Spectroscopic imaging of D-2-hydroxyglutarate and other metabolites in pre-surgical patients with IDH-mutant lower-grade gliomas

Abstract

Purpose Prognostically favorable IDH-mutant gliomas are known to produce oncometabolite D-2-hydroxyglutarate (2HG). In this study, we investigated metabolite-based features of patients with grade 2 and 3 glioma using 2HG-specific in vivo MR spectroscopy, to determine their relationship with image-guided tissue pathology and predictive role in progression-free survival (PFS). Methods Forty-five patients received pre-operative MRIs that included 3-D spectroscopy optimized for 2HG detection. Spectral data were reconstructed and quantified to compare metabolite levels according to molecular pathology (IDH1R132H, 1p/19q, and p53); glioma grade; histological subtype; and T2 lesion versus normal-appearing white matter (NAWM) ROIs. Levels of 2HG were correlated with other metabolites and pathological parameters (cellularity, MIB-1) from image-guided tissue samples using Pearson’s correlation test. Metabolites predictive of PFS were evaluated with Cox proportional hazards models. Results Quantifiable levels of 2HG in 39/42 (93%) IDH+ and 1/3 (33%) IDH– patients indicated a 91.1% apparent detection accuracy. Myo-inositol/total choline (tCho) showed reduced values in astrocytic (1p/19q-wildtype), p53-mutant, and grade 3 (vs. 2) IDH-mutant gliomas (p < 0.05), all of which exhibited higher proportions of astrocytomas. Compared to NAWM, T2 lesions displayed elevated 2HG+ γ-aminobutyric acid (GABA)/total creatine (tCr) (p < 0.001); reduced glutamate/tCr (p < 0.001); increased myo-inositol/tCr (p < 0.001); and higher tCho/tCr (p < 0.001). Levels of 2HG at sampled tissue locations were significantly associated with tCho (R = 0.62; p = 0.002), total NAA (R = − 0.61; p = 0.002) and cellularity (R = 0.37; p = 0.04) but not MIB-1. Increasing levels of 2HG/tCr (p = 0.0007, HR 5.594) and thresholding (≥ 0.905, median value; p = 0.02) predicted adverse PFS. Conclusion In vivo 2HG detection can reasonably be achieved on clinical scanners and increased levels may signal adverse PFS.

Prognostic Value of Choline and Other Metabolites Measured Using 1H-Magnetic Resonance Spectroscopy in Gliomas: A Meta-Analysis and Systemic Review

“…Consistent with clinical experience, Tiwari et al [3] found that lower survival risk was associated with higher levels of 2-HG and the presence of IDH mutations. Interestingly, Autry et al [18] revealed that higher levels of 2-HG/Cr indicated a significant reduction in PFS, which contradicts our clinical impression. However, this study enrolled patients with IDH mutations, suggesting that in patients with IDH mutation, 2-HG levels might play an adverse role in survival, and a more complicated metabolic network might be involved in glioma growth.…”

“…After excluding studies evaluating the prognostic value of Cho in gliomas, there was not enough data to conduct a meta-analysis of other metabolites, including Cr [11], lipidlactate [14], lactate [8,9,13], myo-inositol [15], glycine [3], 2-HG [3,18], and glutamate [18]. The associations between these metabolites and prognoses are summarized in Table 3.…”

“…Multiple studies have investigated the potential prognostic value of metabolites estimated using 1 H-MRS, and several potential biomarkers have been identified [3,5,[7][8][9][10][11][12][13][14][15][16][17][18], such as Cho/Cr, Cho/NAA, and 2-HG. However, some of the results of these studies were contradictory, and no consensus has been reached.…”

Imaging 2-hydroxyglutarate and other brain oncometabolites pertinent to critical genomic alterations in brain tumors

“… 30 3D spectroscopy techniques, such as 3D PRESS, echo-planar acquisition with spin-echo excitation (3D-EPSI), and functional spectroscopic mapping (fSM) allow for whole tumor and/or whole brain coverage to fully interrogate irregular and potentially heterogeneous tumors, which should then improve imaging monitoring during treatment. 31–33 Imminent improvements may include matched accumulation and sparse sampling to both reduce scan times (currently 5–15 min) and harness the potential of 7T and higher field strengths.…”

Utilidad de la Espectroscopía por Resonancia Magnética para la diferenciación de gliomas de alto y bajo grado.

“…30 También puede resultar una infraestimación del mismo en caso de volumen parcial en lesiones de pequeño tamaño y en concentraciones bajas del mismo. 28 Sin embargo surgen posibles soluciones como la utilización de la relación 2HG/Lip+Lact en vez de únicamente el valor absoluto de 2HG para mejorar la sensibilidad y la especificidad, tomando el valor de corte de 0,63 31 y la relación 2HG/Cr con valor de corte de 0,085. 32 El rol de otros metabolitos como predictores de pronostico aún requiere de mucho estudio.…”