title: Assessment of hypoxia and perfusion in human brain tumors using PET with 18F-fluoromisonidazole and 15O-H2O.
abstract: Hypoxia predicts poor treatment response of malignant tumors. We used PET with (18)F-fluoromisonidazole ((18)F-FMISO) and (15)O-H(2)O to measure in vivo hypoxia and perfusion in patients with brain tumors.
  
  
  METHODS
  Eleven patients with various brain tumors were investigated. We performed dynamic (18)F-FMISO PET, including arterial blood sampling and the determination of (18)F-FMISO stability in plasma with high-performance liquid chromatography (HPLC). The (18)F-FMISO kinetics in normal brain and tumor were assessed quantitatively using standard 2- and 3-compartment models. Tumor perfusion ((15)O-H(2)O) was measured immediately before (18)F-FMISO PET in 10 of the 11 patients.
  
  
  RESULTS
  PET images acquired 150-170 min after injection revealed increased (18)F-FMISO tumor uptake in all glioblastomas. This increased uptake was reflected by (18)F-FMISO distribution volumes >1, compared with (18)F-FMISO distribution volumes <1 in normal brain. The (18)F-FMISO uptake rate K(1) was also higher in all glioblastomas than in normal brain. In meningioma, which lacks the blood-brain barrier (BBB), a higher K(1) was observed than in glioblastoma, whereas the (18)F-FMISO distribution volume in meningioma was <1. Pixel-by-pixel image analysis generally showed a positive correlation between (18)F-FMISO tumor uptake at 0-5 min after injection and perfusion ((15)O-H(2)O) with r values between 0.42 and 0.86, whereas late (18)F-FMISO images (150-170 min after injection) were (with a single exception) independent of perfusion. Spatial comparison of (18)F-FMISO with (15)O-H(2)O PET images in glioblastomas showed hypoxia both in hypo- and hyperperfused tumor areas. HPLC analysis showed that most of the (18)F-FMISO in plasma was still intact 90 min after injection, accounting for 92%-96% of plasma radioactivity.
  
  
  CONCLUSIONS
  Our data suggest that late (18)F-FMISO PET images provide a spatial description of hypoxia in brain tumors that is independent of BBB disruption and tumor perfusion. The distribution volume is an appropriate measure to quantify (18)F-FMISO uptake. The perfusion-hypoxia patterns described in glioblastoma suggest that hypoxia in these tumors may develop irrespective of the magnitude of perfusion.
authors.affiliation: Paul Scherrer Institute, Center for Radiopharmaceutical Science, Villigen, Switzerland. matthias.bruehlmeier@ksa.ch
authors.forename: Matthias
authors.initials: M
authors.lastname: Bruehlmeier
authors.forename: Ulrich
authors.initials: U
authors.lastname: Roelcke
authors.forename: Pius A
authors.initials: PA
authors.lastname: Schubiger
authors.forename: Simon Mensah
authors.initials: SM
authors.lastname: Ametamey
mesh_terms: D000328:Adult; D000368:Aged; D001783:Blood Flow Velocity; D001921:Brain / Q000098:blood supply* / Q000000981:diagnostic imaging*; D001932:Brain Neoplasms / Q000150:complications / Q000000981:diagnostic imaging* / Q000503:physiopathology; D005260:Female; D006801:Humans; D002534:Hypoxia, Brain / Q000000981:diagnostic imaging* / Q000209:etiology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D008920:Misonidazole / Q000031:analogs & derivatives*; D010104:Oxygen Radioisotopes; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013382:Subtraction Technique; D014867:Water
chemical_list: D010104:Oxygen Radioisotopes; D019275:Radiopharmaceuticals; D014867:Water; C031843:fluoromisonidazole; D008920:Misonidazole