title: Correlation of FMISO simulations with pimonidazole-stained tumor xenografts: A question of O2 consumption?
abstract: OBJECTIVE
  To compare a dedicated simulation model for hypoxia PET against tumor microsections stained for different parameters of the tumor microenvironment. The model can readily be adapted to a variety of conditions, such as different human head and neck squamous cell carcinoma (HNSCC) xenograft tumors.
  
  
  METHODS
  Nine different HNSCC tumor models were transplanted subcutaneously into nude mice. Tumors were excised and immunoflourescently labeled with pimonidazole, Hoechst 33342, and CD31, providing information on hypoxia, perfusion, and vessel distribution, respectively. Hoechst and CD31 images were used to generate maps of perfused blood vessels on which tissue oxygenation and the accumulation of the hypoxia tracer FMISO were mathematically simulated. The model includes a Michaelis-Menten relation to describe the oxygen consumption inside tissue. The maximum oxygen consumption rate M0 was chosen as the parameter for a tumor-specific optimization as it strongly influences tracer distribution. M0 was optimized on each tumor slice to reach optimum correlations between FMISO concentration 4 h postinjection and pimonidazole staining intensity.
  
  
  RESULTS
  After optimization, high pixel-based correlations up to R(2) = 0.85 were found for individual tissue sections. Experimental pimonidazole images and FMISO simulations showed good visual agreement, confirming the validity of the approach. Median correlations per tumor model varied significantly (p < 0.05), with R(2) ranging from 0.20 to 0.54. The optimum maximum oxygen consumption rate M0 differed significantly (p < 0.05) between tumor models, ranging from 2.4 to 5.2 mm Hg/s.
  
  
  CONCLUSIONS
  It is feasible to simulate FMISO distributions that match the pimonidazole retention patterns observed in vivo. Good agreement was obtained for multiple tumor models by optimizing the oxygen consumption rate, M0, whose optimum value differed significantly between tumor models.
authors.affiliation: Section for Biomedical Physics, Department of Radiation Oncology, University Hospital Tübingen, Tübingen 72076, Germany.
authors.forename: L J
authors.initials: LJ
authors.lastname: Wack
authors.affiliation: Section for Biomedical Physics, Department of Radiation Oncology, University Hospital Tübingen, Tübingen 72076, Germany; German Cancer Consortium (DKTK), Tübingen 72076, Germany; and German Cancer Research Center (DKFZ), Heidelberg 69121, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Mönnich
authors.affiliation: OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden 01309, Germany and Department of Radiation Oncology (MAASTRO), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht 6229 ET, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Yaromina
authors.affiliation: German Cancer Consortium (DKTK), Tübingen 72076, Germany; German Cancer Research Center (DKFZ), Heidelberg 69121, Germany and Department of Radiation Oncology, University Hospital Tübingen, Tübingen 72076, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Zips
authors.affiliation: German Cancer Consortium (DKTK), Dresden 01307, Germany; German Cancer Research Center (DKFZ), Heidelberg 69121, Germany; OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden 01309, Germany; Department of Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden 01307, Germany; and Institute of Radiooncology, Helmholtz-Zentrum Dresden-Rossendorf, Dresden 01328, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Baumann
authors.affiliation: Section for Biomedical Physics, Department of Radiation Oncology, University Hospital Tübingen, Tübingen 72076, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Thorwarth
mesh_terms: D000818:Animals; D001562:Benzimidazoles; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D003198:Computer Simulation; D005240:Feasibility Studies; D005455:Fluorescent Antibody Technique; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D008819:Mice, Nude; D008920:Misonidazole / Q000031:analogs & derivatives; D008954:Models, Biological; D009368:Neoplasm Transplantation; D009593:Nitroimidazoles; D010101:Oxygen Consumption / Q000502:physiology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D059016:Tumor Microenvironment / Q000502:physiology
chemical_list: D001562:Benzimidazoles; D009593:Nitroimidazoles; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C031843:fluoromisonidazole; C033815:pimonidazole; D008920:Misonidazole; C017807:bisbenzimide ethoxide trihydrochloride