title: Whole-brain spectroscopic MRI biomarkers identify infiltrating margins in glioblastoma patients.
abstract: The standard of care for glioblastoma (GBM) is maximal safe resection followed by radiation therapy with chemotherapy. Currently, contrast-enhanced MRI is used to define primary treatment volumes for surgery and radiation therapy. However, enhancement does not identify the tumor entirely, resulting in limited local control. Proton spectroscopic MRI (sMRI), a method reporting endogenous metabolism, may better define the tumor margin. Here, we develop a whole-brain sMRI pipeline and validate sMRI metrics with quantitative measures of tumor infiltration.
  
  
  
  Whole-brain sMRI metabolite maps were coregistered with surgical planning MRI and imported into a neuronavigation system to guide tissue sampling in GBM patients receiving 5-aminolevulinic acid fluorescence-guided surgery. Samples were collected from regions with metabolic abnormalities in a biopsy-like fashion before bulk resection. Tissue fluorescence was measured ex vivo using a hand-held spectrometer. Tissue samples were immunostained for Sox2 and analyzed to quantify the density of staining cells using a novel digital pathology image analysis tool. Correlations among sMRI markers, Sox2 density, and ex vivo fluorescence were evaluated.
  
  
  
  Spectroscopic MRI biomarkers exhibit significant correlations with Sox2-positive cell density and ex vivo fluorescence. The choline to N-acetylaspartate ratio showed significant associations with each quantitative marker (Pearson's ρ = 0.82, P < .001 and ρ = 0.36, P < .0001, respectively). Clinically, sMRI metabolic abnormalities predated contrast enhancement at sites of tumor recurrence and exhibited an inverse relationship with progression-free survival.
  
  
  
