Comparison between Short and Long Echo Time Magnetic Resonance Spectroscopic Imaging at 3T and 7T for Evaluating Brain Metabolites in Patients with Glioma

Three-dimensional proton magnetic resonance spectroscopic imaging (MRSI) is a powerful non-invasive tool for characterizing spatial variations in metabolic profiles for patients with glioma. Metabolic parameters obtained using this technique have been shown to predict treatment response, disease progression, and transformation to a more malignant phenotype. The availability of ultra-high-field MR systems has the potential to improve the characterization of metabolites. The purpose of this study was to compare the metabolite profiles acquired with conventional long echo time (TE) MRSI at 3T with those obtained with short TE MRSI at 3T and 7T in patients with glioma. The data acquisition parameters were optimized separately for each echo time and field strength to obtain volumetric coverage within clinically feasible data acquisition times of 5-10 min. While a higher field strength did provide better detection of metabolites with overlapping peaks, spatial coverage was reduced and the use of inversion recovery to reduce lipid precluded the detection of lipid in regions of necrosis. For serial evaluation of large, heterogeneous lesions, the use of 3T short TE MRSI may thus be preferred. Despite the limited number of metabolites that it is able to detect, the use of 3T long TE MRSI gives the best contrast in choline/N-acetyl aspartate between normal appearing brain and tumor and also allows the separate detection of lactate and lipid. It may therefore be preferred for serial evaluation of patients with high-grade glioma and for detection of malignant transformation in patients with low-grade glioma

NIMG-64. THE POTENTIAL OF 7T ANATOMICAL IMAGING FOR CLINICAL ASSESSMENT OF CONTRAST-ENHANCING AND T2-HYPERINTENSE LESIONS IN PATIENTS WITH GLIOMA

Abstract PURPOSE 7 Tesla (7T) MRI scanners can provide novel information to improve the characterization of gliomas. However, patients who receive 7T scans must undergo separate clinical evaluations at lower field strengths due to a lack of clinical validation of 7T anatomical imaging. The purpose of this study was to develop a robust volumetric anatomical imaging protocol for the clinical evaluation of patients with glioma at 7T and compare lesion definition to standard 3T imaging. METHODS 3D T2-weighted, T2 FLAIR, and T1-weighted sequences at 7T were optimized to match the contrast, resolution, and scan time of corresponding clinical sequences at 3T. Ten patients with contrast-enhancing glioma (grades II-IV) were scanned with a protocol consisting of pre-contrast anatomical imaging and post-contrast T1-weighted imaging at both field strengths, with the 7T scan occurring in between the pre- and post-contrast 3T imaging. A half-dose of contrast was used at 7T, with an additional half-dose given immediately afterwards at 3T to provide similar lesion contrast given the 2.3-fold difference in field strength. Metrics for comparison between field strengths included volumes of T2 and contrast-enhancing lesions, and Likert-scale ratings (1-5) of lesion definition by a neuro-radiologist. RESULTS T2 and contrast-enhancing lesion volumes were not significantly different between field strengths, despite the trend in larger enhancing lesion volumes at 3T, which was expected given the protocol design. 7T T2-weighted and post-contrast T1-weighted images received on average half-point higher Likert-scale ratings than corresponding 3T images, whereas the opposite trend was observed with the T2 FLAIR and pre-contrast T1-weighted images. CONCLUSION Our pilot study suggests that clinical assessment of contrast-enhancing and T2-hyperintense lesions in glioma is feasible at 7T, which would obviate the need for two scans, allowing patients to take advantage of the increased sensitivity in metabolic and physiologic imaging available at 7T and ultimately improve patient care

ATIM-22. PROGNOSTIC VALUE OF PTEN LOSS IN NEWLY DIAGNOSED GBM PATIENTS TREATED WITH AUTOLOGOUS HEAT SHOCK PROTEIN VACCINE

