, but increased glioma-to-nonpathological cell interactions.ConclusionsThis comprehensive analysis illustrates differing tumor and nontumor landscapes of CE and NE regions in high-grade gliomas, highlighting the NE region as an area harboring likely initiators of recurrence in a pro-tumor microenvironment and identifying possible targets for future design of NE-specific adjuvant therapy. These findings also support the aggressive approach to resection of tumor-bearing NE regions.

PurposeAntiangiogenic therapies are known to cause high radiographic response rates due to reduction in vascular permeability resulting in a lower degree of contrast extravasation. In this study, we investigate the prognostic ability for model-derived parameters describing enhancing tumor volumetric dynamics to predict survival in recurrent glioblastoma treated with antiangiogenic therapy.Experimental designN = 276 patients in two phase II trials were used as training data, including bevacizumab ± irinotecan (NCT00345163) and cabozantinib (NCT00704288), and N = 74 patients in the bevacizumab arm of a phase III trial (NCT02511405) were used for validation. Enhancing volumes were estimated using T1 subtraction maps, and a biexponential model was used to estimate regrowth (g) and regression (d) rates, time to tumor regrowth (TTG), and the depth of response (DpR). Response characteristics were compared to diffusion MR phenotypes previously shown to predict survival.ResultsOptimized thresholds occurred at g = 0.07 months-1 (phase II: HR = 0.2579, P = 5 × 10-20; phase III: HR = 0.2197, P = 5 × 10-5); d = 0.11 months-1 (HR = 0.3365, P < 0.0001; HR = 0.3675, P = 0.0113); TTG = 3.8 months (HR = 0.2702, P = 6 × 10-17; HR = 0.2061, P = 2 × 10-5); and DpR = 11.3% (HR = 0.6326, P = 0.0028; HR = 0.4785, P = 0.0206). Multivariable Cox regression controlling for age and baseline tumor volume confirmed these factors as significant predictors of survival. Patients with a favorable pretreatment diffusion MRI phenotype had a significantly longer TTG and slower regrowth.ConclusionsRecurrent glioblastoma patients with a large, durable radiographic response to antiangiogenic agents have significantly longer survival. This information is useful for interpreting activity of antiangiogenic agents in recurrent glioblastoma.

PurposeThere is limited knowledge about the associations between sodium and proton MRI measurements in brain tumors. The purpose of this study was to quantify intra- and intertumoral correlations between sodium, diffusion, and perfusion MRI in human gliomas.MethodsTwenty glioma patients were prospectively studied on a 3T MRI system with multinuclear capabilities. Three mutually exclusive tumor volumes of interest (VOIs) were segmented: contrast-enhancing tumor (CET), T2/FLAIR hyperintense non-enhancing tumor (NET), and necrosis. Median and voxel-wise associations between apparent diffusion coefficient (ADC), normalized relative cerebral blood volume (nrCBV), and normalized sodium measurements were quantified for each VOI.ResultsBoth relative sodium concentration and ADC were significantly higher in areas of necrosis compared to NET (P = 0.003 and P = 0.008, respectively) and CET (P = 0.02 and P = 0.02). Sodium concentration was higher in CET compared to NET (P = 0.04). Sodium and ADC were higher in treated compared to treatment-naïve gliomas within NET (P = 0.006 and P = 0.01, respectively), and ADC was elevated in CET (P = 0.03). Median ADC and sodium concentration were positively correlated across patients in NET (r = 0.77, P

