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Aim: In Japan, transcatheter arterial chemoembolization (TACE) refractoriness for hepatocellular carcinoma has been defined as an insufficient therapeutic effect after ≥2 procedures. Insufficient TACE for intrahepatic lesions is defined as the presence of > 50% viable lesions (ineffective) or an increase in their number (progressive). This study aimed to examine the possibility of earlier evaluation of TACE refractoriness. Methods: Patients who underwent TACE for hepatocellular carcinomas > 3 cm in size or with > 3 nodules at our hospital between 2010 and 2014 were analyzed. The cases assessed as TACE insufficient for the first time were divided into 2 groups: the “either” group, evaluated as either “ineffective” or “progressive,” and the “both” group, that is, both “ineffective” and “progressive.” Results: The study participants included 40 of 212 consecutive patients who underwent TACE, divided into the either (n = 23) and both (n = 17) groups. Seventeen of 23 (73.9%) patients in the either group and all 17 (100%) in the both group had TACE refractoriness (p = 0.0295). Conclusions: Patients with both “ineffective” and “progressive” lesions are extremely likely to be TACE ­refractory at a significantly higher frequency than are those with either condition. Thus, when both of these factors are observed, switching to other therapies should be considered. [ABSTRACT FROM AUTHOR]

Aim Some patients with non-alcoholic fatty liver disease ( NAFLD) develop hepatocellular carcinoma ( HCC) and have higher mortality than others. The evidence causally linking NAFLD to extrahepatic malignancies is scarce. Our aim was to determine the incidence of and risk factors for HCC, extrahepatic cancer and mortality in Japanese patients with biopsy-proven NAFLD. Methods This retrospective cohort study analyzed outcomes including onset of malignant tumors and death in 312 patients with NAFLD diagnosed by liver biopsy. Results Of 312 patients, 176 (56.4%) were diagnosed with non-alcoholic steatohepatitis. During a median follow-up period of 4.8 years (range, 0.3-15.8), six patients (1.9%) developed HCC, and 20 (6.4%) developed extrahepatic cancer. Multivariate analysis identified fibrosis stage (≥3; hazard ratio [ HR], 12.3; 95% confidence interval [ CI], 1.11-136.0; P = 0.041) as a predictor for HCC and type IV collagen 7s (>5 ng/mL; HR, 1.74; 95% CI, 1.08-2.79; P = 0.022) as a predictor for extrahepatic cancer. Eight patients (2.6%) died during the follow-up period. The most common cause of death was extrahepatic malignancy. None died of cardiovascular disease. Multivariate analysis identified type IV collagen 7s (>5 ng/mL; HR, 3.38; 95% CI, 1.17-9.76; P = 0.024) as a predictor for mortality. Conclusion The incidence of extrahepatic cancer was higher than that of HCC. Severe fibrosis was a predictor for HCC. Patients with NAFLD and elevated type IV collagen 7s levels are at increased risk for extrahepatic cancer and overall mortality. [ABSTRACT FROM AUTHOR]

Aim Sorafenib is the standard systemic therapy for patients with advanced hepatocellular carcinoma ( HCC). We aimed to assess the efficacy and safety of sorafenib therapy in very elderly patients aged 80 years and older with advanced HCC. Methods In a retrospective multicenter study in Japan, we reviewed 185 patients (median age, 71 years; 82% male; 95% Child-Pugh class A) with advanced HCC who received sorafenib therapy. Data were compared between 24 (13%) patients aged 80 years and older and 161 (87%) patients aged less than 80 years. We used propensity score matching to adjust for differences between the two groups. Results Median overall survival was 10.6 months in all patients: 11.7 months in patients aged 80 years and older and 10.5 months in those aged less than 80 years. There were no significant differences in overall survival, tumor response, and frequency and severity of drug-related adverse events between patients aged 80 years and older and those aged less than 80 years in both the entire study cohort and the propensity-matched cohort. Conclusion Sorafenib may be effective and well tolerated, even in patients with advanced HCC who are aged 80 years and older, as well as those aged less than 80 years. [ABSTRACT FROM AUTHOR]

