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Examples of metabolic responders to GDC-0084 as indicated by a decrease in 18F-FDG PET uptake. A-B) Examples of a clear reduction in focal 18F-FDG uptake within the tumor. C-E) Example of more subtle reduction in 18F-FDG uptake after GDC-0084. C and E) demonstrate both focal (tumor) and global (gray matter) reductions in 18F-FDG uptake.

Post-treatment multi-parametric MR-PET imaging measurements and responses for each oral dose of GDC-0084. Post-treatment measurements of A) contrast enhancing tumor volume, B) median 18F-FDG uptake relative to white matter, C) median ADC, D) median FA, E) median Ktrans, F) median vp¬, and G) median rCBV and change in measurements of H) contrast enhancing tumor volume, I) median 18F-FDG uptake relative to white matter, J) median ADC, K) median FA, L) median Ktrans, M) median vp¬, and N) median rCBV for dose levels of 2, 4, 8, 15, 20, 30, 45, and 65mg.

Correlation between multi-parametric MR-PET imaging changes before and after GDC-0084. A) Pearson's correlation coefficient (R) and B) resulting p-values describing the association between all imaging measurements. No significant correlations (P

Correlation between Cmax and AUC.

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.

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

INTRODUCTION Sodium MRI has been recently explored in brain tumors to potentially reveal complementary information with proton MRI about the tumor microenvironment. However, there remains limited investigation combining sodium and quantitative proton MRI techniques. This pilot study explored the associations of sodium MRI with diffusion-, pH-, and hypoxia-weighted MRI biomarkers in gliomas. METHODS Eleven patients with gliomas (n=8 IDH-wild-type; n=3 IDH-mutant) who obtained sodium, anatomical, diffusion-, pH-, and hypoxia-weighted MRI were studied. All images were obtained on a 3T Siemens Prisma with a dedicated multi-nuclear head coil. Regions-of-interest were segmented on the contrast-enhancing (CE) (n=10), FLAIR (n=11), and necrotic regions (n=9). Sodium values were normalized to the mean values of the eyes. Median sodium, apparent diffusion coefficient (ADC), ADC(L) from bimodal histogram analyses, MTRasym (acidity), and R2’ (hypoxia) values were obtained. RESULTS There was increased sodium in necrosis compared to FLAIR regions (mean difference=0.24; P/i>< 0.05) and compared to CE regions (mean difference=0.17; P/i>=0.07). There were significant positive correlations between sodium and ADC in CE (R=0.94; P/i>< 0.0001) and FLAIR regions (ρ=0.77; P/i>< 0.01), but not in necrosis (R=0.44; P/i>=0.24). There was also a significant positive correlation with ADC(L) in CE regions (R=0.90; P< 0.001) but not in FLAIR regions (ρ=0.50; P/i>=0.12). Furthermore, there was a significant positive correlation between sodium and MTRasym in necrosis (R=0.74; P/i>< 0.05) and a positive trend in CE regions (R=0.55; P=0.10). There was also a negative trend between sodium and R2’ in FLAIR regions (ρ=-0.58; P/i>=0.11). CONCLUSIONS Because ADC and ADC(L) are inversely related to cell density, increased sodium in gliomas may reflect increased extracellular space stemming from lower cell density, as sodium concentration is higher extracellularly. Positive associations between sodium and acidity as well as negative associations between sodium and hypoxia may reflect alterations in coupled sodium-pH and sodium-hypoxia homeostasis in gliomas.