PurposeThere remains no consensus normal-appearing white matter (NAWM) normalization method to compute normalized relative cerebral blood volume (nrCBV) and apparent diffusion coefficient (nADC) in brain tumors. This reader study explored nrCBV and nADC differences using different NAWM normalization methods.MethodsThirty-five newly diagnosed glioma patients were studied. For each patient, two readers created four NAWM regions of interests: (1) a single plane in the centrum semiovale (CSOp), (2) 3 spheres in the centrum semiovale (CSOs), (3) a single plane in the slice of the tumor center (TUMp), and (4) 3 spheres in the slice of the tumor center (TUMs). Readers repeated NAWM segmentations 1 month later. Differences in nrCBV and nADC of the FLAIR hyperintense tumor, inter-/intra-reader variability, and time to segment NAWM were assessed. As a validation step, the diagnostic performance of each method for IDH-status prediction was evaluated.ResultsBoth readers obtained significantly different nrCBV (P < .001), nADC (P < .001), and time to segment NAWM (P < .001) between the four normalization methods. nrCBV and nADC were significantly different between CSO and TUM methods, but not between planar and spherical methods in the same NAWM region. Broadly, CSO methods were quicker than TUM methods, and spherical methods were quicker than planar methods. For all normalization techniques, inter-reader reproducibility and intra-reader repeatability were excellent (intraclass correlation coefficient > 0.9), and the IDH-status predictive performance remained similar.ConclusionThe selected NAWM region significantly impacts nrCBV and nADC values. CSO methods, particularly CSOs, may be preferred because of time reduction, similar reader variability, and similar diagnostic performance compared to TUM methods.

BackgroundAlterations in tumor growth rate (TGR) in recurrent glioblastoma (rGBM) after treatment may be useful for identifying therapeutic activity. The aim of this study was to assess the impact of volumetric TGR alterations on overall survival (OS) in rGBM treated with chemotherapy with or without radiation therapy (RT).MethodsSixty-one rGBM patients treated with chemotherapy with or without concomitant radiation therapy (RT) at 1st or 2nd recurrence were retrospectively examined. Pre- and post-treatment contrast enhancing volumes were computed. Patients were considered "responders" if they reached progression-free survival at 6 months (PFS6) and showed a decrease in TGR after treatment and "non-responders" if they didn't reach PFS6 or if TGR increased.ResultsStratification by PFS6 and based on TGR resulted in significant differences in OS both for all patients and for patients without RT (P < 0.05). A decrease of TGR (P = 0.009), smaller baseline tumor volume (P = 0.02), O6-methylguanine-DNA methyltransferase promoter methylation (P = 0.048) and fewer number of recurrences (P = 0.048) were significantly associated with longer OS after controlling for age, sex and concomitant RT.ConclusionA decrease in TGR in patients with PFS6, along with smaller baseline tumor volume, were associated with a significantly longer OS in rGBM treated with chemotherapy with or without radiation. Importantly, all patients that exhibited PFS6 also showed a measurable decrease in TGR.

PurposeTo quantify the radiation dose distribution and lesion morphometry (shape) at baseline, prior to chemoradiation, and at the time of radiographic recurrence in patients with glioblastoma (GBM).MethodsThe IMRT dose distribution, location of the center of mass, sphericity, and solidity of the contrast enhancing tumor at baseline and the time of tumor recurrence was quantified in 48 IDH wild-type GBM who underwent postoperative IMRT (2 Gy daily for total of 60 Gy) with concomitant and adjuvant temozolomide.ResultsAverage radiation dose within enhancing tumor at baseline and recurrence was ≥ 60 Gy. Centroid location of the enhancing tumor shifted an average of 11.3 mm at the time of recurrence with respect to pre-IMRT location. A positive correlation was observed between change in centroid location and PFS in MGMT methylated patients (P = 0.0007) and Cox multivariate regression confirmed centroid distance from baseline was associated with PFS when accounting for clinical factors (P = 0.0189). Lesion solidity was higher at recurrence compared to baseline (P = 0.0118). Tumors that progressed > 12 weeks after IMRT were significantly more spherical (P = 0.0094).ConclusionMost GBMs recur local within therapeutic IMRT doses; however, tumors with longer PFS occurred further from the original tumor location and were more solid and/or nodular.

