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Sample records for liver cancer hepatocellular

  1. Liver (Hepatocellular) Cancer Prevention

    MedlinePlus

    ... are being studied in clinical trials. Avoiding risk factors and increasing protective factors may help prevent cancer. Avoiding cancer risk factors ... lower your risk of cancer. The following risk factors may increase the risk of liver cancer: Hepatitis ...

  2. Liver (Hepatocellular) Cancer Screening

    MedlinePlus

    ... United States than in other parts of the world. Liver cancer is uncommon in the United States, ... is the fourth most common cancer in the world. In the United States, men, especially Chinese American ...

  3. General Information about Liver (Hepatocellular) Cancer

    MedlinePlus

    ... are being studied in clinical trials. Avoiding risk factors and increasing protective factors may help prevent cancer. Avoiding cancer risk factors ... lower your risk of cancer. The following risk factors may increase the risk of liver cancer: Hepatitis ...

  4. Risks of Liver (Hepatocellular) Cancer Screening

    MedlinePlus

    ... United States than in other parts of the world. Liver cancer is uncommon in the United States, ... is the fourth most common cancer in the world. In the United States, men, especially Chinese American ...

  5. Liver (Hepatocellular) Cancer Prevention (PDQ®)—Patient Version

    Cancer.gov

    Hepatitis B and C, cirrhosis, and aflatoxin (poison from certain foods) are important risk factors for liver cancer. Learn about all of the risk factors for liver cancer and how to prevent liver cancer in this expert-reviewed summary.

  6. Methyleugenol hepatocellular cancer initiating effects in rat liver.

    PubMed

    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.

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

    PubMed Central

    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

  8. The Progress and Prospects of Putative Biomarkers for Liver Cancer Stem Cells in Hepatocellular Carcinoma

    PubMed Central

    Yang, Ting

    2016-01-01

    Accumulating evidence suggests that hepatocellular carcinoma (HCC) is organized by liver cancer stem cells (LCSCs), which are a subset of cells with “stem-like” characteristics. Identification of the LCSCs is a fundamental and important problem in HCC research. LCSCs have been investigated by various stem cell biomarkers. There is still lack of consensus regarding the existence of a “global” marker for LCSCs in HCC. In this review article, we summarize the progress and prospects of putative biomarkers for LCSCs in the past decades, which is essential to develop future therapies targeting CSCs and to predict prognosis and curative effect of these therapies. PMID:27610139

  9. Sorafenib Tosylate in Treating Patients With Liver Cancer Who Have Undergone a Liver Transplant

    ClinicalTrials.gov

    2015-03-25

    Adult Primary Hepatocellular Carcinoma; Advanced Adult Primary Liver Cancer; Localized Resectable Adult Primary Liver Cancer; Localized Unresectable Adult Primary Liver Cancer; Recurrent Adult Primary Liver Cancer

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

    PubMed

    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.

  11. NSAID use and risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: The Liver Cancer Pooling Project

    PubMed Central

    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.

    2015-01-01

    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 non-steroidal 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 ten US-based prospective cohort studies. Cox proportional hazards regression models were used to evaluate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). 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, pinteraction=0.01). The observed inverse association between aspirin use and liver cancer in our study, together with previous data, suggest the merit of future intervention studies of aspirin and other agents that affect chronic inflammatory pathways for HCC and possibly ICC. PMID:26391917

  12. Grey zone in the Barcelona Clinic Liver Cancer Classification for hepatocellular carcinoma: Surgeons’ perspective

    PubMed Central

    Yang, Tian; Lau, Wan-Yee; Zhang, Han; Huang, Bin; Lu, Jun-Hua; Wu, Meng-Chao

    2015-01-01

    Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most common cause of cancer-related deaths worldwide. The Barcelona Clinic Liver Cancer (BCLC) classification has been endorsed as the optimal staging system and treatment algorithm for HCC by the European Association for the Study of Liver Disease and the American Association for the Study of Liver Disease. However, in real life, the majority of patients who are not considered ideal candidates based on the BCLC guideline still were performed hepatic resection nowadays, which means many hepatic surgeons all around the world do not follow the BCLC guidelines. The accuracy and application of the BCLC classification has constantly been challenged by many clinicians. From the surgeons’ perspectives, we herein put forward some comments on the BCLC classification concerning subjectivity of the assessment criteria, comprehensiveness of the staging definition and accuracy of the therapeutic recommendations. We hope to further discuss with peers and colleagues with the aim to make the BCLC classification more applicable to clinical practice in the future. PMID:26217077

  13. Do We Know What Causes Liver Cancer?

    MedlinePlus

    ... Factors, and Prevention Do We Know What Causes Liver Cancer? Although several risk factors for hepatocellular cancer ... Cancer? Can Liver Cancer Be Prevented? More In Liver Cancer About Liver Cancer Causes, Risk Factors, and ...

  14. Chinese Herbal Formulation PHY906 and Sorafenib Tosylate in Treating Patients With Advanced Liver Cancer

    ClinicalTrials.gov

    2017-03-08

    Adult Primary Hepatocellular Carcinoma; Advanced Adult Primary Liver Cancer; Advanced Adult Hepatocellular Carcinoma; BCLC Stage B Adult Hepatocellular Carcinoma; BCLC Stage C Adult Hepatocellular Carcinoma

  15. Nutrition and Hepatocellular Cancer

    PubMed Central

    Schütte, Kerstin; Schulz, Christian; Malfertheiner, Peter

    2016-01-01

    Background Hepatocellular carcinoma (HCC) significantly contributes to the global burden of cancer. Liver cancer is the third most frequent cause of cancer-related death with HCC representing more than 90% of primary liver cancers. The majority of patients are not only affected by the malignant disease but do also suffer from chronic liver disease. Therefore, several factors impact on the prognosis of patients with HCC, including tumor-related factors, liver function and patient-related factors such as performance status and other comorbidities. The nutritional status is of high significance for the patients' performance status, the tolerance of tumor-targeting therapy and the prognosis of cancer of any type and is specially referenced in HCC. This overview is on current concepts on the role of nutritional factors in hepatocarcinogenesis and the role of nutrition in patients affected by HCC. Summary Nutritional status and composition of diet are relevant factors related to the risk of HCC. They also have an important role concerning the prognosis of patients with HCC. Besides risk factors, several macro- and micronutrient components have been found to be inversely correlated with the risk of HCC. To prevent disease progression to liver cirrhosis or HCC in patients with nonalcoholic steatohepatitis, it is crucial to optimize the metabolic state Key Message and Practical Implication Evidence from well-designed prospective interventional trials with the aim to reduce the HCC incidence or to prolong survival in patients with HCC based on nutritional modification is still to be generated. PMID:27403413

  16. BETA-CATENIN SIGNALING, LIVER REGENERATION AND HEPATOCELLULAR CANCER: SORTING THE GOOD FROM THE BAD

    PubMed Central

    Nejak-Bowen, Kari Nichole; Monga, Satdarshan P. S.

    2011-01-01

    Among the adult organs, liver is unique for its ability to regenerate. A concerted signaling cascade enables optimum initiation of the regeneration process following insults brought about by surgery or a toxicant. Additionally, there exists a cellular redundancy, whereby a transiently amplifying progenitor population appears and expands to ensure regeneration, when differentiated cells of the liver are unable to proliferate in both experimental and clinical scenarios. One such pathway of relevance in these phenomena is Wnt/β-catenin signaling, which is activated relatively early during regeneration mostly through post-translational modifications. Once activated, β-catenin signaling drives the expression of target genes that are critical for cell cycle progression and contribute to initiation of the regeneration process. The role and regulation of Wnt/β-catenin signaling is now documented in rats, mice, zebrafish and patients. More recently, a regenerative advantage of the livers in β-catenin overexpressing mice was reported, as was also the case after exogenous Wnt-1 delivery to the liver paving the way for assessing means to stimulate the pathway for therapeutics in liver failure. β-Catenin is also pertinent in hepatic oval cell activation and differentiation. However, aberrant activation of the Wnt/β-catenin signaling is reported in a significant subset of hepatocellular cancers (HCC). While many mechanisms of such activation have been reported, the most functional means of aberrant and sustained activation is through mutations in the β-catenin gene or in AXIN1/2, which encodes for a scaffolding protein critical for β-catenin degradation. Intriguingly, in experimental models hepatic overexpression of normal or mutant β-catenin is insufficient for tumorigenesis. In fact β-catenin loss promoted chemical carcinogenesis in the liver due to alternate mechanisms. Since most HCC occur in the backdrop of chronic hepatic injury, where hepatic regeneration is

  17. Diagnostic and Therapeutic Approaches to Hepatocellular Carcinoma: Understanding the Barcelona Clínic Liver Cancer Protocol

    PubMed Central

    Soldera, Jonathan; Balbinot, Silvana Sartori; Balbinot, Raul Angelo; Cavalcanti, Andreza Gautério

    2016-01-01

    Each year, hepatocellular carcinoma is diagnosed in more than half a million people worldwide and it is the fifth most common cancer in men and the seventh most common cancer in women. This article reviews the Barcelona-Clínic Liver Cancer protocol for the diagnosis, staging, and treatment of this disease, and four cases are presented for the discussion of the therapeutic approach. Understanding the diagnostic and therapeutic approaches to this disease is essential, especially if we keep in mind the quintessential basics of prevention and early detection. PMID:27812296

  18. 2014 Korean Liver Cancer Study Group-National Cancer Center Korea practice guideline for the management of hepatocellular carcinoma.

    PubMed

    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.

  19. 2014 Korean Liver Cancer Study Group-National Cancer Center Korea Practice Guideline for the Management of Hepatocellular Carcinoma

    PubMed Central

    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

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

    PubMed Central

    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

  1. Liver resection for early hepatocellular cancer: Comparison of centers in 3 different countries

    PubMed Central

    Wong, Linda L; Hernandez, Brenda Y; Shvetsov, Yurii B; Kawano, Yoichi; Tang, Zhao-You; Ji, Jun-Fang

    2016-01-01

    AIM To compare patients who underwent resection of early stage hepatocellular cancer (HCC) in three different countries. METHODS This retrospective study characterizes 573 stage I/II HCC patients treated with liver resection in 3 tertiary-referral centers: Tokyo (n = 250), Honolulu (n = 146) and Shanghai (n = 177). RESULTS Shanghai patients were younger, predominantly male, hepatitis-B seropositive (94%) and cirrhotic (93%). Tokyo patients were older and more likely to have hepatitis-C (67%), smaller tumors, low albumin, and normal alpha-fetoprotein. The Honolulu cohort had the largest tumors and 30% had no viral hepatitis. Age-adjusted mortality at 1 and 5-years were lower in the Tokyo cohort compared to Honolulu and there was no difference in mortality between Shanghai and Honolulu cohorts. Elevated alpha-fetoprotein, low albumin and tumor > 5 cm were associated with increased 1-year mortality. These factors and cirrhosis were independently associated with increased 5-year mortality. Independent risk factors of survival varied when examined separately by center. CONCLUSION The profile of early-stage HCC patients is strikingly different across countries and likely contributes to survival differences. Underlying differences in patient populations including risk factors/comorbidities influencing disease progression may also account for variation in outcomes. PMID:27872684

  2. Adjuvant sorafenib after heptectomy for Barcelona Clinic Liver Cancer-stage C hepatocellular carcinoma patients.

    PubMed

    Xia, Feng; Wu, Li-Li; Lau, Wan-Yee; Huan, Hong-Bo; Wen, Xu-Dong; Ma, Kuan-Sheng; Li, Xiao-Wu; Bie, Ping

    2016-06-21

    To investigate the efficacy and safety of adjuvant sorafenib after curative resection for patients with Barcelona Clinic Liver Cancer (BCLC)-stage C hepatocellular carcinoma (HCC). Thirty-four HCC patients, classified as BCLC-stage C, received adjuvant sorafenib for high-risk of tumor recurrence after curative hepatectomy at a tertiary care university hospital. The study group was compared with a case-matched control group of 68 patients who received curative hepatectomy for HCC during the study period in a 1:2 ratio. The tumor recurrence rate was markedly lower in the sorafenib group (15/34, 44.1%) than in the control group (51/68, 75%, P = 0.002). The median disease-free survival was 12 mo in the study group and 10 mo in the control group. Tumor number more than 3, macrovascular invasion, hilar lymph nodes metastasis, and treatment with sorafenib were significant factors of disease-free survival by univariate analysis. Tumor number more than 3 and treatment with sorafenib were significant risk factors of disease-free survival by multivariate analysis in the Cox proportional hazards model. The disease-free survival and cumulative overall survival in the study group were significantly better than in the control group (P = 0.034 and 0.016, respectively). Our study verifies the potential benefit and safety of adjuvant sorafenib for both decreasing HCC recurrence and extending disease-free and overall survival rates for patients with BCLC-stage C HCC after curative resection.

  3. A diet-induced animal model of non-alcoholic fatty liver disease and hepatocellular cancer

    PubMed Central

    Asgharpour, Amon; Cazanave, Sophie C.; Pacana, Tommy; Seneshaw, Mulugeta; Vincent, Robert; Banini, Bubu A.; Kumar, Divya Prasanna; Daita, Kalyani; Min, Hae-Ki; Mirshahi, Faridoddin; Bedossa, Pierre; Sun, Xiaochen; Hoshida, Yujin; Koduru, Srinivas V.; Contaifer, Daniel; Warncke, Urszula Osinska; Wijesinghe, Dayanjan S.; Sanyal, Arun J.