In recently published work, we demonstrated that acute inhibition of the EGFR – the most frequently altered oncogene in GBM – can rapidly reduce glycolysis in a subset of GBM. To quantify this effect, we propose a new combination metabolic MR-PET imaging biomarker that combines 18F-FDG PET, DSC perfusion MRI, diffusion MRI, and pH- and oxygen-sensitive amine CEST-SAGE-EPI. Specifically, this “glycolytic index” or GI, can be defined as elevated glucose uptake (18F-FDG standard uptake value), elevated tumor acidity (MTRasym@3ppm), and lower oxygen utilization (relative cerebral metabolic rate of oxygen, rCMRO2, defined as R2’ x rCBF/rCBV from oxygen-sensitive SAGE-EPI and DSC perfusion), normalized to cell density (using ADC from diffusion MRI). In the current study, we explored the use of Tagrisso® (Osimertinib or AZD9291), which has very high brain to plasma ratios (> 1) and has proven effective in CNS metastasis of EGFR mutant lung cancer, as a potential treatment for EGFR amplified recurrent GBM. We have conducted a clinical trial (NCT03732352) to determine whether we observe similar metabolic imaging changes in EGFR mutated or amplified recurrent glioblastoma patients after treatment with osimertinib. Consistent with prior in vitro and in vivo results, treated patients exhibited a reduced glycolytic flux as indicated by reduction in 18F-FDG PET uptake (-3% change in SUV), tumor acidity (-19% change in MTRasym@3ppm) on pH-weighted CEST MRI, and glycolytic index (GI) (-25% change) in EGFR amplified recurrent GBM within 24 hours of treatment. Preliminary data suggests early change in GI correlates with and predicts both PFS (Pearson correlation, R2=0.3463, P=0.0441; Log-rank, P=0.0467) and OS (R2=0.6368, P=0.0019; Log-rank, P=0.0192). These preliminary data establish the scientific premise that a “glycolytic index” created using 18F-FDG PET, DSC perfusion, diffusion MRI, and pH- and oxygen-weighted amine CEST-SAGE-EPI may be an important tool for quantifying and visualizing glycolytic flux in GBM.

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.

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.

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

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

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.

Background Inhibition 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. Methods Twenty-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. Results After 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. Conclusions Increased 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.

Purpose: To identify correlations of gliomas between 18F-fluorodihydroxyphenylalanine (FDOPA) uptake and physiological magnetic resonance imaging (MRI) including relative cerebral blood volume (rCBV) and apparent diffusion coefficient (ADC) with different molecular subtypes, and to evaluate their prognostic values. Methods: Sixty-eight treatment-naive glioma patients who underwent FDOPA positron emission tomography (PET) and physiological MRI were retrospectively selected (isocitrate dehydrogenase wild-type [IDHwt], 36; mutant 1p/19q non-codeleted [IDHm-non-codel], 16; mutant codeleted [IDHm-codel], 16). Fluid-attenuated inversion recovery hyperintense areas were segmented and used as regions-of-interest. For voxel-wise and patient-wise analyses, Pearson’s correlation coefficients (rvoxel-wise and rpatient-wise) between the normalized standardized uptake value (nSUV), rCBV, and ADC were evaluated. Cox regression analysis was performed to investigate the associations between the overall survival (OS) and rvoxel-wise, max/median nSUV, median CBV, or median ADC. Results: For IDHwt and IDHm-non-codel gliomas, nSUV demonstrated significant positive correlations with rCBV (rvoxel-wise = 0.25 and 0.31, and rpatient-wise = 0.50 and 0.70, respectively), and negative correlations with ADC (rvoxel-wise = −0.19 and −0.19, and rpatient-wise = −0.58 and −0.61, respectively) in both voxel-wise and patient-wise analyses. IDHm-codel gliomas only demonstrated a significant positive correlation between nSUV and ADC in voxel-wise analysis (rvoxel-wise = 0.18). In Cox regression analysis, only rvoxel-wise between nSUV and rCBV (hazard ratio [HR] = 28.82) or ADC (HR = 0.085) had significant associations with OS for IDHwt gliomas. Conclusion: IDHm-codel gliomas showed distinctive patterns of correlations between amino acid PET and physiological MRI. Stronger correlations of nSUV and rCBV or ADC may result in worse prognosis for IDHwt gliomas.

