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1.
J Hepatol ; 64(5): 1090-1098, 2016 05.
Article in English | MEDLINE | ID: mdl-26809111

ABSTRACT

BACKGROUND & AIMS: Transarterial chemoembolization with doxorubicin-eluting beads (DC Bead®; DEB-TACE) is effective in patients with Barcelona clinic liver cancer stage B hepatocellular carcinoma (HCC). The multikinase inhibitor sorafenib enhances overall survival (OS) and time-to-tumor progression (TTP) in patients with advanced HCC. This exploratory phase II trial tested the efficacy and safety of DEB-TACE plus sorafenib in patients with intermediate stage HCC. METHODS: Patients with intermediate stage multinodular HCC without macrovascular invasion (MVI) or extrahepatic spread (EHS) were randomized 1:1 to DEB-TACE (150 mg doxorubicin) plus sorafenib 400 mg twice daily or placebo. The primary endpoint was TTP by blinded central review. Secondary endpoints included time to MVI/EHS, OS, overall response rate (ORR) using modified response evaluation criteria in solid tumors, disease control rate (DCR), time to unTACEable progression (TTUP), and safety. RESULTS: Of 307 patients randomized, 154 received sorafenib and 153 received placebo. Median TTP for subjects receiving sorafenib plus DEB-TACE or placebo plus DEB-TACE was similar (169 vs. 166 days, respectively; hazard ratio (HR) 0.797, p=0.072). Median time to MVI/EHS (HR 0.621, p=0.076) and OS (HR 0.898, p=0.29) had not been reached. The ORRs for patients in the sorafenib and placebo groups with post-baseline scans were 55.9% and 41.3%, respectively, and the DCRs were 89.2% and 76.1%, respectively. TTUP was lower with sorafenib than with placebo (HR 1.586; 95% confidence intervals, 1.200-2.096; median 95 vs. 224 days). No unexpected adverse events related to sorafenib were observed. CONCLUSION: Sorafenib plus DEB-TACE was technically feasible, but the combination did not improve TTP in a clinically meaningful manner compared with DEB-TACE alone.


Subject(s)
Carcinoma, Hepatocellular/drug therapy , Chemoembolization, Therapeutic/methods , Doxorubicin/administration & dosage , Liver Neoplasms/drug therapy , Neoplasm Staging , Niacinamide/analogs & derivatives , Phenylurea Compounds/administration & dosage , Antineoplastic Agents/administration & dosage , Carcinoma, Hepatocellular/pathology , Double-Blind Method , Drug Carriers/administration & dosage , Female , Follow-Up Studies , Humans , Injections, Intra-Arterial , Liver Neoplasms/pathology , Male , Niacinamide/administration & dosage , Sorafenib , Time Factors , Treatment Outcome
3.
Hepatology ; 48(4): 1193-201, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18816630

ABSTRACT

UNLABELLED: Apelin is a peptide that plays an important role in heart physiology and pathophysiology, inflammation, and angiogenesis. We evaluated whether the endogenous apelin system is involved in the pathogenesis of the hepatic remodeling and cardiovascular and renal complications occurring in advanced liver disease. The circulating levels of apelin, the messenger RNA (mRNA) and protein expression of apelin and apelin receptor, the immunohistological detection of apelin and apelin receptor, and the effects induced by the chronic administration of an apelin receptor antagonist on fibrosis and vessel density were evaluated in rats with cirrhosis and ascites and in control rats. The serum levels of apelin in patients with cirrhosis were also measured. Apelin levels were higher in rats with cirrhosis than in controls. Apelin mRNA showed a four-fold rise only in hepatic tissue, but not in the lung, heart, or kidney of rats with cirrhosis. These animals also showed hepatic apelin receptor mRNA levels 300 times higher than controls. Apelin was highly expressed by stellate cells, whereas apelin receptor was overexpressed in the hepatic parenchyma of animals with cirrhosis. Rats with cirrhosis treated with the apelin receptor antagonist showed diminished hepatic fibrosis and vessel density, improved cardiovascular performance, and renal function and lost ascites. Human patients also showed a marked increase in apelin levels. CONCLUSION: The selective hepatic activation of the apelin system, together with the drop in fibrosis and neoangiogenesis and the improvement in cardiovascular and excretory function resulting from apelin receptor blockade, points to the hepatic apelin system as a novel therapeutic target in liver disease.


Subject(s)
Carrier Proteins/metabolism , Intercellular Signaling Peptides and Proteins/metabolism , Liver Cirrhosis/drug therapy , Liver Cirrhosis/metabolism , Liver/metabolism , Adult , Animals , Apelin , Blood Pressure/drug effects , Carbon Tetrachloride , Carrier Proteins/antagonists & inhibitors , Carrier Proteins/drug effects , Case-Control Studies , Disease Models, Animal , Female , Humans , Intercellular Signaling Peptides and Proteins/pharmacology , Intercellular Signaling Peptides and Proteins/therapeutic use , Liver Cirrhosis/chemically induced , Liver Cirrhosis/prevention & control , Male , Middle Aged , RNA, Messenger/metabolism , Rats , Rats, Wistar , Renin-Angiotensin System/physiology , Sympathetic Nervous System/physiology , Vascular Resistance/drug effects
4.
Hepatology ; 48(1): 204-13, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18508290

