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

Purpose: Distinguishing 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 Methods: A 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. Results: Differences 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 DCE_AUC 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. Conclusions: These 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.