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

BACKGROUND Laser Interstitial Thermal Therapy (LITT) is a novel treatment for brain metastases (BMs), and data regarding radiologic changes and long-term efficacy is sparse. This study explored volumetric changes in responding and non-responding BMs and their associations with lesion-specific progression-free survival (PFS-L). METHODS Patients with BMs treated with LITT were retrospectively enrolled. 3D volumes-of-interest of the contrast-enhancing BM tissue (CE) on pre-, post-LITT, and follow-up MRI scans were obtained. BMs were followed until progression or censoring. PFS-L was determined using the modified RANO criteria to assess treatment efficacy on each lesion. RESULTS Thirty-one BMs (from 30 patients) were preliminarily analyzed. 2 BMs had no follow-up scans. Median follow-up for 29 BMs was 248 days (range 28-2200). Median time to response was 430 days (responders n=7/29), median time to progression was 176 days (progressive disease n=7/29). Pre-LITT CE volume was a predictor of PFS-L (p=0.001), with BMs> 2.5 cc being 14 times more likely to undergo progression. Differences in age and primary tumor site did not impact PFS-L, whereas PFS-L tended to be longer in females (p=0.059), and in frontal and deep grey matter BMs (p=0.11). Post-LITT CE volume was higher than pre-LITT (p< 0.0001, median increase 59%), with no significant differences among responders, stable disease, and progressive disease. In each responding BM, the CE volume shrinkage over time was described by an exponential decay (R2 ranging 0.92-1.0 and half-life ranging 16.55-204 days). All responding BMs showed a pooled exponential decay with R2=0.88 and half-life=75.6 days. CONCLUSIONS Our data suggest that smaller BMs may have improved outcomes from LITT treatment. CE volumes may increase in the early post-procedural scans, possibly due to both inflammatory changes and thermal damage. The characterization of the volumetric changes across time for responding lesions may be useful for an early detection of BMs at risk for progression.

BACKGROUND In a classic DSC perfusion sequence, T1 and T2* leakage effects compete in determining the post-bolus signal, and are influenced by tissue geometry (i.e. cell density, cell size). Different DSC sequences can be variously influenced by these effects, depending on the different degree of T1 weighting and the pre-bolus administration. Multi-echo spin-and-gradient echo (SAGE) perfusion MRI enables to disentangle T2* and T1 components that contribute to the classic DSC curve, and to simultaneously compute DSC and DCE perfusion metrics. METHODS We retrospectively selected patients with: diagnosis of primary brain tumor, availability of SAGE-based DSC perfusion and DWI datasets, availability of histopathological images from targeted biopsies located within contrast-enhancing tissue. Post-processing allowed to distinguish the pure T2* component from the pure T1 component, and to perform a DCE analysis on the latter. Quantitative perfusion MRI measurements were then evaluated with respect to underlying histopathology. RESULTS Histopathological images were available for 22 targeted biopsies (across 10 patients) meeting the inclusion criteria. The following novel MRI quantitative maps were successfully computed voxelwise: ΔR2* at steady state (reflecting T2* leakage effects), ΔR1 at steady state (reflecting T1 leakage effects), transverse relaxivity at tracer equilibrium (TRATE, reflecting the combination of T2* and T1 leakage effects). In addition, Ve and ktrans were computed from the DCE analysis, and the percentage of signal recovery (PSR) was computed from the second echo of the multi-echo DSC (comparable to a classic single-echo DSC sequence). CONCLUSIONS Histopathological validation will assess the usefulness of these novel multi-echo derived quantitative maps for the non-invasive prediction of tumor microstructure. This would be particularly relevant for: 1) differential diagnosis between brain tumors with different cell size and cell density (e.g. lymphoma vs glioblastoma); 2) treatment response assessment (as pre-existing studies proved that cell shrinkage is an early event in treatment response).

BACKGROUND The blood brain barrier (BBB) is a major obstacle to the delivery of chemotherapy to the CNS. Regadenoson is an FDA approved adenosine A2 agonist used for cardiac stress tests. In murine models, it transiently increases BBB permeability to a 70KD dextran. This multi-institutional, NIH funded, Adult Brain Tumor Consortium trial was designed to discover a dose of regadenoson that substantially increases vascular permeability in normal appearing white matter (NAWM) where drug delivery is particularly challenging. METHODS Adults ages 18-45 with supratentorial gliomas at low-risk for regadenoson complications were recruited (n = 7). One patient was treated at each of seven dose levels (from 0.05 to 1.4 mg) that are known to be safe in humans. The primary outcome measure is change in vascular permeability via dynamic contrast enhanced (DCE) perfusion MRI estimates of Ktrans. The primary outcome measure was a 10-fold higher Ktrans in NAWM than reported in literature (Ktrans > 0.04 min-1). Contrast-enhanced T1 subtraction map estimates of change in contrast enhancement and other measurements in normal brain and non-enhancing tumor were quantified. RESULTS Ktrans measures in NAWM averaged 1.13x10-3 ± 0.44x10-3 (SEM) min-1, lower than the target of 0.04 min-1. Normalized, contrast enhanced T1-weighted MR signal intensity in NAWM increased an average of 74.0 ± 22.4% min-1 (SEM) min-1, which was significantly higher than zero (P = 0.0163). Data available from this limited sample failed to meet the target goal in Ktrans increase or change in contrast enhancing signal intensity. CONCLUSION Administration of regadenoson at seven different doses did not significantly elevate Ktrans for gadolinium in NAWM. This data suggests that single doses of regadenoson are unlikely to substantially increase the delivery of therapeutic agents in non-enhancing brain tissue. This trial design is appropriate for further human testing of other regadenoson schedules and other novel approaches aimed at transiently modifying BBB permeability.

