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Sample records for human hepatocellular liver

  1. Liver cancer - hepatocellular carcinoma

    Science.gov (United States)

    Primary liver cell carcinoma; Tumor - liver; Cancer - liver; Hepatoma ... Hepatocellular carcinoma accounts for most liver cancers. This type of cancer occurs more often in men than women. It is usually diagnosed in people age 50 or ...

  2. Effects of recombinant human growth hormone on remnant liver after hepatectomy in hepatocellular carcinoma with cirrhosis

    Institute of Scientific and Technical Information of China (English)

    Shi-Min Luo; Li-Jian Liang; Jia-Ming Lai

    2004-01-01

    AIM: To explore the effects of recombinant human growth hormone (rhGH) on the remnant liver after hepatectomy in hepatocellular carcinoma with liver cirrhosis.METHODS: Twenty-four patients with hepatocellular carcinoma who underwent hepatectomy were randomly divided into 2groups: parenteral nutrition (PN) group (n=12) and rhGH+PN group (n=12). Liver function, blood glucose, AFP, serum prealbumin and transferrin were detected before operation,at post-operative d 1 and d 6. Albumin (ALB) mRNA in liver biopsy specimens was detected by RT-PCR at post-operative d 6. Liver Ki67 immunohistochemical staining was studied.RESULTS: On post-operative d 6, compared with PN group,the levels of blood glucose, serum prealbumin, transferrin,the expression of hepatic ALB mRNA and liver Ki67 labeling index were higher in rhGH+PN group.CONCLUSION: rhGH can improve protein synthesis and liver regeneration after hepatectomy in hepatocellular carcinoma with liver cirrhosis.

  3. [Vitamin D metabolism and signaling in human hepatocellular carcinoma and surrounding non-tumorous liver].

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    Horváth, Evelin; Balla, Bernadett; Kósa, János; Lakatos, Péter András; Lazáry, Áron; Németh, Dániel; Jozilan, Hasan; Somorácz, Áron; Korompay, Anna; Gyöngyösi, Benedek; Borka, Katalin; Kiss, András; Kupcsulik, Péter; Schaff, Zsuzsa; Szalay, Ferenc

    2016-11-01

    1,25-Dihydroxy vitamin D3 mediates antitumor effects in hepatocellular carcinoma. We examined mRNA and protein expression differences in 1,25-Dihydroxy vitamin D3-inactivating CYP24A1, mRNA of activating CYP27B1 enzymes, and that of VDR between human hepatocellular carcinoma and surrounding non-tumorous liver. Snap-frozen tissues from 13 patients were studied for mRNA and protein expression of CYP24A1. Paraffin-embedded tissues from 36 patients were used to study mRNA of VDR and CYP27B1. mRNA expression was measured by RT-PCR, CYP24A1 protein was detected by immunohistochemistry. Expression of VDR and CYP27B1 was significantly lower in hepatocellular carcinoma compared with non-tumorous liver (p<0.05). The majority of the HCC samples expressed CYP24A1 mRNA, but neither of the non-tumorous liver. The gene activation was followed by CYP24A1 protein synthesis. The presence of CYP24A1 mRNA and the reduced expression of VDR and CYP27B1 mRNA in human hepatocellular carcinoma samples indicate decreased bioavailability of 1,25-Dihydroxy vitamin D3, providing an escape mechanism from the anti-tumor effect. Orv. Hetil., 2016, 157(48), 1910-1918.

  4. SIRT1 and c-Myc Promote Liver Tumor Cell Survival and Predict Poor Survival of Human Hepatocellular Carcinomas

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    Jang, Kyu Yun; Noh, Sang Jae; Lehwald, Nadja; Tao, Guo-Zhong; Bellovin, David I.; Park, Ho Sung; Moon, Woo Sung; Felsher, Dean W.; Sylvester, Karl G.

    2012-01-01

    The increased expression of SIRT1 has recently been identified in numerous human tumors and a possible correlation with c-Myc oncogene has been proposed. However, it remains unclear whether SIRT1 functions as an oncogene or tumor suppressor. We sought to elucidate the role of SIRT1 in liver cancer under the influence of c-Myc and to determine the prognostic significance of SIRT1 and c-Myc expression in human hepatocellular carcinoma. The effect of either over-expression or knock down of SIRT1 on cell proliferation and survival was evaluated in both mouse and human liver cancer cells. Nicotinamide, an inhibitor of SIRT1, was also evaluated for its effects on liver tumorigenesis. The prognostic significance of the immunohistochemical detection of SIRT1 and c-Myc was evaluated in 154 hepatocellular carcinoma patients. SIRT1 and c-Myc regulate each other via a positive feedback loop and act synergistically to promote hepatocellular proliferation in both mice and human liver tumor cells. Tumor growth was significantly inhibited by nicotinamide in vivo and in vitro. In human hepatocellular carcinoma, SIRT1 expression positively correlated with c-Myc, Ki67 and p53 expression, as well as high á-fetoprotein level. Moreover, the expression of SIRT1, c-Myc and p53 were independent prognostic indicators of hepatocellular carcinoma. In conclusion, this study demonstrates that SIRT1 expression supports liver tumorigenesis and is closely correlated with oncogenic c-MYC expression. In addition, both SIRT1 and c-Myc may be useful prognostic indicators of hepatocellular carcinoma and SIRT1 targeted therapy may be beneficial in the treatment of hepatocellular carcinoma. PMID:23024800

  5. Detection of anti-liver cell membrane antibody using a human hepatocellular carcinoma cell line

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    Lobo-Yeo, A.; McSorley, C.; McFarlane, B.M.; Mieli-Vergani, G.; Mowat, A.P.; Vergani, D.

    1989-02-01

    A radioimmunometric technique for the detection of autoantibodies to liver membrane antigens has been developed using Alexander cells, a human hepatocellular carcinoma cell line. After incubation of Alexander cells with serum, antimembrane antibodies were detected by addition of /sup 125/I-labeled Protein A. Binding ratios in 15 children with uncontrolled autoimmune chronic active hepatitis and in seven children with primary sclerosing cholangitis were significantly higher than in 18 age-matched normal controls. Nine patients with inactive autoimmune chronic active hepatitis, 13 with alpha 1-antitrypsin deficiency and five with fulminant hepatic failure had ratios similar to controls. In nine patients with Wilson's disease, there was a modest but significant increase in binding ratio. In four children with autoimmune chronic active hepatitis, binding ratios fell during effective immunosuppressive therapy. Sera from patients with systemic lupus erythematosus or rheumatoid arthritis gave normal results, excluding that binding derives from Fc-mediated immune complex capture. A positive correlation was found between Alexander cell binding values and anti-liver-specific protein antibody titers, suggesting that the two assays detect antibodies against shared antigenic determinants. The Alexander cell assay is a simple, rapid and sensitive technique to detect antibody to liver cell membrane antigens.

  6. Mutation analysis of novel human liver-related putative tumor suppressor gene in hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Cheng Liao; Tsai-Ping Li; Mu-Jun Zhao; Jing Zhao; Hai Song; Pascal Pineau; Agnès Marchio; Anne Dejean; Pierre Tiollais; Hong-Yang Wang

    2003-01-01

    AIM: To find the point mutations meaningful for inactivationof liver-related putative tumor suppressor gene (LPTS) gene,a human novel liver-related putative tumor suppressor geneand telomerase inhibitor in hepatocellular carcinoma.METHODS: The entire coding sequence of LPTS genewas examined for mutations by single strand conformationpolymorphism (SSCP) assay and PCR products directsequencing in 56 liver cancer cell lines, 7 ovarian cancerand 7 head & neck tumor cell lines and 70 pairs of HCCtissues samples. The cDNA fragment coding for the mostfrequent mutant protein was subcloned into GST fusionexpression vector. The product was expressed in E. coliand purified by glutathione-agarose column. Telomericrepeat amplification protocol (TRAP) assays wereperformed to study the effect of point mutation totelomerase inhibitory activity.RESULTS: SSCP gels showed the abnormal shifting bandsand DNA sequencing found that there were 5 differentmutations and/or polymorphisms in 12 tumor cell lineslocated at exon2, exon5 and exon7. The main alterationswere A(778)A/G and A(880)T in exon7. The change in siteof 778 could not be found in HCC tissue samples, while themutation in position 880 was seen in 7 (10 %) cases. Themutation in the site of 880 had no effect on telomeraseinhibitory activity.CONCLUSION: Alterations identified in this study arepolymorphisms of LPTS gene. LPTS mutations occur in HCCbut are infrequent and of little effect on the telomeraseinhibitory function of the protein. Epigenetics, such asmethylation, acetylation, may play the key role in inactivationof LPTS.

  7. Xmrk, kras and myc transgenic zebrafish liver cancer models share molecular signatures with subsets of human hepatocellular carcinoma.

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    Weiling Zheng

    Full Text Available Previously three oncogene transgenic zebrafish lines with inducible expression of xmrk, kras or Myc in the liver have been generated and these transgenic lines develop oncogene-addicted liver tumors upon chemical induction. In the current study, comparative transcriptomic approaches were used to examine the correlation of the three induced transgenic liver cancers with human liver cancers. RNA profiles from the three zebrafish tumors indicated relatively small overlaps of significantly deregulated genes and biological pathways. Nevertheless, the three transgenic tumor signatures all showed significant correlation with advanced or very advanced human hepatocellular carcinoma (HCC. Interestingly, molecular signature from each oncogene-induced zebrafish liver tumor correlated with only a small subset of human HCC samples (24-29% and there were conserved up-regulated pathways between the zebrafish and correlated human HCC subgroup. The three zebrafish liver cancer models together represented nearly half (47.2% of human HCCs while some human HCCs showed significant correlation with more than one signature defined from the three oncogene-addicted zebrafish tumors. In contrast, commonly deregulated genes (21 up and 16 down in the three zebrafish tumor models generally showed accordant deregulation in the majority of human HCCs, suggesting that these genes might be more consistently deregulated in a broad range of human HCCs with different molecular mechanisms and thus serve as common diagnosis markers and therapeutic targets. Thus, these transgenic zebrafish models with well-defined oncogene-induced tumors are valuable tools for molecular classification of human HCCs and for understanding of molecular drivers in hepatocarcinogenesis in each human HCC subgroup.

  8. Integrative Quantitative Proteomics Unveils Proteostasis Imbalance in Human Hepatocellular Carcinoma Developed on Nonfibrotic Livers*

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    Negroni, Luc; Taouji, Said; Arma, Daniela; Pallares-Lupon, Nestor; Leong, Kristen; Beausang, Lee Anne; Latterich, Martin; Bossé, Roger; Balabaud, Charles; Schmitter, Jean-Marie; Bioulac-Sage, Paulette; Zucman-Rossi, Jessica; Rosenbaum, Jean; Chevet, Eric

    2014-01-01

    Proteomics-based clinical studies represent promising resources for the discovery of novel biomarkers or for unraveling molecular mechanisms underlying particular diseases. Here, we present a discovery study of hepatocellular carcinoma developed on nonfibrotic liver (nfHCC) that combines complementary quantitative iTRAQ-based proteomics and phosphoproteomics approaches. Using both approaches, we compared a set of 24 samples (18 nfHCC versus six nontumor liver tissue). We identified 43 proteins (67 peptides) differentially expressed and 32 peptides differentially phosphorylated between the experimental groups. The functional analysis of the two data sets pointed toward the deregulation of a protein homeostasis (proteostasis) network including the up-regulation of the Endoplasmic Reticulum (ER) resident HSPA5, HSP90B1, PDIA6, and P4HB and of the cytosolic HSPA1B, HSP90AA1, HSPA9, UBC, CNDP2, TXN, and VCP as well as the increased phosphorylation of the ER resident calnexin at Ser583. Antibody-based validation approaches (immunohistochemistry, immunoblot, Alphascreen®, and AMMP®) on independent nfHCC tumor sets (up to 77 samples) confirmed these observations, thereby indicating a common mechanism occurring in nfHCC tumors. Based on these results we propose that adaptation to proteostasis imbalance in nfHCC tumors might confer selective advantages to those tumors. As such, this model could provide an additional therapeutic opportunity for those tumors arising on normal liver by targeting the tumor proteostasis network. Data are available via ProteomeXchange with identifier PXD001253. PMID:25225353

  9. Integrative quantitative proteomics unveils proteostasis imbalance in human hepatocellular carcinoma developed on nonfibrotic livers.

    Science.gov (United States)

    Negroni, Luc; Taouji, Said; Arma, Daniela; Pallares-Lupon, Nestor; Leong, Kristen; Beausang, Lee Anne; Latterich, Martin; Bossé, Roger; Balabaud, Charles; Schmitter, Jean-Marie; Bioulac-Sage, Paulette; Zucman-Rossi, Jessica; Rosenbaum, Jean; Chevet, Eric

    2014-12-01

    Proteomics-based clinical studies represent promising resources for the discovery of novel biomarkers or for unraveling molecular mechanisms underlying particular diseases. Here, we present a discovery study of hepatocellular carcinoma developed on nonfibrotic liver (nfHCC) that combines complementary quantitative iTRAQ-based proteomics and phosphoproteomics approaches. Using both approaches, we compared a set of 24 samples (18 nfHCC versus six nontumor liver tissue). We identified 43 proteins (67 peptides) differentially expressed and 32 peptides differentially phosphorylated between the experimental groups. The functional analysis of the two data sets pointed toward the deregulation of a protein homeostasis (proteostasis) network including the up-regulation of the Endoplasmic Reticulum (ER) resident HSPA5, HSP90B1, PDIA6, and P4HB and of the cytosolic HSPA1B, HSP90AA1, HSPA9, UBC, CNDP2, TXN, and VCP as well as the increased phosphorylation of the ER resident calnexin at Ser583. Antibody-based validation approaches (immunohistochemistry, immunoblot, Alphascreen(®), and AMMP(®)) on independent nfHCC tumor sets (up to 77 samples) confirmed these observations, thereby indicating a common mechanism occurring in nfHCC tumors. Based on these results we propose that adaptation to proteostasis imbalance in nfHCC tumors might confer selective advantages to those tumors. As such, this model could provide an additional therapeutic opportunity for those tumors arising on normal liver by targeting the tumor proteostasis network. Data are available via ProteomeXchange with identifier PXD001253.

  10. Liver transplantation in patients with hepatocellular carcinoma

    NARCIS (Netherlands)

    Polak, Wojciech G.; Soyama, Akihiko; Slooff, Maarten J. H.

    2008-01-01

    Liver transplantation has a definitive place in the treatment of patients with hepatocellular carcinoma (HCC) in a cirrhotic liver. Patients with a tumor load within the Milan criteria have excellent survival comparable to survival in patients with benign indications. When tumor load exceeds the Mil

  11. Prokineticin 2/Bv8 is expressed in Kupffer cells in liver and is down regulated in human hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    AIM: To study the implication of prokineticin 1 (PK1/EG VEGF) and prokineticin 2 (PK2/Bv8) in hepatocellular carcinoma angiogenesis. METHODS: The gene induction of PK1/EG-VEGF and PK2/Bv8 was investigated in 10 normal, 28 fibrotic and 28 tumoral livers by using real time PCR. Their expression was compared to the expression of VEGF (an angiogenesis marker), vWF (an endothelial cell marker) and to CD68 (a monocyte/macrophage marker). Furthermore, the mRNA levels of PK1/EG-VEGF, PK2/Bv8, prokineticin receptor 1 and 2 were evaluated by real time PCR in isolated liver cell populations. Finally, PK2/Bv8protein was detected in normal liver paraffin sections and in isolated liver cells by immunohistochemistry and immunocytochemistry.RESULTS:PK2/Bv8 mRNA but not PK1/EG-VEGF was expressed in all types of normal liver samples examined. In the context of liver tumor development, we reported that PK2/Bv8 correlates only with CD68 and showed a significant decrease in expression as the pathology evolves towards cancer. Whereas, VEGF and vWF mRNA were significantly upregulated in both fibrosis and HCC, as expected. In addition, out of all isolated liver cells examined, only Kupffer cells (liver resident macrophages) express significant levels of PK2/Bv8 and its receptors, prokineticin receptor 1 and 2.CONCLUSION:In normal liver PK2/Bv8 and its receptors were specifically expressed by Kupffer cells. PK2/Bv8 expression decreased as the liver evolves towards cancer and did not correlate with HCC angiogenesis.

  12. Metabolomic analysis of human cirrhosis, hepatocellular carcinoma, non-alcoholic fatty liver disease and non-alcoholic steatohepatitis diseases.

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    Safaei, Akram; Arefi Oskouie, Afsaneh; Mohebbi, Seyed Reza; Rezaei-Tavirani, Mostafa; Mahboubi, Mohammad; Peyvandi, Maryam; Okhovatian, Farshad; Zamanian-Azodi, Mona

    2016-01-01

    Metabolome analysis is used to evaluate the characteristics and interactions of low molecular weight metabolites under a specific set of conditions. In cirrhosis, hepatocellular carcinoma, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatotic hepatitis (NASH) the liver does not function thoroughly due to long-term damage. Unfortunately the early detection of cirrhosis, HCC, NAFLD and NASH is a clinical problem and determining a sensitive, specific and predictive novel method based on biomarker discovery is an important task. On the other hand, metabolomics has been reported as a new and powerful technology in biomarker discovery and dynamic field that cause global comprehension of system biology. In this review, it has been collected a heterogeneous set of metabolomics published studies to discovery of biomarkers in researches to introduce diagnostic biomarkers for early detection and the choice of patient-specific therapies.

  13. Hepatocellular transport proteins and their role in liver disease

    Institute of Scientific and Technical Information of China (English)

    Carmen Stanca; Diana Jung; Peter J. Meier; Gerd A. Kullak-Ublick

    2001-01-01

    @@MOLECULAR PHYSIOLLGY OF HEPATOCELLULAR TRANSPORT PROTEINS Basolaferal transport systems Na+-dependent bile salt uptake Uptake of bile salts into the liver was first isolated perfused rat liver[1],isolated hepatocyte cultures and basolateral plasma membrane vesicles [2,4].

  14. Methyleugenol hepatocellular cancer initiating effects in rat liver.

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    Williams, Gary M; Iatropoulos, Michael J; Jeffrey, Alan M; Duan, Jian-Dong

    2013-03-01

    Methyleugenol (MEG), a constituent of plants used in the human diet, is hepatocarcinogenic in rodents. In an experiment to elucidate its mode of action in rat liver, male F344 rats were administered MEG intragastrically at 3 doses per week for up to 16 weeks in an initiation phase, after which half the rats were fed 500 ppm phenobarbital (PB) in the diet to promote liver neoplasia and the other half were maintained on control diet for 24 weeks. At 8 and 16 week interim terminations, (32)P-nucleotide postlabeling assay revealed 3 adducts in livers of all MEG groups. The hepatocellular replicating fractions, measured by proliferating cell nuclear antigen immunohistochemistry, were doubled or more in all MEG groups. Hepatocellular altered foci, detected by glutathione S-transferase-placental type (π) immunohistochemistry, were present beginning with the high dose group at 8 weeks and extending to all MEG groups at 16 weeks. At the end of maintenance/promotion phase, the incidences, multiplicity and size of foci was similar between control and low dose groups, while those of mid and high dose groups were increased. Hepatocellular adenomas occurred in the mid and high dose groups, attaining higher multiplicity and size with PB. Thus, MEG had rapid initiating activity, reflecting the formation of DNA adducts and possibly cell proliferation. Copyright © 2012 Elsevier Ltd. All rights reserved.

  15. Dietary administration of Nexrutine inhibits rat liver tumorigenesis and induces apoptotic cell death in human hepatocellular carcinoma cells

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    Shamshad Alam

    2015-01-01

    Full Text Available Epidemiological studies suggested that plant-based dietary supplements can reduce the risk of liver cancer. Nexrutine (NX, an herbal extract from Phellodendronamurense, has been shown to have anti-inflammatory, anti-microbial and anti-tumor activities. In the present study, we have shown the anti-tumor potential of NX against Solt-Farber model with elimination of PH, rat liver tumor induced by diethylnitrosoamine (DEN as carcinogen and 2-acetylaminofluorene (2-AAF as co-carcinogen. The elucidation of mechanistic pathways was explored in human liver cancer cells. Dietary intake of NX significantly decreased the cell proliferation and inflammation, as well as increased apoptosis in the liver sections of DEN/2-AAF-treated rats. Moreover, NX (2.5–10 μg/ml exposure significantly decreased the viability of liver cancer cells and modulated the levels of Bax and Bcl-2 proteins levels. NX treatment resulted in increased cytochrome-c release and cleavage of caspases 3 and 9. In addition, NX decreased the expression of CDK2, CDK4 and associated cyclins E1 and D1, while up-regulated the expression of p21, p27 and p53 expression. NX also enhanced phosphorylation of the mitogen-activated protein kinases (MAPKs ERK1/2, p38 and JNK1/2. Collectively, these findings suggested that NX-mediated protection against DEN/2-AAF-induced liver tumorigenesis involves decrease in cell proliferation and enhancement in apoptotic cell death of liver cancer cells.

  16. Human tetraspanin transmembrane 4 superfamily member 4 or intestinal and liver tetraspan membrane protein is overexpressed in hepatocellular carcinoma and accelerates tumor cell growth

    Institute of Scientific and Technical Information of China (English)

    Ying Li; Leiming Wang; Jie Qiu; Liang Da; Pierre Tiollais; Zaiping Li; Mujun Zhao

    2012-01-01

    The human transmembrane 4 superfamily member 4 or intestinal and liver tetraspan membrane protein (TM4SF4/il-TMP) was originally cloned as an intestinal and liver tetraspan membrane protein and mediates density-dependent cell proliferation.The rat homolog of TM4SF4 was found to be up-regulated in regenerating liver after two-thirds hepatectomy and overexpression of TM4SF4 could enhance liver injury induced by CCl4.However,the expression and significance of TM4SF4/il-TMP in liver cancer remain unknown.Here,we report that TM4SF4/il-TMP is frequently and significantly overexpressed in hepatocellular carcinoma (HCC).Real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) and western blot analysis showed that TM4SF4/il-TMP mRNA and protein levels were upregulated in ~80% of HCC tissues,Immunohistochemical analysis of a 75 paired HCC tissue microarray revealed that TM4SF4/il-TMP was significantly overexpressed in HCC tissues (P < 0.001),and high immunointensity of TM4SF4/iI-TMP tended to be in well-to-moderately differentiated HCC compared with poorly differentiated tumors.Functional studies showed that overexpression of TM4SF4/il-TMP in QGY-7701 and BEL-7404 HCC cell lines through stable transfection of TM4SF4 expression plasmid significantly promoted both cell growth and colony formation of HCC cells.Reduction of TM4SF4/il-TMP expression in QGY-7701 and BEL-7404 cells by stably transfecting TM4SF4 antisense plasmid caused great inhibition of cell proliferation.Our findings suggest that TM4SF4/il-TMP has the potential to be biomarker in HCC and plays a crucial role in promotion of cancer cell proliferation.

  17. Liver transplantation for hepatocellular carcinoma: an update.

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    Zarrinpar, Ali; Kaldas, Fady; Busuttil, Ronald W

    2011-06-01

    Hepatocellular carcinoma (HCC) is a heterogeneous malignancy with multiple etiologies, high incidence, and high mortality. The standard surgical management for patients with HCC consists of locoregional ablation, surgical resection, or liver transplantation, depending on the background state of the liver. Eighty percent of patients initially presenting with HCC are unresectable, either due to the extent of tumor or the level of underlying hepatic dysfunction. While in patients with no evidence of cirrhosis and good hepatic function resection has been the surgical treatment of choice, it is contraindicated in patients with moderate to severe cirrhosis. Liver transplantation is the optimal surgical treatment. PubMed search of recent articles (from January 2000 to March 2011) was performed looking for relevant articles about hepatocellular carcinoma and its treatment. Additional articles were identified by evaluating references from selected articles. Here we review criteria for transplantation, the types, indications, and role of locoregional therapy in treating the cancer and in downstaging for possible later transplantation. We also summarize the contribution of immunosuppression and adjuvant chemotherapy in the management and prevention of HCC recurrence. Finally we discuss recent advances in imaging, tumor biology, and genomics as we delineate the remaining challenges for the diagnosis and treatment of this disease. Much can be improved in the diagnosis and treatment of HCC. A great challenge will be to improve patient selection to criteria based on tumor biology. Another will be to incorporate systemic agents post-operatively in patients at high risk for recurrence, paying close attention to efficacy and safety. The future direction of the effort in treating HCC will be to stimulate prospective trials, develop molecular imaging of lymphovascular invasion, to improve recipient selection, and to investigate biomarkers of tumor biology.

  18. BIOCHEMICAL NUTRITIONAL PROFILE OF LIVER CIRRHOSIS PATIENTS WITH HEPATOCELLULAR CARCINOMA

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    Gabriela Zanatta PORT

    2014-03-01

    Full Text Available Context Liver cirrhosis patients with hepatocellular carcinoma present nutritional alterations and metabolic disorders that negatively impact the prognosis. Objective The objective is to identify alterations in the metabolism of macro and micronutrients among liver cirrhosis patients with and without hepatocellular carcinoma and their relation to the Child-Turcote-Pugh score and Barcelona Clinic Liver Cancer staging. Methods Analytical transversal study, with 31 hepatocellular carcinoma patients and 48 liver cirrhosis patients. Laboratorial exams were carried out. The existence of an association between the biochemical parameters and the disease severity as well as the presence of hepatocellular carcinoma was assessed. Results The metabolic-nutritional profile of liver cirrhosis patients caused by the hepatitis C virus and hepatocellular carcinoma showed alterations, specifically the lipid (total cholesterol, HDL and triglycerides, protein (albumin, creatinine and uric acid, iron (transferrin, iron and ferritin saturation, hematocrit and hemoglobin, zinc and B12 vitamin profiles. There is a relation between nutritional biochemical markers and the Child-Turcote-Pugh, as well as Barcelona Clinic Liver Cancer staging. Conclusions Considering the existence of alterations in the metabolism of nutrients in liver cirrhosis patients with and without hepatocellular carcinoma, and also that conventional nutritional assessment methods present limitations for this population, the biochemical laboratorial exams are valid to complement the diagnosis of the nutritional state in a quick and practical manner.

  19. VEGF in hepatocellular carcinoma and surrounding cirrhotic liver tissues

    Institute of Scientific and Technical Information of China (English)

    Muriel Mathonnet; Bernard Descottes; Denis Valleix; Francois Labrousse; Yves Denizot

    2006-01-01

    @@ TO THE EDITOR We read with a great interest the recent work of Deli and colleagues.[1] in the World Journal of Gastroenterology reporting vascular endothelial growth factor (VEGF) expression in hepatocellular carcinoma (HCC) and cirrhotic liver tissues.

  20. Immunosupression in liver transplant for hepatocellular carcinoma

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    Juan Carlos Restrepo Restrepo

    2007-02-01

    Full Text Available

    The hepatocellular carcinoma (HCC has turned into a frequent indication for liver transplant. The reports of different series indicate that it represents at least 12% of all liver transplants in Europe. But what kind of inmunosuppression is better in these patients is an unanswered question. Our intension with this review is to give basic information to define which would be the best immunosuppression alternative. There is enough information on the relationship between immunosuppression and cancer, as it is seen in states of primary immunodeficiency or infection with the Human Immunodeficiency virus (HIV. The immune system offers a state of permanent guard to avoid the arousal of neoplasic diseases in immunocompetent patients and from this point of view it has been seen that in immunosuppressed patients there is an association with this condition and the development of lymphoproliferative disorders, which can range from reversible diseases (polyclonal proliferation of B type lymphocytes to the development of a lymphoma and other types of tumors, like the ones observed in skin, genital region or oropharynx. Colon tumors and breast tumors have not been associated with immunosuppression. Immunosuppressive medication takes part in a different manner in the development of tumors, it has been said that steroids that are associated with some tumors, especially those regarding skin, paradoxically have a protective role in the development of lymph tissue tumors.

    It has been said about Azathioprine and Mycophenolate mofetil (MMF that its immunosuppressive effect is an antiproliferative type of immunosuppression, inhibiting the synthesis of purinic nucleotides, especially in lymphocytes. Azathioprine has been involved in the development of hepatic tumors, especially in the era previous

  1. Nonalcoholic fatty liver disease and hepatocellular carcinoma

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    LI Liangping

    2016-03-01

    Full Text Available As the etiology of hepatocellular carcinoma (HCC has been changing, the incidence of HCC related to nonalcoholic fatty liver disease (NAFLD is gradually increasing in developed countries in Europe and America and some countries in Asia. This article introduces the close association between NAFLD and HCC, risk factors, clinicopathological features, and prevention and screening, and points out that although the incidence of NAFLD is not as high as that of hepatitis B- or hepatitis C-related HCC, there are a large absolute number of NAFLD patients, especially the high-risk patients with diabetes and obesity, or liver fibrosis/cirrhosis, due to a huge base number of NAFLD patients. NAFLD-related HCC is commonly seen in the elderly with various comorbidities and a poor prognosis. This article also points out that the prevention should focus on the effective treatment of NAFLD. The strict screening of high-risk population is the strategy for the diagnosis of early-stage HCC. At present, the sensitivity of alpha-fetoprotein is relatively low, and imaging examinations including computed tomography are the main screening methods; however, there are no measures for early warning of NAFLD-related HCC.

  2. Loss of fragile histidine triad protein in human hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Po Zhao; Xin Song; Yuan-Yuan Nin; Ya-Li Lu; Xiang-Hong Li

    2003-01-01

    AIM: To investigate the expression of fragile histidine triad (FHIT) gene protein, Fhit, which is recently thought to be a candidate tumor suppressor. Abnormal expression of fragile histidine triad has been found in a variety of human cancers,but little is known about its expression in human hepatocellular carcinogenesis and evolution.METHODS: Sections of 83 primary human hepatocellular carcionoma with corresponding para-neoplastic liver tissue and 10 normal liver tissue were evaluated immunohistochemically for Fhit protein expression.RESULTS: All normal liver tissue and para-neoplastic liver tissue showed a strong expression of Fhit, whereas 50 of 83(65.0 %) carcinomas showed a marked loss or absence of Fhit expression. The differences of Fhit expression between carcinoma and normal or para-neoplastic liver tissue werehighly significant (P=0.000). The proportion of carcinomas with reduced Fhit expression showed an increasing trend (a) with decreasing differentiation or higher histological grade (P=0.219); (b) in tumors with higher clinical stage Ⅲ and ⅣV (91.3 %, P=0.000), compared with tumors with lower stage Ⅰ and Ⅱ (27.6 %); and (c) in cancers with bigger tumor size (>50 mm) (75.0 %, P=0.017), compared withsmaller tumor size (≤ 50 mm). CONCLUSION: FHIT inactivation seems to be both an earlyand a later event, associated with carcinogenesis andprogression to more aggressive hepatocellular carcinomas.Thus, evaluation of Fhit expression by immunohistochemistryin hepatocellular carcinoma may provide important diagnosticand prognostic information in clinical application.

  3. Hepatocellular carcinoma arising from hepatocellular adenoma in a hepatitis B virus-associated cirrhotic liver

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    Seo, J.M. [Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Lee, S.J., E-mail: lucia@skku.edu [Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Kim, S.H. [Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Park, C.K.; Ha, S.Y. [Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

    2012-04-15

    Hepatocellular adenoma (HCA) is a rare, benign proliferation of hepatocytes that occurs mostly in a normal liver and in extreme rare cases, occurs in a cirrhotic liver. Hepatocellular carcinomas (HCC) arising within HCA through malignant transformation is rare. The specific incidence and mechanism of malignant transformation has not been established, but the long term use of oral contraceptives is considered a causative agent. We report a case of HCC arising from HCA detected in a hepatitis B-related cirrhotic liver with serial radiologic images.

  4. Gremlin in the pathogenesis of hepatocellular carcinoma complicating chronic hepatitis C: an immunohistochemical and PCR study of human liver biopsies

    Directory of Open Access Journals (Sweden)

    Guimei Maha

    2012-07-01

    Full Text Available Abstract Background The possible role of secretory products of fibrous tissue in the development of hepatocellular carcinoma (HCC complicating chronic hepatitis C was investigated. Our hypothesis was that gremlin, secreted by fibroblasts, inhibited bone morphogenic protein (BMP, which mediates stem cell maturation into adult functioning hepatocytes, and thus, arrest stem cell maturation and promoted their proliferation in an immature state possibly culminating into development of HCCs. Results Protein expression of cytokeratin 19 (CK19 and fibroblast growth factor 2 (FGF-2, and mRNA expression of gremlin and BMP-7 were studied in 35 cases of chronic hepatitis, cirrhosis and HCC complicating chronic hepatitis C. CK19 expression was higher in cases of cirrhosis (0.004, which correlated with the grade (r = 0.64, p = 0.009 and stage (r = 0.71, p = 0.001. All HCCs were negative for CK19. Stem cell niche activation (as indicated as a ductular reaction was highest in cases of cirrhosis (p = 0.001 and correlated with CK19 expression (r = 0.42, p = 0.012, the grade(r = 0.56, p = 0.024 and stage (0.66, p = 0.006. FGF-2 expression was highest in HCCs and correlated with the grade (r = 0.6, p = 0.013, stage (0.72, p = 0.002, CK19 expression (r = 0.71, p = 002 and ductular reaction (0.68, p = 0.004 in hepatitis cases. Higher numbers of cirrhosis cases and HCCs (p = 0.009 showed gremlin expression, which correlated with the stage (r = 0.7, p = 0.002. Gremlin expression correlated with that of CK19 (r = 0.699, p = 0.003 and FGF2 (r = 0.75, p = 0.001 in hepatitis cases. Conclusions Fibrosis promotes carcinogenesis by fibroblast-secreted gremlin that blocks BMP function and promotes stem cell activation and proliferation as well as possibly HCC development.

  5. Laparoscopic liver resection for hepatocellular carcinoma in patients with cirrhosis

    Institute of Scientific and Technical Information of China (English)

    Jai Young Cho; Ho-Seong Han

    2016-01-01

    Hepatocellular carcinoma (HCC) is a common malignant tumor and many cases occur in patients with liver cirrhosis. Although liver transplantation is the most effective treatment option, hepatectomy is still the ifrst curative treatment option because liver transplantation is limited by the donors and high cost. In recent years, laparoscopic liver resection (LLR) has increasingly been performed in patients with liver cirrhosis, and has several advantages over open liver resection. Besides less pain and shorter hospital stay, LLR in patients with liver cirrhosis is also associated with lower incidences of postoperative liver failure and ascites because of greater preservation of collateral veins and less liver manipulation. With increasing experience, LLR for HCC located in segments 7 or 8 is now feasible, and anatomic LLR could be performed in patients with cirrhosis. Many comparative studies have shown that LLR is better than open liver resection in patients with liver cirrhosis in terms of a lower incidence of postoperative liver failure and similar patient survival. In conclusion, LLR is a promising treatment modality for HCC in patients with liver cirrhosis.

  6. Liver regeneration microenvironment of hepatocellular carcinoma for prevention and therapy

    Science.gov (United States)

    Li, Hanmin; Zhang, Lisheng

    2017-01-01

    Research on liver cancer prevention and treatment has mainly focused on the liver cancer cells themselves. Currently, liver cancers are no longer viewed as only collections of genetically altered cells but as aberrant organs with a plastic stroma, matrix, and vasculature. Improving the microenvironment of the liver to promote liver regeneration and repair by affecting immune function, inflammation and vasculature can regulate the dynamic imbalance between normal liver regeneration and repair and abnormal liver regeneration, thus improving the microenvironment of liver regeneration for the prevention and treatment of liver cancer. This review addresses the basic theory of the liver regeneration microenvironment, including the latest findings on immunity, inflammation and vasculature. Attention is given to the potential design of molecular targets in the microenvironment of hepatocellular carcinoma (HCC). In an effort to improve the liver regeneration microenvironment of HCC, researchers have extensively utilized the enhancement of immunity, anti-inflammation and the vasculature niche, which are discussed in detail in this review. In addition, the authors summarize the latest pro-fibrotic transition characteristics of the vascular niche and review potential cell therapies for liver disease. PMID:27655683

  7. Liver transplantation for unresectable hepatocellular carcinoma in patients without liver cirrhosis

    NARCIS (Netherlands)

    Mergental, Hynek; Porte, Robert J.

    2010-01-01

    P>Hepatocellular carcinoma (HCC) arising in noncirrhotic and nonfibrotic liver (NC-HCC) is a rare type of malignancy frequently found in healthy young individuals. Partial liver resection is the treatment of choice with expected 5-year survival rates between 40% and 70%. As a result of absence of an

  8. HGF, MET, and matrix-related proteases in hepatocellular carcinoma, fibrolamellar variant, cirrhotic and normal liver.

    Science.gov (United States)

    Schoedel, Karen E; Tyner, Valerie Zajac; Kim, Tae-Hyoung; Michalopoulos, George K; Mars, Wendy M

    2003-01-01

    Fibrolamellar variant is an uncommon subcategory of hepatocellular carcinoma with a better prognostic outcome. Proteinases and growth factors that are involved in the remodeling of extracellular matrix may influence the behavior of cancers. To determine whether these factors contribute to the distinct etiologies of fibrolamellar hepatocellular carcinoma and traditional hepatocellular carcinoma, we assayed hepatocyte growth factor, the hepatocyte growth factor receptor, and two hepatocyte growth factor activators, hepatocyte growth factor activator and urokinase-type plasminogen activator, in hepatocellular carcinoma, fibrolamellar hepatocellular carcinoma, cirrhotic liver and normal liver. In addition, we examined the urokinase-type plasminogen activator receptor, the type 1 plasminogen activator inhibitor, plasmin, fibrinogen, and the type IV matrix metalloproteinases. Eighteen hepatocellular carcinomas and 11 fibrolamellar hepatocellular carcinomas were obtained as paraffin embedded sections from the University of Pittsburgh Department of Pathology. Frozen tissues from a subset of cases (9 hepatocellular carcinomas, 4 fibrolamellar hepatocellular carcinomas, 12 cirrhotic livers and 2 normal livers) were also available for analysis. Antibodies against urokinase-type plasminogen activator, urokinase-type plasminogen activator receptor, hepatocyte growth factor and hepatocyte growth factor receptor were used to analyze immunoperoxidase stained slides from the paraffin blocks. Western blot analyses using antibodies against hepatocyte growth factor, hepatocyte growth factor receptor, phosphotyrosine, hepatocyte growth factor activator, urokinase-type plasminogen activator receptor, urokinase-type plasminogen activator, plasminogen activator inhibitor-1, fibrinogen and plasmin were performed on membrane-enriched fractions from the frozen tissue, as was collagen zymography for matrix metalloproteinase-2 and matrix metalloproteinase-9. The most notable findings are as

  9. Hepatocellular carcinoma and liver metastases: Diagnosis and treatment

    Energy Technology Data Exchange (ETDEWEB)

    Hoogewoud, H.M.

    1993-12-31

    The state of the art concerning hepatocellular carcinoma and liver metastases is given in this review of the literature. The results of the author`s analysis are frequently summarized in tables that are easy to understand. The book covers the broad range of possible diagnostic and management techniques: pathology, imaging, surgery, radiotherapy and chemotherapy. The gamut of indications, contra-indications, results and complications is discussed. Emphasis is placed particularly on catheter techniques. (orig.). 41 figs., 21 tabs.

  10. Nonalcoholic Fatty liver disease, diabetes, obesity, and hepatocellular carcinoma.

    Science.gov (United States)

    Noureddin, Mazen; Rinella, Mary E

    2015-05-01

    Diabetes and obesity are associated with nonalcoholic fatty liver disease (NAFLD) and an increased incidence of hepatocellular carcinoma (HCC). NAFLD is the commonest cause of chronic liver disease. HCC can develop in NAFLD patients even without cirrhosis, suggesting an association between the metabolic process and HCC and raising a concern that many cancers could be missed given high NAFLD prevalence and screening limitations. The increasing prevalence of these conditions and lack of effective treatments necessitate a better understanding of their connection. This article defines the known interrelationships and common pathways between NAFLD, diabetes, obesity and HCC and possible chemoprevention strategies. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. Hepatocellular alterations and dysregulation of oncogenic pathways in the liver of transgenic mice overexpressing growth hormone.

    Science.gov (United States)

    Miquet, Johanna G; Freund, Thomas; Martinez, Carolina S; González, Lorena; Díaz, María E; Micucci, Giannina P; Zotta, Elsa; Boparai, Ravneet K; Bartke, Andrzej; Turyn, Daniel; Sotelo, Ana I

    2013-04-01

    Growth hormone (GH) overexpression throughout life in transgenic mice is associated with the development of liver tumors at old ages. The preneoplastic pathology observed in the liver of young adult GH-overexpressing mice is similar to that present in humans at high risk of hepatic cancer. To elucidate the molecular pathogenesis underlying the pro-oncogenic liver pathology induced by prolonged exposure to elevated GH levels, the activation and expression of several components of signal transduction pathways that have been implicated in hepatocellular carcinogenesis were evaluated in the liver of young adult GH-transgenic mice. In addition, males and females were analyzed in parallel in order to evaluate sexual dimorphism. Transgenic mice from both sexes exhibited hepatocyte hypertrophy with enlarged nuclear size and exacerbated hepatocellular proliferation, which were higher in males. Dysregulation of several oncogenic pathways was observed in the liver of GH-overexpressing transgenic mice. Many signaling mediators and effectors were upregulated in transgenic mice compared with normal controls, including Akt2, NFκB, GSK3β, β-catenin, cyclin D1, cyclin E, c-myc, c-jun and c-fos. The molecular alterations described did not exhibit sexual dimorphism in transgenic mice except for higher gene expression and nuclear localization of cyclin D1 in males. We conclude that prolonged exposure to GH induces in the liver alterations in signaling pathways involved in cell growth, proliferation and survival that resemble those found in many human tumors.

  12. Usage of adenovirus expressing thymidine kinase mediated hepatocellular damage for enabling mouse liver repopulation with allogenic or xenogenic hepatocytes.

    Directory of Open Access Journals (Sweden)

    Daniel Moreno

    Full Text Available It has been shown that the liver of immunodeficient mice can be efficiently repopulated with human hepatocytes when subjected to chronic hepatocellular damage. Mice with such chimeric livers represent useful reagents for medical and clinical studies. However all previously reported models of humanized livers are difficult to implement as they involve cross-breeding of immunodeficient mice with mice exhibiting genetic alterations causing sustained hepatic injury. In this paper we attempted to create chimeric livers by inducing persistent hepatocellular damage in immunodeficient Rag2(-/- γc(-/- mice using an adenovirus encoding herpes virus thymidine kinase (AdTk and two consecutive doses of ganciclovir (GCV. We found that this treatment resulted in hepatocellular damage persisting for at least 10 weeks and enabled efficient engraftment and proliferation within the liver of either human or allogenic hepatocytes. Interestingly, while the nodules generated from the transplanted mouse hepatocytes were well vascularized, the human hepatocytes experienced progressive depolarization and exhibited reduced numbers of murine endothelial cells inside the nodules. In conclusion, AdTk/GCV-induced liver damage licenses the liver of immunodeficient mice for allogenic and xenogenic hepatocyte repopulation. This approach represents a simple alternative strategy for chimeric liver generation using immunodeficient mice without additional genetic manipulation of the germ line.

  13. Percutaneous laser ablation of hepatocellular carcinoma in patients with liver cirrhosis awaiting liver transplantation

    Energy Technology Data Exchange (ETDEWEB)

    Pompili, Maurizio, E-mail: mpompili@rm.unicatt.i [Department of Internal Medicine, Universita Cattolica del Sacro Cuore, Largo A. Gemelli, 8, 00168 Roma (Italy); Pacella, Claudio Maurizio, E-mail: claudiomauriziopacella@gmail.co [Department of Diagnostic Imaging and Interventional Radiology, Ospedale Regina Apostolorum, Via S. Francesco D' Assisi, 50, 00041 Albano Laziale (RM) (Italy); Francica, Giampiero, E-mail: giampierofrancica@tin.i [Department of Interventional Ultrasound, Presidio Ospedaliero Camilliani, S. Maria della Pieta, Via S. Rocco, 9, 80026 Casoria (Namibia) (Italy); Angelico, Mario, E-mail: angelico@med.uniroma2.i [Hepatology Unit, Universita di Tor Vergata, Viale Oxford, 81, 00133 Rome (Italy); Tisone, Giuseppe, E-mail: tisone@med.uniroma2.i [Transplant and General Surgery Unit, Universita di Tor Vergata, Ospedale S. Eugenio, Piazzale dell' Umanesimo 10-00144 Rome (Italy); Craboledda, Paolo, E-mail: paolo.craboledda@virgilio.i [Department of Pathology, Ospedale S. Eugenio, Piazzale dell' Umanesimo, 10-00144 Rome (Italy); Nicolardi, Erica; Rapaccini, Gian Ludovico; Gasbarrini, Giovanni [Department of Internal Medicine, Universita Cattolica del Sacro Cuore, Largo A. Gemelli, 8, 00168 Roma (Italy)

    2010-06-15

    Objective: The aim of this study was to determine the effectiveness and safety of percutaneous laser ablation for the treatment of cirrhotic patients with hepatocellular carcinoma awaiting liver transplantation. Materials and methods: The data of 9 male cirrhotic patients (mean age 50 years, range 45-60 years) with 12 biopsy proven nodules of hepatocellular carcinoma (mean diameter 2.0 cm, range 1.0-3.0 cm) treated by laser ablation before liver transplantation between June 2000 and January 2006 were retrospectively reviewed. Laser ablation was carried out by inserting 300 nm optical fibers through 21-Gauge needles (from two to four) positioned under ultrasound guidance into the target lesions. A continuous wave Neodymium:Yttrium Aluminium Garnet laser was used. Transarterial chemoembolization prior to liver transplantation was performed in two incompletely ablated tumors. Results: No procedure-related major complications were recorded. During the waiting time to liver transplantation local tumor progression after ablation occurred in 3 nodules (25%). At histological examination of the explanted livers complete necrosis was found in 8 nodules (66.7%, all treated exclusively with laser ablation), partial necrosis >50% in 3 nodules (25%), and partial necrosis <50% in 1 nodule. Conclusion: In patients with cirrhotic livers awaiting liver transplantation, percutaneous laser ablation is safe and effective for the management of small hepatocellular carcinoma.

  14. Current status of laparoscopic liver resection for hepatocellular carcinoma.

    Science.gov (United States)

    Guro, Hanisah; Cho, Jai Young; Han, Ho-Seong; Yoon, Yoo-Seok; Choi, YoungRok; Periyasamy, Mohan

    2016-06-01

    Laparoscopic liver resection (LLR) is becoming widely accepted for the treatment of hepatocellular carcinoma (HCC). Laparoscopic left lateral sectionectomy and minor laparoscopic liver resection are now considered standard approaches, especially for tumors located in the anterolateral segments of the liver. Laparoscopic left lateral sectionectomy in adult donors is also gaining acceptance for child liver transplantation in many centers. Major LLRs, including left hepatectomy and right hepatectomy, have been recently attempted. Laparoscopic donor hepatectomy is becoming more popular owing to increasing demand from young living donors who appreciate its minimal invasiveness and excellent cosmetic outcomes. Several centers have performed total laparoscopic donor right hepatectomy in adult-to-adult living donor liver transplantation. Many meta-analyses have shown that LLR is better than open liver resection in terms of short-term outcomes, principally cosmetic outcomes. Although no randomized control trials have compared LLR with open liver resection, the long-term oncologic outcomes were similar for both procedures in recent case-matched studies.

  15. Hedgehog signaling antagonist promotes regression of both liver fibrosis and hepatocellular carcinoma in a murine model of primary liver cancer.

    Directory of Open Access Journals (Sweden)

    George M Philips

    Full Text Available OBJECTIVE: Chronic fibrosing liver injury is a major risk factor for hepatocarcinogenesis in humans. Mice with targeted deletion of Mdr2 (the murine ortholog of MDR3 develop chronic fibrosing liver injury. Hepatocellular carcinoma (HCC emerges spontaneously in such mice by 50-60 weeks of age, providing a model of fibrosis-associated hepatocarcinogenesis. We used Mdr2(-/- mice to investigate the hypothesis that activation of the hedgehog (Hh signaling pathway promotes development of both liver fibrosis and HCC. METHODS: Hepatic injury and fibrosis, Hh pathway activation, and liver progenitor populations were compared in Mdr2(-/- mice and age-matched wild type controls. A dose finding experiment with the Hh signaling antagonist GDC-0449 was performed to optimize Hh pathway inhibition. Mice were then treated with GDC-0449 or vehicle for 9 days, and effects on liver fibrosis and tumor burden were assessed by immunohistochemistry, qRT-PCR, Western blot, and magnetic resonance imaging. RESULTS: Unlike controls, Mdr2(-/- mice consistently expressed Hh ligands and progressively accumulated Hh-responsive liver myofibroblasts and progenitors with age. Treatment of aged Mdr2-deficient mice with GDC-0449 significantly inhibited hepatic Hh activity, decreased liver myofibroblasts and progenitors, reduced liver fibrosis, promoted regression of intra-hepatic HCCs, and decreased the number of metastatic HCC without increasing mortality. CONCLUSIONS: Hh pathway activation promotes liver fibrosis and hepatocarcinogenesis, and inhibiting Hh signaling safely reverses both processes even when fibrosis and HCC are advanced.

  16. Hedgehog signaling antagonist promotes regression of both liver fibrosis and hepatocellular carcinoma in a murine model of primary liver cancer.

    Science.gov (United States)

    Philips, George M; Chan, Isaac S; Swiderska, Marzena; Schroder, Vanessa T; Guy, Cynthia; Karaca, Gamze F; Moylan, Cynthia; Venkatraman, Talaignair; Feuerlein, Sebastian; Syn, Wing-Kin; Jung, Youngmi; Witek, Rafal P; Choi, Steve; Michelotti, Gregory A; Rangwala, Fatima; Merkle, Elmar; Lascola, Christopher; Diehl, Anna Mae

    2011-01-01

    Chronic fibrosing liver injury is a major risk factor for hepatocarcinogenesis in humans. Mice with targeted deletion of Mdr2 (the murine ortholog of MDR3) develop chronic fibrosing liver injury. Hepatocellular carcinoma (HCC) emerges spontaneously in such mice by 50-60 weeks of age, providing a model of fibrosis-associated hepatocarcinogenesis. We used Mdr2(-/-) mice to investigate the hypothesis that activation of the hedgehog (Hh) signaling pathway promotes development of both liver fibrosis and HCC. Hepatic injury and fibrosis, Hh pathway activation, and liver progenitor populations were compared in Mdr2(-/-) mice and age-matched wild type controls. A dose finding experiment with the Hh signaling antagonist GDC-0449 was performed to optimize Hh pathway inhibition. Mice were then treated with GDC-0449 or vehicle for 9 days, and effects on liver fibrosis and tumor burden were assessed by immunohistochemistry, qRT-PCR, Western blot, and magnetic resonance imaging. Unlike controls, Mdr2(-/-) mice consistently expressed Hh ligands and progressively accumulated Hh-responsive liver myofibroblasts and progenitors with age. Treatment of aged Mdr2-deficient mice with GDC-0449 significantly inhibited hepatic Hh activity, decreased liver myofibroblasts and progenitors, reduced liver fibrosis, promoted regression of intra-hepatic HCCs, and decreased the number of metastatic HCC without increasing mortality. Hh pathway activation promotes liver fibrosis and hepatocarcinogenesis, and inhibiting Hh signaling safely reverses both processes even when fibrosis and HCC are advanced.

  17. Hepatocellular carcinoma complicating cystic fibrosis related liver disease.

    LENUS (Irish Health Repository)

    O'Donnell, D H

    2012-02-01

    Early diagnosis and treatment of the respiratory and gastrointestinal complications of cystic fibrosis (CF) have led to improved survival with many patients living beyond the fourth decade. Along with this increased life expectancy is the risk of further disease associated with the chronic manifestations of their condition. We report a patient with documented CF related liver disease for which he was under routine surveillance that presented with histologically proven hepatocellular carcinoma (HCC). It is important that physicians are aware of this association as increased vigilance may lead to earlier diagnosis and perhaps, a better outcome.

  18. Liver transplantation for hepatocellular carcinoma: recent advances in China.

    Science.gov (United States)

    Lu, Tian Fei; Hua, Xiang Wei; Cui, Xiao Lan; Xia, Qiang

    2014-02-01

    Orthotopic liver transplantation is currently the best treatment option for selected patients with hepatocellular carcinoma (HCC). From 1980 to 2011, 8874 patients with HCC in China underwent liver transplantation. The organ donation classification criteria of China (China criteria), which are established by the Government of China, are divided into three parts: China criteria I, donation after brain death; China criteria II, donation after cardiac death and China criteria III, donation after dual brain-cardiac death. Data from the China Liver Transplant Registry(CLTR) System shows that patients within the Milan criteria have higher survival rates than those who are beyond these criteria. Based on CLTR data, altogether 416 patients received living-donor liver transplantation(LDLT) in China. Their 1-year and 3-year survival rates were significantly higher than those of the non-LDLT recipients. The most common early stage(transplantation) complications include pleural effusion, diabetes, peritoneal effusion or abscess, postoperative infection, hypertension and intraperitoneal hemorrhage; while the most common late stage (≥ 30 days after liver transplantation) complications were diabetes, hypertension, biliary complications,postoperative infection, tacrolimus toxicity and chronic graft rejection. The incidence of vascular complication, which is the main reason for acute graft failure and re-transplantation, was 2.4%. Liver transplantation is an effective treatment for patients with HCC in China.

  19. Liver Transplantation and Cirrhotomimetic Hepatocellular Carcinoma: Classification and Outcomes

    Science.gov (United States)

    Clayton, Erica F; Malik, Saloni; Bonnel, Alexander; Mu, Yifei; Olthoff, Kim; Shaked, Abraham; Abt, Peter L; Peterman, Heather; Reddy, K. Rajender; Ottmann, Shane; Furth, Emma E; Levine, Matthew H

    2014-01-01

    Background & Aims Liver transplantation has become the standard of care treatment for hepatocellular carcinoma (HCC) that falls within size and numeric criteria in cirrhotic patients. Cirrhotomimetic (CMM) hepatocellular carcinoma is an uncommon growth pattern that infiltrates cirrhotic parenchyma, can become extensive in size, and can evade detection via radiologic studies. Liver transplant outcomes for this type of HCC is not well reported but generally considered to be poor. We wished to better describe this variant of HCC in explanted livers, derive a classification system for this tumor type, and assess the outcomes of liver transplantation for this tumor variant. Methods Upon retrospective analysis of all patients transplanted at a single center for HCC in 1996–2009 (358 patients) a series of 26 patients exhibiting CMM growth pattern were identified. We developed a classification system for this tumor growth pattern variant and determined patient and tumor-specific outcomes. Results We derived a classification schema of CMM HCC based upon tumor extent and cellular histopathology with clear cell pathology being associated with favorable outcome. We note a 100% 3-year and 58.3% 5-year recurrence free survival after transplant in those with tumor confined to one lobe who have clear cell pathology versus 16.2% 3- and 5-year recurrence free survival in those who do not meet these criteria. Conclusion Cirrhotomimetic HCC features are noted in 7% of patients transplanted for HCC in our center with favorable outcomes inpatients with clear cell histology and growth involving less than 50% of the liver. PMID:24668931

  20. Portal vein arterialization increases hepatocellular apoptosis and inhibits liver regeneration.

    Science.gov (United States)

    Schleimer, Karina; Stippel, Dirk L; Kasper, Hans U; Prenzel, Klaus; Gaudig, Cindy; Tawadros, Samir; Hoelscher, Arnulf H; Beckurts, K Tobias E

    2008-10-01

    Portal vein arterialization is performed in particular situations to guarantee sufficient blood flow in the portal vein. In addition, some authors have postulated a proliferation-promoting influence of portal vein arterialization on the liver tissue. However, portal vein arterialization is an unphysiological procedure: It increases portal blood flow and blood pressure as well as oxygenation of the liver tissue. On the other hand, it reduces the influx of hepatotrophic factors from the portal venous blood. The aim of these experiments was to investigate apoptosis and proliferation of hepatocytes during various conditions of the portal perfusion. After 70% liver resection in Lewis rats, the following four experimental groups were formed differing in portal perfusion: (I) hyperperfused, nonarterialized; (II) flow-regulated, nonarterialized; (III) hyperperfused, arterialized; (IV) flow-regulated, arterialized. A warm ischemia of 30 min was kept in all groups. Portal vein arterialization of 70% reduced rat livers significantly reduced liver regeneration as shown by a significant reduction in liver weight, body weight, and liver function after 6 wk, in contrast to the group with 70% liver mass reduction and portal venous inflow of the portal vein. Furthermore, we found a significantly elevated number of apoptotic hepatocytes after portal vein arterialization. These results were independent from blood flow regulation of the arterialized portal vein, which caused no improvement of the results. Portal vein arterialization should be performed only temporarily and is clinically not recommended as a permanent option, because of the increased hepatocellular apoptosis and the very distinctive, negative long-term effects on liver weight.

  1. Early steroid withdrawal after liver transplantation for hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    AIM: To evaluate the impact of early steroid withdrawal on the incidence of rejection, tumor recurrence and complications after liver transplantation for advancedstage hepatocellular carcinoma.METHODS: Fifty-four patients underwent liver transplantation for advanced-stage hepatocellular carcinoma from April 2003 to June 2005. These cases were divided into a steroid-withdrawal group (group A, n = 28) and a steroid-maintenance group (group B,n = 26). In group A, steroid was withdrawn 3 mo after transplantation. In group B, steroid was continuously used postoperatively. The incidence of rejection, 6-mo and 1-year recurrence rate of carcinoma, 1-year survival rate, mean serum tacrolimus trough level, and liver and kidney function were compared between the two groups.RESULTS: In the two groups, no statistical difference was observed in the incidence of rejection (14.3 vs 11.5%, P > 0.05), mean serum tacrolimus trough levels (6.9 ± 1.4 vs 7.1 ± 1.1 μg/L, P > 0.05), liver and kidney function after 6 mo [alanine aminotransferase (ALT):533 ± 183 vs 617 ± 217 nka/L, P > 0.05; creatinine:66 ± 18 vs 71 ± 19 μmol/L, P > 0.05], 6-mo recurrence rate of carcinoma (25.0 vs 42.3%, P > 0.05), and 1-year survival rate (64.2 vs 46.1%, P > 0.05). The 1-year tumor recurrence rate (39.2 vs 69.2%, P < 0.05), serum cholesterol level (3.9 ± 1.8 vs 5.9 ± 2.6 mmol/L, P < 0.01)and fasting blood sugar (5.1 ± 2.1 vs 8.9 ± 3.6 mmol/L,P < 0.01) were significantly different. These were lower in the steroid-withdrawal group than in the steroidmaintenance group.CONCLUSION: Early steroid withdrawal was safe after liver transprantation in patients with advanced-stage hepatocellular carcinoma. When steroids were withdrawn 3 mo post-operation, the incidence of rejection did not increase, and there was no demand to maintain tacrolimus at a high level. In contrast, the tumor recurrence rate and the potential of adverse effects decreased significantly. This may have led to an

  2. Early steroid withdrawal after liver transplantation for hepatocellular carcinoma

    Science.gov (United States)

    Chen, Zhi-Shui; He, Fan; Zeng, Fan-Jun; Jiang, Ji-Pin; Du, Dun-Feng; Liu, Bin

    2007-01-01

    AIM: To evaluate the impact of early steroid withdrawal on the incidence of rejection, tumor recurrence and complications after liver transplantation for advanced-stage hepatocellular carcinoma. METHODS: Fifty-four patients underwent liver transplantation for advanced-stage hepatocellular carcinoma from April 2003 to June 2005. These cases were divided into a steroid-withdrawal group (group A, n = 28) and a steroid-maintenance group (group B, n = 26). In group A, steroid was withdrawn 3 mo after transplantation. In group B, steroid was continuously used postoperatively. The incidence of rejection, 6-mo and 1-year recurrence rate of carcinoma, 1-year survival rate, mean serum tacrolimus trough level, and liver and kidney function were compared between the two groups. RESULTS: In the two groups, no statistical difference was observed in the incidence of rejection (14.3 vs 11.5%, P > 0.05), mean serum tacrolimus trough levels (6.9 ± 1.4 vs 7.1 ± 1.1 μg/L, P > 0.05), liver and kidney function after 6 mo [alanine aminotransferase (ALT): 533 ± 183 vs 617 ± 217 nka/L, P > 0.05; creatinine: 66 ± 18 vs 71 ± 19 μmol/L, P > 0.05], 6-mo recurrence rate of carcinoma (25.0 vs 42.3%, P > 0.05), and 1-year survival rate (64.2 vs 46.1%, P > 0.05). The 1-year tumor recurrence rate (39.2 vs 69.2%, P < 0.05), serum cholesterol level (3.9 ± 1.8 vs 5.9 ± 2.6 mmol/L, P < 0.01) and fasting blood sugar (5.1 ± 2.1 vs 8.9 ± 3.6 mmol/L, P < 0.01) were significantly different. These were lower in the steroid-withdrawal group than in the steroid-maintenance group. CONCLUSION: Early steroid withdrawal was safe after liver transplantation in patients with advanced-stage hepatocellular carcinoma. When steroids were withdrawn 3 mo post-operation, the incidence of rejection did not increase, and there was no demand to maintain tacrolimus at a high level. In contrast, the tumor recurrence rate and the potential of adverse effects decreased significantly. This may have led to an increase

  3. Platelet-activating factor in cirrhotic liver and hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Muriel Mathonnet; Bernard Descottes; Denis Valleix; Véronique Truffinet; Francois Labrousse; Yves Denizot

    2006-01-01

    AIM: Platelet-activating factor (PAF) is a pro-inflammatory and angiogenic lipid mediator. Here we aimed to investigate levels of PAF, lyso-PAF (the PAF precursor),phospholipase A2 (PLA2, the enzymatic activity generating lyso-PAF), acetylhydrolase activity (AHA, the PAF degrading enzyme) and PAF receptor (PAF-R) transcripts in cirrhotic liver and hepatocellular carcinoma (HCC).METHODS: Twenty-nine patients with HCC were ehrolled in this study. Cirrhosis was present in fourteen patients and seven had no liver disease. Tissue PAF levels were investigated by a platelet-aggregation assay. LysoPAF was assessed after its chemical acetylation into PAF.AHA was determined by degradation of [3H]-PAF. PLA2 levels were assessed by EIA. PAF-R transcripts were investigated using RT-PCR.RESULTS: Elevated amounts of PAF and PAF-R transcripts 1 (leukocyte-type) were found in cirrhotic tissues as compared with non-cirrhotic ones. Higher amounts of PAF and PAF-R transcripts 1 and 2 (tissue-type) were found in HCC tissues as compared with non-tumor tissues. PLA2, lyso-PAF and AHA levels were not changed in cirrhotic tissues and HCC.CONCLUSION: While the role of PAF is currently unknown in liver physiology, this study suggests its potential involvement in the inflammatory network found in the cirrhotic liver and in the angiogenic response during HCC.

  4. Liver transplantation for hepatocellular carcinoma:an update

    Institute of Scientific and Technical Information of China (English)

    Ali Zarrinpar; Fady Kaldas; RonaldW Busuttil

    2011-01-01

    BACKGROUND: Hepatocellular carcinoma (HCC) is a heterogeneous malignancy with multiple etiologies, high incidence, and high mortality. The standard surgical management for patients with HCC consists of locoregional ablation, surgical resection, or liver transplantation, depending on the background state of the liver. Eighty percent of patients initially presenting with HCC are unresectable, either due to the extent of tumor or the level of underlying hepatic dysfunction. While in patients with no evidence of cirrhosis and good hepatic function resection has been the surgical treatment of choice, it is contraindicated in patients with moderate to severe cirrhosis. Liver transplantation is the optimal surgical treatment. DATA  SOURCES: PubMed search of recent articles (from January 2000 to March 2011) was performed looking for relevant articles about hepatocellular carcinoma and its treatment. Additional articles were identified by evaluating references from selected articles. RESULTS: Here we review criteria for transplantation, the types, indications, and role of locoregional therapy in treating the cancer and in downstaging for possible later transplantation. We also summarize the contribution of immunosuppression and adjuvant chemotherapy in the management and prevention of HCC recurrence. Finally we discuss recent advances in imaging, tumor biology, and genomics as we delineate the remaining challenges for the diagnosis and treatment of this disease. CONCLUSIONS: Much can be improved in the diagnosis and treatment of HCC. A great challenge will be to improve patient selection to criteria based on tumor biology. Another will be to incorporate systemic agents post-operatively in patients at high risk for recurrence, paying close attention to efficacy and safety. The future direction of the effort in treating HCC will be to stimulate prospective trials, develop molecular imaging of lymphovascular invasion, to improve recipient selection, and to investigate

  5. Hepatocellular proliferation and hepatocarcinogen bioactivation in mice with diet-induced fatty liver and obesity.

    Science.gov (United States)

    Iatropoulos, M J; Duan, J-D; Jeffrey, A M; Leach, M W; Hayes, A N; Stedman, N L; Williams, G M

    2013-05-01

    Human liver cancer is in part associated with obesity and related metabolic diseases. The present study was undertaken in a mouse model of diet-induced obesity (DIO) and hepatic steatosis, conditions which can be associated with hepatic neoplasia, to determine whether the rates of cell proliferation or hepatocarcinogen bioactivation were altered in ways which could facilitate hepatocarcinogenesis. DIO mice were generated by feeding C57BL/6 (B6) male mice a high-fat diet beginning at 4 weeks of age; age-matched conventional lean (LEAN) B6 mice fed a low fat diet (10% Kcal from fat) were used for comparison. Groups of 28 week old DIO and LEAN mice were dosed with the bioactivation-dependent DNA-reactive hepatocarcinogen 2-acetylaminofluorene (AAF), at 2.24 or 22.4 mg/kg, given by gavage 3 times per week for 31 days, or received no treatment (DIO and LEAN control groups). Compared with the LEAN control group, the DIO control group had a higher mean body weight (16.5 g), higher mean absolute (1.4 g) and mean relative (25.5%) liver weights, higher (394%) liver triglyceride concentrations, and an increased incidence and severity of hepatocellular steatosis at the end of the dosing phase. The DIO control group also had a higher mean hepatocellular replicating fraction (31% increase, determined by proliferating cell nuclear antigen immunohistochemistry). Hepatocarcinogen bioactivation, based on formation of AAF DNA adducts as measured by nucleotide (32)P-postlabeling, was similar in both DIO and LEAN AAF-dosed groups. Thus, hepatocellular proliferation, but not hepatocarcinogen bioactivation, was identified as an alteration in livers of DIO mice which could contribute to their susceptibility to hepatocarcinogenesis. Copyright © 2012 Elsevier GmbH. All rights reserved.

  6. Chemokine expression in hepatocellular carcinoma versus colorectal liver metastases

    Institute of Scientific and Technical Information of China (English)

    Claudia Rubie; Vilma Oliveira Frick; Mathias Wagner; Christina Weber; Bianca Kruse; Katja Kempf; Jochen K(o)nig; Bettina Rau; Martin Schilling

    2006-01-01

    AIM: To evaluate and compare the expression profiles of CXCL12 (SDF-1), CCL19 (MIP-3β), CCL20 (MIP-3α) and CCL21 (6Ckine, Exodus2) and their receptors on RNA and protein levels in hepatocellular carcinoma (HCC) versus colorectal liver metastases (CRLM) and to elucidate their impact on the carcinogenesis and progression of malignant liver diseases.METHODS: Chemokine expression was analyzed by RT-PCR and ELISA in 11 cases of HCC specimens and in 23 cases of CRLM and corresponding adjacent nontumorous liver tissues, respectively. Expressions of their receptors CXCR4, CCR6 and CCR7 were analyzed by RTPCR and Western blot analysis in the same cases of HCC and CRLM.RESULTS: Significant up-regulation for CCL20/CCR6 was detected in both cancer types. Moreover, CCL20demonstrated significant overexpression in CRLM in relation to the HCC tissues. Being significantly upregulated only in CRLM, CXCR4 displayed an aberrant expression pattern with respect to the HCC tissues.CONCLUSION: Correlation of CXCR4 expression with CRLM suggests CXCR4 as a potential predictive factor for CRLM. High level expression of CCL20 and its receptor CCR6 in HCC and CRLM with marked upregulation of CCL20 in CRLM in relation to HCC tissues indicates involvement of the CCL20/CCR6 ligand-receptor pair in the carcinogenesis and progression of hepatic malignancies.

  7. Indications and technique for laparoscopic liver resection in patients with hepatocellular carcinoma and liver cirrhosis

    Institute of Scientific and Technical Information of China (English)

    Yuichiro Otsuka; Masaru Tsuchiya; Toshio Katagiri; Yoshihisa Kubota; Jun Ishii; Tetsuya Maeda; Hironori Kaneko

    2016-01-01

    Liver resection is the preferred initial treatment option for solitary or limited multifocal hepatocellular carcinoma (HCC). However, because of the characteristics of HCC, including its high recurrence rate and the frequent presence of chronic hepatitis and cirrhosis, both curability and invasiveness must be considered when selecting a treatment for HCC. Laparoscopic liver resection (LLR) is minimally invasive and increasingly performed worldwide as a curative surgical option for treatment of liver tumors. The 2014 International Consensus Conference on LLR concluded that minor LLRs are now standard practice. Meta-analyses suggest that, as compared with open hepatectomy, LLR for patients with HCC, including those with cirrhosis, resulted in less blood loss, lower postoperative hospitalization rates, and similar oncological outcomes. Although candidates for this procedure should be carefully evaluated, LLR appears to be a feasible option for treatment of HCC with liver cirrhosis. This review describes the indications for LLR in this patient subgroup and offers guidance on appropriate surgical technique.

  8. Expression and survival prediction of microRNA-155 in hepatocellular carcinoma after liver transplantation

    Institute of Scientific and Technical Information of China (English)

    韩中博

    2013-01-01

    Objective To explore the expression of microRNA-155in hepatocellular carcinoma(HCC)and its contribution to recurrence and prognosis of HCC after liver transplantation(LT).Methods The expression levels

  9. Expression and survival prediction of microRNA-155 in hepatocellular carcinoma after liver transplantation

    Institute of Scientific and Technical Information of China (English)

    韩中博

    2013-01-01

    Objective To explore the expression of microRNA-155in hepatocellular carcinoma(HCC)and its contribution to recurrence and prognosis of HCC after liver transplantation(LT).Methods The expression levels of

  10. Surveillance for hepatocellular carcinoma in chronic liver disease: Evidence and controversies

    NARCIS (Netherlands)

    S. van Meer (Suzanne); R.A. de Man (Robert); P.D. Siersema (Peter); K.J. van Erpecum (Karel)

    2013-01-01

    textabstractPrimary liver cancer is the sixth most common cancer in the world and the third cause of cancer-related death. Hepatocellular carcinoma (HCC) represents more than 90% of primary liver cancers and generally occurs in patients with underlying chronic liver disease such as viral hepatitis,

  11. A case of spontaneous regression of hepatocellular carcinoma after ultrasound guided liver biopsy

    Energy Technology Data Exchange (ETDEWEB)

    Jo, Jeong Hyun [Dept. of Radiology, Dong A University Hospital, Dong A University College of Medicine, Busan (Korea, Republic of)

    2014-10-15

    Spontaneous regression of hepatocellular carcinoma after liver biopsy has not been reported in the English literature. Herein, we present a case of partial spontaneous regression of hepatocellular carcinoma after ultrasound guided liver biopsy in a 64-year-old female. During 28 months, the tumor, which had been shrinking, showed no interval change. However, after 28 months, tumor showed regrowth, which led to a segmentectomy.

  12. Small hepatocellular carcinomas in chronic liver disease: Detection with SPECT

    Energy Technology Data Exchange (ETDEWEB)

    Kudo, M.; Hirasa, M.; Takakuwa, H.; Ibuki, Y.; Fujimi, K.; Miyamura, M.; Tomita, S.; Komori, H.; Todo, A.; Kitaura, Y.

    1986-06-01

    Single-photon emission computed tomography (SPECT) performed using a rotating gamma camera was compared with ..cap alpha../sub 1/-fetoprotein (AFP) assay, conventional liver scintigraphy, ultrasound (US) imaging, computed tomography (CT), and selective celiac angiography in 40 patients with a total of 50 small hepatocellular carcinomas (HCCs;<5 cm). The detection rates of US and CT were determined on an initial screening study and on a second, more precisely focused study. The detection rate of small HCCs by the various modalities was as follows: AFP, 13%; liver scintigraphy, 36%; SPECT, 72%; initial screening US, 80%; second, more precise US studies, 94%; initial screening CT, 64%; second, more precise CT study, 82%; angiography, 88%. Although SPECT was inferior to the initial screening US examination in detecting HCCs less than 2 cm in size, its sensitivity was identical to that of the initial screening US study for detecting HCCs of 2-5 cm. The combination of SPECT and US was an excellent method for the early detection of HCCs, yielding a detection rate of 94%.

  13. Liver Surgery for Hepatocellular Carcinoma: Laparoscopic versus Open Approach

    Directory of Open Access Journals (Sweden)

    C. G. Ker

    2011-01-01

    Full Text Available In this study, we try to compare the benefit of laparoscopic versus open operative procedures. Patients and Methods. One hundred and sixteen patients underwent laparoscopic liver resection (LR and another 208 patients went for open liver resection (OR for hepatocellular carcinoma (HCC. Patients' selection for open or laparoscopic approach was not randomized. Results. The CLIP score for LR and OR was 0.59 ± 0.75 and 0.86 ± 1.04, respectively, (=.016. The operation time was 156.3 ± 308.2 and 190.9 ± 79.2 min for LR and OR groups, respectively. The necessity for blood transfusion was found in 8 patients (6.9% and 106 patients (50.9% for LR and OR groups. Patients resumed full diet on the 2nd and 3rd postoperative day, and the average length of hospital stay was 6 days and 12 days for LR and OR groups. The complication rate and mortality rate were 0% and 6.0%, 2.9% and 30.2% for LR and OR groups, respectively. The 1-yr, 3-yr, and 5-yr survival rate was 87.0%, 70.4%, 62.2% and 83.2%, 76.0%, 71.8% for LR and OR group, respectively, of non-significant difference. From these results, HCC patients accepted laparoscopic or open approach were of no significant differences between their survival rates.

  14. Sorafenib in Liver Function Impaired Advanced Hepatocellular Carcinoma

    Institute of Scientific and Technical Information of China (English)

    You-xin Ji; Lei Sun; Zong-chun Zhang; Zhong-fa Zhang; Ke-tao Lan; Ke-ke Nie; Chuan-xin Geng; Shi-chao Liu; Ling Zhang; Xing-jun Zhuang; Xiao Zou

    2014-01-01

    Objective To explore the efficacy and safty of sorafenib in Child-Pugh class B to class C hepatocellular carcinoma (HCC). Methods In this three-center open-label study from November 2011 to May 2013, we randomly assigned 189 patients with advanced Child-Pugh class B or C HCC patients into two groups, one group with 95 patient to receive sorafenib (400 mg a time, twice a day) and the other group with 94 patients to receive best supportive care. The primary end points were progression-free survival and overall survival. Results The median progression-free survival was 2.2 months and 1.9 months in the sorafenib group and best supportive care group respectively (Hazard ratio in the sorafenib group, 0.55; 95% confidence interval, 0.40-0.75;P=0.002). The median overall survival was 4.0 months and 3.5 months in the sorafenib group and best supportive care group respectively (Hazard ratio in the sorafenib group, 0.48;95%confidence interval, 0.35-0.68;P Conclusions Sorafenib is safe in patients with liver function impaired advanced HCC. It is effective in terms of progression-free survival and overall survival compared with best supportive care. Liver functions are the important predictive factors.

  15. Hepatic progenitor cells in human liver tumor development

    Institute of Scientific and Technical Information of China (English)

    Louis Libbrecht

    2006-01-01

    In recent years, the results of several studies suggest that human liver tumors can be derived from hepatic progenitor cells rather than from mature cell types.The available data indeed strongly suggest that most combined hepatocellular-cholangiocarcinomas arise from hepatic progenitor cells that retained their potential to differentiate into the hepatocytic and biliary lineages.Hepatic progenitor cells could also be the basis for some hepatocellular carcinomas and hepatocellular adenomas, although it is very difficult to determine the origin of an individual hepatocellular carcinoma. There is currently not enough data to make statements regarding a hepatic progenitor cell origin of cholangiocarcinoma.The presence of hepatic progenitor cell markers and the presence and extent of the cholangiocellular component are factors that are related to the prognosis of hepatocellular carcinomas and combined hepatocellularcholangiocarcinomas, respectively.

  16. Salvage Liver Transplantation Leads to Poorer Outcome in Hepatocellular Carcinoma Compared with Primary Liver Transplantation

    Science.gov (United States)

    Shan, Yuhua; Huang, Lifeng; Xia, Qiang

    2017-01-01

    Hepatocellular carcinoma is the most common liver malignancy. Salvage liver transplantation (SLT) is viewed as a feasible cure for recurrence of HCC after resectomy, but the effect is under dispute. A retrospective study examined data at Renji Hospital for 239 transplants from January 2006 to December 2015, including 211 who received primary liver transplantation (PLT) and 28 who underwent SLT. A multivariable cox regression model was employed to pick out relative factors to overall survival (OS) and recurrence free survival (RFS). Propensity score matching (PSM) was used to balance the bias. Both OS and RFS were worse in SLT group than in PLT group, especially for those patients within Milan criteria. Our study demonstrates that SLT bears higher risk of recurrence and death than PLT, indicating that SLT should be given a more careful thought at performance. PMID:28294176

  17. Human arylacetamide deacetylase hydrolyzes ketoconazole to trigger hepatocellular toxicity.

    Science.gov (United States)

    Fukami, Tatsuki; Iida, Azumi; Konishi, Keigo; Nakajima, Miki

    2016-09-15

    Ketoconazole (KC), an antifungal agent, rarely causes severe liver injury when orally administered. It has been reported that KC is mainly hydrolyzed to N-deacetyl ketoconazole (DAK), followed by the N-hydroxylation of DAK by flavin-containing monooxygenase (FMO). Although the metabolism of KC has been considered to be associated with hepatotoxicity, the responsible enzyme(s) remain unknown. The purpose of this study was to identify the responsible enzyme(s) for KC hydrolysis in humans and to clarify their relevance to KC-induced toxicity. Kinetic analysis and inhibition studies using human liver microsomes (HLM) and recombinant enzymes revealed that human arylacetamide deacetylase (AADAC) is responsible for KC hydrolysis to form DAK, and confirmed that FMO3 is the enzyme responsible for DAK N-hydroxylation. In HLM, the clearance of KC hydrolysis occurred to the same extent as DAK N-hydroxylation, which indicates that both processes are not rate-limiting pathways. Cytotoxicity of KC and DAK was evaluated using HepaRG cells and human primary hepatocytes. Treatment of HepaRG cells with DAK for 24h showed cytotoxicity in a dose-dependent manner, whereas treatment with KC did not show due to the low expression of AADAC. Overexpression of AADAC in HepaRG cells with an adenovirus expression system elicited the cytotoxicity of KC. Cytotoxicity of KC in human primary hepatocytes was attenuated by diisopropylfluorophosphate, an AADAC inhibitor. In conclusion, the present study demonstrated that human AADAC hydrolyzes KC to trigger hepatocellular toxicity.

  18. Effect of living donor liver transplantation on outcome of children with inherited liver disease and hepatocellular carcinoma.

    Science.gov (United States)

    Ozçay, Figen; Canan, Oğuz; Bilezikçi, Banu; Torgay, Adnan; Karakayali, Hamdi; Haberal, Mehmet

    2006-01-01

    We described six children with heritable liver disease and hepatocellular carcinoma treated with living-related liver transplantation. Underlying liver diseases were type-1 tyrosinemia (three patients), progressive familial intrahepatic cholestasis type II (two patients), and Wilson's disease (one patient). Two of the tumors were found incidentally during liver transplantation. Number of nodules was 12, 15, 3, 2, and 1 (in two patients). Three patients were treated with chemotherapy before the procedure. Chemotherapy was not given to any patient after liver transplantation. The mean follow-up was 17.7 +/- 6 months (range: 7-24). All patients are tumor recurrence free. Both graft and patient survival rates are 100% at a median of 18.5 months follow-up. Physicians in charge of treating children with heritable liver disease should screen them periodically for the development of hepatocellular carcinoma. Liver transplantation may offer these children better survival rates.

