title: Multikinase inhibitor sorafenib transiently promotes necrosis after radiofrequency ablation in rat liver but activates growth signals.
abstract: OBJECTIVE
  To investigate the effects of sorafenib when combined with radiofrequency ablation treatment in liver tissue, the necrosis volume, tissue repair and hepatocellular growth signals were analyzed in rats. Radiofrequency ablation (RFA) is a widely applied treatment for hepatocellular carcinoma (HCC). Radiofrequency ablation is combined with the multi-tyrosinkinase-inhibitor sorafenib in ongoing clinical trials. Whether this combination treatment affects liver tissue repair is unknown.
  
  
  METHODS
  Male Sprague Dawley (SD) rats received RFA or sham puncture with concomitant sorafenib (5mg/kg qd from day 2) or vehicle. Necrosis volume was calculated from resected specimens. Proliferation and micro vessel density were determined by Ki67 and CD31 immunofluorescence, respectively. mRNA expression of hepatocyte growth factor (HGF), epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) was quantified.
  
  
  RESULTS
  While ablation size was identical in all treatment groups at day 1, sorafenib treated animals showed sustained necroses (219 ± 24 vs. 88 ± 52 mm(3) in controls; P = 0.03), elevated alanine aminotransferase (ALT) and elevated glutamate dehydrogenase (GLDH) (76 ± 37 vs. 47 ± 58 mm(3); P=0.50) at day 3. By day 7 necrosis volumes equalized for the treatment groups. Ki67 and CD31 staining showed reduced proliferation and micro vessel density at days 1 and 3 following sorafenib. Growth factors HGF and EGF were significantly overexpressed in liver tissue after sorafenib.
  
  
  CONCLUSIONS
  Sorafenib initially promotes necrosis after RFA in liver tissue. The delay in tissue repair is overcome at day 7 presumably by transient compensatory overexpression of growth signals. Based on these data from animal studies further investigation of adjuvant sorafenib in humans is warranted.
authors: Department of Internal Medicine, Division of Gastroenterology & Hepatology, University Hospital Zurich, CH-8091 Zurich, Switzerland.
authors: Joachim C
authors: JC
authors: Mertens
authors: Ina V
authors: IV
authors: Martin
authors: Johannes
authors: J
authors: Schmitt
authors: Pascal
authors: P
authors: Frei
authors: Philipp
authors: P
authors: Bruners
authors: Christine
authors: C
authors: Herweg
authors: Andreas H
authors: AH
authors: Mahnken
authors: Beat
authors: B
authors: Müllhaupt
authors: Andreas
authors: A
authors: Geier