Early detection of tumor cell death in glioblastoma following treatment with chemoradiation has the potential to distinguish between true disease progression and pseudoprogression. Tumor cell death can be detected noninvasively in vivo by imaging the production of [2,3-2H2]malate from [2,3-2H2]fumarate using 2H magnetic resonance (MR) spectroscopic imaging. We show here that 2H MR spectroscopy and spectroscopic imaging measurements of [2,3-2H2]fumarate metabolism can detect tumor cell death in orthotopically implanted glioblastoma models within 48 hours following the completion of chemoradiation. Following the injection of [2,3-2H2]fumarate into tumor-bearing mice, production of [2,3-2H2]malate was measured in a human cell line–derived model and in radiosensitive and radioresistant patient-derived models of glioblastoma that were treated with temozolomide followed by targeted fractionated irradiation. The increase in the [2,3-2H2]malate/[2,3-2H2]fumarate signal ratio posttreatment, which correlated with histologic assessment of cell death, was a more sensitive indicator of treatment response than diffusion-weighted and contrast agent–enhanced 1H MRI measurements, which have been used clinically to detect responses of glioblastoma to chemoradiation. Overall, early detection of glioblastoma cell death using 2H MRI of malate production from fumarate could help improve the clinical evaluation of response to chemoradiation. Significance: 2H magnetic resonance imaging of labeled fumarate metabolism can detect early evidence of tumor cell death following chemoradiation, meeting a clinical need to reliably detect treatment response in glioblastoma.

中文翻译：

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使用富马酸盐代谢的 2H 磁共振波谱测量来成像胶质母细胞瘤对放射治疗的反应


放化疗后早期检测胶质母细胞瘤中的肿瘤细胞死亡有可能区分真正的疾病进展和假性进展。通过使用 2H 磁共振 (MR) 光谱成像对从 [2,3-2H2] 富马酸盐产生 [2,3-2H2] 苹果酸盐进行成像，可以在体内无创地检测肿瘤细胞死亡。我们在此表明​​，[2,3-2H2]富马酸代谢的 2H MR 光谱和光谱成像测量可以在放化疗完成后 48 小时内检测原位植入的胶质母细胞瘤模型中的肿瘤细胞死亡。将[2,3-2H2]富马酸注射到荷瘤小鼠体内后，在人类细胞系衍生模型以及放射敏感和放射抗性患者衍生的胶质母细胞瘤模型中测量了[2,3-2H2]苹果酸的产生，使用替莫唑胺治疗，然后进行靶向分次照射。治疗后[2,3-2H2]苹果酸/[2,3-2H2]富马酸信号比的增加与细胞死亡的组织学评估相关，是比扩散加权和造影剂更敏感的治疗反应指标–增强的 1H MRI 测量，已在临床上用于检测胶质母细胞瘤对放化疗的反应。总体而言，使用富马酸盐产生的苹果酸的 2H MRI 早期检测胶质母细胞瘤细胞死亡可能有助于改善对放化疗反应的临床评估。意义：标记富马酸代谢的 2H 磁共振成像可以检测放化疗后肿瘤细胞死亡的早期证据，满足可靠检测胶质母细胞瘤治疗反应的临床需求。