  19. Proteome Characteristics of Non-Alcoholic Steatohepatitis Liver Tissue and Associated Hepatocellular Carcinomas

    Science.gov (United States)

    Kakehashi, Anna; Stefanov, Vasily E.; Ishii, Naomi; Okuno, Takahiro; Fujii, Hideki; Kawai, Kazuaki; Kawada, Norifumi; Wanibuchi, Hideki

    2017-01-01

    To uncover mechanisms of nonalcoholic steatohepatitis (NASH) associated hepatocarcinogenesis, we compared the proteomes of human NASH-associated liver biopsies, resected hepatocellular carcinomas (HCCs) and HCCs of HCV+ patients with normal liver tissue of patients with gastrointestinal tumor metastasis, in formalin-fixed paraffin-embedded samples obtained after surgery in our hospital during the period from 2006 to 2011. In addition, proteome analysis of liver tumors in male STAM NASH-model mice was performed. Similar changes in the proteome spectrum such as overexpression of enzymes involved in lipid, cholesterol and bile acid biosynthesis and examples associated with suppression of fatty acid oxidation and catabolism, alcohol metabolism, mitochondrial function as well as low expression levels of cytokeratins 8 and 18 were observed in both human NASH biopsies and NASH HCCs, but not HCV+ HCCs. Alterations in downstream protein expression pointed to significant activation of transforming growth factor β, SMAD family member 3, β-catenin, Nrf2, SREBP-LXRα and nuclear receptor-interacting protein 1 (NRIP1), and inhibition of PPARs and p53 in human NASH biopsies and/or HCCs, suggesting their involvement in accumulation of lipids, development of fibrosis, oxidative stress, cell proliferation and suppression of apoptosis in NASH hepatocarcinogenesis. In STAM mice, PPARs inhibition was not obvious, while expression of cytokeratins 8 and 18 was elevated, indicative of essential differences between human and mouse NASH pathogenesis. PMID:28218651

  20. Clinical studies of hepatocellular carcinoma with liver cirrhosis and ascites.

    Directory of Open Access Journals (Sweden)

    Yuasa,Shiro

    1984-06-01

    Full Text Available A comparison was made of the clinical findings of 59 patients with liver cirrhosis (LC accompanied with hepatocellular carcinoma (HCC (of which 35 had ascites and 24 did not at the time of admission and 164 patients with LC, but without HCC (of which 39 had ascites and 125 did not. HCC patients were older and more often had hepatomegaly, vascular spider and pleural effusion than LC patients. Ascites was more frequently observed in HCC than in LC patients when the serum albumin level and the indocyanine green disappearance rate were relatively well maintained and when peripheral edema was absent. There was no difference in the ascitic protein concentration between LC and HCC patients. Malignant cells were detected in ascites only in 14% of the HCC patients. These facts indicate the presence of ascites-inducing factors in HCC patients which have no direct relation to serum colloid osmotic pressure and effective hepatic blood flow. Almost all of the HCC patients with ascites (96% died with ascites, whereas 54% of the LC patients with ascites recovered from the ascitic condition.

  1. Major liver resection for hepatocellular carcinoma in the morbidly obese: A proposed strategy to improve outcome

    Directory of Open Access Journals (Sweden)

    Ozaki Claire F

    2008-09-01

    Full Text Available Abstract Background Morbid obesity strongly predicts morbidity and mortality in surgical patients. However, obesity's impact on outcome after major liver resection is unknown. Case presentation We describe the management of a large hepatocellular carcinoma in a morbidly obese patient (body mass index >50 kg/m2. Additionally, we propose a strategy for reducing postoperative complications and improving outcome after major liver resection. Conclusion To our knowledge, this is the first report of major liver resection in a morbidly obese patient with hepatocellular carcinoma. The approach we used could make this operation nearly as safe in obese patients as it is in their normal-weight counterparts.

  2. Hepatocellular carcinoma in noncirrhotic livers is associated with steatosis rather than steatohepatitis: potential implications for pathogenesis

    NARCIS (Netherlands)

    van Meer, S; van Erpecum, KJ; Sprengers, Dave; Klümpen, Heinz-Josef; Jansen, P.L.M.; Ijzermans, Jan N. M.; Siersema, PD; de Man, R.A.

    2016-01-01

    Objective: The risk of hepatocellular carcinoma (HCC) is increased in patients with metabolic syndrome (MS), possibly related to nonalcoholic fatty liver disease (NAFLD). As histological features of NAFLD may regress in cirrhosis, we compared steatosis versus steatohepatitis in the nontumoral liver

  3. Hepatitis C impairs survival following liver transplantation irrespective of concomitant hepatocellular carcinoma

    DEFF Research Database (Denmark)

    Melum, Espen; Friman, Styrbjörn; Bjøro, Kristian;

    2007-01-01

    BACKGROUND/AIMS: Liver transplantation (LTX) is the only curative treatment for end-stage liver disease caused by hepatitis C (HCV). Hepatocellular carcinoma (HCC) is common in patients with HCV cirrhosis. METHODS: Two hundred and eighty-two HCV patients listed for LTX in the Nordic countries...

  4. Hand-Assisted Laparoscopic Hepatectomy for Primary Clear Cell Hepatocellular Carcinoma of the Liver

    Directory of Open Access Journals (Sweden)

    Kazutoshi Kida

    2012-05-01

    Full Text Available We report a case of primary clear cell hepatocellular carcinoma of the liver (PCCCL for which we performed hand-assisted laparoscopic hepatectomy. A 71-year-old female with hepatitis C infection and diabetes mellitus was admitted to our department for a hepatic tumor with gallstone. Abdominal computed tomography revealed a tumor 25 mm in diameter on the surface in segment 5 of the liver. The imaging results suggested small hepatocellular carcinoma located on the surface in segment 5 of the liver, and we performed laparoscopic surgery aiming at a minimally invasive procedure. We performed laparoscopic cholecystectomy and hand-assisted laparoscopic hepatectomy. Histopathological findings showed moderately differentiated hepatocellular carcinoma, and as the proportion of clear cells was 75%, the tumor was diagnosed as PCCCL. This is the first report of hand-assisted laparoscopic hepatectomy for PCCCL. Laparoscopic hepatectomy is a useful minimally invasive surgical procedure when the tumor is located on the surface of the liver.

  5. Chemopreventive effect of corosolic acid in human hepatocellular ...

    African Journals Online (AJOL)

    Chemopreventive effect of corosolic acid in human hepatocellular carcinoma cells. ... The anticancer activity of corosolic acid through cell growth inhibition by 3-(4 ... and apoptotic fragmentations by fluorescence microscope was evaluated.

  6. Gastric Metastasis of Hepatocellular Carcinoma With Gastrointestinal Bleeding After Liver Transplant: A Case Report.

    Science.gov (United States)

    Li, L; Zhang, W H; Meng, F P; Ma, X M; Shen, L J; Jin, B; Li, H W; Han, J; Zhou, G D; Liu, S H

    2015-10-01

    Gastrointestinal (GI) metastasis of hepatocellular carcinoma is very rare. This is the first report of post-transplantation gastric metastasis. A 43-year-old man with a history of hepatitis B-related hepatocellular carcinoma (HCC) in the right anterior segment of the liver received an orthotopic liver transplant. Three months after the transplantation, pulmonary metastasis was found by chest computed tomography, and he received 1 course of gamma knife treatment. He complained of melena with anemia 17 months post liver transplantation. Abdominal CT scan showed new occupying lesions in the liver and a mass in the stomach and around the spleen with embolus in the splenic vein. Endoscopy revealed a large irregular cauliflower-like mass in fundus with ulceration and bleeding on the surface. He received symptomatic treatment, but died of cancer-related bleeding 4 months later. GI bleeding may due to gastric metastasis after liver transplantation.

  7. Mast cells and human hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Fabio Grizzi; Barbara Franceschini; Maurizio Chiriva-Internati; Young Liu; Paul L. Hermonat; Nicola Dioguardi

    2003-01-01

    AIM: To investigate the density of mast cells (MCs) in human hepatocellular carcinoma (HCC), and to determine whether the MCs density has any correlations with histopathological grading, staging or some baseline patient characteristics.METHODS: Tissue sections of 22 primary HCCs were histochemically stained with toluidine blue, in order to be able to quantify the MCs in and around the neoplasm using a computer-assisted image analysis system. HCC was staged and graded by two independent pathologists. To identify the sinusoidal capillarisation of each specimen 3μm thick sections were histochemically stained with sirius red, and semi-quantitatively evaluated by two independent observers. The data were statistically analysed using Spearman′s correlation and Student′s t-test when appropriate.RESULTS: MCs density did not correlate with the age or sex of the patients, the serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels, or the stage or grade of the HCC. No significant differences were found between the MCs density of the patients with and without hepatitis C virus infection, but they were significantly higher in the specimens showing marked sinusoidal capillarisation.CONCLUSION: The lack of any significant correlation between MCs density and the stage or grade of the neoplastic lesions suggests that there is no causal relationship between MCs recruitment and HCC. However, as capillarisation proceeds concurrently with arterial blood supply during hepatocarcinogenesis, MCs may be considered of primary importance in the transition from sinusoidal to capillary-type endothelial cells and the HCC growth.

  8. Preoperative Alpha-Fetoprotein Slope is Predictive of Hepatocellular Carcinoma Recurrence after Liver Transplantation

    Directory of Open Access Journals (Sweden)

    Kathy Han

    2007-01-01

    Full Text Available BACKGROUND: Liver transplantation (LT offers a possible cure for patients with hepatocellular carcinoma (HCC and cirrhosis. However, tumour progression while on the waiting list and tumour recurrence after LT are common. The prognostic significance of various pre- and postoperative variables were investigated in regard to tumour recurrence, with an emphasis on the slope of preoperative serum alpha-fetoprotein (AFP levels.

  9. Serologic and molecular biomarkers for recurrence of hepatocellular carcinoma after liver transplantation

    DEFF Research Database (Denmark)

    Pommergaard, Hans-Christian; Burcharth, Jakob Hornstrup Frølunde; Rosenberg, Jacob

    2016-01-01

    and molecular biomarkers for recurrence of hepatocellular carcinoma after liver transplantation. METHODS: A literature search was performed in the databases PubMed and Scopus to identify observational studies evaluating serological or molecular biomarkers for recurrence of HCC after LT using adjusted analysis...

  10. Diagnosis of. Hepatocellular Carcinoma in Patients with Liver Cir­rhosis Using Liver Function Assays

    Directory of Open Access Journals (Sweden)

    Itoshima,Tatsuya

    1984-04-01

    Full Text Available Sex, age and 21 routine liver function assays were analyzed by stepwise selection and the best-of-all-possible-combinations method to identify a small group of assays valuable in establishing which liver cirrhosis (LC patients have a high risk of hepatocellular carcinoma (HCC, when alpha-fetoprotein (AFP is not elevated. Data was obtained from 115 HCC and 122 LC patients on admission. Tumor size correlated with AFP (0.73, alkaline phosphatase (ALP, 0.47, leucine aminopeptidase (LAP, 0.42, lactic dehydrogenase (LDH, 0.42, and the glutamic oxaloacetic transaminase (GOT/glutamic pyruvic transaminase (GPT ratio (GOT/GPT, 0.41. The mean of the correct diagnosis rates (CDR of HCC and LC utilizing AFP as the sole parameter (89% was markedly higher than those of the other parameters. The best-of-all-possible-combinations method presented a more powerful combination than stepwise selection. The best combination of 7 parameters (LAP, GOT/GPT, choline esterase, one-hour erythrocyte sedimentation rate, age, albumin/globulin ratio, and total bilirubin presented a mean CDR of 80%, HCC CDR of 77%, and false positive rate of 18%. LC patients statistically diagnosed as having HCC by these 7 parameters are proposed as high risk patients. Fourteen (78% of 18 HCC patients who were AFP-negative were statistically diagnosed. This analysis can be applied to LC patients to distinguish those that should be followed closely by imaging diagnostic techniques.

  11. Carcinogen-Induced Hepatic Tumors in KLF6+/- Mice Recapitulate Aggressive Human Hepatocellular Carcinoma Associated with p53 Pathway Deregulation

    NARCIS (Netherlands)

    Tarocchi, Mirko; Hannivoort, Rebekka; Hoshida, Yujin; Lee, Ursula E.; Vetter, Diana; Narla, Goutham; Villanueva, Augusto; Oren, Moshe; Llovet, Josep M.; Friedman, Scott L.

    2011-01-01

    Inactivation of KLF6 is common in hepatocellular carcinoma (HCC) associated with hepatitis C virus (HCV) infection, thereby abrogating its normal antiproliferative activity in liver cells. The aim of the study was to evaluate the impact of KLF6 depletion on human HCC and experimental hepatocarcinoge

  12. Liver transplantation for patients with hepatocellular carcinoma at the Liver Cancer Institute of Fudan University, China

    Institute of Scientific and Technical Information of China (English)

    ZHOU Jian; HE Yi-feng; YANG Guo-huan; SONG Kang; YUAN Zhou; WANG Yu-qi; TANG Zhao-you; FAN Jia; WU Zhi-quan; QIU Shuang-jian; HUANG Xiao-wu; YU Yao; WANG Zheng; SUN Jian; XIAO Yong-sheng

    2005-01-01

    Background Selection of patients with hepatocellular carcinoma (HCC) for orthotopic liver transplantation (OLT) remains controversial. Since there is a trend to expand the transplant criteria for HCC patients, we reviewed the data of patients with HCC who had received OLT at our institute to determine their survival and prognostic factors.Methods A total of 67 patients with HCC who had undergone OLT from April 2001 through December 2003 were reviewed retrospectively. Selection OLT candidates with HCC was dependent on the anatomical characteristics and/or the severity of underlying liver cirrhosis. The 67 patients were followed up for more than 6 months after transplantation. Their survival rate was calculated by the Kaplan-Meier method. Univariate and multivariate analyses using the Cox proportional hazards regression model were performed to reveal the factors affecting the survival rate.Results No perioperative death occurred in this series. The 1- and 2-year cumulative survival rates were 90.0% and 65.6%, and the disease-free survival (DFS) rates were 77.5% and 62.5% respectively. Univariate analysis revealed the tumor size, portal vein tumor thrombus (PVTT), serum alpha-fetoprotein level, bilobular distribution of tumors, pTNM stage and histological differentiation were statistically significant factors affecting the DFS (P<0.05). Multivariate analysis showed tumor size and PVTT were independent and statistically significant factors affecting the DFS (P=0.005 and 0.010, respectively). In this series, all but 2 received systemic chemotherapy, among them 13 had tumor recurrence within 8 months after OLT.Conclusions OLT is indicated for patients with HCC, even for some patients with end-stage liver disease who may survive longer without tumor recurrence. Adjuvant chemotherapy may decrease the recurrence of HCC after OLT.

  13. Decreased PCSK9 expression in human hepatocellular carcinoma

    OpenAIRE

    2015-01-01

    Background The management of hepatocellular carcinoma (HCC) is limited by the lack of adequate screening biomarkers and chemotherapy. In response, there has been much interest in tumor metabolism as a therapeutic target. PCSK9 stimulates internalization of the LDL-receptor, decreases cholesterol uptake into hepatocytes and affects liver regeneration. Thus, we investigated whether PCSK9 expression is altered in HCC, influencing its ability to harness cholesterol metabolism. Methods Thirty-nine...

  14. CD151 supports VCAM-1-mediated lymphocyte adhesion to liver endothelium and is upregulated in chronic liver disease and hepatocellular carcinoma.

    Science.gov (United States)

    Wadkin, James C R; Patten, Daniel A; Kamarajah, Sivesh K; Shepherd, Emma L; Novitskaya, Vera; Berditchevski, Fedor; Adams, David H; Weston, Chris J; Shetty, Shishir

    2017-08-01

    CD151, a member of the tetraspanin family of receptors, is a lateral organizer and modulator of activity of several families of transmembrane proteins. It has been implicated in the development and progression of several cancers, but its role in chronic inflammatory disease is less well understood. Here we show that CD151 is upregulated by distinct microenvironmental signals in a range of chronic inflammatory liver diseases and in primary liver cancer, in which it supports lymphocyte recruitment. CD151 was highly expressed in endothelial cells of the hepatic sinusoids and neovessels developing in fibrotic septa and tumor margins. Primary cultures of human hepatic sinusoidal endothelial cells (HSECs) expressed CD151 at the cell membrane and in intracellular vesicles. CD151 was upregulated by VEGF and HepG2 conditioned media but not by proinflammatory cytokines. Confocal microscopy confirmed that CD151 colocalized with the endothelial adhesion molecule/immunoglobulin superfamily member, VCAM-1. Functional flow-based adhesion assays with primary human lymphocytes and HSECs demonstrated a 40% reduction of lymphocyte adhesion with CD151 blockade. Inhibition of lymphocyte adhesion was similar between VCAM-1 blockade and a combination of CD151/VCAM-1 blockade, suggesting a collaborative role between the two receptors. These studies demonstrate that CD151 is upregulated within the liver during chronic inflammation, where it supports lymphocyte recruitment via liver endothelium. We propose that CD151 regulates the activity of VCAM-1 during lymphocyte recruitment to the human liver and could be a novel anti-inflammatory target in chronic liver disease and hepatocellular cancer prevention.NEW & NOTEWORTHY Chronic hepatitis is characterized by lymphocyte accumulation in liver tissue, which drives fibrosis and carcinogenesis. Here, we demonstrate for the first time that the tetraspanin CD151 supports lymphocyte adhesion to liver endothelium. We show that CD151 is upregulated in

  15. Solitary pulmonary metastasis arising thirteen years after liver transplantation for HBV-related hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Chiara Viola; Tarik Asselah; Didier Samuel; Fran(c)ois Durand; Hamza Boudjema; Dominique Vaila; Patrick Marcellin

    2006-01-01

    We described a 59-year-old male patient who underwent liver transplantation in 1989 for hepatocellular carcinoma (HCC) complicating hepatitis B virus (HBV) cirrhosis. In 2001 (12 years after liver transplantation), he developed a lung metastasis of HCC without intrahepatic recurrence and the resection was done. In July 2003, he was symptom free without any recurrence. HCCmetastasis can develop even after a very long time of liver transplantation. Many HCCs grow slowly, and the growth rate of recurrent tumors in patients receiving immunosuppressive therapy is significantly greater thanthat of those who do not receive immunosuppressive therapy.

  16. Up-regulation of fibroblast growth factor 19 and its receptor associates with progression from fatty liver to hepatocellular carcinoma

    Science.gov (United States)

    Doughtie, Anne; Cui, Guozhen; Li, Xuanyi; Pandit, Harshul; Yang, Yingbin; Li, Suping; Martin, Robert

    2016-01-01

    Background Human fibroblast growth factor 19 (FGF19), its receptor (FGFR4) and EpCAM play an important role in cell proliferation, differentiation, motility, and overexpression have been linked to hepatocellular carcinoma (HCC). The aim of this study was to evaluate the FGF19 signals responsible for the progression of HCC arising from fatty liver. Results FGF19 level was significantly increased in the HCC patients' serum compared to non-HCC controls. The IHC results demonstrated significant increases of protein expressions of FGF19, FGFR4 and EpCAM in specimens with fatty liver, NASH, cirrhosis, and HCC compared to healthy liver tissue. There was a significant positive correlation between the protein expressions (FGF19, FGFR4, and EpCAM) and histopathologic changes from FL to HCC. Furthermore, FGF19 was positively correlated with FGFR4 and with EpCAM. Materials and Methods FGF19 protein levels in serum and tissues were determined by ELISA assay. The FGFR4, and EpCAM expression and tissue distribution were further evaluated by immunohistochemical staining in tissue array samples. FGF19, FGFR4 and EpCAM expressions between the different histologic stages of fatty liver steatohepatitis-cirrhosis-HCC carcinogenesis sequence were compared to healthy hepatic tissue. Conclusions Overexpression of FGF19/FGFR4 significantly correlated with EpCAM as a marker of hepatic cancer stem cells within the fatty liver-steatosis-cirrhosis-HCC sequence. Impact This is the first study to elucidate FGF19/FGFR4 signaling in favor of HCC cells developing as indicated by increased EpCAM within the carcinogenesis sequence from fatty liver to hepatocellular carcinoma. Our study has the potential to yield novel and cost effective screening strategies for HCC patients. PMID:27447573

  17. Trends in Incidences and Risk Factors for Hepatocellular Carcinoma and Other Liver Events in HIV and Hepatitis C Virus-coinfected Individuals From 2001 to 2014

    DEFF Research Database (Denmark)

    Gjærde, Lars Iversen; Shepherd, Leah; Jablonowska, Elzbieta

    2016-01-01

    BACKGROUND: While liver-related deaths in human immunodeficiency virus (HIV) and hepatitis C virus (HCV)-coinfected individuals have declined over the last decade, hepatocellular carcinoma (HCC) may have increased. We describe the epidemiology of HCC and other liver events in a multicohort...... collaboration of HIV/HCV-coinfected individuals. METHODS: We studied HCV antibody-positive adults with HIV in the EuroSIDA study, the Southern Alberta Clinic Cohort, the Canadian Co-infection Cohort, and the Swiss HIV Cohort study from 2001 to 2014. We calculated the incidence of HCC and other liver events...

  18. Serine protease HtrA1 expression in human hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Feng Zhu; Lei Jin; Tian-Ping Luo; Guang-Hua Luo; Yan Tan; Xi-Hu Qin

    2010-01-01

    BACKGROUND: HtrA1, a serine protease, is down-regulated in various human solid tumors. Overexpression of HtrA1 in human cancer cells inhibits cell growth and proliferation in vitro and in vivo, suggesting its possible role as a tumor suppressor. METHODS: Immunohistochemistry was used to determine the expression of HtrA1 in 50 hepatocellular carcinoma specimens and adjacent liver tissues. The correlation between the expression of HtrA1 and the clinico-pathologic data were analyzed. RESULTS:  The levels of HtrA1 were lower in tumor tissues than in their adjacent liver tissues. Moreover, an inverse relationship was found between HtrA1 expression and the differentiation of hepatocellular carcinoma. Loss of HtrA1 was more frequently found in tumors in Edmondson grade III-IV, especially in those with venous invasion, compared to tumors in Edmondson grade I-II. Most importantly, patients with higher HtrA1 expression had a better survival rate. CONCLUSION: All these data suggest an important role of HtrA1 in hepatocellular carcinoma development and progression, which may be a new target for its treatment.

  19. Antitumor Effects of Soluble TRAIL in Human Hepatocellular Carcinoma

    Institute of Scientific and Technical Information of China (English)

    HE Songqing; CHEN Yan; CHEN Xiaoping; ZHAO Yongzhong; WANG Haiping; ZHANG Wanguang; WANG Shaofa

    2005-01-01

    The therapeutic potential of soluble TRAIL (sTRAIL) in hepatocellular carcinoma(HCC) was studied. The expression of TRAIL receptors was detected in 60 HCC tissues, 20 normal liver samples and 2 HCC cell lines (HepG2 and SMMC-7721) by in situ hybridization. Before and after HepG2 and SMMC-7721 were treated with sTRAIL protein with various concentrations,the apoptosis rate was observed by using flow cytometry and in situ terminal deoxynucleotidyl tranferase (TdT) labeling. The results showed death receptor 4 (DR4) and DR5 were expressed in 60 HCC tissues and 20 normal liver samples, while the expression intensity of DR in HCC tissues was stronger than in normal liver samples. DcR1and DcR2 were not detectable in 54 (90 %) and 25 (41.7 %)HCC tissues, while in 20 normalliver samples, DcR was detectable. The high expressionof DR and low expression of DcR in HCC tissues were significantly differed from the low expression and high expression in normal liver samples. The expression of DR5, DR4 and DcR2 in both HCC cell lines was detectable, but the expression of DcR1 was not detectable. The expression of DR in HCC tissues was related to the differentiation and grades of HCC. In the poor differentiated HCC, the expression of DR was decreased (P<0.01). The expression of DR in Ⅲ/Ⅳ grades was significantly lower than that in Ⅰ / Ⅱ grades (P<0.05). The expression of DR was not related to gender, age, HBsAg, AFP, tumor sizeand metastasis. The expression of DR in the HCC drugresistant lines was decreased. After treatment with TRAIL (100 ng/ml) for 24 h, the apoptosis rate of HCC cells, Jurkat cells and human cholangiocarcinoma cell line QBC939 was 10 %, 70 %,50 % respectively. It was suggested that the TRAILR expression is prevalent in HCC with different expression patterns of different receptor types. HCC is resistant to TRAIL-mediated apoptosis.The treatment of TRAIL alone has a limited effect on inducing apoptosis of HepG2 and SMMC-7721.

  20. Liver cell adenoma showing sequential alteration of radiological findings suggestive of well-differentiated hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Takayuki Kogure; Yoshiyuki Ueno; Satoshi Sekiguchi; Kazuyuki Ishida; Takehiko Igarashi; Yuta Wakui; Takao Iwasaki; Tooru Shimosegawa

    2009-01-01

    A liver tumor 35 mm in diameter was found incidentally in a 40-year-old woman who had no history of liver diseases or the use of oral contraceptives. Radiological diagnostics showed the typical findings of liver cell adenoma (LCA). Dynamic computed tomography revealed that the tumor showed a homogenous enhancement in the arterial phase and almost the same enhancement as the surrounding liver parenchyma in the delayed phase. The tumor was found to contain fat on magnetic resonance imaging. A benign fat containing liver tumor was suggested. However, radiological findings altered, which caused us to suspect that a welldifferentiated hepatocellular carcinoma (HCC) containing fat was becoming dedifferentiated. Partial hepatectomy was performed and the pathological findings showed the typical findings of LCA. This case was an extremely rare LCA, which had no background of risk for LCA and developed the sequential alteration of the radiological findings to suspect well-differentiated HCC.

  1. Reactive lymphoid hyperplasia of the liver mimicking hepatocellular carcinoma: incidental finding of two cases.

    Science.gov (United States)

    Lv, Ang; Liu, Wendy; Qian, Hong-Gang; Leng, Jia-Hua; Hao, Chun-Yi

    2015-01-01

    Reactive lymphoid hyperplasia is a rare disease that forms a mass-like lesion and is characterized by the proliferation of non-neoplastic, polyclonal lymphocytes forming follicles. We recently encountered 2 cases of reactive lymphoid hyperplasia of liver, both of which were asymptomatic and mimicked hepatocellular carcinoma by various imaging modalities. Based on the clinical impression of hepatocellular carcinoma, surgical resections were performed. Microscopic findings revealed that both lesions consisted of an aggregation of lymphocytes consisting of predominantly B-cells, with multiple lymphoid follicles positive for CD10 and negative for bcl-2, consistent with the diagnosis of reactive lymphoid hyperplasia. Polyclonality of both lesions was further confirmed by B cell receptor gene rearrangement study. The incidence of reactive lymphoid hyperplasia in the liver is exceedingly rare, and it is difficult to differentiate such lesions from hepatic malignancies based upon clinical grounds. The clinicopathological findings and literature review of this report may be helpful to improve the clinical decision-making.

  2. Hepatocellular Carcinoma in a Noncirrhotic Liver after Long-Term Use of Danazol for Hereditary Angioedema

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    Soraya Rahal

    2014-12-01

    Full Text Available We report a 57-year-old male who was treated with high-dose danazol for hereditary angioedema for more than 30 years; he developed hepatocellular carcinoma in the absence of cirrhosis. Despite surgical resection, he had a recurrence and received sorafenib, but had a poor skin tolerance. Such tumors arising after danazol are infrequent, and this case is highly unique due to the minor lesions found on the liver.

  3. Primary hepatocellular carcinoma in ectopic liver masquerading as left adrenal carcinoma: a rare occurrence

    Directory of Open Access Journals (Sweden)

    Shailendra Kumar

    2010-06-01

    Full Text Available We report a unique case of primary hepatocellular carcinoma in an ectopic liver rest in the left renal hilum masquerading as a left adrenal tumor. Adrenal tumors have been reported within adrenal rests inside the liver but hepatocellular carcinoma in ectopic liver rests in the adrenal area is an extremely rare entity. To the best of our knowledge, this is the first case report from the Indian subcontinent to describe this event in the English literature. Our patient, a sixty-year-old, non-diabetic, non-hypertensive male, presented with a history of left flank pain for the past six months. He was a chronic smoker and also consumed excessive amounts of alcohol. He had chronic obstructive pulmonary disease and was hepatitis B surface antigen positive. A contrast enhanced computer tomography scan of the abdomen showed an 8¥8¥8 cm, well-defined, heterogeneously enhancing mass with central necrosis, in the left suprarenal region. The provisional diagnosis of an adrenal tumor was made and open transperitoneal excision of the tumor along with two enlarged lymph nodes was done. Immunohistochemistry staining of the specimen revealed it to be a primary hepatocellular carcinoma. The patient died within six months of surgery owing to extensive metastases. We concluded that chronic hepatitis B infection and chronic and excessive alcohol consumption and/or chronic smoking may have been the predisposing factors for the occurrence of primary hepatocellular carcinoma in the liver rest in our patient. The prognosis appears to be poor despite surgical management.

  4. Predictive factors for liver dysfunction and failure after hepatectomy: Analysis of 467 patients with hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Guangjin Du; Liqun Wu; Chengzhan Zhu; Rong Ye; Xin Yi

    2012-01-01

    Objective: The aim of our study was to analyze hepatic dysfunction and failure after hepatocellular carcinoma (HCC) resection and relationship of clinical and pathological factors.Methods: Clinical and pathological data of 467 HCC patients was retrospectively reviewed, who underwent liver resection from January 2002 to December 2008 in the Affiliated Hospital of Medical College, Qingdao University, and the post-resectional liver dysfunction and failure risk factors were analyzed by univariate and multivariate analysis.Results: The morbidity of post-resectional liver dysfunction and failure was 1.7% and 2.1%.The post-resectional liver dysfunction and failure after HCC hepatectomy into the statistical analysis: univariate analysis revealed preoperative platelet level ( 64 U/L), Child-Pugh classification (B), MELD score (≥ 9), intraoperative bleeding (≥ 1000 mL), blood transfusion were positive factors, multivariate analysis (Logistic) revealed that preoperative platelet level (0.983, 95% CI = 0.971-0.995) and intraoperative blood transfusion (3.145, 95% CI = 1.027-12.028) were independent risk factors for post-resectional liver dysfunction and failure.Conclusion: Prevented liver failure and liver dysfunction occurring after liver resection, it is the key to accurate preoperative assessment of liver function and the patient's reserved liver functional, precise hepatectomy and reasonable blockage of hepatic inflow.

  5. Inflammatory hepatocellular adenomas developed in the setting of chronic liver disease and cirrhosis.

    Science.gov (United States)

    Calderaro, Julien; Nault, Jean C; Balabaud, Charles; Couchy, Gabrielle; Saint-Paul, Marie-Christine; Azoulay, Daniel; Mehdaoui, Dalila; Luciani, Alain; Zafrani, Elie S; Bioulac-Sage, Paulette; Zucman-Rossi, Jessica

    2016-01-01

    Hepatocellular adenoma is considered to occur exclusively in non-fibrotic livers. It is a heterogeneous entity and a molecular classification is now widely accepted. The most frequent hepatocellular adenoma subtype, namely inflammatory adenoma, harbor somatic activating mutations of genes involved in the interleukin-6 pathway that lead to high C-reactive protein and serum amyloid A expression. The aim of our study was to investigate a series of benign hepatocellular neoplasms developed on cirrhotic livers and characterized by an unequivocal histological diagnosis. We performed a clinical, pathological, and molecular study of 10 benign hepatocellular neoplasms developed in three patients with cirrhosis. Markers allowing hepatocellular adenoma classification were assessed by quantitative real-time PCR and immunohistochemistry. Samples were sequenced for CTNNB1, HNF1A, IL6ST, GNAS, STAT3, and TERT (promoter) mutations. A control series of 32 classical macronodules developed in cirrhosis related to various etiologies was screened by immunohistochemistry and gene sequencing. The three patients had cirrhosis related to metabolic syndrome and/or alcohol intake; two had a single tumor, while the third developed more than 30 lesions. Microscopic examination showed well-differentiated neoplasms sharing features with inflammatory adenoma including inflammatory infiltrates, sinusoidal dilatation, and dystrophic vessels. Sequencing revealed classical hotspot somatic mutations (IL6ST, n=8; STAT3, n=1; and GNAS, n=1) known to be responsible for IL-6/JAK/STAT pathway activation. Two classical high-grade macronodules demonstrated high serum amyloid A and/or C-reactive protein expression, without gene mutations. Altogether, our findings support the existence of rare inflammatory adenoma developed in cirrhosis.

  6. Growth arrest and apoptosis of human hepatocellular carcinoma cells induced by hexamethylene bisacetamide

    Science.gov (United States)

    Ouyang, Gao-Liang; Cai, Qiu-Feng; Liu, Min; Chen, Rui-Chuan; Huang, Zhi; Jiang, Rui-Sheng; Chen, Fu; Hong, Shui-Gen; Bao, Shi-Deng

    2004-01-01

    AIM: To investigate the cellular effects of hybrid polar compound hexamethylene bisacetamide (HMBA) on the growth and apoptosis of human hepatocellular carcinoma cells and to provide the molecular mechanism for potential application of HMBA in the treatment of liver cancer. METHODS: Effects of HMBA on the growth of human hepatocellular carcinoma SMMC-7721 cells were assayed by MTT chronometry. Apoptosis induced by HMBA was detected by phase-contrast microscopy, flow cytometry, propidium iodide staining and immunocytochemical analysis. RESULTS: The growth of SMMC-7721 cells was significantly inhibited by HMBA, and the growth inhibitory rate was 51.1%, 62.6%, 68.7% and 73.9% respectively after treatment with 5.0, 7.5, 10.0 and 12.5 mmol/L of HMBA. In the cells treated with 10 mmol/L of HMBA for 72 h, the population of cells at sub-G1 phase significantly increased, and the apoptotic bodies and condensed nuclei were detected. Moreover, treatment of SMMC-7721 cells with 10 mmol/L of HMBA down-regulated the expression of Bcl-2 anti-apoptotic protein, while slightly up-regulated the level of pro-apoptotic protein Bax. CONCLUSION: Treatment with 10.0 mmol/L of HMBA can significantly inhibit the growth and induce apoptosis of human hepatocellular carcinoma SMMC-7721 cells by decreasing the ratio of Bcl-2 to Bax. PMID:15052673

  7. Growth arrest and apoptosis of human hepatocellular carcinoma cells induced by hexamethylene bisacetamide

    Institute of Scientific and Technical Information of China (English)

    Gao-Liang Ouyang; Qiu-Feng Cai; Min Liu; Rui-Chuan Chen; Zhi Huang; Rui-Sheng Jiang; Fu Chen; Shui-Gen Hong; Shi-Deng Bao

    2004-01-01

    AIM: To investigate the cellular effects of hybrid polar compound hexamethylene bisacetamide (HMBA) on the growth and apoptosis of human hepatocellular carcinoma cells and to provide the molecular mechanism for potential application of HMBA in the treatment of liver cancer.METHODS: Effects of HMBA on the growth of human hepatocellular carcinoma SMMC-7721 cells were assayed by MTT chronometry. Apoptosis induced by HMBA was detected by phase-contrast microscopy, flow cytometry,propidium iodide staining and immunocytochemical analysis.RESULTS: The growth of SMMC-7721 cells was significantly inhibited by HMBA, and the growth inhibitory rate was 51.1%, 62.6%, 68.7% and 73.9% respectively after treatment with 5.0, 7.5, 10.0 and 12.5 mmol/L of HMBA.In the cells treated with 10 mmol/L of HMBA for 72 h, the population of cells at sub-G1 phase significantly increased,and the apoptotic bodies and condensed nuclei were detected. Moreover, treatment of SMMC-7721 cells with 10 mmol/L of HMBA down-regulated the expression of Bcl2 anti-apoptotic protein, while slightly up-regulated the level of pro-apoptotic protein Bax.CONCLUSION: Treatment with 10.0 mmol/L of HMBA can significantly inhibit the growth and induce apoptosis of human hepatocellular carcinoma SMMC-7721 cells by decreasing the ratio of Bcl-2 to Bax.

  8. Anatomic trisegmentectomy: An alternative treatment for huge or multiple hepatocellular carcinoma of right liver.

    Science.gov (United States)

    Jia, Changku; Weng, Jie; Qin, Qifan; Chen, Youke; Huang, Xiaolong; Fu, Yu

    2017-04-01

    The patients with huge (≥10cm) or multiple hepatocellular carcinoma (HCC) in the right liver and insufficient size of the remnant left liver can not be performed an operation of right hemihepatectomy because of that liver failure will occur post operation. We designed anatomic trisegmentectomy in right liver to increase the ratio of future liver remnant volume (%FLRV), thus increasing resectability of huge or multiple HCC. Thirteen patients were analyzed by preoperative CT scan for liver and tumor volumetries. If the right hemihepatectomy was done, %FLRV would be at the range of 29.6%-37.5%. However, if trisegmentectomy was done, %FLRV would increase by an average of 14.0%. So patients will not undergo postoperative liver failure due to sufficient %FLRV. Therefore, we designed anatomic trisegmentectomy, with retention of segment 5 or segment 8, to increase %FLRV and increase the resectability for huge or multiple HCC. After trisegmentectomy, the inflow and outflow of remnant liver were maintained well. Severe complications and mortality were not happened post operation. Of the 13 patients, 10 survived up to now. Of the 10 living cases, postoperative lung metastasis was found in 2 and intrahepatic recurrence was found in 1. These 3 patients survive with tumor after comprehensive therapies including oral administration of Sorafenib. Compared to right hemihepatectomy, anatomic trisegmentectomy in right liver guarantees the maximum preservation of %FLRV to increase the resectability of huge or multiple HCC, thus improving the overall resection rate. Copyright © 2017. Published by Elsevier Masson SAS.

  9. Helicobacter species sequences in liver samples from patients with and without hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Rinaldo Pellicano; Vincenzo Mazzaferro; Walter Franco Grigioni; Miguel Angel Cutufia; Sharmila Fagoonee; Lorenzo Silengo; Mario Rizzetto; Antonio Ponzetto

    2004-01-01

    AIM: Only a minority of patients carrying a defined viral aetiologic agent develop cirrhosis and ultimately hepatocellular carcinoma (HCC), the mechanism underlying the worsening is still undefined. Experimental infection by Helicobacter hepaticusin mice causes chronic hepatitis and HCC and recently, more Helicobacterspecies (Helicobacter spp.) have been detected in the liver of patients suffering from cholestatic diseases and HCC arising from non-cirrhotic liver. We investigated whether Helicobacterspp. sequences could be detected in the liver of patients with cirrhosis and HCC compared to subjects with metastasis to liver from colon cancer.METHODS: Twenty-three liver samples from patients operated upon for HCC superimposed on hepatitis C virus (HCV)-related cirrhosis and 6 from patients with resected metastases from colorectal cancer, were tested by polymerase chain reaction for presence of genomic 16S rRNA of Helicobacter genus using specific primers. DNA sequencing and cagA gene analysis were also performed.RESULTS: Genomic sequences of Helicobacter spp. were found in 17 of 20 (85%) liver samples from patients with HCC and in 2 of 6 samples from patients with liver metastasis.In three samples of the first group the result was uncertain.Hpyloriwas revealed in 16 out of 17 positive samples and Helicobacter pullorum in the other.CONCLUSION: Helicobacter spp., carcinogenic in mice,were found at a higher frequency in the liver of patients with HCV-related cirrhosis and HCC than those in patients without primary liver disease.

  10. Nerve growth factor involvement in liver cirrhosis and hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    AIM: To define NGF (nerve growth factor) and its highaffinity receptor trkANGF presence and distribution in fibrotic liver and in HCC, and to verify if NGF might have a role in fibrosis and HCC.METHODS: Intracellular distribution of NGF and trkANGF were assessed by immunohistochemistry and immunoelectron microscopy in liver specimens from HCC,cirrhosis or both. ELISA was used to measure circulating NGF levels.RESULTS: NGF and trkANGF were highly expressed in HCC tissue, mainly localized in hepatocytes, endothelial and some Kupffer cells. In the cirrhotic part of the liver they were also markedly expressed in bile ducts epithelial and spindle-shaped cells. Surprisingly, in cirrhotic tissue from patients without HCC, both NGF and trkANGF were negative. NGF serum levels in cirrhotic and/or HCC patient were up to 25-fold higher than in controls.CONCLUSION: NGF was only detected in liver tissue with HCC present. Intracellular distribution suggests paracrine and autocrine mechanisms of action. Better definition of mechanisms may allow for therapeutic and diagnostic/prognostic use of NGF.

  11. Development of hepatocellular adenomas and carcinomas in mice with liver-specific G6Pase-α deficiency

    Directory of Open Access Journals (Sweden)

    Roberta Resaz

    2014-09-01

    Full Text Available Glycogen storage disease type 1a (GSD-1a is caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α, and is characterized by impaired glucose homeostasis and a high risk of developing hepatocellular adenomas (HCAs. A globally G6Pase-α-deficient (G6pc−/− mouse model that shows pathological features similar to those of humans with GSD-1a has been developed. These mice show a very severe phenotype of disturbed glucose homeostasis and rarely live beyond weaning. We generated liver-specific G6Pase-α-deficient (LS‑G6pc−/− mice as an alternative animal model for studying the long-term pathophysiology of the liver and the potential treatment strategies, such as cell therapy. LS‑G6pc−/− mice were viable and exhibited normal glucose profiles in the fed state, but showed significantly lower blood glucose levels than their control littermates after 6 hours of fasting. LS‑G6pc−/− mice developed hepatomegaly with glycogen accumulation and hepatic steatosis, and progressive hepatic degeneration. Ninety percent of the mice analyzed developed amyloidosis by 12 months of age. Finally, 25% of the mice sacrificed at age 10–20 months showed the presence of multiple HCAs and in one case late development of hepatocellular carcinoma (HCC. In conclusion, LS‑G6pc−/− mice manifest hepatic symptoms similar to those of human GSD-1a and, therefore, represent a valid model to evaluate long-term liver pathogenesis of GSD-1a.

  12. Area between the hepatic and heart curves of (99m)Tc-galactosyl-human serum albumin scintigraphy represents liver function and disease progression for preoperative evaluation in hepatocellular carcinoma patients.

    Science.gov (United States)

    Harada, Kohei; Mizuguchi, Toru; Katagiri, Yoshimi; Kawamoto, Masaki; Nakamura, Yukio; Meguro, Makoto; Ota, Shigenori; Sasaki, Shigeru; Miyanishi, Koji; Sonoda, Tomoko; Mori, Mitsuru; Shinomura, Yasuhisa; Kato, Junji; Hirata, Koichi

    2012-11-01

    We developed software to calculate the pixels of interest in the area between the hepatic and heart curves (ABC) of (99m)Tc-galactosyl human serum albumin (GSA) scintigraphy. The aim of this study was to examine the accuracy of the ABC to evaluate liver function before hepatectomy. Between January 2005 and December 2010, 205 consecutive patients who underwent initial hepatectomy were enrolled in this study. The ABC was calculated using original computer software. The area under the receiver operating characteristic curve (AUC) was calculated for evaluation of Child-Pugh score grade B (Child B), pathological chronic hepatitis (CH), and liver cirrhosis (LC). The AUC of any indicator for Child B was more than 0.900 except bilirubin. The AUC of ABC for CH and LC (AUC 0.734 each) was comparable to those of HH15 (clearance index; AUC 0.704 and 0.700, respectively) and LHL15 (receptor index; AUC 0.703 and 0.706, respectively) in multiple receiver operating characteristic comparison. We have developed a novel liver function indicator, the ABC, to count radioactivity in sequence. The ABC reflects liver function according to pathological deterioration of the liver. Although the ABC gave no significant advantage compared to HH15 and LHL15, it improved the AUC evaluation by 0.028-0.034.

  13. Haemodynamic changes in hepatocellular carcinoma and liver parenchyma under balloon occlusion of the hepatic artery

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    Sugihara, Fumie; Murata, Satoru; Ueda, Tatsuo; Yasui, Daisuke; Yamaguchi, Hidenori; Miki, Izumi; Kumita, Shin-ichiro [Nippon Medical School, Department of Radiology, Center for Advanced Medical Technology, Tokyo (Japan); Kawamoto, Chiaki [Nippon Medical School, Department of Internal Medicine, Tokyo (Japan); Uchida, Eiji [Nippon Medical School, Department of Surgery, Tokyo (Japan)

    2017-06-15

    To investigate haemodynamic changes in hepatocellular carcinoma (HCC) and liver under hepatic artery occlusion. Thirty-eight HCC nodules in 25 patients were included. Computed tomography (CT) during hepatic arteriography (CTHA) with and without balloon occlusion of the hepatic artery was performed. CT attenuation and enhancement volume of HCC and liver with and without balloon occlusion were measured on CTHA. Influence of balloon position (segmental or subsegmental branch) was evaluated based on differences in HCC-to-liver attenuation ratio (H/L ratio) and enhancement volume of HCC and liver. In the segmental group (n = 20), H/L ratio and enhancement volume of HCC and liver were significantly lower with balloon occlusion than without balloon occlusion. However, in the subsegmental group (n = 18), H/L ratio was significantly higher and liver enhancement volume was significantly lower with balloon occlusion; HCC enhancement volume was similar with and without balloon occlusion. Rate of change in H/L ratio and enhancement volume of HCC and liver were lower in the segmental group than in the subsegmental group. There were significantly more perfusion defects in HCC in the segmental group. Hepatic artery occlusion causes haemodynamic changes in HCC and liver, especially with segmental occlusion. (orig.)

  14. Lessons Learned From a Case of Gastric Cancer After Liver Transplantation for Hepatocellular Carcinoma

    Science.gov (United States)

    Yang, Kun; Zhu, Hong; Chen, Chong-Cheng; Wen, Tian-Fu; Zhang, Wei-Han; Liu, Kai; Chen, Xin-Zu; Guo, Dong-Jiao; Zhou, Zong-Guang; Hu, Jian-Kun

    2016-01-01

    Abstract Nowadays, de novo malignancies have become an important cause of death after transplantation. According to the accumulation of cases with liver transplantation, the incidence of de novo gastric cancer is anticipated to increase among liver transplant recipients in the near future, especially in some East Asian countries where both liver diseases requiring liver transplantation and gastric cancer are major burdens. Unfortunately, there is limited information regarding the relationship between de novo gastric cancer and liver transplantation. Herein, we report a case of stage IIIc gastric cancer after liver transplantation for hepatocellular carcinoma, who was successfully treated by radical distal gastrectomy with D2 lymphadenectomy but died 15 months later due to tumor progression. Furthermore, we extract some lessons to learn from the case and review the literatures. The incidence of de novo gastric cancer following liver transplantations is increasing and higher than the general population. Doctors should be vigilant in early detection and control the risk factors causing de novo gastric cancer after liver transplantation. Curative gastrectomy with D2 lymphadenectomy is still the mainstay of treatment for such patients. Preoperative assessments, strict postoperative monitoring, and managements are mandatory. Limited chemotherapy could be given to the patients with high risk of recurrence. Close surveillance, early detection, and treatment of posttransplant cancers are extremely important and essential to improve the survival. PMID:26886605

  15. Riboflavin (vitamin B-2) reduces hepatocellular injury following liver ischaemia and reperfusion in mice.

    Science.gov (United States)

    Sanches, Sheila Cristina; Ramalho, Leandra Naira Z; Mendes-Braz, Mariana; Terra, Vânia Aparecida; Cecchini, Rubens; Augusto, Marlei Josiele; Ramalho, Fernando Silva

    2014-05-01

    Riboflavin has been shown to exhibit anti-inflammatory and antioxidant properties in the settings of experimental sepsis and ischaemia/reperfusion (I/R) injury. We investigated the effect of riboflavin on normothermic liver I/R injury. Mice were submitted to 60 min of ischaemia plus saline or riboflavin treatment (30 μmoles/kg BW) followed by 6 h of reperfusion. Hepatocellular injury was evaluated by aminotransferase levels, reduced glutathione (GSH) content and the histological damage score. Hepatic neutrophil accumulation was assessed using the naphthol method and by measuring myeloperoxidase activity. Hepatic oxidative/nitrosative stress was estimated by immunohistochemistry. Liver endothelial and inducible nitric oxide synthase (eNOS/iNOS) and nitric oxide (NO) amounts were assessed by immunoblotting and a chemiluminescence assay. Riboflavin significantly reduced serum and histological parameters of hepatocellular damage, neutrophil infiltration and oxidative/nitrosative stress. Furthermore, riboflavin infusion partially recovered hepatic GSH reserves and decreased the liver contents of eNOS/iNOS and NO. These data indicate that riboflavin exerts antioxidant and anti-inflammatory effects in the ischaemic liver, protecting hepatocytes against I/R injury. The mechanism of these effects appears to be related to the intrinsic antioxidant potential of riboflavin/dihydroriboflavin and to reduced hepatic expression of eNOS/iNOS and reduced NO levels, culminating in attenuation of oxidative/nitrosative stress and the acute inflammatory response.

  16. Albumin Suppresses Human Hepatocellular Carcinoma Proliferation and the Cell Cycle

    Directory of Open Access Journals (Sweden)

    Shunsuke Nojiri

    2014-03-01

    Full Text Available Many investigations have revealed that a low recurrence rate of hepatocellular carcinoma (HCC is associated with high serum albumin levels in patients; therefore, high levels of serum albumin are a major indicator of a favorable prognosis. However, the mechanism inhibiting the proliferation of HCC has not yet been elucidated, so we investigated the effect of serum albumin on HCC cell proliferation. Hep3B was cultured in MEM with no serum or containing 5 g/dL human albumin. As control samples, Prionex was added to generate the same osmotic pressure as albumin. After 24-h incubation, the expressions of α-fetoprotein (AFP, p53, p21, and p57 were evaluated with real-time PCR using total RNA extracted from the liver. Protein expressions and the phosphorylation of Rb (retinoblastoma were determined by Western blot analysis using total protein extracted from the liver. For flow cytometric analysis of the cell cycle, FACS analysis was performed. The percentages of cell cycle distribution were evaluated by PI staining, and all samples were analyzed employing FACScalibur (BD with appropriate software (ModFit LT; BD. The cell proliferation assay was performed by counting cells with using a Scepter handy automated cell counter (Millipore. The mRNA levels of AFP relative to Alb(−: Alb(−, Alb(+, and Prionex, were 1, 0.7 ± 0.2 (p < 0.001 for Alb(−, and 1 ± 0.3, respectively. The mRNA levels of p21 were 1, 1.58 ± 0.4 (p = 0.007 for Alb(− and p = 0.004 for Prionex, and 0.8 ± 0.2, respectively. The mRNA levels of p57 were 1, 4.4 ± 1.4 (p = 0.002 for Alb(− and Prionex, and 1.0 ± 0.1, respectively. The protein expression levels of Rb were similar in all culture media. The phosphorylation of P807/811 and P780 of Rb protein was reduced in Alb(+. More cells in the G0/G1 phase and fewer cells in S and G2/M phases were obtained in Alb(+ than in Alb(− (G0/G1: 60.9%, 67.7%, 61.5%; G2/M: 16.5%, 13.1%, 15.6%; S: 22.6%, 19.2%, 23.0%, Alb(−, Alb

  17. Co-localization of the heat shock protein and human immunoglobulin G in hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    DUAN Chun-guang; LIU Yan-fang; LI Kai-nan; YU Lu; CUI Ji-hong; LI Jing; YANG Shou-jing

    2005-01-01

    @@ Elevated levels of serum immunoglobulin observed in patients with cancers of epithelial origin, including carcinomas of breast, colon, and liver1,2 have been interpreted as humoral responses of host to cancer growth.3 Recently, Qiu et al4 described in detail that human cancers of epithelial origin, including carcinomas of breast, colon, liver, lung, established epithelial cancer lines, produce immunoglobulin G (IgG) in their cytoplasm. Under normal conditions, heat shock proteins (HSPs) have multiple cellular functions, such as folding and translocating newly synthesized proteins. When a cell is injured or under stress, HSPs refold damaged protein or facilitate degradation of proteins. In most cancers, heat shock proteins can capture tumour specific peptide to inhibit the growth of cancer. This study demonstrated that human IgG and HSPs are co-localized in hepatocellular carcinoma.

  18. Is high AgNOR quantity in hepatocytes associated with increased risk of hepatocellular carcinoma in chronic liver disease?

    Science.gov (United States)

    Derenzini, M; Trerè, D; Oliveri, F; David, E; Colombatto, P; Bonino, F; Brunetto, M R

    1993-01-01

    AIMS--To evaluate whether high numbers of silver staining nucleolar organiser regions (AgNORs) in hepatocytes are associated with increased risk of hepatocellular carcinoma in chronic liver disease. METHODS--The quantitative distribution of AgNORs was studied in the liver biopsy specimens of 33 patients with chronic liver disease, 11 of whom developed hepatocellular carcinoma. The interval between liver biopsy and diagnosis of hepatocellular carcinoma was 26 months (range one to 61 months); the mean follow up of patients without hepatocellular carcinoma was 45 months (range 24-59 months). Quantitative evaluation of AgNORs was carried out on silver stained routine sections by morphometric analysis, using a computer assisted image analysis system. RESULTS--High interphase AgNOR values (> 3 microns2) were found in hepatocytes of nine out of the 11 (82%) patients in whom neoplastic transformation occurred. Of the remaining 22 patients, only seven (31%) had AgNOR values higher than > 3 microns2 (chi 2 4.83; p = 0.036). CONCLUSIONS--These results indicate that high numbers of interphase AgNORs are associated with increased risk of hepatocellular carcinoma in patients with chronic liver disease. Images PMID:8408696

  19. Inhibitory effects of xanthohumol from hops (Humulus lupulus L.) on human hepatocellular carcinoma cell lines.

    Science.gov (United States)

    Ho, Yi-Chien; Liu, Chi-Hsien; Chen, Chien-Nan; Duan, Kow-Jen; Lin, Ming-Tse

    2008-11-01

    Xanthohumol is one of the main flavonoids in hop extracts and in beer. Very few investigations of xanthohumol have studied hepatocellular carcinoma. In this study, the inhibitory effects of xanthohumol on human hepatocellular carcinoma cell lines were investigated. The IC(50) values of xanthohumol for two hepatocellular carcinoma cell lines and one normal hepatocyte cell line were 108, 166 and 211 microm, respectively. Normal murine hepatocyte cell line had more resistance to xanthohumol than hepatocellular carcinoma cell lines. Besides, the inhibitory effects of xanthohumol on human hepatocellular carcinoma cell lines were attributed to apoptosis as indicated in the results of flow cytometry, fluorescent nuclear staining and electrophoresis of oligonucleosomal DNA fragments. Hop xanthohumol was more efficient in the growth inhibition of hepatocellular carcinoma cell lines than the flavonoids silibinin and naringin from thistle and citrus. It was shown for the first time that xanthohumol from hops effectively inhibits proliferation of human hepatocellular carcinoma cells in vitro.

  20. Hepatic Artery Chemoembolization for Hepatocellular Carcinoma Recurrence Confined to the Transplanted Liver

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    Brian I. Carr

    2012-09-01

    Full Text Available Background: Careful hepatocellular carcinoma (HCC case selection permits orthotopic liver transplantation with the expectation of around 70% plus 5-year survival. However, many patients have tumor recurrences and there is little literature guidance in the management of these patients. Aims: A retrospective examination of patients transplanted with HCC who subsequently developed liver recurrence. Methods: A case cohort series of patients was prospectively followed who had liver-only multifocal tumor recurrence of HCC after liver transplant and were then treated with chemoembolization. Results: All 6 patients had recurrent HCC. 2 had no response, 1 had stable disease, 2 had partial response (PR and 1 had complete disappearance (CR of disease. Their survival (in months was: 13 (no response, 18 (no response, 12 (stable disease, 19 (PR, 30 (PR and 50 (CR. There were no liver toxicities. Conclusions: Chemoembolization for tumor recurrence in the transplanted liver is as safe as or safer than in the pre-transplant liver, due to the absence of cirrhosis. In this series, there were 3 of 6 responses with some long survivors.

  1. Molecular signatures associated with HCV-induced hepatocellular carcinoma and liver metastasis.

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    Valeria De Giorgi

    Full Text Available Hepatocellular carcinomas (HCCs are a heterogeneous group of tumors that differ in risk factors and genetic alterations. In Italy, particularly Southern Italy, chronic hepatitis C virus (HCV infection represents the main cause of HCC. Using high-density oligoarrays, we identified consistent differences in gene-expression between HCC and normal liver tissue. Expression patterns in HCC were also readily distinguishable from those associated with liver metastases. To characterize molecular events relevant to hepatocarcinogenesis and identify biomarkers for early HCC detection, gene expression profiling of 71 liver biopsies from HCV-related primary HCC and corresponding HCV-positive non-HCC hepatic tissue, as well as gastrointestinal liver metastases paired with the apparently normal peri-tumoral liver tissue, were compared to 6 liver biopsies from healthy individuals. Characteristic gene signatures were identified when normal tissue was compared with HCV-related primary HCC, corresponding HCV-positive non-HCC as well as gastrointestinal liver metastases. Pathway analysis classified the cellular and biological functions of the genes differentially expressed as related to regulation of gene expression and post-translational modification in HCV-related primary HCC; cellular Growth and Proliferation, and Cell-To-Cell Signaling and Interaction in HCV-related non HCC samples; Cellular Growth and Proliferation and Cell Cycle in metastasis. Also characteristic gene signatures were identified of HCV-HCC progression for early HCC diagnosis.A diagnostic molecular signature complementing conventional pathologic assessment was identified.

  2. Comparative immunohistochemical characteristics of hepatocellular, cholangiocellular cancer and liver metastases of pancreatic cancer in puncture trephine biopsy of the liver

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    V. A. Tumanskiy

    2015-10-01

    Full Text Available Aim. Differential immunohistochemical parameters of primary liver cancer and liver metastases of ductal pancreatic cancer (DPC were studied in puncture trephine biopsy of the liver of 23 patients with hepatocellular carcinoma (HCC, 2 patients combined hepato-cholangiocellular cancer (CHCC, 15 patients cholangiocellular cancer (CCC and 12 patients with metastatic DPC. Results. It was found that HCC liver is characterized by high levels of expression of HepPar 1 and alpha-fetoprotein, the lack of expression of MUC1 mucins, MUC5AC and CA125, and variable expression of CK8, CK7, SK19 and CK20, which depends on the degree of tumor differentiation and embodiment. Cholangiocellular liver cancer differs from others expressed desmoplastic stroma, high levels of expression of cytokeratins 7 and 19, MUC1 and MUC5AC, lack expression of HepPar 1 and variable expression of alpha-fetoprotein, cytokeratin 8 and20. Insolid and trabecular patterns of CHCC expression of HepRar 1, AFP and CK20 were determined, and in ductual patterne- CK7 and CK19 were determined. CCC and liver metastases of DPC which have the similar microstructure were characterized with the same spectrum characteristic of expressed cytokeratin (SK7, + 19, + 20, + and mucin (MUC1 + MUC5AC +, and variable expression of CA125 and CA19-9. Conclusion. Therefore, the differential diagnosis in immunohistochemistry of liver trepanobioptate between CCC and liver metastases of DPC is only possible based on the data of computed tomography or ultrasound examination of the liver and pancreas.

  3. Diphenyl difluoroketone: a potent chemotherapy candidate for human hepatocellular carcinoma.

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    Yingjian Liang

    Full Text Available Diphenyl difluoroketone (EF24, a molecule having structural similarity to curcumin, was recently reported to inhibit proliferation of various cancer cells significantly. Here we try to determine the effect and mechanism of EF24 on hepatocellular carcinoma. 2 µM EF24 was found to inhibit the proliferation of PLC/PRF/5, Hep3B, HepG2, SK-HEP-1 and Huh 7 cell lines. However, even 8 µM EF24 treatment did not affect the proliferation of normal liver LO2 cells. Accordingly, 20 mg/kg/d EF24 inhibited the growth of the tumor xenografts conspicuously while causing no apparent change in liver, spleen or body weight. In addition, significant apoptosis and G(2/M phase cell cycle arrest were found using flow cytometry. Besides, caspases and PARP activation and features typical of apoptosis including fragmented nuclei with condensed chromatin were also observed. Furthermore, the mechanism was targeted at the reduction of nuclear factor kappa b (NF-κB pathway and the NF-κB-regulated gene products Bcl-2, COX-2, Cyclin B1. Our study has offered a strategy that EF24 being a therapeutic agent for hepatocellular carcinoma.

  4. Radiofrequency ablation of hepatocellular carcinoma located in the liver dome under intermittent CT fluoroscopy guidance

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    Park, Darlene; Cho, Yun Ku; Cho, Hyun Je; KIm, Mi Young [Dept. of Radiology, VHS Medical Center, Seoul (Korea, Republic of)

    2014-02-15

    To evaluate the clinical effectiveness of an intermittent computed tomography (CT) fluoroscopy-guided radiofrequency (RF) ablation of hepatocellular carcinoma located in the liver dome. Between 2005 and 2010 23 patients with hepatocellular carcinoma (HCC) nodules located in the liver dome underwent an intermittent CT fluoroscopy-guided RF ablation. The primary endpoint was the local tumor progression. Procedure-related complications occurred in 3 of 23 patients. To evaluate the prognostic factors for the local tumor progression, univariate and multivariate analyses were performed using the Cox proportional hazards model. The chi-squared test was performed to evaluate the association of access route and procedure-related complication. The study was approved by the Institutional Review Board of our hospital. The Tumor sizes ranged between 1.0 and 2.9 cm. An initial complete ablation was achieved in all patients. The median follow-up period was 31 months and the major complication rate was 4.3%. The cumulative rate of local tumor progression at 3 years was 20%. The univariate analysis revealed that only serum total bilirubin level (p = 0.048) and prior chemoembolization were statistically significant (p = 0.044), but there was no independently significant prognostic factor on multivariate analysis. Procedure-related complications occurred in 3 of 23 patients. For HCC located in the liver dome an intermittent CT fluoroscopy-guided RF ablation could be performed safely and effectively.

  5. Comparative study and systematic review of laparoscopic liver resection for hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Wei; Qi; Leong; Iyer; Shridhar; Ganpathi; Alfred; Wei; Chieh; Kow; Krishnakumar; Madhavan; Stephen; Kin; Yong; Chang

    2015-01-01

    AIM: To compare the surgical outcomes between laparoscopic liver resection(LLR) and open liver resection(OLR) as a curative treatment in patients with hepatocellular carcinoma(HCC). METHODS: A Pub Med database search was performed systematically to identify comparative studies of LLR vs OLR for HCC from 2000 to 2014. An extensive text word search was conducted, using combinations of search headings such as "laparoscopy", "hepatectomy", and "hepatocellular carcinoma". A comparative study was also performed in our institution where we analysed surgical outcomes of 152 patients who underwent liver resection between January 2005 to December 2012, of which 42 underwent laparoscopic or hand-assisted laparoscopic resection and 110 underwent open resection. RESULTS: Analysis of our own series and a review of 17 high-quality studies showed that LLR was superior to OLR in terms of short-term outcomes, as patients in the laparoscopic arm were found to have less intraoperative blood loss, less blood transfusions, and a shorter length of hospital stay. In our own series, both LLR and OLR groups were found to have similar overall survival(OS) rates, but disease-free survival(DFS) rates were higher in the laparoscopic arm. CONCLUSION: LLR is associated with better short-term outcomes compared to OLR as a curative treatment for HCC. Long-term oncologic outcomes with regards to OS and DFS rates were found to be comparable in both groups. LLR is hence a safe and viable option for curative resection of HCC.

  6. Low Utility of Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography for Detecting Hepatocellular Carcinoma in Patients Before Liver Transplantation.

    Science.gov (United States)

    Alotaibi, Faisal; Kabbani, Monther; Abaalkhail, Faisal; Chorley, Alicia; Elbeshbeshy, Hany; Al-Hamoudi, Waleed; Alabbad, Saleh; Boehnert, Markus U; Alsofayan, Mohammad; Al-Kattan, Wael; Ahmed, Baderaldeen; Broering, Dieter; Al Sebayel, Mohamed; Elsiesy, Hussien

    2017-02-01

    Our program routinely used fluorodeoxyglucose-positron emission tomography/computed tomography as part of the liver transplant evaluation of patients with hepatocellular carcinoma. The aim of this study was to evaluate the role of this imaging modality in the pretransplant work-up. This was a retrospective chart review of our liver transplant database from January 2011 to December 2014 for all patients with hepatocellular carcinoma who underwent a liver transplant. Collected data included age, sex, cause of liver disease, imaging modality, fluorodeoxyglucose-positron emission tomography/computed tomography results, explant tissue analysis, type of transplant, and transplant outcome. During the study period, 275 liver transplants were performed. Fifty-three patients had hepatocellular carcinoma; 41 underwent fluorodeoxyglucose-positron emission tomography/computed tomography. Twenty-nine patients underwent living-donor liver transplant, and 12 patients underwent deceased-donor liver transplant. One of the 41 patients with negative FDG-imaging results had no evidence of hepatocellular carcinoma in the explant and was excluded from the study. The patients' average age was 58 years (range, 22-72 y), and 28 patients were men. The cause of liver disease was hepatitis C virus in 24 patients, cryptogenic cirrhosis in 12 patients, and hepatitis B virus in 5 patients. One patient had no hepatocellular carcinoma on explants and was excluded from the study. Twenty-five patients had hepatocellular carcinoma that met the Milan criteria, 7 were within the UCSF (University of California, San Francisco) criteria, and 8 exceeded the UCSF criteria. Of the 40 patients, 11 had positive fluorodeoxyglucose-positron emission tomography/computed tomography results (27.5%) with evidence of hepatocellular carcinoma in the explant; the remaining 29 patients (72.5%) had negative results. The fluorodeoxyglucose-positron emission tomography/computed tomography results were positive in 16% (4 of

  7. Case of clear-cell hepatocellular carcinoma that developed in the normal liver of a middle-aged woman

    Institute of Scientific and Technical Information of China (English)

    Atsushi Takahashi; Hiromasa Ohira; Hironobu Saito; Yukiko Kanno; Kazumichi Abe; Junko Yokokawa; Atsushi Irisawa; Akira Kenjo; Takuro Saito; Mitsukazu Gotoh

    2008-01-01

    A 36-year-old woman was admitted to our department for close examination of a liver tumor that was found during a medical checkup. Abdominal US, CT and MRI showed a tumor in segment 7 (S7) of the liver. Although imaging suggested hepatocellular carcinoma, laboratory tests showed no abnormality in liver function, hepatitis virus markers were negative, and tumor markers including protein induced by vitamin K absence or antagonist Ⅱ (PIVKA-Ⅱ), a-fetoprotein (AFP), carbohydrate antigen 19-9 (CA19-9), and carcinoembryonic antigen (CEA)were all within normal ranges. Upon aspiration biopsy of the liver, the histopathological diagnosis was moderately differentiated hepatocellular carcinoma. Therefore, right hepatectomy was performed. Although a part of the tumor was necrotic, about 60% of the viable part showed a clear-cell variant. Consequently, it was diagnosed as clear-cell hepatocellular carcinoma. It was noted that the background liver tissue was normal. This case is worthy of reporting because development of clear-cell hepatocellular carcinoma in the normal liver of a middle-aged woman is rarely seen.

  8. Prevention and management of recurrence and metastasis of hepatocellular carcinoma after liver transplantation

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    JI Ru

    2014-01-01

    Full Text Available Hepatocellular carcinoma (HCC is still a prevalent gastrointestinal cancer. Liver transplantation (LT is one of the main means in the comprehensive treatment of HCC because it radically removes the tumor. However, tumor recurrence and metastasis after LT remain the main obstacles to long-term survival. In recent years, substantial progress has been made in the diagnosis and treatment of HCC thanks to the technological improvement and experience accumulation worldwide. The HCC indications for LT, prediction of HCC recurrence and metastasis, perioperative management in LT, and comprehensive treatment of recurrent HCC after LT are reviewed.

  9. Adrenalectomy for solitary metastasis of Hepatocellular carcinoma post liver transplantation: Case report and literature review.

    Science.gov (United States)

    Jalbani, Imran Khan; Nazim, Syed M; Tariq, Muhammad Usman; Abbas, Farahat

    2016-01-01

    Liver transplantation (LT) is the treatment of choice for localized hepatocellular carcinoma (HCC) associated with cirrhosis. Extra hepatic metastasis is the most common cause of death in these patients. There is very little evidence regarding the natural history and treatment options for patients developing HCC recurrence after LT. Surgical resection offers a unique opportunity for solitary metastasis. We report a 61 year old male with solitary right adrenal metastasis 15 months post LT which was managed with open adrenalectomy. The patient is alive and disease free 24 months after the surgery. The case, histo-pathological findings and literature review is discussed.

  10. Primary study of leptin and human hepatocellular carcinoma in vitro

    Institute of Scientific and Technical Information of China (English)

    Jing Zhou; Wei Lei; Lei Shen; He-Sheng Luo; Zhi-Xiang Shen

    2008-01-01

    AIM: To investigate the expression level and effects of leptin in human hepatocellular carcinoma cells in vitro and to explore the correlation between them.METHODS: Human hepatocellular carcinoma cell line HepG2 was cultured in vitro, and (the expression level)mRNA of leptin and leptin receptors in HepG2 were assessed using reverse transcription polymerase chain reaction (RT-PCR). Effects of different concentrations of leptin (50 ng/mL, 100 ng/mL, 200 ng/mL) on HepG2 were detected with colorimetric assay by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) after incubation periods of 24 h, 48 h,and 72 h. Flow cytometry was performed to assess cell cycle progression of different concentrations of leptin as stated above after each 24 h incubation period.RESULTS: mRNA of leptin and leptin receptors (including short and long isoforms) were expressed in HepG2.The 72 h incubation of leptin at different concentrations (50 ng/mL, 100 ng/mL, 200 ng/mL) promoted proliferation of HepG2 in a concentration- and timedependent manner. The experimental group shows significant statistical differences when compared to the controlled group which contained 0 ng/mL of leptin. As the concentration of leptin increases, significant fewer cells were detected in G0-G1 phase and more cells in S and G2-M phases.CONCLUSION: Leptin and leptin receptor are simultaneously expressed in human hepatocellular carcinoma cell line HepG2. Addition of leptin (O ng/mL200 ng/mL) in 72 h periods indicated there is a concentration- and time-dependent correlation in the stimulation of HepG2 cell proliferation. The effect of proliferation by leptin is due to promotion of DNA synthesis and enhancement of mitotic activity. The relationship between leptin and human hepatocellular carcinoma cells might indicate that adipokine could be associated with the progression of human hepatocellular carcinoma.

  11. Integrative and comparative genomics analysis of early hepatocellular carcinoma differentiated from liver regeneration in young and old

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    Ozand Pinar T

    2010-06-01

    Full Text Available Abstract Background Hepatocellular carcinoma (HCC is the third-leading cause of cancer-related deaths worldwide. It is often diagnosed at an advanced stage, and hence typically has a poor prognosis. To identify distinct molecular mechanisms for early HCC we developed a rat model of liver regeneration post-hepatectomy, as well as liver cells undergoing malignant transformation and compared them to normal liver using a microarray approach. Subsequently, we performed cross-species comparative analysis coupled with copy number alterations (CNA of independent early human HCC microarray studies to facilitate the identification of critical regulatory modules conserved across species. Results We identified 35 signature genes conserved across species, and shared among different types of early human HCCs. Over 70% of signature genes were cancer-related, and more than 50% of the conserved genes were mapped to human genomic CNA regions. Functional annotation revealed genes already implicated in HCC, as well as novel genes which were not previously reported in liver tumors. A subset of differentially expressed genes was validated using quantitative RT-PCR. Concordance was also confirmed for a significant number of genes and pathways in five independent validation microarray datasets. Our results indicated alterations in a number of cancer related pathways, including p53, p38 MAPK, ERK/MAPK, PI3K/AKT, and TGF-β signaling pathways, and potential critical regulatory role of MYC, ERBB2, HNF4A, and SMAD3 for early HCC transformation. Conclusions The integrative analysis of transcriptional deregulation, genomic CNA and comparative cross species analysis brings new insights into the molecular profile of early hepatoma formation. This approach may lead to robust biomarkers for the detection of early human HCC.

  12. Salvage liver transplantation in the treatment of hepatocellular carcinoma: A Meta-analysis

    Institute of Scientific and Technical Information of China (English)

    Hong-Yu Li; Yong-Gang Wei; Lv-Nan Yan; Bo Li

    2012-01-01

    AIM:To evaluate survival and recurrence after salvage liver transplantation (SLT) for the treatment of hepatocellular carcinoma (HCC) compared with primary liver transplantation (PLT) using a meta-analysis.METHODS:Literature on SLT versus PLT for the treatment of HCC published between 1966 and July 2011 was retrieved.A meta-analysis was conducted to estimate pooled survival and disease-free rates.A fixed or random-effect model was established to collect the data.RESULTS:The differences in overall survival and disease-free survival rates at 1-year,3-year and 5-year survival rates were not statistically significant between SLT group and PLT group (P > 0.05).After stratifying the various studies by donor source and Milan criteria,we found that:(1) Living donor liver transplantation recipients had significantly higher 1-year survival rate,lower 3-year and 5-year survival rates compared with deceased-donor liver transplantation (DDLT) recipients.And in DDLT recipients they had better 1-year and 5-year disease-free survival rate in SLT group; and (2)No difference was seen in 1-year,3-year and 5-year survival rates between two groups who beyond Milan criteria at the time of liver transplantation.CONCLUSION:SLT can be effectively performed for patients with recurrence or deterioration of liver function after hepatectomy for HCC.It does not increase the perioperative mortality and has a similar long-term survival rates compared to PLT.

  13. Current strategies for preventing the recurrence of hepatocellular carcinoma after liver transplantation

    Institute of Scientific and Technical Information of China (English)

    Zhuo-Yi Wang; Lei Geng; Shu-Sen Zheng

    2015-01-01

    BACKGROUND:Liver transplantation is the optimal treat-ment for a selected group of patients with moderate to severe cirrhosis and hepatocellular carcinoma (HCC). Despite the strict selection of candidates, post-transplant recurrence often occurs and markedly reduces the long-term survival of patients with HCC. The present review focuses on the current strategies on preventing the recurrence of HCC after liver transplantation. DATA SOURCES:Relevant articles were identiifed by exten-sive searching of PubMed using the keywords "hepatocellular carcinoma", "recurrence" and "liver transplantation" between January 1996 and January 2014. Additional papers were searched manually from the references in key articles. RESULTS:The current theories of HCC recurrence after liver transplantation are: (i) the growth of pre-transplant occult metastases; (ii) the engraftment of circulating tumor cells re-leased at the time of transplantation. Pre-transplant treatment aims to control local tumor by radiofrequency ablation, tran-sarterial embolization and transarterial chemoembolization. The main objective during the operation is to prevent tumor cell dissemination. Post-transplant treatment includes sys-temic anticancer therapy, antiviral therapy, and most recently, immunotherapy. These strategies concentrate on the control of the tumor when the patients are waiting for transplant, to reduce the release of HCC cells during surgical procedures and to clear the occult HCC cells after transplantation. CONCLUSIONS:Much can be done to prevent HCC recurrence after liver transplantation. In future, effort is likely to be di-rected towards combining multidisciplinary approaches and various treatment modalities.

  14. Constructing the HBV-human protein interaction network to understand the relationship between HBV and hepatocellular carcinoma

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    Huang De-Rong

    2010-11-01

    Full Text Available Abstract Background Epidemiological studies have clearly validated the association between hepatitis B virus (HBV infection and hepatocellular carcinoma (HCC. Patients with chronic HBV infection are at increased risk of HCC, in particular those with active liver disease and cirrhosis. Methods We catalogued all published interactions between HBV and human proteins, identifying 250 descriptions of HBV and human protein interactions and 146 unique human proteins that interact with HBV proteins by text mining. Results Integration of this data set into a reconstructed human interactome showed that cellular proteins interacting with HBV are made up of core proteins that are interconnected with many pathways. A global analysis based on functional annotation highlighted the enrichment of cellular pathways targeted by HBV. Conclusions By connecting the cellular proteins targeted by HBV, we have constructed a central network of proteins associated with hepatocellular carcinoma, which might be to regard as the basis of a detailed map for tracking new cellular interactions, and guiding future investigations.

  15. Hepatocellular carcinoma in the native liver of a 38-year-old female patient with biliary atresia

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    Yutaka Kanamori

    2015-11-01

    Full Text Available We report a rare case of hepatocellular carcinoma in native liver in a case of biliary atresia. The patient was a 38-year-old female with three children who had an aggressive tumor, resulting in her subsequent death. We also review 14 reports, published previously in the English language medical literature, concerning hepatocellular carcinoma originating from native liver in biliary atresia cases and discuss the possible etiology, and propose more careful follow up for the patients with biliary atresia who suffer from repetitive cholangitis and/or experience the child delivery.

  16. Selective tropism of liver stem cells to hepatocellular carcinoma in vivo

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    AIM: To investigate the selective tropism of liver stem cells to hepatocellular carcinoma (HCC) in an animal model and its feasibility as a vector to deliver therapeutic genes for targeted therapy of HCC.METHODS: WB-F344, a kind of rat liver stem cell,was infected with recombinant virus to establish a cell line with stable, high-level expressing enhanced green fluorescent protein (EGFP). An animal model of HCC in Wistar rats was established by implanting HCC cells (CBRH7919) combined with an immunosuppressive drug.EGFP labeled liver stem cells were injected into caudal veins of the animals and distribution was observed at different time points after injection. SDF-1 and c-kit expression in non-tumor liver and tumor tissue were analysed by immunohistochemistry for the relationshiop between the expression and migration of liver stem cells.Furthermore, hepatic stem cells were injected via the portal vein, hepatic artery, caudal vein, or directly into the pericancerous liver tissue, respectively, and effects on migration, localization, and proliferation of the hepatic stem cells within the tumor tissue were observed and analyzed.RESULTS: Recombinant adenovirus could deliver the EGFP gene to hepatic stem cells. A new stem cell line,named WB-EGFP, was established that stably expressed EGFP. WB-EGFP cells still showed selective tropism towards HCC and EGFP expression was stable in vivo.According to immunohistochemistry results, SDF-1 may not be related to the mechanisms of tropism of hepatic stem cells. Different application sites affected the distribution of liver stem cells. Injection via the portal vein was superior with regard to selective migration,localization, and proliferation of the hepatic stem cells within the tumor tissue.CONCLUSION: Liver stem cells have the biological behavior of selective migration to HCC in vivo and they could localize and proliferate within HCC tissue stably expressing the target gene. Liver stem cells are a potential tool for a targeted

  17. A microfluidically perfused three dimensional human liver model.

    Science.gov (United States)

    Rennert, Knut; Steinborn, Sandra; Gröger, Marko; Ungerböck, Birgit; Jank, Anne-Marie; Ehgartner, Josef; Nietzsche, Sandor; Dinger, Julia; Kiehntopf, Michael; Funke, Harald; Peters, Frank T; Lupp, Amelie; Gärtner, Claudia; Mayr, Torsten; Bauer, Michael; Huber, Otmar; Mosig, Alexander S

    2015-12-01

    Within the liver, non-parenchymal cells (NPCs) are critically involved in the regulation of hepatocyte polarization and maintenance of metabolic function. We here report the establishment of a liver organoid that integrates NPCs in a vascular layer composed of endothelial cells and tissue macrophages and a hepatic layer comprising stellate cells co-cultured with hepatocytes. The three-dimensional liver organoid is embedded in a microfluidically perfused biochip that enables sufficient nutrition supply and resembles morphological aspects of the human liver sinusoid. It utilizes a suspended membrane as a cell substrate mimicking the space of Disse. Luminescence-based sensor spots were integrated into the chip to allow online measurement of cellular oxygen consumption. Application of microfluidic flow induces defined expression of ZO-1, transferrin, ASGPR-1 along with an increased expression of MRP-2 transporter protein within the liver organoids. Moreover, perfusion was accompanied by an increased hepatobiliary secretion of 5(6)-carboxy-2',7'-dichlorofluorescein and an enhanced formation of hepatocyte microvilli. From this we conclude that the perfused liver organoid shares relevant morphological and functional characteristics with the human liver and represents a new in vitro research tool to study human hepatocellular physiology at the cellular level under conditions close to the physiological situation.

  18. Oncological Impact of M-Tor Inhibitor Immunosuppressive Therapy after Liver Transplantation for Hepatocellular Carcinoma: Review of the Literature

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    Giuseppe Tarantino

    2016-10-01

    Full Text Available Background: Hepatocellular Carcinoma (HCC represents the fifth most common malignancy and the third cancer-related cause of death worldwide. Hepatitis B (HBV and C (HCV viral infections and alcohol abuse are the principal etiological factors for HCC. Liver transplantation (LT is oncologically the preferable approach to HCC, as it can remove all the intrahepatic tumor foci, and also the oncogenic cirrhotic liver. The use of mTOR inhibitors (mTORi for immunosuppression after LT for HCC has been proposed due to rapamycin antitumor activity. We decided to review the literature to clarify the oncological role of mTORi after liver transplantation for HCC, analyzing both present condition and future perspectives.Material and Methods: A systematic literature search was performed using PubMed, EMBASE, Scopus and the Cochrane Library Central. The search was limited to studies in humans and to those reported in the English language in the period of time between January 2005 and December 2015. Results: The literature search yielded 93 articles; after duplicates were removed, 77 titles and abstracts were reviewed. Most relevant data and papers are herein reported and discussed.Conclusions: So far, the use of mTORi is encouraging in terms of oncological outcomes for patients underwent LT for HCC, both for prevention and treatment of HCC recurrence although definitive data are still awaited.

