Development of a Proton-Frequency-Transparent Birdcage Radiofrequency Coil for In Vivo 13C MRS/MRSI Study in a 3.0 T MRI System

A proton-frequency-transparent (PFT) birdcage RF coil that contains carbon-proton switching circuits (CPSCs) is presented to acquire 13C MR signals, which, in turn, enable 1H imaging with existing 1H RF coils without being affected by a transparent 13C birdcage RF coil. CPSCs were installed in the PFT 13C birdcage RF coil to cut the RF coil circuits during 1H MR imaging. Finite-difference time-domain (FDTD) electromagnetic (EM) simulations were performed to verify the performance of the proposed CPSCs. The performance of the PFT 13C birdcage RF coil with CPSCs was verified via phantom and in vivo MR studies. In the phantom MR studies, 1H MR images and 13C MR spectra were acquired and compared with each other using the 13C birdcage RF coil with and without the CPSCs. For the in vivo MR studies, hyperpolarized 13C cardiac MRS and MRSI of swine were performed. The proposed PFT 13C birdcage RF coil with CPSCs led to a percent image uniformity (PIU) reduction of 1.53% in the proton MR images when compared with the case without it. FDTD EM simulations revealed PIU reduction of 0.06% under the same conditions as the phantom MR studies. Furthermore, an SNR reduction of 5.5% was observed at 13C MR spectra of corn-oil phantom using the PFT 13C birdcage RF coil with CPSCs compared with that of the 13C birdcage RF coil without CPSCs. Utilizing the PFT 13C birdcage RF coil, 13C-enriched compounds were successfully acquired via in vivo hyperpolarized 13C MRS/MRSI experiments. In conclusion, the applicability and utility of the proposed 16-leg low-pass PFT 13C birdcage RF coil with CPSCs were verified via 1H MR imaging and hyperpolarized 13C MRS/MRSI studies using a 3.0 T MRI system.

EXTH-46. MRS BASED BIOMARKERS OF IDH1 MUTANT GLIOMA RESPONSE TO THE IDH INHIBITOR BAY-1436032

Gliomas are the most prevalent type of brain tumor in the central nervous system. Mutations in the cytosolic enzyme isocitrate dehydrogenase 1 (IDH1) are a common feature of primary low-grade gliomas, catalyzing the conversion of α-ketoglutarate (αKG) to the oncometabolite 2-hydroxyglutarate (2HG), and mutant IDH1 is a therapeutic target for these tumors. Several mutant IDH inhibitors are currently in clinical trials, nonetheless, complementary non-invasive early biomarkers to assess drug delivery and potential therapeutic response are still needed. The goal of this study was therefore to determine the potential of 1H and hyperpolarized 13C magnetic resonance spectroscopy (MRS)-based biomarkers as indicators of mutant IDH1 low-grade glioma response to treatment with the clinically-relevant IDH1 inhibitor BAY-1436032 in cells and animal models. Immortalized human astrocytes engineered to express mutant IDH1 were treated with 500nM (IC50 value) of BAY-1436032 and BT257 tumors implanted in rats were treated with 150mg/kg of BAY-1436032. To assess steady-state metabolite levels, 1H MRS spectra were acquired on a 500 MHz MRS cancer for cells and a 3 T scanner for animal studies. To assess metabolic fluxes, we used hyperpolarized 13C MRS and probed the fate of hyperpolarized [1-13C]αKG. 1H MRS showed a significant decrease in 2HG as well as a significant increase in glutamate (Glu) and phosphocholine (PCh) following BAY-1436032 treatment in both cell and animal models compared to controls. Furthermore, hyperpolarized 13C MRS showed that hyperpolarized 2HG production from hyperpolarized [1-13C]αKG was decreased and hyperpolarized glutamate production from hyperpolarized [1-13C]αKG was increased in the BAY-1436032 treated groups compared to controls. These findings are consistent with our previous study, which investigated the MRS-detectable consequences of two other mutant IDH inhibitors: AG120 and AG881. Collectively, our work identifies translatable MRS-based metabolic biomarkers of mutant IDH1 inhibition.

NIMG-43. ADVANCED MULTI-PARAMETRIC HYPERPOLARIZED 13C/1H IMAGING OF GBM

INTRODUCTION The goal of this study was to characterize progressive and pseudoprogressive GBM using multi-parametric hyperpolarized (HP)-13C / 1H MRI. METHODS Dynamic HP-13C MRI was acquired from 13 patients with progressive GBM [patients (scans): 2(3) IDH-mutant; 11(13) IDH-wildtype] and 2 IDH-wildtype patients (3 scans) demonstrating pseudo-progression following intravenous injection of HP [1-13C]pyruvate. Frequency-selective echo-planar imaging (3s temporal resolution, 3.38 cm3 spatial resolution) captured [1-13C]pyruvate metabolism to [1-13C]lactate and 13C-bicarbonate in the brain. Dynamic 13C data were kinetically modeled to obtain the pyruvate-to-lactate conversion rate constant k PL and temporally summed to calculate 13C-metabolite percentiles and ratios (linearly interpolated 2x in-plane). 1H imaging included T2, post-Gd T1, perfusion (nCBV, %recovery), diffusion (ADC), and lactate-edited spectroscopy (CNI, choline-to-NAA index; 1H-lactate). The normal-appearing white matter (NAWM), non-enhancing lesion (NEL), and contrast-enhancing lesion (CEL) were segmented from 1H images. 13C-resolution masks were iteratively applied on a voxel-wise basis to evaluate 1H imaging parameters within each ROI and multi-parametric data were collectively evaluated using a mixed effects model in R. RESULTS Progressive IDH-mutant GBM compared to wildtype counterparts displayed increased perfusion %recovery (p < 0.001) and k PL (p < 0.01), together with reduced 1H-lactate (p < 0.001) and pyruvate percentile (p < 0.01), in the T2 lesion. Among IDH-wildtype progressive GBM, the CEL was distinguished from NEL/NAWM by increased nCBV (p < 0.05/0.001), 1H-lactate (p < 0.05/0.001); and decreased bicarbonate / lactate (p < 0.05/0.001). The CEL and NEL were collectively distinguished from NAWM by elevated CNI (p < 0.001/0.001), ADC (p < 0.05/0.001), pyruvate percentile (p < 0.001/0.001), lactate percentile (p < 0.001/0.001), and relative lactate / pyruvate (p < 0.001/0.05). Psuedo-progressive IDH-wildtype GBM displayed lower k PL (T2 Lesion; p < 0.01) and nCBV (CEL; p < 0.01) compared to progressive GBM. CONCLUSION HP-13C parameters can potentially augment proton imaging and demonstrated Warburg-associated metabolic alterations.

