Abstract 1498: Feasibility of 2-hydroxyglutarate 1H-MR spectroscopy for routine clinical glioma imaging
Authors: de la Fuente Macarena I. , Young Robert , Rubel Jennifer , Tisnado Jamie , Briggs Samuel , Holodny Andrei I. , Deasy Joseph , DeAngelis Lisa M. , Cross Justin , Mellinghoff Ingo K. , Thakur Sunitha 
Published: August 2015

Abstract
The metabolic genes isocitrate dehydrogenase 1 (IDH1) or IDH2 are mutated in 70-80% of WHO grade II and III glioma. The mutant IDH enzyme gains a new function producing D-2-hydroxyglutarate (2-HG). 2-HG is a small molecule that accumulates in IDH mutant gliomas as high as 5 to 35 mM and is considered the principal effector of IDH mutation in cancers. Proton magnetic resonance spectroscopy (MRS) is an approved method in brain tumors to identify and quantify metabolites within brain lesions by using signals emitted by proton nuclei (1H). The 2-HG molecule has five nonexchangeable scalar-coupled protons that give rise to multiplet resonances in MR spectra. First attempts to measure 2-HG in IDH mutant glioma have been promising but were limited to scanners dedicated to research MRIs, long scanning times, and large tumors. The goal of this study was to explore the feasibility of performing 2HG-MRS as part of standard glioma imaging.
We developed single and multivoxel spectroscopy techniques using unique alterations of pulse sequence parameters and software routines on clinical 3Tesla MRI scanners. We added those sequences to our clinical MRI protocol. All metabolites, including 2-HG, were estimated by linear combination of model (LC Model). 107 consecutive glioma patients were evaluated, including 48 (45%) WHO grade II glioma, 40 (37%) grade III glioma and 19(18%) grade IV glioma. 80/107 (75%) patients had IDH mutant gliomas. At the time of MRS, 42(39%) patients were on active treatment with radiation or chemotherapy, 19(18%) had received such treatment in the past, and 46(43%) had never received radiation or chemotherapy. MRI tumor volume was &lt;8cc in 38 (36%) patients and ≥8cc in 69 (64%) patients. 2-HG MRS was negative in all patients with IDH-wild type tumors and in all IDH-mutant gliomas with a tumor volume &lt;8cc. In the group of IDH-mutant tumors with a tumor volume ≥8cc, 2-HG MRS was positive in approximately 35% of the untreated patients and in approximately 30% of the treated patients. For a subset of patients we measured dynamic changes in 2-HG over time (multiple times MRS). A drop in 2HG-MRS signal was associated with treatment response.
2-HG MRS in the clinical setting is feasible. Specificity was 100%. Sensitivity appears, at least in part, dependent on tumor volume with higher sensitivity in larger tumors. In patients with a detectable 2-HG peak, 2HG-MRS represents a promising non-invasive biomarker to monitor tumor growth and treatment response. Final results for the entire cohort will be presented at the meeting.
Citation Format: Macarena I. de la Fuente, Robert Young, Jennifer Rubel, Jamie Tisnado, Samuel Briggs, Andrei I. Holodny, Joseph Deasy, Lisa M. DeAngelis, Justin Cross, Ingo K. Mellinghoff, Sunitha Thakur. Feasibility of 2-hydroxyglutarate 1H-MR spectroscopy for routine clinical glioma imaging. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1498. doi:10.1158/1538-7445.AM2015-1498