ABSTRACT

UNLABELLED: Hyponatremia in cirrhosis is associated with significant morbidity and mortality and complicates ascites management. Vasopressin receptor antagonists improve serum sodium concentration by increasing renal solute-free water excretion, but their effects on the management of ascites have not been assessed. Our aim was to investigate the effects of satavaptan, a highly selective vasopressin V(2) receptor antagonist, on ascites management and serum sodium in hyponatremic patients with cirrhosis. A total of 110 patients with cirrhosis, ascites, and hyponatremia (serum sodium < or =130 mmol/L) were included in a multicenter, double-blind, randomized, controlled study comparing three fixed doses of satavaptan (5 mg, 12.5 mg, or 25 mg once daily) versus placebo. Duration of treatment was 14 days and all patients received spironolactone at 100 mg/day. Satavaptan treatment was associated with improved control of ascites, as indicated by a reduction in body weight (mean change at Day 14 was +0.49 kg [+/-4.99] for placebo versus +0.15 kg [+/-4.23], -1.59 kg [+/-4.60] and -1.68 kg [+/-4.98] for the 5 mg, 12.5 mg, and 25 mg doses, respectively; P = 0.05 for a dose-effect relationship overall) and a parallel reduction in abdominal girth. This beneficial effect on ascites was associated with improvements in serum sodium (mean change from baseline to day 5 was 1.3 +/- 4.2, 4.5 +/- 3.5, 4.5 +/- 4.8, and 6.6 +/- 4.3 mmol/L for the placebo group and the groups on satavaptan at 5 mg, 12.5 mg, and 25 mg/day, respectively; P < 0.01 for all compared to placebo). Thirst was significantly more common in patients treated with satavaptan compared to those treated with placebo, whereas the frequency of other adverse events was similar among groups. CONCLUSION: The V(2) receptor antagonist satavaptan improves the control of ascites and increases serum sodium in patients with cirrhosis, ascites, and hyponatremia under diuretic treatment.


Subject(s)
Antidiuretic Hormone Receptor Antagonists , Ascites/drug therapy , Diuretics/therapeutic use , Hyponatremia/drug therapy , Liver Cirrhosis/complications , Morpholines/therapeutic use , Sodium/blood , Spiro Compounds/therapeutic use , Aged , Ascites/etiology , Blood Circulation/drug effects , Dose-Response Relationship, Drug , Double-Blind Method , Female , Humans , Hyponatremia/blood , Hyponatremia/etiology , Hyponatremia/physiopathology , Kidney/physiopathology , Male , Middle Aged , Morpholines/administration & dosage , Morpholines/adverse effects , Renin-Angiotensin System/drug effects , Spiro Compounds/administration & dosage , Spiro Compounds/adverse effects , Treatment Outcome
5.
Gastroenterology ; 123(6): 1839-47, 2002 Dec.
Article in English | MEDLINE | ID: mdl-12454841

ABSTRACT

BACKGROUND & AIMS: The transjugular intrahepatic portosystemic shunt (TIPS) has been shown to be more effective than repeated paracentesis plus albumin in the control of refractory ascites. However, its effect on survival and healthcare costs is still uncertain. METHODS: Seventy patients with cirrhosis and refractory ascites were randomly assigned to TIPS (35 patients) or repeated paracentesis plus intravenous albumin (35 patients). The primary endpoint was survival without liver transplantation. Secondary endpoints were complications of cirrhosis and costs. RESULTS: Twenty patients treated with TIPS and 18 treated with paracentesis died during the study period, whereas 7 patients in each group underwent liver transplantation (mean follow-up 282 +/- 43 vs. 325 +/- 61 days, respectively). The probability of survival without liver transplantation was 41% at 1 year and 26% at 2 years in the TIPS group, as compared with 35% and 30% in the paracentesis group (P = 0.51). In a multivariate analysis, only baseline blood urea nitrogen levels and Child-Pugh score were independently associated with survival. Recurrence of ascites and development of hepatorenal syndrome were lower in the TIPS group compared with the paracentesis group, whereas the frequency of severe hepatic encephalopathy was greater in the TIPS group. The calculated costs were higher in the TIPS group than in the paracentesis group. CONCLUSIONS: In patients with refractory ascites, TIPS lowers the rate of ascites recurrence and the risk of developing hepatorenal syndrome. However, TIPS does not improve survival and is associated with an increased frequency of severe encephalopathy and higher costs compared with repeated paracentesis plus albumin.


Subject(s)
Ascites/etiology , Liver Cirrhosis/therapy , Paracentesis , Portasystemic Shunt, Transjugular Intrahepatic , Serum Albumin/therapeutic use , Bacterial Infections , Female , Gastrointestinal Hemorrhage/etiology , Hepatic Encephalopathy/physiopathology , Hormones/blood , Humans , Injections, Intravenous , Kidney/physiopathology , Liver/physiopathology , Liver Cirrhosis/blood , Liver Cirrhosis/complications , Liver Cirrhosis/physiopathology , Male , Middle Aged , Peritonitis/complications , Peritonitis/microbiology , Retreatment , Serum Albumin/administration & dosage , Severity of Illness Index , Survival Analysis
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