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Purpose: This study compared the classification performance of normalized apparent diffusion coefficient (nADC) with percentage T2-FLAIR mismatch-volume (%T2FM-volume) for differentiating between IDH-mutant astrocytoma (IDHm-A) and other glioma molecular subtypes., Methods: A total of 105 non-enhancing gliomas were studied. T2-FLAIR digital subtraction maps were used to identify T2FM and T2-FLAIR non-mismatch (T2FNM) subregions within tumor volumes of interest (VOIs). Median nADC from the whole tumor, T2FM, and T2NFM subregions and %T2FM-volume were obtained. IDHm-A classification analyses using receiver-operating characteristic curves and multiple logistic regression were performed in addition to exploratory survival analyses., Results: T2FM subregions had significantly higher nADC than T2FNM subregions within IDHm-A with ≥ 25% T2FM-volume (P < 0.0001). IDHm-A with ≥ 25% T2FM-volume demonstrated significantly higher whole tumor nADC compared to IDHm-A with < 25% T2FM-volume (P < 0.0001), and both IDHm-A subgroups demonstrated significantly higher nADC compared to IDH-mutant oligodendroglioma and IDH-wild-type gliomas (P < 0.05). For classification of IDHm-A vs. other gliomas, the area under curve (AUC) of nADC was significantly greater compared to the AUC of %T2FM-volume (P = 0.01, nADC AUC = 0.848, %T2FM-volume AUC = 0.714) along with greater sensitivity. In exploratory survival analyses within IDHm-A, %T2FM-volume was not associated with overall survival (P = 0.2), but there were non-significant trends for nADC (P = 0.07) and tumor volume (P = 0.051)., Conclusion: T2-FLAIR subtraction maps are useful for characterizing IDHm-A imaging characteristics. nADC outperforms %T2FM-volume for classifying IDHm-A amongst non-enhancing gliomas with preserved high specificity and increased sensitivity, which may be related to inherent diffusivity differences regardless of T2FM. In line with previous findings on visual T2FM-sign, quantitative %T2FM-volume may not be prognostic., (© 2024. The Author(s).)

Background and purposeAcidification of the tumor microenvironment from abnormal metabolism along with angiogenesis to meet metabolic demands are both hallmarks of malignant brain tumors; however, the interdependency of tumor acidity and vascularity has not been explored. Therefore, our aim was to investigate the association between pH-sensitive amine chemical exchange saturation transfer echoplanar imaging (CEST-EPI) and relative cerebral blood volume (CBV) measurements obtained from dynamic susceptibility contrast (DSC) perfusion MRI in patients with gliomas.Materials and methodsIn this retrospective study, 90 patients with histologically confirmed gliomas were scanned between 2015 and 2018 (median age, 50.3 years; male/female ratio = 59:31). pH-weighting was obtained using chemical exchange saturation transfer echo-planar imaging estimation of the magnetization transfer ratio asymmetry at 3 ppm, and CBV was estimated using DSC-MR imaging. The voxelwise correlation and patient-wise median value correlation between the magnetization transfer ratio asymmetry at 3 ppm and CBV within T2-hyperintense lesions and contrast-enhancing lesions were evaluated using the Pearson correlation analysis.ResultsGeneral colocalization of elevated perfusion and high acidity was observed in tumors, with local intratumor heterogeneity. For patient-wise analysis, median CBV and magnetization transfer ratio asymmetry at 3 ppm within T2-hyperintense lesions were significantly correlated (R = 0.3180, P = .002), but not in areas of contrast enhancement (P = .52). The positive correlation in T2-hyperintense lesions remained within high-grade gliomas (R = 0.4128, P = .001) and in isocitrate dehydrogenase wild-type gliomas (R = 0.4300, P = .002), but not in World Health Organization II or in isocitrate dehydrogenase mutant tumors. Both magnetization transfer ratio asymmetry at 3 ppm and the voxelwise correlation between magnetization transfer ratio asymmetry and CBV were higher in high-grade gliomas compared with low-grade gliomas in T2-hyperintense tumors (magnetization transfer ratio asymmetry, P = .02; Pearson correlation, P = .01). The same trend held when comparing isocitrate dehydrogenase wild-type gliomas and isocitrate dehydrogenase mutant gliomas (magnetization transfer ratio asymmetry, P = .04; Pearson correlation, P = .01).ConclusionsA positive linear correlation between CBV and acidity in areas of T2-hyperintense, nonenhancing tumor, but not enhancing tumor, was observed across patients. Local heterogeneity was observed within individual tumors.

Background and purposeOur aim was to evaluate whether serial administration of the macrocyclic gadolinium-based contrast agent gadoteridol in children is associated with T1-weighted hyperintensity within the dentate nucleus, an imaging surrogate for gadolinium deposition.Materials and methodsWe identified a retrospective cohort of 10 patients younger than 18 years of age who underwent between 4 and 8 gadoteridol-enhanced MR imaging examinations of the brain from 2016 to 2017. For comparison, we identified a retrospective cohort of 9 pediatric patients who each underwent 6 gadodiamide-enhanced MR imaging examinations. For each examination, both dentate nuclei were contoured on unenhanced images and the mean dentate-to-pons signal intensity ratio was calculated. Dentate-to-pons signal intensity ratios from the first and last scans were compared using paired t tests.ResultsIn the gadoteridol group, there was no significant change in the mean dentate-to-pons signal intensity ratio from the first to the last scan (0.99 versus 0.99, P = .59). In the gadodiamide group, there was a significant increase in the mean dentate-to-pons signal intensity ratio from the first to the last scan (0.99 versus 1.10, P = .001).ConclusionsRepeat administration of the macrocyclic gadolinium-based contrast agent gadoteridol in children was not associated with T1-weighted dentate hyperintensity, while the repeat administration of the linear gadolinium-based contrast agent gadodiamide was associated with T1-weighted dentate hyperintensity, presumably due to gadolinium deposition.