    2016-01-01

    Background & Aims The lack of a preclinical model of progressive non-alcoholic steatohepatitis (NASH) that recapitulates human disease is a barrier to therapeutic development. Methods A stable isogenic cross between C57BL/6J (B6) and 129S1/SvImJ (S129) mice were fed a high fat diet with ad libitum consumption of glucose and fructose in physiologically relevant concentrations and compared to mice fed a chow diet and also to both parent strains. Results Following initiation of the obesogenic diet, B6/129 mice developed obesity, insulin resistance, hypertriglyceridemia and increased LDL-cholesterol. They sequentially also developed steatosis (4–8 weeks), steatohepatitis (16–24 weeks), progressive fibrosis (16 weeks onwards) and spontaneous hepatocellular cancer (HCC). There was a strong concordance between the pattern of pathway activation at a transcriptomic level between humans and mice with similar histological phenotypes (FDR 0.02 for early and 0.08 for late time points). Lipogenic, inflammatory and apoptotic signaling pathways activated in human NASH were also activated in these mice. The HCC gene signature resembled the S1 and S2 human subclasses of HCC (FDR 0.01 for both). Only the B6/129 mouse but not the parent strains recapitulated all of these aspects of human NAFLD. Conclusions We here describe a diet-induced animal model of non-alcoholic fatty liver disease (DIAMOND) that recapitulates the key physiological, metabolic, histologic, transcriptomic and cell-signaling changes seen in humans with progressive NASH. Lay summary We have developed a diet-induced mouse model of non-alcoholic steatohepatitis (NASH) and hepatic cancers in a cross between two mouse strains (129S1/SvImJ and C57Bl/6J). This model mimics all the physiological, metabolic, histological, transcriptomic gene signature and clinical endpoints of human NASH and can facilitate preclinical development of therapeutic targets for NASH. PMID:27261415

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

    ClinicalTrials.gov

    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

  5. 3-Tesla MRI Response to TACE in HCC (Liver Cancer)

    ClinicalTrials.gov

    2016-08-22

    Adult Primary Hepatocellular Carcinoma; Advanced Adult Primary Liver Cancer; Localized Resectable Adult Primary Liver Cancer; Localized Unresectable Adult Primary Liver Cancer; Stage A Adult Primary Liver Cancer (BCLC); Stage B Adult Primary Liver Cancer (BCLC)

  6. Limitations of predicting microvascular invasion in patients with hepatocellular cancer prior to liver transplantation

    PubMed Central

    Grąt, Michał; Stypułkowski, Jan; Patkowski, Waldemar; Bik, Emil; Krasnodębski, Maciej; Wronka, Karolina M.; Lewandowski, Zbigniew; Wasilewicz, Michał; Grąt, Karolina; Masior, Łukasz; Ligocka, Joanna; Krawczyk, Marek

    2017-01-01

    Microvascular invasion (MVI) is well known to negatively influence outcomes following surgical treatment of hepatocellular cancer (HCC) patients. The aim of this study was to evaluate the rationale for prediction of MVI before liver transplantation (LT). Data of 200 HCC patients after LT were subject to retrospective analysis. MVI was present in 57 patients (28.5%). Tumor number (p = 0.001) and size (p = 0.009), and alpha-fetoprotein (p = 0.049) were independent predictors of MVI used to create a prediction model, defined as: 0.293x(tumor number) + 0.283x(tumor size in cm) + 0.164xloge(alpha-fetoprotein in ng/ml) (c statistic  =  0.743). The established cut-off (≥2.24) was associated with sensitivity and specificity of 72%. MVI was not an independent risk factor for recurrence (p = 0.307), in contrast to tumor number (p = 0.047) and size (p < 0.001), alpha-fetoprotein (p < 0.001) and poor differentiation (p = 0.039). Recurrence-free survival at 5 years for patients without MVI was 85.9% as compared to 83.3% (p = 0.546) and 55.3% (p = 0.001) for patients with false negative and true positive prediction of MVI, respectively. The use of both morphological and biological tumor features enables effective pre-transplant prediction of high-risk MVI. Provided that these parameters are combined in selection of HCC patients for LT, pre-transplant identification of all patients with MVI does not appear necessary. PMID:28057916

  7. Hedgehog Signaling Antagonist Promotes Regression of Both Liver Fibrosis and Hepatocellular Carcinoma in a Murine Model of Primary Liver Cancer

    PubMed Central

    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

    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. PMID:21912653

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

    PubMed

    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.

  9. Expression of CHODL in hepatocellular carcinoma affects invasion and migration of liver cancer cells

    PubMed Central

    Huang, Zejian; Zhang, Ning; Li, Wenda; Cao, Jun; Zhang, Lei; Chen, Yajin

    2017-01-01

    Hepatocellular carcinoma (HCC) is the third leading cause of cancer-associated death. Due to rapid progression and metastasis, the long-term survival remains poor for most patients. Thus, it is important to discover and develop novel preventive strategies and therapeutic approaches for HCC. Recent data show that chondrolectin (CHODL) is commonly overexpressed in the majority of lung cancers, indicating a possible correlation between CHODL and metastasis of lung cancer cells. Our investigation shows that the expression of CHODL is significantly decreased in HCC clinical samples and in HCC cell lines. Overexpression of CHODL in SMMC7721 cells with a lentiviral vector increased SMMC7721 cell migration and invasion. Our findings establish for the first time an association between human CHODL and HCC metastasis. PMID:28356950

  10. Can More Aggressive Treatment Improve Prognosis in Patients with Hepatocellular Carcinoma? A Direct Comparison of the Hong Kong Liver Cancer and Barcelona Clinic Liver Cancer Algorithms.

    PubMed

    Lee, Young-Sun; Seo, Yeon Seok; Kim, Ji Hoon; Lee, Juneyoung; Kim, Hae Rim; Yoo, Yang Jae; Kim, Tae Suk; Kang, Seong Hee; Suh, Sang Jun; Joo, Moon Kyung; Jung, Young Kul; Lee, Beom Jae; Yim, Hyung Joon; Yeon, Jong Eun; Kim, Jae Seon; Park, Jong-Jae; Um, Soon Ho; Bak, Young-Tae; Byun, Kwan Soo

    2017-09-07

    In addition to the globally endorsed Barcelona Clinic Liver Cancer (BCLC) staging system, other algorithms or staging systems have been developed, including the Hong Kong Liver Cancer (HKLC) staging system. This study aimed to validate the HKLC staging system relative to the BCLC staging system for predicting survival for hepatocellular carcinoma (HCC) patients in Korea. From 2004 to 2013, 2,571 patients newly diagnosed with HCC were consecutively enrolled at three Korea University medical centers. Both staging systems differentiated survival well (p<0.001). However, 1-year and 3-year survival were predicted better using the HKLC system than the BCLC system (area under the receiver operating characteristic curve: 0.869 vs 0.856 for 1 year, p=0.002; 0.841 vs 0.827 for 3 years, p=0.010). In hypothetical survival curves, the HKLC system exhibited better median overall survival than the BCLC system (33.1 months vs 19.2 months). In evaluations of prognosis according to either BCLC or HKLC treatment guidelines, risk of death was reduced in the group following only HKLC guidelines compared with the group following only BCLC guidelines (hazard ratio, 0.601; 95% confidence interval, 0.443 to 0.816; p=0.001). Although both staging systems predicted and discriminated HCC prognoses well, the HKLC system showed more encouraging survival benefits than the BCLC system.

  11. De novo Hepatocellular Carcinoma after Liver Transplantation

    PubMed Central

    Saab, Sammy; Zhou, Kali; Chang, Edward K; Busuttil, Ronald W

    2015-01-01

    Liver transplantation is the definitive therapy for patients with advanced liver disease and its complications. Patients who are transplanted with a diagnosis of hepatocellular carcinoma (HCC) are at risk of recurrent cancer, and these patients are monitored on a regular basis for recurrence. In contrast, de novo HCC following liver transplantation is a very rare complication, and recipients without HCC at the time of transplantation are not screened. We describe the clinical features of de novo HCC over a decade after achieving a sustained viral response with treatment of hepatitis C and two decades after liver transplantation. Our case highlights the necessity of screening for HCC in the post-transplant patient with advanced liver disease even after viral clearance. PMID:26807385

  12. Bone morphogenetic protein-9 is a potent growth inhibitor of hepatocellular carcinoma and reduces the liver cancer stem cells population

    PubMed Central

    Jung, Jae Woo; Yoon, So-Mi; Kim, Subin; Jeon, Yun-Hui; Yoon, Byung-Hak; Yang, Su-Geun; Kim, Min Kyoung; Choe, Senyon; Kuo, Mario Meng-Chiang

    2016-01-01

    The biological role of BMP-9 signaling in liver cancer remains dubious. To explore the potential use of BMP-9 signaling for anti-cancer therapy, we used recombinant human BMP-9, which we referred to as MB109, to study the effect on growth of fifteen hepatocellular carcinoma (HCC) cell lines. MB109 effectively inhibits the proliferation of nine HCC cells in vitro. The anti-proliferative effect was found to be induced by turning on p21 signaling, which caused survivin suppression and G0/G1 cell cycle arrest. ID3 was identified to be the mediator of the MB109-induced p21 expression. Blocking the activity of p38 MAPK diminished ID3 and p21 expression, indicating that MB109 signals through a p38 MAPK/ID3/p21 pathway to arrest cell cycle progression. Moreover, prolonged MB109 treatment suppressed the expression of five prominent liver cancer stem cell (LCSC) markers, including CD44, CD90, AFP, GPC3 and ANPEP. Xenograft model confirmed the anti-tumor and LCSC-suppression capability of MB109 in vivo. Contrary to ongoing efforts of suppressing BMP-9 signaling to inhibit angiogenesis of cancer tissue, these results demonstrate an unexpected therapeutic potential of MB109 to stimulate BMP-9 signaling for anti-cancer therapies. PMID:27650540

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

    PubMed

    Zheng, Weiling; Li, Zhen; Nguyen, Anh Tuan; Li, Caixia; Emelyanov, Alexander; Gong, Zhiyuan

    2014-01-01

    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.

  14. Xmrk, Kras and Myc Transgenic Zebrafish Liver Cancer Models Share Molecular Signatures with Subsets of Human Hepatocellular Carcinoma

    PubMed Central

    Zheng, Weiling; Li, Zhen; Nguyen, Anh Tuan; Li, Caixia; Emelyanov, Alexander; Gong, Zhiyuan

    2014-01-01

    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. PMID:24633177

  15. 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.

    PubMed

    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 <2 cups (300 mL)/d was 0.25 (95% CI: 0.11, 0.62; P-trend = 0.006). A statistically significant attenuation of the association between 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

  16. [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].

    PubMed

    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.

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

    PubMed

    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 = <0.0001). More notable reduced 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.

  18. PET-CT in Determining the Radioembolization Dose Delivered to Patients With Liver Metastasis, Primary Liver Cancer, or Biliary Cancer

    ClinicalTrials.gov

    2017-01-24

    Adult Primary Hepatocellular Carcinoma; Advanced Adult Primary Liver Cancer; Metastatic Extrahepatic Bile Duct Cancer; Recurrent Adult Primary Liver Cancer; Recurrent Extrahepatic Bile Duct Cancer; Stage D Adult Primary Liver Cancer (BCLC); Unspecified Adult Solid Tumor, Protocol Specific

  19. Spontaneous development of hepatocellular carcinoma with cancer stem cell properties in PR-SET7-deficient livers

    PubMed Central

    Nikolaou, Kostas C; Moulos, Panagiotis; Chalepakis, George; Hatzis, Pantelis; Oda, Hisanobu; Reinberg, Danny; Talianidis, Iannis

    2015-01-01

    PR-SET7-mediated histone 4 lysine 20 methylation has been implicated in mitotic condensation, DNA damage response and replication licensing. Here, we show that PR-SET7 function in the liver is pivotal for maintaining genome integrity. Hepatocyte-specific deletion of PR-SET7 in mouse embryos resulted in G2 phase arrest followed by massive cell death and defect in liver organogenesis. Inactivation at postnatal stages caused cell duplication-dependent hepatocyte necrosis, accompanied by inflammation, fibrosis and compensatory growth induction of neighboring hepatocytes and resident ductal progenitor cells. Prolonged necrotic regenerative cycles coupled with oncogenic STAT3 activation led to the spontaneous development of hepatic tumors composed of cells with cancer stem cell characteristics. These include a capacity to self-renew in culture or in xenografts and the ability to differentiate to phenotypically distinct hepatic cells. Hepatocellular carcinoma in PR-SET7-deficient mice displays a cancer stem cell gene signature specified by the co-expression of ductal progenitor markers and oncofetal genes. PMID:25515659

  20. The Singapore Liver Cancer Recurrence (SLICER) Score for Relapse Prediction in Patients with Surgically Resected Hepatocellular Carcinoma

    PubMed Central

    Ang, Soo Fan; Ng, Elizabeth Shu-Hui; Li, Huihua; Ong, Yu-Han; Choo, Su Pin; Ngeow, Joanne; Toh, Han Chong; Lim, Kiat Hon; Yap, Hao Yun; Tan, Chee Kiat; Ooi, London Lucien Peng Jin; Chung, Alexander Yaw Fui; Chow, Pierce Kah Hoe; Foo, Kian Fong; Tan, Min-Han; Cheow, Peng Chung

    2015-01-01

    Background and Aims Surgery is the primary curative option in patients with hepatocellular carcinoma (HCC). Current prognostic models for HCC are developed on datasets of primarily patients with advanced cancer, and may be less relevant to resectable HCC. We developed a postoperative nomogram, the Singapore Liver Cancer Recurrence (SLICER) Score, to predict outcomes of HCC patients who have undergone surgical resection. Methods Records for 544 consecutive patients undergoing first-line curative surgery for HCC in one institution from 1992–2007 were reviewed, with 405 local patients selected for analysis. Freedom from relapse (FFR) was the primary outcome measure. An outcome-blinded modeling strategy including clustering, data reduction and transformation was used. We compared the performance of SLICER in estimating FFR with other HCC prognostic models using concordance-indices and likelihood analysis. Results A nomogram predicting FFR was developed, incorporating non-neoplastic liver cirrhosis, multifocality, preoperative alpha-fetoprotein level, Child-Pugh score, vascular invasion, tumor size, surgical margin and symptoms at presentation. Our nomogram outperformed other HCC prognostic models in predicting FFR by means of log-likelihood ratio statistics with good calibration demonstrated at 3 and 5 years post-resection and a concordance index of 0.69. Using decision curve analysis, SLICER also demonstrated superior net benefit at higher threshold probabilities. Conclusion The SLICER score enables well-calibrated individualized predictions of relapse following curative HCC resection, and may represent a novel tool for biomarker research and individual counseling. PMID:25830231

  1. Coffee consumption and risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma by sex: The Liver Cancer Pooling Project

    PubMed Central

    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.

