title: (15)O-Water PET Study of the Effect of Imatinib, a Selective Platelet-Derived Growth Factor Receptor Inhibitor, Versus Anakinra, an IL-1R Antagonist, on Water-Perfusable Tissue Fraction in Colorectal Cancer Metastases.
abstract: High interstitial fluid pressure (IFP) in colorectal cancer metastases may decrease the uptake and, thus, the effects of antitumor drugs. Imatinib, a selective inhibitor of platelet-derived growth factor receptors, and anakinra, an interleukin-1 receptor antagonist, respectively, increase drug uptake or decrease IFP in preclinical models of carcinoma. Drug-induced decrease in IFP in human metastases has not been objectively shown but should be reflected by an increase in water-perfusable tissue fraction (PTF) or tumor blood flow (TBF) using (15)O-water PET/CT and kinetic modeling. Hence, the aim of this study was to assess the effects of imatinib and anakinra on PTF and TBF in colorectal cancer metastases in patients.
  
  
  METHODS
  Nine patients with documented progressive disease despite all established therapy underwent (15)O-water PET/CT at baseline and at 2 d and 6-7 d after the start of oral administration of imatinib (400 mg/d). After a washout period of 1 wk, the protocol was repeated with anakinra (100 mg/d) subcutaneously. Six patients underwent a second baseline scan on the same day to assess reproducibility of PTF and TBF measurements. Volumes of interest were drawn over liver metastases and aorta. PTF and TBF were calculated using the standard single-tissue-compartment model.
  
  
  RESULTS
  Imatinib administration during 6-7 d increased PTF from 0.62 ± 0.12 to 0.69 ± 0.13, compared with baseline and day 2 (P = 0.02, Wilcoxon test). No significant changes were found in TBF. PTF values were no longer significantly different from baseline 1 wk after the last imatinib dosage. Anakinra induced no significant change in PTF or TBF. The repeatability coefficients of PTF and TBF in liver lesions were 22% and 28%, respectively.
  
  
  CONCLUSIONS
  Imatinib increases PTF of colorectal cancer metastases in patients and hence may increase the delivery of antitumor drugs. (15)O-water PET/CT and kinetic modeling provide insights into the microenvironment of human cancers.
authors.affiliation: Nuclear Medicine and PET, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Mark
authors.initials: M
authors.lastname: Lubberink
authors.affiliation: Nuclear Medicine and PET, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Sanjeep S V
authors.initials: SS
authors.lastname: Golla
authors.affiliation: Nuclear Medicine and PET, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: My
authors.initials: M
authors.lastname: Jonasson
authors.affiliation: Department of Experimental Medicine, University of Lund, Lund, Sweden; and.
authors.forename: Kristofer
authors.initials: K
authors.lastname: Rubin
authors.affiliation: Oncology Section, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Glimelius
authors.affiliation: Nuclear Medicine and PET, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden jens.sorensen@pet.uu.se.
authors.forename: Jens
authors.initials: J
authors.lastname: Sörensen
authors.affiliation: Oncology Section, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Nygren
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001549:Benzamides / Q000008:administration & dosage*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D053590:Interleukin 1 Receptor Antagonist Protein / Q000008:administration & dosage* / Q000378:metabolism*; D007700:Kinetics; D008113:Liver Neoplasms / Q000556:secondary; D008175:Lung Neoplasms / Q000556:secondary; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010104:Oxygen Radioisotopes; D010477:Perfusion; D010879:Piperazines / Q000008:administration & dosage*; D049268:Positron-Emission Tomography / Q000379:methods*; D011743:Pyrimidines / Q000008:administration & dosage*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D015203:Reproducibility of Results; D013997:Time Factors; D014867:Water / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D053590:Interleukin 1 Receptor Antagonist Protein; D010104:Oxygen Radioisotopes; D010879:Piperazines; D011743:Pyrimidines; D014867:Water; D000068877:Imatinib Mesylate; D017479:Receptors, Platelet-Derived Growth Factor
keywords: interstitial fluid pressure; metastatic colorectal cancer; positron emission tomography; tumor blood flow; water-perfusable tissue fraction