title: Evaluation of 11C-acetate and 18F-FDG PET/CT in mouse multidrug resistance gene-2 deficient mouse model of hepatocellular carcinoma.
abstract: BACKGROUND
  Hepatocellular carcinoma (HCC) remains a global health problem with unique diagnostic and therapeutic challenges, including difficulties in identifying the highest risk patients. Previous work from our lab has established the murine multidrug resistance-2 mouse (MDR2) model of HCC as a reasonable preclinical model that parallels the changes seen in human inflammatory associated HCC. The purpose of this study is to evaluate modalities of PET/CT in MDR2(-/-) mice in order to facilitate therapeutic translational studies from bench to bedside.
  
  
  METHODS
  18F-FDG and 11C-acetate PET/CT was performed on 12 m MDR2(-/-) mice (n = 3/tracer) with HCC and 12 m MDR2(-/+) control mice (n = 3/tracer) without HCC. To compare PET/CT to biological markers of HCC and cellular function, serum alpha-fetoprotein (AFP), lysophosphatidic acid (LPA), cAMP and hepatic tumor necrosis factor α (TNFα) were quantified in 3-12 m MDR2(-/-) (n = 10) mice using commercially available ELISA analysis. To translate results in mice to patients 11C-acetate PET/CT was also performed in 8 patents suspected of HCC recurrence following treatment and currently on the liver transplant wait list.
  
  
  RESULTS
  Hepatic18F-FDG metabolism was not significantly increased in MDR2(-/-) mice. In contrast, hepatic 11C-acetate metabolism was significantly elevated in MDR2(-/-) mice when compared to MDR2(-/+) controls. Serum AFP and LPA levels increased in MDR2(-/-) mice contemporaneous with the emergence of HCC. This was accompanied by a significant decrease in serum cAMP levels and an increase in hepatic TNFα. In patients suspected of HCC recurrence there were 5 true positives, 2 true negatives and 1 suspected false 11C-acetate negative.
  
  
  CONCLUSIONS
  Hepatic 11C-acetate PET/CT tracks well with HCC in MDR2(-/-) mice and patients with underlying liver disease. Consequently 11C-acetate PET/CT is well suited to study (1) HCC emergence/progression in patients and (2) reduce animal numbers required to study new chemotherapeutics in murine models of HCC.
authors.affiliation: Department of Surgery, Radiology and Imaging Sciences, Indianapolis, IN, 46202, USA. pterrito@iupui.edu.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Territo
authors.affiliation: Department of Surgery, Indiana University School of Medicine, C519 Walthur Cancer Research Building (R3), 980 W Walnut Street, Indianapolis, IN, 46077, USA. mmalucci@iupui.edu.
authors.forename: Mary
authors.initials: M
authors.lastname: Maluccio
authors.affiliation: Department of Surgery, Radiology and Imaging Sciences, Indianapolis, IN, 46202, USA. amariley@iupui.edu.
authors.forename: Amanda A
authors.initials: AA
authors.lastname: Riley
authors.affiliation: Department of Surgery, Radiology and Imaging Sciences, Indianapolis, IN, 46202, USA. brpmccar@iupui.edu.
authors.forename: Brian P
authors.initials: BP
authors.lastname: McCarthy
authors.affiliation: Department of Surgery, Radiology and Imaging Sciences, Indianapolis, IN, 46202, USA. jfletcher@IUHealth.org.
authors.forename: James
authors.initials: J
authors.lastname: Fletcher
authors.affiliation: Department of Surgery, Radiology and Imaging Sciences, Indianapolis, IN, 46202, USA. MTann2@iuhealth.org.
authors.forename: Mark
authors.initials: M
authors.lastname: Tann
authors.affiliation: Department of Surgery, Radiology and Imaging Sciences, Indianapolis, IN, 46202, USA. rsaxena@iu.edu.
authors.forename: Romil
authors.initials: R
authors.lastname: Saxena
authors.affiliation: Department of Surgery, Indiana University School of Medicine, C519 Walthur Cancer Research Building (R3), 980 W Walnut Street, Indianapolis, IN, 46077, USA. nskill@iupui.edu.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Skill
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000085:Acetates; D000818:Animals; D002244:Carbon; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis*; D004195:Disease Models, Animal; D019788:Fluorodeoxyglucose F18; D008113:Liver Neoplasms / Q000175:diagnosis*; D051379:Mice; D018345:Mice, Knockout; D064847:Multimodal Imaging / Q000379:methods; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014057:Tomography, X-Ray Computed / Q000379:methods; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000085:Acetates; D002244:Carbon; D019788:Fluorodeoxyglucose F18; D019275:Radiopharmaceuticals; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C438206:carbon-11 acetate