    2015-01-01

    Background 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. Methods 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 (HRs) and 95% confidence intervals (CI) were estimated using proportional hazards regression. Results 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=<0.0001). More notable reduced 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 relationship between coffee consumption and ICC. Conclusions These findings suggest that, in a U.S. population, coffee consumption is associated with reduced risk of HCC. Impact Further research into specific coffee compounds and mechanisms that may account for these associations is needed. PMID:26126626

  2. Liver resection for intermediate hepatocellular carcinoma

    PubMed Central

    Yi, Peng-Sheng; Zhang, Ming; Zhao, Ji-Tong; Xu, Ming-Qing

    2016-01-01

    Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in China. The Barcelona Clinic Liver Cancer (BCLC) staging system is regarded as the gold standard staging system for HCC, classifying HCC as early, intermediate, or advanced. For intermediate HCC, trans-catheter arterial chemoembolization (TACE) is recommended as the optimal strategy by the BCLC guideline. This review investigates whether liver resection is better than TACE for intermediate HCC. Based on published studies, we compare the survival benefits and complications of liver resection and TACE for intermediate HCC. We also compare the survival benefits of liver resection in early and intermediate HCC. We find that liver resection can achieve better or at least comparable survival outcomes compared with TACE for intermediate HCC; however, we do not observe a significant difference between liver resection and TACE in terms of safety and morbidity. We conclude that liver resection may improve the short- and long-term survival of carefully selected intermediate HCC patients, and the procedure may be safely performed in the management of intermediate HCC. PMID:27190577

  3. Performance status in patients with hepatocellular carcinoma: determinants, prognostic impact, and ability to improve the Barcelona Clinic Liver Cancer system.

    PubMed

    Hsu, Chia-Yang; Lee, Yun-Hsuan; Hsia, Cheng-Yuan; Huang, Yi-Hsiang; Su, Chien-Wei; Lin, Han-Chieh; Lee, Rheun-Chuan; Chiou, Yi-You; Lee, Fa-Yauh; Huo, Teh-Ia

    2013-01-01

    Performance status is included in the Barcelona Clinic Liver Cancer (BCLC) system for hepatocellular carcinoma (HCC). Few studies specifically evaluated the role of performance status in patients with HCC. This study investigated its distribution, determinants, and prognostic impact, aiming to improve the performance of the BCLC system. A total of 2,381 HCC patients were enrolled. Performance status was determined according to the Eastern Cooperative Oncology Group scale. The prognostic ability of the original and three modified BCLC systems in HCC patients was compared by the Akaike information criterion (AIC). There were 60, 17, 11, 8, and 4% of patients who were classified as performance status 0, 1, 2, 3, and 4, respectively. A worse performance status significantly correlated with age, alcoholism, hypoalbuminemia, hyperbilirubinemia, renal insufficiency, hyponatremia, and prothrombin time prolongation (all P < 0.001). Larger tumor burden, poorer residual liver function, more frequent vascular invasion, and diabetes mellitus were also observed in patients with worse performance status (all P < 0.001). Patients with poorer performance status more often received best supportive care (P < 0.001). In the Cox proportional hazards model, performance status was an independent prognostic predictor and the long-term survival tended to be worse in patients with progressively poor performance status (all P < 0.05). Reassigning patients with performance status 0 or 1 to stage B provided the lowest AIC among the four BCLC-based staging systems. Performance status is strongly associated with both tumoral and cirrhotic factors and accurately predicts long-term survival in HCC patients. Modification of the BCLC system based on performance status may further enhance its prognostic ability in patients with early to advanced cancer stage. Copyright © 2012 American Association for the Study of Liver Diseases.

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

    PubMed Central

    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

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

    PubMed Central

    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

  6. BMS-247550 in Treating Patients With Liver or Gallbladder Cancer

    ClinicalTrials.gov

    2014-05-13

    Adult Primary Cholangiocellular Carcinoma; Adult Primary Hepatocellular Carcinoma; Advanced Adult Primary Liver Cancer; Cholangiocarcinoma of the Extrahepatic Bile Duct; Cholangiocarcinoma of the Gallbladder; Localized Extrahepatic Bile Duct Cancer; Localized Gallbladder Cancer; Localized Resectable Adult Primary Liver Cancer; Localized Unresectable Adult Primary Liver Cancer; Recurrent Adult Primary Liver Cancer; Recurrent Extrahepatic Bile Duct Cancer; Recurrent Gallbladder Cancer; Unresectable Extrahepatic Bile Duct Cancer; Unresectable Gallbladder Cancer

  7. The effect of radiotherapy in liver-confined but non-resectable Barcelona Clinic Liver Cancer stage C large hepatocellular carcinoma

    PubMed Central

    Yoon, Hong In; Jung, Inkyung; Han, Kwang-Hyub; Seong, Jinsil

    2016-01-01

    Background and aims Clinical trials to determine the efficacy of radiotherapy (RT) in liver-confined but non-resectable Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC) are scarce. We aimed to determine the benefit of RT in such tumors and investigated large HCC tumors. Methods HCC data from the Korea Central Cancer Registry recorded from 2008 to 2010 were used. A total of 593 patients met our inclusion criteria; 67 were treated with RT while the remainder made up the non-RT group. Fifty-two RT recipients underwent combination treatments within 4 weeks after the first RT treatment, and were defined as the combination RT group. We performed propensity score matching (PSM) to compare the RT or combination RT groups with the non-RT group. The endpoint was overall survival (OS). Results Median follow-up time for surviving patients was 48 months. After PSM, there was no difference in OS between the RT and non-RT groups or between the combination RT and non-RT groups. However, the combination RT group had a longer median survival time (MST) (10.7 vs. 6.9 months, respectively). Next, we conducted PSM between the combination RT and non-RT groups in patients with tumor sizes ≥10 cm; MST was significantly longer in the former group (10.1 vs. 5.4 months, respectively; bootstrap 95% confidence interval of the difference in MST: 0.2-11.8). Conclusions As a combined modality, RT is a plausible therapeutic option for liver-confined but non-resectable BCLC stage C large HCC patients. PMID:27486881

  8. Lapatinib Ditosylate in Treating Patients With Unresectable Liver or Biliary Tract Cancer

    ClinicalTrials.gov

    2015-04-08

    Adult Primary Hepatocellular Carcinoma; Advanced Adult Primary Liver Cancer; Localized Unresectable Adult Primary Liver Cancer; Recurrent Adult Primary Liver Cancer; Recurrent Extrahepatic Bile Duct Cancer; Recurrent Gallbladder Cancer; Unresectable Extrahepatic Bile Duct Cancer; Unresectable Gallbladder Cancer

  9. Validation of The Hong Kong Liver Cancer Staging System in Patients with Hepatocellular Carcinoma after Curative Intent Treatment

    PubMed

    Chuncharunee, Alan; Siramolpiwat, Sith

    2017-06-25

    Backgrounds: Recently Hong Kong Liver Cancer (HKLC) staging system has been proposed for staging of hepatocellular carcinoma (HCC), and has been shown to provide better prognostic ability than the Barcelona Clinic Liver Cancer (BCLC) system. However, the HKLC system lacks external validation, and its applicability remains uncertain. The present study was aimed to evaluate the prognostic performance of HKLC in HCC patients treated with curative intent. Methods: Medical records of HCC patients treated with either resection or radiofrequency ablation (RFA) from 2011 to 2016 were retrospectively reviewed. The overall survival and the prognostic ability of the HKLC and BCLC system were evaluated. Results: 79 HCC patients were included, of which 64.56% had Child A cirrhosis. Chronic viral hepatitis B infection was the leading cause of HCC, followed by chronic viral hepatitis C infection, alcohol and alcohol with HBV or HCV infection. According to the BCLC system, 82.28% were in stage 0-A, and according to the HKLC system, 93.67% were in stage I-IIb. RFA and liver resection were the primary treatment in 56.96% and 43.04%, respectively. The 5-year survival rate of patients in HKLC stage I, IIa and IIb were 81.64%, 61.66%, and 54.42%, respectively (P<0.001). Whereas, the 5-year survival rate of patients in BCLC stage 0, A and B were 60.00%, 75.90%, and 26.65%, respectively (P=0.053). The AUROC curve of the HKLC and BCLC for the entire cohort was 0.77 and 0.64, respectively (P=0.15). Subgroup analysis showed the AUROC curve of the HKLC and BCLC for the patients with viral-associated HCC was 0.79 and 0.68, respectively (P=0.02). Conclusions: Applying the HKLC staging system provides a good discriminative ability for survival prediction in HCC patients treated with curative intent. Comparing with the BCLC system, the HKLC system tends to yield better prognostic accuracy, particularly in viral-associated HCC. Creative Commons Attribution License

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

    PubMed

    He, Zhen-Xin; Xiang, Pu; Gong, Jian-Ping; Cheng, Nan-Sheng; Zhang, Wei

    2016-01-01

    To compare the long-term survival outcomes of radiofrequency ablation and liver resection for single very early/early stage hepatocellular carcinoma (HCC). 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. 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: 0.60-0.98, P=0.04; and RR =0.70, 95% CI: 0.52-0.94, P=0.02, respectively). Ten studies involving 2,501 patients were identified that compared radiofrequency ablation (n=1,476) to liver resection (n=1,025) for single BCLC early HCC. In these ten studies, the rates of 3-year OS, 5-year OS, 3-year DFS, and 5-year DFS were also significantly lower in the radiofrequency ablation group than in the liver resection group (RR =0.93, 95% CI: 0.88-0.98, P=0.003; RR =0.84, 95% CI

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

    PubMed Central

    He, Zhen-Xin; Xiang, Pu; Gong, Jian-Ping; Cheng, Nan-Sheng; Zhang, Wei

    2016-01-01

    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: 0.60–0.98, P=0.04; and RR =0.70, 95% CI: 0.52–0.94, P=0.02, respectively). Ten studies involving 2,501 patients were identified that compared radiofrequency ablation (n=1,476) to liver resection (n=1,025) for single BCLC early HCC. In these ten studies, the rates of 3-year OS, 5-year OS, 3-year DFS, and 5-year DFS were also significantly lower in the radiofrequency ablation group than in the liver resection group (RR =0.93, 95% CI: 0.88–0

  12. Liver cancer stem cells.

    PubMed

    Sell, Stewart; Leffert, Hyam L

    2008-06-10

    In an effort to review the evidence that liver cancer stem cells exist, two fundamental questions must be addressed. First, do hepatocellular carcinomas (HCC) arise from liver stem cells? Second, do HCCs contain cells that possess properties of cancer stem cells? For many years the finding of preneoplastic nodules in the liver during experimental induction of HCCs by chemicals was interpreted to support the hypothesis that HCC arose by dedifferentiation of mature liver cells. More recently, recognition of the role of small oval cells in the carcinogenic process led to a new hypothesis that HCC arises by maturation arrest of liver stem cells. Analysis of the cells in HCC supports the presence of cells with stem-cell properties (ie, immortality, transplantability, and resistance to therapy). However, definitive markers for these putative cancer stem cells have not yet been found and a liver cancer stem cell has not been isolated.

  13. Liver transplantation for hepatocellular carcinoma: an update.

    PubMed

    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.

  14. Survival comparison between surgical resection and percutaneous radiofrequency ablation for patients in Barcelona Clinic Liver Cancer early stage hepatocellular carcinoma.

    PubMed

    Wong, Kiong-Ming; Yeh, Ming-Lun; Chuang, Shih-Chung; Wang, Liang-Yen; Lin, Zu-Yau; Chen, Shinn-Cherng; Tsai, Jung-Fa; Wang, Shen-Nien; Kuo, Kung-Kai; Dai, Chia-Yen; Yu, Ming-Lung; Lee, King-The; Chuang, Wan-Long

    2013-07-01

    To compare the survival outcome between surgical resection (SR) and radiofrequency ablation (RFA) for Barcelona Clinic Liver Cancer (BCLC) early stage hepatocellular carcinoma (HCC). The retrospective study enrolled eighty-two patients with newly diagnosed BCLC early HCC (single nodule, size ≦3 cm, and Child-Pugh class A) treated either surgically (n = 46) or with RFA (n = 36) from year 2004 to 2009. The patients' survival outcomes were compared. There were no significant differences in overall survival (OS) rates between SR and RFA (p = 0.204). The 3- and 5-year disease-free survival (DFS) rates were 65.8 % and 53.7 % respectively, in the SR group, which were significantly higher than those in the RFA group (34.8 % and 14.9 % respectively) (p = 0.009 and p = 0.001). In subgroup analysis, the DFS was similar between RFA and SR in patients with presentation of lower platelet count (≦100,000/mL) and smaller tumor size (tumor size ≦1 cm). Multivariate analysis showed SR as a procedure type was a significant predictive factor for DFS [HR = 2.26 (CI 1.462-5.227), p = 0.002]. SR yielded similar OS but better DFS when compared to RFA for patients with BCLC early HCC (single nodule, ≦3 cm and Child-Pugh class A). In subgroup patients with lower platelet count (≦100,000/mL) and smaller tumor size (tumor size ≦1 cm), DFS was similar between both treatments.

  15. Obesity and liver cancer.

    PubMed

    Vanni, Ester; Bugianesi, Elisabetta

    2014-02-01

    Obesity is an established risk factor for many types of cancers, particularly for hepatocellular carcinoma (HCC), owing to its carcinogenic potential and the association with nonalcoholic fatty liver disease (NAFLD). HCC may develop in cirrhotic and noncirrhotic livers with NAFLD, particularly in the presence of multiple metabolic risk factors such as obesity and diabetes. This issue is alarming because the population potentially at higher risk is greatly increasing. This review summarizes current evidence linking obesity and liver cancer, and discusses recent advances on the mechanisms underlying this relationship. Copyright © 2014 Elsevier Inc. All rights reserved.

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

    PubMed

    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.

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

    PubMed Central

    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

  18. 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.

    PubMed

    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.