Abstract INTRODUCTION: The safety and efficacy of a heat shock protein peptide complex- 96 vaccine (HSPPC-96, Prophage) has been previously studied in phase II single-arm trials for the treatment of newly diagnosed and recurrent glioblastoma (GBM). These studies demonstrated modest improvements in survival compared with historical standards. PTEN loss has been recently associated with immunoresistance in GBM patients, mediated in part by B7-H1. PTEN status has not shown clear prognostic value in GBM patients treated with standard of care therapies. The aim of this study is to evaluate the prognostic significance of PTEN status in newly diagnosed GBM patients treated with autologous HSP vaccine and standard chemoradiation. METHODS Our institutional cohort of patients enrolled in a single arm, phase II study of adult GBM patients treated with autologous HSP vaccine and standard chemoradiation (n=27) was analyzed. Differences in overall survival (OS) by PTEN status were evaluated via Kaplan-Meier curves and Log-rank test. RESULTS Median overall survival (n=27) was 26 months. 23 patients had PTEN status available. PTEN loss was found in 16 patients (69.6%) whereas retained PTEN was present in 7 patients (30.4%). Median OS was 59 months (95% CI, 0–120 months) in patients with retained PTEN and 23 months (95% CI, 15–30 months) in patients with PTEN loss. The difference in OS was statistically significant (p=0.037). CONCLUSION: Retained PTEN expression was associated with extended survival in GBM patients treated with HSP vaccine. This finding suggests that PTEN loss may be associated with resistance to vaccine treatment and emphasizes the need for subgroup analysis in further immunotherapy studies

Treatment-induced lesions in newly diagnosed glioblastoma patients undergoing chemoradiotherapy and heat-shock protein vaccine therapy

ObjectivesTreatment-induced lesions represent a great challenge in neuro-oncology. The aims of this study were (i) to characterize treatment induced lesions in glioblastoma patients treated with chemoradiotherapy and heat-shock protein (HSP) vaccine and (ii) to evaluate the diagnostic accuracy of diffusion weighted imaging for differentiation between treatment-induced lesions and tumor progression.MethodsTwenty-seven patients with newly diagnosed glioblastoma treated with HSP vaccine and chemoradiotherapy were included. Serial magnetic resonance imaging evaluation was performed to detect treatment-induced lesions and assess their growth. Quantitative analysis of the apparent diffusion coefficient (ADC) was performed to discriminate treatment-induced lesions from tumor progression. Mann-Whitney U-test and receiver operating characteristic (ROC) curves were used for analysis.ResultsThirty-three percent of patients developed treatment-induced lesions. Five treatment-related lesions appeared between end of radiotherapy and the first vaccine administration; 4 lesions within the first 4 months from vaccine initiation and 1 at 3.5 years. Three patients with pathology proven treatment-induced lesions showed a biphasic growth pattern progressed shortly after. ADC ratio between the peripheral enhancing rim and central necrosis showed an accuracy of 0.84 (95% CI 0.63-1) for differentiation between progression and treatment-induced lesions.ConclusionOur findings do not support the iRANO recommendation of a 6-month time window in which progressive disease should not be declared after immunotherapy initiation. A biphasic growth pattern of pathologically proven treatment-induced lesions was associated with a dismal prognosis. The presence of lower ADC values in the central necrotic portion of the lesions compared to the enhancing rim shows high specificity for detection of treatment-induced lesions

Spectroscopic imaging of D-2-hydroxyglutarate and other metabolites in pre-surgical patients with IDH-mutant lower-grade gliomas.

