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      Skeletal Muscle Depletion Predicts the Prognosis of Patients with Hepatocellular Carcinoma Treated with Sorafenib

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          Abstract

          The aim of this study was to determine whether skeletal muscle depletion predicts the prognosis of patients with hepatocellular carcinoma (HCC) that is being treated with sorafenib. We evaluated 40 consecutive HCC patients who received sorafenib treatment. The skeletal muscle cross-sectional area was measured by computed tomography at the third lumbar vertebra (L3), from which the L3 skeletal muscle index (L3 SMI) was obtained. The factors contributing to overall survival, sorafenib dose reduction, and discontinuation of sorafenib were analyzed using the Cox proportional hazards model. L3 SMI ( p = 0.020) and log (α-fetoprotein (AFP)) ( p = 0.010) were identified as independent prognostic factors in HCC patients treated with sorafenib. The initial dose of sorafenib ( p = 0.008) was an independent risk factor for sorafenib dose reduction, and log (AFP) ( p = 0.008) was the only significant risk factor for the discontinuation of this drug. L3 SMI was not a risk factor for either dose reduction ( p = 0.423) or the discontinuation ( p = 0.132) of sorafenib. A multiple linear regression analysis determined the following relationship between skeletal muscle mass (assessed as L3 SMI) and the explanatory factors: L3 SMI = −0.1896 × (Age) − 10.3441 × (Child-Pugh score) − 9.3922 × (log (AFP)) + 1.6139 × (log (AFP)) × (Child-Pugh score) + 112.9166. Skeletal muscle depletion is inversely associated with age, Child-Pugh score, and log (AFP). Moreover, it is an independent prognostic factor for HCC patients treated with sorafenib.

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          Discovery and development of sorafenib: a multikinase inhibitor for treating cancer.

          Since the molecular revolution of the 1980s, knowledge of the aetiology of cancer has increased considerably, which has led to the discovery and development of targeted therapies tailored to inhibit cancer-specific pathways. The introduction and refinement of rapid, high-throughput screening technologies over the past decade has greatly facilitated this targeted discovery and development process. Here, we describe the discovery and continuing development of sorafenib (previously known as BAY 43-9006), the first oral multikinase inhibitor that targets Raf and affects tumour signalling and the tumour vasculature. The discovery cycle of sorafenib (Nexavar; Bayer Pharmaceuticals) - from initial screening for a lead compound to FDA approval for the treatment of advanced renal cell carcinoma in December 2005 - was completed in just 11 years, with approval being received approximately 5 years after the initiation of the first Phase I trial.
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            Prognostic staging system for hepatocellular carcinoma (CLIP score): its value and limitations, and a proposal for a new staging system, the Japan Integrated Staging Score (JIS score).

            A clinical staging system for cancer patients provides guidance for patient assessment and making therapeutic decisions. It is useful in deciding whether to treat a patient aggressively, and in avoiding the overtreatment of patients who would not tolerate the treatment or patients whose life expectancy rules out any chance of treatment. Clinical staging is also an essential tool for comparison between groups in therapeutic trials and for comparison between different studies. The current classifications most commonly used for hepatocellular carcinoma (HCC) are the Okuda stages, the Child-Pugh staging system, tumor node metastasis (TNM) staging, and the Cancer of the Liver Italian Program (CLIP) score. Among these, the CLIP score is currently the most commonly used integrated staging score, including both tumor stage and liver disease stage. Although the CLIP score has been well validated by many authors in terms of its prognostic value in HCC patients, this score has some problems and limitations when applied to currently diagnosed HCC patients, who are diagnosed in the early stage of disease. First, the CLIP score can discriminate score 0- to 3-patient populations, but it is not able to discriminate score 4- to 6-patient groups. Second, the definition of tumor morphology in the best prognostic group is too advanced, i.e., uninodular and a tumor extent of less than 50% of the liver. As a result, the prognosis of the CLIP system best prognostic group is not so good. In other words, this system cannot identify the best prognostic group who would benefit from curative and aggressive treatment. Third, nearly 80% of the patient population is classified as having a CLIP score of 0-2, as confirmed by many studies, which shows poor stratification ability. In contrast, a new staging system based on the Liver Cancer Study Group of Japan (LCSGJ), the Japan Integrated Staging (JIS) score is currently proposed in Japan. This staging system combines Child-Pugh grade (grade A, score 0; grade B, score 1; grade C, score 2) and TNM staging by the LCSGJ criteria (stage I, score 0; stage II, score 1; stage III, score 2; stage IV, score 3). The stratification ability of the JIS scoring system is much better than that of the CLIP scoring system. The JIS scoring system also performed better than the CLIP scoring system in selecting the best prognostic patient group. The cumulative 10-year survival rates of the best prognostic groups in the CLIP staging system (CLIP score 0) and JIS staging system (JIS score 0) were 23% and 65%, respectively (P < 0.01). All scoring systems arise as a compromise between simplicity and discriminatory ability. We confirmed that the JIS score increases predictive efficacy, while remaining simple compared with the CLIP score. Because the JIS score is quite easily obtained and is objective, we strongly propose it for widespread use as a prognostic staging system for HCC in clinical practice.
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              Sarcopenia impairs prognosis of patients with liver cirrhosis.

              Sarcopenia is characterized by the loss of skeletal muscle mass, and is reported to appear in patients with liver cirrhosis (LC). The aim of this study was to investigate the prevalence of sarcopenia in patients with LC, and to test the association between sarcopenia and patient outcomes. We also analyzed the effect of branched-chain amino acid (BCAA) supplementation on sarcopenic LC.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                28 April 2015
                May 2015
                : 16
                : 5
                : 9612-9624
                Affiliations
                Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan; E-Mails: koz@ 123456gifu-u.ac.jp (K.T.); hanai0606@ 123456yahoo.co.jp (T.H.); taka.mailbox.789@ 123456gmail.com (T.I.); tsunemiyazaking@ 123456yahoo.co.jp (T.M.); kottii924@ 123456gmail.com (T.K.); asue327@ 123456yahoo.co.jp (A.S.); mshiraki-gif@ 123456umin.ac.jp (M.S.); shimim-gif@ 123456umin.ac.jp (M.S.)
                Author notes
                [* ]Author to whom correspondence should be addressed; E-Mail: ikenji@ 123456gifu-u.ac.jp ; Tel.: +81-58-230-6308; Fax: +81-58-230-6310.
                Article
                ijms-16-09612
                10.3390/ijms16059612
                4463608
                25927582
                6db0a338-c52c-4fb0-898b-6524c6257180
                © 2015 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 03 February 2015
                : 22 April 2015
                Categories
                Article

                Molecular biology
                hepatocellular carcinoma,skeletal muscle depletion,sarcopenia,prognostic factor,sorafenib

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