  19. Lapatinib in Treating Patients With Locally Advanced or Metastatic Biliary Tract or Liver Cancer That Cannot Be Removed By Surgery

    ClinicalTrials.gov

    2014-12-18

    Adult Primary Hepatocellular Carcinoma; Advanced Adult Primary Liver Cancer; Localized Unresectable Adult Primary Liver Cancer; Recurrent Adult Primary Liver Cancer; Recurrent Extrahepatic Bile Duct Cancer; Recurrent Gallbladder Cancer; Unresectable Extrahepatic Bile Duct Cancer; Unresectable Gallbladder Cancer

  20. Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease

    PubMed Central

    Ur Rahman, Zia; Hurairah, Abu

    2016-01-01

    Our objective was to study nonalcoholic fatty liver disease (NAFLD) as a relevant risk factor associated with hepatocellular carcinoma (HCC) in patients with and without cirrhosis. HCC is a common cancer worldwide that predominantly involves patients with hepatic cirrhosis. HCC has recently been linked to NAFLD, the hepatic manifestation of obesity and related metabolic disorders. This association is alarming due to the high prevalence of NAFLD globally, which may contribute to the rising incidence of HCC. A 31-year-old female with a history of dyslipidemia, hypertension, and diabetes mellitus presented with abdominal pain that persisted for six months. The pain was associated with gastrointestinal symptoms and weight loss. She was drug-free and a nonalcoholic and a nonsmoker. The physical examination was unremarkable. The abdominal exam showed a soft and non-tender abdomen, with no organomegaly or ascites. The laboratory evaluation was unremarkable. The imaging studies showed a hypodense lesion in the right hepatic lobe with strong arterial enhancement. Subsequently, the patient underwent a liver biopsy. The histopathology results were consistent with HCC. The patient underwent an uneventful segment VI liver resection and tumor-free margins were achieved. In our patient, NAFLD was designated as an independent etiology for HCC, without cirrhosis. Our patient recovered well and has been disease free for over a year. HCC may complicate non-cirrhotic NAFLD with mild or absent fibrosis, greatly expanding the population potentially at higher risk of HCC. These results provide new targets for surveillance, prevention, early recognition, and effective treatment of HCC associated with NAFLD. PMID:27733959

  1. Sequential development of hepatocellular carcinoma and liver angiosarcoma in a vinyl chloride-exposed worker.

    PubMed

    Guido, Maria; Sarcognato, Samantha; Pelletti, Guido; Fassan, Matteo; Murer, Bruno; Snenghi, Rossella

    2016-11-01

    Strong experimental and clinical evidences have definitely linked occupational vinyl chloride exposure to development of angiosarcoma of the liver. In contrast, despite the International Agency for Research on Cancer having included vinyl chloride among the causes of hepatocellular carcinoma, the association between vinyl chloride exposure and hepatocellular carcinoma remains debated. This issue is relevant, because occupational exposure to high levels of vinyl chloride may still occur. We report a unique case of sequential occurrences of hepatocellular carcinoma and angiosarcoma of the liver, in a vinyl chloride-exposed worker without cirrhosis and any known risk factor for chronic liver disease. Both the hepatocellular carcinoma and the surrounding normal liver showed micronucleus formation, which reflects genotoxic effect of vinyl chloride. Angiosarcoma showed a KRAS G12D point mutation, which is considered to be characteristic of vinyl chloride-induced angiosarcoma. This case supports the pathogenic role of vinyl chloride in both hepatocellular carcinoma and angiosarcoma development.

  2. Obesity, fatty liver and liver cancer.

    PubMed

    Qian, Yan; Fan, Jian-Gao

    2005-05-01

    It has been suggested that obesity and fatty liver may be associated with the morbidity and mortality of liver cancer, and the early diagnosis and effective treatment of fatty liver coupled with liver cancer are supposed to improve the prognosis of obese patients. This review was attempted to understand the relationship between obesity, fatty liver and liver cancer. An English-language literature search using PUBMED (1990-2004) on obesity, fatty liver and liver cancer and other related articles in Chinese. Obesity is associated with the risk of death from all cancers and from cancers at individual sites including liver cancer, and it is an independent risk factor for hepatocellular carcinoma (HCC) in patients with alcoholic cirrhosis and cryptogenic cirrhosis. Because nonalcoholic steatohepatitis has been implicated as a major cause of cryptogenic cirrhosis, the development of HCC may be part of progressive nature of this condition. Obesity is associated with the incidence and mortality of HCC. More frequent surveillance for HCC may be warranted in obese patients with fatty liver and attempts should be made to interrupt the progression from simple hepatic steatosis to steatohepatitis, cirrhosis and ultimately HCC.

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

    PubMed

    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.

  4. Sorafenib Tosylate in Treating Younger Patients With Relapsed or Refractory Rhabdomyosarcoma, Wilms Tumor, Liver Cancer, or Thyroid Cancer

    ClinicalTrials.gov

    2015-05-14

    Childhood Hepatocellular Carcinoma; Papillary Thyroid Cancer; Previously Treated Childhood Rhabdomyosarcoma; Recurrent Childhood Liver Cancer; Recurrent Childhood Rhabdomyosarcoma; Recurrent Thyroid Cancer; Recurrent Wilms Tumor and Other Childhood Kidney Tumors

  5. Targeting the Wnt/β-Catenin Signaling Pathway in Liver Cancer Stem Cells and Hepatocellular Carcinoma Cell Lines with FH535

    PubMed Central

    Gedaly, Roberto; Galuppo, Roberto; Daily, Michael F.; Shah, Malay; Maynard, Erin; Chen, Changguo; Zhang, Xiping; Esser, Karyn A.; Cohen, Donald A.; Evers, B. Mark; Jiang, Jieyun; Spear, Brett T.

    2014-01-01

    Activation of the Wnt/β-catenin pathway has been observed in at least 1/3 of hepatocellular carcinomas (HCC), and a significant number of these have mutations in the β-catenin gene. Therefore, effective inhibition of this pathway could provide a novel method to treat HCC. The purposed of this study was to determine whether FH535, which was previously shown to block the β-catenin pathway, could inhibit β-catenin activation of target genes and inhibit proliferation of Liver Cancer Stem Cells (LCSC) and HCC cell lines. Using β-catenin responsive reporter genes, our data indicates that FH535 can inhibit target gene activation by endogenous and exogenously expressed β-catenin, including the constitutively active form of β-catenin that contains a Serine37Alanine mutation. Our data also indicate that proliferation of LCSC and HCC lines is inhibited by FH535 in a dose-dependent manner, and that this correlates with a decrease in the percentage of cells in S phase. Finally, we also show that expression of two well-characterized targets of β-catenin, Cyclin D1 and Survivin, is reduced by FH535. Taken together, this data indicates that FH535 has potential therapeutic value in treatment of liver cancer. Importantly, these results suggest that this therapy may be effective at several levels by targeting both HCC and LCSC. PMID:24940873

  6. 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 Nutrition123

    PubMed Central

    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

    2015-01-01

    Background: 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. Objective: 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). Design: 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. Results: The multivariable-adjusted RR of having ≥4 cups (600 mL) coffee/d compared with <2 cups (300 mL)/d was 0.25 (95% CI: 0.11, 0.62; P-trend = 0.006). A statistically significant attenuation of the association between 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. Conclusion: These data suggest that the inverse association of coffee intake

  7. Liver-Directed Radiotherapy for Hepatocellular Carcinoma

    PubMed Central

    Keane, Florence K.; Wo, Jennifer Y.; Zhu, Andrew X.; Hong, Theodore S.

    2016-01-01

    Background The incidence of hepatocellular carcinoma (HCC) continues to increase world-wide. Many patients present with advanced disease with extensive local tumor or vascular invasion and are not candidates for traditionally curative therapies such as orthotopic liver transplantation (OLT) or resection. Radiotherapy (RT) was historically limited by its inability to deliver a tumoricidal dose; however, modern RT techniques have prompted renewed interest in the use of liver-directed RT to treat patients with primary hepatic malignancies. Summary The aim of this review was to discuss the use of external beam RT in the treatment of HCC, with particular focus on the use of stereotactic body radiotherapy (SBRT). We review the intricacies of SBRT treatment planning and delivery. Liver-directed RT involves accurate target identification, precise and reproducible patient immobilization, and assessment of target and organ motion. We also summarize the published data on liver-directed RT, and demonstrate that it is associated with excellent local control and survival rates, particularly in patients who are not candidates for OLT or resection. Key Messages Modern liver-directed RT is safe and effective for the treatment of HCC, particularly in patients who are not candidates for OLT or resection. Liver-directed RT, including SBRT, depends on accurate target identification, precise and reproducible patient immobilization, and assessment of target and organ motion. Further prospective studies are needed to fully delineate the role of liver-directed RT in the treatment of HCC. PMID:27493895

  8. Evaluation of the prognostic value of Okuda, Cancer of the Liver Italian Program, and Japan Integrated Staging systems for hepatocellular carcinoma patients undergoing radiotherapy

    SciTech Connect

    Seong, Jinsil . E-mail: jsseong@yumc.yonsei.ac.kr; Shim, Su Jung; Lee, Ik Jae; Han, Kwang Hyub; Chon, Chae Yoon; Ahn, Sang Hoon

    2007-03-15

    Purpose: The purpose of this study was to compare the validity of staging systems, as well as to identify the staging system with the best prognostic value, in hepatocellular carcinoma (HCC) patients treated with radiotherapy. Methods and Materials: From 1992 to 2003, a total of 305 patients undergoing radiotherapy for HCC were evaluated retrospectively. All patients were classified before radiation therapy by the following systems: tumor-node-metastasis (TNM), Okuda, Cancer of the Liver Italian Program (CLIP), and Japan Integrated Staging (JIS) score. Cumulative survival rates were obtained using the Kaplan-Meier method, and were statistically compared using the log-rank test. Results: Median survival time was 11 months. The 1-, 2-, 3-, 4-, and 5-year survival rates were 45.1%, 24.5%, 14.7%, 10.3%, and 6.4%, respectively. Significant differences in survival were observed between all TNM stages, between CLIP scores 2, 3 and 5, 6, as well as between JIS scores 1, 2, and 2, 3. Conclusions: Among the systems studied, the TNM staging approach appeared to be the best predictor of prognosis. Staging systems that reflect liver disease status (Okuda stage, CLIP, and JIS score) showed limitations in stratifying patients undergoing radiotherapy into different prognostic groups.

  9. Obesity, Inflammation and Liver Cancer

    PubMed Central

    Sun, Beicheng; Karin, Michael

    2012-01-01

    Obesity has become a universal and major public health problem with increasing prevalence in both adults and children in the 21st century, even in developing countries. Extensive epidemiological studies reveal a strong link between obesity and development and progression of various types of cancers. The connection between obesity and liver cancer is particularly strong and obesity often results in liver diseases such as non-alcoholic fatty liver disease (NAFLD) and the more severe non-alcoholic steatohepatitis (NASH). NASH is characterized by fatty liver inflammation and is believed to cause fibrosis and cirrhosis. The latter is a known liver cancer risk factor. In fact, due to its much higher prevalence, obesity may be a more substantial contributor to overall hepatocellular carcinoma burden than infection with hepatitis viruses. Here we review and discuss recent advances in elucidation of cellular and molecular alterations and signaling pathways associated with obesity and liver inflammation, and their contribution to hepatocarcinogenesis. PMID:22120206

  10. Stopping Liver Cancer's Rogue COP | Center for Cancer Research

    Cancer.gov

    Liver cancer is the fourth most common cancer type and the third leading cause of cancer death worldwide. Many liver tumors are actually metastases, tumors seeded in the liver by cancer cells from another organ, but hepatocellular carcinomas (HCCs), the most common liver tumors, are a heterogeneous family of cancers that arise in hepatocytes, the functional cells of the liver. HCCs are often associated with cirrhosis or liver scarring. Because of the variation in tumor phenotypes, the poor understanding of the molecular origins of these tumors, and the increasing number of diagnoses especially in the US, HCC is a major clinical challenge.

  11. Living Donor Liver Transplantation for Combined Hepatocellular Carcinoma and Cholangiocarcinoma: Experience of a Single Center.

    PubMed

    Chang, Cheng-Chih; Chen, Ying-Ju; Huang, Tzu-Hao; Chen, Chun-Han; Kuo, Fang-Ying; Eng, Hock-Liew; Yong, Chee-Chien; Liu, Yueh-Wei; Lin, Ting-Lung; Li, Wei-Feng; Lin, Yu-Hung; Lin, Chih-Che; Wang, Chih-Chi; Chen, Chao-Long

    2017-02-28

    BACKGROUND Because the outcome of liver transplantation for cholangiocarcinoma is often poor, cholangiocarcinoma is a contraindication for liver transplantation in most centers. Combined hepatocellular carcinoma and cholangiocarcinoma is a rare type of primary hepatic malignancy containing features of hepatocellular carcinoma and cholangiocarcinoma. Diagnosing combined hepatocellular carcinoma and cholangiocarcinoma pre-operatively is difficult. Because of sparse research presentations worldwide, we report our experience with living donor liver transplantation for combined hepatocellular carcinoma and cholangiocarcinoma. MATERIAL AND METHODS A total of 710 patients underwent living donor liver transplantation at our institution from April 2006 to June 2014; 377 of them received transplantation because of hepatocellular carcinoma with University of California San Francisco (UCSF) staging criteria fulfilled pre-operatively. Eleven patients (2.92%) were diagnosed with combined hepatocellular carcinoma and cholangiocarcinoma confirmed pathologically from explant livers; we reviewed these cases retrospectively. Long-term survival was compared between patients diagnosed with combined hepatocellular carcinoma and cholangiocarcinoma and patients diagnosed with hepatocellular carcinoma. RESULTS The mean age of the patients in our series was 60.2 years, and the median follow-up period was 23.9 months. Four patients were diagnosed with a recurrence during the follow-up period, including one intra-hepatic and three extra-hepatic recurrences. Four patients died due to tumor recurrence. Except for patients with advanced-stage cancer, disease-free survival of patients with combined hepatocellular carcinoma and cholangiocarcinoma compared with that of patients with hepatocellular carcinoma was 80% versus 97.2% in 1 year, and 46.7% versus 92.5% in 3 years (p<0.001), and overall survival was 90% versus 97.2% in 1 year, and 61.7% versus 95.1% in 3 years (p<0.001). CONCLUSIONS

  12. Liver abscess in advanced hepatocellular carcinoma after sorafenib treatment.

    PubMed

    Shin, Seung Kak; Jung, Young Kul; Yoon, Hyun Hwa; Kwon, Oh Sang; Kim, Yun Soo; Choi, Duck Joo; Kim, Ju Hyun

    2014-01-25

    Hepatocellular carcinoma (HCC) is a critical global health issue and the third most common cause of cancer-related deaths worldwide. The majority of patients who present HCC are already at an advanced stage and their tumors are unresectable. Sorafenib is a multi-kinase inhibitor of the vascular endothelial growth factor pathway and was recently introduced as a therapy for advanced HCC. Furthermore, studies have shown that oral sorafenib has beneficial effects on survival. However, many patients experience diverse side effects, and some of these are severe. Liver abscess development has not been previously documented to be associated with sorafenib administration in HCC. Here, we report the case of a HCC patient that developed a liver abscess while being treated with sorafenib.