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.

Glioblastoma (GBM) has high metabolic demands, which can lead to acidification of the tumor microenvironment. We hypothesize that a machine learning model built on temporal principal component analysis (PCA) of dynamic susceptibility contrast-enhanced (DSC) perfusion MRI can be used to estimate tumor acidity in GBM, as estimated by pH-sensitive amine chemical exchange saturation transfer echo-planar imaging (CEST-EPI). We analyzed 78 MRI scans in 32 treatment naïve and post-treatment GBM patients. All patients were imaged with DSC-MRI, and pH-weighting that was quantified from CEST-EPI estimation of the magnetization transfer ratio asymmetry (MTRasym) at 3 ppm. Enhancing tumor (ET), non-enhancing core (NC), and peritumoral T2 hyperintensity (namely, edema, ED) were used to extract principal components (PCs) and to build support vector machines regression (SVR) models to predict MTRasym values using PCs. Our predicted map correlated with MTRasym values with Spearman’s r equal to 0.66, 0.47, 0.67, 0.71, in NC, ET, ED, and overall, respectively (p

Glioblastoma (GBM) has high metabolic demands, which can lead to acidification of the tumor microenvironment. We hypothesize that a machine learning model built on temporal principal component analysis (PCA) of dynamic susceptibility contrast-enhanced (DSC) perfusion MRI can be used to estimate tumor acidity in GBM, as estimated by pH-sensitive amine chemical exchange saturation transfer echo-planar imaging (CEST-EPI). We analyzed 78 MRI scans in 32 treatment naïve and post-treatment GBM patients. All patients were imaged with DSC-MRI, and pH-weighting that was quantified from CEST-EPI estimation of the magnetization transfer ratio asymmetry (MTRasym) at 3 ppm. Enhancing tumor (ET), non-enhancing core (NC), and peritumoral T2 hyperintensity (namely, edema, ED) were used to extract principal components (PCs) and to build support vector machines regression (SVR) models to predict MTRasym values using PCs. Our predicted map correlated with MTRasym values with Spearman’s r equal to 0.66, 0.47, 0.67, 0.71, in NC, ET, ED, and overall, respectively (p). The results of this study demonstrates that PCA analysis of DSC imaging data can provide information about tumor pH in GBM patients, with the strongest association within the peritumoral regions.

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-[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.Residual CE volume had a significant association with OS [hazard ratio (HR) = 1.26, p = 0.039], but this effect disappeared when controlling for tumor grade. Residual FDOPA hypermetabolic volume best fit the regression model and was significantly associated with OS (HR = 1.18, p = 0.008), even when controlling for tumor grade. FLAIR hyperintense volume showed no significant association with OS.Residual FDOPA hypermetabolic burden predicted OS for IDH wild-type gliomas, regardless of the tumor grade. Furthermore, removing hypermetabolic and CE regions may improve the prognosis.

Degenerative Cervical Myelopathy (DCM) is a spinal cord disorder that causes significant physical disabilities in older patients. While most DCM research focuses on the spinal cord, widespread reorganization of the brain may occur to compensate for functional impairment. This observational study used diffusion spectrum imaging (DSI) to examine reorganization of cerebral white matter associated with neurological impairment as measured by the modified Japanese Orthopedic Association (mJOA), and severity of neck disability as measured by the Neck Disability Index (NDI) score. A total of 47 patients were included in the cervical spondylosis (CS) cohort: 38 patients with DCM (mean mJOA=14.6, and mean NDI=12.0), and 9 neurologically asymptomatic patients with spinal cord compression (mJOA=18, and mean NDI=7.0). 28 healthy volunteers (HCs) served as the control group. Lower generalized fractional anisotropy (GFA) was observed throughout much of the brain in patients compared to HCs (p&nbsp

BACKGROUND AND PURPOSE: Acidification 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 METHODS: In 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. RESULTS: General 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). CONCLUSIONS: A 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.