TAMI-40. PEDIATRIC H3K27M MUTANT GLIOMAS UNDERGO METABOLIC REPROGRAMMING THAT CAN BE LEVERAGED FOR NON-INVASIVE METABOLIC IMAGING

Diffuse midline gliomas (DMGs) are a universally lethal form of childhood cancer. The infiltrative nature of DMGs makes them difficult to visualize by conventional magnetic resonance imaging. Genomics studies indicate that DMGs are driven by unique histone H3K27M mutations that result in broad epigenetic dysregulation. Many of the resulting changes in gene expression have the potential to induce metabolic reprogramming, which has been identified as a hallmark of cancer. The goal of this study was to dissect metabolic reprogramming in preclinical DMG models in order to identify novel magnetic resonance spectroscopy (MRS)-detectable metabolic biomarkers that can be exploited for non-invasive imaging. First, we used 1H-MRS, which reports on steady-state metabolism, to examine H3K27M mutant SF7761 cells and H3 wild-type normal human astrocytes (NHA). Lactate, glutathione and phosphocholine, which are involved in glycolysis, redox and phospholipid metabolism respectively, were elevated in SF7761 cells relative to NHAs. Mechanistically, these metabolic alterations were associated with upregulation of key enzymes including hexokinase 2, glutamate cysteine ligase and choline kinase a. Importantly, in vivo 1H-MRS showed elevated lactate, glutathione and total choline (combined signal from choline, phosphocholine and glycerophosphocholine) in mice bearing orthotopic SF7761 tumors relative to tumor-free controls. We then examined alterations in dynamic metabolic pathways in our models. Using thermally-polarized 13C-MRS, we identified elevated production of [2-13C]-lactate from [2-13C]-glucose in SF7761 cells relative to NHAs. Hyperpolarized 13C-MRS is a method of enhancing the 13C-MR signal such that metabolic fluxes can be interrogated with high sensitivity. Hyperpolarized [1-13C]-pyruvate flux to [1-13C]-lactate non-invasively monitors glycolysis and is in clinical trials in adult glioma patients. Importantly, hyperpolarized [1-13C]-pyruvate metabolism to lactate was elevated in SF7761 cells relative to NHAs. Collectively, our studies suggest that H3K27M mutant DMGs undergo reprogramming of glucose, redox and phospholipid metabolism that can be leveraged for non-invasive 1H- and hyperpolarized 13C-MRS-based imaging.

Radial Flow Perfusion Enables Real-Time Profiling of Cellular Metabolism at Low Oxygen Levels with Hyperpolarized 13C NMR Spectroscopy

In this study, we describe new methods for studying cancer cell metabolism with hyperpolarized 13C magnetic resonance spectroscopy (HP 13C MRS) that will enable quantitative studies at low oxygen concentrations. Cultured hepatocellular carcinoma cells were grown on the surfaces of non-porous microcarriers inside an NMR spectrometer. They were perfused radially from a central distributer in a modified NMR tube (bioreactor). The oxygen level of the perfusate was continuously monitored and controlled externally. Hyperpolarized substrates were injected continuously into the perfusate stream with a newly designed system that prevented oxygen and temperature perturbations in the bioreactor. Computational and experimental results demonstrated that cell mass oxygen profiles with radial flow were much more uniform than with conventional axial flow. Further, the metabolism of HP [1-13C]pyruvate was markedly different between the two flow configurations, demonstrating the importance of avoiding large oxygen gradients in cell perfusion experiments.

Characterization of Distinctive In Vivo Metabolism between Enhancing and Non-Enhancing Gliomas Using Hyperpolarized Carbon-13 MRI

The development of hyperpolarized carbon-13 (13C) metabolic MRI has enabled the sensitive and noninvasive assessment of real-time in vivo metabolism in tumors. Although several studies have explored the feasibility of using hyperpolarized 13C metabolic imaging for neuro-oncology applications, most of these studies utilized high-grade enhancing tumors, and little is known about hyperpolarized 13C metabolic features of a non-enhancing tumor. In this study, 13C MR spectroscopic imaging with hyperpolarized [1-13C]pyruvate was applied for the differential characterization of metabolic profiles between enhancing and non-enhancing gliomas using rodent models of glioblastoma and a diffuse midline glioma. Distinct metabolic profiles were found between the enhancing and non-enhancing tumors, as well as their contralateral normal-appearing brain tissues. The preliminary results from this study suggest that the characterization of metabolic patterns from hyperpolarized 13C imaging between non-enhancing and enhancing tumors may be beneficial not only for understanding distinct metabolic features between the two lesions, but also for providing a basis for understanding 13C metabolic processes in ongoing clinical trials with neuro-oncology patients using this technology.