AIM:To determine whether repeated gadolinium-based contrast agent administration (GBCA) in children is associated with the development of increased T1-weighted signal intensity within the cerebellar dentate nucleus. MATERIALS AND METHODS:With institutional review board approval for this The Health Insurance Portability and Accountability Act-compliant retrospective study, a cohort of 41 patients under the age of 18 years who underwent at least four contrast-enhanced magnetic resonance imaging (MR) examinations of the brain from 2005 to 2015 were identified. For each examination, both dentate nuclei were manually contoured, and the mean dentate nucleus-to-pons signal intensity (DN-P SI) ratio was calculated. The DN-P SI ratios from the last to first MRI examination were compared, and the correlation between DN-P SI ratio and cumulative gadolinium dose was calculated using a linear mixed effect model to control for potentially confounding variables. RESULTS:For the 41 patients in the cohort, there was a significant increase in the mean DN-P SI ratio from the first MRI to the last MRI examination (1.05 versus 1.11, p=0.004). After controlling for patient diagnosis, history of chemotherapy or radiation, sex, and age, there was a significant positive association between DN-P SI ratio and cumulative gadolinium dose (coefficient=0.401, p=0.032). CONCLUSION:Repeated GBCA administration in children is associated with increased T1-weighted signal intensity within the dentate nucleus.

DSC perfusion MR imaging in brain tumors requires a trade-off between spatial and temporal resolution, resulting in less spatial coverage to meet the temporal resolution requirements for accurate relative CBV estimation. DSC-MR imaging could potentially benefit from the advantages associated with simultaneous multi-slice imaging, including increased spatiotemporal resolution. In the current article, we demonstrate how simultaneous multi-slice EPI can be used to improve DSC-MR imaging spatiotemporal resolution in patients with glioblastoma.

Background and Purpose: Normalized relative cerebral blood volume (nrCBV) and percentage of signal recovery (PSR) computed from dynamic susceptibility contrast (DSC) perfusion imaging are useful biomarkers for differential diagnosis and treatment response assessment in brain tumors. However, their measurements are dependent on DSC acquisition factors, and CBV-optimized protocols technically differ from PSR-optimized protocols. This study aimed to generate "synthetic" DSC data with adjustable synthetic acquisition parameters using dual-echo gradient-echo (GE) DSC datasets extracted from dynamic spin-and-gradient-echo echoplanar imaging (dynamic SAGE-EPI). Synthetic DSC was aimed at: 1) simultaneously create nrCBV and PSR maps using optimal sequence parameters, 2) compare DSC datasets with heterogeneous external cohorts, and 3) assess the impact of acquisition factors on DSC metrics., Materials and Methods: Thirty-eight patients with contrast-enhancing brain tumors were prospectively imaged with dynamic SAGE-EPI during a non-preloaded single-dose contrast injection and included in this cross-sectional study. Multiple synthetic DSC curves with desired pulse sequence parameters were generated using the Bloch equations applied to the dual-echo GE data extracted from dynamic SAGE-EPI datasets, with or without optional preload simulation., Results: Dynamic SAGE-EPI allowed for simultaneous generation of CBV-optimized and PSR-optimized DSC datasets with a single contrast injection, while PSR computation from guideline-compliant CBV-optimized protocols resulted in rank variations within the cohort (Spearman's ρ=0.83-0.89, i.e. 31%-21% rank variation). Treatment-naïve glioblastoma exhibited lower parameter-matched PSR compared to the external cohorts of treatment-naïve primary CNS lymphomas (PCNSL) (p<0.0001), supporting a role of synthetic DSC for multicenter comparisons. Acquisition factors highly impacted PSR, and nrCBV without leakage correction also showed parameter-dependence, although less pronounced. However, this dependence was remarkably mitigated by post-hoc leakage correction., Conclusions: Dynamic SAGE-EPI allows for simultaneous generation of CBV-optimized and PSR-optimized DSC data with one acquisition and a single contrast injection, facilitating the use of a single perfusion protocol for all DSC applications. This approach may also be useful for comparisons of perfusion metrics across heterogeneous multicenter datasets, as it facilitates post-hoc harmonization., Abbreviations: DSC = dynamic susceptibility contrast; FA = flip angle; GBCA = gadolinium-based contrast agent; GBM = glioblastoma; GE = gradient echo; IDH = isocitrate dehydrogenase; IDH m = IDH-mutant; IDH wt = IDH-wild-type; 1p19q cod = 1p19q codeleted; 1p19q int = 1p19q intact; MRI = magnetic resonance imaging; PCNSL = primary CNS lymphoma; PSR = percentage of signal recovery; Rec = recurrent; SAGE-EPI = spin-and-gradient-echo echoplanar imaging; CBV = cerebral blood volume; nrCBV = normalized relative CBV; ROI = region of interest; TE = echo time; TN = treatment-naïve; TR = repetition time., (© 2024 by American Journal of Neuroradiology.)

Radiographic assessment plays a crucial role in the management of patients with central nervous system (CNS) tumors, aiding in treatment planning and evaluation of therapeutic efficacy by quantifying response. Recently, an updated version of the Response Assessment in Neuro-Oncology (RANO) criteria (RANO 2.0) was developed to improve upon prior criteria and provide an updated, standardized framework for assessing treatment response in clinical trials for gliomas in adults. This article provides an overview of significant updates to the criteria including (1) the use of a unified set of criteria for high and low grade gliomas in adults; (2) the use of the post-radiotherapy MRI scan as the baseline for evaluation in newly diagnosed high-grade gliomas; (3) the option for the trial to mandate a confirmation scan to more reliably distinguish pseudoprogression from tumor progression; (4) the option of using volumetric tumor measurements; and (5) the removal of subjective non-enhancing tumor evaluations in predominantly enhancing gliomas (except for specific therapeutic modalities). Step-by-step pragmatic guidance is hereby provided for the neuroradiologist and imaging core lab involved in operationalization and technical execution of RANO 2.0 in clinical trials, including the display of representative cases and in-depth discussion of challenging scenarios., (© 2024 by American Journal of Neuroradiology.)