  19. Oncological Impact of M-Tor Inhibitor Immunosuppressive Therapy after Liver Transplantation for Hepatocellular Carcinoma: Review of the Literature

    Science.gov (United States)

    Tarantino, Giuseppe; Magistri, Paolo; Ballarin, Roberto; Di Francia, Raffaele; Berretta, Massimiliano; Di Benedetto, Fabrizio

    2016-01-01

    Background: Hepatocellular Carcinoma (HCC) represents the fifth most common malignancy and the third cancer-related cause of death worldwide. Hepatitis B (HBV) and C (HCV) viral infections and alcohol abuse are the principal etiological factors for HCC. Liver transplantation (LT) is oncologically the preferable approach to HCC, as it can remove all the intrahepatic tumor foci, and also the oncogenic cirrhotic liver. The use of mTOR inhibitors (mTORi) for immunosuppression after LT for HCC has been proposed due to rapamycin antitumor activity. We decided to review the literature to clarify the oncological role of mTORi after liver transplantation for HCC, analyzing both present condition and future perspectives. Material and Methods: A systematic literature search was performed using PubMed, EMBASE, Scopus, and the Cochrane Library Central. The search was limited to studies in humans and to those reported in the English language in the period of time between January 2005 and December 2015. Results: The literature search yielded 93 articles; after duplicates were removed, 77 titles and abstracts were reviewed. Most relevant data and papers are herein reported and discussed. Conclusions: So far, the use of mTORi is encouraging in terms of oncological outcomes for patients underwent LT for HCC, both for prevention and treatment of HCC recurrence although definitive data are still awaited. PMID:27818634

  20. Precore/basal core promoter mutants and hepatitis B viral DNA levels as predictors for liver deaths and hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Myron J Tong; Lawrence M Blatt; Jia-Horng Kao; Jason Tzuying Cheng; William G Corey

    2006-01-01

    AIM: To conduct a retrospective study in 400 chronic hepatitis B patients in order to identify hepatitis B viral factors associated with complications of liver disease or development of hepatocellular carcinoma.METHODS: The mean follow-up time was 83.6 ± 39.6mo. Alpha-fetoprotein test and abdominal ultrasound were used for cancer surveillance. Hepatitis B basal core promoter mutants, precore mutants, genotypes,hepatitis B viral DNA (HBV DNA) level and hepatitis B e antigen (HBeAg) were measured. Univariate analysis and logistic regression were used to assess odds ratios for viral factors related to liver deaths and hepatocellular carcinoma development.RESULTS: During follow-up, 38 patients had liver deaths not related to hepatocellular carcinoma. On multivariate analysis, older age [odds ratio: 95.74 (12.13-891.31);P < 0.0001], male sex [odds ratio: 7.61 (2.20-47.95);P = 0.006], and higher log10 HBV DNA [odds ratio:4.69 (1.16-20.43); P < 0.0001] were independently predictive for these liver related deaths. Also, 31 patients developed hepatocellular carcinoma. Multivariate analysis showed that older age [odds ratio: 26.51 (2.36-381.47);P = 0.007], presence of precore mutants [odds ratio:4.23 (1.53-19.58); P = 0.02] and presence of basal core promoter mutants [odds ratio: 2.93 (1.24-7.57); P =0.02] were independent predictors for progression to hepatocellular carcinoma.CONCLUSION: Our results show that high levels of baseline serum HBV DNA are associated with nonhepatocellular carcinoma-related deaths of liver failure,while genetic mutations in the basal core promoter and precore regions are predictive for development of hepatocellular carcinoma.

  1. Peritoneal Recurrence of Initially Controlled Hepatocellular Carcinoma after Living Donor Liver Transplantation

    Directory of Open Access Journals (Sweden)

    Nariman Sadykov

    2015-01-01

    Full Text Available It is well known that the presence of end-stage liver disease increases the risk of developing hepatocellular carcinoma (HCC. Liver transplantation (LT for patients within the Milan criteria has become a standard treatment for HCC in most developed centers worldwide. However, a major cause of death in cirrhotic patients with HCC after transplantation is tumor recurrence, including peritoneal recurrences, which develops rarely but presents a significant problem with regard to their management. Our experience includes two cases with HCC within the Milan criteria of peritoneal recurrences after living donor LT. Both patients had interventions for HCC in their medical history before LT, and we propose that these might have been a possible cause of the HCC peritoneal recurrence.

  2. Gene signatures derived from a c-MET-driven liver cancer mouse model predict survival of patients with hepatocellular carcinoma.

    Directory of Open Access Journals (Sweden)

    Irena Ivanovska

    Full Text Available Biomarkers derived from gene expression profiling data may have a high false-positive rate and must be rigorously validated using independent clinical data sets, which are not always available. Although animal model systems could provide alternative data sets to formulate hypotheses and limit the number of signatures to be tested in clinical samples, the predictive power of such an approach is not yet proven. The present study aims to analyze the molecular signatures of liver cancer in a c-MET-transgenic mouse model and investigate its prognostic relevance to human hepatocellular carcinoma (HCC. Tissue samples were obtained from tumor (TU, adjacent non-tumor (AN and distant normal (DN liver in Tet-operator regulated (TRE human c-MET transgenic mice (n = 21 as well as from a Chinese cohort of 272 HBV- and 9 HCV-associated HCC patients. Whole genome microarray expression profiling was conducted in Affymetrix gene expression chips, and prognostic significances of gene expression signatures were evaluated across the two species. Our data revealed parallels between mouse and human liver tumors, including down-regulation of metabolic pathways and up-regulation of cell cycle processes. The mouse tumors were most similar to a subset of patient samples characterized by activation of the Wnt pathway, but distinctive in the p53 pathway signals. Of potential clinical utility, we identified a set of genes that were down regulated in both mouse tumors and human HCC having significant predictive power on overall and disease-free survival, which were highly enriched for metabolic functions. In conclusions, this study provides evidence that a disease model can serve as a possible platform for generating hypotheses to be tested in human tissues and highlights an efficient method for generating biomarker signatures before extensive clinical trials have been initiated.

  3. The Expression of Embryonic Liver Development Genes in Hepatitis C Induced Cirrhosis and Hepatocellular Carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Behnke, Martha, E-mail: mbehnke@mcvh-vcu.edu [Transplant Program Administration, Virginia Commonwealth University Health System, 1200 E. Broad St., Richmond, VA 23298 (United States); Reimers, Mark [Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University School of Medicine, 800 E Leigh St., Richmond, VA 23298 (United States); Fisher, Robert [Department of Surgery, Virginia Commonwealth University, 1200 E. Broad St., Richmond, VA 23298 (United States)

    2012-09-18

    Hepatocellular carcinoma (HCC) remains a difficult disease to study even after a decade of genomic analysis. Patient and disease heterogeneity, differences in statistical methods and multiple testing issues have resulted in a fragmented understanding of the molecular basis of tumor biology. Some researchers have suggested that HCC appears to share pathways with embryonic development. Therefore we generated targeted hypotheses regarding changes in developmental genes specific to the liver in HCV-cirrhosis and HCV-HCC. We obtained microarray studies from 30 patients with HCV-cirrhosis and 49 patients with HCV-HCC and compared to 12 normal livers. Genes specific to non-liver development have known associations with other cancer types but none were expressed in either adult liver or tumor tissue, while 98 of 179 (55%) genes specific to liver development had differential expression between normal and cirrhotic or HCC samples. We found genes from each developmental stage dysregulated in tumors compared to normal and cirrhotic samples. Although there was no single tumor marker, we identified a set of genes (Bone Morphogenetic Protein inhibitors GPC3, GREM1, FSTL3, and FST) in which at least one gene was over-expressed in 100% of the tumor samples. Only five genes were differentially expressed exclusively in late-stage tumors, indicating that while developmental genes appear to play a profound role in cirrhosis and malignant transformation, they play a limited role in late-stage HCC.

  4. MicroRNAs as Biomarkers for Liver Disease and Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    C. Nelson Hayes

    2016-02-01

    Full Text Available Serum levels of liver enzymes, such as alanine transaminase, aspartate transaminase, and α-fetoprotein, provide insight into liver function and are used during treatment of liver disease, but such information is limited. In the case of hepatocellular carcinoma (HCC, which is often not detected until an advanced stage, more sensitive biomarkers may help to achieve earlier detection. Serum also contains microRNAs, a class of small non-coding RNAs that play an important role in regulating gene expression. miR-122 is specific to the liver and correlates strongly with liver enzyme levels and necroinflammatory activity, and other microRNAs are correlated with the degree of fibrosis. miR-122 has also been found to be required for hepatitis C virus (HCV infection, whereas other microRNAs have been shown to play antiviral roles. miR-125a-5p and miR-1231 have been shown to directly target hepatitis B virus (HBV transcripts, and others are up- or down-regulated in infected individuals. MicroRNA profiles also differ in the case of HBV and HCV infection as well as between HBeAg-positive and negative patients, and in patients with occult versus active HBV infection. In such patients, monitoring of changes in microRNA profiles might provide earlier warning of neoplastic changes preceding HCC.

  5. Liver transplantation for hepatocellular carcinoma:is zero recurrence theoretically possible?

    Institute of Scientific and Technical Information of China (English)

    Sabine Irtan; Louise Barbier; Claire Francoz; Federica Dondéro; François Durand; Jacques Belghiti

    2016-01-01

    BACKGROUND: Hepatocellular carcinoma (HCC) recurrence remains a key issue after liver transplantation. This study aimed to determine a subgroup of HCC patients within the Milan criteria who could achieve a theoretical goal of zero re-currence rates after liver transplantation. METHODS: Between 1999 and 2009, 179 patients who re-ceived liver transplantation for HCC within the Milan criteria were retrospectively included. Analysis of the factors associ-ated with HCC recurrence was performed to determine the subgroup of patients at the lowest risk of recurrence. RESULTS: Seventy-two percent of the patients received a bridging therapy, including 54 liver resections. Eleven (6.1%) patients recurred within a delay of 19±22 months and ulti-mately died. Factors associated with recurrence were serum alpha-fetoprotein level >400 ng/mL, satellite nodules, poor differentiation, microvascular invasion and cholangiocarci-noma component. Recurrence rates decreased from 6.1% to 3.1% in patients without any of these factors. CONCLUSIONS: Among HCC patients within the Milan cri-teria, selecting patients with factors based on histology would allow tending towards zero recurrence, and prior histological assessment by liver biopsy or resection may be essential to rule out poorly differentiated tumors, microvascular invasion, and cholangiocarcinoma component.

  6. Clinical study of liver cancer (Hepatocellular carcinoma) by 166 Ho-CHICO

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    Lee, J. T.; Yoo, H. S.; Lee, J. D.; Lee, D. Y.; Kim, E. K.; Yoo, N. C.; Shin, S. J.; Han, K. H. [Yonsei University, Seoul (Korea); Park, K. B. [Korea Atomic Energy Research Institute, Taejeon (Korea)

    2000-04-01

    As having used Ho-166 Chitosan complex, this study was designed for the development of new therapeutic agent in the treatment of liver cancer (hepatocellular carcinoma). During the period of 3 years from April 1, 1997 to March 31, 2000, this project was successfully performed on the base of clinical experience with percutaneous Ho-166 CHICO injection in the treatment of liver cancer'. In order to evaluate the biodistribution and effect of Ho-166 CHICO was performed in 50 patients, who had the progressed liver cancer with range of 3-10cm in diameter. After the administration of the complex materials, we evaluated the therapeutic effect as well as complication by the follow-up study that included laboratory examination, radioactivity counting and various imaging modalities. 1) In animal experiment, radioactivity of target liver was ranged between 27-33% of total body one, urine excretion between 0.17-0.24 %. White blood cell and platelet counts start diminishing within 7 days and at maximum within 4 weeks after administration of complex materials. In tissue changes of target liver was revealed no significant change in the tumor dose of Ho-166, but periportal fibrosis and massive tissue necrosis in the high ones. 2) In clinical study, total necrosis of tumor is 66%, partial 10% and non-response 24% among 50 patients' liver cancer. The most important complication were leukopenia and thrombocytopenia (82%), the remained was abdominal pain(34%), skin reaction(12%), bile duct obstruction(10%), liver abscess(6%) etc. Conclusively intraarterial injection of Ho-166 CHICO was effective in the treatment of larger and progressed liver cancer. 19 refs., 14 figs., 8 tabs. (Author)

  7. Hepatocellular adenoma with malignant transformation in male patients with non-cirrhotic livers

    Institute of Scientific and Technical Information of China (English)

    Song-Lin An; Jian-Xiong Wu; Li-Ming Wang; Wei-Qi Rong; Fan Wu; Wei Sun; Wei-Bo Yu; Li Feng; Fa-Qiang Liu; Fei Tian

    2015-01-01

    Introduction:Hepatocellular adenomas (HCAs), with a risk of malignant transformation into hepatocellular carcinoma (HCC), classically develop in young women who are taking oral contraceptives. It is now clear that HCAs may also occur in men. However, it is rarely reported that HCAs with malignant transformation occur in male patients with non-cirrhotic livers. This study aimed to characterize the malignancy of HCAs occurring in male patients. Methods:Al patients with HCAs with malignant transformation who underwent hepatectomy at the Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical Col ege between January 1, 1999 and December 31, 2011 were enrolled in the study. The clinical characteristics as well as radiologic and pathologic data were reviewed. Results:HCAs with malignant transformation were observed in 5 male patients with non-cirrhotic livers, but not in female patients. The alpha-fetoprotein (AFP) levels were higher in patients with HCAs with malignant transformation than in patients with HCAs without malignant transformation. The diameters of the tumors with malignant transformation were larger than 5 cm in 3 cases and smaller than 5 cm in 2 cases. The 5 patients were all alive without recurrence by the end of the study period. The disease-free survival times of the 5 patients were 26, 48, 69, 69, and 92 months. Conclusion:Our results indicate that resection would be advised even if the presumptive diagnosis is adenoma smaller than 5 cm in diameter, especially in male patients.

  8. Acarboxy prothrombin (PIVKA II) as a tumour marker for hepatocellular carcinoma and other liver diseases.

    Science.gov (United States)

    Mohamedein, A; Yousif-Kadaru, A G; Ahmed, S A; Saida, H; Zaki, Z A; Eldin; Fedail, S S

    1995-09-01

    The clinical usefulness of plasma abnormal prothrombin, defined as protein induced by vitamin K absence or antagonist II: (PIVKA II) as a tumour marker for hepatocellular carcinoma (HCC) and other liver diseases has been evaluated. PIVKA II concentrations were determined using an enzyme-linked immunosorbent assay (ELISA) with monoclonal antibody that reacts with PIVKA II but does not cross-react with normal prothrombin. Seventy four patients (74%) out of 100 with HCC had abnormal PIVKA II levels above 0.5 AU/ml (median = 3.4 AU/ml). The level was above 1.0 AU/ml in 66 (66%) of the patients. In contrast the level of PIVKA II was low in patients with bilharzial periportal fibrosis (median = 0.09 AU/ml), patients with liver cirrhosis (median = 0.13 AU/ml), patients with hepatitis (median = 0.025 AU/ml), and essentially undetectable in all the 34 controls. The diagnostic ability of serum alphafoetoprotein (AFP) was also evaluated in these patients. AFP alone can diagnose 51% of the HCC cases. Of the remaining patients with low or negative AFP levels (65%) can be diagnosed using PIVKA II. Abnormal prothrombin is a potential marker for the laboratory diagnosis of hepatocellular carcinoma.

  9. Telomerase-specific oncolytic virotherapy for human hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    AIM: To evaluate the therapeutic efficiency of replicative adenovirus CNHK300 targeted in telomerase-positive hepatocellular carcinoma. METHODS: CNHK300, ONYX-015 (55 kDa protein deleted adenovirus) and wtAd5 (wild type adenovirus 5) were compared, and virus proliferation assay, cell viability assay, Western blot and fluorescence microscopy were used to evaluate the proliferation and cytolysis selectivity of CNHK300.RESULTS:The replicative multiples in Hep3B and HepG after 48 h of CNHK300 proliferation were 40625and 65326 fold, respectively, similar to that of wtAd5..However, CNHK300 exhibited attenuated replicative ability in normal fibroblast cell line BJ.CNHK300 could lyse hepatocellular carcinoma cells at a low multiplicity of infection (MOI),but could not affect growth of normal cells even at a high MOI.CONCLUSION:CNHK300 is a cancer-selective replication-competent adenovirus which can cause oncolysis of liver cancer cells as well as wtAd5 (wild type adenovirus 5),but had severely attenuated replicative and cytolytic ability in normal cells. This novel strategy of cancer treatment offers a promising treatment platform.

  10. Leptin as a critical regulator of hepatocellular carcinoma development through modulation of human telomerase reverse transcriptase

    Directory of Open Access Journals (Sweden)

    Stefanou Nikolaos

    2010-08-01

    Full Text Available Abstract Background Numerous epidemiological studies have documented that obesity is associated with hepatocellular carcinoma (HCC. The aim of this study was to investigate the biological actions regulated by leptin, the obesity biomarker molecule, and its receptors in HCC and the correlation between leptin and human telomerase reverse transcriptase (hTERT, a known mediator of cellular immortalization. Methods We investigated the relationship between leptin, leptin receptors and hTERT mRNA expression in HCC and healthy liver tissue samples. In HepG2 cells, chromatin immunoprecipitation assay was used to study signal transducer and activator of transcription-3 (STAT3 and myc/mad/max transcription factors downstream of leptin which could be responsible for hTERT regulation. Flow cytometry was used for evaluation of cell cycle modifications and MMP1, 9 and 13 expression after treatment of HepG2 cells with leptin. Blocking of leptin's expression was achieved using siRNA against leptin and transfection with liposomes. Results We showed, for the first time, that leptin's expression is highly correlated with hTERT expression levels in HCC liver tissues. We also demonstrated in HepG2 cells that leptin-induced up-regulation of hTERT and TA was mediated through binding of STAT3 and Myc/Max/Mad network proteins on hTERT promoter. We also found that leptin could affect hepatocellular carcinoma progression and invasion through its interaction with cytokines and matrix mettaloproteinases (MMPs in the tumorigenic microenvironment. Furthermore, we showed that histone modification contributes to leptin's gene regulation in HCC. Conclusions We propose that leptin is a key regulator of the malignant properties of hepatocellular carcinoma cells through modulation of hTERT, a critical player of oncogenesis.

  11. Status quo of chronic liver diseases, including hepatocellular carcinoma, in Mongolia.

    Science.gov (United States)

    Jazag, Amarsanaa; Puntsagdulam, Natsagnyam; Chinburen, Jigjidsuren

    2012-06-01

    Because Mongolia has much higher liver disease burden than any other regions of the world, it is necessary to provide information on real-time situation of chronic liver disease in Mongolia. In this article, we reviewed studies performed in Mongolia from 2000 to 2011 on seroprevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) among healthy individuals and patients with chronic liver diseases, and on the practice patterns for the management of liver cirrhosis and hepatocellular carcinoma (HCC). According to previous reports, the seroprevalence of HBV and HCV in general population in Mongolia is very high (11.8% and 15% for HBV and HCV, respectively). Liver cirrhosis is also highly prevalent, and mortality from liver cirrhosis remained high for the past decade (about 30 deaths per 100,000 populations per year). Among patients with cirrhosis, 40% and 39% are positive for HBsAg and anti-HCV, respectively, and 20% are positive for both. The seroprevalence is similar for HCC and more than 90% of HCC patients are positive for either HBV or HCV. The incidence of HCC in Mongolia is currently among the highest in the world. The mortality from HCC is also very high (52.2 deaths per 100,000 persons per year in 2010). Partly due to the lack of established surveillance systems, most cases of HCC are diagnosed at an advanced stage. The mortality from liver cirrhosis and HCC in Mongolia may be reduced by implementation of antiviral therapy program and control of alcohol consumption.

  12. Plasma Adiponectin and Hepatocellular Carcinoma Survival Among Patients Without Liver Transplantation.

    Science.gov (United States)

    Shen, Jing; Yeh, Chih-Ching; Wang, Qiao; Gurvich, Irina; Siegel, Abby B; Santella, Regina M

    2016-10-01

    To investigate the levels of leptin and adiponectin in prediction of hepatocellular carcinoma (HCC) survival among patients without liver transplantation. We measured pretreatment plasma leptin and adiponectin in 172 HCC cases who were prospectively followed-up over 7 years. Gender, hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, high body mass index (BMI), diabetes mellitus (DM) history and Child-Pugh (CP) class were associated with leptin and adiponectin levels, while α-fetoprotein (AFP) and presence of metastasis, being outside the Milan criteria and Barcelona clinic liver cancer (BCLC) stage, were significantly associated with liver transplantation and HCC survival. No significant association was observed for leptin or adiponectin and HCC survival in the overall group. In subgroup analyses among those without liver transplantation, we found significant associations between metastasis, Milan criteria, BCLC stage, hepatitis B surface antigen (HBsAg) and HCC survival. When separately determining the Cox proportional hazard models and Kaplan-Meier survival curves by liver transplantation status, higher adiponectin was significantly associated with an increased hazard ratio (HR) of death of 1.72 (95% confidence interval (CI)=1.12-2.64), i.e. poor survival among patients without liver transplantation. A multivariate Cox proportional hazard model, including adiponectin, CP class, presence of metastasis, tumor outside of Milan criteria, AFP and BCLC stage B/C parameters, also showed significant association with poor HCC survival (likelihood ratio test padiponectin may predict poor HCC survival among patients without liver transplantation. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  13. Detection of HBV, PCNA and GST-π in hepatocellular carcinoma and chronic liver diseases

    Institute of Scientific and Technical Information of China (English)

    Li-Juan Shen; Hua-Xian Zhang; Zong-Ji Zhang; Jin-Yun Li; Ming-Qin Chen; Wei-Bo Yang; Run Huang

    2003-01-01

    AIM: To investigate the change of HBV DNA, PCNA and GST-π in chronic liver disease and hepatocellular carcinoma (HCC).METHODS: Hepatitis B surface antigen (HBsAg), proliferating cell nuclear antigen (PCNA) and glutathione S-transferases (GST-π) were detected by immunohistochemical staining and HBV DNA was detected by in situ hybridization (ISH) in formalin-fixed and paraffin-embedded sections with a total of 111 specimens of chronic hepatitis, liver cirrhosis,paratumorous tissue, HCC and normal liver tissue.RESULTS: The positive rates of HBsAg and HBVDNA were 62.5 %(15/24) and 75.0 %(12/16) in chronic hepatitis,64.0 %(16/25) and 83.3 %(15/18) in liver cirrhosis, 72.7 %(16/22) and 85.7 %(12/14) in the paratumorous tissu and 45.0 %(14/31) and 64.3 %(9/14) in HCC. The positive HBVDNA granules in chronic hepatitis, liver cirrhosis and the paratumorous tissue were more intense than that in HCC.The positive rates of PCNA and GST-π were 34.8 %(8/23)and 25.0 %(4/16) in chronic hepatitis, 73.7 %(14/19) and 17.6 %(3/17) in liver cirrhosis, 86.7 %(13/15) and 53.3 % (8/15) in the paratumorous tissue, 100 %(15/15) and 60.0 %(9/15) in HCC, respectively, and the positive rate of GST-πin the paratumorous tissue was significantly higher than that in the liver cirrhosis without tumor (P<0.05), but same as that in HCC(P>0.05).CONCLUSION: The HBV infection may increase expression of PCNA and GST-π. The paratumor cirrhosis may be a sequential lesion of precancerous cirrhosis around HCC.

  14. Investigating the biochemical progression of liver disease through fibrosis, cirrhosis, dysplasia, and hepatocellular carcinoma using Fourier transform infrared spectroscopic imaging

    Science.gov (United States)

    Sreedhar, Hari; Pant, Mamta; Ronquillo, Nemencio R.; Davidson, Bennett; Nguyen, Peter; Chennuri, Rohini; Choi, Jacqueline; Herrera, Joaquin A.; Hinojosa, Ana C.; Jin, Ming; Kajdacsy-Balla, Andre; Guzman, Grace; Walsh, Michael J.

    2014-03-01

    Hepatocellular carcinoma (HCC) is the most common form of primary hepatic carcinoma. HCC ranks the fourth most prevalent malignant tumor and the third leading cause of cancer related death in the world. Hepatocellular carcinoma develops in the context of chronic liver disease and its evolution is characterized by progression through intermediate stages to advanced disease and possibly even death. The primary sequence of hepatocarcinogenesis includes the development of cirrhosis, followed by dysplasia, and hepatocellular carcinoma.1 We addressed the utility of Fourier Transform Infrared (FT-IR) spectroscopic imaging, both as a diagnostic tool of the different stages of the disease and to gain insight into the biochemical process associated with disease progression. Tissue microarrays were obtained from the University of Illinois at Chicago tissue bank consisting of liver explants from 12 transplant patients. Tissue core biopsies were obtained from each explant targeting regions of normal, liver cell dysplasia including large cell change and small cell change, and hepatocellular carcinoma. We obtained FT-IR images of these tissues using a modified FT-IR system with high definition capabilities. Firstly, a supervised spectral classifier was built to discriminate between normal and cancerous hepatocytes. Secondly, an expanded classifier was built to discriminate small cell and large cell changes in liver disease. With the emerging advances in FT-IR instrumentation and computation there is a strong drive to develop this technology as a powerful adjunct to current histopathology approaches to improve disease diagnosis and prognosis.

  15. Advances in liver-directed gene therapy for hepatocellular carcinoma by non-viral delivery systems.

    Science.gov (United States)

    Ding, Buyun; Li, Tao; Zhang, Jian; Zhao, Lixia; Zhai, Guangxi

    2012-04-01

    Hepatocellular carcinoma (HCC) is a malignancy with a high mortality. Gene therapy provides a promising way for the treatment of HCC. Efficient gene delivery system, suitable gene target and appropriate way of administration together determine the effect of gene therapy for HCC. In recent years, employing non-viral gene delivery systems in gene therapy for HCC has attracted a lot of attention. Compared with viral vectors, non-viral gene delivery systems are nearly non-immunogenic, relatively safer, less expensive to produce and can carry a good many of genetic materials. But the transfection efficiency of these vectors still needs to be improved. And the liver targeting is another problem that needs to be solved. Attaching ligands to the non-viral vectors to enhance the targeting ability to the specific receptor and targeting to molecular targets of HCC are the effective strategies. Adopting suitable ways of administration is also a factor that plays an important role to achieve liver targeting. This review introduced the advances in liver-targeted gene therapy by non-viral vectors including the efforts to overcome the low transfection efficiency and enhance the liver targeting effect.

  16. Systemic chemotherapy for hepatocellular carcinoma in non-cirrhotic liver: A retrospective study

    Institute of Scientific and Technical Information of China (English)

    Julien Edeline; Jean-Luc Raoul; Elodie Vauleon; Anne Guillygomac'h; Karim Boudjema; Eveline Boucher

    2009-01-01

    AIM: To investigate the efficacy and toxicity of systemic chemotherapy in a retrospective study of patients with hepatocellular carcinoma (HCC) occurring in normal or fibrotic liver without cirrhosis. METHODS: Twenty-four patients with metastatic or locally advanced HCC in a normal or a fibrotic liver were given systemic chemotherapy (epirubicin, cisplatin and 5-fluorouracil or epirubicin, cisplatin and capecitabine regimens). Tumor response, time to progression, survival, and toxicity were evaluated. RESULTS: There were 7 women and 17 men, mean 6 had a fibrotic liver (F1/F2 on biopsy). Mean tumor size was 14 cm, 5 patients had portal vein thrombosis and 7 had metastasis. Patients received a median of 4 chemotherapy sessions. Overall tolerance was good. There were 5 partial responses (objective response rate = 22%), and tumor control rate was 52%. Second line surgical resection was possible in two patients. Median survival was 11 mo, and 1- and 2-year overall survival rates were 50% ± 10% and 32% ± 11%, respectively. ``CONCLUSION: In patients with HCC in a non-cirrhotic liver, chemotherapy was well tolerated and associated with an objective response rate of 22%, including two patients who underwent secondary surgical resection.

  17. TISSUE HARMONIC IMAGING IN DIFFERENTIATING HEPATOCELLULAR CARCINOMA, LIVER METASTASIS AND HEMANGIOMA

    Institute of Scientific and Technical Information of China (English)

    赵玉珍; 翟栋材; 纪晓惠

    2003-01-01

    To explore the role of tissue harmonic imaging(THI) in differentiating hepatocellular carcinoma (HCC), liver metastasis and hemangioma.Methods TOSHIBA SSA-370A ultrasonic system with a 3-to 6-MHz convex transducer (PMV-375AT) was utilized for the study.68 patients(30 cases of HCC, 14 liver metastasis, 24 cases of hemangioma) were examined with fundamental imaging(FI) and tissue harmonic imaging ( THI). Signal-to-noise ratio (SNR), tissue structure parameter:coefficient of variation(CTV) and specific coefficient of variation(CTVs) were calculated, then the tendency of each parameter in every group was evaluated.Results CTV and CTVs within group had no difference, but those between the groups had significant difference(P<0. 05). As a good parameter, CTVs could correctly discriminate HCC, liver metastasis and hemangioma in three groups. It showed that the value of SNR was the highest in hemangioma and the lowest in liver metastasis, and it showed the tendency of increment of the value with a decreased frequ

  18. Role of liver resection in the management of multinodular hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Osman; Abbasoglu

    2015-01-01

    Hepatocellular carcinoma(HCC) is the third leadingcause of cancer related deaths worldwide. Various treatment modalities have been applied to HCC depend-ing on the tumor load, functional capacity of the liver and the general condition of the patient. According to Barcelona Clinic Liver Cancer staging strategy and The American Association for the Study of Liver Disease guidelines, surgical resection is not advocated in the tretment of multinodular HCC. Despite this, many recent clinical studies show that, resection can achieve good results in patients with multinodular HCC and 5-year survival rate around 40% can be reached. If resection or transplantation is not performed, these patients are usually managed with palliative procedures such as transarterial chemoembolization, radioembolization and cytotoxic chemotherapy and 5-year survival of this group of patients will be extremely low. Although survival rates are lower and complications may be increased in this group of patients, liver resection can safely be performed in selected patients in experienced centers for the management of multinodular HCC.

  19. Accuracy of hepatocellular carcinoma detection on multidetector CT in a transplant liver population with explant liver correlation

    Energy Technology Data Exchange (ETDEWEB)

    Addley, H.C., E-mail: helenclareaddley@hotmail.co.u [Department of Radiology, Addenbrooke' s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge (United Kingdom); Griffin, N.; Shaw, A.S.; Mannelli, L. [Department of Radiology, Addenbrooke' s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge (United Kingdom); Parker, R.A. [Department of Medical Statistics, Addenbrooke' s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge (United Kingdom); Aitken, S.; Wood, H. [Department of Radiology, Addenbrooke' s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge (United Kingdom); Davies, S. [Department of Histopathology, Addenbrooke' s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge (United Kingdom); Alexander, G.J. [Department of Hepatology, Addenbrooke' s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge (United Kingdom); Lomas, D.J. [Department of Radiology, Addenbrooke' s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge (United Kingdom)

    2011-04-15

    Aim: To evaluate the diagnostic accuracy of multidetector computed tomography (MDCT) for hepatocellular carcinoma (HCC) in cirrhotic patients undergoing liver transplantation. Secondary aims were to examine the effect of radiologist experience and lesion size on diagnostic accuracy. Materials and methods: Thirty-nine patients (72% male with a mean age of 56.5 years) underwent liver transplantation following preoperative triple-phase MDCT examination of the liver. MDCT examinations were retrospectively independently reviewed by three radiologists for the presence and location of suspected HCCs, with the diagnostic confidence recorded using a five-point confidence scale. MDCT examinations were compared with explant specimens for histopathological correlation. Results: Histopathological results demonstrated 46 HCCs in 29 of the 39 patients. Analysis demonstrated a sensitivity of 65-75% and specificity of 47-88% for detection of HCC lesions. The sensitivity dropped to 48-57% for lesions of size {<=}20 mm. As the diagnostic confidence increased, there was a further decrease in the sensitivity (4-26%). The radiologist with the greatest number of years experience was found to have a significantly higher accuracy of detection of HCC lesions compared with the least experienced radiologist. Conclusion: Larger lesion size of HCC and greater number of years experience of the radiologist resulted in significantly higher accuracy of HCC lesion detection. The overall sensitivity and specificity results for MDCT detection of HCC are comparable to previous helical CT imaging.

  20. Liver transplantation for hepatocellular carcinoma on cirrhosis: Strategies to avoid tumor recurrence

    Institute of Scientific and Technical Information of China (English)

    Marco Vivarelli; Andrea Risaliti

    2011-01-01

    Hepatocellular carcinoma (HCC) is one of the most frequent neoplasms worldwide and in most cases it is associated with chronic liver disease. Liver trans-plantation (LT) is potentially the optimal treatment for those patients with HCC who have a poor functional hepatic reserve due to their underlying chronic liver disease. However, due to the limited availability of donors, only those patients whose oncologic profile is favorable can be considered for LT. Despite the care-ful selection of candidates based on strict rules, 10 to 20% of liver transplant recipients who have HCC in the native cirrhotic liver develop tumor recurrence after transplantation. The selection criteria pres-ently employed to minimize the risk of recurrence are based on gross tumor characteristics defined by imaging techniques; unfortunately, the accuracy of imaging is far from being optimal. Furthermore, mi-croscopic tumor features that are strictly linked with prognosis can not be assessed prior to transplanta-tion. Pre-transplantation tumor downstaging may allow transplantation in patients initially outside the selection criteria and seems to improve the progno-sis; it also provides information on tumor biology. The main peculiarity of the transplantation setting, when this is compared with other modalities of treatment, is the need for pharmacological immunosuppression: this is based on drugs that have been demonstrated to increase the risk of tumor development. As HCC is an aggressive malignancy, immunosuppression has to be handled carefully in patients who have HCC at the time of transplantation and new categories of immu-nosuppressive agents should be considered. Adjuvant chemotherapy following transplantation has failed to show any significant advantage. The aim of the pres-ent study is to review the possible strategies to avoid recurrence of HCC after liver transplantation based on the current clinical evidence and the more recent de-velopments and to discuss possible future directions.

  1. Contribution of alpha-fetoprotein in liver transplantation for hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Bérénice; Charrière; Charlotte; Maulat; Bertrand; Suc; Fabrice; Muscari

    2016-01-01

    Alpha-fetoprotein(AFP) is the main tumor biomarker available for the management of hepatocellular carcinoma(HCC). Although it is neither a good screening test nor an accurate diagnostic tool for HCC, it seems to be a possible prognostic marker. However, its contribution in liver transplantation for HCC has not been fully determined, although its use to predict recurrence after liver transplantation has been underlined by international societies. In an era of organ shortages, it could also have a key role in the selection of patients eligible for liver transplantation. Yet unanswered questions remain. First, the cut-off value of serum AFP above which liver transplantation should not be performed is still a subject of debate. We show that a concentration of 1000 ng/m L could be an exclusion criterion, whereas values of < 15 ng/m L indicate patients with an excellent prognosis whatever the size and number of tumors. Monitoring the dynamics of AFP could also prove useful. However, evidence is lacking regarding the values that should be used. Today, the real input of AFP seems to be its integration into new criteria to select patients eligible for a liver transplantation. These recent tools have associated AFP values with morphological criteria, thus refining pre-existing criteria, such as Milan, University of California, San Francisco, or "up-to-seven". We provide a review of the different criteria submitted within the past years. Finally, AFP can be used to monitor recurrence after transplantation, although there is little evidence to support this claim. Future challenges will be to draft new international guidelines to implement the use of AFP as a selection tool, and to determine a clear cut-off value above which liver transplantation should not be performed.

  2. Comparison of the multi-drug resistant human hepatocellular carcinoma cell line Bel-7402/ADM model established by three methods

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    Zhong Xingguo

    2010-08-01

    Full Text Available Abstract Background To compare the biological characteristics of three types of human hepatocellular carcinoma multi-drug resistant cell sub-lines Bel-7402/ADM models established by three methods. Methods Established human hepatocellular carcinoma adriamycin (ADM multi-drug resistant cell sub-lines models Bel-7402/ADMV, Bel-7402/ADML and Bel-7402/ADMS by three methods of in vitro concentration gradient increased induction, nude mice liver-implanted induction and subcutaneous-implanted induction respectively. Phase contrast microscopy was used to observe the cells and the MTT (methyl thiazolyl tetrazolium method was used to detect drug resistance of the three different sub-lines of cells. Results The three groups of drug resistant cells, Bel-7402/ADMV, Bel-7402/ADML and Bel-7402/ADMS generated cross-resistance to ADM and CDDP (cis-Diaminedichloroplatinum, but showed a significant difference in resistance to Bel-7402 IC50 value (P V, 46 h (Bel-7402/ADML, and 45 h (Bel-7402/ADMS. The excretion rates of ADM were significantly increased compared with the parent cell (34.14% line and were 81.06% (Bel-7402/ADMV, 66.56% (Bel-7402/ADML and 61.56% (Bel-7402/ADMS. Expression of P-gp and MRP in the three groups of resistant cells was significantly enhanced (P P > 0.05. Conclusions Stable resistance was involved in the resistant cell line model established by the above three methods. Liver implantation was a good simulation of human hepatocellular and proved to be an ideal model with characteristics similar to human hepatocellular biology and the pharmacokinetics of anticancer drugs.

  3. Immunization With AFP + GM CSF Plasmid Prime and AFP Adenoviral Vector Boost in Patients With Hepatocellular Carcinoma

    Science.gov (United States)

    2015-12-01

    Hepatocellular Carcinoma; Hepatoma; Liver Cancer, Adult; Liver Cell Carcinoma; Liver Cell Carcinoma, Adult; Cancer of Liver; Cancer of the Liver; Cancer, Hepatocellular; Hepatic Cancer; Hepatic Neoplasms; Hepatocellular Cancer; Liver Cancer; Neoplasms, Hepatic; Neoplasms, Liver

  4. Salvage Liver Transplantation Is a Reasonable Option for Selected Patients Who Have Recurrent Hepatocellular Carcinoma after Liver Resection

    Science.gov (United States)

    Hu, Zhenhua; Zhou, Jie; Xu, Xiaofeng; Li, Zhiwei; Zhou, Lin; Wu, Jian; Zhang, Min; Zheng, Shusen

    2012-01-01

    Background Salvage liver transplantation (SLT) has been reported as being feasible for patients who develop recurrent hepatocellular carcinoma (HCC) after primary liver resection, but this finding remains controversial. We retrospectively studied the clinical characteristics of SLT recipients and conducted a comparison between SLT recipients and primary liver transplantation (PLT) recipients. Methodology and Principal Findings A retrospective study examined data from the China Liver Transplant Registry (CLTR) for 6,975 transplants performed from January 1999 to December 2009. A total of 6,087 patients underwent PLT and 888 patients underwent SLT for recurrence. Living donor liver transplantation (LDLT) was performed in 389 patients, while 6,586 patients underwent deceased donor liver transplantation (DDLT). Kaplan-Meier curves were used to compare survival rates. The 1-year, 3-year, and 5-year overall survival of SLT recipients was similar to that of PLT recipients: 73.00%, 51.77%, and 45.84% vs. 74.49%, 55.10%, and 48.81%, respectively (P = 0.260). The 1-year, 3-year and 5-year disease-free survival of SLT recipients was inferior to that of PLT recipients: 64.79%, 45.57%, and 37.78% vs. 66.39%, 50.39%, and 43.50%, respectively (P = 0.048). Similar survival results were observed for SLT and PLT within both the LDLT and DDLT recipients. Within the SLT group, the 1-year, 3-year, and 5-year overall survival for LDLT and DDLT recipients was similar: 93.33%, 74.67%, and 74.67% vs. 80.13%, 62.10%, and 54.18% (P = 0.281), as was the disease-free survival: 84.85%, 62.85%, and 62.85% vs. 70.54%, 53.94%, and 43.57% (P = 0.462). Conclusions Our study demonstrates that for selected patients, SLT has similar survival to that of PLT, indicating that SLT is acceptable for patients with recurrent HCC after liver resection. Given the limited organ donor pool, salvage LDLT might be considered as a possible treatment. PMID:22574187

  5. Socioeconomic Factors Affect Disparities in Access to Liver Transplant for Hepatocellular Cancer

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    Linda L. Wong

    2012-01-01

    Full Text Available Objective. The incidence/death rate of hepatocellular cancer (HCC is increasing in America, and it is unclear if access to care contributes to this increase. Design/Patients. 575 HCC cases were reviewed for demographics, education, and tumor size. Main Outcome Measures. Endpoints to determine access to HCC care included whether an eligible patient underwent liver transplantation. Results. Transplant patients versus those not transplanted were younger (55.7 versus 61.8 yrs, P 35 (20.7% compared to Whites (6.4% and Asians (4.7%. Conclusions. Ethnic differences in access to transplant are associated with socioeconomic status and factors that can disqualify patients (advanced disease/morbid obesity. Efforts to overcome educational barriers and screening for HCC could improve access to transplant.

  6. Ethical selection on liver transplantation and abandoning treatment for hepatocellular carcinoma in China.

    Science.gov (United States)

    Xia, D; Zuo, H-Q; Quan, Y; Dong, H-L; Xu, L

    2011-09-01

    Orthotopic liver transplantation (OLT) has evolved in China over three decades, emerging as the mainstay treatment for hepatocellular carcinoma (HCC). Some Chinese transplantation centers have begun offering OLT for selected patients with HCC exceeding Milan criteria. However, this still remains a controversial subject. In this article, we have weighed arguments for and against OLT for advanced HCC. Meanwhile, the development of OLT for HCC in China has raised problems, mainly focused on ethical and moral concerns. Postmodern philosophy and ethics, particularly the life value theory, shall be the theoretical support to the concept of abandoning treatment. In China, ethical selection for OLT and abandoning treatment for HCC must be made justly and prudently. Copyright © 2011 Elsevier Inc. All rights reserved.

  7. Autophagy and apoptosis-related genes in chronic liver disease and hepatocellular carcinoma

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    Kotsafti Andromachi

    2012-08-01

    Full Text Available Abstract Background Dysregulation of autophagy is important in the pathogenesis of many diseases, including cancer. Several aspects of the biological role of autophagy are however still unclear and the relationship between apoptosis and autophagy, particularly in the liver has yet to be thoroughly explored. In this study we evaluated the expression of Beclin 1 (one of the main autophagocytic agents, which bridges autophagy, apoptosis and both differentiation, and both pro- (Bad, Bax and anti-apoptotic (Bcl-2, Bcl-xL factors in liver samples from patients with different stages of liver disease. Methods The study concerned 93 patients from 49 cases of chronic hepatitis (CH (30 HCV and 19 HBV-related, 13 of cirrhosis (CIRR (10 HCV and 3 HBV-related, 21 of hepatocellular carcinoma (both HCC and peritumoral tissues [PHCC], and 10 controls (CONTR. Real-time PCR and Western blotting were used to measure mRNA and protein expression levels. Results Beclin 1 mRNA levels were lower in HCC than in CH (P = 0.010 or CIRR (P = 0.011, and so were the Bcl-xL transcripts (P  Conclusions High Beclin 1, Bcl-xL and Bad levels in CH and CIRR tissues suggest an interaction between autophagy and apoptosis in the early and intermediate stages of viral hepatitis. In HCC these processes seem to be downregulated, probably enabling the survival and growth of neoplastic hepatocytes.

  8. Hepatocellular carcinoma in cirrhotic patients with portal hypertension: Is liver resection always contraindicated?

    Institute of Scientific and Technical Information of China (English)

    Andrea Ruzzenente; Alessandro Valdegamberi; Tommaso Campagnaro; Simone Conci; Silvia Pachera; Calogero Iacono,; Alfredo Guglielmi

    2011-01-01

    AIM: To analyze the outcome of hepatocellular carcinoma (HCC) resection in cirrhosis patients, related to presence of portal hypertension (PH) and extent of hepatectomy. METHODS: A retrospective analysis of 135 patients with HCC on a background of cirrhosis was submitted to curative liver resection. RESULTS: PH was present in 44 (32.5%) patients. Overall mortality and morbidity were 2.2% and 33.7%, respectively. Median survival time in patients with or without PH was 31.6 and 65.1 mo, respectively (P = 0.047); in the subgroup with Child-Pugh class A cirrhosis, median survival was 65.1 mo and 60.5 mo, respectively (P = 0.257). Survival for patients submitted to limited liver resection was not significantly different in presence or absence of PH. Conversely, median survival for patients after resection of 2 or more segments with or without PH was 64.4 mo and 163.9 mo, respectively (P = 0.035). CONCLUSION: PH is not an absolute contraindication to liver resection in Child-Pugh class A cirrhotic patients, but resection of 2 or more segments should not be recommended in patients with PH.

  9. Fibro markers for prediction of hepatocellular carcinoma in egyptian patients with chronic liver disease.

    Science.gov (United States)

    Mobarak, Lamiaa; Omran, Dalia; Nabeel, Mohammed M; Zakaria, Zeinab

    2016-10-21

    It is well known that hepatocellular carcinoma (HCC) develops as a consequence of hepatic fibrosis progression. In this study, we aimed to evaluate the inflammatory and fibrosis markers as predictors for HCC development among patients with hepatitis C virus (HCV) related chronic liver disease to help in early diagnosis and management of HCC. A total of 280 patients with chronic liver disease were included in this retrospective study, out of them 140 had liver cirrhosis with HCC and 140 had cirrhosis without HCC. Eight readily available blood indices King score, Fibro Q, AST-ALT ratio (AAR), APRI, LOK index, Goteborg University Cirrhosis Index (GUCI), fibro alpha, and Biotechnology Research Center (BRC) were constructed to compare the accuracies of these non invasive scores in predicting HCC development. All fibrosis scores except APRI were significantly higher in HCC. We found that Fibro alpha and BRC had superior diagnostic performance in prediction of HCC based on area under curve of 0.91 and 0.93, respectively compared to other scores with area under curve ranged from poor to failure (0.59-0.66). Almost all cirrhotic cases were secondary to HCV (93.6%), while HBV was detected in 2.1% of cases only. Anti-HCV positive was reported in 100% of HCC cases (P = 0.002). Fibro alpha and BRC scores can be used for prediction of HCC. J. Med. Virol. © 2016 Wiley Periodicals, Inc.

  10. Perfusion computed tomography for detection of hepatocellular carcinoma in patients with liver cirrhosis

    Energy Technology Data Exchange (ETDEWEB)

    Fischer, Michael A.; Kartalis, Nikolaos; Grigoriadis, Aristeidis; Loizou, Louiza; Leidner, Bertil; Aspelin, Peter; Brismar, Torkel B. [Karolinska Institute, Department of Clinical Science, Intervention and Technology, Division of Medical Imaging and Technology, Stockholm (Sweden); Karolinska University Hospital, Department of Radiology, Stockholm (Sweden); Staal, Per [Karolinska University Hospital, Department of Hepatology, Stockholm (Sweden)

    2015-11-15

    To evaluate the diagnostic performance of dynamic perfusion CT (P-CT) for detection of hepatocellular carcinoma (HCC) in the cirrhotic liver. Twenty-six cirrhotic patients (19 men, aged 69 ± 10 years) with suspicion of HCC prospectively underwent P-CT of the liver using the 4D spiral-mode (100/80 kV; 150/175mAs/rot) of a dual-source system. Two readers assessed: (1) arterial liver-perfusion (ALP), portal-venous liver-perfusion (PLP) and hepatic perfusion-index (HPI) maps alone; and (2) side-by-side with maximum-intensity-projections of arterial time-points (art-MIP) for detection of HCC using histopathology and imaging follow-up as standard of reference. Another reader quantitatively assessed perfusion maps of detected lesions. A total of 48 HCCs in 21/26 (81 %) patients with a mean size of 20 ± 10 mm were detected by histopathology (9/48, 19 %) or imaging follow-up (39/48, 81 %). Detection rates (Reader1/Reader2) of HPI maps and side-by-side analysis of HPI combined with arterial MIP were 92/88 % and 98/96 %, respectively. Positive-predictive values were 63/63 % and 68/71 %, respectively. A cut-off value of ≥85 % HPI and ≥99 % HPI yielded a sensitivity and specificity of 100 %, respectively, for detection of HCC. P-CT shows a high sensitivity for detection of HCC in the cirrhotic liver. Quantitative assessment has the potential to reduce false-positive findings improving the specificity of HCC diagnosis. (orig.)

  11. NSAID Use and Risk of Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma: The Liver Cancer Pooling Project.

    Science.gov (United States)

    Petrick, Jessica L; Sahasrabuddhe, Vikrant V; Chan, Andrew T; Alavanja, Michael C; Beane-Freeman, Laura E; Buring, Julie E; Chen, Jie; Chong, Dawn Q; Freedman, Neal D; Fuchs, Charles S; Gaziano, John Michael; Giovannucci, Edward; Graubard, Barry I; Hollenbeck, Albert R; Hou, Lifang; Jacobs, Eric J; King, Lindsay Y; Koshiol, Jill; Lee, I-Min; Linet, Martha S; Palmer, Julie R; Purdue, Mark P; Rosenberg, Lynn; Schairer, Catherine; Sesso, Howard D; Sigurdson, Alice J; Wactawski-Wende, Jean; Zeleniuch-Jacquotte, Anne; Campbell, Peter T; McGlynn, Katherine A

    2015-12-01

    Chronic inflammation plays a pivotal role in the pathogenesis of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), the two most common types of liver cancer. A number of prior experimental studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin and ibuprofen, may potentially protect against liver cancer. However, no observational study has examined the association between aspirin duration and dose or other over-the-counter non-aspirin NSAIDs, such as ibuprofen, and liver cancer incidence. Furthermore, the association between NSAID use and risk of ICC is unclear. As part of the Liver Cancer Pooling Project, we harmonized data on 1,084,133 individuals (HCC = 679, ICC = 225) from 10 U.S.-based prospective cohort studies. Cox proportional hazards regression models were used to evaluate multivariable-adjusted HRs and 95% confidence intervals (CI). Current aspirin use, versus nonuse, was inversely associated with HCC (HR, 0.68; 95% CI, 0.57-0.81), which persisted when restricted to individuals not using non-aspirin NSAIDs and in a 5- and 10-year lag analysis. The association between aspirin use and HCC risk was stronger for users who reported daily use, longer duration use, and lower dosage. Ibuprofen use was not associated with HCC risk. Aspirin use was associated with a reduced ICC risk in men (HR, 0.64; 95% CI, 0.42-0.98) but not women (HR, 1.34; 95% CI, 0.89-2.01; P(interaction) = 0.01). The observed inverse association between aspirin use and liver cancer in our study, together with previous data, suggests the merit of future intervention studies of aspirin and other agents that affect chronic inflammatory pathways for HCC and possibly ICC.

  12. Association of serum level of growth differentiation factor 15 with liver cirrhosis and hepatocellular carcinoma.

    Science.gov (United States)

    Liu, Xiuying; Chi, Xiumei; Gong, Qiaoling; Gao, Lei; Niu, Yuqiang; Chi, Xiaojing; Cheng, Min; Si, Youhui; Wang, Maorong; Zhong, Jin; Niu, Junqi; Yang, Wei

    2015-01-01

    Hepatocellular carcinoma (HCC) and liver cirrhosis are associated with high mortality worldwide. Currently, alpha-fetoprotein (AFP) is used as a standard serum marker for the detection of HCC, but its sensitivity and specificity are unsatisfactory, and optimal diagnostic markers for cirrhosis are lacking. We previously reported that growth differentiation factor 15 (GDF15) was significantly induced in HCV-infected hepatocytes. This study aimed to investigate GDF15 expression and its correlation with hepatitis virus-related liver diseases. A total of 412 patients with various liver diseases were studied. Healthy and Mycobacterium tuberculosis-infected subjects were included as controls. Serum and tissue GDF15 levels were measured. Serum GDF15 levels were significantly increased in patients with HCC (6.66±0.67 ng/mL, pcirrhosis (6.51±1.47 ng/mL, pHBV and HCV carriers were moderately elevated (1.34±0.19 ng/mL and 2.13±0.53 ng/mL, respectively). Compared with HBV or HCV carriers, GDF15 had a sensitivity of 63.1% and a specificity of 86.6% at the optimal cut-off point of 2.463 ng/mL in patients with liver cirrhosis or HCC. In HCC patients, the area under the receiver operating curve was 0.84 for GDF15 and 0.76 for AFP, but 0.91 for the combined GDF15 and AFP. Serum GDF15 levels did not significantly differ between the high-AFP and low-AFP groups. GDF15 protein expression in HCC was significantly higher than that in the corresponding adjacent paracarcinomatous tissue and normal liver. Using a combination of GDF15 and AFP will improve the sensitivity and specificity of HCC diagnosis. Further research and the clinical implementation of serum GDF15 measurement as a biomarker for HCC and cirrhosis are recommended.

  13. DNA methylation-dependent regulation of TrkA, TrkB, and TrkC genes in human hepatocellular carcinoma

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    Jin, Wook [Laboratory of Molecular Disease and Cell Regulation, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Incheon (Korea, Republic of); Lee, Jong-Joo [Department of Environmental Medical Biology, Institute of Tropical Medicine, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul 120-752 (Korea, Republic of); Kim, Min Soo [Laboratory of Molecular Disease and Cell Regulation, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Incheon (Korea, Republic of); Son, Byung Ho [Department of Surgery, Kangbuk Samsung Hospital, Sungkyunkwan University, School of Medicine, 108 Pyung-dong, Jongro-gu, Seoul 110-746 (Korea, Republic of); Cho, Yong Kyun, E-mail: choyk2004@hanmail.net [Division of Gastroenterology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University, School of Medicine, 108 Pyung-dong, Jongro-gu, Seoul 110-746 (Korea, Republic of); Kim, Hyoung-Pyo, E-mail: kimhp@yuhs.ac [Department of Environmental Medical Biology, Institute of Tropical Medicine, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul 120-752 (Korea, Republic of)

    2011-03-04

    Research highlights: {yields} Expression of TrkA, TrkB, and TrkC is significantly elevated in human hepatocellular carcinoma. {yields} Downregulation of Trks is correlated with their promoter hypermethylation. {yields} Inhibiting DNA methylation restored expression of Trks in normal liver cell lines. {yields} Trks promote the proliferation of hepatocellular carcinoma. {yields} Trks induce expression of the metastatic regulator, Twist. -- Abstract: The tropomyosin-related kinase (Trk) family of neurotrophin receptors, TrkA, TrkB and TrkC, has been implicated in the growth and survival of human cancers. Here we report that Trks are frequently overexpressed in hepatocellular carcinoma (HCC) from patients and human liver cancer cell lines. To unravel the underlying molecular mechanism(s) for this phenomenon, DNA methylation patterns of CpG islands in TrkA, TrkB, and TrkC genes were examined in normal and cancer cell lines derived from liver. A good correlation was observed between promoter hypermethylation and lower expression of TrkA, TrkB, and TrkC genes, which was supported by the data that inhibiting DNA methylation with 5-azacytidine restored expression of those genes in normal liver cell lines. Furthermore, Trks promoted the proliferation of HepG2 and induced expression of the metastatic regulator, Twist. These results suggest that Trks may contribute to growth and metastasis of liver cancer.

  14. Hepatocellular carcinoma, human immunodeficiency virus and viral hepatitis in the HAART era

    Institute of Scientific and Technical Information of China (English)

    Douglas C Macdonald; Mark Nelson; Mark Bower; Thomas Powles

    2008-01-01

    The incidence of hepatocellular carcinoma (HCC) in patients with human immunodeficiency virus (HIV) is rising. HCC in HIV almost invariably occurs in the context of hepatitis C virus (HCV) or hepatitis B virus (HBV) co-infection and, on account of shared modes of transmission, this occurs in more than 33% and 10% of patients with HIV worldwide respectively. It has yet to be clearly established whether HIV directly accelerates HCC pathogenesis or whether the rising incidence is an epiphenomenon of the highly active antiretroviral therapy (HAART) era, wherein the increased longevity of patients with HIV allows long-term complications of viral hepatitis and cirrhosis to develop. Answering this question will have implications for HCC surveillance and the timing of HCV/HBV therapy, which in HIV co-infection presents unique challenges. Once HCC develops, there is growing evidence that HIV co-infection should not preclude conventional therapeutic strategies, including liver transplantation.

  15. A new key player in VEGF-dependent angiogenesis in human hepatocellular carcinoma: dimethylarginine dimethylaminohydrolase 1.

    Science.gov (United States)

    Buijs, Nikki; Oosterink, J Efraim; Jessup, Morgan; Schierbeek, Henk; Stolz, Donna B; Houdijk, Alexander P; Geller, David A; van Leeuwen, Paul A

    2017-07-24

    Anti-angiogenic therapies, targeting VEGF, are a promising treatment for hepatocellular carcinoma (HCC). To enhance this potential therapy, identification of novel targets in this pathway is of major interest. Nitric oxide (NO) plays a crucial role in VEGF-dependent angiogenesis. NO production depends on arginine as substrate and asymmetric dimethylarginine (ADMA) as inhibitor. Dimethylarginine dimethylaminohydrolase 1 (DDAH-1) catabolizes ADMA and therefore regulates NO and VEGF expression. This study unravels additional mechanisms to improve VEGF targeting therapies. The expression of DDAH-1 was examined in HCC specimen and non-tumorous background liver of 20 patients undergoing liver resection. Subsequently, arginine/ADMA balance, NO production, and VEGF expression were analyzed. The influence of hypoxia on DDAH-1 and angiogenesis promoting factors was evaluated in HepG2 cells and primary human hepatocytes. DDAH-1 expression was significantly induced in primary HCC tumors compared to non-tumorous background liver. This was associated with an increased arginine/ADMA ratio, higher NO formation, and higher VEGF expression in human HCC compared to non-tumorous liver. Hypoxia induced DDAH-1, iNOS, and VEGF expression in a time-dependent manner in HepG2 cells. Our results indicate that DDAH-1 expression is increased in human HCC, which is associated with an increase in the arginine/ADMA ratio and enhanced NO formation. Hypoxia may be an initiating factor for the increase in DDAH-1 expression. DDAH-1 expression is associated with promotion of angiogenesis stimulating factor VEGF. Together, our findings for the first time identified DDAH-1 as a key player in the regulation of angiogenesis in human HCC, and by understanding this mechanism, future therapeutic strategies targeting VEGF can be improved.

  16. Orthotopic liver transplantation after the combined use of locoregional therapy and sorafenib for advanced hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Yoo EJ

    2013-06-01

    Full Text Available Eun Jin Yoo,1,* Hye Sun Shin,1,* Seung Up Kim,1,2,7 Dong Jin Joo,3,4 Jun Yong Park,1,2,7 Gi Hong Choi,3 Do Young Kim,1,2,7 Sang Hoon Ahn,1,2,7 Jinsil Seong,5 Myung Joo Koh,6 Kwang-Hyub Han,1,2,7 Chae Yoon Chon1,2,7 1Department of Internal Medicine, 2Institute of Gastroenterology, 3Department of Surgery, 4Research Institute for Transplantation, 5Department of Radiation Oncology, 6Department of Pathology, Yonsei University College of Medicine, Seoul, South Korea; 7Liver Cirrhosis Clinical Research Center, Seoul, South Korea *These authors contributed equally to this work Abstract: We herein report a patient with advanced hepatitis B virus-related hepatocellular carcinoma (HCC beyond the Milan criteria. He underwent orthotopic liver transplantation after successful HCC downstaging that satisfied the University of California, San Francisco criteria, using concurrent chemoradiation therapy with a combination of repeated hepatic arterial infusion chemotherapy (HAIC and sorafenib. A 52-year-old male was diagnosed with advanced hepatitis B virus-related HCC beyond the Milan criteria. He underwent concurrent chemoradiation therapy (50 Gy with 20 fractions over 5 weeks with HAIC using 5-fluorouracil at a dose of 500 mg/day, which was administered during the first and fifth weeks of radiation therapy as an initial treatment modality. This was followed by the combined use of HAIC using 5-fluorouracil (500 mg/m2 for 5 hours on days 1–3 and cisplatin (60 mg/m2 for 2 hours on day 2 every 4 weeks (twelve cycles and sorafenib (from the third to the twelfth cycle of HAIC to treat the remaining HCC. Because a remarkable decrease in the tumor burden that satisfied the University of California, San Francisco criteria was observed after these combination treatments, the patient underwent orthotopic liver transplantation with curative aim and survived for 11 months without evidence of HCC recurrence. Keywords: hepatocellular carcinoma, liver transplantation

  17. Clinical effect of laparoscopic versus open liver resection in treatment of patients with hepatocellular carcinoma complicated by liver cirrhosis

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    MA Yiyun

    2016-10-01

    Full Text Available Objective To investigate the clinical effect of laparoscopic liver resection (LLR versus open liver resection (OLR in the treatment of patients with hepatocellular carcinoma (HCC complicated by liver cirrhosis. Methods A total of 136 patients who were diagnosed with HCC complicated by liver cirrhosis in Linxia Municipal People′s Hospital from January 2006 to December 2007 were enrolled and underwent LLR (LLR group, 64 patients or OLR (OLR group, 72 patients. The short-term outcome, pathological factors, and long-term outcome were compared between the two groups. The t-test was used for comparison of continuous data between groups, the chi-square test was used for comparison of categorical data between groups, and the log-rank test was used for comparison of survival functions. Results There were significant differences between the LLR group and the OLR group in time of operation ((86.43±23.55 min vs (62.31±19.61 min, t=8.539, P<0.001 and length of postoperative hospital stay ((7.22±3.45 d vs (12.27±5.31 d, t=2.764, P=0.024, while there were no significant differences in intraoperative blood loss, time of hepatic portal occlusion, and overall fatality rate(all P>0.05. There were also no significant differences in number of tumors, presence or absence of liver cirrhosis, microvascular invasion, resection margin, and maximum tumor diameter between the two groups (all P>0.05. As for long-term outcome, the 1-, 3-, and 5-year disease-free survival rates were 83.30%, 48.61%, and 38.29% in the LLR group and 78.64%, 51.26%, and 43.01% in the OLR group; the 1-, 3-, and 5-year overall survival rates were 97.42%, 95.13%, and 89.23% in the LLR group and 96.41%, 94.28%, and 90.06% in the OLR group. There were no significant differences in these survival rates between the two groups (all P>0.05. Conclusion In patients with HCC complicated by liver cirrhosis, LLR helps to achieve rapid postoperative recovery and similar long-term outcome compared

  18. Experimental study of bioartificial liver with cultured human liver cells

    Institute of Scientific and Technical Information of China (English)

    1999-01-01

    AIM To establish an extracorporeal bioartificial liver support system (EBLSS) using cultured human liver cells and to study its support effect for fulminant hepatic failure (FHF).METHODS The liver support experiment of EBLSS consisting of aggregates cultured human liver cells, hollow fiber bioreactor, and circulation unit was carried out in dizhepatic dogs.RESULTS The viability of isolated hepatocytes and nonparenchymal liver cells reached 96%. These cells were successfully cultured as multicellular spheroids with synthetic technique. The typical morphological appearance was retained up to the end of the artificial liver experiment. Compared with the control dogs treated with EBLSS without liver cells, the survival time of artificial liver support dogs was significantly prolonged. The changes of blood pressure, heart rate and ECG were slow. Both serum ammonia and lactate levels were significantly lowered at the 3rd h and 5th h. In addition, a good viability of human liver cells was noted after 5 h experiment.CONCLUSION EBLSS playing a metabolic role of cultured human hepatocytes, is capable of compensating the function of the liver, and could provide effective artificial liver support and therapy for patients with FHF.

  19. Magnetic resonance imaging of the cirrhotic liver: diagnosis of hepatocellular carcinoma and evaluation of response to treatment - Part 1

    Science.gov (United States)

    Ramalho, Miguel; Matos, António P.; AlObaidy, Mamdoh; Velloni, Fernanda; Altun, Ersan; Semelka, Richard C.

    2017-01-01

    Magnetic resonance imaging (MRI) is the modern gold standard for the noninvasive evaluation of the cirrhotic liver. The combination of arterial phase hyperenhancement and delayed wash-out allows a definitive diagnosis of hepatocellular carcinoma (HCC) in patients with liver cirrhosis or chronic liver disease, without the requirement for confirmatory biopsy. That pattern is highly specific and has been endorsed in Western and Asian diagnostic guidelines. However, the sensitivity of the combination is relatively low for small HCCs. In this two-part review paper, we will address MRI of the cirrhotic liver. In this first part, we provide a brief background on liver cirrhosis and HCC, followed by descriptions of imaging surveillance of liver cirrhosis and the diagnostic performance of the different imaging modalities used in clinical settings. We then describe some of the requirements for the basic MRI technique, as well as the standard MRI protocol, and provide a detailed description of the appearance of various types of hepatocellular nodules encountered in the setting of the carcinogenic pathway in the cirrhotic liver, ranging from regenerative nodules to HCC. PMID:28298731

  20. Diagnosis of hepatocellular carcinoma with delayed computed tomography; Differentiation from metastatic liver cancer

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    Koda, Shojiro; Machida, Keiichi; Ishihara, Manabu; Taniguchi, Yuko; Yamakawa, Fumiko; Kai, Shunkichi; Otsuka, Yukio (Toho Univ., Tokyo (Japan). School of Medicine)

    1990-01-01

    This study examined the capability of delayed contrast-enhanced computed tomography (CT) to differentiate hepatocellular carcinoma (HCC) from metastatic liver cancer (MLC). Plain and contrast-enhanced CT scans were available for review in a total of 25 patients with histologically proven and untreated either HCC (14 patients) or MLC (the other 11). Plain CT failed to reveal significant difference in CT values for tumor and liver parenchyma between the HCC group (23.44{plus minus}14.98 HU) and MLC group (23.40{plus minus}13.82 HU); however, the values were significantly lower in the HCC group (16.84{plus minus}10.45 HU) than the MLC group (31.71{plus minus}7.34 HU) on delayed CT 4 hr after injection of contrast medium. Tumor density index, as obtained from (tumor density-liver density)/(liver density), was not significantly different on plain CT in the two groups (-0.36{plus minus}0.17 for HCC vs -0.45{plus minus}0.17 for MLC). On delayed CT, however, the subjects in the HCC group had significant decrease in tumor density index (-0.25{plus minus}0.14), as compared with the MLC group (-0.44{plus minus}0.12), p<0.01. Clear inside structure and margin of the tumor, as shown on plain CT, became obscure on delayed CT in cases of HCC, which is in contrast with MLC of which margin became clear on delayed CT. These findings suggest the potential of delayed CT for differentiating HCC from MLC. (N.K.).

  1. Risk Factors for Fatal Recurrence of Liver Transplant Recipients with Hepatocellular Carcinoma in the First Year

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Objective: To investigate the clinicopathological risk factors for fatal recurrence of hepatocellular carcinoma (HCC) in orthotopic liver transplant recipients in the first year. Methods: From April 2002 to October 2005, 303 recipients who received orthotopic liver transplantation for HCC were reviewed. Of These patients, those who demonstrated diffuse intra-hepatic or multiple systemic recurrent lesions and died within 1 y after surgery were investigated (fatal recurrence group, 48 cases). The remaining patients were designated as the control group, and the two groups were compared for clinicopathologic risk factors by logistic regression analysis. Results: Among the 303 patients reviewed, 48 patients were enrolled in the fatal recurrence group (15.84%). Multivariate analysis between the fatal recurrence group and control group showed that the presence of vascular invasion, tumor size greater than 6.5 cm, and pre-operative serum alpha-fetoprotein (AFP) level greater than 1000 μg/L were the risk factors in the fatal recurrence group. 85.71% of the patients who had all the three risk factors, 37.84% of those who had two risk factors, 13.64% of those who had one risk factors, and 6.71% of those who had none risk factors died because of recurrence within 1 y after transplantation. Conclusion: Three distinct risk factors attributed to fatal recurrence of liver transplant recipients for HCC are vascular invasion, tumor size ≥6.5 cm, and pre-operative serum AFP level ≥1000 μg/L. The high risk HCC patients with two or more risk factors should not to be the candidates for liver transplantation.

  2. Progress in the treatment of pulmonary metastases after liver transplantation for hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Zhan-Wang; Xiang; Lin; Sun; Guo-Hong; Li; Rakesh; Maharjan; Jin-Hua; Huang; Chuan-Xing; Li

    2015-01-01

    Hepatocellular carcinoma(HCC) is the fifth most common cancer in the world, and is the third leading cause of cancer-related death. Liver transplantation(LT) has become a curative treatment for patients with HCC. However, recurrence and metastasis after LT are the main factors reducing long-term survival in patients, and the lung is the most common site of metastasis after LT for HCC, although metastasis to liver, para-aortic lymph nodes and renal periphery are observed. Thus, the treatment of pulmonary metastases after LT for HCC has become a hot research topic, the successful treatment of pulmonary metastases can significantly prolong the survival of LT patients. Although single conventional treatment(chemotherapy, surgery and external beam radiation therapy), immunosuppression, image-guided minimally invasive therapy(radiofrequency ablation, microwave ablation, cryoablation, and brachytherapy) and molecular targeted drugs have had a significant effect, patients do not have durable remission and the long-term survival rate is disappointing. Therefore, improving existing treatments and identifying a more effective combination therapy are important research issues in the prevention and treatment of pulmonary metastases after LT for HCC. The paper reviewed single conventional treatments, new treatments, and combination therapy, to provide a basis for the best treatment of these patients.

  3. Patients without hepatocellular carcinoma progression after transarterial chemoembolization benefit from liver transplantation

    Institute of Scientific and Technical Information of China (English)

    Aiman Obed; Alexander Beham; Kerstin Püllmann; Heinz Becker; Hans J Schlitt; Thomas Loft

    2007-01-01

    AIM: To assess the outcome of patients, who underwent transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) and subsequently liver transplantation (OLT) irrespective of tumor size when no tumor progression was observed.METHODS: Records, imaging studies and pathology of 84 patients with HCC were reviewed. Ten patients were not treated at all, 67 patients had TACE and 35 of them were listed for OLT. Tumor progression was monitored by ultrasound and AFP level every 6 wk. Fifteen patients showed signs of tumor progression without transplantation. The remaining 20 patients underwent OLT. Further records of 7 patients with HCC seen in histological examination after OLT were included.RESULTS: The patients after TACE without tumor progression underwent transplantation and had a median survival of 92.3 mo. Patients, who did not qualify for liver transplantation or had signs of tumor progression had a median survival of 8.4 mo. The patients without treatment had a median survival of 3.8 mo. Independent of International Union Against Cancer (UICC) stages, the patients without tumor progression and subsequent OLT had longer median survival. No significant difference was seen in the OLT treated patients if they did not fulfill the Mlilan criteria.CONCLUSION: Selection of patients for OLT based on tumor progression results in good survival. The evaluation of HCC patients should not only be based on tumor size and number of foci but also on tumor progression and growth behavior under therapy.

  4. Living-donor vs deceased-donor liver transplantation for patients with hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Nobuhisa; Akamatsu; Yasuhiko; Sugawara; Norihiro; Kokudo

    2014-01-01

    With the increasing prevalence of living-donor liver transplantation(LDLT) for patients with hepatocellular carcinoma(HCC),some authors have reported a potential increase in the HCC recurrence rates among LDLT recipients compared to deceased-donor liver transplantation(DDLT) recipients.The aim of this review is to encompass current opinions and clinical reports regarding differences in the outcome,especially the recurrence of HCC,between LDLT and DDLT.While some studies report impaired recurrence- free survival and increased recurrence rates among LDLT recipients,others,including large database studies,report comparable recurrence- free survival and recurrence rates between LDLT and DDLT.Studies supporting the increased recurrence in LDLT have linked graft regeneration to tumor progression,but we found no association between graft regeneration/initial graft volume and tumor recurrence among our 125 consecutive LDLTs for HCC cases.In the absence of a prospective study regarding the use of LDLT vs DDLT for HCC patients,there is no evidence to support the higher HCC recurrence after LDLT than DDLT,and LDLT remains a reasonable treatment option for HCC patients with cirrhosis.

  5. Loco-regional therapies for patients with hepatocellular carcinoma awaiting liver transplantation: Selecting an optimal therapy.

    Science.gov (United States)

    Byrne, Thomas J; Rakela, Jorge

    2016-06-24

    Hepatocellular carcinoma (HCC) is a common, increasingly prevalent malignancy. For all but the smallest lesions, surgical removal of cancer via resection or liver transplantation (LT) is considered the most feasible pathway to cure. Resection - even with favorable survival - is associated with a fairly high rate of recurrence, perhaps since most HCCs occur in the setting of cirrhosis. LT offers the advantage of removing not only the cancer but the diseased liver from which the cancer has arisen, and LT outperforms resection for survival with selected patients. Since time waiting for LT is time during which HCC can progress, loco-regional therapy (LRT) is widely employed by transplant centers. The purpose of LRT is either to bridge patients to LT by preventing progression and waitlist dropout, or to downstage patients who slightly exceed standard eligibility criteria initially but can fall within it after treatment. Transarterial chemoembolization and radiofrequency ablation have been the most widely utilized LRTs to date, with favorable efficacy and safety as a bridge to LT (and for the former, as a downstaging modality). The list of potentially effective LRTs has expanded in recent years, and includes transarterial chemoembolization with drug-eluting beads, radioembolization and novel forms of extracorporal therapy. Herein we appraise the various LRT modalities for HCC, and their potential roles in specific clinical scenarios in patients awaiting LT.

  6. Oldenlandia diffusa Promotes Antiproliferative and Apoptotic Effects in a Rat Hepatocellular Carcinoma with Liver Cirrhosis

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    Yun-Young Sunwoo

    2015-01-01

    Full Text Available Oldenlandia diffusa (OD is commonly used with various diseases such as cancer, arthritis, and autoimmune disease. Liver cirrhosis is a predominant risk factor for hepatocellular carcinoma (HCC. Here, we show that the therapeutic effect of OD, which was investigated both in vitro and chemically, induced HCC model. OD significantly enhanced apoptosis and antiproliferative activity and reduced migration ability of HCC cells. In vivo, OD was treated twice a day for 28 days after confirmed HCC model through 2-[18F]-fluoro-2-deoxy-D-glucose (18F-FDG imaging. The survival in OD treated groups was shown to have a greater therapeutic effect than the control group. 28 days after OD treatment, OD treated groups resulted in a significant reduction in tumor number, size, 18F-FDG uptake, and serum levels such as alanine transaminase, aspartate transaminase, and alkaline phosphate compared to the control group. Also, proliferated cells in tumor sites by OD were reduced compared to the control group. Furthermore, several rats in OD treated group survived over 60 days and liver morphology of these rats showed the difference between tumor mass and normal tissue. These results suggest that OD may have antiproliferative activity, inhibition of metastasis, and apoptotic effects in chemically induced HCC model and can have the potential use for clinical application as anticancer drug of the herbal extract.

  7. Liver-Specific Inactivation of the Proprotein Convertase FURIN Leads to Increased Hepatocellular Carcinoma Growth

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    Jeroen Declercq

    2015-01-01

    Full Text Available Proprotein convertases are subtilisin-like serine endoproteases that cleave and hence activate a variety of proproteins, including growth factors, receptors, metalloproteases, and extracellular matrix proteins. Therefore, it has been suggested that inhibition of the ubiquitously expressed proprotein convertase FURIN might be a good therapeutic strategy for several tumor types. Whether this is also the case for hepatocellular carcinoma (HCC is currently not clear. In a mouse model for HCC expression of Furin was not altered in the tumors, while those of PC7, PC5/6, and PACE4 significantly decreased, at least at some time points. To investigate the impact of Furin inhibition on the development and progression of HCC in this model, Furin was genetically ablated in the liver. Furin inactivation resulted in an increased tumor mass after 5 weeks. This was not caused by decreased apoptosis, since no differences in the apoptosis index could be observed. However, it could at least partially be explained by increased hepatocyte proliferation at 5 weeks. The tumors of the Furin knockout mice were histologically similar to those in wild type mice. In conclusion, liver-specific Furin inhibition in HCC enhances the tumor formation and will not be a good therapeutic strategy for this tumor type.

  8. Surgical treatment for early hepatocellular carcinoma: comparison of resection and liver transplantation.

    Science.gov (United States)

    Zhou, Jian; Wang, Zheng; Qiu, Shuang-Jian; Huang, Xiao-Wu; Sun, Jian; Gu, Wen; Fan, Jia

    2010-09-01

    The optimum strategy, hepatic resection (HR) or liver transplantation (LT), for treatment of early hepatocellular carcinoma (HCC) associated with liver diseases of Child-Pugh A is far from established. The aim of this study was to compare and determine which strategy is optimal for HCC fulfilling the Milan criteria. Consecutive data were collected in 1,018 HCC patients treated with HR and 89 HCC patients listed for LT (1 drop out for HCC progression) between January of 2003 and December of 2007. The independent prognostic factors identified by multivariate analysis were tumor size-plus-number, microscopic venous invasion, and operation type (LT or HR). When tumor size-plus-number was HR group. When tumor size-plus-number was >4 or microscopic venous invasion was present, OS was higher in the LT group. Since the pathological microscopic venous invasion was not easily available before operation which is limitation for widespread clinical use, thus in practice, we concluded that, for early HCC associated with Child-Pugh A cirrhosis, when tumor size-plus-number is >4, LT provides the best cure; when it is HR remains the initial treatment of choice.

  9. Circulating microRNAs as Potential Biomarkers in Non-Alcoholic Fatty Liver Disease and Hepatocellular Carcinoma

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    Marta B. Afonso

    2016-03-01

    Full Text Available Obesity and metabolic syndrome are growing epidemics worldwide and greatly responsible for many liver diseases, including nonalcoholic fatty liver disease (NAFLD. NAFLD often progresses to cirrhosis, end-stage liver failure and hepatocellular carcinoma (HCC, the most common primary liver cancer and one of the leading causes for cancer-related deaths globally. Currently available tools for the diagnosis of NAFLD staging and progression towards HCC are largely invasive and of limited accuracy. In light of the need for more specific and sensitive noninvasive molecular markers, several studies have assessed the potential of circulating microRNAs (miRNAs as biomarkers of liver injury and hepatocarcinogenesis. Indeed, extracellular miRNAs are very stable in the blood, can be easily quantitated and are differentially expressed in response to different pathophysiological conditions. Although standardization procedures and larger, independent studies are still necessary, miRNAs constitute promising, clinically-useful biomarkers for the NAFLD-HCC spectrum.

  10. Effects of maintenance immunosuppression with sirolimus after liver transplant for hepatocellular carcinoma.

    Science.gov (United States)

    Yanik, Elizabeth L; Chinnakotla, Srinath; Gustafson, Sally K; Snyder, Jon J; Israni, Ajay K; Segev, Dorry L; Engels, Eric A

    2016-05-01

    For recipients of liver transplantations (LTs) for hepatocellular carcinoma (HCC), HCC recurrence after transplantation remains a major concern. Sirolimus (SRL), an immunosuppressant with anticarcinogenic properties, may reduce HCC recurrence and improve survival. In our study, the US Scientific Registry of Transplant Recipients was linked to pharmacy claims. For liver recipients transplanted for HCC, Cox regression was used to estimate associations of early SRL use with recurrence, cancer-specific mortality, and all-cause mortality, adjusting for recipient ethnicity, calendar year of transplant, total tumor volume, alpha-fetoprotein, transplant center size, use of interleukin 2 induction therapy, and allocated and calculated Model for End-Stage Liver Disease score. We performed stratified analyses among recipients who met Milan criteria, among those without renal failure, among those with deceased liver donors, by age at transplantation, and by tumor size. Among the 3936 included HCC LTs, 234 (6%) were SRL users. In total, there were 242 recurrences and 879 deaths, including 261 cancer-related deaths. All-cause mortality was similar in SRL users and nonusers (adjusted hazard ratio [aHR], 1.01; 95% CI, 0.73-1.39). HCC recurrence and cancer-specific mortality rates appeared lower in SRL users, but associations were not statistically significant (recurrence aHR, 0.86; 95% CI, 0.45-1.65; cancer-specific mortality aHR, 0.80; 95% CI, 0.43-1.50). Among recipients >55 years old, associations were suggestive of better outcomes for SRL users (all-cause mortality aHR, 0.62; 95% CI, 0.38-1.01; recurrence aHR, 0.52; 95% CI, 0.19-1.44; cancer-specific mortality aHR, 0.34; 95% CI, 0.11-1.09), whereas among recipients ≤55 years old, SRL users had worse outcomes (all-cause mortality aHR, 1.76; 95% CI, 1.12-2.75; recurrence aHR, 1.49; 95% CI, 0.62-3.61; cancer-specific mortality aHR, 1.54; 95% CI, 0.71-3.32). In conclusion, among HCC liver recipients overall, SRL did not appear

  11. Perfusion computed tomography for detection of hepatocellular carcinoma in patients with liver cirrhosis.

    Science.gov (United States)

    Fischer, Michael A; Kartalis, Nikolaos; Grigoriadis, Aristeidis; Loizou, Louiza; Stål, Per; Leidner, Bertil; Aspelin, Peter; Brismar, Torkel B

    2015-11-01

    To evaluate the diagnostic performance of dynamic perfusion CT (P-CT) for detection of hepatocellular carcinoma (HCC) in the cirrhotic liver. Twenty-six cirrhotic patients (19 men, aged 69 ± 10 years) with suspicion of HCC prospectively underwent P-CT of the liver using the 4D spiral-mode (100/80 kV; 150/175mAs/rot) of a dual-source system. Two readers assessed: (1) arterial liver-perfusion (ALP), portal-venous liver-perfusion (PLP) and hepatic perfusion-index (HPI) maps alone; and (2) side-by-side with maximum-intensity-projections of arterial time-points (art-MIP) for detection of HCC using histopathology and imaging follow-up as standard of reference. Another reader quantitatively assessed perfusion maps of detected lesions. A total of 48 HCCs in 21/26 (81%) patients with a mean size of 20 ± 10 mm were detected by histopathology (9/48, 19%) or imaging follow-up (39/48, 81%). Detection rates (Reader1/Reader2) of HPI maps and side-by-side analysis of HPI combined with arterial MIP were 92/88% and 98/96%, respectively. Positive-predictive values were 63/63% and 68/71%, respectively. A cut-off value of ≥85% HPI and ≥99% HPI yielded a sensitivity and specificity of 100%, respectively, for detection of HCC. P-CT shows a high sensitivity for detection of HCC in the cirrhotic liver. Quantitative assessment has the potential to reduce false-positive findings improving the specificity of HCC diagnosis. • Visual analysis of perfusion maps shows good sensitivity for detection of HCC. • Additional assessment of anatomical arterial MIPs further improves detection rates of HCC. • Quantitative perfusion analysis has the potential to reduce false-positive findings. • In cirrhotic livers, a hepatic-perfusion-index ≥ 9 9% might be specific for HCC.

