Prospective Longitudinal Analysis of 2-Hydroxyglutarate Magnetic Resonance Spectroscopy Identifies Broad Clinical Utility for the Management of Patients With IDH-Mutant Glioma

Abstract

Proton magnetic resonance spectroscopy (MRS) of the brain can detect 2-hydroxyglutarate (2HG), the oncometabolite produced in neoplasms harboring a mutation in the gene coding for isocitrate dehydrogenase (IDH ). We conducted a prospective longitudinal imaging study to determine whether quantitative assessment of 2HG by MRS could serve as a noninvasive clinical imaging biomarker for IDH-mutated gliomas. Patients and Methods2HG MRS was performed in 136 patients using point-resolved spectroscopy at 3 T in parallel with standard clinical magnetic resonance imaging and assessment. Data were analyzed in patient cohorts representing the major phases of the glioma clinical course and were further subgrouped by histology and treatment type to evaluate 2HG. Histologic correlations were performed. ResultsQuantitative 2HG MRS was technically and biologically reproducible. 2HG concentration . 1 mM could be reliably detected with high confidence. During the period of indolent disease, 2HG concentration varied by less than 6 1 mM, and it increased sharply with tumor progression. 2HG concentration was positively correlated with tumor cellularity and significantly differed between high-and lower-grade gliomas. In response to cytotoxic therapy, 2HG concentration decreased rapidly in 1p/19q codeleted oligodendrogliomas and with a slower time course in astrocytomas and mixed gliomas. The magnitude and time course of the decrease in 2HG concentration and magnitude of the decrease in tumor volume did not differ between oligodendrogliomas treated with temozolomide or carmustine. Criteria for 2HG MRS were established to make a presumptive molecular diagnosis of an IDH mutation in gliomas technically unable to undergo a surgical procedure. Conclusion2HG concentration as measured by MRS was reproducible and reliably reflected the disease state. These data provide a basis for incorporating 2HG MRS into clinical management of IDH-mutated gliomas.

Isocitrate dehydrogenase‐mutant glioma: Evolving clinical and therapeutic implications

“…Several 2HG‐edited MRS methods have been proposed to increase the specificity of 2HG detection by MRS . Some of these methods have been evaluated in larger studies that demonstrated that specificity and sensitivity vary according to institution . In the study by de la Fuente et al, detection of 2HG by MRS depended on the tumor size (91% true‐positive rate for tumors measuring >8 cm 3 ), and in the studies by Choi et al and Jafari‐Khouzani et al, a conservative threshold of >1 mM was found to classify gliomas as having mutant IDH .…”

“…Some of these methods have been evaluated in larger studies that demonstrated that specificity and sensitivity vary according to institution . In the study by de la Fuente et al, detection of 2HG by MRS depended on the tumor size (91% true‐positive rate for tumors measuring >8 cm 3 ), and in the studies by Choi et al and Jafari‐Khouzani et al, a conservative threshold of >1 mM was found to classify gliomas as having mutant IDH . However, the sensitivity of MSR is not solely dictated by the tumor size, but by the density of mutant IDH cells and the efficiency of 2HG production.…”

3D high‐resolution imaging of 2‐hydroxyglutarate in glioma patients using DRAG‐EPSI at 3T in vivo

“…Several researchers reported imaging of 2HG in patients with IDH‐mutant gliomas at 3T. In two Choi et al studies that used 2D phase‐encoded CSI with 10 × 10 × 15 mm 3 (1.5 mL) voxel size, the volumes with elevated 2HG were about the same as those with T 2 w‐FLAIR hyperintensity. Using a 3D spiral imaging method with 20 × 20 × 20 mm 3 voxel size (8 mL), Jafari‐Khouzani et al reported larger volumes with elevated 2HG than T 2 w‐FLAIR volumes and partial agreement on the locations of the 2 volumes in more than half of the patients.…”

Clinical Imaging for Diagnostic Challenges in the Management of Gliomas: A Review

“…A recent prospective study of 136 patients followed 2‐HG levels over repeated scans throughout treatment. Using a cutoff of 1 mM 2‐HG, the authors reported 100% sensitivity and 88% specificity for IDH mutation subsequently confirmed by histology, and of patients who were unable to undergo resection, a molecular diagnosis could be established in 67% by MRS. Impressively, the authors were able to measure a rapid increase in 2‐HG concentration in tumors under observation at the time of their progression . Therefore, clinicians may find it useful to track 2‐HG levels in low‐grade gliomas under observation, to identify progression even in the absence of classic features on standard MRI.…”