Abstract Mutations in isocitrate dehydrogenase (mIDH) are common in lower-grade glioma (LGG; mIDH1, 80%; mIDH2, 4%) and lead to epigenetic and genetic changes that promote oncogenesis via production of the oncometabolite 2-hydroxyglutarate (2-HG). AG-120 (ivosidenib) is a first-in-class oral mIDH1 inhibitor associated with a favorable safety profile in an ongoing phase 1 study in 66 glioma patients. AG-881 is a brain-penetrant oral mIDH1/2 inhibitor with an acceptable safety profile at dose levels <100 mg in an ongoing phase 1 study in 52 glioma patients. In an orthotopic mIDH1-R132H glioma model, ivosidenib and AG-881 suppressed 2-HG by 85% and 98%, respectively. This multicenter, open-label, phase 1 study is designed to measure brain tumor 2-HG concentration and drug exposure at two dose levels each of ivosidenib or AG-881 in patients with mIDH1 LGG undergoing craniotomy (NCT03343197). The study will enroll ~45 adults with recurrent WHO 2016-classified Grade 2 or 3 mIDH1 oligodendroglioma/astrocytoma eligible for resection. Key eligibility criteria include: nonenhancing disease by T2 FLAIR MRI, mIDH1-R132H, and Karnofsky Performance Score 60. Cohort 1 patients will be randomized 2:2:1 to 500 mg QD ivosidenib (n=10), 50 mg QD AG-881 (n=10), or no treatment (n=5). Based on the safety, 2-HG, and pharmacokinetic data from cohort 1, cohort 2 may enroll an additional 20 patients randomized 1:1 to 250 mg BID ivosidenib or 10 mg QD AG-881. Patients randomized to either drug will receive treatment for 4 weeks preoperatively and may continue treatment after surgery. Untreated patients can opt to be randomized to either drug postoperatively. The primary endpoint is 2-HG concentration in surgically resected tumors. Secondary endpoints include safety, tumor and plasma pharmacokinetics, and RANO LGG response. Exploratory endpoints include 2-HG and pharmacokinetics in cerebrospinal fluid, and 2-HG magnetic resonance spectroscopy. This study is currently enrolling in the USA.

A large body of published work shows that proton (hydrogen 1 [(1)H]) magnetic resonance (MR) spectroscopy has evolved from a research tool into a clinical neuroimaging modality. Herein, the authors present a summary of brain disorders in which MR spectroscopy has an impact on patient management, together with a critical consideration of common data acquisition and processing procedures. The article documents the impact of (1)H MR spectroscopy in the clinical evaluation of disorders of the central nervous system. The clinical usefulness of (1)H MR spectroscopy has been established for brain neoplasms, neonatal and pediatric disorders (hypoxia-ischemia, inherited metabolic diseases, and traumatic brain injury), demyelinating disorders, and infectious brain lesions. The growing list of disorders for which (1)H MR spectroscopy may contribute to patient management extends to neurodegenerative diseases, epilepsy, and stroke. To facilitate expanded clinical acceptance and standardization of MR spectroscopy methodology, guidelines are provided for data acquisition and analysis, quality assessment, and interpretation. Finally, the authors offer recommendations to expedite the use of robust MR spectroscopy methodology in the clinical setting, including incorporation of technical advances on clinical units.

Proton MRS (¹ H MRS) provides noninvasive, quantitative metabolite profiles of tissue and has been shown to aid the clinical management of several brain diseases. Although most modern clinical MR scanners support MRS capabilities, routine use is largely restricted to specialized centers with good access to MR research support. Widespread adoption has been slow for several reasons, and technical challenges toward obtaining reliable good-quality results have been identified as a contributing factor. Considerable progress has been made by the research community to address many of these challenges, and in this paper a consensus is presented on deficiencies in widely available MRS methodology and validated improvements that are currently in routine use at several clinical research institutions. In particular, the localization error for the PRESS localization sequence was found to be unacceptably high at 3 T, and use of the semi-adiabatic localization by adiabatic selective refocusing sequence is a recommended solution. Incorporation of simulated metabolite basis sets into analysis routines is recommended for reliably capturing the full spectral detail available from short TE acquisitions. In addition, the importance of achieving a highly homogenous static magnetic field (B₀ ) in the acquisition region is emphasized, and the limitations of current methods and hardware are discussed. Most recommendations require only software improvements, greatly enhancing the capabilities of clinical MRS on existing hardware. Implementation of these recommendations should strengthen current clinical applications and advance progress toward developing and validating new MRS biomarkers for clinical use.