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Aim Des-γ-carboxyprothrombin ( DCP) is known to be increased by the use of sorafenib for the treatment of hepatocellular carcinoma ( HCC), despite its therapeutic efficacy. In addition to the tumor progression, hypoxia that impairs vitamin K uptake is known to induce DCP and this mechanism may explain DCP elevation by sorafenib. In this study, we tried to evaluate the effect of sorafenib treatment using a new marker, NX-DCP, which is specific to vitamin K absence. Methods Serum DCP and NX-DCP were measured in 50 consecutive HCC patients before and 1 week after starting sorafenib, and compared with the treatment effect using the modified Response Evaluation Criteria in Solid Tumors guidelines. Results DCP and NX-DCP increased 1.58- (median, range 0.21-28.7) and 1.20-fold (median, range 0.41-14.2) after the administration of sorafenib, respectively. The increases of both markers were less than twofold in approximately half of the patients (low-elevation group). However, 12 patients showed over twofold increase of both DCP and NX-DCP (double-elevation group), and eight patients showed over twofold increase of DCP alone ( DCP-elevation group). The disease control rate ( DCR) of the DCP-elevation group (12.5%) was significantly lower than those of the double-elevation group (75.0%, P = 0.020) and the low-elevation group (60.0%, P = 0.042). Progression-free survival ( PFS) was significantly shorter in the DCP-elevation group than in the double-elevation group ( P = 0.006) and the low-elevation group ( P = 0.001). Conclusion NX-DCP in combination with DCP could be a useful biomarker of sorafenib treatment for advanced HCC. [ABSTRACT FROM AUTHOR]

Aim Oxidative stress is associated with progression of chronic liver disease ( CLD). This association is best established in chronic hepatitis C. However, the anti-oxidative state is not well characterized. The objective of the present study was to investigate the balance of oxidative and anti-oxidative stress in CLD patients. Methods We recruited a study population of 208 patients, including healthy volunteers ( HV; n = 15), patients with hepatitis B virus ( HBV)-related CLD without or with hepatocellular carcinoma ( HBV-non- HCC, n = 25, and HBV-HCC, n = 50, respectively), and patients with hepatitis C virus ( HCV)-related CLD without or with HCC ( HCV-non- HCC, n = 49, and HCV-HCC, n = 69, respectively). Serum levels of reactive oxygen metabolites ( ROM) and anti-oxidative markers ( OXY-adsorbent test; OXY) were determined, and the balance of these values was used as the oxidative index. Correlations among ROM, OXY, oxidative index and clinical characteristics were investigated. Results Patients with CLD exhibited elevated ROM and oxidative index compared to HV. Among patients with CLD, HCV positive status correlated with increased ROM. In CLD, HCV-HCC patients exhibited the highest ROM levels. Among HCV-related CLD patients, lower OXY correlated with HCC positive status, but was recovered by eradication of HCC. In HCV-HCC, lower OXY correlated with high PT-INR. Conclusion HCV positive CLD patients displayed higher oxidative stress and HCV-HCC patients displayed lower anti-oxidative state. Anti-oxidative state depression was associated with liver reservoir-related data in HCV-HCC and could be reversed with HCC eradication. [ABSTRACT FROM AUTHOR]

Background and Aim Follistatin ( FST) is a glycoprotein expressed in most organs, which interacts with activins or other members of the transforming growth factor beta family. Recently, several reports have shown that FST regulates a variety of processes during tumor progression. Here, serum FST in patients with liver diseases was measured, and its clinical utility as a biomarker was assessed. Methods Serum was collected from 162 patients (91 hepatocellular carcinoma [ HCC], 43 liver cirrhosis, and 28 chronic hepatitis) as well as from 16 healthy volunteers. FST was quantified by enzyme-linked immunosorbent assays, and levels were compared with clinical parameters including survival of the HCC patients. Results Median serum FST levels in HCC, liver cirrhosis, chronic hepatitis, and healthy volunteers were 1168, 1606, 1324, and 1661 pg/m L, respectively, not significantly different. In HCC patients, higher serum FST was associated with greater age, hepatitis C virus antibody-negativity, large tumor size, g-glutamyl transpeptidase, des-gamma carboxyprothrombin and presence of portal vein tumor thrombus. Survival of HCC patients with high FST levels was significantly shorter than for those with low levels ( P = 0.004). Multivariate analysis revealed that in addition to large tumor size and presence of portal vein thrombus, high FST levels were independently correlated with poor prognosis (hazard ratio = 2.41, 95% confidence interval = 1.16-5.00, P = 0.02). Conclusions Serum FST levels are significantly associated with HCC prognosis and could represent a predictive biomarker in this disease. [ABSTRACT FROM AUTHOR]