  13. Bioinformatics Analysis Reveals Distinct Molecular Characteristics of Hepatitis B-Related Hepatocellular Carcinomas from Very Early to Advanced Barcelona Clinic Liver Cancer Stages.

    PubMed

    Kong, Fan-Yun; Wei, Xiao; Zhou, Kai; Hu, Wei; Kou, Yan-Bo; You, Hong-Juan; Liu, Xiao-Mei; Zheng, Kui-Yang; Tang, Ren-Xian

    2016-01-01

    Hepatocellular carcinoma (HCC)is the fifth most common malignancy associated with high mortality. One of the risk factors for HCC is chronic hepatitis B virus (HBV) infection. The treatment strategy for the disease is dependent on the stage of HCC, and the Barcelona clinic liver cancer (BCLC) staging system is used in most HCC cases. However, the molecular characteristics of HBV-related HCC in different BCLC stages are still unknown. Using GSE14520 microarray data from HBV-related HCC cases with BCLC stages from 0 (very early stage) to C (advanced stage) in the gene expression omnibus (GEO) database, differentially expressed genes (DEGs), including common DEGs and unique DEGs in different BCLC stages, were identified. These DEGs were located on different chromosomes. The molecular functions and biology pathways of DEGs were identified by gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and the interactome networks of DEGs were constructed using the NetVenn online tool. The results revealed that both common DEGs and stage-specific DEGs were associated with various molecular functions and were involved in special biological pathways. In addition, several hub genes were found in the interactome networks of DEGs. The identified DEGs and hub genes promote our understanding of the molecular mechanisms underlying the development of HBV-related HCC through the different BCLC stages, and might be used as staging biomarkers or molecular targets for the treatment of HCC with HBV infection.

  14. Consensus for Radiotherapy in Hepatocellular Carcinoma from The 5th Asia-Pacific Primary Liver Cancer Expert Meeting (APPLE 2014): Current Practice and Future Clinical Trials

    PubMed Central

    Park, Hee Chul; Yu, Jeong Il; Cheng, Jason Chia-Hsien; Zeng, Zhao Chong; Hong, Ji Hong; Wang, Michael Lian Chek; Kim, Mi Sook; Chi, Kwan Hwa; Liang, Po-Ching; Lee, Rheun-Chuan; Lau, Wan-Yee; Han, Kwang Hyub; Chow, Pierce Kah-Hoe; Seong, Jinsil

    2016-01-01

    A consensus meeting to develop practice guidelines and to recommend future clinical trials for radiation therapy (RT), including external beam RT (EBRT), and selective internal RT (SIRT) in hepatocellular carcinoma (HCC) was held at the 5th annual meeting of the Asia-Pacific Primary Liver Cancer Expert consortium. Although there is no randomized phase III trial evidence, the efficacy and safety of RT in HCC has been shown by prospective and retrospective studies using modern RT techniques. Based on these results, the committee came to a consensus on the utility and efficacy of RT in the management of HCC according to each disease stage as follows: in early and intermediate stage HCC, if standard treatment is not compatible, RT, including EBRT and SIRT can be considered. In locally advanced stage HCC, combined EBRT with transarterial chemoembolization or hepatic arterial infusion chemotherapy, and SIRT can be considered. In terminal stage HCC, EBRT can be considered for palliation of symptoms and reduction of morbidity caused by the primary tumor or its metastases. Despite the currently reported benefits of RT in HCC, the committee agreed that there is a compelling need for large prospective studies, including randomized phase III trial evidence evaluating the role of RT. Specifically studies evaluating the efficacy and safety of sequential combination of EBRT and SIRT are strongly recommended. PMID:27493892

  15. Laparoscopic liver resection for hepatocellular adenoma

    PubMed Central

    Hilal, Mohammed Abu; Fabio, Francesco Di; Wiltshire, Robert David; Hamdan, Mohammed; Layfield, David M; Pearce, Neil William

    2011-01-01

    AIM: To investigate the role of laparoscopy in the surgical management of hepatocellular adenoma (HA). METHODS: We reviewed a prospectively collected database of consecutive patients undergoing laparoscopic liver resection for HA. RESULTS: Thirteen patients underwent fifteen pure laparoscopic liver resections for HA (male/female: 3/10; median age 42 years, range 22-72 years). Two patients with liver adenomatosis required two different laparoscopic operations for ruptured adenomas. Indications for surgery were: symptoms in 12 cases, need to rule out malignancy in 2 cases and preoperative diagnosis of large HA in one case. Symptoms were related to bleeding in 10 cases, sepsis due to liver abscess following embolization of HA in one case and mass effect in one case (shoulder tip pain). Five cases with ruptured bleeding adenoma required emergency admission and treatment with selective arterial embolization. Laparoscopic liver resection was then semi-electively performed. Eight patients (62%) required major hepatectomy [right hepatectomy (n = 5), left hepatectomy (n = 3)]. No conversion to open surgery occurred. The median operative time for pure laparoscopic procedures was 270 min (range 135-360 min). The median size of the excised lesions was 85 mm (range 25-180 mm). One patient with adenomatosis developed postoperative bleeding requiring embolization. Mortality was nil. The median hospital stay was 4 d (range 1-18 d) with a median high dependency unit stay of 1 d (range 0-7 d). CONCLUSION: The laparoscopic approach represents a safe option for the management of HA in a semi-elective setting and when major hepatectomy is required. PMID:21860698

  16. Evaluation of eligibility criteria in living donor liver transplantation for hepatocellular carcinoma by α-SMA-positive cancer-associated fibroblasts.

    PubMed

    Takamura, Hiroyuki; Nakanuma, Shinichi; Hayashi, Hironori; Tajima, Hidehiro; Kakinoki, Kaheita; Sakai, Seisyo; Makino, Isamu; Nakagawara, Hisatoshi; Miyashita, Tomoharu; Okamoto, Koichi; Nakamura, Keishi; Oyama, Katunobu; Inokuchi, Masashi; Ninomiya, Itasu; Kitagawa, Hirohisa; Fushida, Sachio; Fujimura, Takashi; Ohnishi, Ichiro; Kayahara, Masato; Tani, Takashi; Arai, Kuniaki; Yamashita, Taro; Yamashita, Tatsuya; Kitamura, Hoshiko; Ikeda, Hiroko; Kaneko, Shuichi; Nakanuma, Yasuni; Matsui, Osamu; Ohta, Tetsuo

    2013-10-01

    The eligibility criteria of liver transplantation (LT) for hepatocellular carcinoma (HCC) must clearly confirm the prognosis not only from pathological diagnosis but also from pre-operative imaging diagnosis. In the present study, we evaluated published eligibility criteria for LT based on both pre-operative imaging diagnosis and pathological diagnosis using living donor liver transplantation (LDLT) recipients at our hospital by α-smooth muscle actin (SMA)-positive cancer-associated fibroblasts (CAFs) in HCC. The Up-to-seven (Up-to-7), Asan and Tokyo criteria were evaluated, in both overall survival and HCC disease-free survival, to be statistically significantly beneficial criteria to define post-LDLT prognosis. Recipients only within Up-to-7 criteria based on both pre-operative imaging diagnosis and pathological diagnosis survived without HCC recurrence. Recipients with proliferation of α-SMA-positive CAFs in HCC had significantly poorer prognosis. All survival recipients without HCC recurrence, who were above the Up-to-7 criteria in pathological diagnosis, had no proliferation of α-SMA-positive CAFs. As a result of multivariate analysis, the significant independent factors defining prognosis of recipients after LDLT for HCC were Up-to-7 criteria and proliferation of α-SMA-positive CAFs. The ideal eligibility criteria for LDLT with HCC is Up-to-7 criteria and α-SMA-positive CAFs was considered to be an important factor in HCC recurrence. LDLT should be limited to recipients within Up-to-7 criteria or without proliferation of α-SMA-positive CAFs.

  17. Nuclear changes in blood, early liver anomalies and hepatocellular cancers in flounder (Platichthys flesus L.) as prognostic indicator for a higher cancer risk?

    PubMed

    Köhler, Angela; Ellesat, Kathrin

    2008-07-01

    Nuclear changes (micronuclei) in blood are a well-established biomarker of toxic injury and related genotoxicity in mussel, fish and humans, as well. Yet, the relationship between the frequencies of micronuclei in blood and nuclear changes in liver cells itself and the higher potential risk to develop liver cancer is not yet fully implemented. We analysed and diagnosed macroscopic liver changes and H&E and Feulgen stained histological liver sections (2 microm of thickness) together with blood smears (stained with Sytox Green) from same individuals in flounder caught along a well-known contaminant gradient in the North Sea. Results showed an increase in micronuclei frequencies in blood at the more contaminated sites and higher frequencies of macroscopically visible neoplastic liver changes. In livers of the same individuals, nuclear changes were diagnosed in early to degenerative liver lesion, extra-focal tissue surrounding neoplastic lesion and various stages during cancer progression from early neoplastic foci, benign adenomas and malignant carcinomas. The aim of this approach is to expand diagnostic criteria, well-established in the frame of BEQUALM to nuclear changes which might help diagnosis of malignancies in doubtful cases.

  18. What Is Liver Cancer?

    MedlinePlus

    ... hepatocellular carcinoma. Written by References The American Cancer Society medical and editorial content team Our team is ... 2016 Last Revised: April 28, 2016 American Cancer Society medical information is copyrighted material. For reprint requests, ...

  19. Cancer-associated fibroblasts in hepatocellular carcinoma

    PubMed Central

    Kubo, Norio; Araki, Kenichiro; Kuwano, Hiroyuki; Shirabe, Ken

    2016-01-01

    The hepatic stellate cells in the liver are stimulated sustainably by chronic injury of the hepatocytes, activating myofibroblasts, which produce abundant collagen. Myofibroblasts are the major source of extracellular proteins during fibrogenesis, and may directly, or secreted products, contribute to carcinogenesis and tumor progression. Cancer-associated fibroblasts (CAFs) are one of the components of the tumor microenvironment that promote the proliferation and invasion of cancer cells by secreting various growth factors and cytokines. CAFs crosstalk with cancer cells stimulates tumor progression by creating a favorable microenvironment for progression, invasion, and metastasis through the epithelial-mesenchymal transition. Basic studies on CAFs have advanced, and the role of CAFs in tumors has been elucidated. In particular, for hepatocellular carcinoma, carcinogenesis from cirrhosis is a known fact, and participation of CAFs in carcinogenesis is supported. In this review, we discuss the current literature on the role of CAFs and CAF-related signaling in carcinogenesis, crosstalk with cancer cells, immunosuppressive effects, angiogenesis, therapeutic targets, and resistance to chemotherapy. The role of CAFs is important in cancer initiation and progression. CAFtargeted therapy may be effective for suppression not only of fibrosis but also cancer progression. PMID:27570421

  20. Expression of liver fatty acid binding protein in hepatocellular carcinoma☆

    PubMed Central

    Cho, Soo-Jin; Ferrell, Linda D.; Gill, Ryan M.

    2017-01-01

    Summary Loss of expression of liver fatty acid binding protein (LFABP) by immunohistochemistry has been shown to be characteristic of a subset of hepatocellular adenomas (HCAs) in which HNF1A is inactivated. Transformation to hepatocellular carcinoma is thought to be a very rare phenomenon in the HNF1A-inactivated variant of HCA. However, we recently observed 2 cases at our institution, 1 definite hepatocellular carcinoma and 1 possible hepatocellular carcinoma, with loss of LFABP staining, raising the possibility that LFABP down-regulation may be associated with hepatocellular carcinogenesis. Our aim was to evaluate hepatocellular carcinomas arising in various backgrounds and with varying degrees of differentiation for loss of LFABP staining. Twenty total cases of hepatocellular carcinoma were examined. Thirteen cases arose in a background of cirrhosis due to hepatitis C (n = 8) or steatohepatitis (n = 5); 7 cases arose in a noncirrhotic background, with 2 cases arising within HNF1A-inactivated variant HCA and 2 cases arising within inflammatory variant HCA. Complete loss of expression of LFABP was seen in 6 of 20 cases, including 2 cases of hepatocellular carcinoma arising within HNF1A-inactivated variant HCA. Thus, loss of staining for LFABP appears to be common in hepatocellular carcinoma and may be seen in well-differentiated hepatocellular carcinoma. Therefore, LFABP loss should not be interpreted as evidence for hepatocellular adenoma over carcinoma, when other features support a diagnosis of hepatocellular carcinoma. The findings raise consideration for a role of HNF1A inactivation in hepatocellular carcinogenesis, particularly in less differentiated tumors. PMID:26997447

  1. Selective CD4+ T Cell Loss Promotes Liver Cancer Development | Center for Cancer Research

    Cancer.gov

    Hepatocellular carcinoma (HCC), the second leading cause of cancer deaths worldwide, commonly develops in patients with underlying chronic liver disease, such as hepatitis B or C virus infection or non-alcoholic fatty liver disease (NAFLD).