PurposePrognostically favorable IDH-mutant gliomas are known to produce oncometabolite D-2-hydroxyglutarate (2HG). In this study, we investigated metabolite-based features of patients with grade 2 and 3 glioma using 2HG-specific in vivo MR spectroscopy, to determine their relationship with image-guided tissue pathology and predictive role in progression-free survival (PFS).MethodsForty-five patients received pre-operative MRIs that included 3-D spectroscopy optimized for 2HG detection. Spectral data were reconstructed and quantified to compare metabolite levels according to molecular pathology (IDH1R132H, 1p/19q, and p53); glioma grade; histological subtype; and T2 lesion versus normal-appearing white matter (NAWM) ROIs. Levels of 2HG were correlated with other metabolites and pathological parameters (cellularity, MIB-1) from image-guided tissue samples using Pearson's correlation test. Metabolites predictive of PFS were evaluated with Cox proportional hazards models.ResultsQuantifiable levels of 2HG in 39/42 (93%) IDH+ and 1/3 (33%) IDH- patients indicated a 91.1% apparent detection accuracy. Myo-inositol/total choline (tCho) showed reduced values in astrocytic (1p/19q-wildtype), p53-mutant, and grade 3 (vs. 2) IDH-mutant gliomas (p < 0.05), all of which exhibited higher proportions of astrocytomas. Compared to NAWM, T2 lesions displayed elevated 2HG+ γ-aminobutyric acid (GABA)/total creatine (tCr) (p < 0.001); reduced glutamate/tCr (p < 0.001); increased myo-inositol/tCr (p < 0.001); and higher tCho/tCr (p < 0.001). Levels of 2HG at sampled tissue locations were significantly associated with tCho (R = 0.62; p = 0.002), total NAA (R = - 0.61; p = 0.002) and cellularity (R = 0.37; p = 0.04) but not MIB-1. Increasing levels of 2HG/tCr (p = 0.0007, HR 5.594) and thresholding (≥ 0.905, median value; p = 0.02) predicted adverse PFS.ConclusionIn vivo 2HG detection can reasonably be achieved on clinical scanners and increased levels may signal adverse PFS

NIMG-50. INITIAL EXPERIENCE: DETECTION OF ABERRANT HYPERPOLARIZED [1-13C]PYRUVATE METABOLISM IN PATIENTS WITH GBM PRIOR TO RESECTION

Abstract INTRODUCTION Detecting radiological response or resistance to treatment in patients with GBM is difficult with conventional MRI. In response to this challenge, hyperpolarized carbon-13 (HP-13C) MRI techniques were developed to probe real-time [1-13C]pyruvate metabolism. METHODS Dynamic HP-13C MRI was acquired pre-operatively from 6 patientswith recurrent GBM following intravenous injection of HP [1-13C]pyruvate. Five were confirmed with tumor progression and one had treatment effects without progression. Frequency-selective echo-planar imaging (8 slices, 3s temporal resolution, 3.38 cm3 spatial resolution, 60s acquisition) captured [1-13C]pyruvate metabolism to [1-13C]lactate and [1-13C]bicarbonate in the brain. Proton imaging included 3-D FLAIR, T1-weighted post-Gd IRSPGR, and spectroscopy. Carbon-13 voxels with non-enhancing lesion (NEL) or contrast-enhancing lesion (CEL) were identified for subsequent analysis. Temporally-summed HP-13C metabolite data within the CEL and NEL were evaluated using the pyruvate-to-lactate ratio; a modified ratio that takes into account vascular contributions of pyruvate; and parameter percentile ranks over the entire brain. Proton spectroscopy data were processed to obtain choline-to-NAA index (CNI) maps, which provide z-scores of relative tissue abnormality. RESULTS All of the anatomic lesions displayed abnormal CNI with maximum values of 3.22-6.35. The 5 patients with CEL lesions demonstrated 87th– 98thpercentile levels of pyruvate in the brain; and 95th-100thpercentile levels of lactate in 4 progressed patients and 60thpercentile in the patient presenting with treatment effects. For the patient with an exclusively non-enhancing lesion, percentile levels of pyruvate and lactate were 66thand 88thin the brain, respectively. The mean+/-SD percentile of the lactate-to-pyruvate and modified ratios were 75+/-22, 86+/-23 and 60+/-3, 71+/-12 in the progressed and non-progressed patients, respectively. CONCLUSION These data importantly demonstrate aberrant [1-13C]pyruvate metabolism in patients with GBM in both contrast-enhancing and non-enhancing lesions. Ongoing studies will further characterize the utility of HP imaging markers

Improving the Generalizability of Deep Learning for T2-Lesion Segmentation of Gliomas in the Post-Treatment Setting