  12. Tyrosine kinase inhibitors improve parenchymal findings of liver cirrhosis in a patient exhibiting concomitant hepatocellular carcinoma and renal cell cancer

    Science.gov (United States)

    KUS, TULAY; AKTAS, GOKMEN; SEVINC, ALPER; OKTAY, CEMIL; KALENDER, MEHMET EMIN; CAMCI, CELALETDIN

    2016-01-01

    Hepatocellular carcinoma (HCC) and renal cell cancer (RCC) are malignancies, which are chemotherapy resistant and fatal at the advanced stages. Previously developed tyrosine kinase inhibitors are used in the treatment of advanced stage disease. In the present case study, a patient using sunitinib for stage IV RCC presented with HCC following 2 years of treatment. A patient who exhibited Child-Pugh class C cirrhosis initially, exhibited a marked improvement of hepatocellular parenchyma findings following treatment with sunitinib. Sunitinib is suggested to have preventive effects on the pathogenesis of liver fibrosis and cirrhosis in vitro, via an anti-vascular endothelial growth factor and anti-platelet-derived growth factor mechanism. However, no clinical supportive study has been performed until now. Improvement of liver functions may be explained in this manner. Therefore, investigations are required with different doses of sunitinib and other tyrosine kinase inhibitors in order to evaluate the efficacy on treatment of cirrhosis progression. PMID:26893877

  13. Humanization of high-affinity antibodies targeting glypican-3 in hepatocellular carcinoma

    Science.gov (United States)

    Zhang, Yi-Fan; Ho, Mitchell

    2016-01-01

    Glypican-3 (GPC3) is a cell-surface heparan sulfate proteoglycan highly expressed in hepatocellular carcinoma (HCC). We have generated a group of high-affinity mouse monoclonal antibodies targeting GPC3. Here, we report the humanization and testing of these antibodies for clinical development. We compared the affinity and cytotoxicity of recombinant immunotoxins containing mouse single-chain variable regions fused with a Pseudomonas toxin. To humanize the mouse Fvs, we grafted the combined KABAT/IMGT complementarity determining regions (CDR) into a human IgG germline framework. Interestingly, we found that the proline at position 41, a non-CDR residue in heavy chain variable regions (VH), is important for humanization of mouse antibodies. We also showed that two humanized anti-GPC3 antibodies (hYP7 and hYP9.1b) in the IgG format induced antibody-dependent cell-mediated cytotoxicity and complement-dependent-cytotoxicity in GPC3-positive cancer cells. The hYP7 antibody was tested and showed inhibition of HCC xenograft tumor growth in nude mice. This study successfully humanizes and validates high affinity anti-GPC3 antibodies and sets a foundation for future development of these antibodies in various clinical formats in the treatment of liver cancer. PMID:27667400

  14. Promoter hypermethylation mediated downregulation of FBP1 in human hepatocellular carcinoma and colon cancer.

    Directory of Open Access Journals (Sweden)

    Mingquan Chen

    Full Text Available FBP1, fructose-1,6-bisphosphatase-1, a gluconeogenesis regulatory enzyme, catalyzes the hydrolysis of fructose 1,6-bisphosphate to fructose 6-phosphate and inorganic phosphate. The mechanism that it functions to antagonize glycolysis and was epigenetically inactivated through NF-kappaB pathway in gastric cancer has been reported. However, its role in the liver carcinogenesis still remains unknown. Here, we investigated the expression and DNA methylation of FBP1 in primary HCC and colon tumor. FBP1 was lowly expressed in 80% (8/10 human hepatocellular carcinoma, 66.7% (6/9 liver cancer cell lines and 100% (6/6 colon cancer cell lines, but was higher in paired adjacent non-tumor tissues and immortalized normal cell lines, which was well correlated with its promoter methylation status. Methylation was further detected in primary HCCs, gastric and colon tumor tissues, but none or occasionally in paired adjacent non-tumor tissues. Detailed methylation analysis of 29 CpG sites at a 327-bp promoter region by bisulfite genomic sequencing confirmed its methylation. FBP1 silencing could be reversed by chemical demethylation treatment with 5-aza-2'-deoxycytidine (Aza, indicating direct epigenetic silencing. Restoring FBP1 expression in low expressed cells significantly inhibited cell growth and colony formation ability through the induction of G2-M phase cell cycle arrest. Moreover, the observed effects coincided with an increase in reactive oxygen species (ROS generation. In summary, epigenetic inactivation of FBP1 is also common in human liver and colon cancer. FBP1 appears to be a functional tumor suppressor involved in the liver and colon carcinogenesis.

  15. Assessment of the Selenoprotein M (SELM over-expression on human hepatocellular carcinoma tissues by immunohistochemistry

    Directory of Open Access Journals (Sweden)

    E. Guerriero

    2014-10-01

    Full Text Available Selenium is an essential trace mineral of fundamental importance to human healthy and exerts its biological function through selenoproteins. In particular, Selenoprotein M (SELM is located in the endoplasmic reticulum and contains the common redox motif of cysteine-X-X-selenocysteine type. It attracts great attention due to its high expression in brain and its potential roles as antioxidant, neuroprotective, and cytosolic calcium regulator. Recently, our group found SELM over-expression  in human hepatocellular carcinoma (HCC cell lines. In this report some paraffin-embedded tissues from liver biopsy of patients with hepatitis C virus (HCV-related cirrhosis and HCC were immunohistochemically stained and SELM expression scoring was evaluated. Our results evidence for the first time an increase of SELM expression in HCC liver tissues, and its gradual expression raise associated with an increased malignancy grade. Therefore, we propose to use i SELM as putative marker for HCC as well as ii simple immunohistochemistry technique to distinguish between the different grades of malignancy. 

  16. Liver angiogenesis as a risk factor for hepatocellular carcinoma development in hepatitis C virus cirrhotic patients

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    AIM: To evaluate the predictive value of hepatocyte proliferation and hepatic angiogenesis for the occurrence of Hepatocellular carcinoma (HCC) in hepatitis C virus(HCV) cirrhotic patients.METHODS: One hundred-five patients (69 males,36 females; age range, 51-90 year; median 66 year)with biopsy proven HCV cirrhosis were prospectively monitored for HCC occurrence for a median time of 64 mo. Angiogenesis was assessed by using microvessel density (MVD), hepatocyte turnover by MIB1 and PCNA indexes at inclusion in liver biopsies.RESULTS: Forty six patients (43.8%) developed HCC after a median time of 55 (6-120) mo while 59 (56.2%)did not. Patients were divided into two groups according to the median value of each index. The difference between patients with low (median MVD = 3; range 0-20) and high (median MVD = 7; range 1-24) MVD was statistically significant (χ2 = 22.06; P < 0.0001) which was not the case for MIB1 or PCNA (MIB-1: χ2 = 1.41;P = 0.2351; PCNA: χ2 = 1.27; P = 0.2589). The median MVD was higher in patients who developed HCC than in those who did not. HCC-free interval was significantly longer in patients with the MVD ≤ 4 (P = 0.0006).No relationship was found between MIB1 or PCNA and MVD (MIB-1 r2 = 0.00007116, P = 0.9281; PCNA: r2 =0.001950; P = 0.6692). MVD only was able to predict the occurrence of HCC in these patients. Among other known risk factors for HCC, only male sex was statistically associated with an increased risk.CONCLUSION: Liver angiogenesis has a role for in HCVrelated liver carcinogenesis and for defining patients at higher risk.

  17. Conversion to sirolimus immunosuppression in liver transplantation recipients with hepatocellular carcinoma: Report of an initial experience

    Institute of Scientific and Technical Information of China (English)

    Jian Zhou; Yi-Feng He; Yu-Qi Wang; Zhao-You Tang; Jia Fan; Zheng Wang; Zhi-Quan Wu; Shuang-Jian Qiu; Xiao-Wu Huang; Yao Yu; Jian Sun; Yong-Sheng Xiao

    2006-01-01

    AIM: To report a retrospective analysis of preliminary results of 36 patients who received sirolimus (SRL, Rapamune(R), rapamycin) in a consecutive cohort of 248 liver allograft recipients.METHODS: Thirty-six liver transplant patients with hepatocellular carcinoma (HCC) who were switched to SRL-based immunosuppression therapy from tacrolimus were enrolled in this study. The patients who were diagnosed as advanced HCC before orthotopic liver transplantation (OLT) were divided into group A (n = 11), those who were found to have HCC recurrence and/or metastasis after OLT were assigned to group B (n = 18), and those who developed renal insufficiency caused by calcineurin inhibitor (CNI) were assigned to group C (n = 7) after OLT.RESULTS: The patients were followed up for a median of 10.4 mo (range, 3.8-19.1 mo) after conversion to SRL therapy and 12.3 mo (range, 5.1-34.4 mo) after OLT.Three patients developed mild acute cellular rejection 2 wk after initiating SRL therapy, which was fully reversed after prednisolone pulse therapy. In group A, only 1 patient was found to have HCC recurrence and metastasis 12 mo after OLT. In group B, 66.7% (12/18) patients (2 with progressive tumor, 7 with stable tumor and 3 without tumor) were still alive due to conversing to SRL and/or resection for HCC recurrence at the end of a median follow-up of 6.8 mo post conversion and 10.7 mo posttransplant. In group C, no HCC recurrence was demonstrated in 7 patients, and renal function became normal after SRL therapy. Thrombocytopenia (n = 2), anemia (n = 8), and oral aphthous ulcers (n = 7) found in our cohort were easily manageable.CONCLUSION: The conversion to SRL-based immunosuppression may inhibit the recurrence and metastasis of HCC and improve CNI-induced renal insufficiency in OLT patients with HCC.

  18. Clinical features of nonalcoholic fatty liver disease-associated hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Xiao-Yan Duan; Liang Qiao; Jian-Gao Fan

    2012-01-01

    BACKGROUND: Nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis, is a recognized risk factor for hepatocellular carcinoma (HCC). However, detailed analysisoftheclinicalfeaturesinpatientswithNAFLDand their association with HCC is lacking. This study aimed to update the clinical features of patients with NAFLD-associated HCC. DATA SOURCES: The clinical data of patients with NAFLD-associated HCC from 25 studies published between 1990 and 2010 in the Pubmed database were comprehensively reviewed. RESULTS: In a total of 169 patients with NAFLD-associated HCC, 72.8% were male. The median age at abnormal liver function tests and diagnosis of NAFLD and HCC was 60, 64 and 67 years, respectively. Most patients were obese (75%) and diabetic (59.8%), 32.3% had dyslipidemia, and 53%had hypertension. Nearly all patients (98.6%, 71/72) were complicated with at least one metabolic disorder. The majority (76%) of the HCC patients had a solitary tumor nodule, with the tumor size ranging from 0.8 to 20 cm in diameter (mean 3.4 cm). Most (61.1%) of the patients had moderately-differentiated HCC. In 40.2% of the patients, HCC occurred in the absence of cirrhosis. Among 130 patients, 57.7% underwent hepatectomy and 14.6% received liver transplantation. The mean follow-up of the treated patients for 25 months showed that 32.4% (24/74) died and 18.8% (9/48) had recurrence. CONCLUSIONS: Patients with NAFLD-associated HCC are usually accompanied with metabolic disorders. Regular surveillance in patients with NAFLD for HCC is necessary, especially for elderly men with metabolic syndrome.

  19. A proteomic strategy to identify novel serum biomarkers for liver cirrhosis and hepatocellular cancer in individuals with fatty liver disease

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    Stewart Stephen

    2009-08-01

    Full Text Available Abstract Background Non-alcoholic fatty liver disease (NAFLD has a prevalence of over 20% in Western societies. Affected individuals are at risk of developing both cirrhosis and hepatocellular cancer (HCC. Presently there is no cost effective population based means of identifying cirrhotic individuals and even if there were, our ability to perform HCC surveillance in the at risk group is inadequate. We have performed a pilot proteomic study to assess this as a strategy for serum biomarker detection. Methods 2D Gel electrophoresis was performed on immune depleted sera from 3 groups of patients, namely those with (1 pre-cirrhotic NAFLD (2 cirrhotic NAFLD and (3 cirrhotic NAFLD with co-existing HCC. Five spots differentiating at least one of these three groups were characterised by mass spectroscopy. An ELISA assay was optimised and a cross sectional study assessing one of these serum spots was performed on serum from 45 patients with steatohepatitis related cirrhosis and HCC and compared to 77 patients with histologically staged steatohepatitis. Results Four of the spots identified were apolipoprotein isoforms, the pattern of which was able to differentiate the three groups. The 5th spot, seen in the serum of cirrhotic individuals and more markedly in those with HCC, was identified as CD5 antigen like (CD5L. By ELISA assay, although CD5L was markedly elevated in a number of cirrhotic individuals with HCC, its overall ability to distinguish non-cancer from cancer individuals as determined by AUC ROC analysis was poor. However, serum CD5L was dramatically increased, independently of age, sex, and the presence of necroinflammation, in the serum of individuals with NAFLD cirrhosis relative to those with pre-cirrhotic disease. Conclusion This novel proteomic strategy has identified a number of candidate biomarkers which may have benefit in the surveillance and diagnosis of individuals with chronic liver disease and/or HCC.

  20. Effects of carbon tetrachloride and azathioprine on diethylnitrosamine and N-2-fluorenylacetamide-induced hyperplastic liver nodule and hepatocellular carcinoma

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    Sakata,Tatsuro

    1984-12-01

    Full Text Available Effects of carbon tetrachloride (CCl4 and azathioprine (AZP on the evolution of hyperplastic liver nodules and foci and hepatocellular carcinoma (HCC were tested in short- and long-term in vivo experiments. In diethylnitrosamine (DEN-treated rats, which were fed a N-2-fluorenylacetamide (FAA-containing diet and additionally treated with repeated CCl4 injections, gamma-glutamyl transpeptidase (gamma-GTP-positive hyperplastic nodules were markedly developed in the 8th week of the experiment. However, their number and area in liver sections were remarkably small in DEN-treated rats fed a diet containing both FAA and AZP. Increased area of gamma-GTP-positive foci was also observed in the 12th week in DEN-injected rats fed a choline-devoid died alone or treated with repeated doses of CCl4 alone. Hepatocellular carcinoma in DEN-injected rats treated with both FAA and CCl4 was first detected in the 21st week, and the incidence up to the 36th week was very high. However, no hepatocellular carcinoma developed in DEN-injected rats treated with both FAA and AZP. The increased activity of liver aniline hydroxylase observed 12 h after the administration of FAA, AZP or DEN alone was not observed when AZP was administered simultaneously with FAA to DEN-injected rats. The mechanisms of the effects of CCl4 and AZP on hepatocarcinogenesis are discussed with special reference to drug interaction.

  1. Association of serum level of growth differentiation factor 15 with liver cirrhosis and hepatocellular carcinoma.

    Directory of Open Access Journals (Sweden)

    Xiuying Liu

    Full Text Available Hepatocellular carcinoma (HCC and liver cirrhosis are associated with high mortality worldwide. Currently, alpha-fetoprotein (AFP is used as a standard serum marker for the detection of HCC, but its sensitivity and specificity are unsatisfactory, and optimal diagnostic markers for cirrhosis are lacking. We previously reported that growth differentiation factor 15 (GDF15 was significantly induced in HCV-infected hepatocytes. This study aimed to investigate GDF15 expression and its correlation with hepatitis virus-related liver diseases. A total of 412 patients with various liver diseases were studied. Healthy and Mycobacterium tuberculosis-infected subjects were included as controls. Serum and tissue GDF15 levels were measured. Serum GDF15 levels were significantly increased in patients with HCC (6.66±0.67 ng/mL, p<0.0001 and cirrhosis (6.51±1.47 ng/mL, p<0.0001 compared with healthy controls (0.31±0.01 ng/mL, though the GDF15 levels in HBV and HCV carriers were moderately elevated (1.34±0.19 ng/mL and 2.13±0.53 ng/mL, respectively. Compared with HBV or HCV carriers, GDF15 had a sensitivity of 63.1% and a specificity of 86.6% at the optimal cut-off point of 2.463 ng/mL in patients with liver cirrhosis or HCC. In HCC patients, the area under the receiver operating curve was 0.84 for GDF15 and 0.76 for AFP, but 0.91 for the combined GDF15 and AFP. Serum GDF15 levels did not significantly differ between the high-AFP and low-AFP groups. GDF15 protein expression in HCC was significantly higher than that in the corresponding adjacent paracarcinomatous tissue and normal liver. Using a combination of GDF15 and AFP will improve the sensitivity and specificity of HCC diagnosis. Further research and the clinical implementation of serum GDF15 measurement as a biomarker for HCC and cirrhosis are recommended.

  2. Primary liver tumors. Hepatocellular versus intrahepatic cholangiocellular carcinoma; Primaere Lebertumoren. Hepatozellulaeres vs. intrahepatisches cholangiozellulaeres Karzinom

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    Wengert, G.J.; Bickel, H.; Breitenseher, J.; Ba-Ssalamah, A. [Medizinische Universitaet Wien, Universitaetsklinik fuer Radiologie und Nuklearmedizin, Allgemeines Krankenhaus, Wien (Austria)

    2015-01-01

    Hepatocellular carcinoma (HCC) and intrahepatic cholangiocellular carcinoma (ICC) are the most commonly occurring and important primary liver tumors. Originating from one pluripotent liver stem cell both tumor entities can occur in a cirrhotic liver and also in patients without cirrhosis. Several risk factors have been identified as causative for both carcinomas; therefore, tumor screening is advantageous, especially for high-risk patients who could be diagnosed in an early stage to allow curative treatment. Surgical resection, interventional procedures and transplantation are available as curative treatment options when diagnosed in time. Common characteristic features and morphology in cross-sectional imaging by ultrasound (US), multidetector computed tomography (CT) and magnetic resonance imaging (MRI) as well as screening aspects are presented and discussed. Recent findings show a better understanding of the carcinogenesis model of both liver tumors originating from one pluripotent liver stem cell. Further developments of modern cross-sectional imaging modalities, especially MRI in combination with diffusion-weighted imaging and intravenous administration of hepatocyte-specific contrast agents enable early detection, exact differentiation, staging and treatment evaluation of HCC and ICC In this article we discuss modern, multiparametric imaging modalities, which allow a complete and reliable diagnosis of the majority of these tumor entities. Contrast-enhanced MRI, using hepatocyte-specific contrast agents, is currently the most accurate procedure for the noninvasive diagnosis and treatment evaluation of HCC and ICC. (orig.) [German] Das hepatozellulaere Karziom (HCC) sowie das intrahepatische cholangiozellulaere Karzinom (ICC) zaehlen zu den wichtigsten primaeren Lebertumoren. Mit dem Ursprung aus einer pluripotenten Stammzelle koennen beide Tumorentitaeten bei bestehender, aber auch bei nicht bestehender Leberzirrhose auftreten. Im Folgenden werden

  3. Hepatocellular carcinoma: illustrated guide to systematic radiologic diagnosis and staging according to guidelines of the American Association for the Study of Liver Diseases.

    LENUS (Irish Health Repository)

    McEvoy, Sinead H

    2013-10-01

    Hepatocellular carcinoma is a malignancy that predominantly occurs in the setting of cirrhosis. Its incidence is rising worldwide. Hepatocellular carcinoma differs from most malignancies because it is commonly diagnosed on the basis of imaging features alone, without histologic confirmation. The guidelines from the American Association for the Study of Liver Diseases (AASLD) are a leading statement for the diagnosis and staging of hepatocellular carcinoma, and they have recently been updated, incorporating several important changes. AASLD advocates the use of the Barcelona Clinic Liver Cancer (BCLC) staging system, which combines validated imaging and clinical predictors of survival to determine stage and which links staging with treatment options. Each stage of the BCLC system is outlined clearly, with emphasis on case examples. Focal liver lesions identified at ultrasonographic surveillance in patients with cirrhosis require further investigation. Lesions larger than 1 cm should be assessed with multiphasic computed tomography or magnetic resonance imaging. Use of proper equipment and protocols is essential. Lesions larger than 1 cm can be diagnosed as hepatocellular carcinoma from a single study if the characteristic dynamic perfusion pattern of arterial hyperenhancement and venous or delayed phase washout is demonstrated. If the imaging characteristics of hepatocellular carcinoma are not met, the alternate modality should be performed. Biopsy should be used if neither modality is diagnostic of hepatocellular carcinoma. Once the diagnosis has been made, the cancer should be assigned a BCLC stage, which will help determine suitable treatment options. Radiologists require a systematic approach to diagnose and stage hepatocellular carcinoma with appropriate accuracy and precision.

  4. Prognostic value of preoperative peripheral monocyte count in patients with hepatocellular carcinoma after liver transplantation.

    Science.gov (United States)

    Ren, Qing-Qi; Fu, Shun-Jun; Zhao, Qiang; Guo, Zhi-Yong; Ji, Fei; Chen, Mao-Gen; Wu, Lin-Wei; He, Xiao-Shun

    2016-07-01

    Prognostic value of peripheral monocyte, as a member of inflammatory cells, was widely being investigated. The aim of this study was to evaluate the prognostic value of preoperative peripheral blood monocyte count for hepatocellular carcinoma (HCC) patients who underwent liver transplantation (LT) and the relationship between monocyte count and tumor-related characteristics. We retrospectively analyzed the clinical data of 101 HCC patients after LT. Preoperative monocyte count and demographic, clinical, and pathologic data were analyzed. The optimal cutoff value of monocyte count was 456/mm(3), with the sensitivity and specificity of 69.4 and 61.5 %, respectively. Elevated preoperative peripheral blood monocyte count was significantly associated with large tumor size. The 1-, 3-, and 5-year disease-free survival (DFS) (80.9, 70.1, and 53.3 % vs 55.1, 38.7, and 38.7 %, P = 0.007) and overall survival (OS) rates (95.7, 76.6, and 64.8 % vs 72.2, 44.1, and 36.1 %, P = 0.002) of HCC patients in the peripheral blood monocyte count ≤456/mm(3) group were higher than those in the peripheral blood monocyte count >456/mm(3) group. In conclusion, elevated preoperative peripheral blood monocyte count was significantly associated with advanced tumor stage and it can be considered as a prognostic factor for HCC patients after LT.

  5. Ischemic preconditioning protects liver from hepatectomy under hepatic inflow occlusion for hepatocellular carcinoma patients with cirrhosis

    Institute of Scientific and Technical Information of China (English)

    Shao-Qiang Li; Li-Jian Liang; Jie-Fu Huang; Zhi Li

    2004-01-01

    AIM: To investigate the protective effect of ischemic preconditioning (IPC) on hepatocellular carcinoma (HCC)patients with cirrhosis undergoing hepatic resection under hepatic inflow occlusion (HIO) and its possible mechanism.METHODS: Twenty-nine consecutive patients with resectable 0HCC were randomized into two groups: IPC group: before HIO, IPC with 5 min of ischemia and 5 min of reperfusion was given; control group: no IPC was given. Liver functions,hepatic Caspase-3 activity, and apoptotic cells were compared between these two groups.RESULTS: On postoperative days (POD) 1, 3 and 7, the aspartate transaminase (AST) and alanine transaminase (ALT) levels in the IPC group were significantly lower than those in the control group (P<0.05). On POD 3 and 7, the total bilirubin level in the IPC group was significantly lower than that in the control group (P<0.05). On POD 1, the albumin level in the IPC group was higher than that in the control group (P = 0.053). After 1 h of reperfusion, both hepatic Caspase-3 activity and apoptotic sinusoidal endothelial cells in the IPC group were significantly lower than those in the control group (P<0.05).CONCLUSION: IPC has a potential protective effect on HCC patients with cirrhosis. Its protective mechanism underlying the suppression of sinusoidal endothelial cell apoptosis is achieved by inhibiting Caspase-3 activity.

  6. Obesity portends increased morbidity and earlier recurrence following liver transplantation for hepatocellular carcinoma.

    Science.gov (United States)

    Mathur, Abhishek; Franco, Edson S; Leone, John P; Osman-Mohamed, Hussein; Rojas, Haydy; Kemmer, Nyingi; Neff, Guy W; Rosemurgy, Alexander S; Alsina, Angel E

    2013-07-01

    Obesity has been associated with poor oncologic outcomes following pancreatoduodenectomy for pancreatic cancer. However, there is a paucity of evidence on the impact of obesity on postoperative complications, oncologic outcome and survival in patients with hepatocellular carcinoma (HCC) undergoing orthotopic liver transplantation (OLT). From a database of over 1000 patients who underwent OLT during 1996-2008, 159 patients with a diagnosis of HCC were identified. Demographic data, body mass index (BMI), perioperative parameters, recurrence and survival were obtained. Complications were grouped according to Clavien-Dindo grading (Grades I-V). There were increased incidences of life-threatening complications in overweight (58%) and obese (70%) patients compared with the non-obese patient group (41%) (P obesity (15%) compared with non-obesity (7%) (P obese (41 ± 4 months) groups compared with the non-obese group (58 ± 6 months) did not reach statistical significance. These findings indicate that BMI is an important surrogate marker for obesity and portends an increased risk for complications and a poorer oncologic outcome following OLT for HCC. © 2012 International Hepato-Pancreato-Biliary Association.

  7. Sorafenib metabolism is significantly altered in the liver tumor tissue of hepatocellular carcinoma patient.

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    Ling Ye

    Full Text Available BACKGROUND: Sorafenib, the drug used as first line treatment for hepatocellular carcinoma (HCC, is metabolized by cytochrome P450 (CYP 3A4-mediated oxidation and uridine diphosphate glucuronosyl transferase (UGT 1A9-mediated glucuronidation. Liver diseases are associated with reduced CYP and UGT activities, which can considerably affect drug metabolism, leading to drug toxicity. Thus, understanding the metabolism of therapeutic compounds in patients with liver diseases is necessary. However, the metabolism characteristic of sorafenib has not been systematically determined in HCC patients. METHODS: Sorafenib metabolism was tested in the pooled and individual tumor hepatic microsomes (THLMs and adjacent normal hepatic microsomes (NHLMs of HCC patients (n = 18. Commercial hepatic microsomes (CHLMs were used as a control. In addition, CYP3A4 and UGT1A9 protein expression in different tissues were measured by Western blotting. RESULTS: The mean rates of oxidation and glucuronidation of sorafenib were significantly decreased in the pooled THLMs compared with those in NHLMs and CHLMs. The maximal velocity (Vmax of sorafenib oxidation and glucuronidation were approximately 25-fold and 2-fold decreased in the pooled THLMs, respectively, with unchanged Km values. The oxidation of sorafenib in individual THLMs sample was significantly decreased (ranging from 7 to 67-fold than that in corresponding NHLMs sample. The reduction of glucuronidation in THLMs was observed in 15 out of 18 patients' samples. Additionally, the level of CYP3A4 and UGT1A9 expression were both notably decreased in the pooled THLMs. CONCLUSIONS: Sorafenib metabolism was remarkably decreased in THLMs. This result was associated with the down regulation of the protein expression of CYP3A4 and UGT1A9.

  8. Liver expression of steroid hormones and Apolipoprotein D receptors in hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    FJ Vizoso; L Rodrigo; M Rodriguez; A Altadill; ML González-Diéguez; A Linares; LO González; S Junquera; F Fresno-Forcelledo; MD Corte

    2007-01-01

    AIM: To evaluate the tissular expression of Androgen (A), Estrogen (E) and Progesterone (Pg) receptors, and Apolipoprotein D (ApoD), in liver tumors from resected hepatocellular carcinoma (HCC) cases in order to assess their possible relationship to prognosis.METHODS We performed an immunohistochemical study using tissue microarrays (containing more than 260 cancer specimens, from 31 HCC patients and controls)to determine the presence of specific antibodies against AR, ER, PgR and ApoD, correlating their findings with several clinico-pathological and biological variables. The staining results were categorized using a semi-quantitive score based on their intensity, and the percentage of immunostained cells was measured.RESULTS: A total of 21 liver tumors (67.7%) were positive for AR; 16 (51.6%) for ER; 26 (83.9%) for PgR and 12 (38.7%) stained for ApoD. We have found a wide variability in the immunostaining score values for each protein, with a median (range) of 11.5 (11.5-229.5) for AR; 11.1 (8.5-65) for ER; 14.2 (4-61) for PgR; and 37.7 (13.8-81.1) for ApoD. A history of heavy ethanol consumption, correlated positively with AR and PgR and negatively with ER status. HCV chronic infection also correlated positively with AR and PgR status. However,the presence of ApoD immunostaining did not correlate with any of these variables. Tumors with a positive immuno-staining for PgR showed a better prognosis.CONCLUSION: Our results indicate a moderate clinical value of the steroid receptor status in HCC, emphasizing the need to perform further studies in order to evaluate the possible role of new hormonal-based therapies.

  9. Prognostic value of glypican-3 in patients with HBV-associated hepatocellular carcinoma after liver transplantation

    Institute of Scientific and Technical Information of China (English)

    Xiao Cui; Zhao Li; Peng-Ji Gao; Jie Gao; Ji-Ye Zhu

    2015-01-01

    BACKGROUND:Glypican-3 (GPC-3) is frequently overexpressed in hepatocellular carcinoma (HCC). Recent studies have shown that GPC-3 is a highly efifcient diagnostic biomarker of HCC and an indicator of poor prognosis in HCC patients who have undergone hepatectomy. However, its prognostic value in pa-tients with HBV-associated HCC after liver transplantation (LT) is not clear. The present study is to evaluate the prognostic value of GPC-3 in patients with HBV-associated HCC after LT. METHODS:A cohort of 104 HCC patients with HBV-associ-ated cirrhosis who had undergone LT at our hospital between 2002 and 2011 were enrolled in this study. Samples of HCC were taken from these patients. GPC-3 protein expression was detected in parafifn-embedded specimens using immunohis-tochemistry. All related clinical data were obtained from the China Liver Transplant Registry. The relationship between GPC-3 expression and clinicopathological parameters was analyzed. Univariate and multivariate Cox-regression analyses were used to identify risk factors for poor prognosis. RESULTS:GPC-3 was expressed in samples from 74 (71.2%) of the 104 patients. GPC-3 was expressed only in HCC cells. Positive staining was correlated with tumor size (P=0.004), encapsulation (P=0.018), pathological stage (P=0.027), portal vein invasion (P=0.043), tumor differentiation (P=0.002) and the Milan criteria (P=0.016). The 5-year survival rate and dis-ease-free survival rate of patients with GPC-3-positive were lower than those (38.2% vs 75.4%,P CONCLUSION:GPC-3 is a potential biomarker for poor prog-nosis after LT in HCC patients with HBV-associated cirrhosis.

  10. From big data to diagnosis and prognosis: gene expression signatures in liver hepatocellular carcinoma

    Science.gov (United States)

    Cai, Xiao-yong; Wen, Dong-yue; Ye, Zhi-hua; Liang, Liang; Zhang, Lu; Wang, Han-lin

    2017-01-01

    Background Liver hepatocellular carcinoma accounts for the overwhelming majority of primary liver cancers and its belated diagnosis and poor prognosis call for novel biomarkers to be discovered, which, in the era of big data, innovative bioinformatics and computational techniques can prove to be highly helpful in. Methods Big data aggregated from The Cancer Genome Atlas and Natural Language Processing were integrated to generate differentially expressed genes. Relevant signaling pathways of differentially expressed genes went through Gene Ontology enrichment analysis, Kyoto Encyclopedia of Genes and Genomes and Panther pathway enrichment analysis and protein-protein interaction network. The pathway ranked high in the enrichment analysis was further investigated, and selected genes with top priority were evaluated and assessed in terms of their diagnostic and prognostic values. Results A list of 389 genes was generated by overlapping genes from The Cancer Genome Atlas and Natural Language Processing. Three pathways demonstrated top priorities, and the one with specific associations with cancers, ‘pathways in cancer,’ was analyzed with its four highlighted genes, namely, BIRC5, E2F1, CCNE1, and CDKN2A, which were validated using Oncomine. The detection pool composed of the four genes presented satisfactory diagnostic power with an outstanding integrated AUC of 0.990 (95% CI [0.982–0.998], P big data, featuring the cancer-specific pathway with priority, ‘pathways in cancer.’ The detection pool of the four highlighted genes, namely BIRC5, E2F1, CCNE1 and CDKN2A, should be further investigated given its high evidence level of diagnosis, whereas the prognostic powers of BIRC5 and CCNE1 are equally attractive and worthy of attention.

  11. Impact of pre-operative transarterial embolization on the treatment of hepatocellular carcinoma with liver transplantation

    Institute of Scientific and Technical Information of China (English)

    Yu-Fan Cheng; Bruno Jawan; Hock-Liew Eng; Chao-Long Chen; Tung-Liang Huang; Tai-Yi Chen; Yaw-Sen Chen; Chih-Chi Wang; Sheng-Lung Hsu; Leo Leung-Chit Tsang; Po-Lin Sun; King-Wah Chiu

    2005-01-01

    AIM: To determine the effectiveness of pre-liver transplant (LT) transarterial embolization (TAE) in treating hepatocellular carcinoma (HCC) and the patient categories,which are likely to have a good outcome after LT.METHODS: Twenty-nine patients with hepatitis-related cirrhosis and unresectable HCC after LT were studied over a 7-year period. The patients were divided into two groups: group A patients (19/29) received pre-LT TAE,whereas group B (10/29) underwent LT without prior TAE.According to Milan criteria, group A patients were further subdivided into: group A1 (12/19) who met the criteria,and group A2 (7/19) who did not. Patient survivals were compared.RESULTS: In the explanted liver, CT images correlated well with pathological specimens showing that TAE induced massive tumor necrosis (>85%) in 63.1% of patients in group A and all 7 patients in group A2 exhibited tumor downgrading that met Milan criteria. The overall 5-year actuarial survival rate was 80.6%. The TAE group had a better survival (84% at 5 years) than the non-TAE (75% at 4 years). The 3-year survival of group A2 (83%)was also higher than that of group A1 (79%). Tumor necrosis >85% was associated with excellent survival of 100% at 3 years, which was significantly better than the others who showed <85% tumor necrosis (57.1% at 3 years) or who did not have TAE (75% at 3 years).CONCLUSION: TAE is an effective treatment for HCC before LT. Excellent long-term survival was achieved in patients that did not fit Milan criteria. Our results broadened and redefined the selection policy for LT among patients with HCC. Meticulous pre-LT TAE helps in further reducing the rate of dropout from waiting lists and should be considered for patients with advanced HCC.

  12. Mice with humanized liver endothelium

    NARCIS (Netherlands)

    el Filali, E.

    2014-01-01

    The only curative treatment option for a large proportion of patients suffering from a liver disorder is liver transplantation. The use of ex vivo genetically modified autologous liver cells instead of whole liver transplantation could overcome the problem of donor scarcity. Even though clinical

  13. Mice with humanized liver endothelium

    NARCIS (Netherlands)

    el Filali, E.

    2014-01-01

    The only curative treatment option for a large proportion of patients suffering from a liver disorder is liver transplantation. The use of ex vivo genetically modified autologous liver cells instead of whole liver transplantation could overcome the problem of donor scarcity. Even though clinical tri

  14. Liver stiffness measured by magnetic resonance elastography as a risk factor for hepatocellular carcinoma: a preliminary case-control study

    Energy Technology Data Exchange (ETDEWEB)

    Motosugi, Utaroh; Ichikawa, Tomoaki; Koshiishi, Tsuyota; Sano, Katsuhiro; Morisaka, Hiroyuki; Ichikawa, Shintaro; Araki, Tsutomu [University of Yamanashi, Department of Radiology, Yamanashi-ken (Japan); Enomoto, Nobuyuki [University of Yamanashi, 1st Department of Internal Medicine, Yamanashi (Japan); Matsuda, Masanori; Fujii, Hideki [University of Yamanashi, 1st Department of Surgery, Yamanashi (Japan)

    2013-01-15

    To examine if liver stiffness measured by magnetic resonance elastography (MRE) is a risk factor for hepatocellular carcinoma (HCC) in patients with chronic liver disease. By reviewing the records of magnetic resonance (MR) examinations performed at our institution, we selected 301 patients with chronic liver disease who did not have a previous medical history of HCC. All patients underwent MRE and gadoxetic acid-enhanced MR imaging. HCC was identified on MR images in 66 of the 301 patients, who were matched to controls from the remaining patients without HCC according to age. MRE images were obtained by visualising elastic waves generated in the liver by pneumatic vibration transferred via a cylindrical passive driver. Risk factors of HCC development were determined by the odds ratio with logistic regression analysis; gender and liver stiffness by MRE and serum levels of aspartate transferase, alanine transferase, alpha-fetoprotein, and protein induced by vitamin K absence-II. Multivariate analysis revealed that only liver stiffness by MRE was a significant risk factor for HCC with an odds ratio (95 % confidence interval) of 1.38 (1.05-1.84). Liver stiffness measured by MRE is an independent risk factor for HCC in patients with chronic liver disease. (orig.)

  15. Effect of New Water-Soluble Dendritic Phthalocyanines on Human Colorectal and Liver Cancer Cell Lines

    Directory of Open Access Journals (Sweden)

    Ebru YABAŞ

    2017-08-01

    Full Text Available Human hepatocellular carcinoma (HepG2 cells and colorectal adenocarcinoma (DLD-1 cells were treated with the synthesized water soluble phthalocyanine derivatives to understand the effect of the compounds both on colorectal and liver cancer cells. The compounds inhibited cell proliferation and displayed cytotoxic effect on these cancer cell lines however; the effect of the compounds on healthy control fibroblast cell line was comparatively lower. The compounds can be employed for cancer treatment as anticancer agents.

  16. Epigenetic inactivation of SLIT2 in human hepatocellular carcinomas.

    Science.gov (United States)

    Jin, Jie; You, Haiyan; Yu, Bin; Deng, Yun; Tang, Ning; Yao, Genfu; Shu, Huiqun; Yang, Shengli; Qin, Wenxin

    2009-01-30

    Recent findings have shown that SLIT2 appears to function as a novel tumor suppressor gene. In addition, hypermethylation of its promoter region has been detected in various cancers, including breast and lung cancer, colorectal carcinoma, and gliomas. Here, we report for the first time that there is epigenetic silencing of SLIT2 in human hepatocellular carcinoma (HCC). Downregulation of SLIT2 was detected in 6 of 8 (75%) HCC cell lines by quantitative real-time RT-PCR (qRT-PCR), and the downregulation of SLIT2 was generally dependent on the degree of methylation at the promoter region. Furthermore, expression of SLIT2 was restored in relatively low-expressing cell lines after treatment with 5-aza-2-deoxycytidine (5-Aza-dC). Downregulation of SLIT2 expression was also detected in 45 of 54 primary HCC samples (83.3%), and the decrease in expression was significantly correlated with CpG island hypermethylation. This decrease of SLIT2 expression was also associated with lymph node metastasis in HCC. Moreover, overexpression of SLIT2 in SMMC-7721 cells induced by recombinant adenovirus suppressed cell growth, migration, and invasion, These results suggest that epigenetic inactivation of SLIT2 in HCC may be important in the development and progression of HCC. Thus, SLIT2 may be useful as a therapeutic target in the treatment of HCC.

  17. Evaluation of liver cirrhosis and hepatocellular carcinoma using Protein-Protein Interaction Networks.

    Science.gov (United States)

    Ehsani Ardakani, Mohammad Javad; Safaei, Akram; Arefi Oskouie, Afsaneh; Haghparast, Hesam; Haghazali, Mehrdad; Mohaghegh Shalmani, Hamid; Peyvandi, Hassan; Naderi, Nosratollah; Zali, Mohammad Reza

    2016-12-01

    In the current study, we analysised only the articles that investigate serum proteome profile of cirrhosis patients or HCC patients versus healthy controls. Increased understanding of cancer biology has enabled identification of molecular events that lead to the discovery of numerous potential biomarkers in diseases. Protein-protein interaction networks is one of aspect that could elevate the understanding level of molecular events and protein connections that lead to the identification of genes and proteins associated with diseases. Gene expression data, including 63 gene or protein names for hepatocellular carcinoma and 29 gene or protein names for cirrhosis, were extracted from a number of previous investigations. The networks of related differentially expressed genes were explored using Cytoscape and the PPI analysis methods such as MCODE and ClueGO. Centrality and cluster screening identified hub genes, including APOE, TTR, CLU, and APOA1 in cirrhosis. CLU and APOE belong to the regulation of positive regulation of neurofibrillary tangle assembly. HP and APOE involved in cellular oxidant detoxification. C4B and C4BP belong to the complement activation, classical pathway and acute inflammation response pathway. Also, it was reported TTR, TFRC, VWF, CLU, A2M, APOA1, CKAP5, ZNF648, CASP8, and HSP27 as hubs in HCC. In HCC, these include A2M that are corresponding to platelet degranulation, humoral immune response, and negative regulation of immune effector process. CLU belong to the reverse cholesterol transport, platelet degranulation and human immune response. APOA1 corresponds to the reverse cholesterol transport, platelet degranulation and humoral immune response, as well as negative regulation of immune effector process pathway. In conclusion, this study suggests that there is a common molecular relationship between cirrhosis and hepatocellular cancer that may help with identification of target molecules for early treatment that is essential in cancer therapy.

  18. Contrast ultrasound in hepatocellular carcinoma at a tertiary liver center: First Indian experience.

    Science.gov (United States)

    Laroia, Shalini Thapar; Bawa, Simranjeet Singh; Jain, Deepak; Mukund, Amar; Sarin, Shiv

    2013-06-28

    To assess the role of contrast enhanced ultrasonography in evaluation of hepatocellular carcinoma (HCC) at the first Indian tertiary liver center. Retrospective analysis of contrast enhanced ultrasound (CEUS) examinations over 24 mo for diagnosis, surveillance, characterization and follow up of 50 patients in the context of HCC was performed. The source and indication of referrals, change in referral rate, accuracy and usefulness of CEUS in a tertiary liver center equipped with a 64 slice dual energy computer tomography (CT) and 3 tesla magnetic resonance imaging (MRI) were studied. Sonovue (BR1, Bracco, Italy, a second generation contrast agent) was used for contrast US studies. Contrast enhanced CT/MRI or both were performed in all patients. The findings were taken as a baseline reference and correlation was done with respect to contrast US. Contrast enhanced MRI was performed using hepatocyte specific gadobenate dimeglumine (Gd-BOPTA). Iomeron (400 mg; w/v) was used for dynamic CT examinations. About 20 (40%) of the examinations were referred from clinicians for characterization of a mass from previous imaging. About 15 (30%) were performed for surveillance in chronic liver disease; 5 (10%) examinations were performed for monitoring lesions after radiofrequency ablation (RFA); 3 (6%) were post trans-arterial chemo-embolization (TACE) assessments and 3 (6%) were patients with h/o iodinated contrast allergy. About 2 (4%) were performed on hemodynamically unstable patients in the intensive care with raised alpha fetoprotein and 2 (4%) patients were claustrophobic. The number of patients referred from clinicians steadily increased from 12 in the first 12 mo of the study to 38 in the last 12 mo. CEUS was able to diagnose 88% of positive cases of HCC as per reference standards. In the surveillance group, specificity was 53.3% vs 100% by CT/MRI. Post RFA and TACE specificity of lesion characterization by CEUS was 100% in single/large mass assessment, similar to CT

  19. Down-regulated expression of atypical PKC-binding domain deleted asip isoforms in human hepatocellular carcinomas

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Asip is a mammalian homologue of polarity protein Par-3 of Caenorhabditis elegans and Bazooka of Drosophila melanogaster. Asip/Par-3/Bazooka are PDZ-motif containing proteins that localize asymmetrically to the cell periphery and play a pivotal role in cell polarity and asymmetric cell division. In the present study, we have cloned human asip cDNA and its splicing variants by 5'-RACE and RT-PCR using candidate human EST clones which have a high homology to rat asip cDNA. The full-length cDNA of human asip encodes a 1,353 aa protein exhibiting 88% similarity to the rat one. Human asip is a single copy gene consisting of at least 26 exons and localizing in human chromosome 10, band p11.2, with some extraordinarily long introns. All exon/intron boundary nucleotides conform to the “gt-ag” rule. Three main transcripts were detected by Northern blot analysis, and at least five variants, from alternative splicing and polyadenylation, have been identified by RT-PCR and liver cDNA library screening. Exon 17b deleted asip mRNAs expressed ubiquitously in normal human tissues, including liver, on RT-PCR analysis. However, they were absent from most human liver cancer cell lines examined. More interestingly, the expression of exon 17b deleted variants was down regulated in 52.6% (10/19) clinic specimens of human hepatocellular carcinomas (HCCs), compared with the surrounding nontumorous liver tissues from the same patients. The presence of various splicing transcripts, the variation of their distribution among different tissues and cells, and their differential expressions in human HCCs suggest that human Asip isoforms may function in different context.

  20. Cross-species hybridization of woodchuck hepatitis virus-induced hepatocellular carcinoma using human oligonucleotide microarrays

    Institute of Scientific and Technical Information of China (English)

    Paul W Anderson; Bud C Tennant; Zhenghong Lee

    2006-01-01

    AIM: To demonstrate the feasibility of using woodchuck samples on human microarrays, to provide insight into pathways involving positron emission tomography (PET) imaging tracers and to identify genes that could be potential molecular imaging targets for woodchuck hepatocellular carcinoma.METHODS: Labeled cRNA from woodchuck tissue samples were hybridized to Affymetrix U133 plus 2.0 GeneChips(R). Ten genes were selected for validation using quantitative RT-PCR and literature review was made.RESULTS: Testis enhanced gene transcript (BAX Inhibitor 1), alpha-fetoprotein, isocitrate dehydrogenase 3 (NAD+) beta, acetyl-CoA synthetase 2, carnitine palmitoyltransferase 2, and N-myc2 were up-regulated and spermidine/spermine N1-acetyltransferase was down-regulated in the woodchuck HCC. We also found previously published results supporting 8 of the 10 most up-regulated genes and all 10 of the 10 most downregulated genes.CONCLUSION: Many of our microarray results were validated using RT-PCR or literature search. Hence, we believe that woodchuck HCC and non-cancerous liver samples can be used on human microarrays to yield meaningful results.

  1. Expanded criteria for liver transplantation in patients with cirrhosis and hepatocellular carcinoma.

    Science.gov (United States)

    Silva, Mauricio; Moya, Angel; Berenguer, Marina; Sanjuan, Fernando; López-Andujar, Rafael; Pareja, Eugenia; Torres-Quevedo, Rodrigo; Aguilera, Victoria; Montalva, Eva; De Juan, Manuel; Mattos, Angelo; Prieto, Martín; Mir, José

    2008-10-01

    Orthotopic liver transplantation (OLT) selection for patients with hepatocellular carcinoma (HCC) is a matter of debate. The Milan criteria (MC) have been largely adopted by the international community. The main aim of this study was to evaluate the survival rates and recurrence probabilities of a new proposal for criteria (up to 3 tumors, each no larger than 5 cm, and a cumulative tumor burden

  2. Does autologous blood transfusion during liver transplantation for hepatocellular carcinoma increase risk of recurrence?

    Institute of Scientific and Technical Information of China (English)

    Raphael LC Araujo; Carlos Andrés Pantanali; Luciana Haddad; Joel Avancini Rocha Filho; Luiz Augusto Carneiro D’Albuquerque; Wellington Andraus

    2016-01-01

    AIM: To analyze outcomes in patients who underwent liver transplantation(LT) for hepatocellular carcinoma(HCC) and received autologous intraoperative blood salvage(IBS). METHODS: Consecutive HCC patients who underwent LT were studied retrospectively and analyzed according to the use of IBS or not. Demographic and surgical data were collected from a departmental prospective maintained database. Statistical analyses were performed using the Fisher’s exact test and the Wilcoxon rank sum test to examine covariate differences between patients who underwent IBS and those who did not. Univariate and multivariate Cox regression models were developed to evaluate recurrence and death,and survival probabilities were estimated using the Kaplan-Meier method and compared by the log-rank test.RESULTS: Between 2002 and 2012,158 consecutive patients who underwent LT in the same medical center and by the same surgical team were identified. Among these patients,122(77.2%) were in the IBS group and 36(22.8%) in the non-IBS group. The overall survival(OS) and recurrence free survival(RFS) at 5 years were 59.7% and 83.3%,respectively. No differences in OS(P=0.51) or RFS(P=0.953) were detected between the IBS and non-IBS groups. On multivariate analysis for OS,degree of tumor differentiation remained as the only independent predictor. Regarding patients who received IBS,no differences were detected in OS or RFS(P=0.055 and P=0.512,respectively) according to the volume infused,even when outcomes at 90 d or longer were analyzed separately(P=0.518 for both outcomes).CONCLUSION: No differences in RFS or OS were detected according to IBS use. Trials addressing this question are justified and should be designed to detect small differences in long-term outcomes.

  3. Classification tool for the systematic histological assessment of hepatocellular carcinoma, macroregenerative nodules, and dysplastic nodules in cirrhotic liver

    Institute of Scientific and Technical Information of China (English)

    A Quaglia; MA Jutand; A Dhillon; A Godfrey; R Togni; P Bioulac-Sage; C Balabaud; M Winnock; AP Dhillon

    2005-01-01

    AIM: To design a classification tool for the histological assessment of hepatocellular carcinoma (HCC), dysplastic nodules (DN), and macroregenerative nodules (MRN) in cirrhotic liver.METHODS: Two hundred and twelve hepatocellular nodules (106 HCC;74 MRN;32 DN) were assessed systematically, quantitatively, and semiquantitatively as appropriate for 10 histological features that have been described as helpful in distinguishing small HCC, DN, and MRN in cirrhotic livers. The data were analyzed by multiple correspondence analysis (MCA).RESULTS: MCA distributed HCC, DN, and MRN as defined by traditional histological evaluation as well as the individual histological variables, in a "malignancy scale".Based on the MCA data representation, we created a classification tool, which categorizes an individual nodular lesion as MRN, DN, or HCC based on the balance of all histological features (i.e., vascular invasion, capsular invasion, tumor necrosis, tumor heterogeneity, reticulin loss,capillarization of sinusoids, trabecular thickness, nuclear atypia, and mitotic activity). The classification tool dassified most (83%) of a validation set of 47 nodules in the same way as the routine histological assessment. No discrepandes were present for DN and MRN between the routine histological assignment and the classification tool. Of 25 HCC assigned by routine assessment in the validation set, 8were assigned to the DN category by the classification tool.CONCLUSION: We have designed a classification tool for the histological assessment of HCC and its putative precursors in cirrhotic liver. Application of this tool systematically records histological features of diagnostic importance in the evaluation of small HCC.

  4. Serum Metabolomics to Identify the Liver Disease-Specific Biomarkers for the Progression of Hepatitis to Hepatocellular Carcinoma

    Science.gov (United States)

    Gao, Rong; Cheng, Jianhua; Fan, Chunlei; Shi, Xiaofeng; Cao, Yuan; Sun, Bo; Ding, Huiguo; Hu, Chengjin; Dong, Fangting; Yan, Xianzhong

    2015-12-01

    Hepatocellular carcinoma (HCC) is a common malignancy that has region specific etiologies. Unfortunately, 85% of cases of HCC are diagnosed at an advanced stage. Reliable biomarkers for the early diagnosis of HCC are urgently required to reduced mortality and therapeutic expenditure. We established a non-targeted gas chromatography-time of flight-mass spectrometry (GC-TOFMS) metabolomics method in conjunction with Random Forests (RF) analysis based on 201 serum samples from healthy controls (NC), hepatitis B virus (HBV), liver cirrhosis (LC) and HCC patients to explore the metabolic characteristics in the progression of hepatocellular carcinogenesis. Ultimately, 15 metabolites were identified intimately associated with the process. Phenylalanine, malic acid and 5-methoxytryptamine for HBV vs. NC, palmitic acid for LC vs. HBV, and asparagine and β-glutamate for HCC vs. LC were screened as the liver disease-specific potential biomarkers with an excellent discriminant performance. All the metabolic perturbations in these liver diseases are associated with pathways for energy metabolism, macromolecular synthesis, and maintaining the redox balance to protect tumor cells from oxidative stress.

  5. A new scoring system for assessment of liver function after successful hepatectomy in patients with hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Zheng-GuiDu; BoLi; Yong-GangWei; JieYin; XiFeng; XiChen

    2011-01-01

    BACKGROUND: Whether a major liver resection is safe has been judged mainly from the patient's hepatic reserve. However, a safe limit for liver resection does not exist yet. This study aimed to construct a new scoring system as a guide to determine a safe limit for liver resection and avoid liver dysfunction after hepatectomy. METHODS: Eighty-six patients with hepatocellular carcinoma who had undergone hepatectomy in West China Hospital from March 2007 to June 2010 were reviewed. The patients were classified according to the levels of total bilirubin after hepatectomy and the parameters in the perioperative period were compared. Receiver operating characteristic (ROC) analysis was made to assess the liver function compensatory (LFC) value to predict liver dysfunction of the patients after hepatectomy. LFC value is defined as the preoperative KICG value×22.487+standard remnant liver volume (SRLV)×0.020. RESULTS: Patients were classified into group I (normal group, n=69) and group II (with total bilirubin >85.5 μmol/L for 7 days after hepatectomy, n=17) based on the levels of total bilirubin after hepatectomy. Group II was further divided into two subgroups: recovered subgroup (n=14) and fatal subgroup (n=3). There were no significant differences in preoperative data or intraoperative findings except the indocyanine green test parameters (KICG and ICG R15) and SRLV. ROC analysis showed that the sensitivity and specificity of an LFC value ≤13.01 were 94.1% and 82.6% respectively for predicting liver dysfunction of the patients after hepatectomy. CONCLUSIONS: The LFC value appears to be a good predictor of postoperative liver dysfunction in patients who undergo hepatectomy for HCC. An expected LFC value of 13.01 seems to be a safe limit for liver resection.

  6. Utilization of metabolomics to identify serum biomarkers for hepatocellular carcinoma in patients with liver cirrhosis

    Energy Technology Data Exchange (ETDEWEB)

    Ressom, Habtom W., E-mail: hwr@georgetown.edu [Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057 (United States); Xiao, Jun Feng; Tuli, Leepika; Varghese, Rency S.; Zhou Bin; Tsai, Tsung-Heng; Nezami Ranjbar, Mohammad R.; Zhao Yi; Wang Jinlian; Di Poto, Cristina; Cheema, Amrita K. [Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057 (United States); Tadesse, Mahlet G. [Department of Mathematics and Statistics, Georgetown University, Washington, DC 20057 (United States); Goldman, Radoslav [Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057 (United States); Shetty, Kirti [Department of Surgery, Georgetown University Medical Center, Washington, DC 20057 (United States); Georgetown University Hospital, Washington, DC 20057 (United States)

    2012-09-19

    Highlights: Black-Right-Pointing-Pointer We analyzed sera from HCC and cirrhotic patients by LC-MS in three experiments. Black-Right-Pointing-Pointer Metabolites with significant and consistent changes in HCC vs. cirrhosis were selected. Black-Right-Pointing-Pointer Verification of the identities of selected metabolites was performed by MS/MS. Black-Right-Pointing-Pointer Quantitation of candidate metabolites was conducted using isotope dilution by SRM. - Abstract: Characterizing the metabolic changes pertaining to hepatocellular carcinoma (HCC) in patients with liver cirrhosis is believed to contribute towards early detection, treatment, and understanding of the molecular mechanisms of HCC. In this study, we compare metabolite levels in sera of 78 HCC cases with 184 cirrhotic controls by using ultra performance liquid chromatography coupled with a hybrid quadrupole time-of-flight mass spectrometry (UPLC-QTOF MS). Following data preprocessing, the most relevant ions in distinguishing HCC cases from patients with cirrhosis are selected by parametric and non-parametric statistical methods. Putative metabolite identifications for these ions are obtained through mass-based database search. Verification of the identities of selected metabolites is conducted by comparing their MS/MS fragmentation patterns and retention time with those from authentic compounds. Quantitation of these metabolites is performed in a subset of the serum samples (10 HCC and 10 cirrhosis) using isotope dilution by selected reaction monitoring (SRM) on triple quadrupole linear ion trap (QqQLIT) and triple quadrupole (QqQ) mass spectrometers. The results of this analysis confirm that metabolites involved in sphingolipid metabolism and phospholipid catabolism such as sphingosine-1-phosphate (S-1-P) and lysophosphatidylcholine (lysoPC 17:0) are up-regulated in sera of HCC vs. those with liver cirrhosis. Down-regulated metabolites include those involved in bile acid biosynthesis (specifically

  7. Indicators of prognosis after liver transplantation in Chinese hepatocellular carcinoma patients

    Institute of Scientific and Technical Information of China (English)

    Jin Li; Lu-Nan Yan; Jian Yang; Zhe-Yu Chen; Bo Li; Yong Zeng; Tian-Fu Wen; Ji-Chun Zhao; Wen-Tao Wang; Jia-Yin Yang; Ming-Qing Xu; Yu-Kui Ma

    2009-01-01

    AIM:To identify prognostic factors of patients with hepatocellular carcinoma (HCC), who were treated by orthotopic liver transplantation (OLT).METHODS: From January 2000 to October 2006,165 patients with HCC underwent OLT. Various clinicopathological risk factors for actuarial and recurrencefree survival were identified using the Kaplan-Meier method with the log-rank test. The Cox proportional hazards model was used to identify independently predictive factors for actuarial and recurrence-free survival, which were used to propose new selection criteria. We compared the outcome of the subgroup patients meeting different criteria. Survival analysis was performed using the Kaplan-Meier method with the log-rank test.RESULTS: The median follow-up was 13.0 mo (2.8-69.5 mo). Overall, 1-, 2-, 3- and 5-year actuarial survival was 73.3%, 45.6%, 35.4% and 32.1%, respectively.One-, 2-, 3- and 5-year overall recurrencefree survival was 67.0%, 44.3%, 34.5% and 34.5%,respectively. In univariate analysis, number of tumors,total tumor size, lobar distribution, differentiation, macrovascular invasion, microvascular invasion, capsulation of the tumor, and lymph node metastasis were found to be associated significantly with actuarial and tumor-free survival. By means of using the multivariate Cox proportional hazards model, total tumor size and macrovascular invasion were found to be independent predictors of actuarial and tumor-free survival. When the selection criteria were expanded into the proposed criteria, there was no significant difference in 1-, 2-, 3- and 5-year actuarial and tumor-free survival of the 49 patients who met the proposed criteria (97.6%, 82.8%, 82.8% and 82.8%, and 90.7%, 82.8%, 68.8% and 68.8%, respectively)compared with that of patients who met the Milan or University of California, San Francisco (UCSF) criteria.CONCLUSION: Macrovascular invasion and total tumor diameter are the strongest prognostic factors.The proposed criteria do not adversely affect the

  8. Interleukin-6 and its soluble receptor in patients with liver cirrhosis and hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Soresi Maurizio; Giannitrapani Lydia; D'Antona Fabio; Florena Ada Maria; La Spada Emanuele; Terranova Angela; Cervello Melchiorre; D'Alessandro Natale; Montalto Giuseppe

    2006-01-01

    AIM: To evaluate the immunohistochemical localization of interleukin-6 (IL-6) and IL-6 receptor (IL-6R) on tumor tissue specimens from patients with hepatocellular carcinoma (HCC) and the serum levels of IL-6 and sIL-6R in a group of patients with HCC as well as liver cirrhosis (LC) in a group of patients with LC alone and in a control group.METHODS: Three groups of subjects were studied:group Ⅰ (n=83) suffering from HCC and LC, group Ⅱ (n=72) suffering from LC alone and group Ⅲ (n =42) as healthy controls. All patients had hepatitis C virus infection. Serum IL-6 and IL-6R levels were determined using a commercially available ELISA kit. Immunohistochemistry was performed using the streptavidin-biotin complex and rabbit polyclonal antibodies against IL-6 and IL-6R.RESULTS: Immunohistochemistry analysis showed a medium to strong cytoplasmic and membrane reactivity for IL-6 and IL-6R respectively, in at least 40% of cases of HCC, whereas liver cirrhosis patients and controls were negative for IL-6 or showed a very mild and focal dot-like cytoplasmic reaction for IL-6R. Serum IL-6 levels in HCC group were significantly higher than those in LC and control groups (P< 0.0001). There was no significant difference in sIL-6R concentrations among 3 groups.When the patients with HCC were divided into groups according to Okuda's classification, a significant serum increase of IL-6 and sIL-6R level was observed from stage Ⅰ to stage Ⅲ (P<0.02, P<0.0005). When HCC and LC patients were divided into 3 classes of cirrhosis severity according to Child-Pugh, values in HCC patients were significantly higher than those in LC patients for each corresponding class (P< 0.01).CONCLUSION: IL-6 serum levels in HCC patients are higher than those in LC patients and controls, suggesting an increased production of this cytokine by neoplastic cells. sIL-6R values are similar in all groups, increasing only in stage Ⅲ HCC patients. These data suggest that they have a closer

  9. Effects of parenteral nutrition with and without GH on the GH/IGF-1 axis after hepatectomy in hepatocellular carcinoma with liver cirrhsis

    Institute of Scientific and Technical Information of China (English)

    CAO Jie; LUO Shimin; LIANG Lijian; LAI Jiaming; CHEN Shanming

    2007-01-01

    Postoperative hepatic insulin-like growth factor-1(IGF-1)production may be severely disturbed in patients with liver cirrhosis.Complex alterations in the GH/IGF-1 axis are thought to play an important role in the protein catabolism that complicates major surgical procedures.The aim of this study was to explore the effects of parenteral nutrition (PN)with and without growth hormone(GH) on the GH/IGF-1 axis after hepatectomy for hepatocellular carcinoma(HCC)with cirrhosis and evaluate the potential roles of recombinant human GH(rhGH)therapy.Twenty-four patients with HCC with cirrhosis who underwent hepatectomy were randomly divided into two groups:a PN group (n=12)and an rhGH+PNgroup(n=12).Liver function,serum GH,IGF-1 and IGFBP-3 were measured before the operation and at postoperative days(POD)1 and 6.Insulin-like growth factor-1 and IGFBP-3 mRNA in the liver tissue was detected by RT-PCR.The liver Ki67 immunohistochemistry staining was studied.At the same time,12 patients with cholelithiasis or liver hemangioma who underwent operation served as normal control group.On POD 6,serum prealbumin,GH,IGF-1,IGFBP-3,hepatic IGF-1 mRNA,IGFBP-3 mRNA and liver Ki67 LI were higher in the rhGH+PN group than in the PN group.There was no significant difference in the 6-and 12-month tumor-free survival rate and the median tumor-free survival time between the PN group and the rhGH+PN group (P>0.05).These data indicate that rhGH+PN could ameliorate the changes in the GH/IGF-1 axis after hepatectomy for HCC in the setting of cirrhosis.

  10. Dermatomyositis associated with hepatocellular carcinoma in an elderly female patient with hepatitis C virus-related liver cirrhosis

    Institute of Scientific and Technical Information of China (English)

    Nobuyuki Toshikuni; Rikako Torigoe; Mikio Mitsunaga; Akiyoshi Omoto; Koji Nakashima

    2006-01-01

    A 79-year-old female patient with hepatitis C virusrelated liver cirrhosis was diagnosed as having hepatocellular carcinoma (HCC) with a diameter of 2.0 cm. She refused therapy for HCC. Nine months after the diagnosis, she developed dermatomyositis when the HCC enlarged to a diameter of 6.0 cm. She underwent therapy for dermatomyositis, and then transcatheter arterial chemoembolization for HCC. Although the manifestations of dermatomyositis improved and entire tumor necrosis was achieved, she died of pneumonia 2 mo after the treatment of HCC. HCC and/or chronic hepatitis C virus infection might be involved in the pathogenesis of dermatormyositis.

  11. Liver fatty acid-binding protein (L-FABP) promotes cellular angiogenesis and migration in hepatocellular carcinoma

    OpenAIRE

    Ku, Chung-Yu; Liu, Yu-Huei; Lin, Hsuan-Yuan; Lu, Shao-Chun; Lin, Jung-Yaw

    2016-01-01

    Liver fatty acid-binding protein (L-FABP) is abundant in hepatocytes and known to be involved in lipid metabolism. Overexpression of L-FABP has been reported in various cancers; however, its role in hepatocellular carcinoma (HCC) remains unclear. In this study, we investigated L-FABP and its association with vascular endothelial growth factors (VEGFs) in 90 HCC patients. We found that L-FABP was highly expressed in their HCC tissues, and that this expression was positively correlated with tha...

  12. Stanniocalcin-1 Reduces Tumor Size in Human Hepatocellular Carcinoma

    Science.gov (United States)

    Yeung, Bonnie H. Y.; Shek, Felix H.; Lee, Nikki P.; Wong, Chris K. C.

    2015-01-01

    Growing evidence has revealed high expression levels of stanniocalcin-1 (STC1) in different types of human cancers. Numerous experimental studies using cancer cell lines demonstrated the involvement of STC1 in inflammatory and apoptotic processes; however the role of STC1 in carcinogenesis remains elusive. Hepatocellular carcinoma (HCC) an exemplified model of inflammation-related cancer, represents a paradigm of studying the association between STC1 and tumor development. Therefore, we conducted a statistical analysis on the expression levels of STC1 using clinicopathological data from 216 HCC patients. We found that STC1 was upregulated in the tumor tissues and its expression levels was positively correlated with the levels of interleukin (IL)-6 and IL-8. Intriguingly tumors with greater expression levels of STC1 (tumor/normal ≥ 2) were significantly smaller than the lower level (tumor/normal<2) samples (p = 0.008). A pharmacological approach was implemented to reveal the functional correlation between STC1 and the ILs in the HCC cell-lines. IL-6 and IL-8 treatment of Hep3B cells induced STC1 expression. Lentiviral-based STC1 overexpression in Hep3B and MHCC-97L cells however showed inhibitory action on the pro-migratory effects of IL-6 and IL-8 and reduced size of tumor spheroids. The inhibitory effect of STC1 on tumor growth was confirmed in vivo using the stable STC1-overexpressing 97L cells on a mouse xenograft model. Genetic analysis of the xenografts derived from the STC1-overexpressing 97L cells, showed upregulation of the pro-apoptotic genes interleukin-12 and NOD-like receptor family, pyrin domain-containing 3. Collectively, the anti-inflammatory and pro-apoptotic functions of STC1 were suggested to relate its inhibitory effect on the growth of HCC cells. This study supports the notion that STC1 may be a potential therapeutic target for inflammatory tumors in HCC patients. PMID:26469082

  13. Stanniocalcin-1 Reduces Tumor Size in Human Hepatocellular Carcinoma.

    Directory of Open Access Journals (Sweden)

    Bonnie H Y Yeung

    Full Text Available Growing evidence has revealed high expression levels of stanniocalcin-1 (STC1 in different types of human cancers. Numerous experimental studies using cancer cell lines demonstrated the involvement of STC1 in inflammatory and apoptotic processes; however the role of STC1 in carcinogenesis remains elusive. Hepatocellular carcinoma (HCC an exemplified model of inflammation-related cancer, represents a paradigm of studying the association between STC1 and tumor development. Therefore, we conducted a statistical analysis on the expression levels of STC1 using clinicopathological data from 216 HCC patients. We found that STC1 was upregulated in the tumor tissues and its expression levels was positively correlated with the levels of interleukin (IL-6 and IL-8. Intriguingly tumors with greater expression levels of STC1 (tumor/normal ≥ 2 were significantly smaller than the lower level (tumor/normal<2 samples (p = 0.008. A pharmacological approach was implemented to reveal the functional correlation between STC1 and the ILs in the HCC cell-lines. IL-6 and IL-8 treatment of Hep3B cells induced STC1 expression. Lentiviral-based STC1 overexpression in Hep3B and MHCC-97L cells however showed inhibitory action on the pro-migratory effects of IL-6 and IL-8 and reduced size of tumor spheroids. The inhibitory effect of STC1 on tumor growth was confirmed in vivo using the stable STC1-overexpressing 97L cells on a mouse xenograft model. Genetic analysis of the xenografts derived from the STC1-overexpressing 97L cells, showed upregulation of the pro-apoptotic genes interleukin-12 and NOD-like receptor family, pyrin domain-containing 3. Collectively, the anti-inflammatory and pro-apoptotic functions of STC1 were suggested to relate its inhibitory effect on the growth of HCC cells. This study supports the notion that STC1 may be a potential therapeutic target for inflammatory tumors in HCC patients.

  14. [Comparison liver resection with transarterial chemoembolization for Barcelona Clinic Liver Cancer stage B hepatocellular carcinoma patients on long-term survival after SPSS propensity score matching].

    Science.gov (United States)

    Ke, Yang; Zhong, Jianhong; Guo, Zhe; Liang, Yongrong; Li, Lequn; Xiang, Bangde

    2014-03-18

    To compare the long-term survival of patients with Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma (HCC) undergoing either liver resection or transarterial chemoembolization (TACE) after propensity score matching (PSM). One hundred sixty-seven and 70 BCLC-B HCC patients undergoing liver resection and TACE were retrospectively collected. PSM function of SPSS software was conducted to reduce confounding bias between the groups. And then survival analysis was performed for the matched data. Fifty-three pairs of patients were successfully matched. And then survival analysis showed that the median survival periods and their 95% confidence intervals were 35.0 (26.3-43.7)months in the liver resection group versus 20.0(15.0-25.0) months in the TACE group. The 1, 3, 5 and 7-year survival rates were 91.0%, 49.0%, 30.0% and 17.0% in the liver resection group versus 73.0%, 25.0%, 8.0% and 5.0% respectively in the TACE group (P = 0.001). Cox regression analysis revealed that TACE, total bilirubin ≥ 34.2 µmol/L, alpha fetoprotein ≥ 400 ng/ml and tumor number ≥ 3 were independent risk factors of survival (hazard ratio >1, P < 0.05). The balance of covariates may be achieved through PSM. And for patients with BCLC-B HCC, liver resection provides better long-term overall survival than TACE.

  15. EXPRESSION AND SIGNIFICANCE OF CYCLIN D1 IN HUMAN HEPATOCELLULAR CARCINOMA

    Institute of Scientific and Technical Information of China (English)

    杨连君; 司晓辉

    2001-01-01

    Objective: To elucidate the expression and significance of cell cycle protein cyclin D1 in human hepatocellular carcinoma (HCC). Methods: The expression of cyclin D1 protein in 29 cases of HCC tissues was detected by immunohistochemical ABC method, and the relationship between its positive rate and pathological grades of HCC tissues was analyzed. Results: The positive rate of cyclin D1 in HCC tissues was 58.6%(17 in 29 cases), whereas only 18.2% (2 cases of 11 cases) in the non-tumor liver tissues immediately adjacent to HCC tissues (LAH). There was significant difference between grade II and LAH tissues (P<0.05), and between grade I and grade III on the positive rate of cyclin D1 (P<0.05), respectively. Conclusion: Cyclin D1 may be regarded as an oncogenic marker during the genesis and development of HCC, and its role in the transforming process from G1 phase to S phase of HCC cells needs further studies.

  16. Overexpression of TRIM24 is associated with the onset and progress of human hepatocellular carcinoma.

    Directory of Open Access Journals (Sweden)

    Xiao Liu

    Full Text Available The survival and colonization of tumor cells at new locations involve a variety of complex genetic, epigenetic, and microenvironmental factors. TRIM24 was originally named transcription intermediary factor 1-alpha (TIF1α, which was associated with cellular proliferation and was an oncogene in tumor development. Here we provide the first evidence of the expression profile and clinicopathological significance of TRIM24 in patients with hepatocellular carcinoma (HCC. Immunohistochemistry was employed to determine the expression level of TRIM24 in HCC tissues and noncancerous liver tissues. Elevated TRIM24 level was found in 61.4% HCC samples (51/83 correlating with AFP (P = 0.036, poor differentiation (P = 0.004, intrahepatic metastasis (P = 0.004, recurrence (P = 0.000006, and shorter tumor-free survival time (P = 0.002. Small interfering RNA induced down-regulation of TRIM24 promoted apoptosis in HCC cell line HepG2. Moreover, western blotting analysis revealed that knockdown of TRIM24 increased the protein levels of p53, Bax, and Caspase-8, and decreased Bcl-2, Survivin, Cyclin D1, and CDK4. Depletion of TRIM24 decreased Snail, Slug, β-catenin, and Vimentin, and increased E-cadherin expression, which suggested the involvement of TRIM24 in EMT. These results indicated that TRIM24 plays an important role in the pathogenesis of human HCC.

  17. Establishment of a high metastatic potential human hepatocellular carcinoma orthotopic transplantation model with palliative liver resection in nude mice%高转移MHCC97H细胞裸鼠原位移植瘤姑息性肝癌切除模型的建立

    Institute of Scientific and Technical Information of China (English)

    黄修燕; 黄自丽; 许永华; 黄新余; 周俭; 叶胜龙; 樊嘉; 汤钊猷; 郑起

    2013-01-01

    Objective To construct a high metastatic potential human hepatocellular carcinoma (HCC)orthotopic transplantation model with palliative liver resection in nude mice.Methods A human HCC orthotopic nude mice model was established by administering a single inoculation of the highly metastatic MHCC97H tumor tissue (size 2 mm × 2 mm × 2 mm) into the left liver lobe.At day 14 post-inoculation,a random group of the mice received palliative liver resection; the unresected mice served as controls.Changes in expression levels of 113 genes with metastasis-related functions were evaluated in the residual HCC tissues.At day 35 post-resection,a random group of the mice were sacrificed by cervical dislocation and a comprehensive metastases examination was performed.The remaining mice were used to observe life span.All statistical analyses were performed by the SPSS v17.0 software,and significance was defined as P < 0.05.Results The nude mouse model of highly metastatic HCC with palliative liver resection was successfully established.Incidences of intrahepatic and abdominal metastases were higher in the palliative resected group (vs.unresected group:11.7 ± 4.7 vs.6.3 ± 2.8,t =-2.412,P < 0.05 and 9.8 ± 3.4 vs.5.2 ± 2.6,t =-2.641,P < 0.05respectively).In addition,the palliative resected group showed significantly enhanced pulmonary metastasis (vs.unresected group:14.3 ± 4.7 vs.8.7 ± 4.7,t =-2.348,P < 0.05).Differential gene expression levels were found for MTSS1,TGFβ1,SMAD2,IL-1β,and MMP7,and were situated in the central position of gene function net of residual HCC.The life-span of the palliative resected group was significantly longer than that of the unresected group (60.8 ± 2.7 vs.51.3 ± 1.4days,x2=12.850,P<0.01).Conclusion The highly metastatic human HCC nude mouse model with palliative liver resection that was successfully constructed in this study represents a useful investigational tool to assess the biological characteristics of residual cancer and to

  18. Doxorubicin-eluting bead vs conventional transcatheter arterial chemoembolization for hepatocellular carcinoma before liver transplantation

    Science.gov (United States)

    Nicolini, Daniele; Svegliati-Baroni, Gianluca; Candelari, Roberto; Mincarelli, Cinzia; Mandolesi, Alessandra; Bearzi, Italo; Mocchegiani, Federico; Vecchi, Andrea; Montalti, Roberto; Benedetti, Antonio; Risaliti, Andrea; Vivarelli, Marco

    2013-01-01

    AIM: To assess the possible effect of two different types of preoperative transcatheter arterial chemoembolization (TACE) on recurrence-free survival after liver transplantation (LT) in patients with hepatocellular carcinoma (HCC) and to analyze the effects of TACE on tumor histology. METHODS: We retrospectively analyzed the histological features of 130 HCC nodules in 63 native livers removed at transplantation. Patients who received any other type of treatment such as radiofrequency tumor ablation, percutaneous ethanol ablation or who were not treated at all were excluded. All patients in the present study were within the Milan Criteria at the last imaging findings before transplantation. Doxorubicin-eluting bead TACE (DEB-TACE) was performed in 22 patients (38 nodules), and conventional TACE (c-TACE) in 16 (25 nodules). Patients’ and tumors’ characteristics were retrospectively reviewed. We performed a per-nodule analysis of the explanted livers to establish the mean percentage of necrosis of any nodule treated by TACE (conventional or DEB) and a per-patient analysis to establish the percentage of necrosis in the cumulative tumor area, including 21 nodules not reached by TACE. Inflammatory and fibrotic changes in the tissue surrounding the tumor nodule were analyzed and categorized as poor/absent, moderate and enhanced reaction. Uni- and multivariate analysis of risk factors for HCC-recurrence were performed. RESULTS: The number and diameter of the nodules, the time spent on the waiting list and the number of treatments were similar in the two groups. A trend towards higher appropriate response rates (necrosis ≥ 90%) was observed in the DEB-TACE group (44.7% vs 32.0%, P = 0.2834). The mean percentage of necrosis in the cumulative tumor area was 58.8% ± 36.6% in the DEB-TACE group and 50.2% ± 38.1% in the c-TACE group (P = 0.4856). Fibrotic and inflammatory reactions surrounding the tumor nodule were markedly more common in the DEB-TACE group (P < 0

  19. New multi protein patterns differentiate liver fibrosis stages and hepatocellular carcinoma in chronic hepatitis C serum samples

    Institute of Scientific and Technical Information of China (English)

    Thomas G(o)bel; Sonja Vorderwülbecke; Katarzyna Hauck; Holger Fey; Dieter H(a)ussinger; Andreas Erhardt

    2006-01-01

    AIM: To identify a multi serum protein pattern as well as single protein markers using surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry (SELDI-TOF-MS) for detection and differentiation of liver fibrosis (F1-F2), liver cirrhosis (F4) and hepatocellular carcinoma (HCC) in patients with chronic hepatitis C virus (HCV).METHODS: Serum samples of 39 patients with F1/F2 fibrosis, 44 patients with F4 fibrosis, 34 patients with HCC were applied to CM10 arrays and analyzed using the SELDI-TOF ProteinChip System (PBS-Ⅱ c; Ciphergen Biosystems) after anion-exchange fractionation. All patients had chronic hepatitis C and histologically confirmed fibrosis stage/HCC. Data were analyzed for protein patterns by multivariate statistical techniques and artificial neural networks.RESULTS: A 4 peptide/protein multimarker panel (7486,12843, 44293 and 53598 Da) correctly identified HCCs with a sensitivity of 100% and specificity of 85% in a two way-comparison of HCV-cirrhosis versus HCV-HCC training samples (AUROC 0.943). Sensitivity and specificity for identification of HCC were 68% and 80% for random test samples. Cirrhotic patients could be discriminated against patients with F1 or F2 fibrosisusing a 5 peptide/protein multimarker pattern (2873,6646, 7775, 10525 and 67867 Da) with a specificity of 100% and a sensitivity of 85% in training samples (AUROC 0.976) and a sensitivity and specificity of 80% and 67% for random test samples. Combination of the biomarker classifiers with APRI score and alfa-fetopotein (AFP) improved the diagnostic performance. The 6646 Da marker protein for liver fibrosis was identified as apolipoprotein C-Ⅰ.CONCLJSION: SELDI-TOF-MS technology combined with protein pattern analysis seems a valuable approach for the identification of liver cirrhosis and hepatocellular carcinoma in patients with chronic hepatitis C. Most probably a combination of different serum markers will help to identify liver cirrhosis and early

  20. Assessment of Liver Function in Patients With Hepatocellular Carcinoma: A New Evidence-Based Approach—The ALBI Grade

    Science.gov (United States)

    Johnson, Philip J.; Berhane, Sarah; Kagebayashi, Chiaki; Satomura, Shinji; Teng, Mabel; Reeves, Helen L.; O'Beirne, James; Fox, Richard; Skowronska, Anna; Palmer, Daniel; Yeo, Winnie; Mo, Frankie; Lai, Paul; Iñarrairaegui, Mercedes; Chan, Stephen L.; Sangro, Bruno; Miksad, Rebecca; Tada, Toshifumi; Kumada, Takashi; Toyoda, Hidenori

    2015-01-01

    Purpose Most patients with hepatocellular carcinoma (HCC) have associated chronic liver disease, the severity of which is currently assessed by the Child-Pugh (C-P) grade. In this international collaboration, we identify objective measures of liver function/dysfunction that independently influence survival in patients with HCC and then combine these into a model that could be compared with the conventional C-P grade. Patients and Methods We developed a simple model to assess liver function, based on 1,313 patients with HCC of all stages from Japan, that involved only serum bilirubin and albumin levels. We then tested the model using similar cohorts from other geographical regions (n = 5,097) and other clinical situations (patients undergoing resection [n = 525] or sorafenib treatment for advanced HCC [n = 1,132]). The specificity of the model for liver (dys)function was tested in patients with chronic liver disease but without HCC (n = 501). Results The model, the Albumin-Bilirubin (ALBI) grade, performed at least as well as the C-P grade in all geographic regions. The majority of patients with HCC had C-P grade A disease at presentation, and within this C-P grade, ALBI revealed two classes with clearly different prognoses. Its utility in patients with chronic liver disease alone supported the contention that the ALBI grade was indeed an index of liver (dys)function. Conclusion The ALBI grade offers a simple, evidence-based, objective, and discriminatory method of assessing liver function in HCC that has been extensively tested in an international setting. This new model eliminates the need for subjective variables such as ascites and encephalopathy, a requirement in the conventional C-P grade. PMID:25512453

  1. The human LIS1 is downregulated in hepatocellular carcinoma and plays a tumor suppressor function

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    Xing, Zhen; Tang, Xin; Gao, Yuan; Da, Liang; Song, Hai; Wang, Suiquan [State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai (China); Tiollais, Pierre [Unite' d' Organisation Nucleaire et Oncogenese, INSERM U.579, Institut Pasteur, Paris (France); Li, Tsaiping [State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai (China); Zhao, Mujun, E-mail: mjzhao@sibs.ac.cn [State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai (China)

    2011-06-03

    Highlights: {yields} LIS1 mRNA and protein levels are decreased in 70% HCC tissues. {yields} Downregulation of LIS1 expression induces oncogenic transformation of QSG7701 and NIH3T3 cells in vitro and in vivo. {yields} LIS1 downregulation leads to mitotic errors including spindle and chromosome defects. {yields} Ectopic expression of LIS1 could significantly inhibit HCC cell proliferation and colony formation. {yields} Our results suggest that LIS1 plays a potential tumor suppressor role in the development and progression of HCC. -- Abstract: The human lissencephaly-1 gene (LIS1) is a disease gene responsible for Miller-Dieker lissencephaly syndrome (MDL). LIS1 gene is located in the region of chromosome 17p13.3 that is frequency deleted in MDL patients and in human liver cancer cells. However, the expression and significance of LIS1 in liver cancer remain unknown. Here, we investigated the expression of LIS1 in hepatocellular carcinoma (HCC) tissues by real-time PCR, Western blot, and immunohistochemistry. The results indicated that the mRNA and protein levels of LIS1 were downregulated in about 70% of HCC tissues, and this downregulation was significantly associated with tumor progression. Functional studies showed that the reduction of LIS1 expression in the normal human liver cell line QSG7701 or the mouse fibroblast cell line NIH3T3 by shRNA resulted in colony formation in soft agar and xenograft tumor formation in nude mice, demonstrating that a decrease in the LIS1 level can promote the oncogenic transformation of cells. We also observed that the phenotypes of LIS1-knockdown cells displayed various defective mitotic structures, suggesting that the mechanism by which reduced LIS1 levels results in tumorigenesis is associated with its role in mitosis. Furthermore, we demonstrated that ectopic expression of LIS1 could significantly inhibit HCC cell proliferation and colony formation. Our results suggest that LIS1 plays a potential tumor suppressor role in the

  2. Combined detection of liver stiffness and C-reactive protein in patients with hepatitis B virus-related liver cirrhosis, with and without hepatocellular carcinoma.

