ABSTRACT
BACKGROUND: Recombinant human soluble thrombomodulin (rTM) protects against disseminated intravascular coagulopathy by inhibiting coagulation, inflammation, and apoptosis. This study tests the hypothesis that rTM is hepatoprotective after extensive hepatectomy (Hx) and investigates the mechanisms underlying this effect. MATERIALS AND METHODS: Experiment 1: rats (15 per group) were injected with rTM (1.0 or 2.0 mg/kg) or saline just before 95% Hx and their 7-d survival assessed. Experiment 2: rats were assigned to either a treated (2.0 mg/kg rTM just before Hx) or control group (n = 5 per group). Five rats per group were euthanized immediately after surgery, and at 1, 3, 6, 12, and 24 h postoperatively; serum and liver remnant samples were collected for biochemical and histologic analysis, as well as reverse-transcription polymerase chain reaction and Western blotting. RESULTS: All saline-injected rats died within 52 h of Hx, whereas injection of 2.0 mg/kg rTM prolonged survival (P = 0.003). rTM increased the number of Ki67-positive cells and reduced the number of terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive cells. The number of myeloperoxidase-positive cells and the expression of high-mobility group box 1 protein did not differ. Reverse-transcription polymerase chain reaction revealed that rTM significantly enhanced protease-activated receptor-1 and sphingosine kinase 1 messenger RNA expression and significantly reduced plasminogen activator inhibitor-1 and Bax messenger RNA expression. Immunohistochemistry and Western blotting demonstrated that protease-activated receptor-1 expression 24 h after Hx was significantly higher in rTM-treated than in control rats. CONCLUSIONS: rTM may improve survival after extensive Hx by inhibiting apoptosis and promoting liver regeneration.
Subject(s)
Hepatectomy/adverse effects , Liver Failure/prevention & control , Liver Regeneration/drug effects , Postoperative Complications/prevention & control , Thrombomodulin/therapeutic use , Alanine Transaminase/blood , Animals , Apoptosis/drug effects , Blotting, Western , Drug Evaluation, Preclinical , Hepatectomy/mortality , Hepatocytes/drug effects , Immunohistochemistry , Liver Failure/etiology , Male , Postoperative Complications/etiology , Rats, Wistar , Receptor, PAR-1/metabolism , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
BACKGROUND AND AIM: Advanced hepatocellular carcinoma (HCC) with portal vein invasion or intrahepatic metastases has an unfavorable prognosis, even after curative hepatic resection. The aim of the present study was to evaluate the efficacy of adjuvant hepatic arterial infusion chemotherapy with 5-fluorouracil (5-FU) and systemic interferon (IFN). PATIENTS AND METHODS: Patients who were diagnosed as having HCC with portal vein invasion or intrahepatic metastases were included in the study (n=33). Out of these patients, 16 were treated with adjuvant therapy consisting of continuous arterial infusion of 5-FU and subcutaneous injection of IFN-α. Another 17 patients who underwent hepatic resection without adjuvant chemotherapy served as controls. RESULTS: The five-year cumulative survival rate was significantly higher in the adjuvant treatment group (71.1%) than in the control group (44.0%; p=0.023). The rate of patients with multiple (≥4) recurrent intrahepatic nodules was significantly lower in the adjuvant group (44.4%) than in the control group (100%; p=0.040). The development of intrahepatic recurrence within 12 months was significantly lower in the adjuvant group (33.3%) than in the control group (80.0%; p=0.040). CONCLUSION: Our data suggest that this adjuvant chemotherapy can improve postoperative prognosis by reducing intrahepatic recurrence.
Subject(s)
Antimetabolites, Antineoplastic/administration & dosage , Carcinoma, Hepatocellular/drug therapy , Fluorouracil/administration & dosage , Hepatic Artery , Interferons/administration & dosage , Liver Neoplasms/drug therapy , Aged , Antimetabolites, Antineoplastic/therapeutic use , Carcinoma, Hepatocellular/surgery , Combined Modality Therapy , Female , Fluorouracil/therapeutic use , Humans , Infusions, Intra-Arterial , Interferons/therapeutic use , Liver Neoplasms/surgery , Male , Middle Aged , Survival AnalysisABSTRACT
A58-year-old man with upper abdominal pain had a duodenal perforation and a huge hepatocellular carcinoma (BCC). Atumor embolism in the main portal vein was also seen. Extended right lobectomy against a huge tumor in right lobe and ethanol injection to a tumor in the lateral segment were performed. In addition, fluorouracil arterial infusion and interferon therapy(FAIT)were carried out. He has been for 4 years and 6 months without recurrence. Although prognosis of patients with a huge BCC is miserable even if curative hepatic resection is performed, it may be possible for adjuvant FAIT to suppress the recurrence after hepatic resection for huge BCC.