Background: Oxidative stress (OS) plays an important role in the progression of chronic liver disease and hepatocarcinogenesis. However, the role of OS in the progression of hepatocellular carcinoma (HCC) is unclear. The aim of this study was to assess whether OS promotes angiogenesis in HCC. Methods: The expressions of vascular endothelial growth factor (VEGF), VEGF receptor2 (VEGFR2), and phosphorylated Akt were assessed, and microvessel density (MVD) and the cancer-associated fibroblast (CAF) population were examined by immunohistological staining in 55 HCC samples. The OS level in these tissues was assessed using 8-hydroxy-2′-deoxyguanosine (8-OHdG) and 4-hydroxy-2-nonenal (4-HNE) immunostaining, and an 8-OHdG enzyme-linked immunosorbent assay (ELISA). The expression and activation of angiogenic factors and the effect of growth stimulation of human umbilical vein endothelial cells (HUVECs) were also assessed in vitro, using HLE hepatoma-derived cells and conditioned medium with or without treatment with hydrogen peroxide (HO); a phosphoinositide 3-kinase (PI3K) inhibitor, wortmannin ; and an anti-oxidative agent, N-acetyl- l-cysteine (NAC). Results: A higher OS grade was significantly associated with higher MVD, VEGF expression, Akt activity , and OS grade of CAFs, but not with the percentage of the CAFpopulation in HCC tissues. Additionally, cancer cells constituted a major population of OS marker-positive cells in HCC tissues. In vitro, HO treatment induced up-regulation of VEGF at both the mRNA and protein levels, activated Akt, and resulted in the proliferation of HUVECs; the addition of wortmannin and NAC counteracted the effects of OS. Conclusions: OS enhances the malignant potential of HCC through the stimulation of angiogenesis by activation of the Akt-VEGF pathway. [ABSTRACT FROM AUTHOR]

Aim: Deregulation of E2F1 transcriptional activity is observed in a variety of cancers, including hepatocellular carcinoma (HCC). The aim of the present study is to identify transcriptional target genes of E2F1 in HCC. Methods: We determined expression levels for E2F1 and ten candidate genes thought to be targets of E2F1 in primary HCCs using a real-time quantitative reverse transcription-PCR assay. Following small interfering RNA (siRNA)-mediated knockdown of E2F1 in HCC cell lines, we quantified mRNA levels of the candidate E2F1 target genes. Results: E2F1 was significantly over-expressed in 41 primary HCCs as compared to non-tumorous liver tissues. Among the candidates, MYBL2, whose product is the transcriptional factor B-Myb, which is involved in controlling cell-cycle progression and apoptosis, was significantly over-expressed in primary HCCs. Additionally, expression levels of MYBL2 correlated with those of E2F1. Knockdown of E2F1 resulted in a decrease in expression of MYBL2. A copy-number gain for MYBL2 was observed in 36 of 66 primary HCCs, suggesting that MYBL2 expression is up-regulated by amplification in addition to being regulated by E2F1. Moreover, siRNA-mediated knockdown of MYBL2 led to reduced expression of CDC2 (which encodes CDC2), cyclin A2 ( CCNA2), and topoisomerase II α ( TOP2A), implicating these genes in the cell cycle and suggesting that they may be downstream targets of B-Myb. Conclusion: MYBL2 is a probable transcriptional target of E2F1 in HCC and may therefore be a useful biomarker for diagnosis and an attractive target for molecular therapies useful to treat HCC. [ABSTRACT FROM AUTHOR]

