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.

Purpose: X‐nuclei (also called non‐proton MRI) MRI and spectroscopy are limited by the intrinsic low SNR as compared to conventional proton imaging. Clinical translation of x‐nuclei examination warrants the need of a robust and versatile tool improving image quality for diagnostic use. In this work, we compare a novel denoising method with fewer inputs to the current state‐of‐the‐art denoising method.Methods: Denoising approaches were compared on human acquisitions of sodium (²³Na) brain, deuterium (²H) brain, carbon (¹³C) heart and brain, and simulated dynamic hyperpolarized ¹³C brain scans, with and without additional noise. The current state‐of‐the‐art denoising method Global‐local higher order singular value decomposition (GL‐HOSVD) was compared to the few‐input method tensor Marchenko‐Pastur principal component analysis (tMPPCA). Noise‐removal was quantified by residual distributions, and statistical analyses evaluated the differences in mean‐square‐error and Bland–Altman analysis to quantify agreement between original and denoised results of noise‐added data.Results: GL‐HOSVD and tMPPCA showed similar performance for the variety of x‐nuclei data analyzed in this work, with tMPPCA removing ˜5% more noise on average over GL‐HOSVD. The mean ratio between noise‐added and denoising reproducibility coefficients of the Bland–Altman analysis when compared to the original are also similar for the two methods with 3.09 ± 1.03 and 2.83 ± 0.79 for GL‐HOSVD and tMPPCA, respectively.Conclusion: The strength of tMPPCA lies in the few‐input approach, which generalizes well to different data sources. This makes the use of tMPPCA denoising a robust and versatile tool in x‐nuclei imaging improvements and the preferred denoising method.

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.

This study developed a new approach to produce sterile, hyperpolarized [¹³C,¹⁵N₂]urea as a novel molecular imaging probe and applied it for first-ever healthy brain volunteer studies. Hyperpolarized [¹³C,¹⁵N₂]urea, as a small, metabolically inert molecule, offers significant advantages for perfusion imaging due to its endogenous nature and excellent safety profile. The developed methods achieved a hyperpolarized [¹³C,¹⁵N₂]urea solution (132 ± 6 mM) with 27.4 ± 5.6% polarization and a T₁ = 50.4 ± 0.2 s. In healthy brain volunteer studies, high-resolution ¹³C imaging captured blood flow with a spatial resolution of 7.76 × 7.76 × 15 (or 10) mm³ over ~1 min following hyperpolarized [¹³C,¹⁵N₂]urea injection, visualizing detailed vascular structures. Time-to-peak and centroid analyses showed consistent arterial and venous signal patterns across subjects. Findings suggest hyperpolarized [¹³C,¹⁵N₂]urea may have applications beyond brain imaging, including the non-invasive perfusion assessment in various organs, cancer microenvironment, and renal function, paving the way for clinical translation.