BackgroundDiffusion MRI estimates of the apparent diffusion coefficient (ADC) have been shown to be useful in predicting treatment response in patients with glioblastoma (GBM), with ADC elevations indicating tumor cell death. We aimed to investigate whether the ADC values measured before and after treatment with immune checkpoint inhibitors (ICIs) and the changes in these ADC values could predict overall survival (OS) in patients with recurrent IDH wild-type GBM.MethodsForty-four patients who met the following inclusion criteria were included in this retrospective study: (i) diagnosed with recurrent IDH wild-type GBM and treated with either pembrolizumab or nivolumab and (ii) availability of diffusion data on pre- and post-ICI MRI. Tumor volume and the median relative ADC (rADC) with respect to the normal-appearing white matter within the enhancing tumor were calculated.ResultsMedian OS among all patients was 8.1 months (range, 1.0-22.5 months). Log-rank test revealed that higher post-treatment rADC was associated with a significantly longer OS (median, 10.3 months for rADC ≥ 1.63 versus 6.1 months for rADC < 1.63; P = .02), whereas tumor volume, pretreatment rADC, and changes in rADC after treatment were not significantly associated with OS. Cox regression analysis revealed that post-treatment rADC significantly influenced OS (P = .02, univariate analysis), even after controlling for age and sex (P =.01, multivariate analysis), and additionally controlling for surgery after ICI treatment (P = .045, multivariate analysis).ConclusionsElevated post-treatment rADC may be an early imaging biomarker for OS benefits in GBM patients receiving ICI treatment.

BackgroundInhibition of the isocitrate dehydrogenase (IDH)-mutant enzyme is a novel therapeutic target in IDH-mutant gliomas. Imaging biomarkers of IDH inhibitor treatment efficacy in human IDH-mutant gliomas are largely unknown. This study investigated early volumetric, perfusion, and diffusion MRI changes in IDH1-mutant gliomas during IDH inhibitor treatment.MethodsTwenty-nine IDH1-mutant glioma patients who received IDH inhibitor and obtained anatomical, perfusion, and diffusion MRI pretreatment at 3-6 weeks (n = 23) and/or 2-4 months (n = 14) of treatment were retrospectively studied. Normalized relative cerebral blood volume (nrCBV), apparent diffusion coefficient (ADC), and fluid-attenuated inversion recovery (FLAIR) hyperintensity volume were analyzed.ResultsAfter 3-6 weeks of treatment, nrCBV was significantly increased (P = .004; mean %change = 24.15%) but not FLAIR volume (P = .23; mean %change = 11.05%) or ADC (P = .52; mean %change = -1.77%). Associations between shorter progression-free survival (PFS) with posttreatment nrCBV > 1.55 (P = .05; median PFS, 240 vs 55 days) and increased FLAIR volume > 4 cm3 (P = .06; 227 vs 29 days) trended toward significance. After 2-4 months, nrCBV, FLAIR volume, and ADC were not significantly different from baseline, but an nrCBV increase > 0% (P = .002; 1121 vs 257 days), posttreatment nrCBV > 1.8 (P = .01; 1121 vs. 270 days), posttreatment ADC  0% (P = .02; 1121 vs 270 days), and FLAIR volume change > 4 cm3 (P = .03; 421 vs 226.5 days) were associated with shorter PFS.ConclusionsIncreased nrCBV at 3-6 weeks of treatment may reflect transient therapeutic and/or tumor growth changes, whereas nrCBV, ADC, and FLAIR volume changes occurring at 2-4 months of treatment may more accurately reflect antitumor response to IDH inhibition.