    Science.gov (United States)

    Liu, Xiao-Yan; Ma, Li-Na; Yan, Ting-Ting; Lu, Zhen-Hui; Tang, Yuan-Yuan; Luo, Xia; Ding, Xiang-Chun

    2016-04-01

    The aim of the present study was to investigate the usefulness of combined detection of liver stiffness (LS) and serum C-reactive protein (CRP) level in patients with hepatitis B virus (HBV)-related liver cirrhosis (LC). A total of 156 cases of previously untreated patients with HBV-related LC were classified into the LC group [LC without hepatocellular carcinoma (HCC)] and the HCC group (LC with HCC). Comparative analyses of LS and serum CRP level were conducted between these two groups. LS values and serum CRP levels were found to be significantly higher in the HCC group compared with those in the LC group (PHBV-related HCC, improve the identification of patients with AFP-negative HCC and help distinguish HCC from LC.

  3. Insulin resistance, steatohepatitis, and hepatocellular carcinoma in a new congenic strain of Fatty Liver Shionogi (FLS) mice with the Lep(ob) gene.

    Science.gov (United States)

    Soga, Masahiko; Hashimoto, Setsuko; Kishimoto, Yoshio; Hirasawa, Tsutomu; Makino, Susumu; Inagaki, Shuichiro

    2010-01-01

    In order to examine the influence of obesity on metabolic disorder and liver pathogenesis of the Fatty Liver Shionogi (FLS) mouse, which develops hereditary fatty liver and spontaneous liver tumors, we established a new congenic strain named FLS-Lep(ob). The Lep(ob) gene of the C57BL/6JWakShi (B6)-Lep(ob)/Lep(ob) mouse was transferred into the genome of the FLS mouse, by backcross mating. FLS-Lep(ob)/Lep(ob) mice were maintained by intercrossing between Lep(ob)-heterozygous littermates. The FLS-Lep(ob)/Lep(ob) mice of both sexes developed remarkable hyperphagia, obesity and type 2 diabetes mellitus. At 12 weeks of age, glucosuria was detected in all male and female FLS-Lep(ob)/Lep(ob) mice. Biochemical examination demonstrated that the FLS-Lep(ob)/Lep(ob) mice have severe hyperlipidemia and hyperinsulinemia. The livers of FLS-Lep(ob)/Lep(ob) mice showed microvesicular steatosis and deposition of large lipid droplets in hepatocytes throughout the lobules. The steatohepatitis-like lesions including the multifocal mononuclear cell infiltration and clusters of foamy cells were observed earlier in FLS-Lep(ob)/ Lep(ob) mice than in FLS mice. B6-Lep(ob)/Lep(ob) mice did not show hepatic inflammatory change. Furthermore, FLS-Lep(ob)/Lep(ob) mice developed multiple hepatic tumors including hepatocellular adenomas and carcinomas following steatohepatitis. In conclusion, the FLS-Lep(ob)/Lep(ob) mice developed steatohepatitis and hepatic tumors following hepatic steatosis. The FLS-Lep(ob)/Lep(ob) mouse with obesity and type 2 diabetes mellitus might be a useful animal model for human non-alcoholic steatohepatitis (NASH).

  4. Hepatocellular Carcinoma Metastasis to the Orbit in a Coinfected HIV+ HBV+ Patient Previously Treated with Orthotopic Liver Transplantation: A Case Report

    Directory of Open Access Journals (Sweden)

    S. Guerriero

    2011-01-01

    Full Text Available Hepatocellular carcinoma rarely metastasizes to the orbit. We report a 45-year-old male, HBV+, HIV+, with a past history of a liver transplant for ELSD (end-stage liver disease with hepatocellular carcinoma and recurrent HCC, who presented with proptosis and diplopia of the left eye. CT scans of the head revealed a large, irregular mass in the left orbit causing superior and lateral destruction of the orbital bone. Biopsy specimens of the orbital tumor showed features of metastatic foci of hepatocellular carcinoma. Only 16 other cases of HCC metastasis to the orbit have been described in literature, and this is the first case in a previously transplanted HIV+, HBV+ patient.

  5. Gene expression and pathway analysis of human hepatocellular carcinoma cells treated with cadmium

    Science.gov (United States)

    Cartularo, Laura; Laulicht, Freda; Sun, Hong; Kluz, Thomas; Freedman, Jonathan H.; Costa, Max

    2015-01-01

    Cadmium (Cd) is a toxic and carcinogenic metal naturally occurring in the earth’s crust. A common route of human exposure is via diet and cadmium accumulates in the liver. The effects of Cd exposure on gene expression in human hepatocellular carcinoma (HepG2) cells were examined in this study. HepG2 cells were acutely-treated with 0.1, 0.5, or 1.0 μM Cd for 24 hours; or chronically-treated with 0.01, 0.05, or 0.1 μM Cd for three weeks and gene expression analysis was performed using Affymetrix GeneChip® Human Gene 1.0 ST Arrays. Acute and chronic exposures significantly altered the expression of 333 and 181 genes, respectively. The genes most upregulated by acute exposure included several metallothioneins. Downregulated genes included the monooxygenase CYP3A7, involved in drug and lipid metabolism. In contrast, CYP3A7 was upregulated by chronic Cd exposure, as was DNAJB9, an anti-apoptotic J protein. Genes downregulated following chronic exposure included the transcriptional regulator early growth response protein 1. Ingenuity Pathway Analysis revealed that the top networks altered by acute exposure were lipid metabolism, small molecule biosynthesis, and cell morphology, organization, and development; while top networks altered by chronic exposure were organ morphology, cell cycle, cell signaling, and renal and urological diseases/cancer. Many of the dysregulated genes play important roles in cellular growth, proliferation, and apoptosis, and may be involved in carcinogenesis. In addition to gene expression changes, HepG2 cells treated with cadmium for 24 hours indicated a reduction in global levels of histone methylation and acetylation that persisted 72 hours post-treatment. PMID:26314618

  6. Comparative Study of Human Liver Ferritin and Chicken Liver by Moessbauer Spectroscopy. Preliminary Results

    Energy Technology Data Exchange (ETDEWEB)

    Oshtrakh, M. I. [Ural State Technical University - UPI, Division of Applied Biophysics, Faculty of Physical Techniques and Devices for Quality Control (Russian Federation); Milder, O. B.; Semionkin, V. A. [Ural State Technical University - UPI, Faculty of Experimental Physics (Russian Federation); Prokopenko, P. G. [Russian State Medical University, Faculty of Biochemistry (Russian Federation); Malakheeva, L. I. [Simbio Holding, Science Consultation Department (Russian Federation)

    2004-12-15

    A comparative study of normal human liver ferritin and livers from normal chicken and chicken with Marek disease was made by Moessbauer spectroscopy. Small differences of quadrupole splitting and isomer shift were found for human liver ferritin and chicken liver. Moessbauer parameters for liver from normal chicken and chicken with Marek disease were the same.

  7. Comparative Study of Human Liver Ferritin and Chicken Liver by Mössbauer Spectroscopy. Preliminary Results

    Science.gov (United States)

    Oshtrakh, M. I.; Milder, O. B.; Semionkin, V. A.; Prokopenko, P. G.; Malakheeva, L. I.

    2004-12-01

    A comparative study of normal human liver ferritin and livers from normal chicken and chicken with Marek disease was made by Mössbauer spectroscopy. Small differences of quadrupole splitting and isomer shift were found for human liver ferritin and chicken liver. Mössbauer parameters for liver from normal chicken and chicken with Marek disease were the same.

  8. Overexpression of Cyclooxygenase-2 in Noncancerous Liver Tissue Increases the Postoperative Recurrence of Hepatocellular Carcinoma in Patients with Hepatitis B Virus-Related Cirrhosis

    Directory of Open Access Journals (Sweden)

    Yi-Fu He

    2010-01-01

    Full Text Available BACKGROUND: Many previous studies have evaluated the histopathological features of tumours as risk factors for postoperative recurrence in hepatitis B virus (HBV-associated hepatocellular carcinoma (HCC. However, there have been few large studies investigating the relationship between cyclooxygenase-2 (COX-2 expression in non-cancerous regions of the liver and postoperative recurrence in the remnant liver, especially in HBV-related HCC.

  9. Acyclic retinoid in chemoprevention of hepatocellular carcinoma: Targeting phosphorylated retinoid X receptor-α for prevention of liver carcinogenesis

    Directory of Open Access Journals (Sweden)

    Masahito Shimizu

    2012-01-01

    Full Text Available One of the key features of hepatocellular carcinoma (HCC is the high rate of intrahepatic recurrence that correlates with poor prognosis. Therefore, in order to improve the clinical outcome for patients with HCC, development of a chemopreventive agent that can decrease or delay the incidence of recurrence is a critical issue for urgent investigation. Acyclic retinoid (ACR, a synthetic retinoid, successfully improves HCC patient survival by preventing recurrence and the formation of secondary tumors. A malfunction of the retinoid X receptor-α (RXRα due to phosphorylation by the Ras-MAPK signaling pathway plays a critical role in liver carcinogenesis, and ACR exerts chemopreventive effects on HCC development by inhibiting RXRα phosphorylation. Here, we review the relationship between retinoid signaling abnormalities and liver disease, the mechanisms of how RXRα phosphorylation contributes to liver carcinogenesis, and the detailed effects of ACR on preventing HCC development, especially based on the results of our basic and clinical research. We also outline the concept of "clonal deletion and inhibition" therapy, which is defined as the removal and inhibition of latent malignant clones from the liver before they expand into clinically detectable HCC, because ACR prevents the development of HCC by implementing this concept. Looking toward the future, we discuss "combination chemoprevention" using ACR as a key drug since it can generate a synergistic effect, and may thus be an effective new strategy for the prevention of HCC.

  10. Mechanaism of 5—fluorouracil required resistance in human hepatocellular carcinoma cell line Bel7402

    Institute of Scientific and Technical Information of China (English)

    JingJin; MinHuang; Huai-LingWei; Geng-TaoLiu

    2002-01-01

    AIM:To investigate the resistance mechanism of 5-fluorouracil(5-FU)in Bel7402/5-FU cells which was established in our lab by in vitro continuous stepwise exposure of human hepatocellular carnoma(HCC) cell line Bel7402 to 5-FU.

  11. AGE WISE HISTOMORPHOLOGICAL CHANGES IN HUMAN LIVER

    Directory of Open Access Journals (Sweden)

    Tribeni

    2015-11-01

    Full Text Available CONTEXT: Hepato cellular carcinoma (HCC results in between 2.5 lakhs to 1million deaths globally per annum. Liver transplantation nowadays is a well accepted treatment option for end-stage liver disease and acute liver failure. AIMS: Keeping this concept in view, a study was conducted in the Guwahati Zone of Northeast India, to compare the histomorphological features of the human liver in different age groups. SETTING AND DESIGN: Apparently healthy livers were obtained from 21 subjects on whom medicolegal post-mortems had been performed. Their ages varied from newborn to 90 years. Subjects were divided into 3 groups. 7 specimens were taken from each group. (1 Pediatric (2 Adult (3 Old age. METHODS AND MATERIALS: In all the above age groups, immediately after removal of the livers, they were washed in normal saline, dried with blotting paper and weighed in an electronic weighing machine. Sections of liver were fixed, processed, cut and stained with Harris Haematoxylin and Eosin stain. RESULTS: The liver loses weight from 50 years onwards. There appears to be racial and environmental differences in the change in liver weight in old age. Autopsy studies show a diminution of nearly 46% in liver weight between the 3rd and 10th decades of life. The liver decreases in size with age. The hepatocytes are radially disposed in the liver lobule. They are piled up, forming a layer one cell thick (except in young children in a fashion similar to the bricks of a wall. These plates are directed from the periphery of the lobule to its centre and anastomose freely forming a complex labyrinthine and sponge-like structure. CONCLUSIONS: From the findings in the present study it can be concluded that: 1. Nowadays, the measurement of liver volume has gained practical use in relation to liver transplantation. 2. We have compared the histomorphology of adult liver with a child. The findings in both the groups are very similar. This feature is important, since in

  12. Expression of transforming growth factor-α and hepatitis B surface antigen in human hepatocellular carcinoma tissues and its significance

    Institute of Scientific and Technical Information of China (English)

    Jing Zhang; Wen-Liang Wang; Qing Li; Qing Qiao

    2004-01-01

    AIM: To evaluate the expression of transforming growth factor-alpha (TGF-α) and hepatitis B surface antigen (HBsAg) in human hepatocellular carcinoma (HCC) tissues and its significance. METHODS: Seventy specimens of HCC tissues were detected by immunohistochemical method. Five specimens of normal human liver tissues were used as control. RESULTS: The TGF-α positive expression rates in HCC and its surrounding tissues were 74.3%(52/70) and 88. t%(52/59), respectively. TGF-α positive granules were mainly in the cytoplasm and fewer existed on the karyotheca. The TGF-α positive expressing rate in well differentiated HCC was significantly higher than that in moderately and poorly differentiated HCC (P<0.05). The TGF-α positive expression also was observed in intrahepatic bile ducts (part of those were hyperplastic ducts). The HBsAg positive expression rates in HCC and its surrounding tissues were 21.4%(15/70) and 79.7%(47/59), respectively. HBsAg positive granules were in the cytoplasm, inclusion and on the karyotheca. There was a prominent positive correlation between TGF-α and HBsAg expression in HCC surrounding tissues (P<0.05, γ=0.34). TGF-α was usually existed with HBsAg in regenerated and/or dysplastic liver cells. In the five normal liver tissues, TGF-α and HBsAg were not detectable in hepatocytes and bile ducts.CONCLUSION: Hepatitis B virus infection is closely related with hepatocarcinogenesis. The overexpression of TGF-α in the liver seems to be associated with the regeneration of hepatocytes injured by HBsAg. The continued expression of TGF-α might lead to dysplasia of liver cells and development of HCC. Furthermore, TGF-α might play a role in morphogenesis and regeneration of intrahepatic bile ducts.

  13. Meta-analysis of laparoscopic vs open liver resection for hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Jun-Jie Xiong; Kiran Altaf; Muhammad A Javed; Wei Huang; Rajarshi Mukherjee; Gang Mai; Robert Sutton

    2012-01-01

    AIM:To conduct a meta-analysis to determine the safety and efficacy of laparoscopic liver resection (LLR)and open liver resection (OLR) for hepatocellular carcinoma (HCC).METHODS:PubMed (Medline),EMBASE and Science Citation Index Expanded and Cochrane Central Register of Controlled Trials in the Cochrane Library were searched systematically to identify relevant comparative studies reporting outcomes for both LLR and OLR for HCC between January 1992 and February 2012.Two authors independently assessed the trials for inclusion and extracted the data.Meta-analysis was performed using Review Manager Version 5.0 software (The Cochrane Collaboration,Oxford,United Kingdom).Pooled odds ratios (OR) or weighted mean differences (WMD) with 95%CI were calculated using either fixed effects (Mantel-Haenszel method) or random effects models (DerSimonian and Laird method).Evaluated endpoints were operative outcomes (operation time,intraoperative blood loss,blood transfusion requirement),postoperative outcomes (liver failure,cirrhotic decompensation/ascites,bile leakage,postoperative bleeding,pulmonary complications,intraabdominal abscess,mortality,hospital stay and oncologic outcomes (positive resection margins and tumor recurrence).RESULTS:Fifteen eligible non-randomized studies were identified,out of which,9 high-quality studies involving 550 patients were included,with 234 patients in the LLR group and 316 patients in the OLR group.LLR was associated with significantly lower intraoperative blood loss,based on six studies with 333 patients [WMD:-129.48 mL; 95%CI:-224.76-(-34.21) mL; P =0.008].Seven studies involving 416 patients were included to assess blood transfusion requirement between the two groups.The LLR group had lower blood transfusion requirement (OR:0.49; 95%CI:0.26-0.91;P =0.02).While analyzing hospital stay,six studies with 333 patients were included.Patients in the LLR group were found to have shorter hospital stay [WMD:-3.19 d; 95%CI:-4.09-(-2.28) d; P

  14. Inhibition of tumor growth and metastasis with antisense oligonucleotides(Cantide) targeting hTERT in an in situ human hepatocellular carcinoma model

    Institute of Scientific and Technical Information of China (English)

    Ru-xian LIN; Chao-wei TUO; Qiu-jun L(u); Wei ZHANG; Sheng-qi WANG

    2005-01-01

    Aim: To evaluate the in vivo antitumor effects of Cantide and the combined effect with 5-fluorouracil. Methods: An in situ human hepatocellular carcinoma model was established in mice livers orthotopically. Drugs were administered intravenously and tumor sizes were monitored with calipers. Plasma alpha-fetoprotein (AFP) were detected by radiation immunoassay. Morphology of tumors was evaluated by hematoxylin-eosin (H&E) staining of histological sections. Human telomerase reverse transcriptase (hTERT) protein levels were detected by Western blotting. Results: Cantide significantly inhibit in situ human hepatocellular compared to the saline group in a dose-dependent manner, which included injectthe tumor in liver. Cantide was also found to prevent tumor recurrence in the liver and metastasis in the lung, showing a dose-dependent response. When Cantide was administered by iv combined with 5-fluorouracil, it resulted in a significant reduction in tumor growth compared to either agent alone treatment group. After the treatment with Cantide alone or combined with 5-fluorouracil, plasma AFP concentration decreased in a dose-dependent manner. Conclusion: These results demonstrated that Cantide was an effective antitumor antisense oligonucleotide in vivo and has the potential to be developed into a clinical anti-cancer drug.

  15. Human liver tumors in relation to steroidal usage.

    Science.gov (United States)

    Barrows, G H; Christopherson, W M

    1983-01-01

    Since 1973 a number of investigators have reported an association between liver neoplasia and steroid usage. Through referral material we have examined the histology of over 250 cases of hepatic neoplasia, most in patients receiving steroid medications. The majority have been benign, predominantly focal nodular hyperplasia (55%) and hepatocellular adenoma (39%). The average age was 31.4 years; 83% had significant steroid exposure with an average duration of 71 months for focal nodular hyperplasia and 79.6 months for hepatocellular adenoma. The type of estrogenic agent was predominantly mestranol; however, during the period mestranol was the most frequently used synthetic steroid. A distinct clinical entity of life threatening hemorrhage from the lesion occurred in 31% of patients with hepatocellular adenoma and 9% of patients with focal nodular hyperplasia. Recurrence of benign tumors has occurred in some patients who continued using steroids and regression has been observed in patients who had incomplete tumor removal but discontinued steroid medication. Medial and intimal vascular changes have been present in a large number of the benign tumors. The relationship of these vascular changes to oncogenesis is unclear, but similar lesions have been described in the peripheral vasculature associated with steroid administration. A number of hepatocellular carcinomas have also been seen. Of significance is the young age of these patients and lack of abnormal histology in adjacent nonneoplastic liver. A striking number of the malignant hepatocellular tumors have been of the uncommon type described as "eosinophilic hepatocellular carcinoma with lamellar fibrosis." The epidemiology of liver lesions within this series is difficult to assess, since the material has been referred from very diverse locations. Images FIGURE 1. FIGURE 2. FIGURE 3. FIGURE 4. FIGURE 5. FIGURE 6. FIGURE 7. PMID:6307679

  16. SU-E-J-260: Quantitative Image Feature Analysis of Multiphase Liver CT for Hepatocellular Carcinoma (HCC) in Radiation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Choi, W; Wang, J; Lu, W [University of Maryland School of Medicine, Baltimore, MD (United States); Kang, M [University of Maryland School of Medicine, Baltimore, MD (United States); Yeungnam University Medical Center, Daegu (Korea, Republic of)

    2015-06-15

    Purpose: To identify the effective quantitative image features (radiomics features) for prediction of response, survival, recurrence and metastasis of hepatocellular carcinoma (HCC) in radiotherapy. Methods: Multiphase contrast enhanced liver CT images were acquired in 16 patients with HCC on pre and post radiation therapy (RT). In this study, arterial phase CT images were selected to analyze the effectiveness of image features for the prediction of treatment outcome of HCC to RT. Response evaluated by RECIST criteria, survival, local recurrence (LR), distant metastasis (DM) and liver metastasis (LM) were examined. A radiation oncologist manually delineated the tumor and normal liver on pre and post CT scans, respectively. Quantitative image features were extracted to characterize the intensity distribution (n=8), spatial patterns (texture, n=36), and shape (n=16) of the tumor and liver, respectively. Moreover, differences between pre and post image features were calculated (n=120). A total of 360 features were extracted and then analyzed by unpaired student’s t-test to rank the effectiveness of features for the prediction of response. Results: The five most effective features were selected for prediction of each outcome. Significant predictors for tumor response and survival are changes in tumor shape (Second Major Axes Length, p= 0.002; Eccentricity, p=0.0002), for LR, liver texture (Standard Deviation (SD) of High Grey Level Run Emphasis and SD of Entropy, both p=0.005) on pre and post CT images, for DM, tumor texture (SD of Entropy, p=0.01) on pre CT image and for LM, liver (Mean of Cluster Shade, p=0.004) and tumor texture (SD of Entropy, p=0.006) on pre CT image. Intensity distribution features were not significant (p>0.09). Conclusion: Quantitative CT image features were found to be potential predictors of the five endpoints of HCC in RT. This work was supported in part by the National Cancer Institute Grant R01CA172638.

  17. Genome-wide transcriptional reorganization associated with senescence-to-immortality switch during human hepatocellular carcinogenesis.

    Science.gov (United States)

    Yildiz, Gokhan; Arslan-Ergul, Ayca; Bagislar, Sevgi; Konu, Ozlen; Yuzugullu, Haluk; Gursoy-Yuzugullu, Ozge; Ozturk, Nuri; Ozen, Cigdem; Ozdag, Hilal; Erdal, Esra; Karademir, Sedat; Sagol, Ozgul; Mizrak, Dilsa; Bozkaya, Hakan; Ilk, Hakki Gokhan; Ilk, Ozlem; Bilen, Biter; Cetin-Atalay, Rengul; Akar, Nejat; Ozturk, Mehmet

    2013-01-01

    Senescence is a permanent proliferation arrest in response to cell stress such as DNA damage. It contributes strongly to tissue aging and serves as a major barrier against tumor development. Most tumor cells are believed to bypass the senescence barrier (become "immortal") by inactivating growth control genes such as TP53 and CDKN2A. They also reactivate telomerase reverse transcriptase. Senescence-to-immortality transition is accompanied by major phenotypic and biochemical changes mediated by genome-wide transcriptional modifications. This appears to happen during hepatocellular carcinoma (HCC) development in patients with liver cirrhosis, however, the accompanying transcriptional changes are virtually unknown. We investigated genome-wide transcriptional changes related to the senescence-to-immortality switch during hepatocellular carcinogenesis. Initially, we performed transcriptome analysis of senescent and immortal clones of Huh7 HCC cell line, and identified genes with significant differential expression to establish a senescence-related gene list. Through the analysis of senescence-related gene expression in different liver tissues we showed that cirrhosis and HCC display expression patterns compatible with senescent and immortal phenotypes, respectively; dysplasia being a transitional state. Gene set enrichment analysis revealed that cirrhosis/senescence-associated genes were preferentially expressed in non-tumor tissues, less malignant tumors, and differentiated or senescent cells. In contrast, HCC/immortality genes were up-regulated in tumor tissues, or more malignant tumors and progenitor cells. In HCC tumors and immortal cells genes involved in DNA repair, cell cycle, telomere extension and branched chain amino acid metabolism were up-regulated, whereas genes involved in cell signaling, as well as in drug, lipid, retinoid and glycolytic metabolism were down-regulated. Based on these distinctive gene expression features we developed a 15-gene

  18. Connective tissue growth factor is overexpressed in human hepatocellular carcinoma and promotes cell invasion and growth

    Institute of Scientific and Technical Information of China (English)

    Ming Xiu; Ya-Hui Liu; David R Brigstock; Fang-Hui He; Rui-Juan Zhang; Run-Ping Gao

    2012-01-01

    AIM:To determine the expression characteristics of connective tissue growth factor (CTGF/CCN2) in human hepatocellular carcinoma (HCC) in histology and to elucidate the roles of CCN2 on hepatoma cell cycle progression and metastasis in vitro.METHODS:Liver samples from 36 patients (who underwent hepatic resection for the first HCC between 2006 and 2011) and 6 normal individuals were examined for transforming growth factor β1 (TGF-β1) or CCN2 mRNA by in situ hybridization.Computer image analysis was performed to measure integrated optimal density of CCN2 mRNA-positive cells in carcinoma foci and the surrounding stroma.Fibroblast-specific protein-1 (FSP-1) and E-cadherin were examined to evaluate the process of epithelial to mesenchymal transition,α-smooth muscle actin and FSP-1 were detected to identify hepatic stellate cells,and CD34 was measured to evaluate the extent of vascularization in liver tissues by immunohistochemical staining.CCN2 was assessed for its stimulation of HepG2 cell migration and invasion using commercial kits while flow cytometry was used to determine CCN2 effects on HepG2 cell-cycle.RESULTS:In situ hybridization analysis showed that TGF-β1 mRNA was mainly detected in connective tissues and vasculature around carcinoma foci.In comparison to normal controls,CCN2 mRNA was enhanced 1.9-fold in carcinoma foci (12.36 ± 6.08 vs 6.42 ± 2.35)or 9.4-fold in the surrounding stroma (60.27 ± 28.71 vs 6.42 ± 2.35),with concomitant expression of CCN2 and TGF-β1 mRNA in those areas.Epithelial-mesenchymal transition phenotype related with CCN2 was detected in 12/36 (33.3%) of HCC liver samples at the edges between carcinoma foci and vasculature.Incubation of HepG2 cells with CCN2 (100 ng/mL) resulted in more of the cells transitioning into S phase (23.85 ± 2.35vs 10.94 ± 0.23),and induced a significant migratory (4.0-fold) and invasive (5.7-fold) effect.TGF-β1-induced cell invasion was abrogated by a neutralizing CCN2 antibody showing that CCN2

  19. Liver immune-pathogenesis and therapy of human liver tropic virus infection in humanized mouse models.

    Science.gov (United States)

    Bility, Moses T; Li, Feng; Cheng, Liang; Su, Lishan

    2013-08-01

    Hepatitis B virus (HBV) and hepatitis C virus (HCV) infect and replicate primarily in human hepatocytes. Few reliable and easy accessible animal models are available for studying the immune system's contribution to the liver disease progression during hepatitis virus infection. Humanized mouse models reconstituted with human hematopoietic stem cells (HSCs) have been developed to study human immunology, human immunodeficiency virus 1 infection, and immunopathogenesis. However, a humanized mouse model engrafted with both human immune and human liver cells is needed to study infection and immunopathogenesis of HBV/HCV infection in vivo. We have recently developed the humanized mouse model with both human immune and human liver cells (AFC8-hu HSC/Hep) to study immunopathogenesis and therapy of HCV infection in vivo. In this review, we summarize the current models of HBV/HCV infection and their limitations in immunopathogenesis. We will then present our recent findings of HCV infection and immunopathogenesis in the AFC8-hu HSC/Hep mouse, which supports HCV infection, human T-cell response and associated liver pathogenesis. Inoculation of humanized mice with primary HCV isolates resulted in long-term HCV infection. HCV infection induced elevated infiltration of human immune cells in the livers of HCV-infected humanized mice. HCV infection also induced HCV-specific T-cell immune response in lymphoid tissues of humanized mice. Additionally, HCV infection induced liver fibrosis in humanized mice. Anti-human alpha smooth muscle actin (αSMA) staining showed elevated human hepatic stellate cell activation in HCV-infected humanized mice. We discuss the limitation and future improvements of the AFC8-hu HSC/Hep mouse model and its application in evaluating novel therapeutics, as well as studying both HCV and HBV infection, human immune responses, and associated human liver fibrosis and cancer.

  20. Is there a standard for surgical therapy of hepatocellular carcinoma in healthy and cirrhotic liver? A comparison of eight guidelines.

    Science.gov (United States)

    Manzini, Giulia; Henne-Bruns, Doris; Porzsolt, Franz; Kremer, Michael

    2017-01-01

    Liver resection (LR) and transplantation are the most reliable treatments for hepatocellular carcinoma (HCC). Aim was to compare different guidelines regarding indication for resection and transplantation because of HCC with and without underlying cirrhosis. We compared the following guidelines published after 1 January 2010: American (American Association for the Study of Liver Diseases (AASLD)), Spanish (Sociedad Espanola de Oncologia Medica (SEOM)), European (European Association for the study of liver-European Organization for Research and Treatment of Cancer (EASL-EORTC) and European Society for Medical Oncology-European Society of Digestive Oncology (ESMO-ESDO)), Asian (Asian Pacific Association for the Study of Liver (APASL)), Japanese (Japan Society of Hepatology (JSH)), Italian (Associazione Italiana Oncologia Medica (AIOM)) and German (S3) guidelines. All guidelines recommend resection as therapy of choice in healthy liver. Guidelines based on the Barcelona Clinic Liver Cancer staging system recommend resection for single HCC<2 cm and Child-Pugh A cirrhosis and for HCC≤5 cm with normal bilirubin and portal pressure, whereas transplantation is recommended for multiple tumours between Milan criteria and for single tumours ≤5 cm and advanced liver dysfunction. Patients with HCC and Child-Pugh C cirrhosis are not candidates for transplantation. JSH guidelines recommend LR for patients with Child-Pugh A/B with HCC without tumour size restriction; APASL guidelines in general exclude patients with Child-Pugh A from transplantation. In patients with Child-Pugh B, transplantation is the second-line therapy, if resection is not possible for patients within Milan criteria. German and Italian guidelines recommend transplantation for all patients within Milan criteria. Whereas resection is the standard therapy of HCC in healthy liver, a standard regarding the indication for LR and transplantation for HCC in cirrhotic liver does not exist, although nearly all

  1. 2014 Korean Liver Cancer Study Group-National Cancer Center Korea Practice Guideline for the Management of Hepatocellular Carcinoma

    Science.gov (United States)

    2015-01-01

    The guideline for the management of hepatocellular carcinoma (HCC) was first developed in 2003 and revised in 2009 by the Korean Liver Cancer Study Group and the National Cancer Center, Korea. Since then, many studies on HCC have been carried out in Korea and other countries. In particular, a substantial body of knowledge has been accumulated on diagnosis, staging, and treatment specific to Asian characteristics, especially Koreans, prompting the proposal of new strategies. Accordingly, the new guideline presented herein was developed on the basis of recent evidence and expert opinions. The primary targets of this guideline are patients with suspicious or newly diagnosed HCC. This guideline provides recommendations for the initial treatment of patients with newly diagnosed HCC. PMID:25995680

  2. 2014 Korean Liver Cancer Study Group-National Cancer Center Korea practice guideline for the management of hepatocellular carcinoma.

    Science.gov (United States)

    2015-01-01

    The guideline for the management of hepatocellular carcinoma (HCC) was first developed in 2003 and revised in 2009 by the Korean Liver Cancer Study Group and the National Cancer Center, Korea. Since then, many studies on HCC have been carried out in Korea and other countries. In particular, a substantial body of knowledge has been accumulated on diagnosis, staging, and treatment specific to Asian characteristics, especially Koreans, prompting the proposal of new strategies. Accordingly, the new guideline presented herein was developed on the basis of recent evidence and expert opinions. The primary targets of this guideline are patients with suspicious or newly diagnosed HCC. This guideline provides recommendations for the initial treatment of patients with newly diagnosed HCC.

  3. Arterio-portal shunts in the cirrhotic liver: perfusion computed tomography for distinction of arterialized pseudolesions from hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Fischer, Michael A. [University Hospital Zurich, Department of Diagnostic and Interventional Radiology, Zurich (Switzerland); Karolinska Institutet, Division of Medical Imaging and Technology. Department of Clinical Science, Intervention and Technology (CLINTEC), Stockholm (Sweden); Marquez, Herman P.; Gordic, Sonja; Alkadhi, Hatem [University Hospital Zurich, Department of Diagnostic and Interventional Radiology, Zurich (Switzerland); Leidner, Bertil; Aspelin, Peter; Brismar, Torkel B. [Karolinska Institutet, Division of Medical Imaging and Technology. Department of Clinical Science, Intervention and Technology (CLINTEC), Stockholm (Sweden); Klotz, Ernst [Computed Tomography and Radiation Oncology, Siemens Healthcare, Forchheim (Germany)

    2017-03-15

    To determine perfusion computed tomography (P-CT) findings for distinction of arterial pseudolesions (APL) from hepatocellular carcinoma (HCC) in the cirrhotic liver. 32 APL and 21 HCC in 20 cirrhotic patients (15 men; 65 ± 10 years), who underwent P-CT for evaluation of HCC pre- (N = 9) or post- (N = 11) transarterial chemoembolization, were retrospectively included using CT follow-up as the standard of reference. All 53 lesions were qualitatively (visual) and quantitatively (perfusion parameters) analysed according to their shape (wedge, irregular, nodular), location (not-/adjunct to a fistula), arterial liver perfusion (ALP), portal venous liver perfusion (PLP), hepatic perfusion index (HPI). Accuracy for diagnosis of HCC was determined using receiver operating characteristics. 18/32 (56 %) APL were wedge shaped, 10/32 (31 %) irregular and 4/32 (12 %) nodular, while 11/21 (52 %) HCC were nodular or 10/21 (48 %) irregular, but never wedge shaped. Significant difference between APL and HCC was seen for lesion shape in pretreated lesions (P < 0.001), and for PLP and HPI in both pre- and post-treated lesions (all, P < 0.001). Diagnostic accuracy for HCC was best for combined assessment of lesion configuration and PLP showing an area under the curve of 0.901. Combined assessment of lesion configuration and portal venous perfusion derived from P-CT allows best to discriminate APL from HCC with high diagnostic accuracy. (orig.)

  4. Liver insulin-like growth factor 2 methylation in hepatitis C virus drrhosis and further occurrence of hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Philippe Couvert; Michel Beaugrand; Nathalie Ganne-Carrié; Alain Carrié; Jacques Pariès; Jenny Vaysse; Audrey Miroglio; Antoine Kerjean; Pierre Nahon; Jamel Chelly; Jean-Claude Trinchet

    2008-01-01

    AIM: To assess the predictive value of the insulinlike growth factor 2 (Igf2) methylation profile for the occurrence of Hepatocellular Carcinoma (HCC) in hepatitis C (HCV) cirrhosis.METHODS: Patients with: (I) biopsy-proven compensated HCV cirrhosis; (2) available baseline frozen liver sample; (3) absence of detectable HCC; (4) regular screening for HCC; (5) informed consent for genetic analysis were studied.After DNA extraction from liver samples and bisulfite treatment,unbiased PCR and DHPLC analysis were performed for methylation analysis at the Igf2 locus.The predictive value of the Igf2 methylation profile for HCC was assessed by Kaplan-Meier and Cox methods.RESULTS: Among 94 included patients,20 developed an HCC during follow-up (6.9±3.2 years).The methylation profile was hypomethylated,intermediate and hypermethylated in 13,64 and 17 cases,respectively.In univariate analysis,two baseline parameters were associated with the occurrence of HCC: age (P=0.01) and prothrombin (P=0.04).The test of linear tendency between the three ordered levels of Igf2 methylation and probability of HCC occurrence was significant (Log Rank,P=0.043;Breslow,P=0.037; Tarone-Ware,P=0.039).CONCLUSION: These results suggest that hypomethylation at the Igf2 locus in the liver could be predictive for HCC occurrence in HCV cirrhosis.

  5. Validity of eleven prognostic scores with respect to intra- and extrahepatic recurrence of hepatocellular carcinoma after liver transplantation.

    Science.gov (United States)

    Bauschke, A; Altendorf-Hofmann, A; Kissler, H; Koch, A; Malessa, C; Settmacher, U

    2017-08-28

    Tumor recurrence is the most frequent cause of death after liver transplantation for hepatocellular carcinoma. We selected ten other prognostic classifications to evaluate their potential to predict the risk of recurrence after LT for HCC as compared to the Milan classification. All of the other scores have not been compared with one another in a single cohort. Data of 147 consecutive patients transplanted at our department between 1996 and 2014 were analyzed and staged for morphological and functional scores of underlying liver disease. For long-term follow-up, we analyzed intrahepatic (within the liver ± distant metastases) and extrahepatic (distant metastases only) recurrence separately. The median survival time for all patients was 106 months. The 5- and 10-year observed survival rates were 61 and 43%, respectively. The observed cumulative 5- and 10-year recurrence rates were 37 and 39%, respectively, 10-year intrahepatic and extrahepatic recurrence rates were 12 and 27%, respectively. Median survival time after diagnosis of first recurrence was 7.5 (0-120) months; 2 and 18 months for all, intra- and extrahepatic recurrence, respectively. UCSF-, up to seven-, Shanghai Fudan- or Duvoux classifications can identify patients with a cumulative 10-year recurrence rate below 20%. The pre-therapeutic AFP level should be considered in addition to the geometry of the intrahepatic lesions.

  6. Immunohistochemical Study of Glypican-3 and HepPar-1 in Differentiating Hepatocellular Carcinoma from Metastatic Carcinomas in FNA of the Liver.

    Science.gov (United States)

    Ibrahim, Taiseer R; Abdel-Raouf, Samar M

    2015-04-01

    Hepatocellular carcinoma (HCC) remains a common malignant cancer worldwide, it is considered the fifth most common malignant cancer. On the other hand, metastatic tumors are widespread in the liver , with metastatic adenocarcinoma (MA) constituting the greatest part, therefore differentiation of HCC from MA is a frequent problem facing the pathologist especially in liver fine-needle aspiration biopsies. Evaluating the diagnostic value of glypican-3 (GPC-3) and HepPar-1 immunostaining in differentiating hepatocellular carcinoma from metastatic tumors in liver cell block material. Fourty eight cell blocks prepared from FNA from the liver ( 30 cases HCC, 18 cases metastatic carcinoma in liver) stained by Glypican -3 and HepPar-1 immunohistochemical markers. Glypican-3 was immunoexpressed in 97% of cases of HCC while all cases of metastatic carcinoma were negative. HepPar-1 was expressed in 93% of cases of HCC and 11% of metastatic carcinoma of the liver. In this study the sensitivity of GPC3 in the diagnosis of HCC in cytological material was 96.7% and the specificity was 100% while the sensitivity and specificity of HepPar-1 was 93.3% and 88.9% respectively. Immunohistochemical staining for GPC-3 in cell block material of the liver is highly sensitive and specific and it is a valuable tool capable of differentiating HCC from most of metastatic tumors of the liver.

  7. Evidence of distinct tumour-propagating cell populations with different properties in primary human hepatocellular carcinoma.

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    Federico Colombo

    Full Text Available BACKGROUND AND AIMS: Increasing evidence that a number of malignancies are characterised by tumour cell heterogeneity has recently been published, but there is still a lack of data concerning liver cancers. The aim of this study was to investigate and characterise tumour-propagating cell (TPC compartments within human hepatocellular carcinoma (HCC. METHODS: After long-term culture, we identified three morphologically different tumour cell populations in a single HCC specimen, and extensively characterised them by means of flow cytometry, fluorescence microscopy, karyotyping and microarray analyses, single cell cloning, and xenotransplantation in NOD/SCID/IL2Rγ/⁻ mice. RESULTS: The primary cell populations (hcc-1, -2 and -3 and two clones generated by means of limiting dilutions from hcc-1 (clone-1/7 and -1/8 differently expressed a number of tumour-associated stem cell markers, including EpCAM, CD49f, CD44, CD133, CD56, Thy-1, ALDH and CK19, and also showed different doubling times, drug resistance and tumorigenic potential. Moreover, we found that ALDH expression, in combination with CD44 or Thy-1 negativity or CD56 positivity identified subpopulations with a higher clonogenic potential within hcc-1, hcc-2 and hcc-3 primary cell populations, respectively. Karyotyping revealed the clonal evolution of the cell populations and clones within the primary tumour. Importantly, the primary tumour cell population with the greatest tumorigenic potential and drug resistance showed more chromosomal alterations than the others and contained clones with epithelial and mesenchymal features. CONCLUSIONS: Individual HCCs can harbor different self-renewing tumorigenic cell types expressing a variety of morphological and phenotypical markers, karyotypic evolution and different gene expression profiles. This suggests that the models of hepatic carcinogenesis should take into account TPC heterogeneity due to intratumour clonal evolution.

  8. Radiofrequency ablation versus resection for Barcelona clinic liver cancer very early/early stage hepatocellular carcinoma: a systematic review

    Directory of Open Access Journals (Sweden)

    He ZX

    2016-02-01

    Full Text Available Zhen-Xin He,1 Pu Xiang,2 Jian-Ping Gong,1 Nan-Sheng Cheng,3 Wei Zhang4 1Department of Hepatobiliary Surgery, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 2State Key Laboratory of Biotherapy and Cancer Center, 3Department of Bile Duct Surgery, West China Hospital, Sichuan University, Chengdu, 4Department of Hepatobiliary Surgery, Yue Bei People’s Hospital, Shaoguan, Guangdong, People’s Republic of China Aim: To compare the long-term survival outcomes of radiofrequency ablation and liver resection for single very early/early stage hepatocellular carcinoma (HCC. Methods: The Cochrane Library (Issue 3, 2015, Embase (1974 to March 15, 2015, PubMed (1950 to March 15, 2015, Web of Science (1900 to March 15, 2015, and Chinese Biomedical Literature Database (1978 to March 15, 2015 were searched to identify relevant trials. Only trials that compared radiofrequency ablation and liver resection for single very early stage (≤2 cm or early stage (≤3 cm HCC according to the Barcelona clinic liver cancer (BCLC staging system were considered for inclusion in this review. The primary outcomes that we analyzed were the 3-year and 5-year overall survival (OS rates, and the secondary outcomes that we analyzed were the 3-year and 5-year disease-free survival (DFS rates. Review Manager 5.3 was used to perform a cumulative meta-analysis. Possible publication bias was examined using a funnel plot. A random-effects model was applied to summarize the various outcomes. Results: Six studies involving 947 patients were identified that compared radiofrequency ablation (n=528 to liver resection (n=419 for single BCLC very early HCC. In these six studies, the rates of 3-year OS, 5-year OS, 3-year DFS, and 5-year DFS were significantly lower in the radiofrequency ablation group than in the liver resection group (risk ratio [RR] =0.90, 95% confidence interval [CI]: 0.83–0.98, P=0.01; RR =0.84, 95% CI: 0.75–0.95, P=0.004; RR =0.77, 95% CI

  9. Chronic Liver Disease and the Detection of Hepatocellular Carcinoma by [18F]fluorocholine PET/CT

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    Sandi A. Kwee

    2015-05-01

    Full Text Available Positron emission tomography (PET using the radiopharmaceutical tracer fluorine-18 fluorocholine (FCh can elucidate tumors based on differences in choline phospholipid metabolism between tumor and surrounding tissue. The feasibility of detecting hepatocellular carcinoma (HCC using FCh PET has been shown despite constitutively high parenchymal choline metabolism in the liver. Since HCC frequently develops in the setting of chronic liver disease, we comparatively evaluated FCh PET/CT between cirrhotic and non-cirrhotic patients with HCC to investigate the effects of hepatic dysfunction on tumor detection and the tumor-to-background ratio (TBR of FCh uptake. FCh PET/CT was performed prospectively in 22 consecutive patients with HCC (7 newly diagnosed, 15 previously treated. Of these 22 patients, 14 were cirrhotic and 8 non-cirrhotic. Standardized uptake value (SUV measurements were obtained by region of interest analysis of the PET images. Tumor FCh uptake and the TBR were compared between cirrhotic and non-cirrhotic patients. Liver lesions were confirmed to be HCC by biopsy in 10 patients and by Barcelona criteria in 4 patients. There was correspondingly increased liver tumor FCh uptake in 13/14 of those patients, and iso-intense tumor FCh uptake (TBR 0.94 in one non-cirrhotic patient with newly diagnosed HCC. FCh PET/CT also showed metastatic disease without local tumor recurrence in 2 previously treated patients, and was negative in 6 treated patients without tumor recurrence by radiographic and clinical follow-up. Tumor maximum SUV ranged from 6.4 to 15.3 (mean 12.1 and liver TBR ranged from 0.94 to 2.1 (mean 1.6, with no significant differences between cirrhotic and non-cirrhotic patients (SUVmax 11.9 vs. 12.2, p = 0.83; TBR 1.71 vs. 1.51, p = 0.29. Liver parenchyma mean SUV was significantly lower in cirrhotic patients (6.4 vs. 8.7, p < 0.05. This pilot study supports the general feasibility of HCC detection by FCh PET/CT. However, a broad

  10. Human Ex-Vivo Liver Model for Acetaminophen-induced Liver Damage

    Science.gov (United States)

    Schreiter, Thomas; Sowa, Jan-Peter; Schlattjan, Martin; Treckmann, Jürgen; Paul, Andreas; Strucksberg, Karl-Heinz; Baba, Hideo A.; Odenthal, Margarete; Gieseler, Robert K.; Gerken, Guido; Arteel, Gavin E.; Canbay, Ali

    2016-01-01

    Reliable test systems to identify hepatotoxicity are essential to predict unexpected drug-related liver injury. Here we present a human ex-vivo liver model to investigate acetaminophen-induced liver injury. Human liver tissue was perfused over a 30 hour period with hourly sampling from the perfusate for measurement of general metabolism and clinical parameters. Liver function was assessed by clearance of indocyanine green (ICG) at 4, 20 and 28 hours. Six pieces of untreated human liver specimen maintained stable liver function over the entire perfusion period. Three liver sections incubated with low-dose acetaminophen revealed strong damage, with ICG half-lives significantly higher than in non-treated livers. In addition, the release of microRNA-122 was significantly higher in acetaminophen-treated than in non-treated livers. Thus, this model allows for investigation of hepatotoxicity in human liver tissue upon applying drug concentrations relevant in patients. PMID:27550092

  11. Obesity accelerates epigenetic aging of human liver.

    Science.gov (United States)

    Horvath, Steve; Erhart, Wiebke; Brosch, Mario; Ammerpohl, Ole; von Schönfels, Witigo; Ahrens, Markus; Heits, Nils; Bell, Jordana T; Tsai, Pei-Chien; Spector, Tim D; Deloukas, Panos; Siebert, Reiner; Sipos, Bence; Becker, Thomas; Röcken, Christoph; Schafmayer, Clemens; Hampe, Jochen

    2014-10-28

    Because of the dearth of biomarkers of aging, it has been difficult to test the hypothesis that obesity increases tissue age. Here we use a novel epigenetic biomarker of aging (referred to as an "epigenetic clock") to study the relationship between high body mass index (BMI) and the DNA methylation ages of human blood, liver, muscle, and adipose tissue. A significant correlation between BMI and epigenetic age acceleration could only be observed for liver (r = 0.42, P = 6.8 × 10(-4) in dataset 1 and r = 0.42, P = 1.2 × 10(-4) in dataset 2). On average, epigenetic age increased by 3.3 y for each 10 BMI units. The detected age acceleration in liver is not associated with the Nonalcoholic Fatty Liver Disease Activity Score or any of its component traits after adjustment for BMI. The 279 genes that are underexpressed in older liver samples are highly enriched (1.2 × 10(-9)) with nuclear mitochondrial genes that play a role in oxidative phosphorylation and electron transport. The epigenetic age acceleration, which is not reversible in the short term after rapid weight loss induced by bariatric surgery, may play a role in liver-related comorbidities of obesity, such as insulin resistance and liver cancer.

  12. Use of a rainbow trout oligonucleotide microarray to determine transcriptional patterns in aflatoxin B1-induced hepatocellular carcinoma compared to adjacent liver.

    Science.gov (United States)

    Tilton, Susan C; Gerwick, Lena G; Hendricks, Jerry D; Rosato, Caprice S; Corley-Smith, Graham; Givan, Scott A; Bailey, George S; Bayne, Christopher J; Williams, David E

    2005-12-01

    Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, and its occurrence is associated with a number of environmental factors including ingestion of the dietary contaminant aflatoxin B(1) (AFB(1)). Research over the last 40 years has revealed rainbow trout (Oncorhynchus mykiss) to be an excellent research model for study of AFB(1)-induced hepatocarcinogenesis; however, little is known about changes at the molecular level in trout tumors. We have developed a rainbow trout oligonucleotide array containing 1672 elements representing over 1400 genes of known or probable relevance to toxicology, comparative immunology, carcinogenesis, endocrinology, and stress physiology. In this study, we applied microarray technology to examine gene expression of AFB(1)-induced HCC in the rainbow trout tumor model. Carcinogenesis was initiated in trout embryos with 50 ppb AFB(1), and after 13 months control livers, tumors, and tumor-adjacent liver tissues were isolated from juvenile fish. Global gene expression was determined in histologically confirmed HCCs compared to noncancerous adjacent tissue and sham-initiated control liver. We observed distinct gene regulation patterns in HCC compared to noncancerous tissue including upregulation of genes important for cell cycle control, transcription, cytoskeletal formation, and the acute phase response and downregulation of genes involved in drug metabolism, lipid metabolism, and retinol metabolism. Interestingly, the expression profiles observed in trout HCC are similar to the transcriptional signatures found in human and rodent HCC, further supporting the validity of the model. Overall, these findings contribute to a better understanding of the mechanism of AFB(1)-induced hepatocarcinogenesis in trout and identify conserved genes important for carcinogenesis in species separated evolutionarily by more than 400 million years.

  13. Antiplatelet Therapy is Associated with a Better Prognosis for Patients with Hepatitis B Virus-Related Hepatocellular Carcinoma after Liver Resection.

    Science.gov (United States)

    Lee, Pei-Chang; Yeh, Chiu-Mei; Hu, Yu-Wen; Chen, Chun-Chia; Liu, Chia-Jen; Su, Chien-Wei; Huo, Teh-Ia; Huang, Yi-Hsiang; Chao, Yee; Chen, Tzeng-Ji; Lin, Han-Chieh; Wu, Jaw-Ching

    2016-12-01

    Recurrence of hepatocellular carcinoma (HCC) with unsatisfactory survival is common after surgical resection. Antiplatelet therapy with aspirin or clopidogrel was recently shown to prevent hepatic carcinogenesis in a murine model, but its effect in humans had not been clarified. This study aimed to investigate the association between antiplatelet therapy and the outcomes for patients with hepatitis B virus (HBV)-related HCC after liver resection. By analyzing data from the Taiwan National Health Insurance Research Database, 9461 HBV-related HCC patients who had undergone liver resection between January 1997 and December 2011 were identified. After one-to-four matching by sex, age, and propensity score, 442 patients with antiplatelet therapy and 1768 patients without antiplatelet therapy were enrolled for the analysis. The Kaplan-Meier method and modified Cox proportional hazards models were used for survival and multivariable, stratified analyses. Recurrence-free survival and overall survival after resection surgery were significantly better after 5 years in the treated cohort than in the untreated cohort (52.8 vs 47.9 %; p = 0.021 and 80.3 vs 65.4 %; p antiplatelet therapy reduced the risk of HCC recurrence (hazard ratio [HR] 0.73; p antiplatelet use significantly increased the risk of upper gastrointestinal bleeding (odds ratio [OR] 1.91; p < 0.001). Use of aspirin or clopidogrel was associated with better recurrence-free survival and overall survival among patients with HBV-related HCC after liver resection. However, these agents should be used with caution due to the adverse effects of upper gastrointestinal bleeding.

  14. Establishment and Validation of SSCLIP Scoring System to Estimate Survival in Hepatocellular Carcinoma Patients Who Received Curative Liver Resection.

    Directory of Open Access Journals (Sweden)

    Sha Huang

    Full Text Available There is no prognostic model that is reliable and practical for patients who have received curative liver resection (CLR for hepatocellular carcinoma (HCC. This study aimed to establish and validate a Surgery-Specific Cancer of the Liver Italian Program (SSCLIP scoring system for those patients.668 eligible patients who underwent CLR for HCC from five separate tertiary hospitals were selected. The SSCLIP was constructed from a training cohort by adding independent predictors that were identified by Cox proportional hazards regression analyses to the original Cancer of the Liver Italian Program (CLIP. The prognostic performance of the SSCLIP at 12 and 36-months was compared with data from existing models. The patient survival distributions at different risk levels of the SSCLIP were also assessed.Four independent predictors were added to construct the SSCLIP, including age (HR = 1.075, 95%CI: 1.019-1.135, P = 0.009, albumin (HR = 0.804, 95%CI: 0.681-0.950, P = 0.011, prothrombin time activity (HR = 0.856, 95%CI: 0.751-0.975, P = 0.020 and microvascular invasion (HR = 19.852, 95%CI: 2.203-178.917, P = 0.008. In both training and validation cohorts, 12-month and 36-month prognostic performance of the SSCLIP were significantly better than those of the original CLIP, model of end-stage liver disease-based CLIP, Okuda and Child-Turcotte-Pugh score (all P < 0.05. The stratification of risk levels of the SSCLIP showed an enhanced ability to differentiate patients with different outcomes.A novel SSCLIP to predict survival of HCC patients who received CLR based on objective parameters may provide a refined, useful prognosis algorithm.

  15. Liver Effects of Clinical Drugs Differentiated in Human Liver Slices

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    Alison E. M. Vickers

    2017-03-01

    Full Text Available Drugs with clinical adverse effects are compared in an ex vivo 3-dimensional multi-cellular human liver slice model. Functional markers of oxidative stress and mitochondrial function, glutathione GSH and ATP levels, were affected by acetaminophen (APAP, 1 mM, diclofenac (DCF, 1 mM and etomoxir (ETM, 100 μM. Drugs targeting mitochondria more than GSH were dantrolene (DTL, 10 μM and cyclosporin A (CSA, 10 μM, while GSH was affected more than ATP by methimazole (MMI, 500 μM, terbinafine (TBF, 100 μM, and carbamazepine (CBZ 100 μM. Oxidative stress genes were affected by TBF (18%, CBZ, APAP, and ETM (12%–11%, and mitochondrial genes were altered by CBZ, APAP, MMI, and ETM (8%–6%. Apoptosis genes were affected by DCF (14%, while apoptosis plus necrosis were altered by APAP and ETM (15%. Activation of oxidative stress, mitochondrial energy, heat shock, ER stress, apoptosis, necrosis, DNA damage, immune and inflammation genes ranked CSA (75%, ETM (66%, DCF, TBF, MMI (61%–60%, APAP, CBZ (57%–56%, and DTL (48%. Gene changes in fatty acid metabolism, cholestasis, immune and inflammation were affected by DTL (51%, CBZ and ETM (44%–43%, APAP and DCF (40%–38%, MMI, TBF and CSA (37%–35%. This model advances multiple dosing in a human ex vivo model, plus functional markers and gene profile markers of drug induced human liver side-effects.

  16. Liver Effects of Clinical Drugs Differentiated in Human Liver Slices.

    Science.gov (United States)

    Vickers, Alison E M; Ulyanov, Anatoly V; Fisher, Robyn L

    2017-03-07

    Drugs with clinical adverse effects are compared in an ex vivo 3-dimensional multi-cellular human liver slice model. Functional markers of oxidative stress and mitochondrial function, glutathione GSH and ATP levels, were affected by acetaminophen (APAP, 1 mM), diclofenac (DCF, 1 mM) and etomoxir (ETM, 100 μM). Drugs targeting mitochondria more than GSH were dantrolene (DTL, 10 μM) and cyclosporin A (CSA, 10 μM), while GSH was affected more than ATP by methimazole (MMI, 500 μM), terbinafine (TBF, 100 μM), and carbamazepine (CBZ 100 μM). Oxidative stress genes were affected by TBF (18%), CBZ, APAP, and ETM (12%-11%), and mitochondrial genes were altered by CBZ, APAP, MMI, and ETM (8%-6%). Apoptosis genes were affected by DCF (14%), while apoptosis plus necrosis were altered by APAP and ETM (15%). Activation of oxidative stress, mitochondrial energy, heat shock, ER stress, apoptosis, necrosis, DNA damage, immune and inflammation genes ranked CSA (75%), ETM (66%), DCF, TBF, MMI (61%-60%), APAP, CBZ (57%-56%), and DTL (48%). Gene changes in fatty acid metabolism, cholestasis, immune and inflammation were affected by DTL (51%), CBZ and ETM (44%-43%), APAP and DCF (40%-38%), MMI, TBF and CSA (37%-35%). This model advances multiple dosing in a human ex vivo model, plus functional markers and gene profile markers of drug induced human liver side-effects.

  17. Impact of stem cell marker expression on recurrence of TACE-treated hepatocellular carcinoma post liver transplantation

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    Zeng Zhen

    2012-12-01

    Full Text Available Abstract Background Liver transplantation is the most effective therapy for cirrhosis-associated hepatocellular carcinoma (HCC but its utility is limited by post-transplant tumor recurrence. Use of the Milan, size-based criteria, has reduced recurrence rate to less than 10% but many patients remain ineligible. Reduction of tumor size with local therapies has been used to “downstage” patients to allow them to qualify for transplantation, but the optimal criteria to predict tumor recurrence in these latter patients has not been established. The existence of a progenitor cell population, sometimes called cancer stem cells (CSCs, has been proposed to be one mechanism accounting for the chemotherapy resistance and recurrence of hepatocellular carcinoma. The aim of this study was to determine if transcatheter arterial chemoemolization (TACE treated tumors have increased CSC marker expression and whether these markers could be used to predict tumor recurrence. Methods Formalin fixed specimens were obtained from 39 HCC liver explants (23 with no treatment and 16 after TACE. Immunohistochemical staining was performed for EpCAM, CD44, CD90, and CD133. Staining for each marker was scored 0–3 by evaluating the number and intensity of positive tumor cells in 5 hpf of tumor in each specimen. Results TACE treated tumors displayed greater necrosis and fibrosis than non-TACE treated samples but there were no differences in morphology between the viable tumor cells of both groups. In TACE treated specimens, the staining of both EpCAM and CD133 was greater than in non-TACE specimens but CD44 and CD90 were the same. In the TACE group, the presence of high EpCAM staining was associated with tumor recurrence. Four of ten EpCAM high patients recurred while 0 of 6 EpCAM low patients recurred (P = 0.040. None of the other markers predicted recurrence. Conclusion High pre-transplant EpCAM staining predicted HCC recurrence. This suggests that the abundance of

  18. Risk Assessment of Hepatocellular Carcinoma Using Transient Elastography Vs. Liver Biopsy in Chronic Hepatitis B Patients Receiving Antiviral Therapy.

    Science.gov (United States)

    Seo, Yeon Seok; Kim, Mi Na; Kim, Seung Up; Kim, Sang Gyune; Um, Soon Ho; Han, Kwang-Hyub; Kim, Young Seok

    2016-03-01

    Liver stiffness (LS) assessed using transient elastography (TE) can assess the risk of developing hepatocellular carcinoma (HCC). We evaluated whether TE, when compared with histological data as a reference standard, can predict the risk of HCC development in chronic hepatitis B (CHB) patients starting antiviral therapy.Observational cohort database of 381 patients with CHB who underwent liver biopsy (LB) and TE were reviewed. All patients underwent surveillance for HCC development using ultrasonography and alpha-fetoprotein.During the median follow-up period of 48.1 (interquartile range 30.3-69.3) months, HCC developed in 34 (8.9%) patients. In patients with HCC development, age, proportion of diabetes mellitus, histological fibrosis stage, and LS value were significantly higher than those in patients without (all P 13 kPa; log-rank test, P 0.05).TE predicted HCC development independently in patients with CHB starting antiviral therapy. However, further investigation is needed to determine whether the current surveillance strategy can be optimized based on the LS value at the time of starting antiviral therapy.

  19. Glypican-3 is useful but not superior to Hep Par 1 in differentiating hepatocellular carcinoma from other liver tumours.

    Science.gov (United States)

    Pour, A M; Masir, N; Rose, I M

    2016-12-01

    To assess the diagnostic utility of glypican-3 (GPC-3) in comparison to Hep Par 1 in the diagnosis of liver tumours, a cross-sectional study involving 66 resected liver tumours were tested for the protein expression of these markers by immunohistochemistry using monoclonal antibodies. Of the 66 cases, 26 (39.4%) were hepatocellular carcinoma (HCC), 4 (6.1%) were intrahepatic cholangiocarcinoma and 36 (54.5%) were metastatic tumours. Hep Par 1 and GPC-3 expressions in HCC were 24/26 (92.3%) and 19/26 (73.1%) respectively. In contrast, of non-HCC cases, only 2/40 cases (5.0%) expressed Hep Par 1, including a metastatic colorectal adenocarcinoma and a metastatic gastric adenocarcinoma. GPC-3 was expressed in 3/40 cases (7.5%), i.e. a metastatic adenocarcinoma of unknown origin, a metastatic gastric adenocarcinoma and an intrahepatic cholangiocarcinoma. The sensitivity and specificity for Hep Par 1 were 92.3% and 95% respectively while that of GPC-3 was 73.1% and 92.5% respectively. GPC-3 is a useful marker in the diagnosis of HCC. However it is not superior to Hep Par 1 in its sensitivity and specificity. We recommend that it is utilized together with Hep Par 1 as a panel in the diagnosis of HCC.

  20. Cytotoxic effect of Argentine medicinal plant extracts on human hepatocellular carcinoma cell line.

    Science.gov (United States)

    Ruffa, M J; Ferraro, G; Wagner, M L; Calcagno, M L; Campos, R H; Cavallaro, L

    2002-03-01

    Methanolic extracts from Achyrocline satureioides (Dc.) Lam, Aristolochia macroura Gomez, Lithraea molleoides (Vell.) Engl., Schinus molle L., unlike those from Celtis spinosa Spreng, Chenopodium ambrosioides L., Petiveria alliacea L., and Plantago major L. showed cytotoxic activity against a human hepatocellular carcinoma cell line, Hep G2. Schinus molle L. was the most active (IC50=50+/-7 microg/ml). These results call for further studies of these extracts.

  1. Liver immune-pathogenesis and therapy of human liver tropic virus infection in humanized mouse models

    OpenAIRE

    Bility, Moses T.; Li, Feng; Cheng, Liang; Su, Lishan

    2013-01-01

    Hepatitis B virus (HBV) and hepatitis C virus (HCV) infect and replicate primarily in human hepatocytes. Few reliable and easy accessible animal models are available for studying the immune system’s contribution to the liver disease progression during hepatitis virus infection. Humanized mouse models reconstituted with human hematopoietic stem cells (HSCs) have been developed to study human immunology, human immunodeficiency virus 1 infection, and immunopathogenesis. However, a humanized mous...

  2. Myeloid-MyD88 Contributes to Ethanol-Induced Liver Injury in Mice Linking Hepatocellular Death to Inflammation.

    Science.gov (United States)

    Zhou, Hao; Yu, Minja; Roychowdhury, Sanjoy; Sanz-Garcia, Carlos; Pollard, Katherine A; McMullen, Megan R; Liu, Xiuli; Li, Xiaoxia; Nagy, Laura E

    2017-04-01

    Toll-like receptor 4 (TLR4) is critical for ethanol (EtOH)-induced liver injury. TLR4 signaling is mediated by 2 proximal adaptor molecules: myeloid differentiation primary response protein (MyD88) and TLR-domain-containing adaptor-inducing interferon-β (TRIF). Studies utilizing global knockouts of MyD88 and TRIF identified a predominant role for TRIF signaling in the progression of EtOH-induced liver injury. In contrast, IL-1 receptor, which signals solely via the MyD88 pathway, is also known to mediate EtOH-induced liver injury. We postulated that a cell-specific role for MyD88 in myeloid cells might explain these apparently discrepant roles of MyD88. Here we made use of myeloid-specific MyD88-deficient (MyD88(LysM-)(KO) ) mice generated by crossing LysM-CRE mice with MyD88(fl/fl) mice to test this hypothesis. MyD88(LysM-)(KO) and littermate controls were fed a Lieber-DeCarli EtOH-containing diet or pair-fed control diets for 25 days. Littermate control, but not MyD88(LysM-)(KO) , mice developed early stages of EtOH-induced liver injury including elevated plasma alanine aminotransferase and increased hepatic triglycerides. Lobular inflammation and expression of pro-inflammatory cytokines/chemokines was increased in control but not MyD88(LysM-)(KO) . Further, EtOH-induced inflammasome activation, indicated by the presence of cleaved caspase-1 and mature IL-1β protein, was also ameliorated in livers of MyD88(LysM-)(KO) mice. In contrast, chronic EtOH-induced apoptosis, assessed via TUNEL staining, was independent of myeloid-MyD88 expression. Collectively, these data demonstrate a cell-specific role for MyD88 in the development of chronic EtOH-induced liver injury. While MyD88(LysM-)(KO) still exhibited hepatocellular apoptosis in response to chronic EtOH, the absence of MyD88 on myeloid cells prevented the development of hepatic steatosis and inflammation. Copyright © 2017 by the Research Society on Alcoholism.

  3. Stem cell differentiation and human liver disease

    Institute of Scientific and Technical Information of China (English)

    Wen-Li Zhou; Claire N Medine; Liang Zhu; David C Hay

    2012-01-01

    Human stem cells are scalable cell populations capable of cellular differentiation.This makes them a very attractive in vitro cellular resource and in theory provides unlimited amounts of primary cells.Such an approach has the potential to improve our understanding of human biology and treating disease.In the future it may be possible to deploy novel stem cell-based approaches to treat human liver diseases.In recent years,efficient hepatic differentiation from human stem cells has been achieved by several research groups including our own.In this review we provide an overview of the field and discuss the future potential and limitations of stem cell technology.

  4. Human herpesvirus 6 infections after liver transplantation

    Institute of Scientific and Technical Information of China (English)

    Rima Camille Abdel Massih; Raymund R Razonable

    2009-01-01

    Human herpesvirus 6 (HHV-6) infections occur in > 95% of humans. Primary infection, which occurs in early childhood as an asymptomatic illness or manifested clinically as roseola infantum, leads to a state of subclinical viral persistence and latency. Reactivation of latent HHV-6 is common after liver transplantation, possibly induced and facilitated by allograft rejection and immunosuppressive therapy. Since the vast majority of humans harbor the virus in a latent state, HHV-6 infections after liver transplantation are believed to be mostly due to endogenous reactivation or superinfection (reactivation in the transplanted organ). In a minority of cases, however,primary HHV-6 infection may occur when an HHV-6 negative individual receives a liver allograft from an HHV-6 positive donor. The vast majority of documented HHV-6 infections after liver transplantation are asymptomatic. In a minority of cases, HHV-6 has been implicated as a cause of febrile illness with rash and myelosuppression, hepatitis, pneumonitis, and encephalitis after liver transplantation. In addition,HHV-6 has been associated with a variety of indirect effects such as allograft rejection, and increased predisposition and severity of other infections including cytomegalovirus (CMV), hepatitis C virus, and opportunistic fungi. Because of the uncommon nature of the clinical illnesses directly attributed to HHV-6, there is currently no recommended HHV-6- specific approach to prevention. However, ganciclovir and valganciclovir, which are primarily intended for the prevention of CMV disease, are also active against HHV-6 and may prevent its reactivation after transplantation. The treatment of established HHV-6 disease is usually with intravenous ganciclovir, cidofovir,or foscarnet, complemented by reduction in the degree of immunosuppression. This article reviews the current advances in the pathogenesis, clinical diagnosis, and therapeutic modalities against HHV6 in the setting of liver transplantation.

  5. Deleted in liver cancer 1 (DLC1 negatively regulates Rho/ROCK/MLC pathway in hepatocellular carcinoma.

    Directory of Open Access Journals (Sweden)

    Carmen Chak-Lui Wong

    Full Text Available AIMS: Deleted in liver cancer 1 (DLC1, a member of RhoGTPase activating protein (GAP family, is known to have suppressive activities in tumorigenicity and cancer metastasis. However, the underlying molecular mechanisms of how DLC1 suppresses cell motility have not been fully elucidated. Rho-kinase (ROCK is an immediate down-stream effector of RhoA in mediating cellular cytoskeletal events and cell motility. In the present study, we aimed to investigate the effects of DLC1 on Rho/ROCK signaling pathway in hepatocellular carcinoma (HCC. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrated that DLC1 negatively regulated ROCK-dependent actomyosin contractility. From immunofluorescence study, we found that ectopic expression of DLC1 abrogated Rho/ROCK-mediated cytoskeletal reorganization including formation of stress fibers and focal adhesions. It also downregulated cortical phosphorylation of myosin light chain 2 (MLC2. These inhibitory events by DLC1 were RhoGAP-dependent, as RhoGAP-deficient mutant of DLC1 (DLC1 K714E abolished these inhibitory events. In addition, from western study, DLC1 inhibited ROCK-related myosin light chain phosphatase targeting unit 1 (MYPT1 phosphorylation at Threonine 853. By examining cell morphology under microscope, we found that ectopic expression of dominant-active ROCK released cells from DLC1-induced cytoskeletal collapse and cell shrinkage. CONCLUSION: Our data suggest that DLC1 negatively regulates Rho/ROCK/MLC2. This implicates a ROCK-mediated pathway of DLC1 in suppressing metastasis of HCC cells and enriches our understanding in the molecular mechanisms involved in the progression of hepatocellular carcinoma.

  6. Laparoscopic versus Open Liver Resection: Differences in Intraoperative and Early Postoperative Outcome among Cirrhotic Patients with Hepatocellular Carcinoma—A Retrospective Observational Study

    Directory of Open Access Journals (Sweden)

    Antonio Siniscalchi

    2014-01-01

    Full Text Available Introduction. Laparoscopic liver resection is considered risky in cirrhotic patients, even if minor surgical trauma of laparoscopy could be useful to prevent deterioration of a compromised liver function. This study aimed to identify the differences in terms of perioperative complications and early outcome in cirrhotic patients undergoing minor hepatic resection for hepatocellular carcinoma with open or laparoscopic technique. Methods. In this retrospective study, 156 cirrhotic patients undergoing liver resection for hepatocellular carcinoma were divided into two groups according to type of surgical approach: laparoscopy (LS group: 23 patients or laparotomy (LT group: 133 patients. Perioperative data, mortality, and length of hospital stay were recorded. Results. Groups were matched for type of resection, median number of nodules, and median diameter of largest lesions. Groups were also homogeneous for preoperative liver and renal function tests. Intraoperative haemoglobin decrease and transfusions of red blood cells and fresh frozen plasma were significantly lower in LS group. MELD score lasted stable after laparoscopic resection, while it increased in laparotomic group. Postoperative liver and renal failure and mortality were all lower in LS group. Conclusions. Lower morbidity and mortality, maintenance of liver function, and shorter hospital stay suggest the safety and benefit of laparoscopic approach.

  7. Role of diffusion-weighted imaging, apparent diffusion coefficient and correlation with hepatobiliary phase findings in the differentiation of hepatocellular carcinoma from dysplastic nodules in cirrhotic liver

    Energy Technology Data Exchange (ETDEWEB)

    Inchingolo, Riccardo; De Gaetano, Anna Maria; Curione, Davide; Ciresa, Marzia; Bonomo, Lorenzo [Catholic University of the Sacred Heart, Department of Bioimaging and Radiological Sciences, Institute of Radiology, ' ' Agostino Gemelli' ' Hospital, Rome (Italy); Miele, Luca; Pompili, Maurizio [Catholic University of the Sacred Heart, Department of Internal Medicine, ' ' Agostino Gemelli' ' Hospital, Rome (Italy); Vecchio, Fabio Maria [Catholic University of the Sacred Heart, Department of Anatomo-Pathology, ' ' Agostino Gemelli' ' Hospital, Rome (Italy); Giuliante, Felice [Catholic University of the Sacred Heart, Department of Surgery, ' ' Agostino Gemelli' ' Hospital, Rome (Italy)

    2015-04-01

    To investigate the utility of diffusion-weighted imaging (DWI), apparent diffusion coefficient (ADC) and the correlation with hepatobiliary phase (delayed phase imaging, DPI) findings in the differentiation of cirrhotic hepatocellular nodules. Forty-three patients with 53 pathology-proven nodules (29 hepatocellular carcinomas (HCCs), 13 high-grade (HGDNs) and 11 low-grade dysplastic nodules (LGDNs); mean size 2.17 cm, range 1-4 cm), who underwent liver MRI with DWI and DPI sequences, were retrospectively reviewed. Lesions were classified as hypointense, isointense, or hyperintense relative to the adjacent liver parenchyma. ADC of each nodule, of the surrounding parenchyma, and lesion-to-liver ratio were calculated. Hyperintensity versus iso/hypointensity on DWI, hypointensity versus iso/hyperintensity on DPI, and the mean lesion-to-liver ratio showed a statistically significant difference both between HCCs versus DNs and between ''HCCs + HGDNs'' versus LGDNs (p < 0.05); sensitivity, specificity, and accuracy for the diagnosis of ''HCCs + HGDNs'' were 96.8 %, 100 %, 97.4 % respectively when combining hyperintensity on DWI and hypointensity on DPI, and 90.9 %, 81.0 %, 83.6 % respectively when lesion-to-liver ratio was <0.95. Hyperintensity on DWI, especially in association with hypointensity on DPI, and low lesion-to-liver ratios should raise the suspicion of HCC, or at least of HGDN, thus helping the characterization of atypically enhancing lesions. (orig.)

  8. Activation and dramatically increased cytolytic activity of tumor specific T lymphocytes after radio-frequency ablation in patients with hepatocellular carcinoma and colorectal liver metastases

    Institute of Scientific and Technical Information of China (English)

    Johannes H(a)nsler; Thadd(a)us Till Wissniowski; Detlef Schuppan; Astrid Witte; Thomas Bernatik; Eckhart Georg Hahn; Deike Strobel

    2006-01-01

    AIM: To assess if a specific cytotoxic T cell response can be induced in patients with malignant liver tumors treated with radio-frequency ablation (RFA).METHODS: Six Patients with liver metastases of colorectal cancer and 6 with hepatocellular carcinoma (HCC)underwent RFA. Blood was sampled before, 4 and 8 wk after RFA. Test antigens were autologous liver and tumor lysate obtained from each patient by biopsy. Peripheral T cell activation was assessed by an interferon gamma (IFNγ) secretion assay and flow cytometry. T cells were double-stained for CD4/CD8 and IFNγ to detect cytotoxic T cells. The ratio of IFNγ positive and IFNγ negative T cells was determined as the stimulation index (SI). To assess cytolytic activity, T cells were co-incubated with human CaCo colorectal cancer and HepG2 HCC cells and release of cytosolic adenylate kinase was measured by a luciferase assay.RESULTS: Before RFA SI was 0.021 (±0.006) for CD4+and 0.022 (±0.004) for CD8+T cells against nonmalignant liver tissue and 0.018 (±0.005) for CD4+ and 0.021(±0.004) for CD8+ cells against autologous tumor tissue.Four weeks after RFA SI against tumor tissue increased to 0.109 (±0.005) for CD4+ and 0.11 (±0.012) for CD8+T cells against HCC, and to 0.115 (±0.031) for CD4+ and 0.15 (±0.02) for CD8+ cells for colorectal metastases (P <0.0001). No increased SI was observed with nonmalignant tumor tissue at all time points. Before RFA cytolytic activity against the respective cancer cells was low with 2.62 (±0.37) relative luminescence units (RLU), but rose more than 100 fold 4 and 8 wk after RFA. Spontaneous release was <2% of maximum release in all experiments.CONCLUSION: Patients with primary and secondary tumors of the liver show a significant tumor-specific cytotoxic T-cell stimulation with a dramatically increased tumor specific cytolytic activity of CD8+ T cells after RFA.

  9. Coffee Consumption and Risk of Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma by Sex: The Liver Cancer Pooling Project.

    Science.gov (United States)

    Petrick, Jessica L; Freedman, Neal D; Graubard, Barry I; Sahasrabuddhe, Vikrant V; Lai, Gabriel Y; Alavanja, Michael C; Beane-Freeman, Laura E; Boggs, Deborah A; Buring, Julie E; Chan, Andrew T; Chong, Dawn Q; Fuchs, Charles S; Gapstur, Susan M; Gaziano, John Michael; Giovannucci, Edward L; Hollenbeck, Albert R; King, Lindsay Y; Koshiol, Jill; Lee, I-Min; Linet, Martha S; Palmer, Julie R; Poynter, Jenny N; Purdue, Mark P; Robien, Kim; Schairer, Catherine; Sesso, Howard D; Sigurdson, Alice J; Zeleniuch-Jacquotte, Anne; Wactawski-Wende, Jean; Campbell, Peter T; McGlynn, Katherine A

    2015-09-01

    Coffee consumption has been reported to be inversely associated with hepatocellular carcinoma (HCC), the most common type of liver cancer. Caffeine has chemopreventive properties, but whether caffeine is responsible for the coffee-HCC association is not well studied. In addition, few studies have examined the relationship by sex, and no studies have examined whether there is an association between coffee and intrahepatic cholangiocarcinoma (ICC), the second most common type of liver cancer. In the Liver Cancer Pooling Project, a consortium of U.S.-based cohort studies, data from 1,212,893 individuals (HCC, n = 860; ICC, n = 260) in nine cohorts were pooled. Multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI) were estimated using proportional hazards regression. Higher coffee consumption was associated with lower risk of HCC (HR>3 cups/day vs. non-drinker, 0.73; 95% CI, 0.53-0.99; Ptrend cups/day = risk was seen among women than men (Pinteraction = 0.07). Women who consumed more than three cups of coffee per day were at a 54% lower risk of HCC (HR, 0.46; 95% CI, 0.26-0.81), whereas men had more modest reduced risk of HCC (HR, 0.93; 95% CI, 0.63-1.37). The associations were stronger for caffeinated coffee (HR>3 cups/day vs. non-drinker, 0.71; 95% CI, 0.50-1.01) than decaffeinated coffee (HR, 0.92; 95% CI, 0.55-1.54). There was no association between coffee consumption and ICC. These findings suggest that, in a U.S. population, coffee consumption is associated with reduced risk of HCC. Further research into specific coffee compounds and mechanisms that may account for these associations is needed. ©2015 American Association for Cancer Research.

  10. Transient Expression of Transgenic IL-12 in Mouse Liver Triggers Unremitting Inflammation Mimicking Human Autoimmune Hepatitis.

