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Abou-Alfa, G.K.,Puig, O.,Daniele, B.,Kudo, M.,Merle, P.,Park, J.W.,Ross, P.,Peron, J.M.,Ebert, O.,Chan, S.,Poon, T.P.,Colombo, M.,Okusaka, T.,Ryoo, B.Y.,Minguez, B.,Tanaka, T.,Ohtomo, T.,Ukrainskyj, S Elsevier Science Publishers 2016 Journal of hepatology Vol.65 No.2
<P>Background & Aims: Codrituzumab, a humanized monoclonal antibody against Glypican-3 (GPC3) that is expressed in hepatocellular carcinoma (HCC), interacts with CD16/FccRIIIa and triggers antibody-dependent cytotoxicity. Codrituzumab was studied vs. placebo in a randomized phase II trial in advanced HCC patients who had failed prior systemic therapy. Methods: Patients with advanced HCC who had failed prior systemic therapy, >= 18 years, Eastern cooperative oncology group (ECOG) 0-1, Child-Pugh A were randomized 2: 1 to biweekly codrituzumab 1600 mg vs. placebo. Patients were stratified based on GPC3 immunohistochemical expression: 2+/3+, 1+, and 0. Primary endpoint was progression free survival. Secondary endpoints include overall survival (OS), tolerability, pharmacokinetics, and an exploratory endpoint in biomarkers analysis. Results: 185 patients were enrolled: 125 received codrituzumab and 60 placebo: Median age 64/63, 85/75% male, 46/42% Asian, ECOG 0 65/63%, 74/77% having vascular invasion and/or extrahepatic metastasis. 84%/70% had prior sorafenib. Drug exposure was 98.4% of planned dose, with an identical adverse events profile between the 2 groups. The median progression free survival and overall survival in the codrituzumab vs. placebo groups in months were: 2.6 vs. 1.5 (hazard ratios 0.97, p = 0.87), and 8.7 vs. 10 (hazard ratios 0.96, p = 0.82). Projected Ctrough at cycle 3 day 1 based exposure, high CD16/FccRIIIa on peripheral immune cells, and GPC3 expression in the tumor, were all associated with prolonged progression free survival and overall survival. Conclusions: Codrituzumab did not show clinical benefit in this previously treated HCC population. Whether higher codrituzumab drug exposure or the use of CD16 and GPC3 as potential biomarkers would improve outcome remain unanswered questions. Lay summary: Codrituzumab is a manufactured antibody against a liver cancer protein called glypican-3. In this clinical trial, codrituzumab was not found be effective against liver cancer. It was suggested though that a higher dose of codrituzumab or selecting patients with high level of glypican-3 or its mediator CD16 might improve outcome. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.</P>
The fibrogenic process and the unleashing of acute-on-chronic liver failure
Guillermo Nahúm López-Sánchez,Mayra Dóminguez-Pérez,Misael Uribe,Natalia Nuño-Lámbarri 대한간학회 2020 Clinical and Molecular Hepatology(대한간학회지) Vol.26 No.1
Acute-on-chronic liver failure (ACLF) is a life-threatening condition characterized by a rapid deterioration of previously well-compensated chronic liver diseases. One of the main obstacles in ACLF is the lack of knowledge of the pathogenesis and specific broad-spectrum treatments. An excessive systemic inflammatory response has been proposed to explain the pathogenesis of ACLF; this hypothesis involves stellate cells, which are implicated in many liver homeostatic functions that include vitamin A storage, regulation of sinusoidal blood flow, local inflammation, maintenance of the hepatocyte phenotype and extracellular matrix remodeling. However, when there is damage to the liver, these cells are the main target of the inflammatory stimulus, as a result, the secretion of the extracellular matrix is altered. Activated hepatic stellate cells raise the survival of neutrophils by the stimulation of granulocytes colonies and macrophages, which exacerbates liver inflammation and promotes damage to hepatocytes. Elevation of pathogen-associated molecular patterns is related to liver damage by different pathophysiological mechanisms of decompensation, showing ballooning degeneration and cell death with a predominance of cholestatic infection. Moreover, patients with ACLF present a marked elevation of C-reactive protein together with an elevation of the leukocyte count. Chronic liver disease is a complex pathological state with a heterogeneous pathophysiology in which genetic factors of the host and external triggers interact and culminate in hepatic insufficiency. The better understanding of such interactions should lead to a better comprehension of the disease and to the discovery of new treatment targets that will make acute decompensations preventable and even decrease mortality.