The risk factors associated with poor prognosis of nonalcoholic fatty liver disease (NAFLD) are not fully understood. Our aim was to assess the role of progressive hepatocellular telomere shortening in the clinical course of NAFLD. Methods: We measured average telomere lengths in liver tissue samples from 44 patients with NAFLD by quantitative fluorescence in situ hybridization using a telomere-specific probe. Patients in which telomeres measured at least 80% of the lengths of age-matched controls were categorized as group A. Those patients with telomeres measuring less than 80% of the control lengths formed group B. Results: Within group B, some samples showed a remarkable shortening of hepatocyte telomeres in younger patients, whereas some group A patients showed almost normal telomere lengths until their seventies. Among clinicopathological factors, body mass index (BMI), homeostasis model assessment insulin resistance (HOMA-IR), histological degree of steatosis and intensity of 8-hydroxy-2′-deoxyguanosine (8-OHdG) immunostaining were all significantly higher in group B than in group A. Ki-67 immunohistochemistry demonstrated that group B liver tissues were significantly less proliferative than those from group A, despite no significant difference in the necroinflammatory activities of group A and B samples. In group B patients, the ratios of Ki-67 positive index to alanine aminotransferase value were significantly lower than group A. Conclusions: Greater insulin resistance can result in more severe hepatic steatosis among group B patients, leading to an overproduction of reactive oxygen species, which may accelerate telomere erosion. Furthermore the regenerative response of hepatocytes with prominent telomere shortening may be impaired, making these cells vulnerable to the effect of a ‘second-hit’ insult. [ABSTRACT FROM AUTHOR]

Takashima H, Nakajima T, Moriguchi M, Sekoguchi S, Nishikawa T, Watanabe T, Katagishi T, Kimura H, Minami M, Itoh Y, Kagawa K, Okanoue T.In vivoexpression patterns of survivin and its splicing variants in chronic liver disease and hepatocellular carcinoma.Liver International: DOI: 10.1111/j.1478-3231.2004.0979.x.© Blackwell Munksgaard 2004Our aim was to clarify the significance of expression levels and post-transcriptional splicing patterns of survivin during multistep hepatocarcinogenesis and tumor progression.Using immunohistochemistry, we first elucidated the expression of survivin protein in tissues of hepatocellular carcinoma (HCC) and the adjacent non-cancerous tissues. Furthermore, we investigated survivin gene expression patterns in these tissues.Survivin protein was expressed not only in most HCC tissues but also in some cirrhotic nodules. In non-cancerous regions, the levels of survivin mRNA increased in proportion to their stage of progression. Survivin protein was expressed mainly in periportal areas, where proliferating cells were localized. In HCC, mRNA levels of survivin and survivinΔEx3 correlated with high proliferative activity, whereas the levels of surviving 2B did not.These findings of mRNA and protein expressions of survivin in chronically injured avers indicate that it has an important role in hepatocarcinogenesis. A lack of correlation between proliferative activity and survivin 2B mRNA levels in HCC is suggestive of a previous hypothesis that this variant decreases sruvivin function in a dominan negative manner. Thus, our data suggest different functions of these splicing variants and their important roles in tumor progression. [ABSTRACT FROM AUTHOR]

The development of hepatocellular carcinoma (HCC) was significantly reduced in both sustained responders (SR) and transient biochemical responders (TR) in chronic hepatitis C (CH-C) patients who received interferon (IFN) therapy. However, the long-term clinical outcome of TR remains unclear. One thousand three hundred and seventy CH-C Japanese patients who received IFN therapy and 54 control cirrhotic patients were enrolled. TR were defined as those patients who showed a normal serum alanine aminotransferase level (≦30 IU/l) at the end of therapy and then relapsed. Mean follow-up period was 5.6 years (6.1 years in 48 cirrhotic patients) in the IFN group and 8.3 years in the 54 control cirrhotic patients. HCC was detected in 114 patients in the IFN group among whom 4 were in the 425 SR, 21 were in the 359 TR and 89 were in the 586 non-responders (NR). The cumulative incidence of HCC was significantly (P=0.0001) inhibited in both SR and TR compared with NR. Its inhibitory effect in TR was within 5 years. Platelet count did not significantly decrease for 2–4 years after IFN therapy in TR, but it significantly decreased in NR 2 years after IFN therapy. The cumulative survival in both SR and TR was significantly higher than NR (SR vs NR; P=0.0001, TR vs NR; P=0.0305). These results indicate that IFN therapy lowers the rate of the progression of HCC and improves the long-term survival even in CH-C patients who transiently respond to IFN therapy. [Copyright &y& Elsevier]