Characterization of hypoxia and tissue acidosis could advance the understanding of glioma biology and improve patient management. In this study, we evaluated the ability of a pH- and oxygen-sensitive magnetic resonance imaging (MRI) technique to differentiate glioma genotypes, including isocitrate dehydrogenase (IDH) mutation, 1p/19q co-deletion, and epidermal growth factor receptor (EGFR) amplification, and investigated its prognostic value. A total of 159 adult glioma patients were scanned with pH- and oxygen-sensitive MRI at 3T. We quantified the pH-sensitive measure of magnetization transfer ratio asymmetry (MTRasym) and oxygen-sensitive measure of R2’ within the tumor region-of-interest. IDH mutant gliomas showed significantly lower MTRasym × R2’ (p < 0.001), which differentiated IDH mutation status with sensitivity and specificity of 90.0% and 71.9%. Within IDH mutants, 1p/19q codeletion was associated with lower tumor acidity (p < 0.0001, sensitivity 76.9%, specificity 91.3%), while IDH wild-type, EGFR-amplified gliomas were more hypoxic (R2’ p = 0.024, sensitivity 66.7%, specificity 76.9%). Both R2’ and MTRasym × R2’ were significantly associated with patient overall survival (R2’: p = 0.045; MTRasym × R2’: p = 0.002) and progression-free survival (R2’: p = 0.010; MTRasym × R2’: p < 0.0001), independent of patient age, treatment status, and IDH status. The pH- and oxygen-sensitive MRI is a clinically feasible and potentially valuable imaging technique for distinguishing glioma subtypes and providing additional prognostic value to clinical practice.

This study aimed to differentiate isocitrate dehydrogenase (IDH) mutation status with the voxel-wise clustering method of multiparametric magnetic resonance imaging (MRI) and to discover biological underpinnings of the clusters. A total of 69 patients with treatment-naïve diffuse glioma were scanned with pH-sensitive amine chemical exchange saturation transfer MRI, diffusion-weighted imaging, fluid-attenuated inversion recovery, and contrast-enhanced T1-weighted imaging at 3 T. An unsupervised two-level clustering approach was used for feature extraction from acquired images. The logarithmic ratio of the labels in each class within tumor regions was applied to a support vector machine to differentiate IDH status. The highest performance to predict IDH mutation status was found for 10-class clustering, with a mean area under the curve, accuracy, sensitivity, and specificity of 0.94, 0.91, 0.90, and 0.91, respectively. Targeted biopsies revealed that the tissues with labels 7-10 showed high expression levels of hypoxia-inducible factor 1-alpha, glucose transporter 3, and hexokinase 2, which are typical of IDH wild-type glioma, whereas those with labels 1 showed low expression of these proteins. In conclusion, A machine learning model successfully predicted the IDH mutation status of gliomas, and the resulting clusters properly reflected the metabolic status of the tumors.

Background and purposeWhile relative cerebral blood volume (rCBV) may be diagnostic and prognostic for survival in glioblastoma (GBM), changes in rCBV during chemoradiation in the subset of newly diagnosed GBM with subtotal resection and the impact of MGMT promoter methylation status on survival have not been explored. This study aimed to investigate the association between rCBV response, MGMT methylation status, and progression-free (PFS) and overall survival (OS) in newly diagnosed GBM with measurable enhancing lesions.Methods1,153 newly diagnosed IDH wild-type GBM patients were screened and 53 patients (4.6%) had measurable post-surgical tumor (>1mL). rCBV was measured before and after patients underwent chemoradiation. Patients with a decrease in rCBV >10% were considered rCBV Responders, while patients with an increase or a decrease in rCBV

BackgroundThe purpose of this study was to develop a voxel-wise clustering method of multiparametric magnetic resonance imaging (MRI) and 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (FDOPA) positron emission tomography (PET) images using an unsupervised, two-level clustering approach followed by support vector machine in order to classify the isocitrate dehydrogenase (IDH) status of gliomas.MethodsSixty-two treatment-naïve glioma patients who underwent FDOPA PET and MRI were retrospectively included. Contrast enhanced T1-weighted images, T2-weighted images, fluid-attenuated inversion recovery images, apparent diffusion coefficient maps, and relative cerebral blood volume maps, and FDOPA PET images were used for voxel-wise feature extraction. An unsupervised two-level clustering approach, including a self-organizing map followed by the K-means algorithm was used, and each class label was applied to the original images. The logarithmic ratio of labels in each class within tumor regions was applied to a support vector machine to differentiate IDH mutation status. The area under the curve (AUC) of receiver operating characteristic curves, accuracy, and F1-socore were calculated and used as metrics for performance.ResultsThe associations of multiparametric imaging values in each cluster were successfully visualized. Multiparametric images with 16-class clustering revealed the highest classification performance to differentiate IDH status with the AUC, accuracy, and F1-score of 0.81, 0.76, and 0.76, respectively.ConclusionsMachine learning using an unsupervised two-level clustering approach followed by a support vector machine classified the IDH mutation status of gliomas, and visualized voxel-wise features from multiparametric MRI and FDOPA PET images. Unsupervised clustered features may improve the understanding of prioritizing multiparametric imaging for classifying IDH status.