  2. Liver transplantation as a management of hepatocellular carcinoma

    PubMed Central

    Azzam, Ayman Zaki

    2015-01-01

    Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and has a poor prognosis if untreated. It is ranked the third among the causes of cancer-related death. There are multiple etiologic factors that can lead to HCC. Screening for early HCC is challenging due to the lack of well specific biomarkers. However, early diagnosis through successful screening is very important to provide cure rate. Liver transplantation (LT) did not gain wide acceptance until the mid-1980s, after the effective immunosuppression with cyclosporine became available. Orthotopic LT is the best therapeutic option for early, unresectable HCC. It is limited by both, graft shortage and the need for appropriate patient selection. It provides both, the removal of tumor and the remaining cirrhotic liver. In Milan, a prospective cohort study defined restrictive selection criteria known as Milan criteria (MC) that led to superior survival for transplant patients in comparison with any other previous experience with transplantation or other options for HCC. When transplantation occurs within the established MC, the outcomes are similar to those for nonmalignant liver disease after transplantation. The shortage of organs from deceased donors has led to the problems of long waiting times and dropouts. This has led to the adoption of extended criteria by many centers. Several measures have been taken to solve these problems including prioritization of patients with HCC, use of pretransplant adjuvant treatment, and living donor LT. PMID:26052380

  3. Nomogram for preoperative estimation of long-term survival of patients who underwent curative resection with hepatocellular carcinoma beyond Barcelona clinic liver cancer stage A1

    PubMed Central

    Zhao, Hui; Wu, Dong-Hao; Chen, Jie; Dong, Min; Lin, Qu; Wu, Xiang-Yuan; Li, Yang

    2016-01-01

    Background and Aims This retrospective cohort study developed a prognostic nomogram to predict the survival of hepatocellular carcinoma (HCC) patients diagnosed as beyond Barcelona clinic liver cancer stage A1 after resection and evaluated the possibility of using the nomogram as a treatment algorithm reference. Results The predictors included in the nomogram were total tumour volume, Child-Turcotte-Pugh class, plasma fibrinogen and portal vein tumour thrombus. Patients diagnosed as beyond A1 were stratified into low-, medium- and high-risk groups using nomogram scores of 0 and 51 with the total points of 225. Patients within A1 exhibited similar recurrence-free survival (RFS) and overall survival (OS) rates compared with the low-risk group. Patients in the medium-risk group exhibited a similar OS but a worse RFS rates compared with patients within A1. The high-risk group was associated with worse RFS and OS rates compared with the patients within A1 (3-year RFS rates, 27.0% vs. 60.3%, P < 0.001; 3-year OS rates, 49.2% vs. 83.1%, P < 0.001). Methods A total of 352 HCC patients undergoing curative resection from September 2003 to December 2012 were included to develop a nomogram to predict overall survival after resection. Univariate and multivariate survival analysis were used to identify prognostic factors. A visually orientated nomogram was constructed using a Cox proportional hazards model. Conclusions This user-friendly nomogram offers an individualized preoperative recurrence risk estimation and stratification for HCC patients beyond A1 undergoing resection. Resection should be considered the first-line treatment for low-risk patients. PMID:27542216

  4. Results of surgical and nonsurgical treatment for small-sized hepatocellular carcinomas: a retrospective and nationwide survey in Japan. The Liver Cancer Study Group of Japan.

    PubMed

    Arii, S; Yamaoka, Y; Futagawa, S; Inoue, K; Kobayashi, K; Kojiro, M; Makuuchi, M; Nakamura, Y; Okita, K; Yamada, R

    2000-12-01

    Hepatic resection (HX), percutaneous ethanol injection (PEI), and transcatheter arterial embolization (TCAE) have all been used in the treatment of patients with small-sized hepatocellular carcinomas (HCCs). However, the indications for these therapeutic modalities remain unclear. Therefore, the first step to minimize the debate on these indications is to review the standard results from each treatment based on an extensive survey. The participants in this study were patients with HCCs less than 5 cm in diameter who were enrolled in The Liver Cancer Study Group of Japan. The survival rates in the HX (n = 8,010), PEI (n = 4,037), and TCAE (n = 841) groups were calculated in relation to the number of tumors and the clinical stage. In the clinical stage I cases with a solitary tumor less than 2 cm in diameter and in all clinical stages with a solitary tumor greater than 2 cm and in the clinical stage II cases with 2 tumors greater than 2 cm, the HX group showed higher survival rates than the nonsurgical groups. The HX group had a higher male/female ratio and a younger mean age than the PEI or TCAE group. The ratio of HBs antigen-positive cases/hepatitis C virus antibody-positive cases in the PEI group was lower than that in the corresponding HX group. In contrast, the PIVKA-II values in the HX group tended to be higher than in the PEI group. In conclusion, these findings will provide useful information for selection of a therapeutic modality for small-sized HCCs.

  5. Erlotinib in Treating Patients With Unresectable Liver, Bile Duct, or Gallbladder Cancer

    ClinicalTrials.gov

    2013-06-03

    Adult Primary Cholangiocellular Carcinoma; Adult Primary Hepatocellular Carcinoma; Advanced Adult Primary Liver Cancer; Cholangiocarcinoma of the Extrahepatic Bile Duct; Cholangiocarcinoma of the Gallbladder; Localized Unresectable Adult Primary Liver Cancer; Recurrent Adult Primary Liver Cancer; Recurrent Extrahepatic Bile Duct Cancer; Recurrent Gallbladder Cancer; Unresectable Extrahepatic Bile Duct Cancer; Unresectable Gallbladder Cancer

  6. AFP, PIVKAII, GP3, SCCA-1 and follisatin as surveillance biomarkers for hepatocellular cancer in non-alcoholic and alcoholic fatty liver disease

    PubMed Central

    Beale, Gary; Chattopadhyay, Dipankar; Gray, Joe; Stewart, Stephen; Hudson, Mark; Day, Christopher; Trerotoli, Paolo; Giannelli, Gianluigi; Manas, Derek; Reeves, Helen

    2008-01-01

    Background The incidence and mortality of hepatocellular cancer (HCC) complicating alcoholic and non-alcoholic fatty liver diseases (ALD and NAFLD) is rising in western societies. Despite knowing the at risk populations for HCC development, the lack of sensitive and specific means of surveillance hampers disease detection at curable stages. The most widely used serum HCC marker is alpha-fetoprotein (AFP), while PIVKA-II, glypican-3 (GP3) and Squamous Cell Carcinoma Antigen -1 (SCCA-1) have been proposed as new biomarkers. Assessment of these HCC biomarkers has largely been performed in patients with viral hepatitis. We conducted a cross sectional study assessing the value of these serum proteins, as well a novel candidate biomarker -follistatin – in patients with HCC arising on a background of ALD or NAFLD. Methods Pre-treatment serum samples from 50 patients with HCC arising on a background of ALD (n = 31) or NAFLD (n = 19) were assessed by specific ELISA assay for PIVKAII, Glypican-3, SCCA-1 and Follistatin. Results were compared and contrasted with a control patient group with biopsy proven steatohepatitis-related cirrhosis (n = 41). The diagnostic accuracy of each of the candidate biomarkers was evaluated using receiver operating characteristic (ROC) curve analysis, reporting the area under the curve (AUC) and its 95% confidence interval (CI). Performance was compared to that of the established biomarker, AFP. Results Serum levels of all proteins were assessed by specific ELISA assays. GP3, SCCA-1 and follistatin had no HCC surveillance benefit in these patients. AFP and PIVKAII were superior to the other markers, particularly in combination. Conclusion We conclude that while novel means of surveillance are urgently required, the combination of AFP and PIVKAII for HCC is an improvement on AFP alone in ALD/NAFLD patients. Furthermore, our data in this homogenous subset of patients- particularly that confirming no role for SCCA-1 – suggests that the choice of

  7. Obesity, inflammation, and liver cancer.

    PubMed

    Sun, Beicheng; Karin, Michael

    2012-03-01

    Obesity has become a universal and major public health problem with increasing prevalence in both adults and children in the 21st century, even in developing countries. Extensive epidemiological studies reveal a strong link between obesity and development and progression of various types of cancers. The connection between obesity and liver cancer is particularly strong and obesity often results in liver diseases such as non-alcoholic fatty liver disease (NAFLD) and the more severe non-alcoholic steatohepatitis (NASH). NASH is characterized by fatty liver inflammation and is believed to cause fibrosis and cirrhosis. The latter is a known liver cancer risk factor. In fact due to its much higher prevalence obesity may be a more substantial contributor to overall hepatocellular carcinoma burden than infection with hepatitis viruses. Here we review and discuss recent advances in elucidation of cellular and molecular alterations and signaling pathways associated with obesity and liver inflammation and their contribution to hepatocarcinogenesis. Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  8. Hepatocellular Carcinoma and Liver Transplantation: State of the Art

    PubMed Central

    Mancuso, Andrea; Perricone, Giovanni

    2014-01-01

    Hepatocellular carcinoma (HCC) is an aggressive tumor that often occurs in chronic liver disease and cirrhosis. The incidence of HCC is growing worldwide. With respect to any other available treatment for liver cancer, liver transplantation (LT) has the highest potential to cure. LT allows for removal at once of both the tumor (“seed”) and the damaged-hepatic tissue (“soil”) where cancerogenesis and chronic liver disorders have progressed together. The Milan criteria (MC) have been applied worldwide to select patients with HCC for LT, yielding a 4-year survival rate of 75%. These criteria represent the benchmark for patient selection and are the basis for comparison with any other suggested criteria. However, MC are often considered to be too restrictive, and recent data show that between 25% and 50% of patients with HCC are currently transplanted beyond conventional indications. Consequently, any unrestricted expansion of selection criteria will increase the need for donor organs, lengthen waiting periods, increase drop-out rates, and impair outcomes on intention-to-treat analysis. Management of HCC recurrence after LT is challenging. There are a few reports available regarding the safety and efficacy of sorafenib for HCC recurrence after LT, but the data are heterogeneous. A multi-center prospective randomized controlled trial comparing placebo with sorafenib is advised. Alternatively, a meta-analysis of patient survival with sorafenib for HCC recurrence after LT could be helpful to characterize the therapeutic benefit and safety of sorafenib. Here, we review the use of LT for HCC, with particular emphasis on the selection criteria for transplantation in patients with HCC and management of HCC recurrence after LT. PMID:26357625

  9. [Non-alcoholic fatty liver disease and hepatocellular carcinoma - 2016].

    PubMed

    Pár, Alajos; Pár, Gabriella

    2016-06-19

    In the past decade non-alcoholic liver disease became the most frequently diagnosed liver disease in developed countries. At the same time, the dramatic rise in the incidence of hepatocellular carcinoma is attributed to this common metabolic disorder, and mainly to its severe form, non-alcoholic steatohepatitis. The risk factors of these associated diseases are genetic predisposition, obesity and diabetes as well as chronic low grade necro-infammation, which often leads to liver fibrosis. Free fatty acids, cytokines, lipotoxicity, insulin resistance, microRNS dysregulation and alteration in intestinal microbiota play a pivotal role in the pathogenesis. Treatment of non-alcoholic fatty liver disease - weight reduction and physical exercise in obesity, metformin in diabetes, statins in dyslipidemia and, as a new option, obeticholic acid - may diminish the risk of the hepatocellular carcinoma related to this metabolic disease.

  10. Liver transplantation for small hepatocellular carcinoma

    PubMed Central

    Kamo, Naoko; Yagi, Shintaro; Okajima, Hideaki; Uemoto, Shinji

    2016-01-01

    Background We treat small hepatocellular carcinoma (HCC) ≤3 cm in diameter by liver transplantation (LT) considering liver reserve and HCC localization, and when other treatment would be ineffective. However, the outcomes of LT and the clinicopathological features of small HCC ≤3 cm in diameter are not clear. We analyzed the outcomes of LT for small HCC ≤3 cm in diameter. Methods Between February 1999 and August 2015, 223 patients underwent LT for HCC at Kyoto University Hospital. We analyzed the proportion of small HCC ≤3 cm in diameter (small HCC) among all patients, the background of small HCC, survival and recurrence rates within and beyond the Milan criteria (MC), Kyoto criteria (KC) [≤5 cm, N ≤10, des-gamma-carboxy prothrombin (DCP) ≤400], and rates of survival and recurrence after LT with or without pretreatment. Results Among the 223 patients, 159 (71%) had small HCC accompanied by hepatitis B virus (HBV), 43 (27%); hepatitis C virus (HCV), 96 (61%); HBV, HCV, 5 (3%) and non B non C, 15 (9%). One hundred and fourteen (72%) patients were male with a tumor radius of 2 (range, 0.4–3) cm; number of tumors, 2 (range, 1–186); alpha-fetoprotein (AFP) 28.5 (range, 1.3–12,727) and DCP 42 (range, 5–20,600). The tumors were well, moderately and poorly differentiated in 22 (14%), 105 (66%) and 24 (15%) patients, respectively. Among the patients, 124 (78%) and 132 (83%) were within the MC and KC, respectively. One-, three- and five-year survival rates associated with tumors within and beyond the MC were 87%, 81% and 79% vs. 94%, 76%, and 70%, respectively (P=0.430) and recurrence rates were significantly lower in patients within MC than in patients beyond MC (P<0.001). One-, three- and five-year survival rates associated with tumors within and beyond KC were 89%, 85%, and 83% vs. 89%, 58%, and 50%, respectively (P<0.001) and recurrence rates were 2%, 3%, and 4% vs. 21%, 37%, and 47%, respectively (P<0.001). Survival and recurrence rates were

  11. Viral hepatitis and liver cancer

    PubMed Central

    Ringehan, Marc

    2017-01-01

    Hepatitis B and C viruses are a global health problem causing acute and chronic infections that can lead to liver cirrhosis and hepatocellular carcinoma (HCC). These infections are the leading cause for HCC worldwide and are associated with significant mortality, accounting for more than 1.3 million deaths per year. Owing to its high incidence and resistance to treatment, liver cancer is the second leading cause of cancer-related death worldwide, with HCC representing approximately 90% of all primary liver cancer cases. The majority of viral-associated HCC cases develop in subjects with liver cirrhosis; however, hepatitis B virus infection can promote HCC development without prior end-stage liver disease. Thus, understanding the role of hepatitis B and C viral infections in HCC development is essential for the future design of treatments and therapies for this cancer. In this review, we summarize the current knowledge on hepatitis B and C virus hepatocarcinogenesis and highlight direct and indirect risk factors. This article is part of the themed issue ‘Human oncogenic viruses’. PMID:28893941

  12. Prophylactic liver transplantation for high-risk recurrent hepatocellular carcinoma

    PubMed Central

    Yang, Po-Chih; Ho, Cheng-Maw; Hu, Rey-Heng; Ho, Ming-Chih; Wu, Yao-Ming; Lee, Po-Huang

    2016-01-01

    Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death in the world. Radical treatment of HCC in early stages results in a long disease-free period and improved overall survival. The choice of optimal management strategy for HCC mainly depends on the severity of the underlying liver disease. For patients with decompensated liver cirrhosis and HCC within Milan criteria (MC), liver transplant (LT) is the choice of treatment. However, for patients with good residual liver reserve and HCC within MC, selection of other curative treatments such as liver resection (LR) or radiofrequency ablation may be a reasonable alternative. For patients without cirrhosis, LR can result in an overall survival similar to that provided by LT. Therefore, it is an accepted alternative to LT especially in areas with organ shortage. However, the cumulative 5-year recurrence rate of HCC post LR might be as high as 70%. For initial transplant-eligible (within MC) patients with recurrent HCC post LR, salvage liver transplant (SLT) was first proposed in 2000. However, most patients with recurrent HCC considered for SLT are untransplantable cases due to HCC recurrence beyond MC or comorbidity. Thus, the strategy of opting for SLT results in the loss of the opportunity of LT for these patients. Some authors proposed the concept of “de principe liver transplant” (i.e., prophylactic LT before HCC recurrence) to prevent losing the chance of LT for these potential candidates. Factors associated with the failure of SLT will be dissected and discussed in three parts: Patient, tumor, and underlying liver disease. Regarding patient-related factors, the rate of transplantability depends on patient compliance. Patients without regular follow-up tend to develop HCC recurrence beyond MC at the time of tumor detection. Advancing age is another factor related to severe comorbidities when LT is considered for HCC recurrence, and these elderly candidates become ineligible as

  13. Feature statistic analysis of ultrasound images of liver cancer

    NASA Astrophysics Data System (ADS)

    Huang, Shuqin; Ding, Mingyue; Zhang, Songgeng

    2007-12-01

    In this paper, a specific feature analysis of liver ultrasound images including normal liver, liver cancer especially hepatocellular carcinoma (HCC) and other hepatopathy is discussed. According to the classification of hepatocellular carcinoma (HCC), primary carcinoma is divided into four types. 15 features from single gray-level statistic, gray-level co-occurrence matrix (GLCM), and gray-level run-length matrix (GLRLM) are extracted. Experiments for the discrimination of each type of HCC, normal liver, fatty liver, angioma and hepatic abscess have been conducted. Corresponding features to potentially discriminate them are found.