    Science.gov (United States)

    Gil-Farina, Irene; Di Scala, Marianna; Salido, Eduardo; López-Franco, Esperanza; Rodríguez-García, Estefania; Blasi, Mercedes; Merino, Juana; Aldabe, Rafael; Prieto, Jesús; Gonzalez-Aseguinolaza, Gloria

    2016-09-15

    The etiopathogenesis of autoimmune hepatitis (AIH) remains poorly understood. In this study, we sought to develop an animal model of human AIH to gain insight into the immunological mechanisms driving this condition. C57BL/6 mice were i.v. injected with adeno-associated viral vectors encoding murine IL-12 or luciferase under the control of a liver-specific promoter. Organ histology, response to immunosuppressive therapy, and biochemical and immunological parameters, including Ag-specific humoral and cellular response, were analyzed. Mechanistic studies were carried out using genetically modified mice and depletion of lymphocyte subpopulations. Adeno-associated virus IL-12-treated mice developed histological, biochemical, and immunological changes resembling type 1 AIH, including marked and persistent liver mononuclear cell infiltration, hepatic fibrosis, hypergammaglobulinemia, anti-nuclear and anti-smooth muscle actin Abs, and disease remission with immunosuppressive drugs. Interestingly, transgenic IL-12 was short-lived, but endogenous IL-12 expression was induced, and both IL-12 and IFN-γ remained elevated during the entire study period. IFN-γ was identified as an essential mediator of liver damage, and CD4 and CD8 T cells but not NK, NKT, or B cells were essential executors of hepatic injury. Furthermore, both MHC class I and MHC class II expression was upregulated at the hepatocellular membrane, and induction of autoreactive liver-specific T cells was detected. Remarkably, although immunoregulatory mechanisms were activated, they only partially mitigated liver damage. Thus, low and transient expression of transgenic IL-12 in hepatocytes causes loss of tolerance to hepatocellular Ags, leading to chronic hepatitis resembling human AIH type 1. This model provides a practical tool to explore AIH pathogenesis and novel therapies.

  11. Is human hepatocellular carcinoma a hormone-responsive tumor?

    Institute of Scientific and Technical Information of China (English)

    Massimo Di Maio; Bruno Daniele; Sandra Pignata; Ciro Gallo; Ermelinda De Maio; Alessandro Morabito; Maria Carmela Piccirillo; Francesco Perrone

    2008-01-01

    Before the positive results recently obtained with multitarget tyrosine kinase inhibitor sorafenib, there was no standard systemic treatment for patients with advanced hepatocellular carcinoma (HCC). Sex hormones receptors are expressed in a significant proportion of HCC samples. Following preclinical and epidemiological studies supporting a relationship between sex hormones and HCC tumorigenesis, several randomized controlled trials (RCTs) tested the efficacy of the anti-estrogen tamoxifen as systemic treatment. Largest among these trials showed no survival advantage from the administration of tamoxifen, and the recent Cochrane systematic review produced a completely negative result. This questions the relevance of estrogen receptor-mediated pathways in HCC. However, a possible explanation for these disappointing results is the lack of proper patients selection according to sex hormones receptors expression, but unfortunately the interaction between this expression and efficacy of tamoxifen has not been studied adequately. It has been also proposed that negative results might be explained if tamoxifen acts in HCC via an estrogen receptor-independent pathway, that requires higher doses than those usually administered, but an Asian RCT conducted to assess dose-response effect was completely negative. Interesting, preliminaryresults have been obtained when hormonal treatment (tamoxifen or megestrol) has been selected according to the presence of wild-type or variant estrogen receptors respectively, but no large RCTs are available to support this strategy. Negative results have been obtained also with anti-androgen therapy. In conclusion, there is no robust evidence to consider HCC a hormone-responsive tumor. Hormonal treatments should not be part of the current management of HCC.

  12. Noscapine inhibits human hepatocellular carcinoma growth through inducing apoptosis in vitro and in vivo.

    Science.gov (United States)

    Xu, G; Niu, Z; Dong, J; Zhao, Y; Zhang, Y; Li, X

    2016-01-01

    Noscapine, a phthalideisoquinoline alkaloid derived from opium, has been demonstrated as a promising anti-tumor compound against various cancers. However, the anti-cancer activity of noscapine in hepatocellular carcinoma has not been defined. In this study, we investigate the inhibitive effects of noscapine on human hepatocellular carcinoma (HCC) using both in vitro and in vivo models. In vitro proliferation assay showed that noscapine suppressed HepG2 and Huh7 cells in dose- and time-dependent manners. With a mouse xenograft model, noscapine showed notable inhibition on HCC tumor growth in vivo without suppression of body weight. Moreover, apoptotic induction and regulation of related signalings by noscapine were examined by nuclear DNA staining, TUNEL, and western blotting assays. Results showed that noscapine induced apoptosis in HCC cells both in vitro and in vivo. Further studies indicated that noscapine induced antive-capsase-3, cleavage PARP, and decreased the ratio of Bcl-2/Bax. Hence, these data indicates that noscapine selectively suppresses HCC cell growth through apoptosis induction, providing evidence for application of noscapine as a novel agent against human hepatocellular carcinoma.

  13. A potential oral anticancer drug candidate, Moringa oleifera leaf extract, induces the apoptosis of human hepatocellular carcinoma cells.

    Science.gov (United States)

    Jung, Il Lae; Lee, Ju Hye; Kang, Se Chan

    2015-09-01

    It has previously been reported that cold water-extracts of Moringa oleifera leaf have anticancer activity against various human cancer cell lines, including non-small cell lung cancer. In the present study, the anticancer activity of M. oleifera leaf extracts was investigated in human hepatocellular carcinoma HepG2 cells. By the analysis of apoptotic signals, including the induction of caspase or poly(ADP-ribose) polymerase cleavage, and the Annexin V and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assays, it was demonstrated that M. oleifera leaf extracts induce the apoptosis of HepG2 cells. In the hollow fiber assay, oral administration of the leaf extracts significantly reduced (44-52%) the proliferation of the HepG2 cells and A549 non-small cell lung cancer cells. These results support the potential of soluble extracts of M. oleifera leaf as orally administered therapeutics for the treatment of human liver and lung cancers.

  14. Hepatocellular carcinoma in patients with hepatitis C virus-related chronic liver disease

    Institute of Scientific and Technical Information of China (English)

    Jean-Claude Trinchet; Nathalie Ganne-Carrié; Pierre Nahon; Gisèle N'kontchou; Michel Beaugrand

    2007-01-01

    Hepatitis C virus (HCV) is a major cause of hepatocellular carcinoma (HCC) worldwide due to the high prevalence of HCV infection and the high rate of HCC occurrence in patients with HCV cirrhosis. A striking increase in HCC incidence has been observed during the past decades in most industrialized countries, partly related to the growing number of patients infected by HCV. HCC is currently the main cause of death in patients with HCV-related cirrhosis, a fact that justifies screening as far as curative treatments apply only in patients with small tumors. As a whole, treatment options are similar in patients with cirrhosis whatever the cause. Chemoprevention could be also helpful in the near future. It is strongly suggested that antiviral treatment of HCV infection could prevent HCC occurrence, even in cirrhotic patients, mainly when a sustained virological response is obtained.

  15. Subcellular localization of APE1/Ref-1 in human hepatocellular carcinoma: possible prognostic significance.

    Science.gov (United States)

    Di Maso, Vittorio; Avellini, Claudio; Crocè, Lory Saveria; Rosso, Natalia; Quadrifoglio, Franco; Cesaratto, Laura; Codarin, Erika; Bedogni, Giorgio; Beltrami, Carlo Alberto; Tell, Gianluca; Tiribelli, Claudio

    2007-01-01

    APE1/Ref-1, normally localized in the nucleus, is a regulator of the cellular response to oxidative stress. Cytoplasmic localization has been observed in several tumors and correlates with a poor prognosis. Because no data are available on liver tumors, we investigated APE1/Ref-1 subcellular localization and its correlation with survival in 47 consecutive patients undergoing hepatocellular carcinoma (HCC) resection. APE1/Ref-1 expression was determined by immunohistochemistry in HCC and surrounding liver cirrhosis (SLC) and compared with normal liver tissue. Survival probability was evaluated using Kaplan-Meier curves (log-rank test) and Cox regression. Cytoplasmic expression of APE1/Ref-1 was significantly higher in HCC than in SLC (P = 0.00001); normal liver showed only nuclear reactivity. Patients with poorly differentiated HCC showed a cytoplasmic expression three times higher than those with well-differentiated HCC (P = 0.03). Cytoplasmic localization was associated with a median survival time shorter than those with negative cytoplasmic reactivity (0.44 compared with 1.64 years, P = 0.003), and multivariable analysis confirmed that cytoplasmic APE1/Ref-1 localization is a predictor of survival. Cytoplasmic expression of APE1/Ref-1 is increased in HCC and is associated with a lower degree of differentiation and a shorter survival time, pointing to the use of the cytoplasmic localization of APE1/Ref-1 as a prognostic marker for HCC.

  16. The secretion of high molecular weight cathepsin B from cultured human liver cancers.

    Directory of Open Access Journals (Sweden)

    Ohsawa,Toshiya

    1989-02-01

    Full Text Available The biochemical characteristics of cathepsin B secreted from cultured human liver cancer cells were examined. The enzyme activity of culture medium against a synthetic substrate, N-carbobenzoxy-L-arginyl-L-arginine-4-methyl-coumaryl-7-amide, was dependent on the addition of cysteine, and the optimal pH was found to be 6.0. No activity was observed when the enzyme source was fresh medium not used for culture. These results suggest that the enzyme released from liver cancer cells is the thiol-protease cathepsin B. The molecular weight of the enzyme with 90% of the total activity was 40,000. Two cathepsin B molecules were found in liver tissue from patients with hepatocellular carcinoma (HCC; one was equivalent in size to the secreted enzyme, and a smaller one was the same as normal liver cathepsin B (27,000, which was also obtained from HCC-bearing cirrhotic liver. These results demonstrate that two molecules of cathepsin B are synthesized in liver cancer, and that the larger one is released into the surrounding tissue.

  17. Clinical Utility of Alpha Fetoprotein and HCCR-1, Alone or in Combination, in Patients with Chronic Hepatitis, Liver Cirrhosis and Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Peng Jirun

    2011-01-01

    Full Text Available Serum alpha fetoprotein (AFP is the most widely used tumor marker in detecting patients with hepatocellular carcinoma (HCC. However, it has been indicated that HCCR-1 (human cervical cancer oncogene 1 might be supplementary to AFP in the detection. We conducted a prospective study in 120 normal and 524 liver disease patients to evaluate the significance of simultaneous measurement of 2 tumor markers (AFP and HCCR-1 in the diagnosis of HCC through the cohort study in Korea and China. We also performed immunohistochemical studies using 25 normal subjects (N, 32 liver cirrhosis (LC and 116 HCC tissues. The sensitivities of AFP (20 ng/mL and HCCR-1 (10 ng/mL in HCC were 55.8% (164/294 and 44.2% (130/294, respectively. When AFP was combined with HCCR-1, sensitivities increased to 4.2% (N, 12.7% (chronic hepatitis; CH, 50.0% (LC, and 77.2% (HCC, respectively. Although there was no significant difference in the diagnostic rate for HCC between AFP and HCCR-1, many cases for AFP-negative HCC were positive for HCCR-1 and vice versa. Moreover, the combined use of AFP and HCCR-1 improved the diagnostic rate to 70.8% in small HCC (< 2 cm and 81.6% in large HCC (≥ 2 cm, respectively. AFP and HCCR-1 are independent markers. Our result suggests that the HCCR-1 could be an useful biomarker for HCC while the diagnostic rate could be significantly improved in the combined use of HCCR-1 and AFP.

  18. Towards a Humanized Mouse Model of Liver Stage Malaria Using Ectopic Artificial Livers

    Science.gov (United States)

    Ng, Shengyong; March, Sandra; Galstian, Ani; Gural, Nil; Stevens, Kelly R.; Mota, Maria M.; Bhatia, Sangeeta N.

    2017-01-01

    The malaria liver stage is an attractive target for antimalarial development, and preclinical malaria models are essential for testing such candidates. Given ethical concerns and costs associated with non‐human primate models, humanized mouse models containing chimeric human livers offer a valuable alternative as small animal models of liver stage human malaria. The best available human liver chimeric mice rely on cellular transplantation into mice with genetically engineered liver injury, but these systems involve a long and variable humanization process, are expensive, and require the use of breeding-challenged mouse strains which are not widely accessible. We previously incorporated primary human hepatocytes into engineered polyethylene glycol (PEG)-based nanoporous human ectopic artificial livers (HEALs), implanted them in mice without liver injury, and rapidly generated human liver chimeric mice in a reproducible and scalable fashion. By re-designing the PEG scaffold to be macroporous, we demonstrate the facile fabrication of implantable porous HEALs that support liver stage human malaria (P. falciparum) infection in vitro, and also after implantation in mice with normal liver function, 60% of the time. This proof-of-concept study demonstrates the feasibility of applying a tissue engineering strategy towards the development of scalable preclinical models of liver stage malaria infection for future applications. PMID:28361899

  19. Multimodal imaging of a humanized orthotopic model of hepatocellular carcinoma in immunodeficient mice

    Science.gov (United States)

    Wu, Tao; Heuillard, Emilie; Lindner, Véronique; Bou About, Ghina; Ignat, Mihaela; Dillenseger, Jean-Philippe; Anton, Nicolas; Dalimier, Eugénie; Gossé, Francine; Fouré, Gael; Blindauer, Franck; Giraudeau, Céline; El-Saghire, Hussein; Bouhadjar, Mourad; Calligaro, Cynthia; Sorg, Tania; Choquet, Philippe; Vandamme, Thierry; Ferrand, Christophe; Marescaux, Jacques; Baumert, Thomas F.; Diana, Michele; Pessaux, Patrick; Robinet, Eric

    2016-01-01

    The development of multimodal strategies for the treatment of hepatocellular carcinoma requires tractable animal models allowing for advanced in vivo imaging. Here, we characterize an orthotopic hepatocellular carcinoma model based on the injection of luciferase-expressing human hepatoma Huh-7 (Huh-7-Luc) cells in immunodeficient mice. Luciferase allows for an easy repeated monitoring of tumor growth by in vivo bioluminescence. The intrahepatic injection was more efficient than intrasplenic or intraportal injection in terms of survival, rate of orthotopic engraftment, and easiness. A positive correlation between luciferase activity and tumor size, evaluated by Magnetic Resonance Imaging, allowed to define the endpoint value for animal experimentation with this model. Response to standard of care, sorafenib or doxorubicin, were similar to those previously reported in the literature, with however a strong toxicity of doxorubicin. Tumor vascularization was visible by histology seven days after Huh-7-Luc transplantation and robustly developed at day 14 and day 21. The model was used to explore different imaging modalities, including microtomography, probe-based confocal laser endomicroscopy, full-field optical coherence tomography, and ultrasound imaging. Tumor engraftment was similar after echo-guided intrahepatic injection as after laparotomy. Collectively, this orthotopic hepatocellular carcinoma model enables the in vivo evaluation of chemotherapeutic and surgical approaches using multimodal imaging. PMID:27739457

  20. Desensitization oft lymphocyte function by CXCR3 ligands in human hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Yu-Qing Liu; Ronnie T. Poon; Jeremy Hughes; Qin-Yu Li; Wan-Ching Yu; Sheung-Tat Fan

    2005-01-01

    AIM: Despite the presence of lymphocyte infiltration, human hepatocellular carcinoma (HCC) is typically a rapidly progressive disease. The mechanism of regulation of lymphocyte migration is poorly understood. In this study,we investigated various factors regulating T cell migration in HCC patients. We examined serum CXC chemokine levels in HCC patients and demonstrated the production of CXC chemokines by HCC cell lines. We determined the effect of both HCC patient serum and tumor cell conditioned supernatant upon lymphocyte expression of chemokine receptor CXCR3 as well as lymphocyte migration. Lastly,we examined the chemotactic responses of lymphocytes derived from HCC patients.METHODS: The serum chemokines IP-10 (CXCL10) and Mig (CXCL9) levels were measured by cytometric bead array (CBA) and the tumor tissue IP-10 concentration was measured by ELISA. The surface expression of CXCR3 on lymphocytes was determined by flow cytometry. The migratory function of lymphocytes to the corresponding chemokines was assessed using an in vitro chemotactic assay. Phosphorylation of extracellular signal-regulated kinase (ERK) was determined by Western blot analysis.RESULTS: Increased levels of IP-10 and Mig were detected in HCC patient serum and culture supernatants of HCC cell lines. The IP-10 concentration in the tumor was significantly higher than that in the non-involved adjacent liver tissues.HCC cell lines secreted functional chemokines that induced a CXCR3-specific chemotactic response of lymphocytes.Furthermore, tumor-cell-derived chemokines induced initial rapid phosphorylation of lymphocyte ERK followed by later inhibition of ERK phosphorylation. The culture of normal lymphocytes with HCC cell line supernatants or medium containing serum from HCC patients resulted in a significant reduction in the proportion of lymphocytes exhibiting surface expression of CXCR3. The reduction in T cell expression of CXCR3 resulted in reduced migration toward the ligand IP-10, and both

  1. Predictability of liver-related seromarkers for the risk of hepatocellular carcinoma in chronic hepatitis B patients.

    Directory of Open Access Journals (Sweden)

    Yu-Ju Lin

    Full Text Available BACKGROUND: Hepatitis B virus (HBV-related hepatocellular carcinoma (HCC is a major global health problem. A few risk calculators have been developed using mainly HBV seromarkers as predictors. However, serum HBV DNA level, HBV genotype, and mutants are not routinely checked in regular health examinations. This study aimed to assess the predictability of HCC risk in chronic hepatitis B patients, using a combination of liver-related seromarkers combined with or without HBV seromarkers. METHODS: A prospective cohort of 1,822 anti-HCV-seronegative chronic HBV carriers was included in this study. Liver-related seromarkers including aspartate aminotransferase (AST, alanine aminotransferase (ALT, alpha-fetoprotein (AFP, gamma-glutamyltransferase (GGT, total bilirubin, total protein, albumin, serum globulins, apolipoprotein A1, and apolipoprotein B were examined. Hazard ratios of HCC with 95% confidence intervals were estimated using Cox proportional hazards regression models. Regression coefficients of seromarkers significantly associated with HCC risk in multivariate analyses were used to create integer risk scores. The predictability of various risk models were assessed by area under receiver operating characteristic curves (AUROCs. RESULTS: During a median follow-up of 5.9 years, 48 newly-developed HCC cases were ascertained. Elevated serum levels of ALT (≥ 28 U/L, AFP (≥ 5 ng/mL, and GGT (≥ 41 U/L, an increased AST/ALT ratio (AAR, ≥ 1, and lowered serum levels of albumin (≤ 4.1 g/dL and alpha-1 globulin (≤ 0.2 g/dL were significantly associated with an increased HCC risk (P<0.05 in multivariate analysis. The risk model incorporating age, gender, AAR, and serum levels of ALT, AFP, GGT, albumin, and alpha-1 globulin had an AUROC of 0.89 for predicting 6-year HCC incidence. The AUROC was 0.91 after the addition of HBV seromarkers into the model, and 0.83 for the model without liver-related seromarkers, with the exception of ALT

  2. Clinicopathological and prognostic implications of endoglin (CD105) expression in hepatocellular carcinoma and its adjacent non-tumorous liver

    Institute of Scientific and Technical Information of China (English)

    Joanna W. Ho; Ronnie T. Poon; Chris K. Sun; Wei-Cheng Xue; Sheung-Tat Fan

    2005-01-01

    AIM: The expression pattern of endoglin (CD105) in hepatocellular carcinoma (HCC) has not been reported so far. We hypothesized that CD105 could differentially highlight a subset of microvessels in HCC, and intratumoral microvessel density (IMVD) by CD105 immunostaining (IMVD-CD105) could provide better prognostic information than IMVD by CD34 immunostaining (IMVD-CD34).METHODS: Paraffin blocks of tumor and adjacent nontumorous liver tissues from 86 patients who underwent curative resection of HCC were used for this study. Serial sections were stained for CD105 and CD34, respectively,to highlight the microvessels. IMVD was counted according to a standard protocol.RESULTS: In the HCC tissues, CD105 was either negatively or positively stained only in a subset of microvessels. In contrast, CD34 showed positive and more extensive microvessel staining in all cases examined. However, in the adjacent non-tumorous liver sections, CD105 showed a diffuse pattern of microvessel staining in 20 of 86 cases,while CD34 showed negative or only focal staining of the sinusoids around portal area. Correlation with clinicopathological data demonstrated that lower scores of IMVD-CD105 were found in larger sized tumors [mean 41.4/0.74 mm2 (>5 cm tumor) vs 65.9/0.74 mm2(≤ 5 cm tumor), P = 0.043] and more aggressive tumors,as indicated by venous infiltration [36.8/0.74 mm2 (present)vs 64.2/0.74 mm2 (absent), P = 0.020], microsatellite nodules [35.1/0.74 mm2 (present) vs 65.9/0.74 mm2(absent), P = 0.012], and advanced TNM tumor stage [38.8/0.74 mm2 (stage 3 or 4) vs 68.3/0.74 mm2 (stage 1or 2), P = 0.014]. No prognostic significance was observed when median values were used as cut-off points using either IMVD-CD105 or IMVD-CD34. However, the presence of the diffuse pattern of CD105 expression in the adjacent non-tumorous liver tissues predicted a poorer disease-free survival (median 8.6 vs 21.5 mo, P = 0.026).CONCLUSION: Our data demonstrate that a lower IMVDCD105 is associated with

  3. Peri-Transplant Change in AFP Level: a Useful Predictor of Hepatocellular Carcinoma Recurrence Following Liver Transplantation.

    Science.gov (United States)

    Yoo, Tae; Lee, Kwang-Woong; Yi, Nam-Joon; Choi, Young Rok; Kim, Hyeyoung; Suh, Suk-Won; Jeong, Jae Hong; Lee, Jeong-Moo; Suh, Kyung-Suk

    2016-07-01

    Pretransplant alpha-fetoprotein (AFP) is a useful tumor marker predicting recurrence of hepatocellular carcinoma (HCC). Little is known, however, about the relationship between changes in AFP concentration and prognosis. This study investigated the clinical significance of change in peri-transplant AFP level as a predictor of HCC recurrence. Data from 125 HCC patients with elevated pretransplant AFP level who underwent liver transplantation (LT) between February 2000 and December 2010 were retrospectively reviewed. Patients with AFP normalization within 1 month after LT were classified into the rapid normalization group (n = 97), with all other patients classified into the non-rapid normalization group (n = 28). Tumor recurrence was observed in 17 of the 97 patients (17.5%) with rapid normalization; of these, 11 patients had high AFP levels and six had normal levels at recurrence. In contrast, tumor recurrence was observed in 24 of the 28 patients (85.7%) without rapid normalization, with all 24 having high AFP levels at recurrence. Multivariate analysis showed that non-rapid normalization (harzard ratio [HR], 4.41, P AFP level at 1 month is a useful clinical marker for HCC recurrence. Therefore, an adjuvant strategy and/or intensive screening are needed for patients who do not show rapid normalization.

  4. Simple Risk Score for Prediction of Early Recurrence of Hepatocellular Carcinoma within the Milan Criteria after Orthotopic Liver Transplantation

    Science.gov (United States)

    Feng, Jiliang; Wu, Jushan; Zhu, Ruidong; Feng, Dezhao; Yu, Lu; Zhang, Yan; Bu, Dayu; Li, Chenlei; Zhou, Yuyan; Si, Lianghao; Liu, Yuhan; Liang, Ziwei; Xu, Jianing; Wu, Tianjun

    2017-01-01

    Ten to twenty percent of the hepatocellular carcinoma (HCC) patients fulfilling the Milan criteria (MC) recurred within three years after orthotopic liver transplantation (OLT). We therefore utilize a training cohort to develop an improved prognostic model for predicting the recurrence in these patients. By univariate and multivariate analysis, AFP level [cut-off value: 321 ng/mL, area under the curve (AUC) = 0.724, 95% confidence interval (CI) = 0.604–0.843, P < 0.001] and cytokeratin-19 (CK19) and glypican-3 (GPC3) expression pattern from nine putative prognostic factors were entered in risk factor scoring model to conjecture the tumor recurrence. In the training cohort, the AUC value of the model was 0.767 (95% CI = 0.645–0.890, P < 0.001), which was the highest among all the elements. The model’s performance was then assessed using a validation cohort. In the validation cohort, the AUC value of the model was 0.843 (95% CI = 0.720−0.966, P < 0.001) which was higher than any other elements. The results indicated that model had high performance with good discrimination ability and significantly improved the predictive capacity for the recurrence of HCC patients within MC after OLT. PMID:28276470

  5. Transient suppression of hepatocellular replication in the mouse liver following transduction with recombinant adeno-associated virus.

    Science.gov (United States)

    Dane, A P; Cunningham, S C; Kok, C Y; Logan, G J; Alexander, I E

    2015-11-01

    Recombinant vectors based on adeno-associated virus (AAV) are proving to be powerful tools for genetic manipulation of the liver, for both discovery and therapeutic purposes. The system can be used to deliver transgene cassettes for expression or, alternatively, DNA templates for genome editing via homologous recombination. The replicative state of target cells is known to influence the efficiency of these processes and knowledge of the host-vector interactions involved is required for optimally effective vector deployment. Here we show, for the first time in vivo, that in addition to the known effects of hepatocellular replication on AAV-mediated gene transfer, the vector itself exerts a potent, albeit transient suppressive effect on cell cycle progression that is relieved on a time course that correlates with the known rate of clearance of input single-stranded vector DNA. This finding requires further mechanistic investigation, delineates an excellent model system for such studies and further deepens our insight into the complexity of interactions between AAV vectors and the cell cycle in a clinically promising target tissue.

  6. Association between Pre-Transplant Serum Malondialdehyde Levels and Survival One Year after Liver Transplantation for Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Leonardo Lorente

    2016-04-01

    Full Text Available Previous studies have found higher levels of serum malondialdehyde (MDA in hepatocellular carcinoma (HCC patients compared to healthy controls and higher MDA concentrations in tumoral tissue of HCC patients than in non-tumoral tissue. However, the association between pre-transplant serum levels of MDA and survival in HCC patients after liver transplantation (LT has not been described, and the aim of the present study was to determine whether such an association exists. In this observational study we measured serum MDA levels in 127 patients before LT. We found higher pre-LT serum MDA levels in 15 non-surviving than in 112 surviving patients one year after LT (p = 0.02. Exact binary logistic regression analysis revealed that pre-LT serum levels of MDA over 3.37 nmol/mL were associated with mortality after one year of LT (Odds ratio = 5.38; 95% confidence interval (CI = from 1.580 to infinite; p = 0.007 adjusting for age of the deceased donor. The main finding of our study was that there is an association between serum MDA levels before LT for HCC and 1-year survival after LT.

  7. Transjugular Retrograde Obliteration prior to Liver Resection for Hepatocellular Carcinoma Associated with Hyperammonemia due to Spontaneous Portosystemic Shunt

    Directory of Open Access Journals (Sweden)

    Fumio Chikamori

    2013-01-01

    Full Text Available A 67-year-old woman had hepatocellular carcinoma (HCC measuring 3.7 cm at S8 of the liver with hyperammonemia due to a spontaneous giant mesocaval shunt. Admission laboratory data revealed albumin, 2.9 g/dL; total bilirubin, 1.3 mg/dL; plasma ammonia level (NH3, 152 g/dL; total bile acid (TBA 108.5 μmoL/L; indocyanine green retention rate at 15 min (ICG15, 63%. Superior mesenteric arterial portography revealed a hepatofugal giant mesocaval shunt, and the portal vein was not visualized. Before surgery, transjugular retrograde obliteration (TJO for the mesocaval shunt was attempted to normalize the portal blood flow. Via the right internal jugular vein, a 6 F occlusive balloon catheter was inserted superselectively into the mesocaval shunt. The mesocaval shunt was successfully embolized using absolute ethanol and a 50% glucose solution. Eleven days after TJO, NH3, TBA, and ICG15 decreased to 56, 44, and 33, respectively. Superior mesenteric arterial portography after TJO revealed a hepatopetal portal flow. Partial hepatectomy of S8 was performed 25 days after TJO. The subsequent clinical course showed no complications, and the woman was discharged on postoperative day 14. We conclude that the combined therapy of surgery and TJO is an effective means of treating HCC with hyperammonemia due to a spontaneous portosystemic shunt.

  8. Barcelona clinic liver cancer nomogram and others staging/scoring systems in a French hepatocellular carcinoma cohort

    Science.gov (United States)

    Adhoute, Xavier; Pénaranda, Guillaume; Raoul, Jean Luc; Edeline, Julien; Blanc, Jean-Frédéric; Pol, Bernard; Campanile, Manuela; Perrier, Hervé; Bayle, Olivier; Monnet, Olivier; Beaurain, Patrick; Muller, Cyril; Castellani, Paul; Le Treut, Yves Patrice; Bronowicki, Jean Pierre; Bourlière, Marc

    2017-01-01

    AIM To compare the performances of the Barcelona clinic liver cancer (BCLC) nomogram and others systems (BCLC, HKLC, CLIP, NIACE) for survival prediction in a large hepatocellular carcinoma (HCC) French cohort. METHODS Data were collected retrospectively from 01/2007 to 12/2013 in five French centers. Newly diagnosed HCC patients were analyzed. The discriminatory ability, homogeneity ability, prognostic stratification ability Akaike information criterion (AIC) and C-index were compared among scoring systems. RESULTS The cohort included 1102 patients, mostly men, median age 68 [60-74] years with cirrhosis (81%), child-Pugh A (73%), alcohol-related (41%), HCV-related (27%). HCC were multinodular (59%) and vascular invasion was present in 41% of cases. At time of HCC diagnosis BCLC stages were A (17%), B (16%), C (60%) and D (7%). First line HCC treatment was curative in 23.5%, palliative in 59.5%, BSC in 17% of our population. Median OS was 10.8 mo [4.9-28.0]. Each system distinguished different survival prognosis groups (P < 0.0001). The nomogram had the highest discriminatory ability, the highest C-index value. NIACE score had the lowest AIC value. The nomogram distinguished sixteen different prognosis groups. By classifying unifocal large HCC into tumor burden 1, the nomogram was less powerful. CONCLUSION In this French cohort, the BCLC nomogram and the NIACE score provided the best prognostic information, but the NIACE could even help treatment strategies. PMID:28465639

  9. Liver fatty acid-binding protein (L-FABP) promotes cellular angiogenesis and migration in hepatocellular carcinoma.

    Science.gov (United States)

    Ku, Chung-Yu; Liu, Yu-Huei; Lin, Hsuan-Yuan; Lu, Shao-Chun; Lin, Jung-Yaw

    2016-04-01

    Liver fatty acid-binding protein (L-FABP) is abundant in hepatocytes and known to be involved in lipid metabolism. Overexpression of L-FABP has been reported in various cancers; however, its role in hepatocellular carcinoma (HCC) remains unclear. In this study, we investigated L-FABP and its association with vascular endothelial growth factors (VEGFs) in 90 HCC patients. We found that L-FABP was highly expressed in their HCC tissues, and that this expression was positively correlated with that of VEGF-A. Additionally, L-FABP significantly promoted tumor growth and metastasis in a xenograft mouse model. We also assessed the mechanisms of L-FABP activity in tumorigenesis; L-FABP was found to associate with VEGFR2 on membrane rafts and subsequently activate the Akt/mTOR/P70S6K/4EBP1 and Src/FAK/cdc42 pathways, which resulted in up-regulation of VEGF-A accompanied by an increase in both angiogenic potential and migration activity. Our results thus suggest that L-FABP could be a potential target for HCC chemotherapy.

  10. A possible role of microRNAs as predictive markers for the recurrence of hepatocellular carcinoma after liver transplantation.

    Science.gov (United States)

    Liese, Juliane; Peveling-Oberhag, Jan; Doering, Claudia; Schnitzbauer, Andreas A; Herrmann, Eva; Zangos, Stephan; Hansmann, Martin L; Moench, Christian; Welker, Martin W; Zeuzem, Stefan; Bechstein, Wolf O; Ulrich, Frank

    2016-03-01

    With favourable 5-year survival rates up to 75%, liver transplantation (LT) is the treatment of choice for hepatocellular carcinoma (HCC). Nonetheless, tumour recurrence after LT remains a challenge. The aim of this retrospective study was to develop a predictive score for tumour recurrence after LT by combining clinical parameters with HCC biomarkers (microRNA). A microRNA (miRNA) microarray analysis was used to compare miRNA expression patterns in tissue samples of 40 patients with and without HCC recurrence after LT. In a screening cohort (n = 18), the miRNA analysis identified significant differences in the expression of 13 miRNAs in patients with tumour recurrence. Using the most significant miRNAs in this screening cohort, we could develop a predictive score, which combined the expression levels of miR-214, miR-3187 and the Milan criteria, and we could define low- and high-risk groups for tumour recurrence and death. The above score was evaluated in a second and independent cohort (n = 22). In contrast to the Milan criteria alone, this score was significantly associated with tumour recurrence. Our analysis indicated that the use of a specific miRNA expression pattern in combination with a limited tumour burden as defined by the Milan criteria may lead to a more accurate prediction of tumour recurrence.

  11. The Hepatitis Viral Status in Patients With Hepatocellular Carcinoma: a Study of 3843 Patients From Taiwan Liver Cancer Network

    Science.gov (United States)

    Chang, Il-Chi; Huang, Shiu-Feng; Chen, Pei-Jer; Chen, Chi-Ling; Chen, Chao-Long; Wu, Cheng-Chung; Tsai, Cheng-Chung; Lee, Po-Huang; Chen, Miin-Fu; Lee, Chuan-Mo; Yu, Hsien-Chung; Lo, Gin-Ho; Yeh, Chau-Ting; Hong, Chih-Chen; Eng, Hock-Liew; Wang, John; Tseng, Hui-Hwa; Hsiao, Cheng-Hsiang; Wu, Hong-Dar Isaac; Yen, Tseng-Chang; Liaw, Yun-Fan

    2016-01-01

    Abstract Hepatocellular carcinoma (HCC) is the leading cancer death in Taiwan. Chronic viral hepatitis infections have long been considered as the most important risk factors for HCC in Taiwan. The previously published reports were either carried out by individual investigators with small patient numbers or by large endemic studies with limited viral marker data. Through collaboration with 5 medical centers across Taiwan, Taiwan liver cancer network (TLCN) was established in 2005. All participating centers followed a standard protocol to recruit liver cancer patients along with their biosamples and clinical data. In addition, detailed viral marker analysis for hepatitis B virus (HBV) and hepatitis C virus (HCV) were also performed. This study included 3843 HCC patients with available blood samples in TLCN (recruited from November 2005 to April 2011). There were 2153 (56.02%) patients associated with HBV (HBV group); 969 (25.21%) with HCV (HCV group); 310 (8.07%) with both HBV and HCV (HBV+HCV group); and 411 (10.69%) were negative for both HBV and HCV (non-B non-C group). Two hundred two of the 2463 HBV patients (8.20%) were HBsAg(-), but HBV DNA (+). The age, gender, cirrhosis, viral titers, and viral genotypes were all significantly different between the above 4 groups of patients. The median age of the HBV group was the youngest, and the cirrhotic rate was lowest in the non-B non-C group (only 25%). This is the largest detailed viral hepatitis marker study for HCC patients in the English literatures. Our study provided novel data on the interaction of HBV and HCV in the HCC patients and also confirmed that the HCC database of TLCN is highly representative for Taiwan and an important resource for HCC research. PMID:27082566

  12. The European Policy for Liver Allocation in Patients Affected by Hepatocellular Carcinoma.

    Science.gov (United States)

    Sandro, Stefano Di; Ferla, Fabio; Lauterio, Andrea; Mangoni, Iacopo; Carlis, Riccardo De; Buscemi, Vincenzo; Carlis, Luciano De

    2017-01-01

    The main goal of allocation system is to guarantee an equal access to the limited resource of liver grafts for every class of patients on the waiting list, balancing between the ethical principles of equity, utility, benefit, need, and fairness. The aim of this review was to analyze liver allocation policies among these organizations, focusing on HCC. The European area considered for this analysis included 6 macro-areas or countries, which are congregated from the same policy of liver sharing and allocation. By this definition, the 6 areas identified are: Centro Nazionale Trapianti (CNT) in Italy; Eurotransplant (Germany, the Netherlands, Belgium, Luxembourg, Austria, Hungary, Slovenia, and Croatia); Organizacion Nacional de Transplantes (ONT) in Spain; Etablissement francais des Greffes (EfG) in France; NHS Blood Transplant (NHSBT) in the United Kingdom and Ireland; Scandiatransplant (Sweden, Norway, Finland, Denmark, and Iceland); Romanian National Policy. Each identified area, as network for organ sharing in Europe, adopts a basic allocation system that consider a policy center oriented or patient oriented. Priorization of patients affected by HCC in the waiting list for deceased donors liver transplant worldwide is dominated by 2 main principles: urgency and utility. The main message of this review is the absence of a common organs allocation policy over the Eurpean countries. Despite that, long-term survival of the community of patients listed for transplant due to HCC results, however, highly acceptable in Europe and comparable to the long-term survial reported in the UNOS register. Celsius.

  13. Identifying candidates with favorable prognosis following liver transplantation for hepatocellular carcinoma: Data mining analysis.

    Science.gov (United States)

    Tanaka, Tomohiro; Kurosaki, Masayuki; Lilly, Leslie B; Izumi, Namiki; Sherman, Morris

    2015-07-01

    The optimal cutoff of each value in configuring selection criteria for pre-transplant assessment of hepatocellular carcinoma (HCC) remains uncertain. To build a predictive model for recurrent HCC, we performed data mining analysis on patients who underwent LT for HCC at University Health Network (n = 246). The model was externally validated using a cohort from the Scientific Registry of Transplant Recipients (SRTR) database (n = 9,769). Among 246 patients, 14.6% (n = 36) experienced recurrent HCC within 2.5 years post-LT. The risk prediction model for recurrent HCC identified two subgroups with low-risk (total tumor diameter [TTD] 4 cm and/or AFP >73 ng/ml, n = 111). The reproducibility of the model was validated through the SRTR database; overall patient survival rate was significantly better in low-risk group than high-risk group (P data mining analysis efficiently classify patients according by the post-transplant prognosis. © 2015 Wiley Periodicals, Inc.

  14. RASSF1A and DOK1 Promoter Methylation Levels in Hepatocellular Carcinoma, Cirrhotic and Non-Cirrhotic Liver, and Correlation with Liver Cancer in Brazilian Patients

    Science.gov (United States)

    Araújo, Oscar C.; Rosa, Agatha S.; Fernandes, Arlete; Niel, Christian; Villela-Nogueira, Cristiane A.; Pannain, Vera; Araujo, Natalia M.

    2016-01-01

    Hepatocellular carcinoma (HCC) is the second most common cause of cancer mortality worldwide. Most cases of HCC are associated with cirrhosis related to chronic hepatitis B virus or hepatitis C virus infections. Hypermethylation of promoter regions is the main epigenetic mechanism of gene silencing and has been involved in HCC development. The aim of this study was to determine whether aberrant methylation of RASSF1A and DOK1 gene promoters is associated with the progression of liver disease in Brazilian patients. Methylation levels were measured by pyrosequencing in 41 (20 HCC, 9 cirrhotic, and 12 non-cirrhotic) liver tissue samples. Mean rates of methylation in RASSF1A and DOK1 were 16.2% and 12.0% in non-cirrhotic, 26.1% and 19.6% in cirrhotic, and 59.1% and 56.0% in HCC tissues, respectively, showing a gradual increase according to the progression of the disease, with significantly higher levels in tumor tissues. In addition, hypermethylation of RASSF1A and DOK1 was found in the vast majority (88%) of the HCC cases. Interestingly, DOK1 methylation levels in HCC samples were significantly higher in the group of younger (<40 years) patients, and higher in moderately differentiated than in poorly differentiated tumors (p < 0.05). Our results reinforce the hypothesis that hypermethylation of RASSF1A and DOK1 contributes to hepatocarcinogenesis and is associated to clinicopathological characteristics. RASSF1A and DOK1 promoter hypermethylation may be a valuable biomarker for early diagnosis of HCC and a potential molecular target for epigenetic-based therapy. PMID:27078152

  15. Comparative Analysis of Ο-glycans from Human Hepatocellular Carcinoma HepG2 and Normal Liver Cells L02†%人肝癌细胞HepG2与正常肝细胞L02的Ο-糖链的比较分析

    Institute of Scientific and Technical Information of China (English)

    潘丽英; 顾笑; 王承健; 强珊; 黄琳娟; 张英; 王仲孚

    2015-01-01

    HepG2 ( a primary hepatocellular carcinoma cell line ) and L02 ( ones derived from normal liver tissue) cells were chosen as model cell lines for research. The O-glycans of the total proteins extracted from HepG2 and L02 cells were released by Carlson reductive β-elimination. The released O-glycans previously purified by Dowex 50 WX8-400 cation exchange resin and C18 cartridges were identified by electrospray ioniza-tion mass spectrometry( ESI-MS) and MS/MS. For comparision studies, β-cyclodextrin was used as the inter-nal standard for relative quantitative analysis of the O-glycans derived from HepG2 and L02 cells by MS. As results, 10 O-glycans were observed in HepG2 cell line and 9 O-glycans were detected in L02 cell line. More-over, 9 O-glycans were observed in both HepG2 and L02 cells, wherears 1 truncated O-glycan assigned as H1A1(NeuAc-GalNAc, sialyl Tn antigen, ubiquitous in cancer cells), was only found in HepG2 cells. t-Test results show that 5 and 2 O-glycans in HepG2 cells have significant differences ( P<0. 01 and P<0. 05 , recpectively) , when compared to those of L02 cells. Our studies show methodological significance in structural investigation of O-glycans expressed in hepatocellular carcinoma and early biomarker discovery in clinical diag-nose.%以培养的原发性肝细胞癌HepG2细胞和正常肝细胞L02为研究对象,用细胞裂解液提取总蛋白,然后采用Carlson还原性β-消除法释放O-糖链,以阳离子交换柱结合C18柱纯化分离O-糖链,用电喷雾电离质谱( ESI-MS)和串联质谱( MS/MS)对O-糖链进行序列鉴定,以β-环糊精为内标对2种细胞系的O-糖链进行定量比较分析.结果表明,在肝癌细胞系HepG2中检测到10种O-糖链,正常细胞系L02中检测到9种O-糖链,其中9种O-糖链是2种细胞系中共有的,但HepG2中存在癌细胞中特有的缩短的O-糖链N1A1( NeuAc-GalNAc, sialyl Tn 抗原). t检验结果表明, HepG2与L02相比,在检测到的10种O-糖链中有5种的

  16. Expression of class Ⅰ MHC molecule, HSP70 and TAP in human hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Xiao-Ling Deng; Wei Chen; Mei-Ying Cai; Da-Peng Wei

    2003-01-01

    AIM: To demonstrate whether class Ⅰ MHC molecule,transporter associated with antigen processing (TAP), and heat-shock proteion70 (HSP70) expressed in liver cancer cells before the design and construction of CTL vaccine against hepatocellular carcinoma (HCC).METHODS: We studied 30 HCC specimens by labeled streptavidin biotin (LSAB) method of immunohistochemistry.RESULTS: The results showed that the majority of HCC cells investigated naturally expressed class Ⅰ MHC and TAP,which were different from other tumor cells. Furthermore,we found that HSP70 expressed not only in cellular cytoplasm, but also on the cell surface in HCC.CONCLUSION: Our findings indicate that our understanding about immune escape mechanisms employed by HCC cells may be further improved. It is important to design and construct CTL vaccine against HCC.

  17. Role of diffusion-weighted imaging, apparent diffusion coefficient and correlation with hepatobiliary phase findings in the differentiation of hepatocellular carcinoma from dysplastic nodules in cirrhotic liver.

    Science.gov (United States)

    Inchingolo, Riccardo; De Gaetano, Anna Maria; Curione, Davide; Ciresa, Marzia; Miele, Luca; Pompili, Maurizio; Vecchio, Fabio Maria; Giuliante, Felice; Bonomo, Lorenzo

    2015-04-01

    To investigate the utility of diffusion-weighted imaging (DWI), apparent diffusion coefficient (ADC) and the correlation with hepatobiliary phase (delayed phase imaging, DPI) findings in the differentiation of cirrhotic hepatocellular nodules. Forty-three patients with 53 pathology-proven nodules (29 hepatocellular carcinomas (HCCs), 13 high-grade (HGDNs) and 11 low-grade dysplastic nodules (LGDNs); mean size 2.17 cm, range 1-4 cm), who underwent liver MRI with DWI and DPI sequences, were retrospectively reviewed. Lesions were classified as hypointense, isointense, or hyperintense relative to the adjacent liver parenchyma. ADC of each nodule, of the surrounding parenchyma, and lesion-to-liver ratio were calculated. Hyperintensity versus iso/hypointensity on DWI, hypointensity versus iso/hyperintensity on DPI, and the mean lesion-to-liver ratio showed a statistically significant difference both between HCCs versus DNs and between "HCCs + HGDNs" versus LGDNs (p Correlation of DWI with DPI improves differential diagnosis of cirrhotic nodules. • Characterization of atypically enhancing lesions becomes more confident.

  18. Molecular Structure of Human-Liver Glycogen.

    Directory of Open Access Journals (Sweden)

    Bin Deng

    Full Text Available Glycogen is a highly branched glucose polymer which is involved in maintaining blood-sugar homeostasis. Liver glycogen contains large composite α particles made up of linked β particles. Previous studies have shown that the binding which links β particles into α particles is impaired in diabetic mice. The present study reports the first molecular structural characterization of human-liver glycogen from non-diabetic patients, using transmission electron microscopy for morphology and size-exclusion chromatography for the molecular size distribution; the latter is also studied as a function of time during acid hydrolysis in vitro, which is sensitive to certain structural features, particularly glycosidic vs. proteinaceous linkages. The results are compared with those seen in mice and pigs. The molecular structural change during acid hydrolysis is similar in each case, and indicates that the linkage of β into α particles is not glycosidic. This result, and the similar morphology in each case, together imply that human liver glycogen has similar molecular structure to those of mice and pigs. This knowledge will be useful for future diabetes drug targets.

  19. Molecular Structure of Human-Liver Glycogen

    Science.gov (United States)

    Deng, Bin; Sullivan, Mitchell A.; Chen, Cheng; Li, Jialun; Powell, Prudence O.; Hu, Zhenxia; Gilbert, Robert G.

    2016-01-01

    Glycogen is a highly branched glucose polymer which is involved in maintaining blood-sugar homeostasis. Liver glycogen contains large composite α particles made up of linked β particles. Previous studies have shown that the binding which links β particles into α particles is impaired in diabetic mice. The present study reports the first molecular structural characterization of human-liver glycogen from non-diabetic patients, using transmission electron microscopy for morphology and size-exclusion chromatography for the molecular size distribution; the latter is also studied as a function of time during acid hydrolysis in vitro, which is sensitive to certain structural features, particularly glycosidic vs. proteinaceous linkages. The results are compared with those seen in mice and pigs. The molecular structural change during acid hydrolysis is similar in each case, and indicates that the linkage of β into α particles is not glycosidic. This result, and the similar morphology in each case, together imply that human liver glycogen has similar molecular structure to those of mice and pigs. This knowledge will be useful for future diabetes drug targets. PMID:26934359

  20. Hepatocellular carcinoma (HCC) in non-cirrhotic liver: clinical, radiological and pathological findings

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    Di Martino, Michele; Di Miscio, Rossella; Lombardo, Concetta Valentina; Catalano, Carlo [University of Rome ' ' Sapienza' ' , Department of Radiological Sciences, Oncology and Anatomical Pathology, Rome (Italy); Saba, Luca; Piga, Mario [Department of Radiology Azienda Ospedaliera Universitaria (A.O.U.), Monserrato (Italy); Bosco, Sandro [University of Rome ' ' Sapienza' ' , Department of Molecular Medicine, Rome (Italy); Rossi, Massimo [University of Rome ' ' Sapienza' ' , Department of General Surgery, Division of Organ Transplantation, Rome (Italy); Miles, Kirchin A. [Worldwide Medical and Regulatory Affairs, Milan (Italy); Tamponi, Elisabetta [Azienda Ospedaliera Universitaria (A.O.U.), Department of Anatomical Pathology, Monserrato (Italy)

    2014-07-15

    Our aim was to evaluate the clinical and pathological findings, mutidetector-row computed tomography (MDCT) and magnetic resonance imaging (MRI) appearances, treatment and 1-year survival of patients with HCC in non-cirrhotic liver. Histopathological and laboratory findings of 30 non-cirrhotic patients with 32 HCCs were reviewed retrospectively. MDCT and gadobenate dimeglumine-enhanced MR images were evaluated in consensus by two radiologists in terms of HCC size, presence of tumour capsule, necrosis, haemorrhage, fat and calcification, and vascular involvement. Imaging patterns were compared directly with HCC findings in a matched group of cirrhotic patients. No differences between non-cirrhotic and cirrhotic patients were noted in terms of serum α-fetoprotein levels (elevated in 11 [36.7 %] and 21 [35 %] patients, respectively). The imaging appearance at CT and contrast-enhanced MRI was typical in 27 (84.3 %) and 28 (87.5 %) cases respectively. Most lesions presented as a well-differentiated large solitary mass, with well-defined margins, areas of necrosis and peripheral capsule. No significant differences in HCC pattern were observed between cirrhotic and non-cirrhotic liver. In non-cirrhotic patients, HCC is more likely to manifest as an asymptomatic mass with elevation of serum tumour markers similar to that seen in cirrhotic patients. HCC in cirrhotic and non-cirrhotic livers show similar enhancement patterns. (orig.)

  1. The association of coffee intake with liver cancer risk is mediated by biomarkers of inflammation and hepatocellular injury: data from the European Prospective Investigation into Cancer and Nutrition.

    Science.gov (United States)

    Aleksandrova, Krasimira; Bamia, Christina; Drogan, Dagmar; Lagiou, Pagona; Trichopoulou, Antonia; Jenab, Mazda; Fedirko, Veronika; Romieu, Isabelle; Bueno-de-Mesquita, H Bas; Pischon, Tobias; Tsilidis, Kostas; Overvad, Kim; Tjønneland, Anne; Bouton-Ruault, Marie-Christine; Dossus, Laure; Racine, Antoine; Kaaks, Rudolf; Kühn, Tilman; Tsironis, Christos; Papatesta, Eleni-Maria; Saitakis, George; Palli, Domenico; Panico, Salvatore; Grioni, Sara; Tumino, Rosario; Vineis, Paolo; Peeters, Petra H; Weiderpass, Elisabete; Lukic, Marko; Braaten, Tonje; Quirós, J Ramón; Luján-Barroso, Leila; Sánchez, María-José; Chilarque, Maria-Dolores; Ardanas, Eva; Dorronsoro, Miren; Nilsson, Lena Maria; Sund, Malin; Wallström, Peter; Ohlsson, Bodil; Bradbury, Kathryn E; Khaw, Kay-Tee; Wareham, Nick; Stepien, Magdalena; Duarte-Salles, Talita; Assi, Nada; Murphy, Neil; Gunter, Marc J; Riboli, Elio; Boeing, Heiner; Trichopoulos, Dimitrios

    2015-12-01

    Higher coffee intake has been purportedly related to a lower risk of liver cancer. However, it remains unclear whether this association may be accounted for by specific biological mechanisms. We aimed to evaluate the potential mediating roles of inflammatory, metabolic, liver injury, and iron metabolism biomarkers on the association between coffee intake and the primary form of liver cancer-hepatocellular carcinoma (HCC). We conducted a prospective nested case-control study within the European Prospective Investigation into Cancer and Nutrition among 125 incident HCC cases matched to 250 controls using an incidence-density sampling procedure. The association of coffee intake with HCC risk was evaluated by using multivariable-adjusted conditional logistic regression that accounted for smoking, alcohol consumption, hepatitis infection, and other established liver cancer risk factors. The mediating effects of 21 biomarkers were evaluated on the basis of percentage changes and associated 95% CIs in the estimated regression coefficients of models with and without adjustment for biomarkers individually and in combination. The multivariable-adjusted RR of having ≥4 cups (600 mL) coffee/d compared with coffee intake and HCC risk and thereby suspected mediation was confirmed for the inflammatory biomarker IL-6 and for the biomarkers of hepatocellular injury glutamate dehydrogenase, alanine aminotransferase, aspartate aminotransferase (AST), γ-glutamyltransferase (GGT), and total bilirubin, which-in combination-attenuated the regression coefficients by 72% (95% CI: 7%, 239%). Of the investigated biomarkers, IL-6, AST, and GGT produced the highest change in the regression coefficients: 40%, 56%, and 60%, respectively. These data suggest that the inverse association of coffee intake with HCC risk was partly accounted for by biomarkers of inflammation and hepatocellular injury.

  2. Antidiabetic therapy and increased risk of hepatocellular carcinoma in chronic liver disease

    Institute of Scientific and Technical Information of China (English)

    Valter Donadon; Massimiliano Balbi; Michela Ghersetti; Silvia Grazioli; Antonio Perciaccante; Giovanni Della Valentina; Rita Gardenal; Maria Dal Mas; Pietro Casarin; Giorgio Zanette; Cesare Miranda

    2009-01-01

    AIM:To explore the association between hepatocellular carcinoma (HCC) and type 2 diabetes mellitus,describe the temporal relations between the onset of diabetes and the development of HCC and evaluate the possible effects of antidiabetic therapy on HCC risk.METHODS:We recruited 465 HCC patients, 618 with cirrhosis and 490 control subjects. We evaluated the odds ratio (OR) for HCC by univariate and multivariate analysis. Moreover, OR for HCC in diabetic subjects treated with insulin or sulphanylureas and with metformin were calculated.RESULTS:The prevalence of diabetes mellitus was 31.2% in HCC, 23.3% in cirrhotic patients and 12.7% in the Control group. By univariate and multivariate analysis, the OR for HCC in diabetic patients were respectively 3.12 (CI 2.2-4.4, P < 0.001) and 2.2 (CI 1.2-4.4, P = 0.01). In 84.9% of cases, type 2 diabetes mellitus was present before the diagnosis of HCC. Moreover, we report an OR for HCC of 2.99 (CI 1.34-6.65, P = 0.007) in diabetic patients treated with insulin or sulphanylureas, and an OR of 0.33 (CI 0.1-0.7,P = 0.006) in diabetic patients treated with metformin.= 0.006) in diabetic patients treated with metformin.CONCLUSION:Our study confirms that type 2 diabetes mellitus is an independent risk factor for HCC and pre-exists in the majority of HCC patients. Moreover, in male patients with type 2 diabetes mellitus, our data shows a direct association of HCC with insulin and sulphanylureas treatment and an inverse relationship with metformin therapy.

  3. The Effect of Nano-apatite on the Expression of Telomerase Gene of Human Hepatocellular Carcinoma Cells

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    To investigate the effect of nano- apatite on the expression of the telomerase gene of human hepatocellular carcinoma cell lines and further explore the mechanism of the nano-apatite inhibiting cancer cells. Using the hybridization in situ method to detect the expression of the telomerase gene of human hepatocellular carcinoma cells treated with the nano- apatite for 4 h at 37 ℃. The hybridization in situ showed that the cytoplasm of the positive cells was stained in nigger-brown. The positive cell rate of the control group was 88.49% , the cisplatin group was 25.6% , the nano-apatite group was 63.6% . The activity oftelomerase gene was both obviously declined comparing with the control group and the difference had significance (p < 0.05, p < 0.01 ). The nanoapatite obviously inhabit the expression of the telomerase gene of human hepatocellular carcinoma cells.

  4. Risk factors for fatal recurrence of hepatocellular carcinoma and their role in selecting candidates for liver transplantation

    Institute of Scientific and Technical Information of China (English)

    Wei-Long Zou; Yun-Jin Zang; Xin-Guo Chen; Zhong-Yang Shen

    2008-01-01

    BACKGROUND:With the maturation and popularization of skills in liver transplantation (LT), patients with hepatocellular carcinoma (HCC) have an alternative choice. LT as a curative treatment for HCC provides good liver function and systemic condition to recipients. Preoperative tumor characteristics are critical in selecting optimal candidates for LT to optimize the use of donor livers and to achieve a long-term survival. The present study aimed to elucidate the risk factors of HCC involved in fatal recurrence in the ifrst year after LT and to investigate their utility in selecting suitable candidates for LT. METHODS:From April 2002 to October 2005, 303 patients who had received orthotopic LT for HCC were reviewed. Of these patients, those with diffuse intrahepatic or multiple systemic recurrent lesions who died within 1 year after surgery were investigated as fatal recurrence group (48 patients) and the remaining patients including those who were disease-free without recurrence, those who were alive with recurrence in the ifrst year, or those who died in the ifrst year of other causes, served as control group (255). The two groups were compared by demographics, tumor, and histopathological characteristics for their prognostic signiifcance by logistic regression analysis. RESULTS:Multivariate analysis between the fatal recurrence group and the control group showed that the presence of vascular invasion, a tumor size greater than 6.5 cm, and a preoperative serum alpha-fetoprotein (AFP) level greater than 1000 μg/L were risk factors for fatal recurrence. Increased risk factors reduced the suitability of candidates for LT and diminished survival in the ifrst year. 85.71% of the patients with all three risk factors, 37.84%of those with two factors, 13.64%of those with one factor, and 6.71%of those without risk factors died from tumor recurrence within 1 year after transplantation. CONCLUSIONS:Vascular invasion, tumor size ≥6.5 cm, and preoperative serum AFP level

  5. MCM3AP,a Novel HBV Integration Site in Hepatocellular Carcinoma and Its Implication in Hepatocarcinogenesis

    Institute of Scientific and Technical Information of China (English)

    王晶; 林菊生; 常莹; 黎培元; 杨玉珍

    2010-01-01

    A novel HBV integration site involved in hepatocarcinogenesis was investigated. The HBV DNA integration sites were detected by Alu-PCR in hepatocellular carcinoma tissues, matched surrounding liver tissues in 30 patients with hepatitis B-related hepatocellular carcinoma (HCC) and 3 cases of normal liver tissues. The integration sites and flanking sequences in human genome were sequenced and blasted, and the expression of integrated HBV genes was determined by reverse transcriptase-polymerase chain reaction ...

  6. Apoptosis induced by propolis in human hepatocellular carcinoma cell line.

    Science.gov (United States)

    Choi, Y H; Lee, W Y; Nam, S Y; Choi, K C; Park, Y E

    1999-07-01

    Propolis has been reported to exhibit a wide spectrum of activities including antibiotic, antiviral, anti-inflammatory, immunostimulatory and tumor carcinostatic properties. We showed propolis induced apoptosis in a human hepatoma cell line (SNU449) by FITC-Annexin V/PI staining. We also compared the apoptosis inducing effect between Korean and Commercial (Sigma # p-1010) propolis. There was no difference on apoptosis between them.

  7. Heat shock protein 70 chaperoned alpha-fetoprotein in human hepatocellular carcinoma cell line BEL-7402

    Institute of Scientific and Technical Information of China (English)

    Xiao-Ping Wang; Qiao-Xia Wang; Hai-Yan Li; Rui-Fen Chen

    2005-01-01

    AIM: To investigate the interaction between heat shock protein 70 (HSP70) and α-fetoprotein (AFP) in human hepatocellular carcinoma (HCC) cell line BEL7402.METHODS: The expression and localization of HSP70 and AFP in human HCC cell line BEL-7402 were determined by immunocytochemistry and indirect immunofluorescence cytochemical staining. The interaction between HSP70 and AFP in HCC cells was analyzed by immunoprecipitation and Western blot.RESULTS: Immunocytochemical staining detection showed that HCC cell BEL-7402 expressed a high level of HSP70 and AFP synchronously. Both were stained in cell plasma.AFP existed in the immunoprecipitate of anti-HSP70 mAb,while there was HSP70 in the immunoprecipitate of antiAFP mAb.CONCLUSION: HSP70 chaperones AFP in human HCCcell BEL-7402. The interaction between HSP70 and AFP in human HCC cell can be a new route to study the pathogenesis and immunotherapy of HCC.

  8. Alpha-1-antitrypsin deficiency: from genoma to liver disease. PiZ mouse as model for the development of liver pathology in human.

    Science.gov (United States)

    Giovannoni, Isabella; Callea, Francesco; Stefanelli, Marta; Mariani, Riccardo; Santorelli, Filippo M; Francalanci, Paola

    2015-01-01

    Homozygous individuals with alpha-1-antitrypsin deficiency (AATD) type PiZ have an increased risk of chronic liver disease and hepatocellular carcinoma (HCC). It is noteworthy that HCCs are composed by hepatocytes without accumulation of AAT, but the reason for this remains unclear. The aim of this study was to determine liver pathology in PiZ mice, focusing the attention on the distribution of AAT globules in normal liver, regenerative foci and neoplastic nodules. Liver of 79 PiZ mice and 18 wild type (Wt) was histologically analysed for steatosis, clear cell foci, hyperplasia and neoplasia. The expression of human-AAT transgene and murine AAT, in non-neoplastic liver and in hyperplastic/neoplastic nodules was tested by qPCR and qRT-PCR. RT-PCR was used to study expression of hepatic markers: albumin, α-foetoprotein, transthyretin, AAT, glucose-6-phospate, tyrosine aminotransferase. Liver pathology was seen more frequently in PiZ (47/79) than in Wt (5/18) and its development was age related. In older PiZ mice (18-24 m), livers showed malignant tumours (HCC and angiosarcoma) (17/50), hyperplastic nodules (28/50), non-specific changes (33/50), whereas only 9/50 were normal. Both human-AATZ DNA and mRNA showed no differences between tumours/nodules and normal liver, while murine-AAT mRNA was reduced in tumours/nodules. Accumulation of AAT is associated with an increased risk of liver nodules. The presence of globule-devoid hepatocytes and the reduced expression of murine-AAT mRNA in hyperplastic and neoplastic nodules suggest that these hepatic lesions in AATD could originate from proliferating dedifferentiated cells, lacking AAT storage and becoming capable of AFP re-expression. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  9. Trisomy 1 and 8 occur frequently in hepatocellular carcinoma but not in liver cell adenoma and focal nodular hyperplasia. A fluorescence in situ hybridization study.

    Science.gov (United States)

    Nasarek, A; Werner, M; Nolte, M; Klempnauer, J; Georgii, A

    1995-01-01

    Conventional cytogenetic studies revealed gains and structural aberrations of chromosome 1 to be the most consistent chromosomal aberrations in hepatocellular carcinoma (HCC). We investigated touch preparations of eight HCC, five cholangiocellular carcinomas (CCC), five liver cell adenomas (LCA), four focal nodular hyperplasias (FNH) as well as nine specimens of normal liver tissue using fluorescence in situ hybridization (FISH) with centromere specific probes for chromosomes 1 and 8. Polysomies of chromosome 1, especially trisomy 1, were found in five of eight HCC and four of five CCC but in no normal liver tissue or benign tumour. Only three of seven cases of HCC revealed trisomy 8 whereas the five benign liver tumours and all normal liver tissues examined had disomy 8. Our results confirm conventional cytogenetic findings in terms of chromosome 1 aberrations in HCC although they are not specific for these types of malignant liver tumours. Since alpha-satellite probes were used in our study, only gains or losses including the centromeric regions of the chromosomes 1 and 8 could be detected. Nevertheless, our findings suggest that FISH may help in the differential diagnosis of malignant versus benign neoplasms of the liver.

  10. [Two cases of patients with hepatocellular carcinoma (HCC) that developed in cryptogenic cirrhosis suggestive of nonalcoholic steatohepatitis (NASH) as background liver disease after clinical courses of 26 years].

    Science.gov (United States)

    Tsutsumi, Koichiro; Nakayama, Haruo; Sakai, Yoshitaka; Kojima, Yasuhiro; Dairaku, Naohiro; Ojima, Toshiaki; Kusano, Masao; Ikeya, Shinichi; Sugai, Yoshiki; Hiwatashi, Nobuo

    2007-05-01

    We report two cases of patients with hepatocellular carcinoma (HCC) that developed in cryptogenic cirrhosis suggestive of nonalcoholic steatohepatitis (NASH) as background liver disease. Case 1 was a 68-year-old woman, and case 2 was a 46-year-old man. They were admitted to our department for evaluation and treatment of HCC. The causes of the underlying liver disease were not determined from blood tests. However, histological analysis of non-tumor tissues of the liver revealed cirrhosis with few fat droplets. Both patients had undergone liver biopsy 26 years before the treatment of HCC. Histological review of the biopsy specimens revealed NASH (case 1) and fatty liver (case 2), respectively. It was suggested that these cases progressed from NASH and fatty liver, respectively, to NASH-related cirrhosis (so called burned-out NASH), eventually, developing HCC. These findings suggest that substantial number of burned-out NASH cases may be included in those with cryptogenic cirrhosis. These two patients are indicative cases that may reveal the long-term natural course of fatty liver and NASH.

  11. Hepatocellular Carcinoma Mimicking Liver Abscesses in a Cirrhotic Patient with Severe Septic Shock as a Result of Salmonella O9 HG Infection

    Directory of Open Access Journals (Sweden)

    Shuichi Hagiwara

    2009-04-01

    Full Text Available We describe a case of severe Salmonella O9 HG sepsis with a mass in the liver, which was diagnosed as hepatocellular carcinoma (HCC by autopsy of the liver. The patient was a 67-year-old man with chronic high blood pressure. In addition, he was an alcoholic and had been drinking every day for many years. He had had a dinner of ‘sukiyaki’ with a raw egg two days before admission. The next morning, he had developed vomiting, diarrhea, and abdominal pain. Salmonella O9 HG was found in the blood and stool cultures. In the computed tomography (CT finding of the liver, there was a 2 cm early-enhanced mass with a multilocular structure, with ringed enhancement and daughter nodes. Since we thought that the mass was a liver abscess, we performed needle aspiration from the liver mass and were able to withdraw blood. Despite adequate antibiotic treatment, the patient died as a result of complications on the 55th day after admission. After the patient’s death, we conducted an autopsy. There were two HCC masses, a moderately-differentiated and a well-differentiated mass, as a result of alcoholic cirrhosis of the liver. As the HCC had multilocular cyst-like structures, which were fiber- and necrosis-rich, CT images of the liver masses resembled abscesses.

  12. [Hepatocellular carcinoma. Part 2. Treatment].

    Science.gov (United States)

    Conte, V P

    2000-01-01

    Recent improvements on the therapeutical management of hepatocellular carcinoma are revised with special attention to evaluate the role of surgery for the disease. Considering that definitive surgical intervention is not feasible in most cases because of extreme tumor extension, multiplicity of tumor foci, and associated advanced liver cirrhosis at the time of diagnosis, others forms of treatment are listed, such as transcatheterarterial chemoembolization, percutaneous ethanol and acetic acid injections, and chemotherapy only to a small portion of patients with no indication for standard treatments. The emerging role of retinoic acid metabolism blocking agents, was examined and may offer a significant new potential treatment for cancer, inclusive the possibility of combining other anticancer drugs with exogenous retinoids or modulation of endogenous retinoids as a real opportunity to advance our ability to treat or prevent human cancer effectively Octreotide, nitrosamine and other drugs are analyzed and is concluded that improves survival and is a valuable alternative in the treatment of inoperable hepatocellular carcinoma. The potential role of intersticial laser coagulation for patients with irresectable hepatic tumors was investigated, and in terms of experience, it has now been developed sufficiently to study its effect on these patients survival. The homeostatic control of angiogenesis and its influences on the tumor growth and for migration of metastatic cells, was focused in this concise review, given that hepatocytes are the source of much of the precursor pool, regulation of angiogenesis may be regarded as a new liver function with important consequences for tissue repair and cancer. Early hepatocellular carcinoma and its recognition in routine clinical practice contributes to improved patients survival. Recombinant-Interferon-alpha therapy surely prevents, the development of cirrhosis or hepatocellular carcinoma in about one-third of patients, with

  13. Safety of frozen liver for human consumption

    Directory of Open Access Journals (Sweden)

    Ghada A.K. Kirrella

    2017-07-01

    Full Text Available The objective of this study was to ensure and evaluate the safety of imported frozen beef liver traded in supermarkets of Kafr El-Sheikh Governorate, Egypt, through detection of Salmonella typhimurium, Salmonella enteritidies, Escherichia coli O157:H7, antibiotic residues, and aflatoxin B1 residue. Fifty samples of imported frozen liver were randomly collected from different shops at Kafr El-Sheikh Governorate for isolation of S. typhimurium, S. enteritidies, and E. coli O157:H7. The results revealed that for both microorganisms 4% of the examined samples presumed to contain Salmonella and E. coli O157:H7 organisms, according to the colonial character on Harlequin Salmonella ABC agar media and Harlequin SMAC-BCIG agar media. According to biochemical and serological identifications, both organisms could not be detected in the examined samples. A total of 29 (58% samples were positive for antibiotic residues, using the Premi test (a broad-spectrum screening test for the detection of antibiotic residues in meat at or below the maximum residue limits. In addition, aflatoxin B1 was detected in one (2% samples with a concentration of 1.1 μg/kg. The results reflect that there was good hygiene practice for handling and preparation of frozen liver while selling to consumers. However, a high percentage of antibiotic residues reflect ignorance of withdrawal time before slaughtering of animals as well as misuse of antibiotics in veterinary fields. Furthermore, aflatoxin B1 residue was detected in examined frozen liver samples at a concentration below the maximum residual level, which is not enough to cause threat to humans, but it is enough to cause problem if it is eaten regularly reflect contamination of animal feed with aflatoxins.

  14. A scoring model based on neutrophil to lymphocyte ratio predicts recurrence of HBV-associated hepatocellular carcinoma after liver transplantation.

    Directory of Open Access Journals (Sweden)

    Guo-Ying Wang

    Full Text Available BACKGROUND: Neutrophil to lymphocyte ratio (NLR has been proposed to predict prognosis of hepatocellular carcinoma (HCC. However, the cut-off values are empirical. We determined the optimal cut-off value to predict HCC recurrence after liver transplantation (LT and further established a scoring model based on NLR. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed the outcome of 101 HBV-associated HCC patients undergoing LT. Preoperative risk factors for tumor recurrence were evaluated by univariate analysis. By using ROC analysis, NLR≥3 was considered elevated. The disease-free survival (DFS and overall survival (OS for patients with high NLR was significantly worse than that for patients with normal NLR (the 5-year DFS and OS of 28.5% and 19.5% vs. 64.9% and 61.8%, respectively; P5 cm, tumor number >3, macrovascular invasion, AFP≥400 µg/L, NLR≥3, and HBV-DNA level >5 log10 copies/mL were preoperative predictors of DFS. Cox regression analysis showed macrovascular invasion, tumor number, and high NLR were independent prognostic factors. We then established a preoperative prognostic score based on multivariate analysis. Each factor was given a score of 1. Area under the ROC curve of the score was 0.781. All nine patients with score 3 developed recurrence within 6 months after LT. Of 71 patients without vascular invasion, three patients with both tumor number >3 and NLR≥3 developed recurrence within 14 months after LT while the 5-year DFS and OS for patients with a score of 0 or 1 were 68.1% and 62.8%, respectively. CONCLUSIONS/SIGNIFICANCE: Preoperative elevated NLR significantly increases the risk of recurrence in patients underwent LT for HCC. Patients with both NLR≥3 and tumor number >3 are not a good indication for LT. Our score model may aid in the selection of patients that would most benefit from transplantation for HCC.

  15. Apigenin inhibits NF-κB and snail signaling, EMT and metastasis in human hepatocellular carcinoma.

    Science.gov (United States)

    Qin, Yuan; Zhao, Dong; Zhou, Hong-Gang; Wang, Xing-Hui; Zhong, Wei-Long; Chen, Shuang; Gu, Wen-Guang; Wang, Wei; Zhang, Chun-Hong; Liu, Yan-Rong; Liu, Hui-Juan; Zhang, Qiang; Guo, Yuan-Qiang; Sun, Tao; Yang, Cheng

    2016-07-05

    Apigenin is a naturally occurring compound with anti-inflammatory, antioxidant, and anticancer properties. In this study, we investigated the effects of apigenin on migration and metastasis in experimental human hepatocellular carcinoma (HCC) cell lines in vitro and in vivo. Apigenin dose-dependently inhibited proliferation, migration, and invasion by PLC and Bel-7402 human HCC cells. It also suppressed tumor growth in PLC cell xenografts without altering body weight, thereby prolonging survival. Apigenin reduced Snai1 and NF-κB expression, reversed increases in epithelial-mesenchymal transition (EMT) marker levels, increased cellular adhesion, regulated actin polymerization and cell migration, and inhibited invasion and migration by HCC cells. Apigenin may therefore inhibit EMT by inhibiting the NF-κB/Snail pathway in human HCC.

  16. GPX4 and GPX7 Over-Expression in Human Hepatocellular Carcinoma Tissues

    Science.gov (United States)

    Guerriero, E.; Capone, F.; Accardo, M.; Sorice, A.; Costantini, M.; Colonna, G.; Castello, G.

    2015-01-01

    Hepatocellular carcinoma (HCC) is the most common type of liver cancer and is still one of the most fatal cancers. Hence, it needs to identify always new putative markers to improve its diagnosis and prognosis. The selenium is an essential trace mineral implicated as a key factor in the early stage of cancer and exerts its biological function through the selenoproteins. In the last years our group has been studying the involvement of some selenoproteins in HCC. However, no many data are reported in literature about the correlation between HCC and the glutathione peroxidases (GPXs), both selenium and non selenium-containing GPXs. In this paper we have evaluated the GPX4 and GPX7 expression in some paraffin-embedded tissues from liver biopsy of patients with hepatitis C virus (HCV)-related cirrhosis and HCC by immunohistochemistry and RT-qPCR analysis. Our results evidenced that i) GPX4 and GPX7 had a statistically significant over-expression in HCC tissues compared to cirrhotic counterparts used as non tumor tissues, and ii) their expression was higher in grade III HCC tissues with respect to grade I-II samples. Therefore, we propose to use GPX4 and GPX7 as possible markers for improving HCC diagnosis/prognosis. PMID:26708178

  17. Association between anti-HBc positivity and hepatocellular carcinoma in HBsAg-negative subjects with chronic liver disease

    Science.gov (United States)

    Coppola, Nicola; Onorato, Lorenzo; Sagnelli, Caterina; Sagnelli, Evangelista; Angelillo, Italo F.

    2016-01-01

    Abstract A meta-analysis was performed to ascertain to what extent hepatitis B surface antigen (HBsAg)-negative/anti-hepatitis B core (anti-HBc)-positive subjects with chronic liver disease are at a higher risk of developing hepatocellular carcinoma (HCC) than the anti-HBc-negative. All studies included had to fulfill the following characteristics and inclusion criteria: they investigated the relationship between HBsAg-negative/anti-HBc-positive serology and the occurrence of HCC, whether a case–control or cohort study, they provided relative risk (RR) or odds ratios (ORs) and 95% confidence intervals (CIs), were available as a full text written in English, and were published and indexed up to April 2015. Twenty-six original studies met the inclusion criteria, allowing a meta-analysis on 44,553 patients. The risk of HCC among the 9986 anti-HBc-positive subjects was 67% higher than in the 34,567 anti-HBc-negative (95% CI = 1.44–1.95, P HCV and non-HCV) were considered. The risk of HCC was significantly higher in the 651 anti-HBs/anti-HBc-positive patients (RR = 1.36; 95% CI = 1.17–1.58, P = 0.03) and in the 595 anti-HBs-negative/anti-HBc-positive subjects (RR = 2.15; 95% CI = 1.58–2.92, P < 0.0001) than in the 1242 anti-HBs/anti-HBc negative. However, the RR from 8 studies indicated that the risk of HCC was 35% lower among the anti-HBs/anti-HBc-positive subjects compared to the anti-HBs-negative/anti-HBc-positive (RR = 0.65; 95% CI = 0.52–0.8, P < 0.0001). This meta-analysis shows that in HBsAg-negative subjects with chronic liver disease, anti-HBc positivity is strongly associated with the presence of HCC, an association observed in all subgroups according to the stage of the disease, etiology, and ethnicity. PMID:27472708

  18. [{sup 68}Ga]NODAGA-RGD - Metabolic stability, biodistribution, and dosimetry data from patients with hepatocellular carcinoma and liver cirrhosis

    Energy Technology Data Exchange (ETDEWEB)

    Haubner, Roland; Rangger, Christine; Decristoforo, Clemens; Virgolini, Irene J. [Medical University of Innsbruck, Department of Nuclear Medicine, Innsbruck (Austria); Finkenstedt, Armin; Zoller, Heinz [Medical University of Innsbruck, Department of Internal Medicine II, Innsbruck (Austria); Stegmayr, Armin [Medical University of Innsbruck, Department of Nuclear Medicine, Innsbruck (Austria); FH Gesundheit/University of Applied Sciences Tyrol, Innsbruck (Austria)

    2016-10-15

    This study was designed to determine safety, tolerability, and radiation burden of a [{sup 68}Ga]NODAGA-RGD-PET for imaging integrin α{sub v}β{sub 3} expression in patients with hepatocellular carcinoma (HCC) and liver cirrhosis. Moreover, metabolic stability and biokinetic data were compiled. After injection of 154-184 MBq [{sup 68}Ga]NODAGA-RGD three consecutive PET/CT scans were acquired starting 8.3 ± 2.1, 36.9 ± 2.8, and 75.1 ± 3.4 min after tracer injection. For metabolite analysis, blood and urine samples were analyzed by HPLC. For dosimetry studies, residence time VOIs were placed in the corresponding organs. The OLINDA/EXM program was used to estimate the absorbed radiation dose. The radiopharmaceutical was well tolerated and no drug-related adverse effects were observed. No metabolites could be detected in blood (30 and 60 min p.i.) and urine (60 min p.i.). [{sup 68}Ga]NODAGA-RGD showed rapid and predominantly renal elimination. Background radioactivity in blood, intestine, lung, and muscle tissue was low (%ID/l 60 min p.i. was 0.56 ± 0.43, 0.54 ± 0.39, 0.22 ± 0.05, and 0.16 ± 0.8, respectively). The calculated effective dose was 21.5 ± 5.4 μSv/MBq, and the highest absorbed radiation dose was found for the urinary bladder wall (0.26 ± 0.09 mSv/MBq). No increased uptake of the tracer was found in HCC compared with the background liver tissue. [{sup 68}Ga]NODAGA-RGD uptake in the HCCs lesions was not sufficient to use this tracer for imaging these tumors. [{sup 68}Ga]NODAGA-RGD was well tolerated and metabolically stable. Due to rapid renal excretion, background radioactivity was low in most of the body, resulting in low radiation burden and indicating the potential of [{sup 68}Ga]NODAGA-RGD PET for non-invasive determination of integrin α{sub v}β{sub 3} expression. (orig.)

  19. Quantitative ATP synthesis in human liver measured by localized 31P spectroscopy using the magnetization transfer experiment.

    Science.gov (United States)

    Schmid, A I; Chmelík, M; Szendroedi, J; Krssák, M; Brehm, A; Moser, E; Roden, M

    2008-06-01

    The liver plays a central role in intermediate metabolism. Accumulation of liver fat (steatosis) predisposes to various liver diseases. Steatosis and abnormal muscle energy metabolism are found in insulin-resistant and type-2 diabetic states. To examine hepatic energy metabolism, we measured hepatocellular lipid content, using proton MRS, and rates of hepatic ATP synthesis in vivo, using the 31P magnetization transfer experiment. A suitable localization scheme was developed and applied to the measurements of longitudinal relaxation times (T1) in six healthy volunteers and the ATP-synthesis experiment in nine healthy volunteers. Liver 31P spectra were modelled and quantified successfully using a time domain fit and the AMARES (advanced method for accurate, robust and efficient spectral fitting of MRS data with use of prior knowledge) algorithm describing the essential components of the dataset. The measured T1 relaxation times are comparable to values reported previously at lower field strengths. All nine subjects in whom saturation transfer was measured had low hepatocellular lipid content (1.5 +/- 0.2% MR signal; mean +/- SEM). The exchange rate constant (k) obtained was 0.30 +/- 0.02 s(-1), and the rate of ATP synthesis was 29.5 +/- 1.8 mM/min. The measured rate of ATP synthesis is about three times higher than in human skeletal muscle and human visual cortex, but only about half of that measured in perfused rat liver. In conclusion, 31P MRS at 3 T provides sufficient sensitivity to detect magnetization transfer effects and can therefore be used to assess ATP synthesis in human liver.

  20. Zonation related function and ubiquitination regulation in human hepatocellular carcinoma cells in dynamic vs. static culture conditions

    Directory of Open Access Journals (Sweden)

    Cheng Shu

    2012-02-01

    Full Text Available Abstract Background Understanding hepatic zonation is important both for liver physiology and pathology. There is currently no effective systemic chemotherapy for human hepatocellular carcinoma (HCC and its pathogenesis is of special interest. Genomic and proteomic data of HCC cells in different culture models, coupled to pathway-based analysis, can help identify HCC-related gene and pathway dysfunctions. Results We identified zonation-related expression profiles contributing to selective phenotypes of HCC, by integrating relevant experimental observations through gene set enrichment analysis (GSEA. Analysis was based on gene and protein expression data measured on a human HCC cell line (HepG2/C3A in two culture conditions: dynamic microfluidic biochips and static Petri dishes. Metabolic activity (HCC-related cytochromes P450 and genetic information processing were dominant in the dynamic cultures, in contrast to kinase signaling and cancer-specific profiles in static cultures. That, together with analysis of the published literature, leads us to propose that biochips culture conditions induce a periportal-like hepatocyte phenotype while standard plates cultures are more representative of a perivenous-like phenotype. Both proteomic data and GSEA results further reveal distinct ubiquitin-mediated protein regulation in the two culture conditions. Conclusions Pathways analysis, using gene and protein expression data from two cell culture models, confirmed specific human HCC phenotypes with regard to CYPs and kinases, and revealed a zonation-related pattern of expression. Ubiquitin-mediated regulation mechanism gives plausible explanations of our findings. Altogether, our results suggest that strategies aimed at inhibiting activated kinases and signaling pathways may lead to enhanced metabolism-mediated drug resistance of treated tumors. If that were the case, mitigating inhibition or targeting inactive forms of kinases would be an alternative.