Background and purposeMenière disease and idiopathic sudden sensorineural hearing loss can have overlapping clinical presentation and may have similar pathophysiology. Prior studies using postcontrast 3D-FLAIR MR imaging suggest abnormal blood-labyrinth barrier permeability in both conditions, but the 2 diseases have not been directly compared by using the same imaging techniques. We hypothesized that delayed postcontrast 3D-FLAIR MR imaging would show differences in blood-labyrinth barrier permeability between Menière disease and idiopathic sudden sensorineural hearing loss.Materials and methodsPatients with unilateral Menière disease (n = 32) and unilateral idiopathic sudden sensorineural hearing loss (n = 11) imaged with delayed postcontrast 3D-FLAIR MR imaging were retrospectively studied. Signal intensities of the medulla and perilymph of the cochlear basal turns of both ears in each patient were measured in a blinded fashion. Cochlea/medulla ratios were calculated for each ear as a surrogate for blood-labyrinth barrier permeability. The ears were segregated by clinical diagnosis.ResultsCochlea/medulla ratio was higher in symptomatic ears of patients with Menière disease (12.6 ± 7.4) than in patients with idiopathic sudden sensorineural hearing loss (5.7 ± 2.0) and asymptomatic ears of patients with Menière disease (8.0 ± 3.1), indicating increased blood-labyrinth barrier permeability in Menière disease ears. The differences in cochlea/medulla ratio between symptomatic and asymptomatic ears were significantly higher in Menière disease than in idiopathic sudden sensorineural hearing loss. Asymptomatic ears in patients with Menière disease showed higher cochlea/medulla ratio than symptomatic and asymptomatic ears in patients with idiopathic sudden sensorineural hearing loss.ConclusionsIncreased cochlea/medulla ratio indicates increased blood-labyrinth barrier permeability in Menière disease compared with idiopathic sudden sensorineural hearing loss. Increased cochlea/medulla ratio in asymptomatic ears of patients with Menière disease also suggests an underlying systemic cause of Menière disease and may provide a pathophysiologic biomarker.

Background and purposeContrast agent extravasation through a disrupted blood-brain barrier potentiates inaccurate DSC MR imaging estimation of relative CBV. We explored whether incorporation of an interstitial washout rate in a leakage-correction model for single-echo, gradient-echo DSC MR imaging improves relative CBV estimates in high-grade gliomas.Materials and methodsWe modified the traditional model-based postprocessing leakage-correction algorithm, assuming unidirectional contrast agent extravasation (Boxerman-Weisskoff model) to account for bidirectional contrast agent exchange between intra- and extravascular spaces (bidirectional model). For both models, we compared the goodness of fit with the parent leakage-contaminated relaxation rate curves by using the Akaike Information Criterion and the difference between modeled interstitial relaxation rate curves and dynamic contrast-enhanced MR imaging by using Euclidean distance in 21 patients with glioblastoma multiforme.ResultsThe bidirectional model had improved Akaike Information Criterion versus the bidirectional model in >50% of enhancing tumor voxels in all 21 glioblastoma multiformes (77% ± 9%; P < .0001) and had reduced the Euclidean distance in >50% of enhancing tumor voxels for 17/21 glioblastoma multiformes (62% ± 17%; P = .0041). The bidirectional model and dynamic contrast-enhanced-derived kep demonstrated a strong correlation (r = 0.74 ± 0.13). On average, enhancing tumor relative CBV for the Boxerman-Weisskoff model exceeded that for the bidirectional model by 16.6% ± 14.0%.ConclusionsInclusion of the bidirectional exchange in leakage-correction models for single-echo DSC MR imaging improves the model fit to leakage-contaminated DSC MR imaging data and significantly improves the estimation of relative CBV in high-grade gliomas.

Purpose: Diffusion magnetic resonance imaging (MRI) and 6-[18F]fluoro-l-dopa ([18F]FDOPA) positron emission tomography (PET) are used to interrogate malignant tumor microenvironment. It remains unclear whether there is a relationship between [18F]FDOPA uptake, diffusion MRI estimates of apparent diffusion coefficient (ADC), and mitotic activity in the context of recurrent malignant gliomas, where the tumor may be confounded by the effects of therapy. The purpose of the current study is to determine whether there is a correlation between these imaging techniques and mitotic activity in malignant gliomas.Procedures: We retrospectively examined 29 patients with recurrent malignant gliomas who underwent structural MRI, diffusion MRI, and [18F]FDOPA PET prior to surgical resection. Qualitative associations were noted, and quantitative voxel-wise and median measurement correlations between [18F]FDOPA PET, ADC, and mitotic index were performed.Results: Areas of high [18F]FDOPA uptake exhibited low ADC and areas of hyperintensity T2/fluid-attenuated inversion recovery (FLAIR) with low [18F]FDOPA uptake exhibited high ADC. There was a significant inverse voxel-wise correlation between [18F]FDOPA and ADC for all patients. Median [18F]FDOPA uptake and median ADC also showed a significant inverse correlation. Median [18F]FDOPA uptake was positively correlated, and median ADC was inversely correlated with mitotic index from resected tumor tissue.Conclusions: A significant association may exist between [18F]FDOPA uptake, diffusion MRI, and mitotic activity in recurrent malignant gliomas.

Bevacizumab is a therapeutic drug used in treatment of recurrent glioblastoma to inhibit angiogenesis. Treatment response is often monitored through the use of perfusion MRI measures of cerebral blood volume, flow, and other pharmacokinetic parameters; however, most methods for deriving these perfusion parameters can produce errors depending on bolus kinetics. Recently, a number of new methods have been developed to overcome these challenges. In the current study we examine cerebral blood volume and blood flow characteristics in 45 recurrent glioblastoma patients before and after treatment with bevacizumab. Perfusion MRI data was processed using a standard single value decomposition (SVD) technique, two block-circulant SVD techniques, and a Bayesian estimation technique. A proportional hazards model showed that patients with a large decrease in relative blood volume (RBV) after treatment had extended overall survival (P = 0.0048). Patients with large pre-treatment relative blood flow (RBF) showed extended progression-free survival (P = 0.0216) and overall survival (P = 0.0112), and patients with a large decrease in RBF following treatment showed extended overall survival (P = 0.0049). These results provide evidence that blood volume and blood flow measurements can be used as biomarkers in patients treated with bevacizumab.