  14. Liver Cancer: Connections with Obesity, Fatty Liver, and Cirrhosis.

    PubMed

    Marengo, Andrea; Rosso, Chiara; Bugianesi, Elisabetta

    2016-01-01

    The burden of hepatocellular carcinoma (HCC), the most common form of liver cancer, is steadily growing because obesity, type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD) are replacing viral- and alcohol-related liver disease as major pathogenic promoters. The most worrisome aspects of these new risk factors are their large spread in the general population and their link with HCC arising in noncirrhotic livers. HCC may be the presenting feature of an asymptomatic nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD. The HCC risk connected to metabolic factors has been underestimated so far, and a poorer surveillance has prevented an adequate treatment. Systemic and hepatic molecular mechanisms involved in obesity- and NAFLD-induced hepatocarcinogenesis as well as potential early markers of HCC are being extensively investigated. This review summarizes current evidence linking obesity, NAFLD and liver cancer, discusses its clinical impact and describes the main mechanisms underlying this complex relationship.

  15. Successful Liver Transplantation for Hyperammonemic Fibrolamellar Hepatocellular Carcinoma

    PubMed Central

    Alsina, Angel E.; Franco, Edson; Nakshabandi, Ahmad; Albers, Christopher; Kemmer, Nyingi; Finan, Jon

    2016-01-01

    Fibrolamellar hepatocellular carcinoma is a rare hepatocellular tumor usually arising in noninfected and noncirrhotic livers. Only 2 cases accompanied by hyperammonemia due to intrahepatic shunting have been reported. A 23-year-old white woman presented with a 2-week history of nausea, vomiting, generalized weakness, and intermittent right upper quadrant pain. Abdominal computerized tomography revealed a 13 x 9-cm hepatic mass. Core-needle biopsy revealed fibrolamellar hepatocellular carcinoma. She presented with coma due to hyperammonemia levels (peak at 437 mcg/dL) but without metastatic disease. She was urgently transplanted, started on daily sorafenib 8 weeks after transplantation, and was free of disease at 1 year after transplantation. PMID:27807568

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

    PubMed Central

    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

  17. Obesity and Liver Cancer.

    PubMed

    Aleksandrova, Krasimira; Stelmach-Mardas, Marta; Schlesinger, Sabrina

    Obesity and related metabolic disorders have become globally prevalent posing a challenge for the chronically damaged liver and predisposing the development and progression of cancer. The rising phenomenon of "obesity epidemic" may provide means for understanding why liver cancer is one of the few malignancies with rising incidence in developed countries over the last decades. Non-alcoholic fatty liver disease associated with obesity, insulin resistance, and type 2 diabetes is an increasingly recognized trigger for liver cancer in Western populations characterized by low prevalence of established risk factors for liver cancer such as viral hepatitis and hepatotoxin exposure. Accumulating evidence has established an association between higher body mass index as an indicator of general obesity and higher risk of primary liver cancer. The associations are stronger in men, in patients with underlying liver disease and in white ethnic groups. Abdominal obesity, weight gain in adult life and metabolic factors related to visceral fat accumulation were also suggested as important risk factors for liver cancer; however, more studies are needed to evaluate these associations. The association of obesity and metabolic parameters with liver cancer survival remains controversial. It is unclear which exact mechanisms could provide links between obesity and liver cancer risk. Recent evidence has implicated several molecular pathways in obesity-associated liver cancer. These include insulin resistance leading to increased levels of insulin and insulin-like growth factors, chronic inflammation, adipose tissue remodeling, pro-inflammatory cytokine and adipokine secretion, and altered gut microbiota. These mechanisms coincide with inflammatory and metabolic processes occurring in non-alcoholic fatty liver disease predisposing cancer development and progression. In the context of the current evidence, better understanding of the role of obesity and related metabolic factors may help in

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

    PubMed Central

    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.

    2013-01-01

    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. PMID:23428905

  19. Hepatitis B virus PreS1 facilitates hepatocellular carcinoma development by promoting appearance and self-renewal of liver cancer stem cells.

    PubMed

    Liu, Zhixin; Dai, Xuechen; Wang, Tianci; Zhang, Chengcheng; Zhang, Wenjun; Zhang, Wei; Zhang, Qi; Wu, Kailang; Liu, Fang; Liu, Yingle; Wu, Jianguo

    2017-08-01

    Hepatitis B virus (HBV) is a major etiologic agent of hepatocellular carcinoma (HCC). However, the molecular mechanism by which HBV infection contributes to HCC development is not fully understood. Here, we initially showed that HBV stimulates the production of cancer stem cells (CSCs)-related markers (CD133, CD117 and CD90) and CSCs-related genes (Klf4, Sox2, Nanog, c-Myc and Oct4) and facilitates the self-renewal of CSCs in human hepatoma cells. Cellular and clinical studies revealed that HBV facilitates hepatoma cell growth and migration, enhances white blood cell (WBC) production in the sera of patients, stimulates CD133 and CD117 expression in HCC tissues, and promotes the CSCs generation of human hepatoma cells and clinical cancer tissues. Detailed studies revealed that PreS1 protein of HBV is required for HBV-mediated CSCs generation. PreS1 activates CD133, CD117 and CD90 expression in normal hepatocyte derived cell line (L02) and human hepatoma cell line (HepG2 and Huh-7); facilitates L02 cells migration, growth and sphere formation; and finally enhances the abilities of L02 cells and HepG2 cells to induce tumorigeneses in nude mice. Thus, PreS1 acts as a new oncoprotein to play a key role in the appearance and self-renewal of CSCs during HCC development. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Cancer and liver cirrhosis: implications on prognosis and management

    PubMed Central

    Pinter, Matthias; Trauner, Michael; Peck-Radosavljevic, Markus; Sieghart, Wolfgang

    2016-01-01

    Liver cirrhosis, the end-stage of every chronic liver disease, is not only the major risk factor for the development of hepatocellular carcinoma but also a limiting factor for anticancer therapy of liver and non-hepatic malignancies. Liver cirrhosis may limit surgical and interventional approaches to cancer treatment, influence pharmacokinetics of anticancer drugs, increase side effects of chemotherapy, render patients susceptible for hepatotoxicity, and ultimately result in a competitive risk for morbidity and mortality. In this review, we provide a concise overview about the impact of liver cirrhosis on the management and prognosis of patients with primary liver cancer or non-hepatic malignancies. PMID:27843598

  1. Liver transplantation for fibrolamellar hepatocellular carcinoma: A national perspective.

    PubMed

    Atienza, Leonardo Garcia; Berger, Jonathan; Mei, Xiaonan; Shah, Malay B; Daily, Michael F; Grigorian, Alla; Gedaly, Roberto

    2017-03-01

    Fibrolamellar Hepatocellular Carcinoma (FL-HCC) is a rare primary liver tumor that usually presents in younger patients without underlying liver disease. We queried the United Network of Organ Sharing (UNOS) database between October 1988 and January 2013 to evaluate outcomes in patients with FL-HCC undergoing liver transplantation in the United States compared to patients with conventional Hepatocellular Carcinoma (HCC). Sixty-three patients were identified (57% female, mean age 30 years). Only one patient (2%) had an associated Hepatitis C Virus. Mean Model for End-Stage Liver Disease (MELD) score at the time of transplantation was 11.3. Mean waiting time was 325 days and mean cold ischemic time was 6 hr. Overall survival of FL-HCC patients at 1, 3, and 5 years was 96%, 80%, and 48% as compared to HCC patients whose rates were 89%, 77%, and 68%. Six patients had tumor recurrence (10%). The Cox Model demonstrated that MELD and cold ischemic time are the strongest predictors of overall survival in FL-HCC patients. Age and wait time were not associated with poor patient survival in this series. Good results can be obtained in selected patients transplanted for FL-HCC. FL-HCC patients had similar survival compared to those transplanted for HCC. J. Surg. Oncol. 2017;115:319-323. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  2. National Cancer Centre Singapore Consensus Guidelines for Hepatocellular Carcinoma

    PubMed Central

    Chow, Pierce K. H.; Choo, Su Pin; Ng, David C. E.; Lo, Richard H. G.; Wang, Michael L. C.; Toh, Han Chong; Tai, David W. M.; Goh, Brian K. P.; Wong, Jen San; Tay, Kiang Hiong; Goh, Anthony S. W.; Yan, Sean X.; Loke, Kelvin S. H.; Thang, Sue Ping; Gogna, Apoorva; Too, Chow Wei; Irani, Farah Gillian; Leong, Sum; Lim, Kiat Hon; Thng, Choon Hua

    2016-01-01

    Hepatocellular carcinoma (HCC) is the 6th most common cancer in the world, but the second most common cause of cancer death. There is no universally accepted consensus practice guidelines for HCC owing to rapid developments in new treatment modalities, the heterogeneous epidemiology and clinical presentation of HCC worldwide. However, a number of regional and national guidelines currently exist which reflect practice relevant to the epidemiology and collective experience of the consensus group. In 2014, clinicians at the multidisciplinary Comprehensive Liver Cancer Clinic (CLCC) at the National Cancer Centre Singapore (NCCS) reviewed the latest published scientific data and existing international and regional practice guidelines, such as those of the National Comprehensive Cancer Network, American Association for the Study of Liver Diseases and the Asian Pacific Association for the Study of the Liver, and modified them to reflect local practice. These would serve as a template by which treatment outcomes can be collated and benchmarked against international data. The NCCS Consensus Guidelines for HCC have been successfully implemented in the CLCC since their publication online on 26th September 2014, and the guidelines allow outcomes of treatment to be compared to international data. These guidelines will be reviewed periodically to incorporate new data. PMID:27386428

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

    PubMed

    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(<30 days after liver 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.

  4. Immune-Mediated Therapies for Liver Cancer

    PubMed Central

    Aravalli, Rajagopal N.; Steer, Clifford J.

    2017-01-01

    In recent years, immunotherapy has gained renewed interest as an alternative therapeutic approach for solid tumors. Its premise is based on harnessing the power of the host immune system to destroy tumor cells. Development of immune-mediated therapies, such as vaccines, adoptive transfer of autologous immune cells, and stimulation of host immunity by targeting tumor-evasive mechanisms have advanced cancer immunotherapy. In addition, studies on innate immunity and mechanisms of immune evasion have enhanced our understanding on the immunology of liver cancer. Preclinical and clinical studies with immune-mediated therapies have shown potential benefits in patients with liver cancer. In this review, we summarize current knowledge and recent developments in tumor immunology by focusing on two main primary liver cancers: hepatocellular carcinoma and cholangiocarcinoma. PMID:28218682

  5. Screening for Viral Hepatitis and Hepatocellular Cancer.

    PubMed

    Cameron, Andrew M

    2015-10-01

    Accurate tests for at-risk populations are available for hepatitis B virus, hepatitis C virus (HCV), and hepatocellular carcinoma (HCC). Effective treatments for all three diseases exist if diagnosed early. New antivirals are making a significant impact on HCV. Liver transplant is curative for early HCC and is prioritized by the United Network for Organ Sharing in the United States. Screening and surveillance for deadly disease only makes sense if there are identifiable populations at risk for the condition, there are sensitive and specific low-cost tests available for the condition, and there are effective treatments for the condition. Copyright © 2015 Elsevier Inc. All rights reserved.

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

    NASA Astrophysics Data System (ADS)

    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.

