Abstract
Infiltrating low grade gliomas (LGGs) are heterogeneous in their behavior and the strategies used for clinical management are highly variable. A key factor in clinical decision-making is that patients with mutations in the isocitrate dehydrogenase 1 and 2 (IDH1/2) oncogenes are more likely to have a favorable outcome and be sensitive to treatment. Because of their relatively long overall median survival, more aggressive treatments are typically reserved for patients that have undergone malignant progression (MP) to an anaplastic glioma or secondary glioblastoma (GBM). In the current study, ex vivo metabolic profiles of image-guided tissue samples obtained from patients with newly diagnosed and recurrent LGG were investigated using proton high-resolution magic angle spinning spectroscopy (1H HR-MAS). Distinct spectral profiles were observed for lesions with IDH-mutated genotypes, between astrocytoma and oligodendroglioma histologies, as well as for tumors that had undergone MP. Levels of 2-hydroxyglutarate (2HG) were correlated with increased mitotic activity, axonal disruption, vascular neoplasia, and with several brain metabolites including the choline species, glutamate, glutathione, and GABA. The information obtained in this study may be used to develop strategies for in vivo characterization of infiltrative glioma, in order to improve disease stratification and to assist in monitoring response to therapy.
Highlights
Infiltrating gliomas comprise 80% of malignant brain tumors and consist primarily of astrocyte and oligodendrocyte cell types
A summary of the patient population is presented in Metabolic differences associated with isocitrate dehydrogenase (IDH) mutation and malignant progression (MP)
This study identified distinctive metabolic profiles for gliomas according to the status of IDH mutation, histological subtype, and malignant progression
Summary
Infiltrating gliomas comprise 80% of malignant brain tumors and consist primarily of astrocyte and oligodendrocyte cell types. In 2009, Yan et al discovered novel missense mutations in the isocitrate dehydrogenase 1 & 2 (IDH1/2) oncogenes, which are present in upwards of 70–80% of lesions that arise from low-grade lineage and confer a significant survival advantage over wild-type tumors[5]. Given the limited therapeutic options available for LGGs, IDH mutations have garnered significant attention as a targetable therapeutic pathway with several novel therapies currently in development and under investigation in clinical trials[7,8,9]. While 2HG is readily detectable in an ex vivo setting using HR-MAS, it has proved to be a difficult biomarker in vivo owing to low signal-to-noise and significant overlap with neighboring metabolites at clinical field strengths. We further hypothesized that there are differences in metabolite levels for lesions that contain the IDH-mutated genotype, as well as those that have undergone MP
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