Background and purposeGlioblastoma is a common primary brain tumor with a poor but variable prognosis. Our aim was to investigate the feasibility of MR perfusion imaging by using arterial spin-labeling for determining the prognosis of patients with glioblastoma.Materials and methodsPseudocontinuous arterial spin-labeling with 3D background-suppressed gradient and spin-echo was acquired before surgery on 53 patients subsequently diagnosed with glioblastoma. The calculated CBF color maps were visually evaluated by 3 independent readers blinded to patient history. Pathologic and survival data were correlated with CBF map findings. Arterial spin-labeling values in tumor tissue were also quantified by using manual fixed-size ROIs.ResultsTwo perfusion patterns were characterized by visual evaluation of CBF maps on the basis of either the presence (pattern 1) or absence (pattern 2) of substantial hyperperfused tumor tissue. Evaluation of the perfusion patterns was highly concordant among the 3 readers (κ = 0.898, P < .001). Pattern 1 (versus pattern 2) was associated with significantly shorter progression-free survival by Kaplan-Meier analysis (median progression-free survival of 182 days versus 485 days, P < .01) and trended with shorter overall survival (P = .079). There was a significant association between pattern 1 and epidermal growth factor receptor variant III expression (P < .01).ConclusionsQualitative evaluation of arterial spin-labeling CBF maps can be used to stratify survival and predict epidermal growth factor receptor variant III expression in patients with glioblastoma.

Background and purposePre-treatment ADC characteristics have been shown to predict response to bevacizumab in recurrent glioblastoma multiforme. However, no studies have examined whether ADC characteristics are specific to this particular treatment. The purpose of the current study was to determine whether ADC histogram analysis is a bevacizumab-specific or treatment-independent biomarker of treatment response in recurrent glioblastoma multiforme.Materials and methodsEighty-nine bevacizumab-treated and 43 chemotherapy-treated recurrent glioblastoma multiformes never exposed to bevacizumab were included in this study. In all patients, ADC values in contrast-enhancing ROIs from MR imaging examinations performed at the time of recurrence, immediately before commencement of treatment for recurrence, were extracted and the resulting histogram was fitted to a mixed model with a double Gaussian distribution. Mean ADC in the lower Gaussian curve was used as the primary biomarker of interest. The Cox proportional hazards model and log-rank tests were used for survival analysis.ResultsCox multivariate regression analysis accounting for the interaction between bevacizumab- and non-bevacizumab-treated patients suggested that the ability of the lower Gaussian curve to predict survival is dependent on treatment (progression-free survival, P = .045; overall survival, P = .003). Patients with bevacizumab-treated recurrent glioblastoma multiforme with a pretreatment lower Gaussian curve > 1.2 μm(2)/ms had a significantly longer progression-free survival and overall survival compared with bevacizumab-treated patients with a lower Gaussian curve < 1.2 μm(2)/ms. No differences in progression-free survival or overall survival were observed in the chemotherapy-treated cohort. Bevacizumab-treated patients with a mean lower Gaussian curve > 1.2 μm(2)/ms had a significantly longer progression-free survival and overall survival compared with chemotherapy-treated patients.ConclusionsThe mean lower Gaussian curve from ADC histogram analysis is a predictive imaging biomarker for bevacizumab-treated, not chemotherapy-treated, recurrent glioblastoma multiforme. Patients with recurrent glioblastoma multiforme with a mean lower Gaussian curve > 1.2 μm(2)/ms have a survival advantage when treated with bevacizumab.

Amine-weighted chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) is particularly valuable as an amine- and pH-sensitive imaging technique in brain tumors, targeting the intrinsically high concentration of amino acids with exchangeable amine protons and reduced extracellular pH in brain tumors. Amine-weighted CEST MRI contrast is dependent on the glioma genotype, likely related to differences in degree of malignancy and metabolic behavior. Amine-weighted CEST MRI may provide complementary value to anatomic imaging in conventional and exploratory therapies in brain tumors, including chemoradiation, antiangiogenic therapies, and immunotherapies. Continual improvement and clinical testing of amine-weighted CEST MRI has the potential to greatly impact patients with brain tumors by understanding vulnerabilities in the tumor microenvironment that may be therapeutically exploited., (© 2022 John Wiley & Sons Ltd.)

Background and purposeA substantial portion of clinically diagnosed TIA cases is imaging-negative. The purpose of the current study is to determine if arterial spin-labeling is helpful in detecting perfusion abnormalities in patients presenting clinically with TIA.Materials and methodsPseudocontinuous arterial spin-labeling with 3D background-suppressed gradient and spin-echo was acquired on 49 patients suspected of TIA within 24 hours of symptom onset. All patients were free of stroke history and had no lesion-specific findings on general MR, DWI, and MRA sequences. The calculated arterial spin-labeling CBF maps were scored from 1-3 on the basis of presence and severity of perfusion disturbance by 3 independent observers blinded to patient history. An age-matched cohort of 36 patients diagnosed with no cerebrovascular events was evaluated as a control. Interobserver agreement was assessed by use of the Kendall concordance test.ResultsScoring of perfusion abnormalities on arterial spin-labeling scans of the TIA cohort was highly concordant among the 3 observers (W = 0.812). The sensitivity and specificity of arterial spin-labeling in the diagnosis of perfusion abnormalities in TIA was 55.8% and 90.7%, respectively. In 93.3% (70/75) of the arterial spin-labeling CBF map readings with positive scores (≥2), the brain regions where perfusion abnormalities were identified by 3 observers matched with the neurologic deficits at TIA onset.ConclusionsIn this preliminary study, arterial spin-labeling showed promise in the detection of perfusion abnormalities that correlated with clinically diagnosed TIA in patients with otherwise normal neuroimaging results.

