title: Hypoxic glucose metabolism in glioblastoma as a potential prognostic factor.
abstract: OBJECTIVE
  Metabolic activity and hypoxia are both important factors characterizing tumor aggressiveness. Here, we used F-18 fluoromisonidazole (FMISO) and F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) to define metabolically active hypoxic volume, and investigate its clinical significance in relation to progression free survival (PFS) and overall survival (OS) in glioblastoma patients.
  
  
  METHODS
  Glioblastoma patients (n = 32) underwent FMISO PET, FDG PET, and magnetic resonance imaging (MRI) before surgical intervention. FDG and FMISO PET images were coregistered with gadolinium-enhanced T1-weighted MR images. Volume of interest (VOI) of gross tumor volume (GTV) was manually created to enclose the entire gadolinium-positive areas. The FMISO tumor-to-normal region ratio (TNR) and FDG TNR were calculated in a voxel-by-voxel manner. For calculating TNR, standardized uptake value (SUV) was divided by averaged SUV of normal references. Contralateral frontal and parietal cortices were used as the reference region for FDG, whereas the cerebellar cortex was used as the reference region for FMISO. FDG-positive was defined as the FDG TNR ≥1.0, and FMISO-positive was defined as FMISO TNR ≥1.3. Hypoxia volume (HV) was defined as the volume of FMISO-positive and metabolic tumor volume in hypoxia (hMTV) was the volume of FMISO/FDG double-positive. The total lesion glycolysis in hypoxia (hTLG) was hMTV × FDG SUVmean. The extent of resection (EOR) involving cytoreduction surgery was volumetric change based on planimetry methods using MRI. These factors were tested for correlation with patient prognosis.
  
  
  RESULTS
  All tumor lesions were FMISO-positive and FDG-positive. Univariate analysis indicated that hMTV, hTLG, and EOR were significantly correlated with PFS (p = 0.007, p = 0.04, and p = 0.01, respectively) and that hMTV, hTLG, and EOR were also significantly correlated with OS (p = 0.0028, p = 0.037, and p = 0.014, respectively). In contrast, none of FDG TNR, FMISO TNR, GTV, HV, patients' age, or Karnofsky performance scale (KPS) was significantly correlated with PSF or OS. The hMTV and hTLG were found to be independent factors affecting PFS and OS on multivariate analysis.
  
  
  CONCLUSIONS
  We introduced hMTV and hTLG using FDG and FMISO PET to define metabolically active hypoxic volume. Univariate and multivariate analyses demonstrated that both hMTV and hTLG are significant predictors for PFS and OS in glioblastoma patients.
authors.affiliation: Department of Nuclear Medicine, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Toyonaga
authors.affiliation: Department of Nuclear Medicine, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan.|Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Yamaguchi
authors.affiliation: Department of Nuclear Medicine, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan. khirata@med.hokudai.ac.jp.
authors.forename: Kenji
authors.initials: K
authors.lastname: Hirata
authors.affiliation: Department of Nuclear Medicine, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Department of Nuclear Medicine, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Manabe
authors.affiliation: Department of Nuclear Medicine, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Terasaka
authors.affiliation: Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kobayashi
authors.affiliation: Department of Nuclear Medicine, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Hattori
authors.affiliation: Department of Nuclear Medicine, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Shiga
authors.affiliation: Central Institute of Isotope Science, Hokkaido University, Sapporo, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kuge
authors.affiliation: Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Tanaka
authors.affiliation: Department of Biostatistics, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Yoichi M
authors.initials: YM
authors.lastname: Ito
authors.affiliation: Department of Nuclear Medicine, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan.
authors.forename: Nagara
authors.initials: N
authors.lastname: Tamaki
mesh_terms: D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000378:metabolism*; D001932:Brain Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism; D015687:Cell Hypoxia; D005260:Female; D019788:Fluorodeoxyglucose F18; D005909:Glioblastoma / Q000000981:diagnostic imaging* / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D008920:Misonidazole / Q000031:analogs & derivatives; D010100:Oxygen / Q000378:metabolism*; D000072078:Positron Emission Tomography Computed Tomography; D019275:Radiopharmaceuticals
chemical_list: D001786:Blood Glucose; D019275:Radiopharmaceuticals; C031843:fluoromisonidazole; D019788:Fluorodeoxyglucose F18; D008920:Misonidazole; D010100:Oxygen
keywords: Anaerobic glycolysis; Fluorodeoxyglucose; Fluoromisonidazole; Glioblastoma; Positron emission tomography