BACKGROUND AND PURPOSE: Pediatric CNS tumors commonly present challenges for radiographic interpretation on conventional MR imaging. This study sought to investigate the safety and tolerability of hyperpolarized carbon-13 (HP-¹³C) metabolic imaging in pediatric patients with brain tumors. MATERIALS AND METHODS: Pediatric patients 3 to 18 years of age who were previously diagnosed with a brain tumor and could undergo MR imaging without sedation were eligible to enroll in this safety study of HP [1-¹³C]pyruvate. Participants received a one-time injection of HP [1-¹³C]pyruvate and were imaged using dynamic HP-¹³C MR imaging. We assessed 2 dose levels: 0.34 mL/kg and the highest tolerated adult dose of 0.43 mL/kg. Participants were monitored throughout imaging and for 60 minutes postinjection, including pre- and postinjection electrocardiograms and vital sign measurements. RESULTS: Between February 2017 and July 2019, ten participants (9 males; median age, 14 years; range, 10–17 years) were enrolled, of whom 6 completed injection of HP [1-¹³C]pyruvate and dynamic HP-¹³C MR imaging. Four participants failed to undergo HP-¹³C MR imaging due to technical failures related to generating HP [1-¹³C]pyruvate or MR imaging operability. HP [1-¹³C]pyruvate was well-tolerated in all participants who completed the study, with no dose-limiting toxicities or adverse events observed at either 0.34 (n = 3) or 0.43 (n = 3) mL/kg. HP [1-¹³C]pyruvate demonstrated characteristic conversion to [1-¹³C]lactate and [¹³C]bicarbonate in the brain. Due to poor accrual, the study was closed after only 3 participants were enrolled at the highest dose level. CONCLUSIONS: Dynamic HP-¹³C MR imaging was safely performed in 6 pediatric patients with CNS tumors and demonstrated HP [1-¹³C]pyruvate brain metabolism.

Although the contrast-enhancing (CE) lesion on T₁-weighted MR images is widely used as a surrogate for glioblastoma (GBM), there are also non-enhancing regions of infiltrative tumor within the T₂-weighted lesion, which elude radiologic detection. Because non-enhancing GBM (Enh-) challenges clinical patient management as latent disease, this study sought to characterize ex vivo metabolic profiles from Enh- and CE GBM (Enh+) samples, alongside histological and in vivo MR parameters, to assist in defining criteria for estimating total tumor burden. Fifty-six patients with newly diagnosed GBM received a multi-parametric pre-surgical MR examination. Targets for obtaining image-guided tissue samples were defined based on in vivo parameters that were suspicious for tumor. The actual location from where tissue samples were obtained was recorded, and half of each sample was analyzed for histopathology while the other half was scanned using HR-MAS spectroscopy. The Enh+ and Enh- tumor samples demonstrated comparable mitotic activity, but also significant heterogeneity in microvascular morphology. Ex vivo spectroscopic parameters indicated similar levels of total choline and N-acetylaspartate between these contrast-based radiographic subtypes of GBM, and characteristic differences in the levels of myo-inositol, creatine/phosphocreatine, and phosphoethanolamine. Analysis of in vivo parameters at the sample locations were consistent with histological and ex vivo metabolic data. The similarity between ex vivo levels of choline and NAA, and between in vivo levels of choline, NAA and nADC in Enh+ and Enh- tumor, indicate that these parameters can be used in defining non-invasive metrics of total tumor burden for patients with GBM.

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. Multi-parametric ¹H/HP-¹³C MRI data were acquired from fifteen patients with progressive/treatment-naïve glioblastoma [prog/TN GBM, IDH-wildtype (n = 11)], progressive astrocytoma, IDH-mutant, grade 4 (G4A^IDH+, n = 2) and GBM manifesting treatment effects (n = 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 G4A^IDH+ and treatment effects. 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 (CEL_val > NEL_val > NAWM_val); [1-¹³C]lactate-to-[¹³C]bicarbonate ratio (CEL_val > NEL_val/NAWM_val); and ¹H-lactate (CEL_val/NEL_val > NAWM_undetected). 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 CNI_max and levels of [1-¹³C]pyruvate, [1-¹³C]lactate and modified ratio. GBM, by comparison to G4A^IDH+, displayed lower perfusion %-recovery and modeled rate constants for [1-¹³C]pyruvate-to-[1-¹³C]lactate conversion (k_PL), and higher ¹H-lactate and [1-¹³C]pyruvate levels, while having higher nCBV, %-recovery, k_PL, [1-¹³C]pyruvate-to-[1-¹³C]lactate and modified ratios relative to treatment effects. GBM consistently displayed aberrant, Warburg-related metabolism and regional heterogeneity detectable by novel HP-¹³C/¹H imaging techniques.