Background and purposeTumor location is a significant prognostic factor in glioblastoma, which may reflect the genetic profile of tumor precursor cells. The purpose of the current study was to construct and analyze probabilistic radiographic atlases reflecting preoperative tumor locations and corresponding demographic, "-omic," and interventional phenotypes to provide insight into potential niche locations of glioblastoma cells of origin.Materials and methodsPreoperative anatomic MR images in 507 patients with de novo glioblastoma were analyzed. Images were registered to stereotactic space, tumors were segmented, and the stereospecific frequency of tumor occurrence was analyzed statistically by age, extent of resection, MGMT methylation, IDH1 mutation, gene expression subclassification, PTEN loss, PTEN deficiency, EGFR amplification, EGFR variant 3 expression, progression-free survival from the start of radiochemotherapy, and overall survival from initial diagnosis.ResultsMost glioblastomas grow into the periventricular white matter regions adjacent to the subventricular zone. MGMT promoter methylated tumors occur more frequently in the left temporal lobe, in young patients with glioblastoma, in IDH1 mutant tumors, in tumors having the proneural gene expression subtype, and in tumors lacking loss of PTEN occurring most frequently in the frontal lobe. MGMT methylated tumors with the IDH1 mutation tended to occur in the left frontal lobe. EGFR amplified and EGFR variant 3-expressing tumors occurred most frequently in the left temporal lobe. A similar region in the left temporal lobe was associated with favorable response to radiochemotherapy and increased survival.ConclusionsRadiographic atlases for specific phenotypes provide insight into overlap between prognostic variables and may help to identify niche locations for cancer cells of origin.

Background and purposeA subset of patients with malignant glioma develops conspicuous lesions characterized by persistent restricted diffusion during treatment with bevacizumab. The purpose of the current study was to characterize the evolution of these lesions and to determine their relationship to patient outcome.Materials and methodsTwenty patients with malignant glioma with persistent restricted-diffusion lesions undergoing treatment with bevacizumab were included in the current study. Mean ADC and the volume of restricted diffusion were computed for each patient during serial follow-up. Differences in TTP, TTS, and OS were compared between patients with restricted diffusion and matched controls by using Kaplan-Meier analysis with the logrank test and Cox hazard models.ResultsMean ADC values were generally stable with time (mean, 5.2 ± 12.6% change from baseline). The volume of restricted diffusion increased a median of 23% from baseline by 6 months. Patients with restricted-diffusion lesions had significantly greater TTP (logrank, P = .013), TTS (logrank, P = .008), and OS (logrank, P = .010) than matched controls. When available, advanced physiologic imaging of restricted-diffusion lesions showed hypovascularity on perfusion MR imaging and decreased amino acid uptake on (18)F-FDOPA PET scans. Atypical gelatinous necrotic tissue was confirmed in the area of restricted diffusion in 1 patient.ConclusionsRestricted-diffusion lesions in malignant gliomas treated with bevacizumab are generally stable with time and are associated with improved outcomes. These results combined with physiologic imaging and histopathologic data suggest that these lesions are not consistent with aggressive tumor.

Background and purposeBoth IDH1 mutation and MGMT promoter methylation are associated with longer survival. We investigated the ability of imaging correlates to serve as noninvasive biomarkers for these molecularly defined GBM subtypes.Materials and methodsMR imaging from 202 patients with GBM was retrospectively assessed for nonenhancing tumor and edema among other imaging features. IDH1 mutational and MGMT promoter methylation status were determined by DNA sequencing and methylation-specific PCR, respectively. Overall survival was determined by using a multivariate Cox model and the Kaplan-Meier method with a log rank test. A logistic regression model followed by ROC analysis was used to classify the IDH1 mutation and methylation status by using imaging features.ResultsMGMT promoter methylation and IDH1 mutation were associated with longer median survival. Edema levels stratified survival for methylated but not unmethylated tumors. Median survival for methylated tumors with little/no edema was 2476 days (95% CI, 795), compared with 586 days (95% CI, 507-654) for unmethylated tumors or tumors with edema. All IDH1 mutant tumors were nCET positive, and most (11/14, 79%) were located in the frontal lobe. Imaging features including larger tumor size and nCET could be used to determine IDH1 mutational status with 97.5% accuracy, but poorly predicted MGMT promoter methylation.ConclusionsImaging features are potentially predictive of IDH1 mutational status but were poorly correlated with MGMT promoter methylation. Edema stratifies survival in MGMT promoter methylated but not in unmethylated tumors; patients with methylated tumors with little or no edema have particularly long survival.