Aim: Hepatocellular carcinoma (HCC) is a common clinical problem all over the world. Fucosylated hemopexin (Fuc-Hpx) is a newly reported glycoprotein for the diagnosis of HCC, however, its clinical implications are unclear. The aim of this study was to elucidate the clinical utility of Fuc-Hpx in Japanese patients with HCC. Methods: The sera from 331 HCC patients, 45 with liver cirrhosis (LC), 85 with chronic hepatitis (CH) and 22 healthy people were examined for the expression of Fuc-Hpx; the level was compared with clinical parameters as well as hemopexin (Hpx) expression. The expressions of Fuc-Hpx in 12 HCC tissues and corresponding adjacent non-cancerous liver tissues were also examined. Results: No correlation was observed between Hpx and Fuc-Hpx level. The median Fuc-Hpx levels in healthy people and CH, LC and HCC patients were 3.8, 3.7, 6.1 and 7.6 AU/mL, respectively (CH vs LC, P = 0.002; CH vs HCC, P < 0.001; LC vs HCC, P = 0.02). Multivariate analysis revealed that low albumin, low prothrombin time and the presence of HCC were significantly correlated with high Fuc-Hpx ( P = 0.013, =0.001 and <0.001, respectively). Among the HCC patients, albumin was correlated with high Fuc-Hpx; however, none of the tumor factors, such as tumor size, tumor number and tumor stage, was correlated with Fuc-Hpx level. The expression of Fuc-Hpx in cancer tissue was not different from that in non-cancerous tissue. Conclusion: Fuc-Hpx is a valuable biomarker for HCC but it might be a marker for hypercarcinogenic liver rather than a marker for tumor-bearing liver. [ABSTRACT FROM AUTHOR]

Backgroud and Aim: Chronic hepatitis C virus (HCV) infection is a well known risk factor for hepatocellular carcinoma (HCC). The aim of this study is to elucidate the genetic risk of development and recurrence of HCC in patients with HCV. Methods: A total of 468 patients with HCV, including 265 with HCC were enrolled. We genotyped 88 single nucleotide polymorphisms (SNPs) in 81 genes expected to influence hepatocarcinogenesis using the iPLEX assay. Risk of HCC was clarified by stratifying patients into risk groups based on the multiplied odds ratio (MOR) for SNPs associated with HCC, and the cumulative effects on the development and recurrence of HCC were analyzed. Results: Six SNPs associated with risk of HCC were identified (OR range: 0.29-1.76). These included novel SNPs for hepatocarcinogenesis with HCV CCND2 rs1049606, RAD23B rs1805329, CEP164 rs573455, and GRP78rs430397 in addition to the known SNPs MDM2 rs2279744 and ALDH2 rs671. MOR analysis revealed that the highest risk group exerted about a 19-fold higher relative OR compared with the lowest risk group ( P = 1.08 × 10−5). Predicted 10-year HCC risk ranged from 1.7% to 96% depending on the risk group and the extent of fibrosis. Recurrence-free survival of radiofrequency ablation-treated HCC in the high risk group ( n = 53) was lower than that of low risk group ( n = 58, P = 0.038). Conclusion: Single nucleotide polymorphisms of CCND2, RAD23B, GRP78, CEP164, MDM2, and ALDH2 genes were significantly associated with development and recurrence of HCC in Japanese patients with HCV. [ABSTRACT FROM AUTHOR]

Background and Aim: Sorafenib, the first agent demonstrated to have efficacy to improve the survival of patients with advanced hepatocellular carcinoma (HCC), is an active multikinase inhibitor affecting angiogenesis and tumor proliferation. We analyzed cytokines related to angiogenesis or cell proliferation, and tried to determine their utility as biomarkers of sorafenib treatment effect for HCC. Methods: Nine serum cytokines (angiopoietin-2 [Ang-2], follistatin, granulocyte colony-stimulating factor [G-CSF], hepatocyte growth factor [HGF], interleukin-8 [IL-8], leptin, platelet-derived growth factor-BB, platelet endothelial cell adhesion molecule-1, and vascular endothelial growth factor) were measured in 30 HCC patients treated with sorafenib, and the effects of treatment were compared using modified Response Evaluation Criteria in Solid Tumors. Results: All but IL-8 were significantly higher at baseline in patients with progressive disease. Progression-free survival was significantly shorter in patients with high levels of Ang-2, G-CSF, HGF, and leptin, and the hazard ratios were 2.51, 6.89, 2.55, and 4.14, respectively. As the number of cytokines at a high level increased, the treatment response deteriorated. Disease progression was seen in three of 12 (25.0%) patients with zero to two high biomarkers, two of six (33.3%) patients with 3-5 high biomarkers, and 10 of 12 (83.3%) patients with six to eight high biomarkers ( P = 0.008). The prognosis of all patients with eight high biomarkers was progressive disease. Conclusion: High levels of serum cytokines at baseline were correlated with poor effects of sorafenib treatment in patients with HCC. [ABSTRACT FROM AUTHOR]