title: Quantitative evaluation of oxygen metabolism in the intratumoral hypoxia:18F-fluoromisonidazole and15O-labelled gases inhalation PET.
abstract: BACKGROUND
  Intratumoral hypoxia is one of the resistant factors in radiotherapy and chemotherapy for cancer. Although it is detected by18F-fluoromisonidazole (FMISO) PET, the relationship between intratumoral hypoxia and oxygen metabolism has not been studied. The purpose of this study was to evaluate the intratumoral perfusion and oxygen metabolism in hypoxic regions using the rat xenograft model. Ten male Fischer rats with C6 glioma (body weight = 220 ± 15 g) were investigated with18F-FMISO PET and steady-state inhalation method of15O-labelled gases PET. The tumoral blood flow (TBF), tumoral metabolic rate of oxygen (TMRO2), oxygen extraction fraction (OEF), and tumoral blood volume (TBV) were measured under artificial ventilation with15O-CO2,15O-O2, and15O-CO gases. Multiple volumes of interest (1-mm diameter sphere) were placed on the co-registered18F-FMISO (3 h post injection) and functional15O-labelled gases PET images. The TBF, TMRO2, OEF, and TBV values were compared among the three groups classified by the18F-FMISO uptake as follows: group Low (L), less than 1.0; group Medium (M), between 1.0 and 2.0; and group High (H), more than 2.0 in the18F-FMISO standardized uptake value (SUV).
  
  
  RESULTS
  There were moderate negative correlations between18F-FMISO SUV and TBF (r = -0.56 and p < 0.01), and weak negative correlations between18F-FMISO SUV and TMRO2(r = -0.38 and p < 0.01) and18F-FMISO SUV and TBV (r = -0.38 and p < 0.01). Quantitative values were as follows: TBF, (L) 55 ± 30, (M) 32 ± 17, and (H) 30 ± 15 mL/100 mL/min; OEF, (L) 33 ± 14, (M) 36 ± 17, and (H) 41 ± 16%; TMRO2, (L) 2.8 ± 1.3, (M) 1.9 ± 1.0, and (H) 2.1 ± 1.1 mL/100 mL/min; and TBV, (L) 5.7 ± 2.1, (M) 4.3 ± 1.9, and (H) 3.9 ± 1.2 mL/100 mL, respectively. Intratumoral hypoxic regions (M and H) showed significantly lower TBF, TMRO2, and TBV values than non-hypoxic regions (L). OEF showed significant increase in the severe hypoxic region compared to non-hypoxic and mild hypoxic regions.
  
  
  CONCLUSIONS
  This study demonstrated that intratumoral hypoxic regions showed decreased blood flow with increased oxygen extraction, suggesting the need for a treatment strategy to normalize the blood flow for oxygen-avid active tumor cells in hypoxic regions.
authors.affiliation: Department of Nuclear Medicine and Tracer Kinetics, Osaka University Graduate School of Medicine, Suita, Japan. watabe@tracer.med.osaka-u.ac.jp.|Medical Imaging Center for Translational Research, Osaka University Graduate School of Medicine, Suita, Japan. watabe@tracer.med.osaka-u.ac.jp.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Watabe
authors.affiliation: Medical Imaging Center for Translational Research, Osaka University Graduate School of Medicine, Suita, Japan.|Department of Molecular Imaging in Medicine, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Yasukazu
authors.initials: Y
authors.lastname: Kanai
authors.affiliation: Department of Nuclear Medicine and Tracer Kinetics, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Hayato
authors.initials: H
authors.lastname: Ikeda
authors.affiliation: Department of Nuclear Medicine and Tracer Kinetics, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Genki
authors.initials: G
authors.lastname: Horitsugi
authors.affiliation: Medical Imaging Center for Translational Research, Osaka University Graduate School of Medicine, Suita, Japan.|Department of Molecular Imaging in Medicine, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Matsunaga
authors.affiliation: Department of Nuclear Medicine and Tracer Kinetics, Osaka University Graduate School of Medicine, Suita, Japan.|Medical Imaging Center for Translational Research, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kato
authors.affiliation: Department of Nuclear Medicine and Tracer Kinetics, Osaka University Graduate School of Medicine, Suita, Japan.|Medical Imaging Center for Translational Research, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Kayako
authors.initials: K
authors.lastname: Isohashi
authors.affiliation: Medical Imaging Center for Translational Research, Osaka University Graduate School of Medicine, Suita, Japan.|Department of Molecular Imaging in Medicine, Osaka University Graduate School of Medicine, Suita, Japan.|Department of Drug Metabolism & Pharmacokinetics, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Kohji
authors.initials: K
authors.lastname: Abe
authors.affiliation: Department of Nuclear Medicine and Tracer Kinetics, Osaka University Graduate School of Medicine, Suita, Japan.|Medical Imaging Center for Translational Research, Osaka University Graduate School of Medicine, Suita, Japan.|Department of Molecular Imaging in Medicine, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Eku
authors.initials: E
authors.lastname: Shimosegawa
authors.affiliation: Department of Nuclear Medicine and Tracer Kinetics, Osaka University Graduate School of Medicine, Suita, Japan.|Medical Imaging Center for Translational Research, Osaka University Graduate School of Medicine, Suita, Japan.|Research Laboratory for Development, Shionogi & Co., Ltd.; Immunology Frontier Research Center, Osaka University, Suita, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Hatazawa
keywords: Blood flow; Fluoromisonidazole; Hypoxia; Oxygen consumption; PET