Hyperpolarized carbon-13 (HP-¹³C) MRI enables the real-time measurement of dynamic metabolism by utilizing molecular probes whose magnetization has been transiently enhanced via dynamic nuclear polarization of ¹³C labels. Based on pre-clinical and clinical investigations demonstrating Warburg-related metabolic dysfunction and tricarboxylic acid (TCA)-cycle alterations in gliomas, HP¹³C techniques appear very promising for overcoming conventional challenges to evaluating tumor burden and extent, early therapeutic response and progression among patients non-invasively. This article surveys the multi-faceted translational development of HP-¹³C MRI in the context of glioma imaging, while emphasizing innovation concerning the pharmacy production of HP probes - [1-¹³C]/[2-¹³C]-pyruvate and [1-¹³C,5-¹²C]-alpha-ketoglutarate - that serve as non-radioactive metabolic contrast agents. Borrowing from practical experience, we present specific probe indications for isocitrate dehydrogenase (IDH)-wildtype glioblastomas and IDH-mutant gliomas together with example data to show the targeted, pathway-dependent function of these agents and their utility. Additional information pertaining to HP-¹³C hardware, acquisition and post-processing techniques provides an overview of the imaging methodology as it is currently performed at a leading institution. Considering the developing markers for progressive disease in glioblastomas and rapidly advancing capability, this unique imaging technology appears poised for translational impact following further evaluation.ABBREVIATIONS: 2-HG = D-2-hydroxyglutarate; α-KG = alpha-ketoglutarate; CSI = chemical shift imaging; d-DNP = dissolution-dynamic nuclear polarization; EPI = echo-planar imaging; EPSI = echo-planar spectroscopic imaging; IDHm = isocitrate dehydrogenasemutant; IR-SPGR = inversion recovery-prepared fast spoiled gradient-recalled (imaging); LrGGs = lower-grade gliomas; NMR = nuclear magnetic resonance; OGC = oxoglutarate carrier; PHIP = parahydrogen-induced polarization; SNR = signal-to-noise ratio; TCA cycle = tricarboxylic acid cycle; WHO = World Health Organization.

This study aimed to implement a multimodal ¹H/HP-¹³C imaging protocol to augment the serial monitoring of patients with glioma, while simultaneously pursuing methods for improving the robustness of HP-¹³C metabolic data. A total of 100 ¹H/HP [1-¹³C]-pyruvate MR examinations (104 HP-¹³C datasets) were acquired from 42 patients according to the comprehensive multimodal glioma imaging protocol. Serial data coverage, accuracy of frequency reference, and acquisition delay were evaluated using a mixed-effects model to account for multiple exams per patient. Serial atlas-based HP-¹³C MRI demonstrated consistency in volumetric coverage measured by inter-exam dice coefficients (0.977 ± 0.008, mean ± SD; four patients/11 exams). The atlas-derived prescription provided significantly improved data quality compared to manually prescribed acquisitions (n = 26/78; p = 0.04). The water-based method for referencing [1-¹³C]-pyruvate center frequency significantly reduced off-resonance excitation relative to the coil-embedded [¹³C]-urea phantom (4.1 ± 3.7 Hz vs. 9.9 ± 10.7 Hz; p = 0.0007). Significantly improved capture of tracer inflow was achieved with the 2-s versus 5-s HP-¹³C MRI acquisition delay (p = 0.007). This study demonstrated the implementation of a comprehensive multimodal ¹H/HP-¹³C MR protocol emphasizing the monitoring of steady-state/dynamic metabolism in patients with glioma.