Background and Purpose: The T2-FLAIR mismatch sign on MR imaging is a highly specific imaging biomarker of isocitrate dehydrogenase ( IDH )-mutant astrocytomas, which lack 1p/19q codeletion. However, most studies using the T2-FLAIR mismatch sign have used visual assessment. This study quantified the degree of T2-FLAIR mismatch using digital subtraction of fluid-nulled T2-weighted FLAIR images from non-fluid-nulled T2-weighted images in human nonenhancing diffuse gliomas and then used this information to assess improvements in diagnostic performance and investigate subregion characteristics within these lesions., Materials and Methods: Two cohorts of treatment-naïve, nonenhancing gliomas with known IDH and 1p/19q status were studied ( n  = 71 from The Cancer Imaging Archive (TCIA) and n  = 34 in the institutional cohort). 3D volumes of interest corresponding to the tumor were segmented, and digital subtraction maps of T2-weighted MR imaging minus T2-weighted FLAIR MR imaging were used to partition each volume of interest into a T2-FLAIR mismatched subregion (T2-FLAIR mismatch, corresponding to voxels with positive values on the subtraction maps) and nonmismatched subregion (T2-FLAIR nonmismatch corresponding to voxels with negative values on the subtraction maps). Tumor subregion volumes, percentage of T2-FLAIR mismatch volume, and T2-FLAIR nonmismatch subregion thickness were calculated, and 2 radiologists assessed the T2-FLAIR mismatch sign with and without the aid of T2-FLAIR subtraction maps., Results: Thresholds of ≥42% T2-FLAIR mismatch volume classified IDH -mutant astrocytoma with a specificity/sensitivity of 100%/19.6% (TCIA) and 100%/31.6% (institutional); ≥25% T2-FLAIR mismatch volume showed 92.0%/32.6% and 100%/63.2% specificity/sensitivity, and ≥15% T2-FLAIR mismatch volume showed 88.0%/39.1% and 93.3%/79.0% specificity/sensitivity. In IDH -mutant astrocytomas with ≥15% T2-FLAIR mismatch volume, T2-FLAIR nonmismatch subregion thickness was negatively correlated with the percentage T2-FLAIR mismatch volume ( P  < .0001) across both cohorts. The percentage T2-FLAIR mismatch volume was higher in grades 3-4 compared with grade 2 IDH -mutant astrocytomas ( P  < .05), and ≥15% T2-FLAIR mismatch volume IDH- mutant astrocytomas were significantly larger than <15% T2-FLAIR mismatch volume IDH -mutant astrocytoma ( P  < .05) across both cohorts. When evaluated by 2 radiologists, the additional use of T2-FLAIR subtraction maps did not show a significant difference in interreader agreement, sensitivity, or specificity compared with a separate evaluation of T2-FLAIR and T2-weighted MR imaging alone., Conclusions: T2-FLAIR digital subtraction maps may be a useful, automated tool to obtain objective segmentations of tumor subregions based on quantitative thresholds for classifying IDH -mutant astrocytomas using the percentage T2 FLAIR mismatch volume with 100% specificity and exploring T2-FLAIR mismatch/T2-FLAIR nonmismatch subregion characteristics. Conversely, the addition of T2-FLAIR subtraction maps did not enhance the sensitivity or specificity of the visual T2-FLAIR mismatch sign assessment by experienced radiologists., (© 2024 by American Journal of Neuroradiology.)

Introduction: Being the most common primary brain tumor, glioblastoma presents as an extremely challenging malignancy to treat with dismal outcomes despite treatment. Varying molecular epidemiology of glioblastoma between patients and intra-tumoral heterogeneity explains the failure of current one-size-fits-all treatment modalities. Radiomics uses machine learning to identify salient features of the tumor on brain imaging and promises patient-specific management in glioblastoma patients., Methods: We performed a comprehensive review of the available literature on studies investigating the role of radiomics and radiogenomics models for the diagnosis, stratification, prognostication as well as treatment planning and monitoring of glioblastoma., Results: Classifiers based on a combination of various MRI sequences, genetic information and clinical data can predict non-invasive tumor diagnosis, overall survival and treatment response with reasonable accuracy. However, the use of radiomics for glioblastoma treatment remains in infancy as larger sample sizes, standardized image acquisition and data extraction techniques are needed to develop machine learning models that can be translated effectively into clinical practice., Conclusion: Radiomics has the potential to transform the scope of glioblastoma management through personalized medicine., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: To assess whether artificial intelligence (AI)-based decision support allows more reproducible and standardized assessment of treatment response on MRI in neuro-oncology as compared to manual 2-dimensional measurements of tumor burden using the Response Assessment in Neuro-Oncology (RANO) criteria., Methods: A series of 30 patients (15 lower-grade gliomas, 15 glioblastoma) with availability of consecutive MRI scans was selected. The time to progression (TTP) on MRI was separately evaluated for each patient by 15 investigators over two rounds. In the first round the TTP was evaluated based on the RANO criteria, whereas in the second round the TTP was evaluated by incorporating additional information from AI-enhanced MRI sequences depicting the longitudinal changes in tumor volumes. The agreement of the TTP measurements between investigators was evaluated using concordance correlation coefficients (CCC) with confidence intervals (CI) and P-values obtained using bootstrap resampling., Results: The CCC of TTP-measurements between investigators was 0.77 (95% CI = 0.69,0.88) with RANO alone and increased to 0.91 (95% CI = 0.82,0.95) with AI-based decision support (P = .005). This effect was significantly greater (P = .008) for patients with lower-grade gliomas (CCC = 0.70 [95% CI = 0.56,0.85] without vs. 0.90 [95% CI = 0.76,0.95] with AI-based decision support) as compared to glioblastoma (CCC = 0.83 [95% CI = 0.75,0.92] without vs. 0.86 [95% CI = 0.78,0.93] with AI-based decision support). Investigators with less years of experience judged the AI-based decision as more helpful (P = .02)., Conclusions: AI-based decision support has the potential to yield more reproducible and standardized assessment of treatment response in neuro-oncology as compared to manual 2-dimensional measurements of tumor burden, particularly in patients with lower-grade gliomas. A fully-functional version of this AI-based processing pipeline is provided as open-source (https://github.com/NeuroAI-HD/HD-GLIO-XNAT)., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: 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-[ 18 F]-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., Methods: Thirty-four patients with treatment-naïve 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., Results: 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., Conclusion: 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., (© 2021. The Japanese Society of Nuclear Medicine.)

Purpose: To 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)., Methods: The 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., Results: Average 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)., Conclusion: Most 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., (© 2022. The Author(s).)

