title: Comparison of (immuno-)fluorescence data with serial [¹⁸F]Fmiso PET/CT imaging for assessment of chronic and acute hypoxia in head and neck cancers.
abstract: OBJECTIVE
  Both, acute and chronic hypoxia can have unfavorable impacts on tumor progression and therapy response. The aim of this study was to optimize a macroscopic technique for the quantification of acute and chronic hypoxia (Wang model assessment of serial [(18)F]Fmiso PET/CT imaging) by comparing with a microscopic technique [(immuno-)fluorescence staining in tumor cryosections].
  
  
  METHODS
  Tumor pieces from the human squamous cell carcinoma lines from the head and neck FaDu and CAL33 were xenografted into the hind leg of NMRI nu/nu mice. Tumor-bearing mice were placed on an in-house developed multi-point fixation system and subjected to two consecutive dynamic [(18)F]Fmiso PET/CTs within a 24h interval. The Wang model was applied to SUV (standard uptake values) to quantify the fractions of acute and chronic hypoxia. Hypoxia subtypes were also assessed in vital tumor tissue of cryosections from the same tumors for (immuno-)fluorescence distributions of Hoechst 33342 (perfusion), pimonidazole (hypoxia), and CD31 (endothelium) using pattern recognition in microcirculatory supply units (defined as vital tumor tissue area supplied by a single microvessel).
  
  
  RESULTS
  Using our multi-point fixation system, acceptable co-registration (registration errors ε ranged from 0.34 to 1.37) between serial PET/CT images within individual voxels was achieved. The Wang model consistently yielded higher fractions of acute hypoxia than the MCSU method. Through specific modification of the Wang model (Wang(mod)), it was possible to reduce the fraction of acute hypoxia. However, there was no significant correlation between the fractions of acute hypoxia in individual tumors assessed by the Wang(mod) model and the MCSU method for either tumor line (FaDu: r=0.68, p=0.21 and CAL33: r=0.71, p=0.18). This lack of correlation is most-likely due to the difference between the non-linear uptake of [(18)F]Fmiso and the spatial assessment of MCSUs.
  
  
  CONCLUSIONS
  Whether the Wang model can be used to predict radiation response after serial [(18)F]Fmiso PET imaging, needs to be confirmed in experimental and clinical studies.
authors: Department of Radiotherapy and Radiation Oncology, Technical University of Munich, Germany.
authors: Constantin-Alin
authors: CA
authors: Maftei
authors: Kuangyu
authors: K
authors: Shi
authors: Christine
authors: C
authors: Bayer
authors: Sabrina T
authors: ST
authors: Astner
authors: Peter
authors: P
authors: Vaupel
mesh_terms: D000208:Acute Disease; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000000981:diagnostic imaging*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002908:Chronic Disease; D018450:Disease Progression; D006258:Head and Neck Neoplasms / Q000000981:diagnostic imaging*; D006801:Humans; D007089:Image Enhancement / Q000379:methods; D007090:Image Interpretation, Computer-Assisted / Q000379:methods; D051379:Mice; D008920:Misonidazole / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D064847:Multimodal Imaging; D049268:Positron-Emission Tomography; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D014057:Tomography, X-Ray Computed; D014183:Transplantation, Heterologous
chemical_list: D011838:Radiation-Sensitizing Agents; D008920:Misonidazole