Noninvasive assessment of isocitrate dehydrogenase mutation status in cerebral gliomas by magnetic resonance spectroscopy in a clinical setting

OBJECTIVEMutations in the isocitrate dehydrogenase (IDH) genes are of proven diagnostic and prognostic significance for cerebral gliomas. The objective of this study was to evaluate the clinical feasibility of using a recently described method for determining IDH mutation status by using magnetic resonance spectroscopy (MRS) to detect the presence of 2-hydroxyglutarate (2HG), the metabolic product of the mutant IDH enzyme.METHODSBy extending imaging time by 6 minutes, the authors were able to include a point-resolved spectroscopy (PRESS) MRS sequence in their routine glioma imaging protocol. In 30 of 35 patients for whom this revised protocol was used the lesions were subsequently diagnosed histologically as gliomas. Of the remaining 5 patients, 1 had a gangliocytoma, 1 had a primary CNS lymphoma, and 3 had nonneoplastic lesions. Immunohistochemistry and/or polymerase chain reaction were used to detect the presence of IDH mutations in the glioma tissue resected.RESULTSIn vivo MRS for 2HG correctly identified the IDH mutational status in 88.6% of patients. The sensitivity and specificity was 89.5% and 81.3%, respectively, when using 2 mM 2HG as threshold to discriminate IDH-mutated from wildtype tumors. Two glioblastomas that had elevated 2HG levels did not have detectable IDH mutations, and in 2 IDH-mutated gliomas 2HG was not reliably detectable.CONCLUSIONSThe noninvasive determination of the IDH mutation status of a presumed glioma by means of MRS may be incorporated into a routine diagnostic imaging protocol and can be used to obtain additional information for patient care.

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Detection of 2-hydroxyglutaric acid in vivo by proton magnetic resonance spectroscopy in U87 glioma cells overexpressing isocitrate dehydrogenase-1 mutation

Neuro-Oncology ◽

10.1093/neuonc/nos258 ◽

2012 ◽

Vol 14 (12) ◽

pp. 1465-1472 ◽

Cited By ~ 29

Author(s):

J. Lazovic ◽

H. Soto ◽

D. Piccioni ◽

J. R. Lo Ru ◽

S. Li ◽

...

Keyword(s):

Magnetic Resonance ◽

Magnetic Resonance Spectroscopy ◽

Isocitrate Dehydrogenase ◽

Proton Magnetic Resonance ◽

Proton Magnetic Resonance Spectroscopy ◽

Glioma Cells ◽

Resonance Spectroscopy ◽

Isocitrate Dehydrogenase 1 ◽

Hydroxyglutaric Acid

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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

Cancers ◽

10.3390/cancers12113406 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3406

Author(s):

Elisabeth Bumes ◽

Fro-Philip Wirtz ◽

Claudia Fellner ◽

Jirka Grosse ◽

Dirk Hellwig ◽

...

Keyword(s):

Machine Learning ◽

Magnetic Resonance ◽

Magnetic Resonance Spectroscopy ◽

Support Vector ◽

Resonance Spectroscopy ◽

Idh Mutation ◽

1H Mrs ◽

1H Magnetic Resonance Spectroscopy ◽

Non Invasive

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 1H-magnetic resonance spectroscopy (1H-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-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) for optimized voxel placement in 1H-MRS. Routine 1H-magnetic resonance (1H-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 1H-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 1H-nuclear magnetic resonance (1H-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.

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Detection of 2-Hydroxyglutarate by 3.0-Tesla Magnetic Resonance Spectroscopy in Gliomas with Rare IDH Mutations: Making Sense of “False-Positive” Cases

Diagnostics ◽

10.3390/diagnostics11112129 ◽

2021 ◽

Vol 11 (11) ◽

pp. 2129

Author(s):

Manabu Natsumeda ◽

Hironaka Igarashi ◽

Ramil Gabdulkhaev ◽

Haruhiko Takahashi ◽

Kunio Motohashi ◽

...

Keyword(s):

Magnetic Resonance ◽

Magnetic Resonance Spectroscopy ◽

Dna Analysis ◽

Resonance Spectroscopy ◽

Lower Grade ◽

Short Article ◽

High Accumulation ◽

Idh1 R132h ◽

Idh Mutations ◽

Idh1 And Idh2 Mutations

We have previously published a study on the reliable detection of 2-hydroxyglutarate (2HG) in lower-grade gliomas by magnetic resonance spectroscopy (MRS). In this short article, we re-evaluated five glioma cases originally assessed as isocitrate dehydrogenase (IDH) wildtype, which showed a high accumulation of 2HG, and were thought to be false-positives. A new primer was used for the detection of IDH2 mutation by Sanger sequencing. Adequate tissue for DNA analysis was available in 4 out of 5 cases. We found rare IDH2 mutations in two cases, with IDH2 R172W mutation in one case and IDH2 R172K mutation in another case. Both cases had very small mutant peaks, suggesting that the tumor volume was low in the tumor samples. Thus, the specificity of MRS for detecting IDH1/2 mutations was higher (81.3%) than that originally reported (72.2%). The detection of 2HG by MRS can aid in the diagnosis of rare, non-IDH1-R132H IDH1 and IDH2 mutations in gliomas.

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