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

Preoperative prediction of isocitrate dehydrogenase mutation status is clinically meaningful, but remains challenging. This study aimed to predict the isocitrate dehydrogenase (IDH) status of gliomas by using the machine learning voxel-wise clustering method of multiparametric physiologic and metabolic magnetic resonance imaging (MRI) and to show the association of the created cluster labels with the glucose metabolism status of the tumors. Sixty-nine patients with diffuse glioma were scanned by pH-sensitive MRI, diffusion-weighted imaging, fluid-attenuated inversion recovery, and contrast-enhanced T1-weighted imaging at 3 T. An unsupervised two-level clustering approach, including the generation of a self-organizing map followed by the K-means clustering, was used for voxel-wise feature extraction from the acquired images. The logarithmic ratio of the labels in each class within tumor regions was applied to a support vector machine to differentiate IDH mutation status. Bootstrapping and leave-one-out cross-validation were used to calculate the area under the curve (AUC) of receiver operating characteristic curves, accuracy, sensitivity, and specificity for evaluating performance. Targeted biopsies were performed for 14 patients to explore the relationship between clustered labels and the expression of key glycolytic proteins determined using immunohistochemistry. The highest prediction performance to differentiate IDH status was found for 10-class clustering, with a mean AUC, accuracy, sensitivity, and specificity of 0.94, 0.91, 0.90, and 0.91, respectively. The tissues with labels 7 + 8 + 9 + 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. Our machine learning model successfully predicted the IDH mutation status of gliomas, and the resulting clusters properly reflected the metabolic status of the tumors.

Hypoxia and tissue acidosis are two key features of the glioma microenvironment, both associated with a more aggressive phenotype through promotion of invasion, angiogenesis, and resistance to a vast number of therapies. In the current study, we demonstrate that higher levels of acidity and hypoxia in glioma are associated with worse prognosis by using simultaneous pH- and oxygen-sensitive amine chemical exchange saturation transfer spin-and-gradient echo echo-planar imaging (CEST-SAGE-EPI). A total of 159 histologically confirmed adult glioma patients (WHO grade II: N = 42; grade III: N = 38; grade IV, N = 79) were retrospectively evaluated. All patients were scanned with a custom amine CEST-SAGE-EPI MRI pulse sequence at 3T. Magnetization transfer ratio asymmetry (MTRasym) at 3ppm was used as a measure of relative acidity, R2’ was used as a surrogate of hypoxia, and their product MTRasym×R2' was used to quantify the degree of both acidity and hypoxia. Cox regression was performed to evaluate prognostic factors for OS and PFS. Univariate results suggested higher hypoxia, R2' (HR = 1.44, p = 0.0002), and higher combined measure of acidity and hypoxia, MTRasym×R2' (HR = 1.14, p = 0.0008), were associated with a shorter OS. When considering age, treatment status, and IDH mutation status as covariates, R2' and MTRasym×R2' remained significantly associated with patient OS (R2': HR = 1.27, p = 0.045; MTRasym×R2': HR = 1.17, p = 0.002). Within the treatment naïve patients, tumor acidity MTRasym, was also associated with OS (HR = 3.72, p = 0.003). R2' and MTRasym×R2' were significantly associated with PFS, both using univariate (R2': p < 0.0001; MTRasym×R2': p < 0.0001) and multivariate analyses including clinical factors (R2': p = 0.010; MTRasym×R2': p < 0.0001). In summary, tumor acidity and hypoxia measured using pH- and oxygen-sensitive metabolic MRI are significant prognostic factors in glioma.

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.

This study aimed to assess the association between biological tumor burden in pre- and post-operative status and overall survival (OS) in isocitrate dehydrogenase (IDH) wild-type gliomas, and to evaluate which volume was the best predictor of OS. Thirty-four patients with treatment-naïve IDH wild-type gliomas (grade II, 6; III, 15; IV, 13) were retrospectively included. Three pre-operative tumor regions of interest (ROIs) were segmented based on the contrast-enhanced (CE), fluid-attenuated inversion recovery (FLAIR) hyperintense, and 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (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 was conducted to investigate the association of OS with the volume of each ROI. 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 was significantly associated with OS (HR = 1.18, P = 0.008), even when controlling for tumor grade. FLAIR hyperintense volume showed no significant association with OS. Residual FDOPA hypermetabolic burden predicted OS for IDH wild-type gliomas, regardless of tumor grade. Furthermore, removing hypermetabolic and CE regions may improve the prognosis.