PurposeEpidermal growth factor receptor (EGFR) amplification promotes gliomagenesis and is linked to lack of oxygen within the tumor microenvironment. Using hypoxia-sensitive spin-and-gradient echo echo-planar imaging and perfusion MRI, we investigated the influence of EGFR amplification on tissue oxygen availability and utilization in human gliomas.MethodsThis study included 72 histologically confirmed EGFR-amplified and non-amplified glioma patients. Reversible transverse relaxation rate (R2'), relative cerebral blood volume (rCBV), and relative oxygen extraction fraction (rOEF) were calculated for the contrast-enhancing and non-enhancing tumor regions. Using Student t test or Wilcoxon rank-sum test, median R2', rCBV, and rOEF were compared between EGFR-amplified and non-amplified gliomas. ROC analysis was performed to assess the ability of imaging characteristics to discriminate EGFR amplification status. Overall survival (OS) was determined using univariate and multivariate cox models. Kaplan-Meier survival curves were plotted and compared using the log-rank test.ResultsEGFR amplified gliomas exhibited significantly higher median R2' and rOEF than non-amplified gliomas. ROC analysis suggested that R2' (AUC = 0.7190; P = 0.0048) and rOEF (AUC = 0.6959; P = 0.0156) could separate EGFR status. Patients with EGFR-amplified gliomas had a significantly shorter OS than non-amplified patients. Univariate cox regression analysis determined both R2' and rOEF significantly influence OS. No significant difference was observed in rCBV between patient cohorts nor was rCBV found to be an effective differentiator of EGFR status.ConclusionImaging of tumor oxygen characteristics revealed EGFR-amplified gliomas to be more hypoxic and contribute to shorter patient survival than EGFR non-amplified gliomas.

PurposeAlthough 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.MethodsFifty-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.ResultsSuperimposition 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.ConclusionRadiographic atlases revealed preferential frontal lobe localization for FDOPA hypometabolic LGGs, which may be associated with relatively early detection.

Our purpose was to identify correlations between 18F-fluorodihydroxyphenylalanine (18F-FDOPA) uptake and physiologic MRI, including relative cerebral blood volume (rCBV) and apparent diffusion coefficient (ADC), in gliomas with different molecular subtypes and to evaluate their prognostic values. Methods: Sixty-eight treatment-naïve glioma patients who underwent 18F-FDOPA PET and physiologic MRI were retrospectively selected (36 with isocitrate dehydrogenase wild-type [IDHwt], 16 with mutant 1p/19q noncodeleted [IDHm-noncodel], and 16 with mutant codeleted [IDHm-codel]). Fluid-attenuated inversion recovery hyperintense areas were segmented and used as regions of interest. For voxelwise and patientwise analyses, Pearson correlation coefficients (r voxelwise and r patientwise) between the normalized SUV (nSUV), rCBV, and ADC were evaluated. Cox regression analysis was performed to investigate the associations between overall survival and r voxelwise, maximum or median nSUV, median rCBV, or median ADC. Results: For IDHwt and IDHm-noncodel gliomas, nSUV demonstrated significant positive correlations with rCBV (r voxelwise = 0.25 and 0.31, respectively; r patientwise = 0.50 and 0.70, respectively) and negative correlations with ADC (r voxelwise = -0.19 and -0.19, respectively; r patientwise = -0.58 and -0.61, respectively) in both voxelwise and patientwise analyses. IDHm-codel gliomas demonstrated a significant positive correlation between nSUV and ADC only in voxelwise analysis (r voxelwise = 0.18). In Cox regression analysis, r voxelwise between nSUV and rCBV (hazard ratio, 28.82) or ADC (hazard ratio, 0.085) had significant associations with overall survival for only IDHwt gliomas. Conclusion: IDHm-codel gliomas showed distinctive patterns of correlations between amino acid PET and physiologic MRI. Stronger correlations between nSUV and rCBV or ADC may result in a worse prognosis for IDHwt gliomas.