  1. 5-Fluorouracil concentration in blood, liver and tumor tissues and apoptosis of tumor cells after preoperative oral 5'-deoxy-5-fluorouridine in patients with hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Jin-Fang Zheng; Hai-Dong Wang

    2005-01-01

    AIM: To study the levels of 5-fluorouracail (5-FU) in plasma,liver and tumor in patients with hepatocellular carcinoma after oral administration of 5'-deoxy-5-fluorouridine (5'-DFUR).METHODS: Thirty-nine patients with hepatocellular carcinoma were treated with oral 5'-DFUR for more than 4 d before operation. The contents of 5-FU in plasma,liver and tumor were measured by high performance liquid chromatography (HPLC) and apoptosis of tumor cells was evaluated by in-situ TUNEL after resection of tumor.RESULTS: The concentrations of 5-FU were 1.1 μg/mL,5.6, 5.9, and 10.5 μg/g in plasma, the liver tissue, the center of tumor and the periphery of tumor, respectively.5-FU concentration was significantly higher in the periphery of tumor than that in the liver tissue and the center of tumor (10.5±1.6 μg/g vs 5.6±0.8 μg/g, t= 21.38, P<0.05;10.5±1.6 μg/g vs 5.9±0.9 μg/g, t= 20.07, P<0.05). 5-FU level was significantly lower in plasma than that in the liver and the tumor (1.1±0.3 μg/mL vs 5.6±0.8 μg/g, t= 19.63,P<0.05; 1.1±0.3 μg/mL vs 10.5±1.6 μg/g, t= 41.01, P<0.05).Apoptosis of tumor cells was significantly increased after oral 5'-DFUR compared to the control group without 5'-DFUR treatment.CONCLUSION: There is a higher concentration of 5-FU distributed in the tumor compared with liver tissue and apoptosis of tumor cells is increased following oral 5'-DFUR compared with the control group. The results indicate that 5'-DFUR is hopeful as neo-adjuvant chemotherapy to prevent recurrence after resection of hepatocellular carcinoma.

  2. Superiority of helical tomotherapy on liver sparing and dose escalation in hepatocellular carcinoma: a comparison study of three-dimensional conformal radiotherapy and intensity-modulated radiotherapy

    Directory of Open Access Journals (Sweden)

    Zhao QQ

    2016-06-01

    Full Text Available Qianqian Zhao,1,2 Renben Wang,2 Jian Zhu,2 Linzhi Jin,1,2 Kunli Zhu,2 Xiaoqing Xu,2 Rui Feng,2 Shumei Jiang,2 Zhonghua Qi,1,2 Yong Yin2 1School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, 2Department of Radiation Oncology, Shandong Cancer Hospital affiliated to Shandong University, Jinan, People’s Republic of China Background and purpose: To compare the difference of liver sparing and dose escalation between three-dimensional conformal radiotherapy (3DCRT, intensity-modulated radiotherapy (IMRT, and helical tomotherapy (HT for hepatocellular carcinoma.Patients and methods: Sixteen unresectable HCC patients were enrolled in this study. First, some evaluation factors of 3DCRT, IMRT, and HT plans were calculated with prescription dose at 50 Gy/25 fractions. Then, the doses were increased using HT or IMRT independently until either the plans reached 70 Gy or any normal tissue reached the dose limit according to quantitative analysis of normal tissue effects in the clinic criteria.Results: The conformal index of 3DCRT was lower than that of IMRT (P<0.001 or HT (P<0.001, and the homogeneity index of 3DCRT was higher than that of IMRT (P<0.001 or HT (P<0.001. HT took the longest treatment time (P<0.001. For V50% (fraction of normal liver treated to at least 50% of the isocenter dose of the normal liver, there was a significant difference: 3DCRT > IMRT > HT (P<0.001. HT had a lower Dmean (mean dose and V20 (Vn, the percentage of organ volume receiving ≥n Gy of liver compared with 3DCRT (P=0.005 and P=0.005, respectively or IMRT (P=0.508 and P=0.007, respectively. Dmean of nontarget normal liver and V30 of liver were higher for 3DCRT than IMRT (P=0.005 and P=0.005, respectively or HT (P=0.005 and P=0.005, respectively. Seven patients in IMRT (43.75% and nine patients in HT (56.25% reached the isodose 70 Gy, meeting the dose limit of the organs at risk.Conclusion: HT may provide significantly better

  3. Cordyceps cicadae induces G2/M cell cycle arrest in MHCC97H human hepatocellular carcinoma cells: a proteomic study

    OpenAIRE

    Wang, Hualin; ZHANG Jing; Sit, Wai-Hung; Lee, Chung-Yung Jetty; Wan, Jennifer Man-Fan

    2014-01-01

    Background Cordyceps cicadae is a medicinal fungus that is often used for treating cancer. However, the anticancer mechanisms of C. cicadae are largely unknown. This study aims to investigate the anticancer mechanisms of C. cicadae against hepatocellular carcinoma cells in vitro using a proteomic approach. Methods Human hepatocellular carcinoma MHCC97H cells were treated with a water extract of C. cicadae (0, 100, 250, 500, and 1000 μg/mL) for 48 h and harvested for cell viability assays. The...

  4. Enhanced radioimmunotherapeutic efficacy of a monoclonal antibody cocktail against SMMC—7721 human hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    SONGYIQIANG; GENFENGWANG; 等

    1998-01-01

    The improved tumoricidal effect of the radioantibody mixture (“cocktail”)has been reported recently for the treatment of colon tumor.In the present study,we demonstrated the enhanced radioimmunotherapeutic efficacy of a monoclonal antibody (MAb) cocktail against human hepatocellular carcinoma.Therapeutic efficacy was determined by measuring the change in tumor size over a period,determining the percentage of growth inhibition of each treatment at various times after radioantibody therapy.Radioimmunotherapy of SMMC-7721 human hepatoma xenografts in athymic unde mice with combination of 131Ilabeled Hepama-1 and 131 I-labeled 9403 mouse MAbs was more effective than using either Hepeam-1 or 9403 MAb alone The MAb cocktail could target a greater number of hepatoma cells and increase the magnitude of hepatoma cell uptake of radioantibodies.The in vitro results explain the enhanced effect of the MAb cocktail in in vivo model system.

  5. Docetaxel inhibits SMMC-7721 human hepatocellular carcinoma cells growth and induces apoptosis

    Institute of Scientific and Technical Information of China (English)

    Chang-Xin Geng; Zhao-Chong Zeng; Ji-Yao Wang

    2003-01-01

    AIM: To investigate the in vitro anti-hepatocellular carcinoma (HCC) activity of docetaxel against SMMC-7721 HCC cells and its possible mechanism.METHODS: The HCC cells were given different concentrations of docetaxel and their growth was measured by colony forming assay. Cell cycle and apoptosis were analyzed by flow cytometry and fluorescence microscopy (acridine orange/ethidium bromide double staining, AO/EB), as well as electronic microscopy. The SMMC-7721 HCC cell reactive oxygen species (ROS) and glutathione (GSH) were measured after given docetaxel.RESULTS: Docetaxel inhibited the hepatocellular carcinoma cells growth in a concentration dependent manner with IC505×10-10 M. Marked cell apoptosis and G2/M phase arrest were observed after treatment with docetaxel ≥10-8M.Docetaxel promoted SMMC-7721 HCC cells ROS generation and GSH deletion.CONCLUSION: Docetaxel suppressed the growth of SMMC7721 HCC cells in vitro by causing apoptosis and G2/M phase arrest of the human hepatoma cells, and ROS and GSH may play a key role in the inhibition of growth and induction of apoptosis.

  6. Hepatic progenitor cells in human liver cirrhosis:Immunohistochemical,electron microscopic and immunofluorencence confocal microscopic findings

    Institute of Scientific and Technical Information of China (English)

    Jia-Cheng Xiao; Xiao-Long Jin; Peter Ruck; Anne Adam; Edwin Kaiserling

    2004-01-01

    AIM: To investigate whether hepatic progenitor cells (HPC),that reveal the features of oval cells in rodents and small epithelial cells (SEC) in certain human liver disease, were also found in human liver cirrhosis (HLC).METHODS: Surgical liver specimens from 20 cases of hepatitis B virus-positive HLC (15 cases containing hepatocellular carcinoma) were investigated by light microscopic immunohistochemistry (LM-IHC). Among them specimens from 15 cases were investigated by electron microscopy (EM)and those from 5 cases by immunofluorencence confocal laser scanning microscopy (ICLSM). Antibodies against cytokeratin 7 and albumin were used and single and/or double labelling were performed respectively.RESULTS: LM-IHC showed that at the margins of regenerating nodules and in the fibrous septae, a small number of cells in the proliferating bile ductules were positive for CK7 and albumin. At the EM level these HPC were morphologically similar to the SEC described previously, and also similar to the oval cells seen in experimental hepatocarcinogenesis.They were characterized by their small size, oval shape, a high nucleus/cytoplasm ratio, a low organelle content in cytoplasm, and existence of tonofilaments and intercellular junctions. ICLSM revealed that HPC expressed both cytokeratin 7 and albumin.CONCLUSION: HPC with ultrastructural and immunophenotypical features of oval cells, i.e., hepatic stem cell-like cells as noted in other liver diseases, were found in HLC. These findings further support the hypothesis that bipotent hepatic stem cells, that may give rise to biliary epithelial cells and hepatocytes, exist in human livers.

  7. A different representation of natural T cells and natural killer cells between tumor-infiltrating and periphery lymphocytes in human hepatocellular carcinoma.

    Science.gov (United States)

    Li, Xiao-Feng; Dai, Dong; Song, Xiu-Yu; Liu, Jian-Jing; Zhu, Lei; Zhu, Xiang; Ma, Wenchao; Xu, Wengui

    2017-05-01

    Natural T cells [cluster of differentiation (CD) 3(+)CD56(+)] and natural killer (NK) cells (CD3(-)CD56(+)) are particularly abundant in the human liver and serve an important role in immune responses in the liver. The aim of the present study was to extensively determine the phenotypic and functional characteristics of natural T and NK cells in human hepatocellular carcinoma (HCC). Tumorous and non-tumorous tissue infiltrating lymphocytes (TILs and NILs, respectively) and peripheral blood mononuclear cells (PBMCs) from patients with hepatocellular carcinoma (HCC) were obtained to determine the frequency and phenotype of natural T/NK cells by a multicolor fluorescence activated cell sorting analysis. The abundance of natural T cells and NK cells was decreased in TILs vs. NILs (natural T cells, 6.315±1.002 vs. 17.16±1.804; NK cells, 6.324±1.559 vs. 14.52±2.336, respectively). However such results were not observed in PBMCs from HCC patients vs. that of healthy donors. Notably, a substantial fraction of the natural T cells (21.96±5.283) in TILs acquired forkhead box P3 (FOXP3) expression, and the FOXP3(+) natural T cells lost the expression of interferon-γ and perforin. Conversely, being similar to the conventional FOXP3(+) regulatory T cells, the FOXP3(+) natural T cells assumed a specific phenotype that was characteristic of CD25(+), CD45RO(+) and cytotoxic T-lymphocyte-associated protein 4(+). Consistent with the phenotypic conversion, the present functional results indicate that FOXP3 expression in natural T cells contributes to the acquisition of a potent immunosuppressive capability. In conclusion, the present study describes a different representation of natural T cells and NK cells in local tumor tissues and in the periphery blood of patients with HCC, and identified a new type of FOXP3-expressing natural T cell spontaneously arising in the TILs of HCC.

  8. Hepatocellular cancer in an extra liver lobe in the lower abdominal cavity - Differential diagnosis and problems; Hepatozellulaeres Karzinom in einem zusaetzlichen gestielten Leberlappen im Unterbauch - differentialdiagnostische Problematik

    Energy Technology Data Exchange (ETDEWEB)

    Leinung, S.; Wuerl, P.; Richter, K.; Frey, A.; Schoenfelder, M. [Leipzig Univ. (Germany). Chirurgische Klinik und Poliklinik 1; Biesold, M. [Leipzig Univ. (Germany). Klinik und Poliklinik fuer Diagnostische Radiologie

    2000-07-01

    The case described is that of a 36 year old patient with a known tumor in her lower abdominal cavity which has been observed to increase in size for the passed 16 years. Intraoperatively, one observed a very rare finding of an extra liver lobe of the left liver lobe and located in the lower abdominal cavity. Located within is a multifocal therapeutically treatable hepatocellular cancer. (orig.) [German] Dargestellt wird der Fall einer 36 jaehrigen Patientin, die seit 16 Jahren die Groessenzunahme eines ihr bekannten Tumors im Unterbauch beobachtete. Intraoperativ zeigte sich der seltene Befund eines zusaetzlichen Leberlappens gestielt am Segment 3 im Unterbauch mit einem auf den linken Leberlappen begrenzten und kurativ therapierbaren multifokalen hepatozellulaeren Karzinoms. (orig.)

  9. Mucinous cystadenoma of the appendix associated with adenocarcinoma of the sigmoid colon and hepatocellular carcinoma of the liver: Report of a case

    Institute of Scientific and Technical Information of China (English)

    Srdjan P Djuranovic; Milan M Spuran; Nada V Kovacevic; Milenko B Ugljesic; Dragutin M Kecmanovic; Marjan T Micev

    2006-01-01

    Mucinous cystadenoma of the appendix is a rare condition and represents one of the three entities with the common name mucocele of the appendix. It is characterized by a cystic dilatation of the lumen with stasis of mucus inside it. Histopathologically mucocele is divided into three groups: focal or diffuse mucosal hyperplasia, mucinous cystadenoma and mucinous cystadenocarcinoma. This condition is often associated with other neoplasia, especially adenocarcinoma of the colon and ovaries. We here describe a 57 year old male patient who presented with abdominal discomfort,constipation, fresh blood in stool and frequent urination.He had a big cystadenoma of the appendix associated with adenocarcinoma of the colon and hepatocellular carcinoma of the liver. The patient underwent right haemicolectomy, sigmoid colon resection and segmental resection of the liver. Now 3 years later he has no evidence of disease relapse. According to this, we stress the need of accurate preoperative diagnosis and intraoperative exploration of the whole abdomen in these patients.

  10. Quercetin-3-O-glucoside induces human DNA topoisomerase II inhibition, cell cycle arrest and apoptosis in hepatocellular carcinoma cells.

    Science.gov (United States)

    Sudan, Sudhanshu; Rupasinghe, H P Vasantha

    2014-04-01

    Dietary flavonoids have been associated with reduced risk of cancer including hepatocellular carcinoma (HCC). Quercetin-3-O-glucoside (Q3G) has been shown to possess anti-proliferative and antioxidant activities. The objectives of this study were to assess the anti-proliferative properties of Q3G in human liver cancer cells (HepG2); assess the cytotoxicity on normal primary cells; and elucidate its possible mechanism of action(s). Using a dose- and time-dependent study, we evaluated the antiproliferative properties of Q3G in HepG2 cells using MTS cell viability assay and lactate dehydrogenase release assay. To elucidate the mechanism of action, we performed cell-cycle analysis using flow cytometry. Cell death via apoptosis was analyzed by DNA fragmentation assay, caspase-3 induction assay and fluorescence microscopy. DNA topoisomerase II drug screening assay was performed to assess the effect of Q3G on DNA topoisomerase II. Q3G treatment inhibited cell proliferation in a dose- and time-dependent manner in HepG2 cells with the blockade of the cell cycle in the S-phase. Additionally, Q3G exhibited a strong ability to inhibit DNA topoisomerase II. Furthermore, DNA fragmentation and fluorescence microscopy analysis suggested that Q3G induced apoptosis in HepG2 cells with the activation of caspase-3. Interestingly, Q3G exhibited significantly lower toxicity to normal cells (primary human and rat hepatocytes and primary lung cells) than sorafenib (papoptosis. Further research should be performed to confirm these results in vivo.

  11. Epigenetic regulation of pluripotent genes mediates stem cell features in human hepatocellular carcinoma and cancer cell lines.

    Directory of Open Access Journals (Sweden)

    Xiao Qi Wang

    Full Text Available Activation of the stem cell transcriptional circuitry is an important event in cancer development. Although cancer cells demonstrate a stem cell-like gene expression signature, the epigenetic regulation of pluripotency-associated genes in cancers remains poorly understood. In this study, we characterized the epigenetic regulation of the pluripotency-associated genes NANOG, OCT4, c-MYC, KLF4, and SOX2 in a variety of cancer cell lines and in primary tumor samples, and investigated the re-activation of pluripotency regulatory circuits in cancer progression. Differential patterns of DNA methylation, histone modifications, and gene expression of pluripotent genes were demonstrated in different types of cancers, which may reflect their tissue origins. NANOG promoter hypomethylation and gene upregulation were found in metastatic human liver cancer cells and human hepatocellular carcinoma (HCC primary tumor tissues. The upregulation of NANOG, together with p53 depletion, was significantly associated with clinical late stage of HCC. A pro-metastatic role of NANOG in colon cancer cells was also demonstrated, using a NANOG-overexpressing orthotopic tumor implantation mouse model. Demethylation of NANOG promoter was observed in CD133+(high cancer cells. In accordance, overexpression of NANOG resulted in an increase in the population of CD133+(high cells. In addition, we demonstrated a cross-regulation between OCT4 and NANOG in cancer cells via reprogramming of promoter methylation. Taken together, epigenetic reprogramming of NANOG can lead to the acquisition of stem cell-like properties. These results underscore the restoration of pluripotency circuits in cancer cells as a potential mechanism for cancer progression.

  12. Activation of sonic hedgehog signaling pathway is an independent potential prognosis predictor in human hepatocellular carcinoma patients

    Institute of Scientific and Technical Information of China (English)

    Li Che; Yan-Hua Yuan; Jun Jia; Jun Ren

    2012-01-01

    Objective:The activation of hedgehog (HH) pathway is implicated in the development of human malignancies including hepatocellular carcinoma (HCC).However,the clinical impact of HH activation in HCC patents is still unclear.This study was conducted to confirm whether the expression of HH pathway components was associated with HCC progression and clinical outcome.Methods:This study was a sample-expanded and prolonged follow up of one of our previous studies.It included 46 HCC patients who underwent surgical treatment from 2002 to 2005.The expression of sonic HH (SHH),patched-1 (PTCH1),smoothened (SMOH) and glioma-associated oncogene-1 (GLI1) genes in tumor and adjacent normal tissues extracted from the patients were examined by reverse transcription-polymerase chain reaction (RT-PCR) to explore the relationship between these genes and the clinical prognosis of HCC.Results:The expression levels of SHH,PTCH1,SMOH and GLI1 in HCC tissues were 60.87%,50.00%,32.61% and 54.35%,respectively.The expression levels of SHH-related molecules were relatively intense in cancer tissue,but insignificantly correlated with any clinicopathological factors of tumor.Transcriptional factor GLI1 was the only molecule associated with poor prognosis among the HCC patients.The expression of GLI1 gene in tumor tissues was significantly related with disease-free survival (DFS) (P=0.042) and overall survival (OS) (P=0.030).The simultaneous expression of GLI1 in tumor and adjacent normal liver tissues correlated with DFS (P<0.029) and OS (P<0.025).Conclusions:HH signaling activation is an important event in the development of human HCC.The expression of GLI1 in SHH pathway is possibly involved in HCC progression,which may be a useful prognostic indicator of HCC.

  13. Liver transplantation in a patient with hepatitis B, C and D coinfection associated with hepatocellular carcinoma: a management strategy for a rare condition. Case report

    Directory of Open Access Journals (Sweden)

    Lucas Carvalho Dantas

    Full Text Available CONTEXT: Orthotopic liver transplantation (OLT is the treatment of choice for end-stage liver disease. Cirrhosis due to hepatitis C infection is the leading indication for liver transplantation worldwide. However, patients who are given transplants because of viral liver diseases often present clinical coinfections, including hepatitis B together with hepatitis D. Currently, different strategies exist for patient management before and after liver transplantation, and these are based on different protocols developed by the specialized transplantation centers. CASE REPORT: We present a rare case of a 58-year-old man with chronic hepatitis B, C and D coinfection. The patient developed cirrhosis and hepatocellular carcinoma. His treatment comprised antiviral therapy for the three viruses and OLT. The patient's outcome was satisfactory. CONCLUSION: OLT, in association with antiviral therapy using entecavir, which was administered before and after transplantation, was effective for sustained clearance of the hepatitis B and D viruses. A recurrence of hepatitis C infection after transplantation responded successfully to standard treatment comprising peginterferon alfa-2A and ribavirin.

  14. Association of early age at establishment of chronic hepatitis B infection with persistent viral replication, liver cirrhosis and hepatocellular carcinoma: a systematic review.

    Directory of Open Access Journals (Sweden)

    Yusuke Shimakawa

    Full Text Available Age at infection with hepatitis B virus (HBV is a known risk factor for chronic HBV infection. However, in addition, there is some evidence that early age at infection further increases the risk of primary liver cancer beyond its association with increased risk of chronic infection. This systematic review of observational studies assesses the association between age at initiation of chronic HBV infection and liver cirrhosis, hepatocellular carcinoma, and their predictors including indicators of ongoing viral replication and hepatic damage. The review includes birth order and maternal HBV serology as proxies for age at infection. Electronic searches in two English-language (Medline and Embase, until Jan 2012 and two Chinese-language (CNKI and SinoMed, until Sep 2012 databases without language restriction and manual search through reference lists identified 7,077 papers, of which 19 studies of 21 outcomes (8 primary liver cancer, 1 liver cirrhosis, 10 viral replication and 2 liver inflammation are included. One study directly examined the age at infection in a longitudinal cohort, 12 assessed maternal sero-status and 6 investigated birth order. The direction of associations in all studies was in accordance with our hypothesis that earlier age at infection is associated with worse outcomes in addition to its effect of increasing the probability of chronic HBV infection. This has implications for the control of hepatitis B.

  15. Hepatocellular carcinoma and liver cirrhosis TP53 mutation analysis reflects a moderate dietary exposure to aflatoxins in Espírito Santo State, Brazil.

    Science.gov (United States)

    de Carvalho, Fernanda Magri; de Almeida Pereira, Thiago; Gonçalves, Patrícia Lofego; Jarske, Robson Dettmann; Pereira, Fausto Edmundo Lima; Louro, Iuri Drumond

    2013-08-01

    The close relationship between aflatoxins and 249ser TP53 gene mutation (AGG to AGT, Arg to Ser) in hepatocellular carcinoma (HCC) makes this mutation an indirect indicator of dietary contamination with this toxin. We have examined the prevalence of codon 249 TP53 mutation in 41 HCC and 74 liver cirrhosis (without HCC) cases diagnosed at the HUCAM University Hospital in Vitoria, Espírito Santo State, Brazil. DNA was extracted from paraffin sections and from plasma. The mutation was detected by DNA amplification, followed by restriction endonuclease digestion and confirmed by direct sequencing. DNA restriction showed 249ser mutation in 16 HCC and 13 liver cirrhosis, but sequencing confirmed mutations in only 6 HCC and 1 liver cirrhosis. In addition, sequencing revealed 4 patients with mutations at codon 250 (250ser and 250leu) in HCC cases. The prevalence of TP53 mutation was 10/41 (24.3%) in HCC and 1/74 (1.4%) in liver cirrhosis. No relationship between the presence of mutations and the etiology of HCC was observed. TP53 exon 7 mutations, which are related to aflatoxins exposure, were found at 14.6% (249ser), 7.3% (250leu) and 2.4% (250ser) in 41 cases of HCC and 1.4% in 74 liver cirrhosis (without HCC) cases, suggesting a moderate dietary exposure to aflatoxins in the Espírito Santo State, Brazil.

  16. Extracellular Matrix Molecular Remodeling in Human Liver Fibrosis Evolution.

    Directory of Open Access Journals (Sweden)

    Andrea Baiocchini

    Full Text Available Chronic liver damage leads to pathological accumulation of ECM proteins (liver fibrosis. Comprehensive characterization of the human ECM molecular composition is essential for gaining insights into the mechanisms of liver disease. To date, studies of ECM remodeling in human liver diseases have been hampered by the unavailability of purified ECM. Here, we developed a decellularization method to purify ECM scaffolds from human liver tissues. Histological and electron microscopy analyses demonstrated that the ECM scaffolds, devoid of plasma and cellular components, preserved the three-dimensional ECM structure and zonal distribution of ECM components. This method has been then applied on 57 liver biopsies of HCV-infected patients at different stages of liver fibrosis according to METAVIR classification. Label-free nLC-MS/MS proteomics and computation biology were performed to analyze the ECM molecular composition in liver fibrosis progression, thus unveiling protein expression signatures specific for the HCV-related liver fibrotic stages. In particular, the ECM molecular composition of liver fibrosis was found to involve dynamic changes in matrix stiffness, flexibility and density related to the dysregulation of predominant collagen, elastic fibers and minor components with both structural and signaling properties. This study contributes to the understanding of the molecular bases underlying ECM remodeling in liver fibrosis and suggests new molecular targets for fibrolytic strategies.

  17. Stem cell research in hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Chengyi SUN; Shi ZUO

    2008-01-01

    The traditional view that adult human liver tumors, mainly hepatocellular carcinoma (HCC), arise from mature cell types has been challenged in recent dec-ades. The results of several studies suggest that HCC can be derived from liver stem cells. There are four levels of cells in the liver stem cell lineage: hepatocytes, hepatic stem cells/oval cells, bone marrow stem cells and hepato-pancreas stem cells. However, whether HCC is resulted from the differentiation block of stem cells and, moreover, which liver stem cell lineage is the source cell of hepatocarcinogenesis remain controversial. In this review, we focus on the current status of liver stem cell research and their roles in carcinogenesis of HCC, in order to explore new approaches for stem cell therapy of HCC.

  18. Molecular Detection of Human Telomerase mRNA (hTERT-mRNA in Egyptian Patients with Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Gahan Kamal El-Saeed

    2009-06-01

    Full Text Available Background and Aims: Diagnostic modalities for hepatocellular carcinoma (HCC as markers, sonography, and CT have contributed to the early detection of HCC but are still not sensitive enough. Human telomerase RNA subunit (hTERT-mRNA has been identified in many cancers and claimed to be reactivated in HCC. To investigate hTERT-mRNA in the peripheral blood of HCC and chronic liver disease (CLD patients and correlate its level with alpha feto protein (AFP, the serological marker for HCC.Methods: The study was conducted on 44 patients selected from the National Liver Institute. Patients included Group I (22 patients diagnosed to have HCC, Group II (22 patients with CLD, and 12 apparently healthy volunteers as controls (Group III. All selected individuals were subjected to history taking, a clinical examination, abdominal sonography and laboratory investigations as liver function tests (LFTs, cell blood count (CBC, hepatitis viral markers, AFP, and real-time polymerase chain reaction (PCR Quantitative detection of -mRNA expression, encoding for telomerase catalytic subunit.Results: There was a significant elevation of AFP levels in the HCC group compared to both the CLD and control groups (P < 0.00, P < 0.001. The mean hTERT-mRNA expression in HCC patients was significantly higher than both CLD patients and controls (P < 0.001, P < 0.001. hTERT-mRNA was correlated with AFP and tumor size (P < 0.05, P < 0.001. The AFP cutoff level (185 ng/ml resulted in a 63.6% sensitivity, a 85.3% specificity; a 89.3% positive predictive value (PPV level, a 76.2 % negative predictive value (NPV level and a 83.4% accuracy for HCC prediction. The hTERT-mRNA cutoff level (112.5 copies/ml showed a 77.3% sensitivity, a 97.1% specificity, a 98% PPV level, a 79.2 % NPV level, and an accuracy of 84% for HCC prediction. Combining hTERT-mRNA and AFP increased diagnostic accuracy to 90.5%. Both markers had a 84.1% sensitivity, a 86.4% specificity, a 86.4% PPV level, and a 88

  19. 肿瘤拒绝抗原1在肝硬化和肝癌组织中的表达及其与肝癌临床病理学特征的关系%Expression and its clinicopathological features of tumor rejective antigen 1 in human tissues of hepatocellular carcinoma and liver cirrhosis

    Institute of Scientific and Technical Information of China (English)

    张弘; 黄东凤; 魏群; 华婷琰; 李峰; 黄介飞

    2010-01-01

    Objective To investigate the expression of tumor rejective antigen 1 in hepatocellular carcinoma (HCC) and liver cirrhosis(LC) tissues, and the relationship between clinicopathological feature and HCC. Methods The expressions of TRA1 mRNA and its protein were detected by reverse transcription polymerase chain reaction (RT-PCR) and Western blot respectively. Immunohistochemical staining was used to further examine the expression of TRA1 protein in LC, HCC and control tissues. The relationship between clinicopathological feature and HCC was analyzed. Data of RT-PCR and Western blot were analyzed by Oneway ANOVA; results of immunohistochemical staining were analyzed by Fisher's exact test and correlation analysis using Spearman rank correlation. Results RT-PCR data showed that the expression of TRA1 mRNA was higher in HCC and LC tissues than that in the normal liver tissues (F values were 20.821 and 12.311respectively, P < 0.05). The expression of TRA1 protein in HCC and LC tissues was signifcantly higher than that in control by Western blot (F values were 21.231 and 20.125 respectively, P < 0.05). The immunohistochemical data showed the expression of TRA1 protein was gradually increased in HCC group than that in the LC group and control group, and the positive expression rate of TRA1 was 57.14%, 78.95% and 93.75%respectively. The expression of TRA1 protein was negatively correlated with HCC differentiation (r =-0.4655, P = 0.0073) and positively correlated with HCC TNM staging (r = 0.5157, P = 0.0025). Conclusion The over-expression of TRA1 in hepatocirrhosis and HCC is correlated with the formation and development of HCC. It may be a prognostic marker for the diagnosis of HCC and be associated with the degree of differentiation and HBV infection. It can be used as a marker for prognostic prediction of HCC.%目的 探讨肿瘤拒绝抗原1(TRA1)在肝细胞癌(HCC)和肝硬化组织中的表达水平及其与HCC临床病理学特征的关系.方法

  20. Hepatocellular carcinoma: Can it be considered a controversial indication for liver transplantation in centers with high rates of hepatitis C?

    Science.gov (United States)

    Moya, Angel; Berenguer, Marina; Aguilera, Victoria; Juan, Fernando San; Nicolás, David; Pastor, Miguel; López-Andujar, Rafael; Rayón, Miguel; Orbis, Francisco; Mora, Julio; De Juan, Manuel; Carrasco, Domingo; Vila, Juan-José; Prieto, Martín; Berenguer, Joaquín; Mir, José

    2002-11-01

    Hepatocellular carcinoma (HCC) is still considered a controversial indication for liver transplantation (LT), mainly because of long waiting times and underlying viral cirrhosis. The goal was to evaluate the outcome of LT in 104 patients with HCC and cirrhosis, mainly hepatitis C virus (HCV)-related, in a center with a short waiting time (median, 105 days). Four groups were formed according to the HCC and HCV status: HCV positive with HCC (group 1, n = 81), HCV negative with HCC (group 2, n = 23), HCV positive without HCC (group 3, n = 200), and HCV negative without HCC (group 4, n = 207). Predictive factors of tumor recurrence were demographics, tumor related (size or number of nodules, capsule, bilobar involvement, vascular or lymphatic invasion, clinical and pathologic TNM staging, pre-LT percutaneous ultrasound-guided ethanol injection or transarterial chemoembolization, alpha-fetoprotein levels), donor and surgery related, and year of transplantation. The same variables and "tumor recurrence (yes/no)" were applied to evaluate the effect on survival. The median follow up was 29 months (range, 0 to 104 months). Patient survival was 70% at 1 year and 59% at 5 years for group 1, 87% at 1 year and 77% at 5 years for group 2, 81% at 1 year and 64% at 5 years for group 3, and 88% at 1 year and 77% at 5 years for group 4 (P =.013). Survival was significantly lower in patients with HCC than in those without (74% and 63% versus 85% and 70%, at 1 and 5 years, respectively; P =.05). The causes of death in those with and without HCC were tumor recurrence (24%) and recurrent HCV (8%) versus sepsis (34%) and recurrent HCV (14%). HCC recurrence occurred in 12 patients (11.5%) at a median of 14 months (range, 3 to 60 months) with a probability increasing from 8% at 1 year to 16% at 5 years. In patients with HCC, tumor recurrence was associated with vascular invasion (P =.0004) by multivariate analysis; variables predictive of survival were donor old age (P =.01), viral

  1. Plasma microRNA might as a potential biomarker for hepatocellular carcinoma and chronic liver disease screening.

    Science.gov (United States)

    Jiang, Li; Li, Xue; Cheng, Qi; Zhang, Bin-Hao

    2015-09-01

    Our study aims to investigate the expression signature of plasma microRNA-106b (miRNA-106b, miR-106b) in hepatocellular carcinoma (HCC) patients and chronic liver disease (CLD) patients compared with healthy controls and further evaluate the potential clinical value of miR-106b as biomarker in HCC detection. In addition, a meta-analysis was conducted to assess the diagnostic performance of miR-106a/b as a biochemical marker for cancer screening. This study was divided into two phases. In the first phase, the expression levels of plasma miR-106b obtained from 108 subjects (47 HCC patients, 25 CLD patients, and 36 healthy controls) were measured by using qRT-PCR. Areas under receiver operating characteristic (ROC) curves (AUCs) were used to evaluate the diagnostic accuracy of plasma miR-106. In the second phase, a meta-analysis based on 11 previous researches as well as our current study was conducted to assess the potential clinical value of miR-106 in cancer detection. Plasma levels of miR-106b in HCC patients were significantly higher compared with CLD patients and healthy individuals. ROC curves suggested that plasma miR-106b yielded relative high sensitivities and specificities in differentiating HCC patients from CLD patients or healthy controls with corresponding AUC values of 0.726 and 0.879, respectively. In addition, miR-106b showed a relatively high accuracy in distinguishing CLD patients from healthy controls with its AUC value of 0.703. Furthermore, the meta-analysis for diagnostic performance of miR-106a/b showed a pooled sensitivity of 0.74, specificity of 0.75, and an AUC of 0.81. Subgroup analysis based on samples types revealed a higher diagnostic performance of miR-106 for cancer detection by using non-blood samples. Similarly, miR-106 as biomarker showed a higher diagnostic accuracy for gastric cancer detection. We found that plasma miR-106b has clinical value in the detection of HCC from healthy people and CLD patients. Further large-scale study

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  16. File list: His.Liv.05.AllAg.Carcinoma,_Hepatocellular [Chip-atlas[Archive

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  18. Reactivation of the insulin-like growth factor-Ⅱ signaling pathway in human hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Kai Breuhahn; Peter Schirmacher

    2008-01-01

    Constitutive activation of the insulin-like growth factor (IGF)-signaling axis is frequently observed in human hepatocellular carcinoma (HCC). Especially the over-expression of the fetal growth factor IGF-Ⅱ, IGF-Ⅰ receptor (IGF-IR), and cytoplasmic downstream effectors such as insulin-receptor substrates (IRS) contribute to proliferation, anti-apoptosis, and invasive behavior. This review focuses on the relevant alterations in this signaling pathway and independent in vivo models that support the central role IGF-Ⅱ signaling during HCC development and progression. Since this pathway has become the center of interest as a target for potential anti-cancer therapy in many types of malignancies, various experimental strategies have been developed, including neutralizing antibodies and selective receptor ki-nase inhibitors, with respect to the specific and efficient reduction of oncogenic IGF-Ⅱ/IGF-IR-signaling.

  19. Links between human LINE-1 retrotransposons and hepatitis virus-related hepatocellular carcinoma

    Science.gov (United States)

    Honda, Tomoyuki

    2016-05-01

    Hepatocellular carcinoma (HCC) accounts for approximately 80% of liver cancers, the third most frequent cause of cancer mortality. The most prevalent risk factors for HCC are infections by hepatitis B or hepatitis C virus. Findings suggest that hepatitis virus-related HCC might be a cancer in which LINE-1 retrotransposons, often termed L1, activity plays a potential role. Firstly, hepatitis viruses can suppress host defense factors that also control L1 mobilization. Secondly, many recent studies also have indicated that hypomethylation of L1 affects the prognosis of HCC patients. Thirdly, endogenous L1 retrotransposition was demonstrated to activate oncogenic pathways in HCC. Fourthly, several L1 chimeric transcripts with host or viral genes are found in hepatitis virus-related HCC. Such lines of evidence suggest a linkage between L1 retrotransposons and hepatitis virus-related HCC. Here, I briefly summarize current understandings of the association between hepatitis virus-related HCC and L1. Then, I discuss potential mechanisms of how hepatitis viruses drive the development of HCC via L1 retrotransposons. An increased understanding of the contribution of L1 to hepatitis virus-related HCC may provide unique insights related to the development of novel therapeutics for this disease.

  20. Encapsulated human hepatocellular carcinoma cells by alginate gel beads as an in vitro metastasis model

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Xiao-xi; Liu, Chang [Laboratory of Biomedical Material Engineering, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023 (China); University of Chinese Academy of Sciences, 19A Yuquanlu, Beijing 100049 (China); Liu, Yang [Laboratory of Biomedical Material Engineering, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023 (China); Li, Nan [Laboratory of Biomedical Material Engineering, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023 (China); University of Chinese Academy of Sciences, 19A Yuquanlu, Beijing 100049 (China); Guo, Xin [Laboratory of Biomedical Material Engineering, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023 (China); Wang, Shu-jun [Laboratory of Biomedical Material Engineering, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023 (China); School of Life Science and Biotechnology, Dalian University of Technology, 2 Linggong Road, Dalian 116024 (China); Sun, Guang-wei, E-mail: sungw@dicp.ac.cn [Laboratory of Biomedical Material Engineering, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023 (China); Wang, Wei [Laboratory of Biomedical Material Engineering, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023 (China); Ma, Xiao-jun, E-mail: maxj@dicp.ac.cn [Laboratory of Biomedical Material Engineering, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023 (China)

    2013-08-15

    Hepatocellular carcinoma (HCC) is the most common primary liver cancer and often forms metastases, which are the most important prognostic factors. For further elucidation of the mechanism underlying the progression and metastasis of HCC, a culture system mimicking the in vivo tumor microenvironment is needed. In this study, we investigated the metastatic ability of HCC cells cultured within alginate gel (ALG) beads. In the culture system, HCC cells formed spheroids by proliferation and maintained in nuclear abnormalities. The gene and protein expression of metastasis-related molecules was increased in ALG beads, compared with the traditional adhesion culture. Furthermore, several gene expression levels in ALG bead culture system were even closer to liver cancer tissues. More importantly, in vitro invasion assay showed that the invasion cells derived from ALG beads was 7.8-fold higher than adhesion cells. Our results indicated that the in vitro three-dimensional (3D) model based on ALG beads increased metastatic ability compared with adhesion culture, even partly mimicked the in vivo tumor tissues. Moreover, due to the controllable preparation conditions, steady characteristics and production at large-scale, the 3D ALG bead model would become an important tool used in the high-throughput screening of anti-metastasis drugs and the metastatic mechanism research. -- Highlights: •We established a 3D metastasis model mimicking the metastatic ability in vivo. •The invasion ability of cells derived from our model was increased significantly. •The model is easy to reproduce, convenient to handle, and amenable for large-scale.

  1. JNK1 activation predicts the prognostic outcome of the human hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Shi Xianglin

    2009-08-01

    Full Text Available Abstract Background Hepatocellular carcinoma (HCC is one of the most common cancers worldwide with an extremely poor prognosis. The classification of HCC based on the molecular signature is not well-established. Results In the present study, we reported HCC signature genes based on the JNK1 activation status in 31 HCC specimens relative to the matched distal noncancerous liver tissue from 31 patients. The HCCs with high JNK1 (H-JNK1 and low JNK1 (L-JNK1 were sub-grouped. Two different signature gene sets for both H-JNK1 and L-JNK1 HCC were identified through gene expression profiling. A striking overlap of signature genes was observed between the H-JNK1 HCC and the hepatoblastoma or hepatoblastoma-type HCC. Many established biomarkers for hepatic progenitor cells were over-expressed in H-JNK1 HCC, including AFP, TACSTD1, KRT19, KRT7, THY1, and PROM1. In addition, the majority of the most up-regulated genes were those associated with metastasis and earlier recurrence, whereas the genes for normal liver function were substantially down-regulated in H-JNK1 HCC tissue. A Kaplan-Meier plot demonstrated that the survival of the patients with H-JNK1 HCC was severely impaired. Conclusion Accordingly, we believe that the H-JNK1 HCC may originate from hepatic progenitor cells and is associated with poorer prognosis. The status of JNK1 activation in HCC tissue, thus, might be a new biomarker for HCC prognosis and therapeutic targeting.

  2. Superiority of helical tomotherapy on liver sparing and dose escalation in hepatocellular carcinoma: a comparison study of three-dimensional conformal radiotherapy and intensity-modulated radiotherapy

    Science.gov (United States)

    Zhao, Qianqian; Wang, Renben; Zhu, Jian; Jin, Linzhi; Zhu, Kunli; Xu, Xiaoqing; Feng, Rui; Jiang, Shumei; Qi, Zhonghua; Yin, Yong

    2016-01-01

    Background and purpose To compare the difference of liver sparing and dose escalation between three-dimensional conformal radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT), and helical tomotherapy (HT) for hepatocellular carcinoma. Patients and methods Sixteen unresectable HCC patients were enrolled in this study. First, some evaluation factors of 3DCRT, IMRT, and HT plans were calculated with prescription dose at 50 Gy/25 fractions. Then, the doses were increased using HT or IMRT independently until either the plans reached 70 Gy or any normal tissue reached the dose limit according to quantitative analysis of normal tissue effects in the clinic criteria. Results The conformal index of 3DCRT was lower than that of IMRT (PV50% (fraction of normal liver treated to at least 50% of the isocenter dose) of the normal liver, there was a significant difference: 3DCRT > IMRT > HT (P<0.001). HT had a lower Dmean (mean dose) and V20 (Vn, the percentage of organ volume receiving ≥n Gy) of liver compared with 3DCRT (P=0.005 and P=0.005, respectively) or IMRT (P=0.508 and P=0.007, respectively). Dmean of nontarget normal liver and V30 of liver were higher for 3DCRT than IMRT (P=0.005 and P=0.005, respectively) or HT (P=0.005 and P=0.005, respectively). Seven patients in IMRT (43.75%) and nine patients in HT (56.25%) reached the isodose 70 Gy, meeting the dose limit of the organs at risk. Conclusion HT may provide significantly better liver sparing and allow more patients to achieve higher prescription dose in HCC radiotherapy. PMID:27445485

  3. Surgery for Intermediate and Advanced Hepatocellular Carcinoma: A Consensus Report from the 5th Asia-Pacific Primary Liver Cancer Expert Meeting (APPLE 2014)

    Science.gov (United States)

    Ho, Ming-Chih; Hasegawa, Kiyoshi; Chen, Xiao-Ping; Nagano, Hiroaki; Lee, Young-Joo; Chau, Gar-Yang; Zhou, Jian; Wang, Chih-Chi; Choi, Young Rok; Poon, Ronnie Tung-Ping; Kokudo, Norihiro

    2016-01-01

    Background The Barcelona Clinic Liver Cancer (BCLC) staging and treatment strategy does not recommended surgery for treating BCLC stage B and C hepatocellular carcinoma (HCC). However, numerous Asia-Pacific institutes still perform surgery for this patient group. This consensus report from the 5th Asia-Pacific Primary Liver Cancer Expert Meeting aimed to share opinions and experiences pertaining to liver resection for intermediate and advanced HCCs and to provide evidence to issue recommendations for surgery in this patient group. Summary Thirteen experts from five Asia-Pacific regions were invited to the meeting; 10 of them (Japan: 2, Taiwan: 3, South Korea: 2, Hong Kong: 1, and China: 2) voted for the final consensus. The discussion focused on evaluating the preoperative liver functional reserve and surgery for large tumors, multiple tumors, HCCs with vascular invasion, and HCCs with distant metastasis. The feasibility of future prospective randomized trials comparing surgery with transarterial chemoembolization for intermediate HCC and with sorafenib for advanced HCC was also discussed. The Child-Pugh score (9/10 experts) and indocyanine green retention rate at 15 min (8/10) were the most widely accepted methods for evaluating the preoperative liver functional reserve. All (10/10) experts agreed that portal hypertension, tumor size >5 cm, portal venous invasion, hepatic venous invasion, and extrahepatic metastasis are not absolute contraindications for the surgical resection of HCC. Furthermore, 9 of the 10 experts agreed that tumor resection may be performed for patients with >3 tumors. The limitations of surgery are associated with a poor liver functional reserve, incomplete tumor resection, and a high probability of recurrence. Key Messages Surgery provides significant survival benefits for Asian-Pacific patients with intermediate and advanced HCCs, particularly when the liver functional reserve is favorable. However, prospective randomized controlled trials

  4. Preparation of human hepatocellular carcinoma-targeted liposome microbubbles and their immunological properties

    Institute of Scientific and Technical Information of China (English)

    Ai-Na Bian; Yun-Hua Gao; Kai-Bin Tan; Ping Liu; Gong-Jun Zeng; Xin Zhang; Zheng Liu

    2004-01-01

    AIM: To prepare the human hepatocellular carcinoma.(HCC)-targeted liposome microbubbles and to investigate their immunological properties.METHODS: Human hepatocarcinoma specific monoclonal antibody HAb18 was attached to the surface of home-made liposome microbubbles by static attraction to prepare the targeted liposome microbubbles. The combination of HAb18 with liposome microbubbles was confirmed by the slide agglutination test and immunofluorescent assay. Their immunological activity was measured by ELISA. Rosette formation test, rosette formation blocking test and immunofluorescent assay were used to identify the specific binding of targeted liposome microbubbles to SMMC-7721 hepatoma cells, and cytotoxicity assay was used to detect their effect on human hepatocytes.RESULTS: The targeted liposome microbubbles were positive in the slide agglutination test and immunofluorescent assay. ELISA indicated that the immunological activity of HAb18 on the liposome microbubbles was similar to that of free HAb18. SMMC-7721 cells were surrounded by the targeting liposome microbubbles to form rosettes, while the control SGC-7901 gastric cancer cells were not. Proliferation of SMMC-7721 cells and normal human hepatocytes was not influenced by the targeted liposome microbubbles.CONCLUSION: The targeted liposome microbubbles with a high specific biological activity have been successfully prepared, which specifically bind to human hepatocarcinoma cells, and are non-cytotoxic to hepatocytes. These results indicate that the liposome microbubbles can be used as a HCC-targeted ultrasound contrast agent that may enhance ultrasound images and thus improve the diagnosis of HCC,especially at the early stage.

  5. Ultrastructural characteristics of novel epithelial cell types identified in human pathologic liver specimens with chronic ductular reaction.

    Science.gov (United States)

    De Vos, R; Desmet, V

    1992-06-01

    Previous immunohistochemical studies on human liver biopsies with chronic ductular reaction revealed the presence of "small cells" with bile-duct type cytokeratin profile in the periportal area. This study identified similar cells by electron microscopy. The authors studied 13 human liver specimens with various liver diseases, but all characterized by chronic ductular reaction. In all specimens, variable numbers of "small cells" with common epithelial characteristics were identified in the periportal area. They could be classified into three types. Type I cells showed an oval cell shape and oval nucleus, early or established formation of junctional complexes with adjacent cells, a full assortment of cytoplasmic organelles, and bundles of tonofilaments. Type II cells showed features of bile-duct cell differentiation, including lateral interdigitations, apical microvilli, basal pinocytotic vacuoles, and basement membrane formation. In contrast, type III cells displayed additional features indicating hepatocellular differentiation, such as a more prominent nucleus, formation of a hemicanaliculus, and glycogen rosettes. It is concluded that these small cells of epithelial nature display variable differentiation characteristics of either bile-duct type cells or hepatocytes. These findings support the existence of bipotential progenitor epithelial cells in human liver. They may have implications for liver regeneration and carcinogenesis.

  6. Phenotypic changes of human cells in human-rat liver during partial hepatectomy-induced regeneration

    Institute of Scientific and Technical Information of China (English)

    Yan Sun; Dong Xiao; Hong-An Li; Jin-Fang Jiang; Qing Li; Ruo-Shuang Zhang; Xi-Gu Chen

    2009-01-01

    AIM: To examine the human hepatic parenchymal and stromal components in rat liver and the phenotypic changes of human cells in liver of human-rat chimera (HRC) generated by in utero transplantation of human cells during partial hepatectomy (PHx)-induced liver regeneration. METHODS: Human hepatic parenchymal and stromal components and phenotypic changes of human cells during liver regeneration were examined by flow cytometry, in situ hybridization and immunohistochemistry. RESULTS: ISH analysis demonstrated human Alupositive cells in hepatic parenchyma and stroma of recipient liver. Functional human hepatocytes generated in this model potentially constituted human hepatic functional units with the presence of donor-derived human endothelial and biliary duct cells in host liver. Alpha fetoprotein (AFP)+, CD34+ and CD45+ cells were observed in the chimeric liver on day 10 after PHxinduced liver regeneration and then disappeared in PHx group, but not in non-PHx group, suggesting that dynamic phenotypic changes of human cells expressing AFP, CD34 and CD45 cells may occur during the chimeric liver regeneration. Additionally, immunostaining for human proliferating cell nuclear antigen (PCNA) showed that the number of PCNA-positive cells in the chimeric liver of PHx group was markedly increased, as compared to that of control group, indicating that donor-derived human cells are actively proliferated during PHx-induced regeneration of HRC liver.

  7. Survival in Liver Transplant Recipients with Hepatitis B- or Hepatitis C-Associated Hepatocellular Carcinoma: The Chinese Experience from 1999 to 2010

    Science.gov (United States)

    Hu, Zhenhua; Zhou, Jie; Wang, Haibo; Zhang, Min; Li, Shaogang; Huang, Yuzhou; Wu, Jian; Li, Zhiwei; Zhou, Lin; Zheng, Shusen

    2013-01-01

    Background Hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC) and hepatitis C virus (HCV)-HCC are the main indications for liver transplantation. We compared differences in survival outcomes between these two conditions. Methods and Findings The China Liver Transplant Registry (CLTR) contains data collated from all transplants performed in 86 liver transplantation centers across China. We analyzed CLTR data from January 1999 to December 2010. In all, 7,658 patients (7,162 with HBV-HCC and 496 with HCV-HCC) were included in this study. Clinical characteristics were compared between the HBV-HCC and HCV-HCC groups; Kaplan–Meier analysis was used to calculate the overall, tumor-free and hepatitis-free survival rates. The 1-year, 3-year and 5-year overall survival was significantly higher in HBV-HCC recipients than in HCV-HCC recipients (76.65%, 56.61% and 49.10% vs. 64.59%, 42.78% and 39.20%, respectively; Ptransplantation were significantly better in HBV-HCC patients than in HCV-HCC patients. This finding may be used to guide donor liver allocation in transplantation programs. PMID:23613886

  8. A comparison of liver protection among 3-D conformal radiotherapy, intensity-modulated radiotherapy and RapidArc for hepatocellular carcinoma

    Science.gov (United States)

    2014-01-01

    Purpose The analysis was designed to compare dosimetric parameters among 3-D conformal radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT) and RapidArc (RA) to identify which can achieve the lowest risk of radiation-induced liver disease (RILD) for hepatocellular carcinoma (HCC). Methods Twenty patients with HCC were enrolled in this study. Dosimetric values for 3DCRT, IMRT, and RA were calculated for total dose of 50 Gy/25f. The percentage of the normal liver volume receiving >40, >30, >20, >10, and >5 Gy (V40, V30, V20, V10 and V5) were evaluated to determine liver toxicity. V5, V10, V20, V30 and Dmean of liver were compared as predicting parameters for RILD. Other parameters included the conformal index (CI), homogeneity index (HI), and hot spot (V110%) for the planned target volume (PTV) as well as the monitor units (MUs) for plan efficiency, the mean dose (Dmean) for the organs at risk (OARs) and the maximal dose at 1% volume (D1%) for the spinal cord. Results The Dmean of IMRT was higher than 3DCRT (p = 0.045). For V5, there was a significant difference: RA > IMRT >3DCRT (p delivery time than 3DCRT or IMRT (p 8 cm in our study, the value of Dmean for 3DCRT was lower than IMRT or RapidArc. This may indicate that 3DCRT is more suitable for larger tumors. PMID:24502643

  9. Hepatic intra-arterial infusion of yttrium-90 microspheres in the treatment of recurrent hepatocellular carcinoma after liver transplantation: A case report

    Institute of Scientific and Technical Information of China (English)

    Louis Rivera; Huan Giap; William Miller; Jonathan Fisher; Donald J Hillebrand; Christopher Marsh; Randolph L Schaffer

    2006-01-01

    Hepatocellular carcinoma (HCC) recurs with a reported frequency of 12%-18% after liver transplantation.Recurrence is associated witha mortality rate exceeding 75%. Approximately one-third of recurrences develop in the transplanted liver and are therefore amenable to local therapy. A variety of treatment modalities have been reported including resection, transarterial chemoembolization (TACE), radiofrequency ablation (RFA),ethanol ablation, cryoablation, and external beam irradiation. Goals of treatment are tumor control and the minimization of toxic effect to functional parenchyma.Efficacy of treatment is mitigated by the need for ongoing immunosuppression. Yttrium-90 microspheres have been used as a treatment modality both for primary HCC and for pre-transplant management of HCC with promising results. Twenty-two months after liver transplantation for hepatitis C cirrhosis complicated by HCC, a 42-year old man developed recurrence of HCC in his transplant allograft. Treatment of multiple right lobe lesions with anatomic resection and adjuvant chemotherapy was unsuccessful. Multifocal recurrence in the remaining liver allograft was treated with hepatic intra-arterial infusion of yttrium-90 microspheres (SIR-Spheres, Sirtex Medical Inc., Lake Forest, IL, USA). Efficacy was demonstrated by tumor necrosis on imaging and a decrease in alpha-fetoprotein (AFP) level. There were no adverse consequences of initial treatment.

  10. Chimeric mice with a humanized liver as an animal model of troglitazone-induced liver injury.

    Science.gov (United States)

    Kakuni, Masakazu; Morita, Mayu; Matsuo, Kentaro; Katoh, Yumiko; Nakajima, Miki; Tateno, Chise; Yokoi, Tsuyoshi

    2012-10-02

    Troglitazone (Tro) is a thiazolidinedione antidiabetic drug that was withdrawn from the market due to its association with idiosyncratic severe liver injury. Tro has never induced liver injury in experimental animals in vivo. It was assumed that the species differences between human and experimental animals in the pharmaco- or toxicokinetics of Tro might be associated with these observations. In this study, we investigated whether a chimeric mouse with a humanized liver that we previously established, whose replacement index with human hepatocytes is up to 92% can reproduce Tro-induced liver injury. When the chimeric mice were orally administered Tro for 14 or 23 days (1000mg/kg/day), serum alanine aminotransferase (ALT) was significantly increased by 2.1- and 3.6-fold, respectively. Co-administration of l-buthionine sulfoximine (10mM in drinking water), an inhibitor of glutathione (GSH) synthesis, unexpectedly prevented the Tro-dependent increase of ALT, which suggests that the GSH scavenging pathway will not be involved in Tro-induced liver injury. To elucidate the mechanism of the onset of liver injury, hepatic GSH content, the level of oxidative stress markers and phase I and phase II drug metabolizing enzymes were determined. However, these factors were not associated with Tro-induced liver injury. An immune-mediated reaction may be associated with Tro-induced liver toxicity in vivo, because the chimeric mouse is derived from an immunodeficient SCID mouse. In conclusion, we successfully reproduced Tro-induced liver injury using chimeric mice with a humanized liver, which provides a new animal model for studying idiosyncratic drug-induced liver injury. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  11. Case study: an evaluation of the human relevance of the synthetic pyrethroid metofluthrin-induced liver tumors in rats based on mode of action.

    Science.gov (United States)

    Yamada, Tomoya; Uwagawa, Satoshi; Okuno, Yasuyoshi; Cohen, Samuel M; Kaneko, Hideo

    2009-03-01

    In recent years, mode of action (MOA) frameworks have been developed through the International Life Sciences Institute Risk Science Institute and the International Programme on Chemical Safety, including an evaluation of the human relevance of the animal MOA data. In the present paper, the MOA for rat liver tumors induced by Metofluthrin is first analyzed through this framework based on data from studies on Metofluthrin and information on related chemicals from the literature. The human relevance of the rat liver carcinogenic response is then discussed based upon the human relevance framework. Two-year treatment with high dose of Metofluthrin produced hepatocellular tumors in both sexes of the Wistar rats. Metofluthrin induced CYP2B (increased smooth endoplasmic reticulum), resulted in increased liver weights which were associated with centrilobular hepatocyte hypertrophy, and induction of increased hepatocellular DNA replications. The above parameters related to the key events in Metofluthrin-induced liver tumors were observed at or below tumorigenic dose levels. Furthermore, CYP2B induction by Metofluthrin was shown to involve activation of the constitutive androstane receptor in rat hepatocytes. Based on the evidence, including a comparison with the results with another chemical, phenobarbital, acting by a similar MOA, it is reasonable to conclude that Metofluthrin will not have any hepatocarcinogenic activity in humans.

  12. Upregulated TRIO expression correlates with a malignant phenotype in human hepatocellular carcinoma.

    Science.gov (United States)

    Wang, Bin; Fang, JiaQing; Qu, Lei; Cao, Zhongwei; Zhou, JianGuo; Deng, Biao

    2015-09-01

    Triple functional domain protein (TRIO) is an evolutionarily conserved Dbl family guanine nucleotide exchange factors (GEFs) involved in cell proliferation and progression of some types of cancer. However, the expression and prognostic role of TRIO in hepatocellular carcinoma (HCC) have not yet been determined. Therefore, we attempted to determine the impact of TRIO on the clinical outcome of HCC patients to further identify its role in HCC. TRIO expression was examined using quantitative real-time PCR (qRT-PCR) and Western blotting in nonmalignant liver cells, HCC cells, and 93 paired of HCC tissues and adjacent noncancerous tissues. Statistical analyses were used to assess associations between TRIO expression and clinicopathological and prognostic factors. Small interfering RNA (siRNA)-mediated TRIO inhibition was performed in Hep3B and Huh7 cells to elucidate its roles in HCC. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was employed to measure cell proliferation, and apoptosis assay was analyzed by flow cytometry, respectively. Adhesion and transwell invasion assay were performed to determine the invasion ability of HCC cells in vitro. TRIO was significantly upregulated in the HCC cell lines and tissues compared with the nonmalignant liver cells and adjacent noncancerous liver tissues. In addition, high TRIO expression level associated with lymph node metastasis (P = 0.0183), clinical tumor node metastasis (TNM) stage (P = 0.0.0106), and decrease in overall survival (OS) (P = 0.017). Knockdown of TRIO on Hep3B and Huh7 cell lines suppressed cell proliferation and migration and induced apoptosis. Furthermore, silencing TRIO expression led to decrease of ras-related C3 botulinum toxin substrate 1 (Rac1), p-P38, B cell lymphoma 2 (BCL-2), and matrix metallopeptidase 9 (MMP-9). Our results demonstrated that TRIO protein expression is elevated and associated with a worse over survival rates in patients with HCC. Aberrant

  13. Antitumor activity of an hTERT promoter-regulated tumor-selective oncolytic adenovirus in human hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Chang-Qing Su; Xing-Hua Wang; Jie Chen; Yong-Jing Liu; Wei-Guo Wang; Lin-Fang Li; Meng-Chao Wu; Qi-Jun Qian

    2006-01-01

    AIM: To construct a tumor-selective replicationcompetent adenovirus (RCAd), SG300, using a modified promoter of human telomerase reverse transcriptase(hTERT).METHODS: The antitumor efficacy of SG300 in epatocellular carcinoma was assessed in vitro and in vivo. In vitro cell viability by MTT assay was used to assess the tumor-selective oncolysis and safety features of SG300, andin vivo antitumor activity of SG300 was assessed in established hepatocellular carcinoma models in nude mice.RESULTS: SG300 could lyse hepatocellular carcinoma cells at a low multiplicity of infection (MOI), but could not affect growth of normal cells even at a high MOI.Both in Hep3B and SMMC-7721 xenograft models of hepatocellular carcinoma, SG300 had an obvious antitumor effect, resulting in a decrease in tumor volume. Its selective oncolysis to tumor cells and safety to normal cells was also superior to that of ONYX-015.Pathological examination of tumor specimens showed that SG300 replicated selectively in cancer cells and resulted in apoptosis and necrosis of cancer cells.CONCLUSION: hTERT promoter-regulated replicative adenovirus SG300 has a better cancer-selective replication-competent ability, and can specifically kill a wide range of cancer cells with positive telomerase activity, and thus has better potential for targeting therapy of hepatocellular carcinoma.

  14. Inflammatory pseudotumor of the liver occurring during the course of hepatitis C virus-related hepatocellular carcinoma treatment: A case report

    Science.gov (United States)

    Honmyo, Naruhiko; Kobayashi, Tsuyoshi; Tashiro, Hirotaka; Ishiyama, Kohei; Ide, Kentaro; Tahara, Hiroyuki; Ohira, Masahiro; Kuroda, Shintaro; Arihiro, Koji; Ohdan, Hideki

    2016-01-01

    Introduction Inflammatory pseudotumor (IPT) of the liver is a rare and benign disease that has a good prognosis. It is often difficult to distinguish IPT from hepatic malignancies, such as hepatocellular carcinoma (HCC), because specific clinical symptoms are absent and the diseases’ radiological findings can be similar. IPT is particularly difficult to distinguish from HCC in livers with hepatitis C virus (HCV)-related cirrhosis. We report a case of IPT of the liver that mimicked HCV-related HCC recurrence. Presentation of case A 78-year-old asymptomatic Japanese man who had undergone hepatectomy for HCV-related HCCs (moderately differentiated type) in segments 7 and 5 four and a half years previously was referred to our hospital for treatment of a 30-mm enhanced tumor in segment 5 (a typical HCC pattern). The tumor was identified via abdominal dynamic computed tomography (CT) and CT with hepatic arteriography and arterial portography. Thereafter, liver segmentectomy 5 was performed, and the histopathological diagnosis was a 10-mm IPT of the liver. After 1.5 years, magnetic resonance imaging revealed two new enhanced lesions in segment 8, which showed the typical pattern of HCC. Because these lesions grew in size for 3 months, liver segmentectomy 8 was performed for HCC recurrence. Histopathological examination showed that both lesions were HCCs. Conclusion HCV-related HCC has a high rate of multicentric recurrence. Our experience suggests that, when a hepatic lesion is suspected to be HCC, surgical resection should be considered for curative treatment and to rule out malignancy, even if the lesion may be an IPT. PMID:26826935

  15. Death receptor-independent FADD signalling triggers hepatitis and hepatocellular carcinoma in mice with liver parenchymal cell-specific NEMO knockout.

    Science.gov (United States)

    Ehlken, H; Krishna-Subramanian, S; Ochoa-Callejero, L; Kondylis, V; Nadi, N E; Straub, B K; Schirmacher, P; Walczak, H; Kollias, G; Pasparakis, M

    2014-11-01

    Hepatocellular carcinoma (HCC) usually develops in the context of chronic hepatitis triggered by viruses or toxic substances causing hepatocyte death, inflammation and compensatory proliferation of liver cells. Death receptors of the TNFR superfamily regulate cell death and inflammation and are implicated in liver disease and cancer. Liver parenchymal cell-specific ablation of NEMO/IKKγ, a subunit of the IκB kinase (IKK) complex that is essential for the activation of canonical NF-κB signalling, sensitized hepatocytes to apoptosis and caused the spontaneous development of chronic hepatitis and HCC in mice. Here we show that hepatitis and HCC development in NEMO(LPC-KO) mice is triggered by death receptor-independent FADD-mediated hepatocyte apoptosis. TNF deficiency in all cells or conditional LPC-specific ablation of TNFR1, Fas or TRAIL-R did not prevent hepatocyte apoptosis, hepatitis and HCC development in NEMO(LPC-KO) mice. To address potential functional redundancies between death receptors we generated and analysed NEMO(LPC-KO) mice with combined LPC-specific deficiency of TNFR1, Fas and TRAIL-R and found that also simultaneous lack of all three death receptors did not prevent hepatocyte apoptosis, chronic hepatitis and HCC development. However, LPC-specific combined deficiency in TNFR1, Fas and TRAIL-R protected the NEMO-deficient liver from LPS-induced liver failure, showing that different mechanisms trigger spontaneous and LPS-induced hepatocyte apoptosis in NEMO(LPC-KO) mice. In addition, NK cell depletion did not prevent liver damage and hepatitis. Moreover, NEMO(LPC-KO) mice crossed into a RAG-1-deficient genetic background-developed hepatitis and HCC. Collectively, these results show that the spontaneous development of hepatocyte apoptosis, chronic hepatitis and HCC in NEMO(LPC-KO) mice occurs independently of death receptor signalling, NK cells and B and T lymphocytes, arguing against an immunological trigger as the critical stimulus driving

  16. Liver (Hepatocellular) Cancer Screening

    Science.gov (United States)

    ... cancer is present in the body. Alpha-fetoprotein (AFP) is the most widely used tumor marker for ... and other types of cancer, may also increase AFP levels. Specific tumor markers that may lead to ...

  17. Liver (Hepatocellular) Cancer Prevention

    Science.gov (United States)

    ... Being infected with certain types of the hepatitis virus can cause hepatitis and increase the risk of ... about health care. Reviewers and Updates Editorial Boards write the PDQ cancer information summaries and keep them ...

  18. Human liver microsomal metabolism of (+)-discodermolide.

    Science.gov (United States)

    Fan, Yun; Schreiber, Emanuel M; Day, Billy W

    2009-10-01

    The polyketide natural product (+)-discodermolide is a potent microtubule stabilizer that has generated considerable interest in its synthetic, medicinal, and biological chemistry. It progressed to early clinical oncology trials, where it showed some efficacy in terms of disease stabilization but also some indications of causing pneumotoxicity. Remarkably, there are no reports of its metabolism. Here, we examined its fate in mixed human liver microsomes. Due to limited availability of the agent, we chose a nanoflow liquid chromatography-electrospray ionization-mass spectrometry analytical approach employing quadrupolar ion trap and quadrupole-quadrupole-time-of-flight instruments for these studies. (+)-Discodermolide was rapidly converted to eight metabolites, with the left-side lactone (net oxidation) and the right-side diene (epoxidation followed by hydrolysis, along with an oxygen insertion product) being the most metabolically labile sites. Other sites of metabolism were the allylic and pendant methyl moieties in the C12-C14 region of the molecule. The results provide information on the metabolic soft spots of the molecule and can be used in further medicinal chemistry efforts to optimize discodermolide analogues.

  19. Association between the HFE C282Y, H63D Polymorphisms and the Risks of Non-Alcoholic Fatty Liver Disease, Liver Cirrhosis and Hepatocellular Carcinoma: An Updated Systematic Review and Meta-Analysis of 5,758 Cases and 14,741 Controls

    Science.gov (United States)

    Yin, Wei-Li; Wang, Feng-Mei; Han, Tao

    2016-01-01

    Background Conflicting results have been obtained for the association between two common polymorphisms (C282Y, H63D) of human HFE (hereditary hemochromatosis) gene and the risks of the liver diseases, including non-alcoholic fatty liver disease (NAFLD), liver cirrhosis and hepatocellular carcinoma (HCC). Methods An updated systematic review and meta-analysis was conducted to evaluate the potential role of HFE polymorphisms in the susceptibility to NAFLD, liver cirrhosis and HCC. After retrieving articles from online databases, eligible studies were enrolled according to the selection criteria. Stata/SE 12.0 software was utilized to perform the statistical analysis. Results In total, 43 articles with 5,758 cases and 14,741 controls were selected. Compared with the control group, a significantly increased risk of NAFLD was observed for the C282Y polymorphism in the Caucasian population under all genetic models and for the H63D polymorphism under the allele, heterozygote and dominant models (all OR>1, Passociation0.05). In addition, we found that HFE C282Y was statistically associated with increased HCC susceptibility in the overall population, while H63D increased the odds of developing non-cirrhotic HCC in the African population (all OR>1, Passociation<0.05). Moreover, a positive association between compound heterozygosity for C282Y/H63D and the risk of NAFLD and HCC, but not liver cirrhosis, was observed. Conclusion Our meta-analysis provides evidence that the HFE C282Y and H63D polymorphisms confer increased genetic susceptibility to NAFLD and HCC but not liver cirrhosis. Additional well-powered studies are required to confirm our conclusion. PMID:27657935

  20. Selective Toxicity of Persian Gulf Sea Cucumber (Holothuria parva and Sponge (Haliclona oculata Methanolic Extracts on Liver Mitochondria Isolated from an Animal Model of Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Seydi

    2015-12-01

    Full Text Available Background Natural products isolated from marine environments are well known for their pharmacodynamic potential in diverse disease treatments, such as for cancer or inflammatory conditions. Sea cucumbers are marine animals of the phylum Echinoderm and the class Holothuroidea, with leathery skin and gelatinous bodies. Sponges are important components of Persian Gulf animal communities, and the marine sponges of the genus Haliclona have been known to display broad-spectrum biological activity. Many studies have shown that sea cucumbers and sponges contain antioxidants and anti-cancer compounds. Objectives This study was designed to determine the selective toxicity of Persian Gulf sea cucumber (Holothuria parva and sponge (Haliclona oculata methanolic extracts on liver mitochondria isolated from an animal model of hepatocellular carcinoma, as part of a national project that hopes to identify novel potential anticancer candidates among Iranian Persian Gulf flora and fauna. Materials and Methods To induce hepatocarcinogenesis, rats were given diethylnitrosamine (DEN injections (200 mg/kg i.p. by a single dose, and then the cancer was promoted with 2-acetylaminofluorene (2-AAF (0.02 w/w for two weeks. Histopathological evaluations were performed, and levels of liver injury markers and a specific liver cancer marker (alpha-fetoprotein, were determined for confirmation of hepatocellular carcinoma induction. Finally, mitochondria were isolated from cancerous and non-cancerous hepatocytes. Results Our results showed that H. parva methanolic extracts (250, 500, and 1000 µg/mL and H. oculata methanolic extracts (200, 400, and 800 µg/mL increased reactive oxygen species (ROS formation, mitochondrial membrane potential (MMP, mitochondrial swelling, and cytochrome c release in the mitochondria obtained from cancerous hepatocytes, but not in mitochondria obtained from non-cancerous liver hepatocytes. These extracts also induced caspase-3 activation, which is

  1. Enantioselective Metabolism of Flufiprole in Rat and Human Liver Microsomes.

    Science.gov (United States)

    Lin, Chunmian; Miao, Yelong; Qian, Mingrong; Wang, Qiang; Zhang, Hu

    2016-03-23

    The enantioselective metabolism of flufiprole in rat and human liver microsomes in vitro was investigated in this study. The separation and determination were performed using a liquid chromatography system equipped with a triple-quadrupole mass spectrometer and a Lux Cellulose-2 chiral column. The enantioselective metabolism of rac-flufiprole was dramatically different in rat and human liver microsomes in the presence of the β-nicotinamide adenine dinucleotide phosphate regenerating system. The half-lives (t1/2) of flufiprole in rat and human liver microsomes were 7.22 and 21.00 min, respectively, for R-(+)-flufiprole, whereas the values were 11.75 and 17.75 min, respectively, for S-(-)-flufiprole. In addition, the Vmax of R-(+)-flufiprole was about 3-fold that of S-(-)-flufiprole in rat liver microsomes, whereas its value in the case of S-(-)-flufiprole was about 2-fold that of R-(+)-flufiprole in human liver microsomes. The CLint of rac-flufiprole also showed opposite enantioselectivy in rat and human liver microsomes. The different compositions and contents of metabolizing enzyme in the two liver microsomes might be the reasons for the difference in the metabolic behavior of the two enantiomers.

  2. Inhibitory effect of humanized anti-VEGFR-2 ScFv-As2O3-stealth nanoparticles conjugate on growth of human hepatocellular carcinoma:in vitro andin vivo studies

    Institute of Scientific and Technical Information of China (English)

    Xiang-Bao Yin; Lin-Quan Wu; Hua-Qun Fu; Ming-Wen Huang; Kai Wang; Fan Zhou; Xin Yu; Kai-Yang Wang

    2014-01-01

    Objective:To investigate the inhibitory effect of humanized anti-VEGFR-2ScFv-As2O3-stealth nanoparticles conjugate on growth of human hepatocellular carcinoma bothin vitro andin vivo, which may be a potential agents with sensitivity and targeting ability for human hepatocellular cancer.Methods:Humanized anti-VEGFR-2ScFv-As2O3-stealth nanoparticles conjugate was previously constructed using ribosome display technology and antibody conjugate technology. In this combinedin vitro andin vivo study, the inhibitory effects of anti-VEGFR-2ScFv-As2O3-stealth nanoparticles conjugate on tumor growth, invasion, and metastasis was observed with human liver carcinoma cell lineBel7402 and normal cellL02 byMTT assay,Tanswell assay, Hochest33258 staining, andDNA ladder analysis.The anticancer activity and distribution of anti-VEGFR-2ScFv-As2O3-stealth nanoparticles was then verified in a mouse model ofBel7402 xenografts.Results:Anti-VEGFR-2ScFv-As2O3-stealth nanoparticles significantly inhibited the proliferation ofBel7402 in the3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay while had almost no effects onL02 cells.And the apoptosis inducing effects were proved byHochest33258 staining andDNA ladder analysis.Transwell assay found that the drug also inhibited the metastasis ability of tumor cells.Furthermore, anti-VEGFR-2ScFv-As2O3-stealth nanoparticles significantly delayed the growth ofBel7402 xenografts after administration(92.9%), followed byAs2O3-stealth nanoparticles, anti-VEGFR-2ScFv, andAs2O3(61.4%,58.8%,20.5%, P<0.05).The concentration ofAs2O3 in anti-VEGFR-2ScFv-As2O3-stealth nanoparticles group was more selectively.Conclusions:Anti-VEGFR-2ScFv-As2O3-stealth nanoparticles is a potent and selective anti-hepatocellular carcinoma agent which could inhibit the growth of liver cancer as a targeting agent bothin vitro andin vivo and also significantly inhibit angiogenesis.

  3. Brain metastasis of hepatocellular carcinoma detected after liver transplantation Metástase cerebral de carcinoma hepatocelular após transplante de fígado

    Directory of Open Access Journals (Sweden)

    Alex Vianey Callado França

    2004-09-01

    Full Text Available AIM: We report the case of a patient with hepatocellular carcinoma submitted to liver transplantation, who subsequently manifested tumor recurrence initially as brain metastasis. CASE DESCRIPTION: A 48-year-old male cirrhotic patient with hepatitis C infection, and two focal hepatic lesions, had a cytologic and histologic diagnosis of hepatocellular carcinoma. Before transplant, he was submitted to adjuvant treatment with a combination of arterial embolization and intratumoral ethanol injection. In the 3rd month post-liver transplantation, the patient developed headache, nausea and vomiting, without any neurological impairment. Brain computed tomography and magnetic resonance imaging identified an expansive hypervascular lesion with internal bleeding. Evaluation of the surgical explant revealed macroscopic invasion of portal vessels. CONCLUSION: Brain metastasis of a hepatocellular carcinoma after liver transplantation may occur. This metastasis may have occurred before or soon after the transplant. Patients with hepatocellular carcinoma, awaiting liver transplant, should be screened for cerebral metastasis. Vascular invasion may indicate hematogenic dissemination of the tumor.OBJETIVO: Relatar o caso de paciente com carcinoma hepatocelular submetido a transplante de fígado, que subseqüentemente manifestou recurrência tumoral em cérebro após o transplante. DESCRIÇÃO DO CASO: Homem de 48 anos de idade, com cirrose hepática secundária à infecção pelo vírus da hepatite C, com duas lesões focais hepáticas diagnosticadas como carcinoma hepatocelular pela citologia e histologia. Antes do transplante, foi submetido a tratamento coadjuvante com embolização da artéria hepática e injeção intra-tumoral de etanol. No terceiro mês pós-transplante, o paciente apresentou cefaléia, náuseas e vômitos, sem déficit neurológico focal. Tomografia computadorizada e ressonância magnética de crânio identificaram lesão expansiva

  4. TALENs-directed knockout of the full-length transcription factor Nrf1α that represses malignant behaviour of human hepatocellular carcinoma (HepG2) cells.

    Science.gov (United States)

    Ren, Yonggang; Qiu, Lu; Lü, Fenglin; Ru, Xufang; Li, Shaojun; Xiang, Yuancai; Yu, Siwang; Zhang, Yiguo

    2016-04-11

    The full-length Nrf1α is processed into distinct isoforms, which together regulate genes essential for maintaining cellular homeostasis and organ integrity, and liver-specific loss of Nrf1 in mice results in spontaneous hepatoma. Herein, we report that the human constitutive Nrf1α, rather than smaller Nrf1β/γ, expression is attenuated or abolished in the case of low-differentiated high-metastatic hepatocellular carcinomas. Therefore, Nrf1α is of importance in the physio-pathological origin and development, but its specific pathobiological function(s) remains elusive. To address this, TALENs-directed knockout of Nrf1α, but not Nrf1β/γ, is created in the human hepatocellular carcinoma (HepG2) cells. The resulting Nrf1α(-/-) cells are elongated, with slender spindle-shapes and enlarged gaps between cells observed under scanning electron microscope. When compared with wild-type controls, the invasive and migratory abilities of Nrf1α(-/-) cells are increased significantly, along with the cell-cycle G2-M arrest and S-phase reduction, as accompanied by suppressed apoptosis. Despite a modest increase in the soft-agar colony formation of Nrf1α(-/-) cells, its loss-of-function markedly promotes malgrowth of the subcutaneous carcinoma xenograft in nude mice with hepatic metastasis. Together with molecular expression results, we thus suppose requirement of Nrf1α (and major derivates) for gene regulatory mechanisms repressing cancer cell process (e.g. EMT) and malignant behaviour (e.g. migration).

  5. Oncological Evaluation by Positron-emission Tomography, Circulating Tumor Cells and Alpha Fetoprotein in Patients With Hepatocellular Carcinoma on the Waiting List for Liver Transplantation.

    Science.gov (United States)

    Ramirez, P; Sáenz, L; Cascales-Campos, P A; González Sánchez, M R; Llàcer-Millán, E; Sánchez-Lorencio, M I; Díaz-Rubio, E; De La Orden, V; Mediero-Valeros, B; Navarro, J L; Revilla Nuin, B; Baroja-Mazo, A; Noguera-Velasco, J A; Sánchez, B F; de la Peña, J; Pons-Miñano, J A; Sánchez-Bueno, F; Robles-Campos, R; Parrilla, P

    2016-11-01

    The objectives of this study are the determination of the number of circulating tumor cells (CTCs), by means of the IsoFlux enrichment system (Fluxion Biosciences Inc, San Francisco, California, United States) in patients with hepatocellular carcinoma (HCC) in compliance with the Milan criteria and on the waiting list for hepatic transplantation, as well as the study of its relation with the of α-fetoprotein levels (AFP) and positron-emission tomography-computed tomography (PET-CT) findings. An oncologycal evaluation with PET-CT, CTCs, and AFP was conducted in 24 consecutive patients with HCC eligible for orthotopic liver transplantation according to the Milan criteria. The diagnosis of HCC was made according to clinical, biological, and radiological findings. We detected CTCs in peripheral blood in 21 of 24 patients (87.5%) before liver transplantation, with a mean number CTCs of 156 ± 370 (range, 2 to 1768) with statistically significant association between number of CTCs detected in peripheral blood and the time within the waiting list (P  .05). PET-TC, CTCs, and AFP levels could be an essential key for the correct management of the patients with HCC on the waiting list for liver transplantation. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. The Proper Scan Delay of the Hepatobiliary Phase of Gadoxetic Acid-Enhanced Magnetic Resonance Imaging to Evaluate Small-Sized ({<=} 3 cm) Hepatocellular Carcinoma in Cirrhotic Liver

    Energy Technology Data Exchange (ETDEWEB)

    Jeong, Yong Yeon; Heo, Sook Hee; Kim, Jin Woong; Kang, Heoung Keun [Dept. of Radiology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun (Korea, Republic of); Lee, Ji Hyun; Shin, Sang Soo [Dept. of Radiology, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju (Korea, Republic of)

    2013-04-15

    To assess the optimal scan delay of hepatobiliary phase of gadoxetic acid (GA)-enhanced magnetic resonance (MR) imaging for small-sized ({<=} 3 cm) hepatocellular carcinomas (HCCs) in cirrhotic liver. There were 71 HCCs included in this study, derived from 53 patients with liver cirrhosis. Hepatobiliary phase MR imaging was obtained at 10, 15 and 20 mins after GA injection. For quantitative analysis, 2 radiologists calculated signal to noise ratio (SNR), enhancement ratio (ER) of the tumor and liver parenchyma and contrast-to-noise ratio (CNR) at 10 min, 15 min, and 20 min images, respectively. For qualitative analysis, 3 radiologists independently reviewed the 3 different phase about HCC possibilities using a 5-point scale. For each observer, the diagnostic accuracy of different hepatobiliary phases was compared using the area under the alternative free-response receiver operating characteristic curve (Az). In addition, sensitivity and specificity were compared. No significant differences in SNR, ER and CNR at 10 min, 15 min, and 20 min were found. The Az values for HCC possibility were not significantly different. Sensitivity and specificity were also not significantly different. Hepatobiliary phase MR imaging were obtained at 10 min, 15 min and 20 min yield comparable diagnostic information, so that the choice of scan delay can be adapted according to the clinical routine needs.