Background: Diffusion 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., Methods: Forty-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., Results: Median 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)., Conclusions: Elevated post-treatment rADC may be an early imaging biomarker for OS benefits in GBM patients receiving ICI treatment., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

This pilot study investigates structural alterations and their relationships with cognitive function in survivors of diffuse gliomas. Twenty-four survivors of diffuse gliomas (mean age 44.5 ± 11.5), from whom high-resolution T1-weighted images, neuropsychological tests, and self-report questionnaires were obtained, were analyzed. Patients were grouped by degree of cognitive impairment, and interregional correlations of cortical thickness were computed to generate morphometric correlation networks (MCNs). The results show that the cortical thickness of the right insula ( R 2 = 0.3025, p = 0.0054) was negatively associated with time since the last treatment, and the cortical thickness of the left superior temporal gyrus ( R 2 = 0.2839, p = 0.0107) was positively associated with cognitive performance. Multiple cortical regions in the default mode, salience, and language networks were identified as predominant nodes in the MCNs of survivors of diffuse gliomas. Compared to cognitively impaired patients, cognitively non-impaired patients tended to have higher network stability in network nodes removal analysis, especially when the fraction of removed nodes (among 66 nodes in total) exceeded 55%. These findings suggest that structural networks are altered in survivors of diffuse gliomas and that their cortical structures may also be adapting to support cognitive function during survivorship.

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.

Background and Purpose: While 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., Methods: 1,153 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 <10% were considered rCBV Non-Responders. The association between change in enhancing tumor volume, change in rCBV, MGMT promotor methylation status, and PFS or OS were explored., Results: A decrease in tumor volume following chemoradiation trended towards longer OS (p=0.12; median OS=26.8 vs. 16.3 months). Paradoxically, rCBV Non-Responders had a significantly improved PFS compared to Responders (p=0.047; median PFS=9.6 vs. 7.2 months). MGMT methylated rCBV Non-Responders exhibited a significantly longer PFS compared to MGMT unmethylated rCBV Non-Responders (p<0.001; median PFS=0.5 vs. 7.1 months), and MGMT methylated rCBV Non-Responders trended towards longer PFS compared to methylated rCBV Responders (p=0.089; median PFS=20.5 vs. 13.8 months)., Conclusions: This preliminary report demonstrates that in newly diagnosed IDH wild-type GBM with measurable enhancing disease after surgery (5% of patients), an enigmatic non-response in rCBV was associated with longer PFS, particularly in MGMT methylated patients., Competing Interests: BME is a paid consultant and an advisor for Medicenna, MedQIA, Servier Pharmaceuticals, Siemens, Janssen, Imaging Endpionts, Kazia Pharmaceuticals, Chimerix, Sumitomo Dainippon Pharma Oncology, ImmunoGenesis, Ellipses Pharma, Monteris, Global Coalition for Adaptive Research, Neosoma, and Alpheus Medical. CC has research funding from Siemens Healthineers and RaySearch Laboratories. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling Editor declared a past co-authorship with one of the authors BME., (Copyright © 2022 Goldman, Hagiwara, Yao, Raymond, Ong, Bakhti, Kwon, Farhat, Torres, Erickson, Curl, Lee, Pope, Salamon, Nghiemphu, Ji, Eldred, Liau, Lai, Cloughesy, Chung and Ellingson.)

As treatments for diffuse gliomas have advanced, survival for patients with gliomas has also increased. However, there remains limited knowledge on the relationships between brain connectivity and the lasting changes to cognitive function that glioma survivors often experience long after completing treatment. This resting-state functional magnetic resonance imaging (rs-fMRI) study explored functional connectivity (FC) alterations associated with cognitive function in survivors of gliomas. In this pilot study, 22 patients (mean age 43.8 ± 11.9) with diffuse gliomas who completed treatment within the past 10 years were evaluated using rs-fMRI and neuropsychological measures. Novel rs-fMRI analysis methods were used to account for missing brain in the resection cavity. FC relationships were assessed between cognitively impaired and non-impaired glioma patients, along with self-reported cognitive impairment, non-work daily functioning, and time with surgery. In the cognitively non-impaired patients, FC was stronger in the medial prefrontal cortex, rostral prefrontal cortex, and intraparietal sulcus compared to the impaired survivors. When examining non-work daily functioning, a positive correlation with FC was observed between the accumbens and the intracalcarine cortices, while a negative correlation with FC was observed between the parietal operculum cortex and the cerebellum. Additionally, worse self-reported cognitive impairment and worse non-work daily functioning were associated with increased FC between regions involved in cognition and sensorimotor processing. These preliminary findings suggest that neural correlates for cognitive and daily functioning in glioma patients can be revealed using rs-fMRI. Resting-state network alterations may serve as a biomarker for patients' cognition and functioning., (© 2021. The Author(s).)

This article reviews recent advances in the use of standard and advanced imaging techniques for diagnosis and treatment of central nervous system (CNS) tumors, including glioma and brain metastasis. Following the recent transition from a histology-based approach in classifying CNS tumors to one that integrates histology with the molecular information of tumor, the approaches for imaging CNS tumors have also been adapted to this new framework. Some challenges related to the diagnosis and treatment of CNS tumors, such as differentiating tumor from treatment-related imaging changes, require further progress to implement advanced imaging for clinical use., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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., (© 2022. The Author(s).)

Purpose: Epidermal 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., Methods: This study included 72 histologically confirmed EGFR-amplified and non-amplified glioma patients. Reversible transverse relaxation rate (R 2 '), 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 R 2 ', 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., Results: EGFR amplified gliomas exhibited significantly higher median R 2 ' and rOEF than non-amplified gliomas. ROC analysis suggested that R 2 ' (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 R 2 ' 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., Conclusion: Imaging of tumor oxygen characteristics revealed EGFR-amplified gliomas to be more hypoxic and contribute to shorter patient survival than EGFR non-amplified gliomas.

Purpose: Although tumor localization and 3,4-dihydroxy-6- 18 F-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., Methods: 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., Results: 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., Conclusion: Radiographic atlases revealed preferential frontal lobe localization for FDOPA hypometabolic LGGs, which may be associated with relatively early detection.

Background: The purpose of this study was to develop a voxel-wise clustering method of multiparametric magnetic resonance imaging (MRI) and 3,4-dihydroxy-6-[ 18 F]-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., Methods: Sixty-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., Results: The 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., Conclusions: Machine 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.

