Distinguishing Tumor Admixed in a Radiation Necrosis (RN) Background: 1H and 2H MR With a Novel Mouse Brain-Tumor/RN Model

Abstract

PurposeDistinguishing radiation necrosis (RN) from recurrent tumor remains a vexing clinical problem with important health-care consequences for neuro-oncology patients. Here, mouse models of pure tumor, pure RN, and admixed RN/tumor are employed to evaluate hydrogen (1H) and deuterium (2H) magnetic resonance methods for distinguishing RN vs. tumor. Furthermore, proof-of-principle, range-finding deuterium (2H) metabolic magnetic resonance is employed to assess glycolytic signatures distinguishing RN vs. tumor.Materials and MethodsA pipeline of common quantitative 1H MRI contrasts, including an improved magnetization transfer ratio (MTR) sequence, and 2H magnetic resonance spectroscopy (MRS) following administration of 2H-labeled glucose, was applied to C57BL/6 mouse models of the following: (i) late time-to-onset RN, occurring 4–5 weeks post focal 50-Gy (50% isodose) Gamma Knife irradiation to the left cerebral hemisphere, (ii) glioblastoma, growing ~18–24 days post implantation of 50,000 mouse GL261 tumor cells into the left cerebral hemisphere, and (iii) mixed model, with GL261 tumor growing within a region of radiation necrosis (1H MRI only). Control C57BL/6 mice were also examined by 2H metabolic magnetic resonance.ResultsDifferences in quantitative 1H MRI parametric values of R1, R2, ADC, and MTR comparing pure tumor vs. pure RN were all highly statistically significant. Differences in these parameter values and DCEAUC for tumor vs. RN in the mixed model (tumor growing in an RN background) are also all significant, demonstrating that these contrasts—in particular, MTR—can effectively distinguish tumor vs. RN. Additionally, quantitative 2H MRS showed a highly statistically significant dominance of aerobic glycolysis (glucose ➔ lactate; fermentation, Warburg effect) in the tumor vs. oxidative respiration (glucose ➔ TCA cycle) in the RN and control brain.ConclusionsThese findings, employing a pipeline of quantitative 1H MRI contrasts and 2H MRS following administration of 2H-labeled glucose, suggest a pathway for substantially improving the discrimination of tumor vs. RN in the clinic.

Subcutaneous deuterated substrate administration in mice: An alternative to tail vein infusion

“…DMRS data were acquired in 5‐min time blocks, two time blocks prior to substrate administration and 14 time blocks following substrate administration. Other data acquisition and analysis details are as described previously 8 . Each 2 H‐labeled substrate was administered individually at a 1‐M concentration in 0.9% saline solution at a dose of 25 μL/g body weight (e.g., 500 μL for a 20‐g mouse).…”

“…Deuterium ( 2 H) MRS (DMRS) and imaging (DMRI) of 2 H‐labeled substrates and their subsequent downstream metabolites is an emerging arena of metabolic imaging 1–28 . With small‐animal models, tail vein catheterization is a common in‐magnet route of substrate administration.…”

Novel Mechanisms and Future Opportunities for the Management of Radiation Necrosis in Patients Treated for Brain Metastases in the Era of Immunotherapy

“…Animal models for radiation necrosis have been proposed to identify imaging biomarkers [74][75][76]. Future research should leverage these preclinical models to elucidate the importance of cGAS-STING and other implicated pathways in radiation necrosis development.…”

Deuterium brain imaging at 7T during D2O dosing

“…The majority of experiments in humans and animals have used [6,6′‐D 2 ] glucose. 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 In this case, lactate and glutamine/glutamate (Glx) are produced alongside deuterated water (HDO), and their relative concentrations reflect the cells' preference for glucose metabolism, i.e., aerobic, anaerobic glycolysis or oxidative phosphorylation. Spatially localized, elevated, lactate production has been observed using DMI in a patient with a glioblastoma, 2 in keeping with an increased glycolysis in neoplastic cells, known as the Warburg effect.…”

“…Deuterium metabolic imaging (DMI) involves using 2 H chemical shift imaging to map the distribution of the metabolic products of administered 2 H‐labeled compounds. The majority of experiments in humans and animals have used [6,6′‐D 2 ] glucose 2–16 . In this case, lactate and glutamine/glutamate (Glx) are produced alongside deuterated water (HDO), and their relative concentrations reflect the cells' preference for glucose metabolism, i.e., aerobic, anaerobic glycolysis or oxidative phosphorylation.…”