Treatment Response Assessment in IDH-Mutant Glioma Patients by Noninvasive 3D Functional Spectroscopic Mapping of 2-Hydroxyglutarate.

Measurements of objective response rates are critical to evaluate new glioma therapies. The hallmark metabolic alteration in gliomas with mutant isocitrate dehydrogenase (IDH) is the overproduction of oncometabolite 2-hydroxyglutarate (2HG), which plays a key role in malignant transformation. 2HG represents an ideal biomarker to probe treatment response in IDH-mutant glioma patients, and we hypothesized a decrease in 2HG levels would be measureable by in vivo magnetic resonance spectroscopy (MRS) as a result of antitumor therapy. We report a prospective longitudinal imaging study performed in 25 IDH-mutant glioma patients receiving adjuvant radiation and chemotherapy. A newly developed 3D MRS imaging was used to noninvasively image 2HG. Paired Student t test was used to compare pre- and posttreatment tumor 2HG values. Test-retest measurements were performed to determine the threshold for 2HG functional spectroscopic maps (fSM). Univariate and multivariate regression were performed to correlate 2HG changes with Karnofsky performance score (KPS). We found that mean 2HG (2HG/Cre) levels decreased significantly (median = 48.1%; 95% confidence interval = 27.3%-56.5%;P= 0.007) in the posttreatment scan. The volume of decreased 2HG correlates (R(2)= 0.88,P= 0.002) with clinical status evaluated by KPS. We demonstrate that dynamic measurements of 2HG are feasible by 3D fSM, and the decrease of 2HG levels can monitor treatment response in patients with IDH-mutant gliomas. Our results indicate that quantitative in vivo 2HG imaging may be used for precision medicine and early response assessment in clinical trials of therapies targeting IDH-mutant gliomas.

Andronesi OC ，Loebel F ，Bogner W ，Marjańska M ，Vander Heiden MG ，Iafrate AJ ，Dietrich J ，Batchelor TT ，Gerstner ER ，Kaelin WG ，Chi AS ，Rosen BR ，Cahill DP ... -  《-》

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

Choi C ，Raisanen JM ，Ganji SK ，Zhang S ，McNeil SS ，An Z ，Madan A ，Hatanpaa KJ ，Vemireddy V ，Sheppard CA ，Oliver D ，Hulsey KM ，Tiwari V ，Mashimo T ，Battiste J ，Barnett S ，Madden CJ ，Patel TR ，Pan E ，Malloy CR ，Mickey BE ，Bachoo RM ，Maher EA ... -  《-》

Integration of 2-hydroxyglutarate-proton magnetic resonance spectroscopy into clinical practice for disease monitoring in isocitrate dehydrogenase-mutant glioma.

The majority of WHO grades II and III gliomas harbor a missense mutation in the metabolic gene isocitrate dehydrogenase (IDH) and accumulate the metabolite R-2-hydroxyglutarate (R-2HG). Prior studies showed that this metabolite can be detected in vivo using proton magnetic-resonance spectroscopy (MRS), but the sensitivity of this methodology and its clinical implications are unknown. We developed an MR imaging protocol to integrate 2HG-MRS into routine clinical glioma imaging and examined its performance in 89 consecutive glioma patients. Detection of 2-hydroxyglutarate (2HG) in IDH-mutant gliomas was closely linked to tumor volume, with sensitivity ranging from 8% for small tumors (<3.4 mL) to 91% for larger tumors (>8 mL). In patients undergoing 2HG-MRS prior to surgery, tumor levels of 2HG corresponded with tumor cellularity but not with tumor grade or mitotic index. Cytoreductive therapy resulted in a gradual decrease in 2HG levels with kinetics that closely mirrored changes in tumor volume. Our study demonstrates that 2HG-MRS can be linked with routine MR imaging to provide quantitative measurements of 2HG in glioma and may be useful as an imaging biomarker to monitor the abundance of IDH-mutant tumor cells noninvasively during glioma therapy and disease monitoring.

de la Fuente MI ，Young RJ ，Rubel J ，Rosenblum M ，Tisnado J ，Briggs S ，Arevalo-Perez J ，Cross JR ，Campos C ，Straley K ，Zhu D ，Dong C ，Thomas A ，Omuro AA ，Nolan CP ，Pentsova E ，Kaley TJ ，Oh JH ，Noeske R ，Maher E ，Choi C ，Gutin PH ，Holodny AI ，Yen K ，DeAngelis LM ，Mellinghoff IK ，Thakur SB ... -  《-》

Volumetric relationship between 2-hydroxyglutarate and FLAIR hyperintensity has potential implications for radiotherapy planning of mutant IDH glioma patients.

Gliomas with mutant isocitrate dehydrogenase (IDH) produce high levels of 2-hydroxyglutarate (2HG) that can be quantitatively measured by 3D magnetic resonance spectroscopic imaging (MRSI). Current glioma MRI primarily relies upon fluid-attenuated inversion recovery (FLAIR) hyperintensity for treatment planning, although this lacks specificity for tumor cells. Here, we investigated the relationship between 2HG and FLAIR in mutant IDH glioma patients to determine whether 2HG mapping is valuable for radiotherapy planning. Seventeen patients with mutant IDH1 gliomas were imaged by 3 T MRI. A 3D MRSI sequence was employed to specifically image 2HG. FLAIR imaging was performed using standard clinical protocol. Regions of interest (ROIs) were determined for FLAIR and optimally thresholded 2HG hyperintensities. The overlap, displacement, and volumes of 2HG and FLAIR ROIs were calculated. In 8 of 17 (47%) patients, the 2HG volume was larger than FLAIR volume. Across the entire cohort, the mean volume of 2HG was 35.3 cc (range, 5.3-92.7 cc), while the mean volume of FLAIR was 35.8 cc (range, 6.3-140.8 cc). FLAIR and 2HG ROIs had mean overlap of 0.28 (Dice coefficients range, 0.03-0.57) and mean displacement of 12.2 mm (range, 3.2-23.5 mm) between their centers of mass. Our results indicate that for a substantial number of patients, the 2HG volumetric assessment of tumor burden is more extensive than FLAIR volume. In addition, there is only partial overlap and asymmetric displacement between the centers of FLAIR and 2HG ROIs. These results may have important implications for radiotherapy planning of IDH mutant glioma.

Jafari-Khouzani K ，Loebel F ，Bogner W ，Rapalino O ，Gonzalez GR ，Gerstner E ，Chi AS ，Batchelor TT ，Rosen BR ，Unkelbach J ，Shih HA ，Cahill DP ，Andronesi OC ... -  《-》

Accumulation of 2-hydroxyglutarate in gliomas correlates with survival: a study by 3.0-tesla magnetic resonance spectroscopy.

Natsumeda M ，Igarashi H ，Nomura T ，Ogura R ，Tsukamoto Y ，Kobayashi T ，Aoki H ，Okamoto K ，Kakita A ，Takahashi H ，Nakada T ，Fujii Y ... -  《Acta Neuropathologica Communications》