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 Evidence from single and multicenter phase II trials have suggested diffusion MRI is a predictive imaging biomarker for survival benefit in recurrent glioblastoma (rGBM) treated with anti-VEGF therapy. The current study confirms these findings in a large, randomized phase III clinical trial. Methods Patients with rGBM were enrolled in a phase III randomized (1:1), controlled trial (NCT02511405) to compare the efficacy and safety of bevacizumab (BV) versus BV in combination with ofranergene obadenovec (BV+VB-111), an anti-cancer viral therapy. In 170 patients with diffusion MRI available, pretreatment enhancing tumor volume and ADC histogram analysis were used to phenotype patients as having high (>1.24 µm2/ms) or low ( Results Baseline tumor volume (P = .3460) and ADCL (P = .2143) did not differ between treatment arms. Univariate analysis showed patients with high ADCL had a significant survival advantage in all patients (P = .0006), as well as BV (P = .0159) and BV+VB-111 individually (P = .0262). Multivariable Cox regression accounting for treatment arm, age, baseline tumor volume, and ADCL identified continuous measures of tumor volume (P < .0001; HR = 1.0212) and ADCL phenotypes (P = .0012; HR = 0.5574) as independent predictors of OS. Conclusion Baseline diffusion MRI and tumor volume are independent imaging biomarkers of OS in rGBM treated with BV or BV+VB-111.

Author(s): Tatekawa, Hiroyuki; Yao, Jingwen; Oughourlian, Talia C; Hagiwara, Akifumi; Wang, Chencai; Raymond, Catalina; Lai, Albert; Cloughesy, Timothy F; Nghiemphu, Phioanh L; Liau, Linda M; Salamon, Noriko; Ellingson, Benjamin M | Abstract: 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 g1), 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.

This study aimed to investigate the potential of a novel MRI metric related to aerobic glycolysis in patients with diffuse gliomas. All subjects (Study I–III; 7, 26, and 11 subjects, respectively) were scanned on 3-T systems and underwent pH-weighted amine chemical exchange saturation transfer spin-and-gradient-echo echoplanar imaging (CEST-SAGE-EPI) or CEST-EPI, and perfusion imaging. Relative oxygen extraction fraction (rOEF) was calculated by dividing hypoxia-sensitive R2’ by normalized relative cerebral blood volume (nrCBV); a novel metric that characterizes glycolytic status (aerobic glycolytic index, AGI) was calculated by dividing amine CEST contrast by rOEF. Patients in Study I were additionally scanned by 18F-fluorodeoxyglucose (FDG)-PET. Stereotactic image-guided biopsies were performed on patients in Study II and III, and samples were analyzed by immunohistochemistry (IHC) and extracellular flux bioenergetic analysis, respectively. Pairwise correlation between MR metrics and standardized uptake value of 18F-FDG, IHC metrics, or indices of cellular metabolism was calculated using Spearman’s correlation analysis. In Study I, AGI showed very strong significant correlation with 18F-FDG uptake in glioma (correlation coefficient ρ = 0.86, P =0.014). In Study II, AGI was significantly correlated with glucose transporter 3 (ρ = 0.71; P = 0.0041) and hexokinase 2 (ρ = 0.73; P = 0.0029) in IDH wild-type glioma, while it was significantly correlated with monocarboxylate transporter 1 (ρ = 0.59; P = 0.0094) in IDH mutant glioma. This result may reflect the different glycolytic statuses of these gliomas; specifically, the rate-limiting steps in glycolysis. In Study III, a strong significant correlation with cellular AGI derived from the bioenergetic analysis was found for AGI derived from MRI (ρ = 0.79, P = .036). In conclusion, AGI derived from MRI was correlated with FDG, IHC measurements, and cellular AGI. Future studies investigating the clinical utility of AGI in prediction and evaluation of treatment effects are warranted.