PurposeTo quantify abnormal metabolism of diffuse gliomas using "aerobic glycolytic imaging" and investigate its biological correlation.MethodsAll subjects underwent a pH-weighted amine chemical exchange saturation transfer spin-and-gradient-echo echoplanar imaging (CEST-SAGE-EPI) and dynamic susceptibility contrast perfusion MRI. Relative oxygen extraction fraction (rOEF) was estimated as the ratio of reversible transverse relaxation rate R2' to normalized relative cerebral blood volume. An aerobic glycolytic index (AGI) was derived by the ratio of pH-weighted image contrast (MTRasym at 3.0 ppm) to rOEF. AGI was compared between different tumor types (N = 51, 30 IDH mutant and 21 IDH wild type). Metabolic MR parameters were correlated with 18F-FDG uptake (N = 8, IDH wild-type glioblastoma), expression of key glycolytic proteins using immunohistochemistry (N = 38 samples, 21 from IDH mutant and 17 from IDH wild type), and bioenergetics analysis on purified tumor cells (N = 7, IDH wild-type high grade).ResultsAGI was significantly lower in IDH mutant than wild-type gliomas (0.48 ± 0.48 vs. 0.70 ± 0.48; P = 0.03). AGI was strongly correlated with 18F-FDG uptake both in non-enhancing tumor (Spearman, ρ = 0.81; P = 0.01) and enhancing tumor (ρ = 0.81; P = 0.01). AGI was significantly correlated with glucose transporter 3 (ρ = 0.71; P = 0.004) and hexokinase 2 (ρ = 0.73; P = 0.003) in IDH wild-type glioma, and monocarboxylate transporter 1 (ρ = 0.59; P = 0.009) in IDH mutant glioma. Additionally, a significant correlation was found between AGI derived from bioenergetics analysis and that estimated from MRI (ρ = 0.79; P = 0.04).ConclusionAGI derived from molecular MRI was correlated with glucose uptake (18F-FDG and glucose transporter 3/hexokinase 2) and cellular AGI in IDH wild-type gliomas, whereas AGI in IDH mutant gliomas appeared associated with monocarboxylate transporter density.

PurposeWe evaluated F-FDOPA PET and MRI characteristics in association with the molecular status and overall survival (OS) in a large number of low-grade gliomas (LGGs).MethodsEighty-six patients who underwent F-FDOPA PET and MRI and were diagnosed with new or recurrent LGGs were retrospectively evaluated with respect to their isocitrate dehydrogenase (IDH) and 1p19q status (10 IDH wild type, 57 mutant, 19 unknown; 1p19q status in IDH mutant: 20 noncodeleted, 37 codeleted). After segmentation of the hyperintense area on fluid-attenuated inversion recovery image (FLAIRROI), the following were calculated: normalized SUVmax (nSUVmax) of F-FDOPA relative to the striatum, F-FDOPA hypermetabolic volume (tumor-to-striatum ratios >1), FLAIRROI volume, relative cerebral blood volume, and apparent diffusion coefficient within FLAIRROI. Receiver operating characteristic curve and Cox regression analyses were performed.ResultsPET and MRI metrics combined with age predicted the IDH mutation and 1p19q codeletion statuses with sensitivities of 73% and 76% and specificities of 100% and 94%, respectively. Significant correlations were found between OS and the IDH mutation status (hazard ratio [HR] = 4.939), nSUVmax (HR = 2.827), F-FDOPA hypermetabolic volume (HR = 1.048), and FLAIRROI volume (HR = 1.006). The nSUVmax (HR = 151.6) for newly diagnosed LGGs and the F-FDOPA hypermetabolic volume (HR = 1.038) for recurrent LGGs demonstrated significant association with OS.ConclusionsCombining F-FDOPA PET and MRI with age proved useful for predicting the molecular status in patients with LGGs, whereas the nSUVmax and F-FDOPA hypermetabolic volume may be useful for prognostication.