Although fully automated volumetric approaches for monitoring brain tumor response have many advantages, most available deep learning models are optimized for highly curated, multi-contrast MRI from newly diagnosed gliomas, which are not representative of post-treatment cases in the clinic. Improving segmentation for treated patients is critical to accurately tracking changes in response to therapy. We investigated mixing data from newly diagnosed (n = 208) and treated (n = 221) gliomas in training, applying transfer learning (TL) from pre- to post-treatment imaging domains, and incorporating spatial regularization for T2-lesion segmentation using only T2 FLAIR images as input to improve generalization post-treatment. These approaches were evaluated on 24 patients suspected of progression who had received prior treatment. Including 26% of treated patients in training improved performance by 13.9%, and including more treated and untreated patients resulted in minimal changes. Fine-tuning with treated glioma improved sensitivity compared to data mixing by 2.5% (p p < 0.05). While training with ≥60 treated patients yielded the majority of performance gain, TL and spatial regularization further improved T2-lesion segmentation to treated gliomas using a single MR contrast and minimal processing, demonstrating clinical utility in response assessment

Tumor metabolism and neurocognition in CNS lymphoma

BackgroundThe mechanistic basis for neurocognitive deficits in central nervous system (CNS) lymphoma and other brain tumors is incompletely understood. We tested the hypothesis that tumor metabolism impairs neurotransmitter pathways and neurocognitive function.MethodsWe performed serial cerebrospinal fluid (CSF) metabolomic analyses using liquid chromatography-electrospray tandem mass spectrometry to evaluate changes in the tumor microenvironment in 14 patients with recurrent CNS lymphoma, focusing on 18 metabolites involved in neurotransmission and bioenergetics. These were paired with serial mini-mental state examination (MMSE) and MRI studies for tumor volumetric analyses. Patients were analyzed in the setting of the phase I trial of lenalidomide/rituximab. Associations were assessed by Pearson and Spearman correlation coefficient. Generalized estimating equation (GEE) models were also established, adjusting for within-subject repeated measures.ResultsOf 18 metabolites, elevated CSF lactate correlated most strongly with lower MMSE score (P &lt; 8E-8, ρ = -0.67). High lactate was associated with lower gamma-aminobutyric acid (GABA), higher glutamate/GABA ratio, and dopamine. Conversely, high succinate correlated with higher MMSE scores. Serial analysis demonstrated a reproducible, time-dependent, reciprocal correlation between changes in lactate and GABA concentrations. While high lactate and low GABA correlated with tumor contrast-enhancing volume, they correlated more significantly with lower MMSE scores than tumor volumes.ConclusionsWe provide evidence that lactate production and Warburg metabolism may impact neurotransmitter dysregulation and neurocognition in CNS lymphomas. We identify novel metabolomic biomarkers that may be applied in future studies of neurocognition in CNS lymphomas. Elucidation of mechanistic interactions between lymphoma metabolism, neurotransmitter imbalance, and neurocognition may promote interventions that preserve cognitive function

Multi-parametric hyperpolarized 13C/1H imaging reveals Warburg-related metabolic dysfunction and associated regional heterogeneity in high-grade human gliomas.

