title: Treatment Response Assessment in IDH-Mutant Glioma Patients by Noninvasive 3D Functional Spectroscopic Mapping of 2-Hydroxyglutarate.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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).
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. ovidiu@nmr.mgh.harvard.edu cahill@mgh.harvard.edu.
authors.forename: Ovidiu C
authors.initials: OC
authors.lastname: Andronesi
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Department of Neurosurgery, Charité Medical University, Berlin, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Loebel
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. High Field MR Center, Department of Biomedical Imaging and Image-guided Therapy, Medical University Vienna, 1090 Vienna, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Bogner
authors.affiliation: Center for Magnetic Resonance Research, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Marjańska
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Vander Heiden
authors.affiliation: Center for Integrated Diagnostics, Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: A John
authors.initials: AJ
authors.lastname: Iafrate
authors.affiliation: Stephen E. and Catherine Pappas Center for Neuro-Oncology, Division of Hematology/Oncology, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jorg
authors.initials: J
authors.lastname: Dietrich
authors.affiliation: Stephen E. and Catherine Pappas Center for Neuro-Oncology, Division of Hematology/Oncology, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Tracy T
authors.initials: TT
authors.lastname: Batchelor
authors.affiliation: Stephen E. and Catherine Pappas Center for Neuro-Oncology, Division of Hematology/Oncology, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Gerstner
authors.affiliation: Dana-Farber/Harvard Cancer Center, Boston, Massachusetts.
authors.forename: William G
authors.initials: WG
authors.lastname: Kaelin
authors.affiliation: Stephen E. and Catherine Pappas Center for Neuro-Oncology, Division of Hematology/Oncology, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Chi
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Rosen
authors.affiliation: Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. ovidiu@nmr.mgh.harvard.edu cahill@mgh.harvard.edu.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Cahill
mesh_terms: D015415:Biomarkers; D001921:Brain / Q000473:pathology; D001932:Brain Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D059186:Chemoradiotherapy, Adjuvant; D005260:Female; D005910:Glioma / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism* / Q000628:therapy; D005977:Glutarates / Q000378:metabolism*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D021621:Imaging, Three-Dimensional; D007521:Isocitrate Dehydrogenase / Q000235:genetics* / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008297:Male; D009154:Mutation; D060787:Neoplasm Grading; D009367:Neoplasm Staging
chemical_list: D015415:Biomarkers; D005977:Glutarates; C019417:alpha-hydroxyglutarate; D007521:Isocitrate Dehydrogenase