Abstract: P300 impacts the transcription of several genes involved in biological behavior of human malignancies including hepatocellular carcinomas (HCC). We found p300 is highly expressed in 47% of surgically resected HCC specimens by immunohistochemistry, which correlated with advanced TNM staging (P =0.034), vascular invasion (P =0.036), intrahepatic metastasis (P =0.001) and shortened overall survival (P =0.028). In vitro study, knocking down of p300 expression in hepatoma cells recovered E-cadherin expression, inhibited the translocation of beta (β)-catenin into the nuclei, decreased cyclin D1 activity and suppressed the migration/invasion of HCC cells. Furthermore, suppression of p300 led to down-regulation of epithelial-mesenchymal transition (EMT)-related molecules such as Snail, Twist and HIF-1 alpha. These observations suggest that p300 contributes to the EMT-related progression of HCCs. [Copyright &y& Elsevier]

Abstract: DNA copy number aberrations in human hepatocellular carcinoma (HCC) cell lines were investigated using a high-density oligonucleotide microarray, and a novel amplification at the chromosomal region 7q21 was detected. Molecular definition of the amplicon indicated that PEG10 (paternally expressed gene 10), a paternally expressed imprinted gene, was amplified together with CDK14 (cyclin-dependent kinase 14; previously PFTAIRE protein kinase 1, PFTK1) and CDK6 (cyclin-dependent kinase 6). An increase in PEG10 copy number was detected in 14 of 34 primary HCC tumors (41%). PEG10, but not CDK14 or CDK6, was significantly overexpressed in 30 of 41 tumors (73%) from HCC patients, compared with their nontumorous counterparts. These results suggest that PEG10 is a probable target, acting as a driving force for amplification of the 7q21 region, and may therefore be involved in the development or progression of HCCs. [Copyright &y& Elsevier]

Abstract: RhoA, a member of the Rho family of small GTPases, directs the organization of the actin cytoskeleton and is involved in regulating cell shape and movement. Its activity is negatively regulated by p190-B RhoGAP (GTPase-activating protein). We investigated DNA copy number aberrations in human hepatocellular carcinoma and esophageal squamous cell carcinoma cell lines using a high-density oligonucleotide microarray and found a novel amplification at chromosomal region 14q12. We identified ARHGAP5 (the gene encoding p190-B RhoGAP) as a probable target for the amplification at 14q12, and our results showed that p190-B RhoGAP promotes cells spreading and migration by negatively regulating RhoA activity in Huh-7 hepatocellular carcinoma cells. [Copyright &y& Elsevier]

Abstract: High-density single nucleotide polymorphism (SNP) array analysis revealed novel amplification at 1q21 in cell lines derived from hepatocellular carcinomas (HCCs). Fluorescence in situ hybridization and real-time quantitative polymerase chain reaction studies verified amplification at 1q21. An increase in copy number at the region was detected in 32 of the 36 primary HCC tumors (89%). To identify the targets for amplification, we examined 19 HCC cell lines for expression levels of all 26 genes located within the 700-kb amplified region. Five genes were overexpressed in cell lines with amplification at 1q21. Among these, CREB3L4 (cAMP responsive element binding protein 3-like 4), INTS3 (integrator complex subunit 3), and SNAPAP (SNAP-associated protein) were significantly overexpressed in tumors from 18 HCC patients, compared with counterpart nontumorous tissues. The findings suggest that CREB3L4, INTS3, and SNAPAP are probable targets for the amplification mechanism and may therefore be involved, together or separately, in the development or progression of HCCs. [Copyright &y& Elsevier]