  As it identifies tumor infiltration and regions at high risk for recurrence, sMRI could complement conventional MRI to improve local control in GBM patients.
authors.affiliation: Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Georgia (J.S.C., Z.L., S.S.G., C.A.H., H.S.); Department of Radiation Oncology, Emory University School of Medicine, Atlanta, Georgia(H.G.S., E.S.); Winship Cancer Institute of Emory University, Atlanta, Georgia(H.G.S., Z.L., J.J.O., C.G.H., H.S.); Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia(S.S.G., L.A.D.C., B.K., H.S.); Department of Biomedical informatics, Emory University School of Medicine, Atlanta, Georgia(L.A.D.C.); Department of Neurosurgery, Emory University School of Medicine, Atlanta, Georgia(J.J.O., C.G.H.); Department of Pathology, Emory University School of Medicine, Atlanta, Georgia(S.G.N.); Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, New York (C.G.H.).
authors.forename: James S
authors.initials: JS
authors.lastname: Cordova
authors.affiliation: Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Georgia (J.S.C., Z.L., S.S.G., C.A.H., H.S.); Department of Radiation Oncology, Emory University School of Medicine, Atlanta, Georgia(H.G.S., E.S.); Winship Cancer Institute of Emory University, Atlanta, Georgia(H.G.S., Z.L., J.J.O., C.G.H., H.S.); Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia(S.S.G., L.A.D.C., B.K., H.S.); Department of Biomedical informatics, Emory University School of Medicine, Atlanta, Georgia(L.A.D.C.); Department of Neurosurgery, Emory University School of Medicine, Atlanta, Georgia(J.J.O., C.G.H.); Department of Pathology, Emory University School of Medicine, Atlanta, Georgia(S.G.N.); Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, New York (C.G.H.).
authors.forename: Hui-Kuo G
authors.initials: HK
authors.lastname: Shu
authors.affiliation: Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Georgia (J.S.C., Z.L., S.S.G., C.A.H., H.S.); Department of Radiation Oncology, Emory University School of Medicine, Atlanta, Georgia(H.G.S., E.S.); Winship Cancer Institute of Emory University, Atlanta, Georgia(H.G.S., Z.L., J.J.O., C.G.H., H.S.); Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia(S.S.G., L.A.D.C., B.K., H.S.); Department of Biomedical informatics, Emory University School of Medicine, Atlanta, Georgia(L.A.D.C.); Department of Neurosurgery, Emory University School of Medicine, Atlanta, Georgia(J.J.O., C.G.H.); Department of Pathology, Emory University School of Medicine, Atlanta, Georgia(S.G.N.); Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, New York (C.G.H.).
authors.forename: Zhongxing
authors.initials: Z
authors.lastname: Liang
authors.affiliation: Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Georgia (J.S.C., Z.L., S.S.G., C.A.H., H.S.); Department of Radiation Oncology, Emory University School of Medicine, Atlanta, Georgia(H.G.S., E.S.); Winship Cancer Institute of Emory University, Atlanta, Georgia(H.G.S., Z.L., J.J.O., C.G.H., H.S.); Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia(S.S.G., L.A.D.C., B.K., H.S.); Department of Biomedical informatics, Emory University School of Medicine, Atlanta, Georgia(L.A.D.C.); Department of Neurosurgery, Emory University School of Medicine, Atlanta, Georgia(J.J.O., C.G.H.); Department of Pathology, Emory University School of Medicine, Atlanta, Georgia(S.G.N.); Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, New York (C.G.H.).
authors.forename: Saumya S
authors.initials: SS
authors.lastname: Gurbani
authors.affiliation: Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Georgia (J.S.C., Z.L., S.S.G., C.A.H., H.S.); Department of Radiation Oncology, Emory University School of Medicine, Atlanta, Georgia(H.G.S., E.S.); Winship Cancer Institute of Emory University, Atlanta, Georgia(H.G.S., Z.L., J.J.O., C.G.H., H.S.); Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia(S.S.G., L.A.D.C., B.K., H.S.); Department of Biomedical informatics, Emory University School of Medicine, Atlanta, Georgia(L.A.D.C.); Department of Neurosurgery, Emory University School of Medicine, Atlanta, Georgia(J.J.O., C.G.H.); Department of Pathology, Emory University School of Medicine, Atlanta, Georgia(S.G.N.); Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, New York (C.G.H.).
authors.forename: Lee A D
authors.initials: LA
authors.lastname: Cooper
authors.affiliation: Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Georgia (J.S.C., Z.L., S.S.G., C.A.H., H.S.); Department of Radiation Oncology, Emory University School of Medicine, Atlanta, Georgia(H.G.S., E.S.); Winship Cancer Institute of Emory University, Atlanta, Georgia(H.G.S., Z.L., J.J.O., C.G.H., H.S.); Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia(S.S.G., L.A.D.C., B.K., H.S.); Department of Biomedical informatics, Emory University School of Medicine, Atlanta, Georgia(L.A.D.C.); Department of Neurosurgery, Emory University School of Medicine, Atlanta, Georgia(J.J.O., C.G.H.); Department of Pathology, Emory University School of Medicine, Atlanta, Georgia(S.G.N.); Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, New York (C.G.H.).
authors.forename: Chad A
authors.initials: CA
authors.lastname: Holder
authors.affiliation: Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Georgia (J.S.C., Z.L., S.S.G., C.A.H., H.S.); Department of Radiation Oncology, Emory University School of Medicine, Atlanta, Georgia(H.G.S., E.S.); Winship Cancer Institute of Emory University, Atlanta, Georgia(H.G.S., Z.L., J.J.O., C.G.H., H.S.); Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia(S.S.G., L.A.D.C., B.K., H.S.); Department of Biomedical informatics, Emory University School of Medicine, Atlanta, Georgia(L.A.D.C.); Department of Neurosurgery, Emory University School of Medicine, Atlanta, Georgia(J.J.O., C.G.H.); Department of Pathology, Emory University School of Medicine, Atlanta, Georgia(S.G.N.); Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, New York (C.G.H.).