PurposeAlthough magnetic resonance imaging (MRI) and 18F-2-fluorodeoxyglucose-positron emission tomography (FDG-PET) are used for pre-surgical assessment of focal cortical dysplasia (FCD), they often disagree. This study aimed to identify factors that contribute to discrepancies in FCD imaging between MRI and FDG-PET.MethodsSixty-two patients (mean age, 18.9 years) with a FCD type I or II were retrospectively selected. These patients were visually categorized into two groups: 1) extent of PET abnormality larger than MRI abnormality and 2) vice versa or equivalent. Predictive factors of these two groups were analyzed by multivariate logistic regression. The extent of hypometabolic transient zone surrounding FCDs and their mean standardized uptake values were measured and compared by the Mann-Whitney U-test.ResultsFCDs were detected on MRI and PET in 46 and 55 patients, respectively, whereas no abnormality was detected in 4 patients. The PET hypometabolic areas were larger than the MRI abnormal areas in 26 patients (88 % in the temporal lobe), whereas the PET hypometabolic areas were equivalent or smaller than the MRI abnormal areas in 32 patients (69 % in the frontal lobe). The temporal lobe location was an independent predictor for differentiating the two groups (OR = 35.2, 95 % CI = 6.81-168.0, P < .001). The temporal lobe lesions had significantly wider transient zones and lower standardized uptake values than those in the other lobes (P < .001, both).ConclusionThe discrepancies between MRI and FDG-PET findings of FCD were associated with temporal lobe location.

PurposeTo assess whether hypermetabolically-defined regions of interest (ROIs) on 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (FDOPA) positron emission tomography (PET) could be used to evaluate physiological features and whether there are measurable differences between molecular subtypes and tumor grades.MethodsSixty-eight treatment-naïve glioma patients who underwent FDOPA PET and magnetic resonance imaging (MRI) were retrospectively included. Fluid-attenuated inversion recovery hyperintense regions (FLAIRROI) were segmented. FDOPA hypermetabolic regions (FDOPAROI, tumor-to-striatum ratios > 1) within FLAIRROI were extracted. Normalized maximum standardized uptake value (nSUVmax), volume of each ROI, and median relative cerebral blood volume (rCBV) and apparent diffusion coefficient (ADC) within FLAIRROI or FDOPAROI were calculated. Imaging metrics were compared using Students t or Mann-Whitney U tests. Area under the curve (AUC) of receiver-operating characteristic curves were used to determine whether imaging metrics within FLAIRROI or FDOPAROI can discriminate different molecular statuses or grades.ResultsUsing either FLAIRROI or FDOPAROI, the nSUVmax and rCBV were significantly higher and the ADC was lower in isocitrate dehydrogenase (IDH) wild-type than mutant gliomas, and in higher-grade gliomas (HGGs) than lower-grade gliomas (LGGs). The FDOPAROI volume was significantly higher in 1p19q codeleted than non-codeleted gliomas, and in HGGs than LGGs. Although not significant, imaging metrics extracted by FDOPAROI discriminated molecular status and tumor grade more accurately than those extracted by FLAIRROI (AUC of IDH status, 0.87 vs. 0.82; 1p19q status, 0.78 vs. 0.73; grade, 0.87 vs. 0.76).ConclusionFDOPA hypermetabolic ROI may extract useful imaging features of gliomas, which can illuminate biological differences between different molecular status or tumor grades.

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.