Non-Invasive Prediction of IDH Mutation in Patients with Glioma WHO II/III/IV Based on F-18-FET PET-Guided In Vivo 1H-Magnetic Resonance Spectroscopy and Machine Learning

Simple Summary Approximately 75-80% of according to the classification of world health organization (WHO) grade II and III gliomas are characterized by a mutation of the isocitrate dehydrogenase (IDH) enzymes, which are very important in glioma cell metabolism. Patients with IDH mutated glioma have a significantly better prognosis than patients with IDH wildtype status, typically seen in glioblastoma WHO grade IV. Here we used a prospective O-(2-F-18-fluoroethyl)-L-tyrosine (F-18-FET) positron emission tomography guided single-voxel H-1-magnetic resonance spectroscopy approach to predict the IDH status before surgery. Finally, 34 patients were included in this neuroimaging study, of whom eight had additionally tissue analysis. Using a machine learning technique, we predicted IDH status with an accuracy of 88.2%, a sensitivity of 95.5% and a specificity of 75.0%. It was newly recognized, that two metabolites (myo-inositol and glycine) have a particularly important role in the determination of the IDH status. Isocitrate dehydrogenase (IDH)-1 mutation is an important prognostic factor and a potential therapeutic target in glioma. Immunohistological and molecular diagnosis of IDH mutation status is invasive. To avoid tumor biopsy, dedicated spectroscopic techniques have been proposed to detect D-2-hydroxyglutarate (2-HG), the main metabolite of IDH, directly in vivo. However, these methods are technically challenging and not broadly available. Therefore, we explored the use of machine learning for the non-invasive, inexpensive and fast diagnosis of IDH status in standard H-1-magnetic resonance spectroscopy (H-1-MRS). To this end, 30 of 34 consecutive patients with known or suspected glioma WHO grade II-IV were subjected to metabolic positron emission tomography (PET) imaging with O-(2-F-18-fluoroethyl)-L-tyrosine (F-18-FET) for optimized voxel placement in H-1-MRS. Routine H-1-magnetic resonance (H-1-MR) spectra of tumor and contralateral healthy brain regions were acquired on a 3 Tesla magnetic resonance (3T-MR) scanner, prior to surgical tumor resection and molecular analysis of IDH status. Since 2-HG spectral signals were too overlapped for reliable discrimination of IDH mutated (IDHmut) and IDH wild-type (IDHwt) glioma, we used a nested cross-validation approach, whereby we trained a linear support vector machine (SVM) on the complete spectral information of the H-1-MRS data to predict IDH status. Using this approach, we predicted IDH status with an accuracy of 88.2%, a sensitivity of 95.5% (95% CI, 77.2-99.9%) and a specificity of 75.0% (95% CI, 42.9-94.5%), respectively. The area under the curve (AUC) amounted to 0.83. Subsequent ex vivo H-1-nuclear magnetic resonance (H-1-NMR) measurements performed on metabolite extracts of resected tumor material (eight specimens) revealed myo-inositol (M-ins) and glycine (Gly) to be the major discriminators of IDH status. We conclude that our approach allows a reliable, non-invasive, fast and cost-effective prediction of IDH status in a standard clinical setting.