title: Quantification in molecular ultrasound imaging: a comparative study in mice between healthy liver and a human hepatocellular carcinoma xenograft.
abstract: OBJECTIVE
  The purpose of this study was to quantitatively assess the contrast kinetics of vascular endothelial growth factor receptor 2 (VEGFR2)-targeted microbubbles (BR55; Bracco Suisse, Geneva, Switzerland) compared to clinically used microbubbles (SonoVue; Bracco SpA, Milan, Italy) in both normal liver and human hepatocellular carcinoma xenograft tumors in mice.
  
  
  METHODS
  Microbubbles were injected intravenously into healthy mice (n = 5) and mice bearing hepatocellular carcinoma xenograft tumors (n = 10). Cine loops of contrast enhancement in normal liver and the tumors were acquired for 10 minutes. Quantitative perfusion parameters were derived by fitting time-intensity curves using a dedicated mathematical model combining a bolus function and a ramp function. Immunohistochemical examinations were also performed for normal liver and tumor specimens to determine the level of VEGFR2 expression.
  
  
  RESULTS
  The peak contrast enhancement observed in normal liver with BR55 was comparable to that with SonoVue, whereas a significant difference was observed in latephase enhancement at 10 minutes (ramp slope: P < .01). In the tumor model, SonoVue was rapidly cleared from the circulation, without any noticeable binding in the tumor, whereas BR55 showed a gradual decline, resulting in a longer wash-out period (mean transit time: P < .01). Immunohistochemical examinations showed that intratumoral vascular endothelial cells had sparse and weak VEGFR2 expression, whereas the sinusoidal capillaries in normal liver had much more diffuse and much stronger expression.
  
  
  CONCLUSIONS
  Our results suggest that BR55 accurately reflects the VEGFR2 status in human hepatocellular carcinoma xenograft tumors. We showed that quantification applied to molecular ultrasound imaging may provide an objective method for measuring the degree of microbubble binding.
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan. sugimoto@tokyo-med.ac.jp
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Sugimoto
authors.forename: Fuminori
authors.initials: F
authors.lastname: Moriyasu
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Negishi
authors.forename: Nobuhito
authors.initials: N
authors.lastname: Hamano
authors.forename: Hisashi
authors.initials: H
authors.lastname: Oshiro
authors.forename: Nicolas G
authors.initials: NG
authors.lastname: Rognin
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Yoshida
authors.forename: Naohisa
authors.initials: N
authors.lastname: Kamiyama
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Aramaki
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Imai
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000000981:diagnostic imaging*; D045744:Cell Line, Tumor; D006801:Humans; D008099:Liver / Q000000981:diagnostic imaging*; D008113:Liver Neoplasms / Q000000981:diagnostic imaging*; D051379:Mice; D008807:Mice, Inbred BALB C; D045423:Microbubbles; D025202:Molecular Diagnostic Techniques / Q000379:methods*; D009368:Neoplasm Transplantation / Q000000981:diagnostic imaging; D014463:Ultrasonography; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000032:analysis*
chemical_list: D040301:Vascular Endothelial Growth Factor Receptor-2