Our purpose was to identify correlations between 18 F-fluorodihydroxyphenylalanine ( 18 F-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 18 F-FDOPA PET and physiologic MRI were retrospectively selected (36 with isocitrate dehydrogenase wild-type [IDH wt ], 16 with mutant 1p/19q noncodeleted [IDH m-noncodel ], and 16 with mutant codeleted [IDH m-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 IDH wt and IDH m-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. IDH m-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 IDH wt gliomas. Conclusion: IDH m-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 IDH wt gliomas., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: To quantify abnormal metabolism of diffuse gliomas using "aerobic glycolytic imaging" and investigate its biological correlation., Methods: All 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 R 2 ' to normalized relative cerebral blood volume. An aerobic glycolytic index (AGI) was derived by the ratio of pH-weighted image contrast (MTR asym 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 18 F-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)., Results: AGI 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 18 F-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)., Conclusion: AGI derived from molecular MRI was correlated with glucose uptake ( 18 F-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., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Diffusion magnetic resonance (MR) characteristics are a predictive imaging biomarker for survival benefit in recurrent glioblastoma treated with anti-vascular endothelial growth factor (VEGF) therapy; however, its use in large volume recurrence has not been evaluated., Objective: To determine if diffusion MR characteristics can predict survival outcomes in patients with large volume recurrent glioblastoma treated with bevacizumab or repeat resection., Methods: A total of 32 patients with large volume (>20 cc or > 3.4 cm diameter) recurrent glioblastoma treated with bevacizumab and 35 patients treated with repeat surgery were included. Pretreatment tumor volume and apparent diffusion coefficient (ADC) histogram analysis were used to phenotype patients as having high (>1.24 μm2/ms) or low (<1.24 μm2/ms) ADCL, the mean value of the lower peak in a double Gaussian model of the ADC histogram within the contrast enhancing tumor., Results: In bevacizumab and surgical cohorts, volume was correlated with overall survival (Bevacizumab: P = .009, HR = 1.02; Surgical: P = .006, HR = 0.96). ADCL was an independent predictor of survival in the bevacizumab cohort (P = .049, HR = 0.44), but not the surgical cohort (P = .273, HR = 0.67). There was a survival advantage of surgery over bevacizumab in patients with low ADCL (P = .036, HR = 0.43) but not in patients with high ADCL (P = .284, HR = 0.69)., Conclusion: Pretreatment diffusion MR imaging is an independent predictive biomarker for overall survival in recurrent glioblastoma with a large tumor burden. Large tumors with low ADCL have a survival benefit when treated with surgical resection, whereas large tumors with high ADCL may be best managed with bevacizumab., (Copyright © 2020 by the Congress of Neurological Surgeons.)

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 ADC L values, the average ADC in the lower distribution using a double Gaussian mixed model. ADC L 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 ADC L 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 ADC L levels and DCN protein expression between tumors (Pearson R 2  = 0.3977; P = 0.0066) and when evaluating different targets within the same tumor (Pearson R 2  = 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 ADC L 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.

Purpose: To 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., Methods: Sixty-eight treatment-naïve glioma patients who underwent FDOPA PET and magnetic resonance imaging (MRI) were retrospectively included. Fluid-attenuated inversion recovery hyperintense regions (FLAIR ROI ) were segmented. FDOPA hypermetabolic regions (FDOPA ROI , tumor-to-striatum ratios > 1) within FLAIR ROI were extracted. Normalized maximum standardized uptake value (nSUV max ), volume of each ROI, and median relative cerebral blood volume (rCBV) and apparent diffusion coefficient (ADC) within FLAIR ROI or FDOPA ROI 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 FLAIR ROI or FDOPA ROI can discriminate different molecular statuses or grades., Results: Using either FLAIR ROI or FDOPA ROI , the nSUV max 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 FDOPA ROI volume was significantly higher in 1p19q codeleted than non-codeleted gliomas, and in HGGs than LGGs. Although not significant, imaging metrics extracted by FDOPA ROI discriminated molecular status and tumor grade more accurately than those extracted by FLAIR ROI (AUC of IDH status, 0.87 vs. 0.82; 1p19q status, 0.78 vs. 0.73; grade, 0.87 vs. 0.76)., Conclusion: FDOPA hypermetabolic ROI may extract useful imaging features of gliomas, which can illuminate biological differences between different molecular status or tumor grades.

Glioblastoma (GBM) metabolism has traditionally been characterized by a primary dependence on aerobic glycolysis, prompting the use of the ketogenic diet (KD) as a potential therapy. In this study we evaluated the effectiveness of the KD in GBM and assessed the role of fatty acid oxidation (FAO) in promoting GBM propagation. In vitro assays revealed FA utilization throughout the GBM metabolome and growth inhibition in nearly every cell line in a broad spectrum of patient-derived glioma cells treated with FAO inhibitors. In vivo assessments revealed that knockdown of carnitine palmitoyltransferase 1A (CPT1A), the rate-limiting enzyme for FAO, reduced the rate of tumor growth and increased survival. However, the unrestricted ketogenic diet did not reduce tumor growth and for some models significantly reduced survival. Altogether, these data highlight important roles for FA and ketone body metabolism that could serve to improve targeted therapies in GBM., Competing Interests: The authors declare no competing interests., (© 2020 The Authors.)

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 (MTR asym ) at 3.0 ppm was used as the pH-sensitive CEST biomarker, with higher MTR asym indicating lower pH. To control for the confounder factors, T 2 relaxometry and L-6- 18 F-fluoro-3,4-dihydroxyphenylalnine ( 18 F-FDOPA) PET data were collected in a subset of patients. We found a significantly lower MTR asym 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 T 2 (P = 0.61) were not significantly affected. Receiver operating characteristic analysis confirmed that MTR asym 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 MTR asym when controlling for age and FDOPA (P = 2.91 × 10 -3 ) or T 2 (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.