  7. Dynamic contrast enhanced MR imaging for evaluation of angiogenesis of hepatocellular nodules in liver cirrhosis in N-nitrosodiethylamine induced rat model

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Wei; Chen, Hui Juan; Huang, Wei; Zhang, Long Jiang [Medical School of Nanjing University, Department of Medical Imaging, Jinling Hospital, Nanjing, Jiangsu (China); Wang, Zhen J. [University of California, Department of Radiology and Biomedical Imaging, San Francisco, CA (United States)

    2017-05-15

    To investigate whether dynamic contrast -enhanced MRI (DCE-MRI) can distinguish the type of liver nodules in a rat model with N-nitrosodiethylamine- induced cirrhosis. Liver nodules in cirrhosis were induced in 60 male Wistar rats via 0.01 % N-nitrosodiethylamine in the drinking water for 35-100 days. The nodules were divided into three groups: regenerative nodule (RN), dysplastic nodule (DN), and hepatocellular carcinoma (HCC). DCE-MRI was performed, and parameters including transfer constant (K{sup trans}), rate constant (K{sub ep}), extravascular extracellular space volume fraction (V{sub e}), and initial area under the contrast concentration versus time curve (iAUC) were measured and compared. The highest K{sup trans} and iAUC values were seen in HCC, followed by DN and RN (all P < 0.05). The area under the receiver operating characteristic curve (AUROC) for DN and HCC were 0.738 and 0.728 for K{sup trans} and iAUC, respectively. The AUROC for HCC were 0.850 and 0.840 for K{sup trans} and iAUC, respectively. Ordinal logistic regression analysis showed that K{sup trans} had a high goodness of fit (0.970, 95 % confidence interval, 13.751-24.958). DCE-MRI is a promising method to differentiate of liver nodules. Elevated K{sup trans} suggested that the nodules may be transformed into HCC. (orig.)

  8. The Risk of Hepatocellular Carcinoma After Directly Acting Antivirals for Hepatitis C Virus Treatment in Liver Transplanted Patients: Is It Real?

    Science.gov (United States)

    Strazzulla, Alessio; Maria Rita Iemmolo, Rosa; Carbone, Ennio; Concetta Postorino, Maria; Mazzitelli, Maria; De Santis, Mario; Di Benedetto, Fabrizio; Maria Cristiani, Costanza; Costa, Chiara; Pisani, Vincenzo; Torti, Carlo

    2016-01-01

    Introduction Since directly acting antivirals (DAAs) for treatment of hepatitis C virus (HCV) were introduced, conflicting data emerged about the risk of hepatocellular carcinoma (HCC) after interferon (IFN)-free treatments. We present a case of recurrent, extra-hepatic HCC in a liver-transplanted patient soon after successful treatment with DAAs, along with a short review of literature. Case Presentation In 2010, a 53-year old man, affected by chronic HCV (genotype 1) infection and decompensated cirrhosis, underwent liver resection for HCC and subsequently received orthotopic liver transplantation. Then, HCV relapsed and, in 2013, he was treated with pegylated-IFN plus ribavirin; but response was null. In 2014, he was treated with daclatasvir plus simeprevir to reach sustained virological response. At baseline and at the end of HCV treatment, computed tomography (CT) scan of abdomen excluded any lesions suspected for HCC. However, alpha-fetoprotein was 2.9 ng/mL before DAAs, increasing up to 183.1 ng/mL at week-24 of follow-up after the completion of therapy. Therefore, CT scan of abdomen was performed again, showing two splenic HCC lesions. Conclusions Overall, nine studies have been published about the risk of HCC after DAAs. Patients with previous HCC should be carefully investigated to confirm complete HCC remission before starting, and proactive follow-up should be performed after DAA treatment. PMID:28070200

  9. Effect of sorafenib on des-γ-carboxyprothrombin secretion by a human hepatocellular carcinoma cell line.

    Science.gov (United States)

    Ogasawara, Sachiko; Nakayama, Masamichi; Akiba, Jun; Kusano, Hironori; Yano, Hirohisa

    2017-08-01

    Patients with hepatocellular carcinoma (HCC) who respond to sorafenib have been reported to exhibit an increase in the level of des-γ-carboxyprothrombin (DCP) in the blood, subsequent to the initiation of sorafenib treatment. In the present study, the levels of secretion of DCP and DCP with more γ-carboxyglutamic residues (NX-DCP) and the effects of hypoxic conditions were examined in 13 liver cancer cell lines, and the presence of vitamin K and sorafenib, in the KYN-2 cell line, which resulted in confirmed DCP and NX-DCP secretion. DCP, NX-DCP and prothrombin secretion were confirmed in 2/13 cell lines, KYN-2 and KIM-1. The level of secretions increased under hypoxic conditions. The addition of vitamin K suppressed cell proliferation, and DCP expression decreased to below detectable levels, however the level of prothrombin expression increased. Sorafenib treatment increased the level of apoptosis and suppressed cell proliferation, and decreased DCP and NX-DCP. In contrast, levels of prothrombin and vascular endothelial growth factor (VEGF) expression exhibited a slight increase. When the same experiment was conducted under hypoxic conditions, DCP secretion significantly decreased in the presence of sorafenib. The level of DCP secretion increased by several fold in the sorafenib-treated and non-treated cells compared with the normoxic conditions. Prothrombin and VEGF values with normoxic conditions remained almost similar with hypoxic conditions. Under hypoxic conditions, NX-DCP significantly decreased below the control values for the first 48 h subsequent to sorafenib treatment, but significantly increased at 72 h. In vivo experiments demonstrated that sorafenib inhibited angiogenesis and tumor proliferation, but the levels of DCP and NX-DCP did not differ significantly from the controls. These findings indicate that the suppression of neovascularization by sorafenib promotes blood vessel ischemia, producing hypoxic conditions whereby vitamin K uptake and

  10. E-CADHERIN AND CD44V6 EXPRESION IN HUMAN HEPATOCELLULAR CARCINOMAS

    Institute of Scientific and Technical Information of China (English)

    郑建明; 郑唯强; 龚志锦; 朱明华; 戴益民; 张照环

    2001-01-01

    To investigate the significance of E- cadherin (E-cad) and CD44v6 expression in human hepatocellular carcinomas (HCCs). Methods: An immunohistochemical method was used to detect E-cad and CD44v6 expression in 66 cases of HCCs. Results: The positive rates of E-cad and CD44v6 expression in human HCCs were 42.4%(28/66) and 39.4%(26/66), respectively. There was an inverse correlation between E-cad expression and invasive and metastatic potential of HCCs (P<0.01), and a positive correlation between the CD44v6 expression and invasive and metastatic potential of HCCs (P<0.01). Moreover, the 5-year survival rate in the E-cad-positive group was higher than in E-cad-negative group (P<0.01), and that in the CD44v6-positive group was lower than in the CD44v6-negative expression group (P<0.05). Conclusion: these data show a possible association between E-cad and CD44v6 expression and the potential of invasion and metastasis in HCCs. E-cad and CD44v6 expression may be used as an auxiliary prognostic indicator in HCCs.

  11. Chalcone-Induced Apoptosis through Caspase-Dependent Intrinsic Pathways in Human Hepatocellular Carcinoma Cells

    Science.gov (United States)

    Ramirez-Tagle, Rodrigo; Escobar, Carlos A.; Romero, Valentina; Montorfano, Ignacio; Armisén, Ricardo; Borgna, Vincenzo; Jeldes, Emanuel; Pizarro, Luis; Simon, Felipe; Echeverria, Cesar

    2016-01-01

    Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed cancers worldwide. Chemoprevention of HCC can be achieved through the use of natural or synthetic compounds that reverse, suppress or prevent the development of cancer progression. In this study, we investigated the antiproliferative effects and the mechanism of action of two compounds, 2,3,4′-trimethoxy-2′-hydroxy-chalcone (CH1) and 3′-bromo-3,4-dimethoxy-chalcone (CH2), over human hepatoma cells (HepG2 and Huh-7) and cultured mouse hepatocytes (HepM). Cytotoxic effects were observed over the HepG2 and Huh-7, and no effects were observed over the HepM. For HepG2 cells, treated separately with each chalcone, typical apoptotic laddering and nuclear condensation were observed. Additionally, the caspases and Bcl-2 family proteins activation by using Western blotting and immunocytochemistry were studied. Caspase-8 was not activated, but caspase-3 and -9 were both activated by chalcones in HepG2 cells. Chalcones also induced reactive oxygen species (ROS) accumulation after 4, 8 and 24 h of treatment in HepG2 cells. These results suggest that apoptosis in HepG2 was induced through: (i) a caspase-dependent intrinsic pathway; and (ii) by alterations in the cellular levels of Bcl-2 family proteins, and also, that the chalcone moiety could be a potent candidate as novel anticancer agents acting on human hepatomas. PMID:26907262

  12. Chalcone-Induced Apoptosis through Caspase-Dependent Intrinsic Pathways in Human Hepatocellular Carcinoma Cells.

    Science.gov (United States)

    Ramirez-Tagle, Rodrigo; Escobar, Carlos A; Romero, Valentina; Montorfano, Ignacio; Armisén, Ricardo; Borgna, Vincenzo; Jeldes, Emanuel; Pizarro, Luis; Simon, Felipe; Echeverria, Cesar

    2016-02-22

    Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed cancers worldwide. Chemoprevention of HCC can be achieved through the use of natural or synthetic compounds that reverse, suppress or prevent the development of cancer progression. In this study, we investigated the antiproliferative effects and the mechanism of action of two compounds, 2,3,4'-trimethoxy-2'-hydroxy-chalcone (CH1) and 3'-bromo-3,4-dimethoxy-chalcone (CH2), over human hepatoma cells (HepG2 and Huh-7) and cultured mouse hepatocytes (HepM). Cytotoxic effects were observed over the HepG2 and Huh-7, and no effects were observed over the HepM. For HepG2 cells, treated separately with each chalcone, typical apoptotic laddering and nuclear condensation were observed. Additionally, the caspases and Bcl-2 family proteins activation by using Western blotting and immunocytochemistry were studied. Caspase-8 was not activated, but caspase-3 and -9 were both activated by chalcones in HepG2 cells. Chalcones also induced reactive oxygen species (ROS) accumulation after 4, 8 and 24 h of treatment in HepG2 cells. These results suggest that apoptosis in HepG2 was induced through: (i) a caspase-dependent intrinsic pathway; and (ii) by alterations in the cellular levels of Bcl-2 family proteins, and also, that the chalcone moiety could be a potent candidate as novel anticancer agents acting on human hepatomas.

  13. Chalcone-Induced Apoptosis through Caspase-Dependent Intrinsic Pathways in Human Hepatocellular Carcinoma Cells

    Directory of Open Access Journals (Sweden)

    Rodrigo Ramirez-Tagle

    2016-02-01

    Full Text Available Hepatocellular carcinoma (HCC is one of the most commonly diagnosed cancers worldwide. Chemoprevention of HCC can be achieved through the use of natural or synthetic compounds that reverse, suppress or prevent the development of cancer progression. In this study, we investigated the antiproliferative effects and the mechanism of action of two compounds, 2,3,4′-trimethoxy-2′-hydroxy-chalcone (CH1 and 3′-bromo-3,4-dimethoxy-chalcone (CH2, over human hepatoma cells (HepG2 and Huh-7 and cultured mouse hepatocytes (HepM. Cytotoxic effects were observed over the HepG2 and Huh-7, and no effects were observed over the HepM. For HepG2 cells, treated separately with each chalcone, typical apoptotic laddering and nuclear condensation were observed. Additionally, the caspases and Bcl-2 family proteins activation by using Western blotting and immunocytochemistry were studied. Caspase-8 was not activated, but caspase-3 and -9 were both activated by chalcones in HepG2 cells. Chalcones also induced reactive oxygen species (ROS accumulation after 4, 8 and 24 h of treatment in HepG2 cells. These results suggest that apoptosis in HepG2 was induced through: (i a caspase-dependent intrinsic pathway; and (ii by alterations in the cellular levels of Bcl-2 family proteins, and also, that the chalcone moiety could be a potent candidate as novel anticancer agents acting on human hepatomas.

  14. Functional analysis of {alpha}1,3/4-fucosyltransferase VI in human hepatocellular carcinoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Guo, Qiya; Guo, Bin; Wang, Yingming; Wu, Jun; Jiang, Wenjun; Zhao, Shenan [State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai 200433 (China); Qiao, Shouyi, E-mail: syqiao@fudan.edu.cn [State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai 200433 (China); Wu, Yanhua, E-mail: yanhuawu@fudan.edu.cn [State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai 200433 (China)

    2012-01-06

    Highlights: Black-Right-Pointing-Pointer Human FUT6 is up-regulated in HCC tissues. Black-Right-Pointing-Pointer Expression of FUT6 promotes G0/G1-S transition and cell growth. Black-Right-Pointing-Pointer FUT6 confers a growth advantage in vivo. Black-Right-Pointing-Pointer FUT6 suppresses p21 expression through modulating PI3K/Akt signaling. -- Abstract: The {alpha}1,3/4-fucosyltransferases (FUT) subfamily are key enzymes in cell surface antigen synthesis during various biological processes. A novel role of FUTs in tumorigenesis has been discovered recently, however, the underlying mechanism remains largely unknown. Here, we characterized FUT6, a member of {alpha}1,3/4-FUT subfamily, in human hepatocellular carcinoma (HCC). In HCC tissues, the expression levels of FUT6 and its catalytic product SLe{sup x} were significantly up-regulated. Overexpression of FUT6 in HCC cells enhanced S-phase cell population, promoted cell growth and colony formation ability. Moreover, subcutaneously injection of FUT6-overexpressing cells in nude mice promoted cell growth in vivo. In addition, elevating FUT6 expression markedly induced intracellular Akt phosphorylation, and suppressed the expression of the cyclin-dependent kinases inhibitor p21. Bath application of the PI3K inhibitor blocked FUT6-induced Akt phosphorylation, p21 suppression and cell proliferation. Our results suggest that FUT6 plays an important role in HCC growth by regulating the PI3K/Akt signaling pathway.

  15. Expression of Bcl-2 inhibited Fas-mediated apoptosis in human hepatocellular carcinoma BEL-7404 cells

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Apoptosis plays an important role in embryonic development, tissue remodeling, immune regulation and tumor regression. Two groups of molecules (Bcl-2 family and"Death factor"family) are involved in regulating apoptosis. In order to know about the effect of Bcl-2 on apoptosis induced by Fas, a typical member of"Death factor" family, the transfection experiments with expression vectors pcDNA3-fland pcDNA3-bcl-2 were performed in BEL-7404 cells, a human hepatocellular carcinoma cell line which expresses endogenous Fas, but not FasL and Bcl2. The data showed that the expression of FasL in pcDNA3fl transfected hepatoma cells obviously induced the apoptosis of the cells. However, the overexpression of Bcl-2 in pcDNA3bcl-2 transfected 7404/b-16 cells counteracted pcDNA3-fltransient transfection mediated apoptosis. Further study by cotransfection experiments indicated that Bid but not Bax (both were pro-apoptotic proteins of Bcl-2 family) blocked the inhibitory effect of Bcl-2 on Fas-mediated apoptosis. These results suggested that Fas-mediated apoptosis in human hcpatoma cells is possibly regulated by Bcl-2 family proteins via mitochondria pathway.

  16. Genetic diversity of hepatitis B virus and mutations associated to hepatocellular carcinoma in patients from Venezuela, with different stages of liver disease.

    Science.gov (United States)

    Puche, Mary L; Kay-Valero, Sharon; Michelli, Pedro; Oropeza, Maria D; Loureiro, Carmen L; Devesa, Marisol; Dagher, Lucy; Pujol, Flor H

    2016-03-01

    Globally, about 50% of liver cancer originates as a result of long term infection with hepatitis B virus (HBV), and some genotypes and mutations have been associated with an increased severity of infection. The aim of this study was to evaluate the genetic diversity of HBV in patients from Venezuela, with chronic infection, cirrhosis and hepatocellular carcinoma (HCC) and to compare the occurrence of mutations in all patient groups. Samples from patients with different pathologies of the liver, associated with HBV infection, were collected. The HBV S region was analyzed for genotype determination and, when available, the whole genome sequence was examined for mutations analysis. Genotype F was the most common genotype (87%). While the HBV subgenotype F3 was the most frequent genotype in the whole group of samples (44%), the subgenotype F2 predominated in HCC patients (56%). Mutations were more common in HCC and cirrhosis cases (p=0.01). The A1762T mutation was significantly associated with the advanced stage of liver disease (p=0.008). Additionally, mutations were more common in early stages of liver disease in HBV subgenotype F2-infected patients, and a significant association between this subgenotype and the emergence of T 1753C, A1762T, A1762T/G1764A (p=0.04) and C1773T (p=0.001) mutations in chronic patients was found, when compared to the HBV subgenotype F3. By comparing F2 with all other HBV subgenotypes, a positive association for the three basal core promoter (BCP) mutants (A1762T, A1762T/G1764A p=0.01, G1764A p=0.04) was found. These results suggest that the HBV subgenotype F2 might be associated to more severe forms of liver disease in comparison with the HBV subgenotype F3.

  17. Effect of bax, bcl-2 and bcl-xL on regulating apoptosis in tissues of normal liver and hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Xiao-Zhong Guo; Xiao-Dong Shao; Min-Pei Liu; Jian-Hua Xu; Li-Nan Ren; Jia-Jun Zhao; Hong-Yu Li; Di Wang

    2002-01-01

    AIM: To investigate the expression of bax, bcl-2 and bcl-xL mRNA in the tissues of normal liver and hepatocellular carcinoma (HCC), and analyze the relationship between the expression of bax, bcl-2 and bcl-xL mRNA and clinical parameters of HCC patients.METHODS: The expression of bax, bcl-2 and bcl-xL mRNA of normal liver and HCC was measured by Northern blot. Statistical analyses were made by t test and correlation analysis.RESULTS: A very low mRNA level was indicated at bax,bcl-2 and bcl-xL in the HCC tissues in contrast to the tissues of normal liver by Northern blot analysis. The analyses of mRNA level revealed that HCC tissues exhibited a mean 7.6-fold decrease in bax, 4.2-fold in bcl-2 and 3.5-fold in bcl-xL in comparison with normal control tissues, respectively. Positive correlation was found between bax and bcl-xL (r=0.7061,P<0.01). There was no significance between the mRNA expression of these three genes and age, gender, tumor differentiation and tumor stage of HCC patients. CONCLUSION: The results are consistent with the fact that apoptosis rarely occurs in normal livers but increases in HCC, indicating that bcl-2 and bcl-xL may play a very important role in regulating the apoptosis of normal liver and HCC.

  18. Eriodictyol-induced anti-cancer and apoptotic effects in human hepatocellular carcinoma cells are associated with cell cycle arrest and modulation of apoptosis-related proteins

    Directory of Open Access Journals (Sweden)

    Fang Wang

    2016-06-01

    Full Text Available The objective of the present study was to investigate the anti-cancer effects of eriodictyol in human hepatocellular carcinoma cells (Hep-G2 and normal liver hepatocyte cell line (AML12 along with evaluating its mode of action. Sulforhodamine B assay was used to evaluate the cytotoxic effect of the compound while as fluorescence microscopy was involved to demonstrate the effect of eriodictyol on cellular apoptosis. Flow cytometry was used to investigate the effect of eriodictyol on cell cycle while Western blot analysis revealed the effect on apoptosis-related protein expressions. Results indicate that eriodictyol-induced selective and concentration-dependent cytotoxic effect on Hep-G2 cancer cells while AML12 normal liver cells were very less susceptible to its effect. Eriodictyol-induced apoptosis related morphological changes including chromatin condensation and nuclear fragmentation. It also induced G2/M cell cycle arrest in these cells. Eriodictyol led to up-regulation of Bax and PARP and down-regulation of Bcl-2 protein.

  19. Proteomics in Discovery of Hepatocellular Carcinoma Biomarkers

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Objective: To discover new proteomic biomarkers of hepatocellular carcinoma. Methods: Surface enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectrometry was used to discover biomarkers for differentiating hepatocellular carcinoma and chronic liver disease. A population of 50 patients with hepatocellular carcinoma and 33 patients with chronic liver disease was studied. Results: Twelve proteomic biomarkers of hepatocellular carcinoma were detected in this study. Three proteomic biomarkers were highly expressed in hepatocellular carcinoma and nine proteomic biomarkers were highly expressed in chronic liver disease. The most valuable proteomic biomarker with m/z=11498 had no similar diagnostic value as α-fetoprotein. Conclusion:Some of the twelve proteomic biomarkers may become new biomarkers of hepatocellular carcinoma.

  20. Stem cell-derived models to improve mechanistic understanding and prediction of human drug-induced liver injury.

    Science.gov (United States)

    Goldring, Christopher; Antoine, Daniel J; Bonner, Frank; Crozier, Jonathan; Denning, Chris; Fontana, Robert J; Hanley, Neil A; Hay, David C; Ingelman-Sundberg, Magnus; Juhila, Satu; Kitteringham, Neil; Silva-Lima, Beatriz; Norris, Alan; Pridgeon, Chris; Ross, James A; Young, Rowena Sison; Tagle, Danilo; Tornesi, Belen; van de Water, Bob; Weaver, Richard J; Zhang, Fang; Park, B Kevin

    2017-02-01

    Current preclinical drug testing does not predict some forms of adverse drug reactions in humans. Efforts at improving predictability of drug-induced tissue injury in humans include using stem cell technology to generate human cells for screening for adverse effects of drugs in humans. The advent of induced pluripotent stem cells means that it may ultimately be possible to develop personalized toxicology to determine interindividual susceptibility to adverse drug reactions. However, the complexity of idiosyncratic drug-induced liver injury means that no current single-cell model, whether of primary liver tissue origin, from liver cell lines, or derived from stem cells, adequately emulates what is believed to occur during human drug-induced liver injury. Nevertheless, a single-cell model of a human hepatocyte which emulates key features of a hepatocyte is likely to be valuable in assessing potential chemical risk; furthermore, understanding how to generate a relevant hepatocyte will also be critical to efforts to build complex multicellular models of the liver. Currently, hepatocyte-like cells differentiated from stem cells still fall short of recapitulating the full mature hepatocellular phenotype. Therefore, we convened a number of experts from the areas of preclinical and clinical hepatotoxicity and safety assessment, from industry, academia, and regulatory bodies, to specifically explore the application of stem cells in hepatotoxicity safety assessment and to make recommendations for the way forward. In this short review, we particularly discuss the importance of benchmarking stem cell-derived hepatocyte-like cells to their terminally differentiated human counterparts using defined phenotyping, to make sure the cells are relevant and comparable between labs, and outline why this process is essential before the cells are introduced into chemical safety assessment. (Hepatology 2017;65:710-721).

  1. Magnetic Nanoparticles for Hepatocellular Carcinoma Diagnosis and Therapy

    DEFF Research Database (Denmark)

    Ungureanu, Bogdan Silviu; Teodorescu, Cristian-Mihail; Săftoiu, Adrian

    2016-01-01

    Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver, ranking as the second most common cause of death from cancer worldwide. Magnetic nanoparticles (MNPs) have been used so far in tumor diagnosis and treatment, demonstrating great potential and promising results. In princ......Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver, ranking as the second most common cause of death from cancer worldwide. Magnetic nanoparticles (MNPs) have been used so far in tumor diagnosis and treatment, demonstrating great potential and promising results...... and treatment of liver cancer and offers a walkthrough from the MNPs imaging applicability to further therapeutic options, including their potential flaws. The MNP unique physical and biochemical properties will be mentioned in close relationship to their subsequent effects on the human body, and, also......, their toxic potential will be noted. A presentation of what barriers the MNPs should overcome to be more successful will conclude this review....

  2. Lipid-lowering agents in nonalcoholic fatty liver disease and steatohepatitis: human studies.

    Science.gov (United States)

    Nseir, William; Mograbi, Julnar; Ghali, Murad

    2012-07-01

    Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease which refers to the presence of hepatic steatosis without significant intake of alcohol. NAFLD is an asymptomatic disease that can progress to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. NAFLD is currently the most common cause of incidental abnormal liver tests and elevated serum liver enzyme activities in the developed world. Obesity, diabetes, and other components of the metabolic syndrome are frequently associated with the NAFLD. The treatment of NAFLD focuses on life-style modifications. Statins, fibrates, and other lipid-lowering agents have been proposed as effective lipid-lowering treatments in patients with NAFLD/NASH. However, clinicians are concerned that hyperlipidemic patients with NAFLD/NASH who are treated with statins could develop transaminitis. We assessed the efficacy and safety of lipid-lowering agents for NAFLD/NASH by reviewing reports of human studies including pilot, prospective, preliminary, and post hoc analysis studies on online databases during the period of 1980 to December 2012. The results of studies provide compelling evidence that lipid-lowering agents are safe and efficacious in patients with NAFLD/NASH and that some of these agents can induce a reduction in the extent of the hepatic steatosis. Well-designed randomized controlled studies of adequate size and duration with histological endpoints are needed in order to establish a suitable lipid-lowering treatment for hyperlipidemic patients with NAFLD/NASH, and for nonhyperlipidemic patients with NAFLD/NASH with a high risk for cardiovascular disease.

  3. Recombinant human acid sphingomyelinase as an adjuvant to sorafenib treatment of experimental liver cancer.

    Directory of Open Access Journals (Sweden)

    Radoslav Savić

    Full Text Available BACKGROUND: Hepatocellular carcinoma (HCC is the most common form of liver cancer and the third leading cause of cancer death worldwide. The only approved systemic treatment for unresectable HCC is the oral kinase inhibitor, sorafenib. Recombinant human acid sphingomyelinase (rhASM, which hydrolyzes sphingomyelin to ceramide, is an orphan drug under development for the treatment of Type B Niemann-Pick disease (NPD. Due to the hepatotropic nature of rhASM and its ability to generate pro-apoptotic ceramide, this study evaluated the use of rhASM as an adjuvant treatment with sorafenib in experimental models of HCC. METHODOLOGY/PRINCIPAL FINDINGS: In vitro, rhASM/sorafenib treatment reduced the viability of Huh7 liver cancer cells more than sorafenib. In vivo, using a subcutaneous Huh7 tumor model, mouse survival was increased and proliferation in the tumors decreased to a similar extent in both sorafenib and rhASM/sorafenib treatment groups. However, combined rhASM/sorafenib treatment significantly lowered tumor volume, increased tumor necrosis, and decreased tumor blood vessel density compared to sorafenib. These results were obtained despite poor delivery of rhASM to the tumors. A second (orthotopic model of Huh7 tumors also was established, but modest ASM activity was similarly detected in these tumors compared to healthy mouse livers. Importantly, no chronic liver toxicity or weight loss was observed from rhASM therapy in either model. CONCLUSIONS/SIGNIFICANCE: The rhASM/sorafenib combination exhibited a synergistic effect on reducing the tumor volume and blood vessel density in Huh7 xenografts, despite modest activity of rhASM in these tumors. No significant increases in survival were observed from the rhASM/sorafenib treatment. The poor delivery of rhASM to Huh7 tumors may be due, at least in part, to low expression of mannose receptors. The safety and efficacy of this approach, together with the novel findings regarding enzyme targeting

  4. Effect of TSLC1 Gene on Proliferation, Invasion and Apoptosis of Human Hepatocellular Carcinoma Cell Line HepG2

    Institute of Scientific and Technical Information of China (English)

    QIN Li; ZHU Wentao; XU Tao; HAO Youhua; ZHANG Zhengmao; TIAN Yongjun; YANG Dongliang

    2007-01-01

    The recombinant plasmid pCI-TSLC1 carrying TSLC1 gene was stably transfected into human hepatocellular carcinoma cell line HepG2. Cell proliferation was analyzed by MTT assay. The ability of migration was determined by transwell and FACSort flow cytometry was used to detect the cell cycle distribution and apoptosis. Western blotting revealed that H4 expressed higher amounts of TSLC1 protein than H15 and H0 did. The growth of TSLC1-transfected cells was significantly sup- pressed in vitro, and the ability of migration was reduced as well. The re-expression of TSLC1 could induce cell apoptosis. It was concluded that TSLC1 strongly inhibited the growth and ability of mi- gration of HepG2 cell line in vitro and also induced apoptosis, suggesting that TSLC1 could reduce the tumorigenicity of human hepatocellular carcinoma cell line HepG2 in vitro, which provided a ba-sis for further exploring the roles of TSLC1 in hepatocellular cellular carcinoma.

  5. Synergy of Raddeanin A and cisplatin induced therapeutic effect enhancement in human hepatocellular carcinoma.

    Science.gov (United States)

    Jian-Nan, Li; Ye, Yu; Yan-Fei, Zhang; Zhi-Meng, Li; Guang-Zhi, Cai; Ji-Yu, Gong

    2017-02-17

    Cisplatin is a main compound for human hepatocellular carcinoma (HCC) chemotherapies, but it has certain cytotoxicity during applications. To release that, combining with other drugs are being as a regular plan in clinic. In our present study, we are focusing on one of active monomers extracted from Anemone Raddeana Regel, Raddeanin A (RA), which is on behalf of the same character like cisplatin in the tumor remedies. In order to investigate whether combination usage of RA and cisplatin can be priority to the later drug's effect development and its toxicity reduction in HCC, both of two drugs were treated 24 h or 48 h in QGY-7703 cells for estimating their abilities in tumor cell proliferation inhibition. Results show RA makes synergistic functions with cisplatin after measuring and analyzing their combination index (CI) values. Meanwhile it can strengthen cisplatin's effect by arresting the tumor cells in G0/G1 cycle and further promoting their apoptosis. Interestingly, the molecule signals correlated to tumor cell apoptosis containing both of p53 and bax are simultaneously activated, but bcl-2 and survivin are all depressed in mRNA level. Meanwhile, combining usage with RA can even raise the intracellular productions of reactive oxygen species (ROS). All these consequences reflect RA plays an important role in enhancing the therapeutic effect of cisplatin in HCC. This finding may guide for the drug usage of cisplatin in clinic practice.

  6. Endoplasmic reticulum stress-induced resistance to doxorubicin is reversed by paeonol treatment in human hepatocellular carcinoma cells.

    Directory of Open Access Journals (Sweden)

    Lulu Fan

    Full Text Available BACKGROUND: Endoplasmic reticulum stress (ER stress is generally activated in solid tumors and results in tumor cell anti-apoptosis and drug resistance. Paeonol (Pae, 2-hydroxy-4-methoxyacetophenone, is a natural product extracted from the root of Paeonia Suffruticosa Andrew. Although Pae displays anti-neoplastic activity and increases the efficacy of chemotherapeutic drugs in various cell lines and in animal models, studies related to the effect of Pae on ER stress-induced resistance to chemotherapeutic agents in hepatocellular carcinoma (HCC are poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we investigated the effect of the endoplasmic reticulum (ER stress response during resistance of human hepatocellular carcinoma cells to doxorubicin. Treatment with the ER stress-inducer tunicamycin (TM before the addition of doxorubicin reduced the rate of apoptosis induced by doxorubicin. Interestingly, co-pretreatment with tunicamycin and Pae significantly increased apoptosis induced by doxorubicin. Furthermore, induction of ER stress resulted in increasing expression of COX-2 concomitant with inactivation of Akt and up-regulation of the pro-apoptotic transcription factor CHOP (GADD153 in HepG2 cells. These cellular changes in gene expression and Akt activation may be an important resistance mechanism against doxorubicin in hepatocellular carcinoma cells undergoing ER stress. However, co-pretreatment with tunicamycin and Pae decreased the expression of COX-2 and levels of activation of Akt as well as increasing the levels of CHOP in HCC cells. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that Pae reverses ER stress-induced resistance to doxorubicin in human hepatocellular carcinoma cells by targeting COX-2 mediated inactivation of PI3K/AKT/CHOP.

  7. Human augmenter of liver regeneration: molecular cloning, biological activity and roles in liver regeneration

    Institute of Scientific and Technical Information of China (English)

    杨晓明; 谢玲; 邱兆华; 吴祖泽; 贺福初

    1997-01-01

    The complete amino acid sequence of human augmenter of liver regeneration (hALR) was reported by deduction from nucleotide sequence of its complementary DNA . The cDNA for hALR was isolated by screening a human fetal liver cDNA library and the sequencing of this insert revealed an open reading frame encoding a protein with 125aa and highly homologous (87% ) with rat ALR encoding sequence. The recombinant hALR expressed from its cDNA in transient expression experiments in cos-7 cells could stimulate DNA synthesis of HTC hepatoma cell in the dose-dependent and heat-resistant way. Northern blot analysis with rat ALR cDNA as probe confirmed that ALR mRNA was expressed in the normal rat liver at low level and that dramatically increased in the regenerating liver after partial hepatectomied rat. This size of hALR mRNA is 1.4 kb long and expressed in human fetal liver, kidney and testis. These findings indicated that liver itself may be the resource of ALR and suggested that ALR seems to be an im-portant parac

  8. Comprehensive comparison of three different immunosuppressive regimens for liver transplant patients with hepatocellular carcinoma: steroid-free immunosuppression, induction immunosuppression and standard immunosuppression.

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    Yuan-Yuan Liu

    Full Text Available The different choices of immunosuppression (IS regimens influenced the outcomes of liver transplantation. Steroid was applied as a standard IS to prevent and treat rejections. However, steroid-related complications were increasingly prominent. This study compared the efficacy and safety of standard IS regimens with the efficacy and safety of steroid-free IS regimen and induction IS regimen in Chinese liver transplantation recipients for hepatocellular carcinoma (HCC. A total of 329 patients who underwent liver transplantation from January 2008 to December 2012 were retrospectively reviewed. Three different groups of patients received standard triple-drug IS regimen of steroid, tacrolimus (TAC and mycophenolate mofetil (MMF (triple-drug regimen group; n=57, induction-contained IS regimen of basiliximab, steroid, TAC and MMF (BS group; n=241, and induction-contained and steroid-free regimen of basiliximab, TAC and MMF (SF group; n=31, respectively. There were no significant differences in terms of patient, tumor-free and graft survival rates. The acute rejection rate and rejection time were equivalent in different groups. But compared with BS group, higher incidences of biliary complications (11.52% vs. 30.77%, p=0.013 and graft dysfunction (0.48% vs. 13.64%, p=0.003 were observed in SF group. Furthermore, compared with the two groups, incidence of pleural effusion was also higher in SF group (15.79%, 11.96% vs. 45.45%, respectively, both p<0.01. And a trend towards less proportion of De novo diabetes was revealed in SF group. Although it was found that patient, tumor-free and graft survival rates were equivalent among three IS regimens, higher incidences of complications were demonstrated in steroid-free regimen in patients for HCC. These findings suggested that steroid-free IS regimen has no clear advantages in comparison with standard IS regimens for liver transplant recipients with HCC and the postoperative complications should be treated with

  9. Branched-chain amino acids ameliorate fibrosis and suppress tumor growth in a rat model of hepatocellular carcinoma with liver cirrhosis.

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    Jung Hoon Cha

    Full Text Available PURPOSE: Recent studies have revealed that branched-chain amino acids (BCAA reduce the development of hepatocellular carcinoma (HCC in patients with obesity and hepatitis C virus infection by improving insulin resistance (IR. The aim of this study was to examine the anti-cancer and anti-fibrotic effects of BCAA on the development of diethylnitrosamine (DEN-induced HCC and liver cirrhosis in a rat model. METHODS: Male SD rats received weekly intraperitoneal injections of DEN (50 mg/kg of body weight for 16 weeks to induce HCC. They were fed a diet containing 3% casein, 3% or 6% BCAA for 13 weeks beginning 6 weeks after DEN administration. DEN was used to induce HCC through stepwise development from cirrhosis to HCC. The effect of BCAA was evaluated in tumor tissues by histopathologic analyses, reverse transcription-polymerase chain reaction, and Western blotting. RESULTS: The mean area and number of dysplastic nodules (DNs and tumors in the casein group tended to be larger than those in the BCAA group 16 weeks after DEN administration. The mean fibrotic area in the BCAA group was smaller than that in the casein group. The BCAA group showed decreased mRNA levels for markers of fibrosis, angiogenesis, and apoptosis inhibition. Compared with the casein group, the BCAA group had lower levels of α-smooth muscle actin, vascular endothelial growth factor, p-β-catenin, p-p38 mitogen-activated protein kinase, proliferating cell nuclear antigen, and caspase-3 protein expression, as well as a higher level of cleaved caspase-3 protein expression. CONCLUSIONS: BCAA supplementation of the diet ameliorated liver fibrosis and HCC development in a DEN-induced rat model of HCC with liver cirrhosis, but not in the IR model. These results provide a rationale for anti-fibrosis and chemoprevention using BCAA treatment for HCC with liver cirrhosis, as well as decreasing the ammonia level.

  10. A Novel Polysaccharide Conjugate from Bullacta exarata Induces G1-Phase Arrest and Apoptosis in Human Hepatocellular Carcinoma HepG2 Cells.

    Science.gov (United States)

    Liao, Ningbo; Sun, Liang; Chen, Jiang; Zhong, Jianjun; Zhang, Yanjun; Zhang, Ronghua

    2017-03-01

    Bullacta exarata has been consumed in Asia, not only as a part of the normal diet, but also as a traditional Chinese medicine with liver- and kidney-benefitting functions. Several scientific investigations involving extraction of biomolecules from this mollusk and pharmacological studies on their biological activities have been carried out. However, little is known regarding the antitumor properties of polysaccharides from B. exarata, hence the polysaccharides from B. exarata have been investigated here. One polysaccharide conjugate BEPS-IA was isolated and purified from B. exarata. It mainly consisted of mannose and glucose in a molar ratio of 1:2, with an average molecular weight of 127 kDa. Thirteen general amino acids were identified to be components of the protein-bound polysaccharide. Methylation and NMR studies revealed that BEPS-IA is a heteropolysaccharide consisting of 1,4-linked-α-d-Glc, 1,6-linked-α-d-Man, 1,3,6-linked-α-d-Man, and 1-linked-α-d-Man residue, in a molar ratio of 6:1:1:1. In order to test the antitumor activity of BEPS-IA, we investigated its effect against the growth of human hepatocellular carcinoma cells HepG2 in vitro. The result showed that BEPS-IA dose-dependently exhibited an effective HepG2 cells growth inhibition with an IC50 of 112.4 μg/mL. Flow cytometry analysis showed that BEPS-IA increased the populations of both apoptotic sub-G1 and G1 phase. The result obtained from TUNEL assay corroborated apoptosis which was shown in flow cytometry. Western blot analysis suggested that BEPS-IA induced apoptosis and growth inhibition were associated with up-regulation of p53, p21 and Bax, down-regulation of Bcl-2. These findings suggest that BEPS-IA may serve as a potential novel dietary agent for hepatocellular carcinoma.

  11. Human platelets inhibit liver fibrosis in severe combined immunodeficiency mice

    Science.gov (United States)

    Takahashi, Kazuhiro; Murata, Soichiro; Fukunaga, Kiyoshi; Ohkohchi, Nobuhiro

    2013-01-01

    AIM: To investigate the role of human platelets in liver fibrosis. METHODS: Severe combined immunodeficiency (SCID) mice were administered CCl4 and either phosphate-buffered saline (PBS group) or human platelet transfusions (hPLT group). Concentrations of hepatocyte growth factor (HGF), matrix metallopeptidases (MMP)-9, and transforming growth factor-β (TGF-β) in the liver tissue were compared between the PBS and the hPLT groups by enzyme-linked immunosorbent assay (ELISA) and Western blotting. The effects of a human platelet transfusion on liver fibrosis included the fibrotic area, hydroxyproline content, and α-smooth muscle actin (α-SMA) expression, which were evaluated by picrosirius red staining, ELISA, and immunohistochemical staining using an anti-mouse α-SMA antibody, respectively. Phosphorylations of mesenchymal-epithelial transition factor (Met) and SMAD3, downstream signals of HGF and TGF-β, were compared between the two groups by Western blotting and were quantified using densitometry. Hepatocyte apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling. Furthermore, the accumulation of human platelets in the liver 2 h after platelet transfusion was compared between normal and fibrotic livers by immunohistochemical staining using an anti-human CD41 antibody. RESULTS: The fibrotic area and hydroxyproline content in the liver were both significantly lower in the hPLT group when compared to the PBS group (fibrotic area, 1.7% ± 0.6% vs 2.5% ± 0.6%, P = 0.03; hydroxyproline content, 121 ± 26 ng/g liver vs 156 ± 47 ng/g liver, P = 0.04). There was less α-smooth muscle actin staining in the hPLT group than in the PBS group (0.5% ± 0.1% vs 0.8% ± 0.3%, P = 0.02). Hepatic expression levels of mouse HGF and MMP-9 were significantly higher in the hPLT group than in the PBS group (HGF, 109 ± 13 ng/g liver vs 88 ± 22 ng/g liver, P = 0.03; MMP-9, 113% ± 7%/GAPDH vs 92% ± 11%/GAPDH, P = 0.04). In contrast, the

  12. Telaprevir-containing regimen for treatment of hepatitis C virus infection in patients with hepatocellular carcinoma awaiting liver transplantation: a case series

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    Torres HA

    2014-07-01

    Full Text Available Harrys A Torres,1 Ahmed Kaseb,2 Parag Mahale,1 Ethan Miller,3 Catherine Frenette4 1Department of Infectious Diseases, Infection Control and Employee Health, 2Department of Gastrointestinal Medical Oncology, 3Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 4Department of Liver Transplantation, Weill Cornell Medical College, The Methodist Hospital, Houston, TX, USA Abstract: In patients who undergo liver transplantation (LT, allograft failure secondary to hepatitis C virus (HCV recurrence after LT accounts for two-thirds of graft failures and deaths. Achievement of sustained virologic response before LT eliminates the risk of HCV recurrence. Only a limited number of studies have evaluated the role of antiviral treatment before LT. No published data are available regarding the use of HCV protease inhibitors before LT. We report our experience using the combination of telaprevir, pegylated interferon alfa-2a (PegIFN alfa-2a, and ribavirin in three patients with HCV-associated hepatocellular carcinoma (HCC awaiting LT. Two patients had not received, and one had had a partial response to HCV therapy (PegIFN alfa-2a plus ribavirin. All three patients had genotype 1b and were started on telaprevir and full doses of PegIFN alfa-2a and ribavirin. Treatment was planned to be continued until the day of LT or 48 weeks total, whichever came first. One patient still had detectable HCV RNA after 24 weeks of antivirals and was, therefore, excluded from further analysis. The other two patients had undetectable HCV RNA at the end of antiviral therapy. In one of these patients, HCV RNA remained undetectable after LT; the other patient experienced viral relapse. HCV therapy was tolerated by all patients; no patient required permanent discontinuation of therapy because of toxic effects. All three patients experienced hematologic toxic effects. Only one patient required treatment

  13. Liver resection for hepatocellular carcinoma within a fast-track management:a propensity-score matched analysis between open and laparoscopic approach

    Institute of Scientific and Technical Information of China (English)

    Francesca Ratti; Federica Cipriani; Raffaella Reineke; Marco Catena; Michele Paganelli; Luigi Beretta; Luca Aldrighetti

    2016-01-01

    Aim: The study was designed to assess the implications of enhanced recovery after surgery (ERAS) approach in patients submitted to open liver resection for hepatocellular carcinoma (HCC) comparing their short term outcome with patients treated by laparoscopic approach, in a case-matched design.Methods: The open-group (n = 60) was matched in a ratio of 1:1 with patients undergoing laparoscopic liver resection for HCC (Lap-group,n= 60), with a matching achieved on a basis of propensity scores including 6 covariates representing patients characteristics and severity of the disease. Primary outcome analysis was performed in terms of ERAS-speciifc items and postoperative morbidity and mortality.Results: Overall morbidity and mortality were comparable between groups. Incidence of ascites was slightly higher in the open- compared with the Lap-group (respectively 11.7% and 13.3%), without statistical signiifcance. The need for introduction or increase of chronic diuretic therapy was signiifcantly higher in the open-compared with the Lap-group (16.7%vs. 11.7%,P = 0.046). Furthermore, ascites more frequently required percutaneous drainage in the open-compared with the Lap-group (5%vs. 1.7% respectively,P = 0.041).Conclusion: In patients who can’t beneift from minimally-invasive approach because of disease characteristics, ERAS management seems to be associated with an improved postoperative functional recovery and postoperative outcomes, comparable to those of the minimally invasive approach.

  14. A score model for predicting post-liver trans-plantation survival in HBV cirrhosis-related hepatocellular carcinoma recipients:a single center 5-year experience

    Institute of Scientific and Technical Information of China (English)

    Li-Ying Wang; Xin-Hua Chen; Tian-An Jiang; Fen Chen; Shu-Sen Zheng; Xiao Xu; Wei-Lin Wang; Jian Wu; Min Zhang; Yan Shen; Sheng Yan; Hai-Yang Xie

    2015-01-01

    BACKGROUND: The prognostic prediction of liver transplan-tation (LT) guides the donor organ allocation. However, there is currently no satisfactory model to predict the recipients' outcome, especially for the patients with HBV cirrhosis-re-lated hepatocellular carcinoma (HCC). The present study was to develop a quantitative assessment model for predicting the post-LT survival in HBV-related HCC patients. METHODS: Two hundred and thirty-eight LT recipients at the Liver Transplant Center, First Affiliated Hospital, Zhejiang University School of Medicine between 2008 and 2013 were included in this study. Their post-LT prognosis was recorded and multiple risk factors were analyzed using univariate and multivariate analyses in Cox regression. RESULTS: The score model was as follows: 0.114×(Child-Pugh score)-0.002×(positive HBV DNA detection time)+0.647× (number of tumor nodules)+0.055×(max diameter of tumor nodules)+0.231×lnAFP+0.437×(tumor differentiation grade). The receiver operating characteristic curve analysis showed that the area under the curve of the scoring model for predict-ing the post-LT survival was 0.887. The cut-off value was 1.27, which was associated with a sensitivity of 72.5% and a speci-ficity of 90.7%, respectively. CONCLUSION: The quantitative score model for predicting post-LT survival proved to be sensitive and specific.

  15. Prognostic Value of Serum Caspase-Cleaved Cytokeratin-18 Levels before Liver Transplantation for One-Year Survival of Patients with Hepatocellular Carcinoma

    Science.gov (United States)

    Lorente, Leonardo; Rodriguez, Sergio T.; Sanz, Pablo; Pérez-Cejas, Antonia; Padilla, Javier; Díaz, Dácil; González, Antonio; Martín, María M.; Jiménez, Alejandro; Barrera, Manuel A.

    2016-01-01

    Cytokeratin (CK)-18 is the major intermediate filament protein in the liver and during hepatocyte apoptosis is cleaved by the action of caspases; the resulting fragments are released into the blood as caspase-cleaved cytokeratin (CCCK)-18. Higher circulating levels of CCCK-18 have been found in patients with hepatocellular carcinoma (HCC) than in healthy controls and than in cirrhotic patients. However, it is unknown whether serum CCCK-18 levels before liver transplantation (LT) in patients with HCC could be used as a prognostic biomarker of one-year survival, and this was the objective of our study with 135 patients. At one year after LT, non-survivors showed higher serum CCCK-18 levels than survivors (p = 0.001). On binary logistic regression analysis, serum CCCK-18 levels >384 U/L were associated with death at one year (odds ratio = 19.801; 95% confidence interval = 5.301–73.972; p < 0.001) after controlling for deceased donor age. The area under the receiver operating characteristic (ROC) curve of serum CCCK-18 levels to predict death at one year was 77% (95% CI = 69%–84%; p < 0.001). The new finding of our study was that serum levels of CCCK-18 before LT in patients with HCC could be used as prognostic biomarker of survival. PMID:27618033

  16. Multistep hepatocarcinogenesis from a dysplastic nodule to well-differentiated hepatocellular carcinoma in a patient with alcohol-related liver cirrhosis

    Institute of Scientific and Technical Information of China (English)

    Soo Ryang Kim; Yoshitake Hayashi; Hirotsugu Ikawa; Kenji Ando; Keiji Mita; Shuichi Fuki; Michiie Sakamoto; Yoshihiro Kanbara; Toshiyuki Matsuoka; Masatoshi Kudo

    2007-01-01

    We describe a rare case of the transformation of a dysplastic nodule into well-differentiated hepatocellular carcinoma (HCC) in a 56-year-old man with alcoholrelated liver cirrhosis. Ultrasound (US) disclosed a 10 mm hypoechoic nodule and contrast enhanced US revealed a hypovascular nodule, both in segment seven.US-guided biopsy revealed a high-grade dysplastic nodule characterized by enhanced cellularity with a high N/C ratio, increased cytoplasmic eosinophilia,and slight cell atypia. One year later, the US pattern of the nodule changed from hypoechoic to hyperechoic without any change in size or hypovascularity. US-guided biopsy revealed well-differentiated HCC of the same features as shown in the first biopsy, but with additional pseudoglandular formation and moderate cell atypia.Moreover, immunohistochemical staining of cyclaseassociated protein 2, a new molecular marker of well-differentiated HCC, turned positive. This is the first case of multistep hepatocarcinogenesis from a dysplastic nodule to well-differentiated HCC within one year in alcohol-related liver cirrhosis.

  17. Changes in the planning target volume and liver volume dose based on the selected respiratory phase in respiratory-gated radiation therapy for a hepatocellular carcinoma

    Science.gov (United States)

    Lee, Jae-Seung; Im, In-Chul; Kang, Su-Man; Goo, Eun-Hoe; Baek, Seong-Min

    2013-11-01

    The aim of this study was to quantitatively analyze the changes in the planning target volume (PTV) and liver volume dose based on the respiratory phase to identify the optimal respiratory phase for respiratory-gated radiation therapy for a hepatocellular carcinoma (HCC). Based on the standardized procedure for respiratory-gated radiation therapy, we performed a 4-dimensional computed tomography simulation for 0 ˜ 90%, 30 ˜ 70%, and 40 ˜ 60% respiratory phases to assess the respiratory stability (S R ) and the defined PTV i for each respiratory phase i. A treatment plan was established, and the changes in the PTV i and dose volume of the liver were quantitatively analyzed. Most patients (91.5%) passed the respiratory stability test (S R = 0.111 ± 0.015). With standardized respiration training exercises, we were able to minimize the overall systematic error caused by irregular respiration. Furthermore, a quantitative analysis to identify the optimal respiratory phase revealed that when a short respiratory phase (40 ˜ 60%) was used, the changes in the PTV were concentrated inside the center line; thus, we were able to obtain both a PTV margin accounting for respiration and a uniform radiation dose within the PTV.

  18. A study of human liver ferritin and chicken liver and spleen using Moessbauer spectroscopy with high velocity resolution

    Energy Technology Data Exchange (ETDEWEB)

    Oshtrakh, M. I., E-mail: oshtrakh@mail.utnet.ru [Ural State Technical University-UPI, Faculty of Physical Techniques and Devices for Quality Control (Russian Federation); Milder, O. B.; Semionkin, V. A. [Ural State Technical University-UPI, Faculty of Experimental Physics (Russian Federation)

    2008-01-15

    Lyophilized samples of human liver ferritin and chicken liver and spleen were measured at room temperature using Moessbauer spectroscopy with high velocity resolution. An increase in the velocity resolution of Moessbauer spectroscopy permitted us to increase accuracy and decrease experimental error in determining the hyperfine parameters of human liver ferritin and chicken liver and spleen. Moessbauer spectroscopy with high velocity resolution may be very useful for revealing small differences in hyperfine parameters during biomedical research.

  19. Inhibitory Effect of Endostar on Specific Angiogenesis Induced by Human Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Qing Ye

    2015-01-01

    Full Text Available To investigate the effect of endostar on specific angiogenesis induced by human hepatocellular carcinoma, this research systematically elucidated the inhibitory effect on HepG2-induced angiogenesis by endostar from 50 ng/mL to 50000 ng/mL. We employed fluorescence quantitative Boyden chamber analysis, wound-healing assay, flow cytometry examination using a coculture system, quantitative analysis of tube formation, and in vivo Matrigel plug assay induced by HCC conditioned media (HCM and HepG2 compared with normal hepatocyte conditioned media (NCM and L02. Then, we found that endostar as a tumor angiogenesis inhibitor could potently inhibit human umbilical vein endothelial cell (HUVEC migration in response to HCM after four- to six-hour action, inhibit HCM-induced HUVEC migration to the lesion part in a dose-dependent manner between 50 ng/mL and 5000 ng/mL at 24 hours, and reduce HUVEC proliferation in a dose-dependent fashion. Endostar inhibited HepG2-induced tube formation of HUVECs which peaked at 50 ng/mL. In vivo Matrigel plug formation was also significantly reduced by endostar in HepG2 inducing system rather than in L02 inducing system. It could be concluded that, at cell level, endostar inhibited the angiogenesis-related biological behaviors of HUVEC in response to HCC, including migration, adhesion proliferation, and tube formation. At animal level, endostar inhibited the angiogenesis in response to HCC in Matrigel matrix.

  20. Interleukin-1β enhances the production of soluble MICA in human hepatocellular carcinoma.

    Science.gov (United States)

    Kohga, Keisuke; Tatsumi, Tomohide; Tsunematsu, Hinako; Aono, Satoshi; Shimizu, Satoshi; Kodama, Takahiro; Hikita, Hayato; Yamamoto, Masashi; Oze, Tsugiko; Aketa, Hiroshi; Hosui, Atsushi; Miyagi, Takuya; Ishida, Hisashi; Hiramatsu, Naoki; Kanto, Tatsuya; Hayashi, Norio; Takehara, Tetsuo

    2012-09-01

    The production of soluble major histocompatibility complex class I-related chain A (MICA) is thought to antagonize NKG2D-mediated immunosurveillance. Interleukin-1β (IL-1β) is elevated in patients with chronic hepatitis C (CH), and this might contribute to the escape of hepatocellular carcinoma (HCC) cells from innate immunity. In this study, we investigated the immunoregulatory role of IL-1β in the production of soluble MICA of HCC cells. First, we investigated the correlation between the serum IL-1β levels and soluble MICA in CH patients. Serum IL-1β levels were associated with soluble MICA levels in CH patients. The serum IL-1β levels of CH patients with the HCC occurrence were significantly higher than those of CH patients without HCC. We next examined the MICA production of IL-1β-treated HCC cells. Addition of IL-1β resulted in significant increase in the production of soluble MICA in HepG2 and PLC/PRF/5 cells, human HCC cells. But soluble MICA was not detected in both non-treated and IL-1β-treated normal hepatocytes. Addition of IL-1β did not increase the expressions of membrane-bound MICA on HCC cells. These were observed similarly in various cancer cells including a gastric cancer (MKN1), two colon cancers (HCT116 and HT29) and a cervical cancer (HeLa). Addition of IL-1β also increased the expression of a disintegrin and metalloproteinase (ADAM)9 in HCC cells, and the knockdown of ADAM9 in IL-1β-treated HCC cells resulted in the decrease in the production of soluble MICA of HCC cells. These findings indicate that IL-1β might enhance the production of soluble MICA by activating ADAM9 in human HCC.

  1. Costunolide causes mitotic arrest and enhances radiosensitivity in human hepatocellular carcinoma cells

    Directory of Open Access Journals (Sweden)

    Chen Chih-Jen

    2011-05-01

    Full Text Available Abstract Purpose This work aimed to investigate the effect of costunolide, a sesquiterpene lactone isolated from Michelia compressa, on cell cycle distribution and radiosensitivity of human hepatocellular carcinoma (HCC cells. Methods The assessment used in this study included: cell viability assay, cell cycle analysis by DNA histogram, expression of phosphorylated histone H3 (Ser 10 by flow cytometer, mitotic index by Liu's stain and morphological observation, mitotic spindle alignment by immunofluorescence of alpha-tubulin, expression of cell cycle-related proteins by Western blotting, and radiation survival by clonogenic assay. Results Our results show that costunolide reduced the viability of HA22T/VGH cells. It caused a rapid G2/M arrest at 4 hours shown by DNA histogram. The increase in phosphorylated histone H3 (Ser 10-positive cells and mitotic index indicates costunolide-treated cells are arrested at mitosis, not G2, phase. Immunofluorescence of alpha-tubulin for spindle formation further demonstrated these cells are halted at metaphase. Costunolide up-regulated the expression of phosphorylated Chk2 (Thr 68, phosphorylated Cdc25c (Ser 216, phosphorylated Cdk1 (Tyr 15 and cyclin B1 in HA22T/VGH cells. At optimal condition causing mitotic arrest, costunolide sensitized HA22T/VGH HCC cells to ionizing radiation with sensitizer enhancement ratio up to 1.9. Conclusions Costunolide could reduce the viability and arrest cell cycling at mitosis in hepatoma cells. Logical exploration of this mitosis-arresting activity for cancer therapeutics shows costunolide enhanced the killing effect of radiotherapy against human HCC cells.

  2. Effects of Ginkgo biloba extract on cell proliferation and cytotoxicity in human hepatocellular carcinoma cells

    Institute of Scientific and Technical Information of China (English)

    Jane CJ Chao; Chia Chou Chu

    2004-01-01

    AIM: To study the effect of Ginkgo biloba extract (EGb 761)containing 22-27% fiavonoids (ginkgo-flavone glycosides)and 5-7% terpenoids (ginkgolides and bilobalides) on cell proliferation and cytotoxicity in human hepatocellular carcinoma (HCC) cells.METHODS: Human HCC cell lines (HepG2 and Hep3B) were incubated with various concentrations (0-1 000 mg/L) of EGb 761 solution. After 24 h incubation, cell proliferation and cytotoxicity were determined by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and lactate dehydrogenase (LDH)release, respectively. After 48 h incubation, the expression of proliferating cell nuclear antigen (PCNA) and p53 protein was measured by Western blotting.RESULTS: The results showed that EGb 761 (50-1 000 mg/L)significantly suppressed cell proliferation and increased LDH release (P<0.05) in HepG2 and Hep3B cells compared with the control group. The cell proliferation of HepG2 and Hep3B cells treated with EGb 761 (1 000 mg/L) was 45% and 39% of the control group (P<0.05), respectively. LDH release of HepG2 cells without and with EGb 761 (1 000 mg/L) treatment was 6.7% and 37.7%, respectively, and that of Hep3B cells without and with EGb 761 (1 000 mg/L) treatment was 7.2% and 40.3%, respectively. The expression of PCNA and p53 protein in HepG2 cells treated with EGb 761 (1 000 mg/L)was 85% and 174% of the control group, respectively.CONCLUSION: Ginkgobilobaextract significantly can suppress proliferation and increase cytotoxicity in HepG2 and Hep3B cells. Additionally, Ginkgo biloba extract can decrease PCNA and increase p53 expression in HepG2 cells.

  3. Biodegradable human serum albumin nanoparticles as contrast agents for the detection of hepatocellular carcinoma by magnetic resonance imaging.

    Science.gov (United States)

    Watcharin, Waralee; Schmithals, Christian; Pleli, Thomas; Köberle, Verena; Korkusuz, Hüdayi; Huebner, Frank; Zeuzem, Stefan; Korf, Hans W; Vogl, Thomas J; Rittmeyer, Claudia; Terfort, Andreas; Piiper, Albrecht; Gelperina, Svetlana; Kreuter, Jörg

    2014-05-01

    Tumor visualization by magnetic resonance imaging (MRI) and nanoparticle-based contrast agents may improve the imaging of solid tumors such as hepatocellular carcinoma (HCC). In particular, human serum albumin (HSA) nanoparticles appear to be a suitable carrier due to their safety and feasibility of functionalization. In the present study HSA nanoparticles were conjugated with gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) using carbodiimide chemistry. The nanoparticles had a uniform spherical shape and a diameter of 235±19nm. For better optical visualization in vitro and in vivo, the HSA-Gd nanoparticles were additionally labeled with rhodamine 123. As shown by confocal microscopy and flow cytometry analysis, the fluorescent nanoparticles were readily taken up by Huh-7 hepatocellular carcinoma cells. After 24h incubation in blood serum, less than 5% of the Gd(III) was released from the particles, which suggests that this nanoparticulate system may be stable in vivo and, therefore, may serve as potentially safe T1 MRI contrast agent for MRI of hepatocellular carcinoma.

  4. Salinomycin inhibits proliferation and induces apoptosis of human hepatocellular carcinoma cells in vitro and in vivo.

    Directory of Open Access Journals (Sweden)

    Fan Wang

    Full Text Available The anti-tumor antibiotic salinomycin (Sal was recently identified as a selective inhibitor of breast cancer stem cells; however, the effect of Sal on hepatocellular carcinoma (HCC is not clear. This study aimed to determine the anti-tumor efficacy and mechanism of Sal on HCC. HCC cell lines (HepG2, SMMC-7721, and BEL-7402 were treated with Sal. Cell doubling time was determinated by drawing growth curve, cell viability was evaluated using the Cell Counting Kit 8. The fraction of CD133(+ cell subpopulations was assessed by flow cytometry. We found that Sal inhibits proliferation and decreases PCNA levels as well as the proportion of HCC CD133(+cell subpopulations in HCC cells. Cell cycle was analyzed using flow cytometry and showed that Sal caused cell cycle arrest of the various HCC cell lines in different phases. Cell apoptosis was evaluated using flow cytometry and Hoechst 33342 staining. Sal induced apoptosis as characterized by an increase in the Bax/Bcl-2 ratio. Several signaling pathways were selected for further mechanistic analyses using real time-PCR and Western blot assays. Compared to control, β-catenin expression is significantly down-regulated upon Sal addition. The Ca(2+ concentration in HCC cells was examined by flow cytometry and higher Ca(2+ concentrations were observed in Sal treatment groups. The anti-tumor effect of Sal was further verified in vivo using the hepatoma orthotopic tumor model and the data obtained showed that the size of liver tumors in Sal-treated groups decreased compared to controls. Immunohistochemistry and TUNEL staining also demonstrated that Sal inhibits proliferation and induces apoptosis in vivo. Finally, the role of Sal on in vivo Wnt/β-catenin signaling was evaluated by Western blot and immunohistochemistry. This study demonstrates Sal inhibits proliferation and induces apoptosis of HCC cells in vitro and in vivo and one potential mechanism is inhibition of Wnt/β-catenin signaling via increased

  5. Development of {sup 68}Ga-labelled DTPA galactosyl human serum albumin for liver function imaging

    Energy Technology Data Exchange (ETDEWEB)

    Haubner, Roland [Innsbruck Medical University, Department of Nuclear Medicine, Innsbruck (Austria); Medizinische Universitaet Innsbruck, Universitaetsklinik fuer Nuklearmedizin, Innsbruck (Austria); Vera, David R.; Farshchi-Heydari, Salman [University of California, Department of Radiology, School of Medicine, and the UCSD Molecular Imaging Program, San Diego, CA (United States); Helbok, Anna; Rangger, Christine; Putzer, Daniel; Virgolini, Irene J. [Innsbruck Medical University, Department of Nuclear Medicine, Innsbruck (Austria)

    2013-08-15

    The hepatic asialoglycoprotein receptor is responsible for degradation of desialylated glycoproteins through receptor-mediated endocytosis. It has been shown that imaging of the receptor density using [{sup 99m}Tc]diethylenetriamine pentaacetic acid (DTPA) galactosyl human serum albumin ([{sup 99m}Tc]GSA) allows non-invasive determination of functional hepatocellular mass. Here we present the synthesis and evaluation of [{sup 68}Ga]GSA for the potential use with positron emission tomography (PET). Labelling of GSA with {sup 68}Ga was carried out using a fractionated elution protocol. For quality control thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC) and size exclusion chromatography (SEC) techniques were evaluated. Stability of [{sup 68}Ga]GSA was studied in phosphate-buffered saline (PBS) and human serum. For in vivo evaluation [{sup 68}Ga]GSA distribution in Lewis rats was compared with [{sup 99m}Tc]GSA by using a dual isotope protocol. PET and planar imaging studies were performed using the same scaled molar dose of [{sup 68}Ga]GSA and [{sup 99m}Tc]GSA. Time-activity curves (TAC) for heart and liver were generated and corresponding parameters calculated (t50, t90). [{sup 68}Ga]GSA can be produced with high radiochemical purity. The best TLC methods for determining potential free {sup 68}Ga include 0.1 M sodium citrate as eluent. None of the TLC methods tested were able to determine potential colloids. This can be achieved by SEC. HPLC confirmed high radiochemical purity (>98 %). Stability after 120 min incubation at 37 C was high in PBS (>95 % intact tracer) and low in human serum ({proportional_to}27 % intact tracer). Biodistribution studies simultaneously injecting both tracers showed comparable liver uptake, whereas activity concentration in blood was higher for [{sup 68}Ga]GSA compared to [{sup 99m}Tc]GSA. The [{sup 99m}Tc]GSA TACs exhibited a small degree of hepatic metabolism compared to the [{sup 68}Ga]GSA curves. The mean

  6. Human umbilical cord mesenchymal stem cells improve liver function and ascites in decompensated liver cirrhosis patients.

    Science.gov (United States)

    Zhang, Zheng; Lin, Hu; Shi, Ming; Xu, Ruonan; Fu, Junliang; Lv, Jiyun; Chen, Liming; Lv, Sa; Li, Yuanyuan; Yu, Shuangjie; Geng, Hua; Jin, Lei; Lau, George K K; Wang, Fu-Sheng

    2012-03-01

    Decompensated liver cirrhosis (LC), a life-threatening complication of chronic liver disease, is one of the major indications for liver transplantation. Recently, mesenchymal stem cell (MSC) transfusion has been shown to lead to the regression of liver fibrosis in mice and humans. This study examined the safety and efficacy of umbilical cord-derived MSC (UC-MSC) in patients with decompensated LC. A total of 45 chronic hepatitis B patients with decompensated LC, including 30 patients receiving UC-MSC transfusion, and 15 patients receiving saline as the control, were recruited; clinical parameters were detected during a 1-year follow-up period. No significant side-effects and complications were observed in either group. There was a significant reduction in the volume of ascites in patients treated with UC-MSC transfusion compared with controls (P decompensated LC. UC-MSC transfusion, therefore, might present a novel therapeutic approach for patients with decompensated LC.

  7. Stem cell-derived models to improve mechanistic understanding and prediction of human drug induced liver injury

    Science.gov (United States)

    Goldring, Christopher; Antoine, Daniel J.; Bonner, Frank; Crozier, Jonathan; Denning, Chris; Fontana, Robert J.; Hanley, Neil A.; Hay, David C.; Ingelman-Sundberg, Magnus; Juhila, Satu; Kitteringham, Neil; Silva-Lima, Beatriz; Norris, Alan; Pridgeon, Chris; Ross, James A.; Sison Young, Rowena; Tagle, Danilo; Tornesi, Belen; van de Water, Bob; Weaver, Richard J.; Zhang, Fang; Park, B. Kevin

    2016-01-01

    Current preclinical drug testing does not predict some forms of adverse drug reactions in humans. Efforts at improving predictability of drug-induced tissue injury in humans include using stem cell technology to generate human cells for screening for adverse effects of drugs in humans. The advent of induced pluripotent stem cells means that it may ultimately be possible to develop personalised toxicology to determine inter-individual susceptibility to adverse drug reactions. However, the complexity of idiosyncratic drug-induced liver injury (DILI) means that no current single cell model, whether of primary liver tissue origin, from liver cell lines, or derived from stem cells, adequately emulates what is believed to occur during human DILI. Nevertheless, a single cell model of a human hepatocyte which emulates key features of a hepatocyte is likely to be valuable in assessing potential chemical risk; furthermore understanding how to generate a relevant hepatocyte will also be critical to efforts to build complex multicellular models of the liver. Currently, hepatocyte-like cells differentiated from stem cells still fall short of recapitulating the full mature hepatocellular phenotype. Therefore, we convened a number of experts from the areas of preclinical and clinical hepatotoxicity and safety assessment, from industry, academia and regulatory bodies, to specifically explore the application of stem cells in hepatotoxicity safety assessment, and to make recommendations for the way forward. In this short review, we particularly discuss the importance of benchmarking stem cell-derived hepatocyte-like cells to their terminally-differentiated human counterparts using defined phenotyping, to make sure the cells are relevant and comparable between labs, and outline why this process is essential before the cells are introduced into chemical safety assessment. PMID:27775817

  8. Study of apoptosis in human liver cancers

    Institute of Scientific and Technical Information of China (English)

    Chang-Min Shan; Juan Li

    2002-01-01

    AIM: To investigate the action of apoptosis in occurrence ofliver cacinornas in vivo and the biological effect of Solanumlyratum Thumb on BEL-7404 cell line inducing apoptosis invitro.METHODS: The apoptosis in the liver carcinoma wasdetected with terminal deoxynucl neotidyl transferasemediated dUTP nick end labelling (TUNEL); the cancer cellscultured in DMED medium were treated with extract ofSolanum lyratum Thumb and observed under microscope,and their DNA was assayed by gel electrophoresis.RESULTS: In vivo apoptotic cells in the cancer adjacenttissues inceased; in vitro treatment of liver cancers withextract of Solanum lyratum Thumb could induce the cells tomanifest a typical apoptotic morphology. Their DNA wasfractured and a characteristic ladder pattem could be foundusing electrophoresis.CONCLUSION: In vivo the apoptosis of carcinomas waslower; maybe the cells divided quickly and then the cancersoccurred. In the cancer adjacent tissues, the apoptosispricked up, and in vitro Solarium lyratum Thumb couldinduce the apoptosis of BEL-7404 cells.

  9. Prognostic Nomograms for Pre- and Postoperative Predictions of Long-Term Survival for Patients Who Underwent Liver Resection for Huge Hepatocellular Carcinoma.

    Science.gov (United States)

    Li, Yuntong; Xia, Yong; Li, Jun; Wu, Dong; Wan, Xuying; Wang, Kui; Wu, Mengchao; Liu, Jingfeng; Lau, Wan Yee; Shen, Feng

    2015-11-01

    Liver resection is an effective treatment in select patients with huge hepatocellular carcinoma (HCC, diameter ≥10 cm). This study aimed to develop nomograms for pre- and postoperative predictions of overall survival (OS) for these patients. There were 464 consecutive patients who underwent liver resection for huge HCC at the Eastern Hepatobiliary Surgery Hospital (EHBH) between January 2008 and December 2009. They were collected and divided into a training cohort (n = 310) and an internal validation cohort (n = 154). Another 90 patients who were operated on at the Fujian Medical University (FMU) between January 2008 and April 2010 served as an external validation cohort. The surgical morbidity, mortality, time to recurrence, and OS were observed. Two prognostic nomograms were developed based separately on the data obtained before and after surgery. Discrimination and predictive accuracy of the models were measured using concordance index (C-index), calibration curves, and validation study. The postoperative 4-year tumor recurrence and OS rates were, respectively, 79.0% and 41.2% in the patients from the EHBH and 78.8% and 37.6% in those from the FMU. Independent predictors of OS on multivariable analysis using pre- and postoperative data were respectively incorporated into the 2 nomograms. In the training cohort, calibration curves for the probability of 4-year postoperative survival fitted well. The C-indexes of the pre- and postoperative nomograms in predicting OS were 0.75 (95% CI 0.72 to 0.78) and 0.78 (95% CI 0.75 to 0.81), respectively. The internal and external validation studies optimally supported these results. The 2 nomograms achieved accurate pre- or postoperative predictions of long-term survival for patients with huge HCC after liver resection. Copyright © 2015 American College of Surgeons. Published by Elsevier Inc. All rights reserved.

  10. Hepatic expression of the proliferative marker Ki-67 and p53 protein in HBV or HCV cirrhosis in relation to dysplastic liver cell changes and hepatocellular carcinoma.

    Science.gov (United States)

    Koskinas, J; Petraki, K; Kavantzas, N; Rapti, I; Kountouras, D; Hadziyannis, S

    2005-11-01

    To evaluate hepatic expression of the nuclear proliferative marker Ki-67 and the p53 oncoprotein in hepatitis B virus (HBV)/HCV cirrhosis in relation to dysplastic liver cell changes and hepatocellular carcinoma (HCC). We studied needle liver biopsies from 107 patients with cirrhosis and no HCC (52 HBV, 55 HCV) who had been assessed for protocol studies, and 57 cirrhotic patients with HCC (40 HBV, 17 HCV). We evaluated small and large cell dysplastic changes along with the expression of Ki-67 and p53 by immunohistochemistry. The labelling index (LI) was defined as the proportion (%) of positive-stained nuclei of the 500 measured. Large and small cell dysplastic changes were observed in 12 and 9% of specimens respectively. Only small cell changes were associated with Ki-67 expression. Ki-67 LI was 5.50 +/- 5.7 in cirrhosis (13.90 +/- 3.84 in those with small cell dysplastic changes vs 4.64 +/- 4.98 in those without, P cirrhosis with HCC (P cirrhosis. Expression of p53 was observed in 30% of the non-tumorous and in 53% of the neoplastic tissue obtained from patients with HCC, with no differences between HCV and HBV. Ki-67 and p53 expression was associated with the tumour grade (P < 0.001). Our observations clearly demonstrate the association between the proliferation activity and the morphological changes in the cirrhotic liver from the non-dysplastic to dysplastic lesion to HCC. They also support the hypothesis that p53 alterations are a rather late event in carcinogenesis and related to HCC grade. And finally, they suggest that the final steps of hepatocarcinogenesis are common and independent of the aetiology of the chronic viral infection.

  11. Noninvasive diagnosis of hepatocellular carcinoma: Elaboration on Korean liver cancer study group-National Cancer Center Korea Practice Guidelines compared with other guidelines and remaining issues

    Energy Technology Data Exchange (ETDEWEB)

    Yoon, Jeong Hee; Lee, Jeong Min [Dept. of Radiology, Seoul National University Hospital, Seoul (Korea, Republic of); Park, Joong Won [Center for Liver Cancer, National Cancer Center, Goyang (Korea, Republic of)

    2016-02-15

    Hepatocellular carcinoma (HCC) can be diagnosed based on characteristic findings of arterial-phase enhancement and portal/delayed 'washout' in cirrhotic patients. Several countries and major academic societies have proposed varying specific diagnostic criteria for HCC, largely reflecting the variable HCC prevalence in different regions and ethnic groups, as well as different practice patterns. In 2014, a new version of Korean practice guidelines for management of HCC was released by the Korean Liver Cancer Study Group (KLCSG) and the National Cancer Center (NCC). According to the KLCSG-NCC Korea practice guidelines, if the typical hallmark of HCC (i.e., hypervascularity in the arterial phase with washout in the portal or 3 min-delayed phases) is identified in a nodule ≥ 1 cm in diameter on either dynamic CT, dynamic MRI, or MRI using hepatocyte-specific contrast agent in high-risk groups, a diagnosis of HCC is established. In addition, the KLCSG-NCC Korea practice guidelines provide criteria to diagnose HCC for subcentimeter hepatic nodules according to imaging findings and tumor marker, which has not been addressed in other guidelines such as Association for the Study of Liver Diseases and European Association for the Study of the Liver. In this review, we briefly review the new HCC diagnostic criteria endorsed by the 2014 KLCSG-NCC Korea practice guidelines, in comparison with other recent guidelines; we furthermore address several remaining issues in noninvasive diagnosis of HCC, including prerequisite of sonographic demonstration of nodules, discrepancy between transitional phase and delayed phase, and implementation of ancillary features for HCC diagnosis.

  12. Noninvasive Diagnosis of Hepatocellular Carcinoma: Elaboration on Korean Liver Cancer Study Group-National Cancer Center Korea Practice Guidelines Compared with Other Guidelines and Remaining Issues.

    Science.gov (United States)

    Yoon, Jeong Hee; Park, Joong-Won; Lee, Jeong Min

    2016-01-01

    Hepatocellular carcinoma (HCC) can be diagnosed based on characteristic findings of arterial-phase enhancement and portal/delayed "washout" in cirrhotic patients. Several countries and major academic societies have proposed varying specific diagnostic criteria for HCC, largely reflecting the variable HCC prevalence in different regions and ethnic groups, as well as different practice patterns. In 2014, a new version of Korean practice guidelines for management of HCC was released by the Korean Liver Cancer Study Group (KLCSG) and the National Cancer Center (NCC). According to the KLCSG-NCC Korea practice guidelines, if the typical hallmark of HCC (i.e., hypervascularity in the arterial phase with washout in the portal or 3 min-delayed phases) is identified in a nodule ≥ 1 cm in diameter on either dynamic CT, dynamic MRI, or MRI using hepatocyte-specific contrast agent in high-risk groups, a diagnosis of HCC is established. In addition, the KLCSG-NCC Korea practice guidelines provide criteria to diagnose HCC for subcentimeter hepatic nodules according to imaging findings and tumor marker, which has not been addressed in other guidelines such as Association for the Study of Liver Diseases and European Association for the Study of the Liver. In this review, we briefly review the new HCC diagnostic criteria endorsed by the 2014 KLCSG-NCC Korea practice guidelines, in comparison with other recent guidelines; we furthermore address several remaining issues in noninvasive diagnosis of HCC, including prerequisite of sonographic demonstration of nodules, discrepancy between transitional phase and delayed phase, and implementation of ancillary features for HCC diagnosis.

  13. Energy metabolism determines the sensitivity of human hepatocellular carcinoma cells to mitochondrial inhibitors and biguanide drugs.

    Science.gov (United States)

    Hsu, Chia-Chi; Wu, Ling-Chia; Hsia, Cheng-Yuan; Yin, Pen-Hui; Chi, Chin-Wen; Yeh, Tien-Shun; Lee, Hsin-Chen

    2015-09-01

    Human hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide particularly in Asia. Deregulation of cellular energetics was recently included as one of the cancer hallmarks. Compounds that target the mitochondria in cancer cells were proposed to have therapeutic potential. Biguanide drugs which inhibit mitochondrial complex I and repress mTOR signaling are clinically used to treat type 2 diabetes mellitus patients (T2DM) and were recently found to reduce the risk of HCC in T2DM patients. However, whether alteration of energy metabolism is involved in regulating the sensitivity of HCC to biguanide drugs is still unclear. In the present study, we treated four HCC cell lines with mitochondrial inhibitors (rotenone and oligomycin) and biguanide drugs (metformin and phenformin), and found that the HCC cells which had a higher mitochondrial respiration rate were more sensitive to these treatments; whereas the HCC cells which exhibited higher glycolysis were more resistant. When glucose was replaced by galactose in the medium, the altered energy metabolism from glycolysis to mitochondrial respiration in the HCC cells enhanced the cellular sensitivity to mitochondrial inhibitors and biguanides. The energy metabolism change enhanced AMP-activated protein kinase (AMPK) activation, mTOR repression and downregulation of cyclin D1 and Mcl-1 in response to the mitochondrial inhibitors and biguanides. In conclusion, our results suggest that increased mitochondrial oxidative metabolism upregulates the sensitivity of HCC to biguanide drugs. Enhancing the mitochondrial oxidative metabolism in combination with biguanide drugs may be a therapeutic strategy for HCC.

  14. Genomic-wide analysis of lymphatic metastasis-associated genes in human hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Chun-Feng Lee; Zhi-Qiang Ling; Ting Zhao; Shih-Hua Fang; Weng-Cheng Chang; San-Chih Lee; Kuan-Rong Lee

    2009-01-01

    AIM: To identify the genes related to lymph node metastasis in human hepatocellular carcinoma (HCC), 32 HCC patients with or without lymph node metastasis were investigated by high-throughput microarray comprising 886 genes.METHODS: The samples of cancerous and non-cancerouspaired tissue were taken from 32 patients with HCC who underwent hepatectomy with lymph node dissection. Total RNA was extracted from the cells obtained by means of laser microdissection (LCM) and was amplified by the T7-based amplification system. Then, the amplified samples were applied in the cDNA microarray comprising of 886 genes.RESULTS: The results demonstrated that 25 upregulated genes such as cell membrane receptor,intracellular signaling and cell adhesion related genes,and 48 down-regulated genes such as intracellular signaling and cell cycle regulator-related genes,were correlated with lymph node metastasis in HCC. Amongst them were included some interesting genes, such as MET, EPHA2, CCND1, MMP2, MMP13,CASP3, CDH1, and PTPN2. Expression of 16 genes ( MET, CCND1, CCND2, VEGF, KRT18, RFC4, BIRC5,CDC6, MMP2, BCL2A1, CDH1, VIM, PDGFRA, PTPN2,SLC25A5 and DSP) were further confirmed by real-time quantitative reverse transcriptional polymerase chain reaction (RT-PCR).CONCLUSION: Tumor metastasis is an important biological characteristic, which involves multiple genetic changes and cumulation. This genome-wide information contributes to an improved understanding of molecular alterations during lymph node metastasis in HCC. It may help clinicians to predict metastasis of lymph nodes and assist researchers in identifying novel therapeutic targets for metastatic HCC patients.

  15. N-glycan