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Olson
authors.affiliation: Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Georgia (J.S.C., Z.L., S.S.G., C.A.H., H.S.); Department of Radiation Oncology, Emory University School of Medicine, Atlanta, Georgia(H.G.S., E.S.); Winship Cancer Institute of Emory University, Atlanta, Georgia(H.G.S., Z.L., J.J.O., C.G.H., H.S.); Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia(S.S.G., L.A.D.C., B.K., H.S.); Department of Biomedical informatics, Emory University School of Medicine, Atlanta, Georgia(L.A.D.C.); Department of Neurosurgery, Emory University School of Medicine, Atlanta, Georgia(J.J.O., C.G.H.); Department of Pathology, Emory University School of Medicine, Atlanta, Georgia(S.G.N.); Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, New York (C.G.H.).
authors.forename: Brad
authors.initials: B
authors.lastname: Kairdolf
authors.affiliation: Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Georgia (J.S.C., Z.L., S.S.G., C.A.H., H.S.); Department of Radiation Oncology, Emory University School of Medicine, Atlanta, Georgia(H.G.S., E.S.); Winship Cancer Institute of Emory University, Atlanta, Georgia(H.G.S., Z.L., J.J.O., C.G.H., H.S.); Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia(S.S.G., L.A.D.C., B.K., H.S.); Department of Biomedical informatics, Emory University School of Medicine, Atlanta, Georgia(L.A.D.C.); Department of Neurosurgery, Emory University School of Medicine, Atlanta, Georgia(J.J.O., C.G.H.); Department of Pathology, Emory University School of Medicine, Atlanta, Georgia(S.G.N.); Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, New York (C.G.H.).
authors.forename: Eduard
authors.initials: E
authors.lastname: Schreibmann
authors.affiliation: Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Georgia (J.S.C., Z.L., S.S.G., C.A.H., H.S.); Department of Radiation Oncology, Emory University School of Medicine, Atlanta, Georgia(H.G.S., E.S.); Winship Cancer Institute of Emory University, Atlanta, Georgia(H.G.S., Z.L., J.J.O., C.G.H., H.S.); Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia(S.S.G., L.A.D.C., B.K., H.S.); Department of Biomedical informatics, Emory University School of Medicine, Atlanta, Georgia(L.A.D.C.); Department of Neurosurgery, Emory University School of Medicine, Atlanta, Georgia(J.J.O., C.G.H.); Department of Pathology, Emory University School of Medicine, Atlanta, Georgia(S.G.N.); Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, New York (C.G.H.).
authors.forename: Stewart G
authors.initials: SG
authors.lastname: Neill
authors.affiliation: Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Georgia (J.S.C., Z.L., S.S.G., C.A.H., H.S.); Department of Radiation Oncology, Emory University School of Medicine, Atlanta, Georgia(H.G.S., E.S.); Winship Cancer Institute of Emory University, Atlanta, Georgia(H.G.S., Z.L., J.J.O., C.G.H., H.S.); Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia(S.S.G., L.A.D.C., B.K., H.S.); Department of Biomedical informatics, Emory University School of Medicine, Atlanta, Georgia(L.A.D.C.); Department of Neurosurgery, Emory University School of Medicine, Atlanta, Georgia(J.J.O., C.G.H.); Department of Pathology, Emory University School of Medicine, Atlanta, Georgia(S.G.N.); Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, New York (C.G.H.).
authors.forename: Constantinos G
authors.initials: CG
authors.lastname: Hadjipanayis
authors.affiliation: Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Georgia (J.S.C., Z.L., S.S.G., C.A.H., H.S.); Department of Radiation Oncology, Emory University School of Medicine, Atlanta, Georgia(H.G.S., E.S.); Winship Cancer Institute of Emory University, Atlanta, Georgia(H.G.S., Z.L., J.J.O., C.G.H., H.S.); Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia(S.S.G., L.A.D.C., B.K., H.S.); Department of Biomedical informatics, Emory University School of Medicine, Atlanta, Georgia(L.A.D.C.); Department of Neurosurgery, Emory University School of Medicine, Atlanta, Georgia(J.J.O., C.G.H.); Department of Pathology, Emory University School of Medicine, Atlanta, Georgia(S.G.N.); Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, New York (C.G.H.).
authors.forename: Hyunsuk
authors.initials: H
authors.lastname: Shim
mesh_terms: D000622:Aminolevulinic Acid / Q000008:administration & dosage; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D002452:Cell Count; D002794:Choline / Q000378:metabolism*; D018572:Disease-Free Survival; D005909:Glioblastoma / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D006801:Humans; D007090:Image Interpretation, Computer-Assisted; D008279:Magnetic Resonance Imaging / Q000379:methods; D038361:Neuronavigation / Q000379:methods; D061848:Optical Imaging / Q000379:methods; D017319:Photosensitizing Agents / Q000008:administration & dosage; D066244:Proton Magnetic Resonance Spectroscopy / Q000379:methods; D012307:Risk Factors; D055748:SOXB1 Transcription Factors / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D017319:Photosensitizing Agents; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D001224:Aspartic Acid; D000622:Aminolevulinic Acid; C000179:N-acetylaspartate; D002794:Choline
keywords: 5-aminolevulinic acid; glioblastoma; quantitative histological image analysis; spectroscopic MRI; surgical and radiation therapy planning