BACKGROUND: Dynamic hyperpolarized (HP)-13C MRI has enabled real-time, non-invasive assessment of Warburg-related metabolic dysregulation in glioma using a [1-13C]pyruvate tracer that undergoes conversion to [1-13C]lactate and [13C]bicarbonate. Using a multi-parametric 1H/HP-13C imaging approach, we investigated dynamic and steady-state metabolism, together with physiological parameters, in high-grade gliomas to characterize active tumor. METHODS: Multi-parametric 1H/HP-13C MRI data were acquired from fifteen patients with progressive/treatment-naïve glioblastoma [prog/TN GBM, IDH-wildtype (n&nbsp;=&nbsp;11)], progressive astrocytoma, IDH-mutant, grade 4 (G4AIDH+, n&nbsp;=&nbsp;2) and GBM manifesting treatment effects (n&nbsp;=&nbsp;2). Voxel-wise regional analysis of the cohort with prog/TN GBM assessed imaging heterogeneity across contrast-enhancing/non-enhancing lesions (CEL/NEL) and normal-appearing white matter (NAWM) using a mixed effects model. To enable cross-nucleus parameter association, normalized perfusion, diffusion, and dynamic/steady-state (HP-13C/spectroscopic) metabolic data were collectively examined at the 13C resolution. Prog/TN GBM were similarly compared against progressive G4AIDH+ and treatment effects. RESULTS: Regional analysis of Prog/TN GBM metabolism revealed statistically significant heterogeneity in 1H choline-to-N-acetylaspartate index (CNI)max, [1-13C]lactate, modified [1-13C]lactate-to-[1-13C]pyruvate ratio (CELval&nbsp;&gt;&nbsp;NELval&nbsp;&gt;&nbsp;NAWMval); [1-13C]lactate-to-[13C]bicarbonate ratio (CELval&nbsp;&gt;&nbsp;NELval/NAWMval); and 1H-lactate (CELval/NELval&nbsp;&gt;&nbsp;NAWMundetected). Significant associations were found between normalized perfusion (cerebral blood volume, nCBV; peak height, nPH) and levels of [1-13C]pyruvate and [1-13C]lactate, as well as between CNImax and levels of [1-13C]pyruvate, [1-13C]lactate and modified ratio. GBM, by comparison to G4AIDH+, displayed lower perfusion %-recovery and modeled rate constants for [1-13C]pyruvate-to-[1-13C]lactate conversion (kPL), and higher 1H-lactate and [1-13C]pyruvate levels, while having higher nCBV, %-recovery, kPL, [1-13C]pyruvate-to-[1-13C]lactate and modified ratios relative to treatment effects. CONCLUSIONS: GBM consistently displayed aberrant, Warburg-related metabolism and regional heterogeneity detectable by novel HP-13C/1H imaging techniques

NIMG-21. VARIABLE RESOLUTION HYPERPOLARIZED [2-13C]PYRUVATE MRI IN HEALTHY VOLUNTEERS AND PATIENTS WITH IDH-MUTANT GLIOMA

Abstract INTRODUCTION Mutations in isocitrate dehydrogenase (IDH) have been investigated as a prognostic biomarker in glioma. The presence of the IDH mutation (IDHm) is associated with 2-hydroxyglutarate (2HG) production and inhibition of glutamate synthesis (McBrayer, Cell 2018). Hyperpolarized carbon-13 (HP-13C) MRI enables dynamic measurements of in-vivo metabolism using a [2-13C]pyruvate labeled probe that undergoes conversion to [2-13C]lactate and [5-13C]glutamate. Here, we present HP [2-13C]pyruvate data from healthy volunteers and patients with IDHm diffuse glioma. Due to its intrinsic low signal-to-noise ratio (SNR), we demonstrate the ability of post-processing denoising to improve its utility and aid in detection of metabolic changes associated with IDHm. METHODS Dynamic HP 13C data were acquired following intravenous injection of [2-13C]pyruvate from five healthy volunteers and one patient with IDHm grade III astrocytoma. A novel multi-resolution frequency specific multislice EPI sequence was used to obtain [2-13C]pyruvate, [5-13C]glutamate, and downfield and upfield [2-13C]lactate signals (3s temporal resolution, pyruvate/lactate/glutamate spatial resolutions = 0.75x0.75cm2/ 2.25x2.25cm2/ 2.25x2.25cm2, 5 slices 3cm thick). Following phase correction, patch-based tensor decomposition denoising was applied to metabolite images. Metabolite differences between normal-appearing white matter (NAWM) and T2 lesion were examined for the patient data. RESULTS HP [2-13C]pyruvate imaging is able to simultaneously probe glycolytic ([2-13C]lactate) and oxidative ([5-13C]glutamate) metabolism. Denoised pyruvate/lactate/glutamate signals achieved a 4-9/3-6/3-7 fold increase in SNR. T2 lesion exhibited decreased glutamate-to-pyruvate and glutamate-to-lactate AUC ratios versus contralateral NAWM (p&lt; 0.018, p &lt; 1.5e-5), consistent with IDH mutant status. CONCLUSION We successfully demonstrated the feasibility of applying variable resolution HP [2-13C]pyruvate metabolic imaging to detect IDHm specific metabolism. This technique addresses a major hurdle in HP 13C MRI by improving SNR while permitting robust metabolism quantification. Future studies will optimize methods for acquiring and processing data to evaluate further data acquired from IDHm glioma patients. Supported by NIH T32 CA151022, P01 CA118816, and NICO