title: Quantitative Analysis of [18F]FMISO PET for Tumor Hypoxia: Correlation of Modeling Results with Immunohistochemistry.
abstract: Quantitative evaluation of tumor hypoxia based on H-1-(3-[18F]fluoro-2-hydroxypropyl)-2-nitroimidazole ([18F]FMISO) positron emission tomography (PET) can deliver important information for treatment planning in radiotherapy. However, the merits and limitations of different analysis methods in revealing the underlying physiological feature are not clear. This study aimed to assess these quantitative analysis methods with the support of immunohistological data.
  
  
  
  Sixteen nude mice bearing xenografted human squamous cell carcinomas (FaDu or CAL-33) were scanned using 2-h dynamic [18F]FMISO PET. Tumors were resected and sliced, and the hypoxia marker pimonidazole was immunostained followed by H&E staining. The pimonidazole signal was segmented using a k-means clustering algorithm, and the hypoxic fraction (HF) was calculated as the hypoxic area/viable tumor-tissue-area ratio pooled over three tissue slices from the apical, center, and basal layers. PET images were analyzed using various methods including static analysis [standard uptake value (SUV), tumor-to-blood ratio (T/B), tumor-to-muscle ratio (T/M)] and kinetic modeling (Casciari αkA, irreversible and reversible two-tissue compartment k3, Thorwarth wAk3, Patlak Ki, Logan Vd, Cho K), and correlated with HF.
  
  
  
  No significant correlation was found for static analysis. A significant correlation between k3of the irreversible two-tissue compartment model and HF was observed (r = 0.61, p = 0.01). The correlation between HF and αkAof the Casciari model could be improved through reducing local minima by testing more sets of initial values (r = 0.59, p = 0.02) or by reducing the model complexity by fixing three parameters (r = 0.63, p = 0.0008).
  
  
  
  With support of immunohistochemistry data, this study shows that various analysis methods for [18F]FMISO PET perform differently for assessment of tumor hypoxia. A better fitting quality does not necessarily mean a higher physiological correlation. Hypoxia PET analysis needs to consider both the mathematical stability and physiological fidelity. Based on the results of this study, preference should be given to the irreversible two-tissue compartment model as well as the Casciari model with reduced parameters.
authors.affiliation: Department of Nuclear Medicine, Klinikum rechts der Isar, Technische Universität München, Ismaningerstrasse. 22, 81675, Munich, Germany. k.shi@tum.de.
authors.forename: Kuangyu
authors.initials: K
authors.lastname: Shi
authors.affiliation: Department of Radiooncology and Radiotherapy, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Bayer
authors.affiliation: Department of Radiooncology and Radiotherapy, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Sabrina T
authors.initials: ST
authors.lastname: Astner
authors.affiliation: Department of Nuclear Medicine, Klinikum rechts der Isar, Technische Universität München, Ismaningerstrasse. 22, 81675, Munich, Germany.
authors.forename: Florian C
authors.initials: FC
authors.lastname: Gaertner
authors.affiliation: Department of Radiooncology and Radiotherapy, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Vaupel
authors.affiliation: Department of Nuclear Medicine, Klinikum rechts der Isar, Technische Universität München, Ismaningerstrasse. 22, 81675, Munich, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Schwaiger
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Sung-Cheng
authors.initials: SC
authors.lastname: Huang
authors.affiliation: Department of Nuclear Medicine, Klinikum rechts der Isar, Technische Universität München, Ismaningerstrasse. 22, 81675, Munich, Germany.
authors.forename: Sibylle I
authors.initials: SI
authors.lastname: Ziegler
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D007150:Immunohistochemistry; D008819:Mice, Nude; D008920:Misonidazole / Q000031:analogs & derivatives* / Q000737:chemistry; D049268:Positron-Emission Tomography / Q000379:methods*; D000072258:Tumor Hypoxia
chemical_list: C031843:fluoromisonidazole; D008920:Misonidazole
keywords: Dynamic PET; Fmiso; Pharmacokinetic modeling; Tumor hypoxia