  7. Healthcare Disparities in Asians and Pacific Islanders with hepatocellular cancer

    PubMed Central

    Wong, Linda L.; Hernandez, Brenda; Kwee, Sandi; Albright, Cheryl L.; Okimoto, Gordon; Tsai, Naoky

    2012-01-01

    Background Hawaii has the highest incidence of hepatocellular cancer (HCC) in the U.S. and the largest proportion of Asian/Pacific Islanders(PI). HCC studies generally combine these groups into one ethnicity and we sought to examine differences between Asian/PI subpopulations. Methods Demographic, clinical, and treatment data for 617 HCC cases ( 420 Asian, 114 white, and 83 PI patients) were reviewed. Main outcome measures included HCC screening and liver transplant. Results Asian/PI subgroups had significantly more immigrants and age was different between groups. Compared to Whites, the PI and Filipinos had less HCC screening and liver transplants, fewer met Milan criteria and a smaller proportion of those with Milan criteria actually underwent transplant. Conclusion There were significant differences in risk factors, clinical presentation, treatment and access to care between Asian, PI and White patients with HCC. Future HCC studies may benefit from differentiating subgroups within Asian/PI populations to better focus these efforts. PMID:22227170

  8. Liver precancerous lesions and hepatocellular carcinoma: the histology report.

    PubMed

    Roncalli, Massimo; Terracciano, Luigi; Di Tommaso, Luca; David, Ezio; Colombo, Massimo

    2011-03-01

    The current ability to increase the survival of patients with hepatocellular carcinoma (HCC) relies upon the surveillance of cirrhotic patients. Surveillance allows HCC precursors (dysplastic nodules) and malignant tumors to be recognized at an earlier stage making cure possible. Radiology plays a major role in HCC diagnosis because HCC is characterized by neoarterial vascularisation with a typical imaging pattern. Current international guidelines have restricted the use of the liver biopsy to the characterization of hepatocellular nodules which remain diagnostically equivocal after imaging. Thus pathologists are today facing very challenging and often well differentiated lesions, leading to difficulties in distinguishing high grade dysplasia and well differentiated HCC. In this scenario novel concepts obtained through international consensus have been proposed with emphasis on HCC of small size (up to 2 cm) which includes 2 distinct types, the early and progressed HCC. In this paper we will report the main histopathological criteria of a biopsy which allow the differentiation of HCC precursors (dysplastic nodules) from well differentiated HCC with attention to the role and weight of both classical histopathological criteria and novel immunocytochemical markers. The second part of the paper is devoted to the histopathology report of HCC on surgical specimens including explanted livers and on the differential diagnosis between HCC and liver metastasis.

  9. Developments in cancer vaccines for hepatocellular carcinoma.

    PubMed

    Buonaguro, Luigi

    2016-01-01

    Hepatocellular carcinoma (HCC) accounts for about 6 % of all new cancers diagnosed worldwide and represents one of the leading causes of cancer-related death globally in men and women, respectively. The overall prognosis for HCC patients is poor, especially in the majority of patients with more advanced stage of disease. Indeed, in such cases immunotherapeutic strategies may represent a novel and effective tool. A few immunotherapy trials conducted for HCC have provided divergent results, urging the scientific community to explore additional paths to improve efficacy of immunotherapeutic approaches. The "Cancer Vaccine development for Hepatocellular Carcinoma"-HEPAVAC Consortium has been funded by the EU within the FP7 with the goal of developing a novel therapeutic peptide-based cancer vaccine strategy for HCC including both "off-the-shelf" and personalized antigens. This will be one of the very few vaccine trials for HCC and the first multi-epitope, multi-target and multi-HLA allele therapeutic cancer vaccine for such a frequent and aggressive disease with a hitherto high unmet medical need. Feasibility, safety and biological efficacy will be evaluated in a randomized, controlled European multicenter phase I/II clinical trial.

  10. Global Gene Profiling of Spontaneous Hepatocellular Carcinoma in B6C3F1 Mice: Similarities in the Molecular Landscape with Human Liver Cancer

    PubMed Central

    Hoenerhoff, Mark J.; Pandiri, Arun R.; Lahousse, Stephanie A.; Hong, Hu-Hua; Ton, Tai-Vu; Masinde, Tiwanda; Auerbach, Scott S.; Gerrish, Kevin; Bushel, Pierre R.; Shockley, Keith R.; Peddada, Shyamal D.; Sills, Robert C.

    2016-01-01

    Hepatocellular carcinoma (HCC) is an important cause of morbidity and mortality worldwide. Although the risk factors of human HCC are well known, the molecular pathogenesis of this disease is complex, and in general, treatment options remain poor. The use of rodent models to study human cancer has been extensively pursued, both through genetically engineered rodents and rodent models used in carcinogenicity and toxicology studies. In particular, the B6C3F1 mouse used in the National Toxicology Program (NTP) two-year bioassay has been used to evaluate the carcinogenic effects of environmental and occupational chemicals, and other compounds. The high incidence of spontaneous HCC in the B6C3F1 mouse has challenged its use as a model for chemically induced HCC in terms of relevance to the human disease. Using global gene expression profiling, we identify the dysregulation of several mediators similarly altered in human HCC, including re-expression of fetal oncogenes, upregulation of protooncogenes, downregulation of tumor suppressor genes, and abnormal expression of cell cycle mediators, growth factors, apoptosis regulators, and angiogenesis and extracellular matrix remodeling factors. Although major differences in etiology and pathogenesis remain between human and mouse HCC, there are important similarities in global gene expression and molecular pathways dysregulated in mouse and human HCC. These data provide further support for the use of this model in hazard identification of compounds with potential human carcinogenicity risk, and may help in better understanding the mechanisms of tumorigenesis resulting from chemical exposure in the NTP two-year carcinogenicity bioassay. PMID:21571946

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

    PubMed Central

    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

  12. Early steroid withdrawal after liver transplantation for hepatocellular carcinoma

    PubMed Central

    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

  13. Microenvironment of liver regeneration in liver cancer.

    PubMed

    Li, Han-Min; Ye, Zhi-Hua

    2017-07-01

    The occurrence and development of liver cancer are essentially the most serious outcomes of uncontrolled liver regeneration. The progression of liver cancer is inevitably related to the abnormal microenvironment of liver regeneration. The deterioration observed in the microenvironment of liver regeneration is a necessary condition for the occurrence, development and metastasis of cancer. Therefore, the use of a technique to prevent and treat liver cancer via changes in the microenvironment of liver regeneration is a novel strategy. This strategy would be an effective way to delay, prevent or even reverse cancer occurrence, development and metastasis through an improvement in the liver regeneration microenvironment along with the integrated regulation of multiple components, targets, levels, channels and time sequences. In addition, the treatment of "tonifying Shen (Kidney) to regulate liver regeneration and repair by affecting stem cells and their microenvironment" can regulate "the dynamic imbalance between the normal liver regeneration and the abnormal liver regeneration"; this would improve the microenvironment of liver regeneration, which is also a mechanism by which liver cancer may be prevented or treated.

  14. Lipid Biomarkers Identified for Liver Cancer | Center for Cancer Research

    Cancer.gov

    Hepatocellular carcinoma (HCC) is an aggressive cancer of the liver with poor prognosis and growing incidence in developed countries. Pathology and genetic profiles of HCC are heterogeneous, suggesting that it can begin growing in different cell types. Although human tumors such as HCC have been profiled in-depth by genomics-based studies, not much is known about their overall metabolite modifications and how these changes can form a network that leads to aggressive disease and poor outcome.

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

    PubMed

    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.

  16. Heterogeneity of liver cancer and personalized therapy.

    PubMed

    Li, Liang; Wang, Hongyang

    2016-09-01

    Liver cancer is an extraordinarily heterogeneous malignant disease among the tumors that have so far been identified. Hepatocellular carcinoma (HCC) arises most frequently in the setting of chronic liver inflammation and fibrosis, and takes a variety of course in individual patients to process to tumor. The risk factors such as HBV and/or HCV infections, aflatoxin infection, abuse alcohol intake, metabolic syndrome, obesity and diabetes are closely related to the environmental and genetic susceptibilities to HCC. The consequent resulting genomic instability, molecular and signal transduction network disorders and microenvironmental discrepancies are characterized by the extraordinary heterogeneity of liver cancer. The histology-based definition of the morphological heterogeneity of liver cancer has been modified and refined to treat patients with targeted therapies, but this still cannot solve all the problems. Lack of consistent outcome for anticancer agents and conventional therapies in liver cancer treatment calls for assessing the benefits of new molecularly targeted drugs and combined therapy, under the heterogeneity condition of tumor. The present review article will provide the complex mechanism and phenotype of liver cancer heterogeneity, and help us to execute precision medicine in a really personalized manner.

  17. Inhibition of heat-shock protein 90 sensitizes liver cancer stem-like cells to magnetic hyperthermia and enhances anti-tumor effect on hepatocellular carcinoma-burdened nude mice

    PubMed Central

    Yang, Rui; Tang, Qiusha; Miao, Fengqin; An, Yanli; Li, Mengfei; Han, Yong; Wang, Xihui; Wang, Juan; Liu, Peidang; Chen, Rong

    2015-01-01

    Purpose To explore the thermoresistance and expression of heat-shock protein 90 (HSP90) in magnetic hyperthermia-treated human liver cancer stem-like cells (LCSCs) and the effects of a heat-shock protein HSP90 inhibitor 17-allylamino-17-demethoxgeldanamycin (17-AAG) on hepatocellular carcinoma-burdened nude mice. Methods CD90+ LCSCs were isolated by magnetic-activated cell sorting from BEL-7404. Spheroid formation, proliferation, differentiation, drug resistance, and tumor formation assays were performed to identify stem cell characteristics. CD90-targeted thermosensitive magnetoliposomes (TMs)-encapsulated 17-AAG (CD90@17-AAG/TMs) was prepared by reverse-phase evaporation and its characteristics were studied. Heat tolerance in CD90+ LCSCs and the effect of CD90@17-AAG/TMs-mediated heat sensitivity were examined in vitro and in vivo. Results CD90+ LCSCs showed significant stem cell-like properties. The 17-AAG/TMs were successfully prepared and were spherical in shape with an average size of 128.9±7.7 nm. When exposed to magnetic hyperthermia, HSP90 was up-regulated in CD90+ LCSCs. CD90@17-AAG/TMs inhibited the activity of HSP90 and increased the sensitivity of CD90+ LCSCs to magnetic hyperthermia. Conclusion The inhibition of HSP90 could sensitize CD90+ LCSCs to magnetic hyperthermia and enhance its anti-tumor effects in vitro and in vivo. PMID:26677324

  18. Atypical Hepatocellular Neoplasm With Peliosis in Cirrhotic Liver Versus Hepatocellular Carcinoma

    PubMed Central

    Gurzu, Simona; Jung, Ioan; Contac, Anca Otilia; Turcu, Mihai; Tudor, Adrian

    2015-01-01

    Abstract Atypical hepatocellular neoplasm (AHN) is an adenoma-like hepatic tumor that even occurs in noncirrhotic liver of males (any age) or females ≥50 years old, or associates focal atypical features. In this article, 2 unusual cases diagnosed in elderly cirrhotic patients, unrelated to steroids, are presented. The first case was incidentally diagnosed in an 83-year-old female. During laparoscopic surgery for cholecystectomy, hemoperitoneum was installed and laparotomy was necessary to remove a 70-mm nodular encapsulated hepatic tumor that was microscopically composed by hepatocyte-like cells with clear cytoplasm, arranged in 1- to 2-cell-thick plates and intermingled with areas of peliosis, negative for alpha fetoprotein (αFP), p53, and keratin 7, with low Ki67 index and intact reticulin framework. The second case was incidentally diagnosed at ultrasound examination in a 66-year-old male. The surgical specimen was a 50-mm solid multinodular tumor that microscopically consisted of 3-cell-thick plates of hepatocyte-like cells with acinar, pseudoglandular, and trabecular architecture, intermingled with peliotic areas, without nuclear atypia and disintegrated reticulin framework. Both of the cases occurred in cirrhotic liver. The tumor cells were marked by AE1/AE3 keratin, displayed a Ki67 index < 5% and were negative for αFP, p53, and keratin 7. No recurrences or any other disorder occurred 6 months after surgery. In cirrhotic liver, adenomas with peliosis that do not satisfy all the diagnosis criteria synthesized in the article should be considered AHNs and differential diagnosis includes hepatocellular carcinoma but also focal nodular hyperplasia, regenerative nodules, and dysplastic nodules. This histological entity is not yet included in the WHO Classification list. PMID:26200629

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

    PubMed Central

    Afonso, Marta B.; Rodrigues, Pedro M.; Simão, André L.; Castro, Rui E.

    2016-01-01

    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. PMID:26950158

  20. Outcomes utilizing imported liver grafts for recipients with hepatocellular carcinoma.

    PubMed

    Battula, Narendra; Reichman, Trevor W; Amiri, Yamah; Carmody, Ian C; Galliano, Gretchen; Seal, John; Bugeaud, Emily; Bohorquez, Humberto; Bruce, David; Cohen, Ari; Loss, George E

    2017-03-01

    Liver transplantation (LT) offers the best chance of survival in selected patients with hepatocellular carcinoma (HCC). Wait-list mortality or dropout due to tumor progression can be significant, and therefore, timely transplantation is critical. Liver grafts discarded by outside organ procurement organizations are a potential source of grafts for low Model for End-Stage Liver Disease tumor patients. The primary aim of this study was to assess the disease-free and overall survival of patients with HCC transplanted with imported liver grafts (ILGs). Review of all patients transplanted for HCC between June 2005 and December 2014 was performed. Data on demographics, survival, and HCC recurrence were analyzed. During this time period, 59 out of 190 (31%) recipients with HCC received ILG. Of these 59 grafts, 54 were imported from within the region and 5 were from national offers (outside the region). The mean cold ischemia time for local liver grafts (LLGs) was 4.1 ± 1.5 hours versus 5.1 ± 1.4 hours for ILG (P < 0.001). The 1-, 3-, and 5-year patient survival was 90%, 85%, and 83% and 85%, 80%, and 79% for LLG and ILG (P = 0.08), respectively. The observed disease recurrence rate for both LLG and ILG recipients was equivalent. The median wait-list time for HCC recipients was 43 days (range, 2-1167 days). In conclusion, with careful graft assessment, the use of ILGs results in comparable outcomes following LT and no increased risk of HCC recurrence. Use of ILGs maximizes the donor pool and results in a higher rate of transplantation for HCC recipients. Liver Transplantation 23 299-304 2017 AASLD.

  1. Novel Antibody Targets Glypican-3 in Liver Cancer | Center for Cancer Research

    Cancer.gov

    New treatments for patients with liver cancer, the third most common cause of cancer-related death, are desperately needed. Hepatocellular carcinoma (HCC) is the most common type of liver cancer, and HCC tumors are particularly insensitive to chemotherapy. Surgery is the standard treatment for HCCs caught early, but only about a third of cases are identified at this stage. Antibody therapy offers a potential alternative for treating later-stage tumors.

  2. Living donor liver transplantation with abdominal wall reconstruction for hepatocellular carcinoma with needle track seeding

    PubMed Central

    Yang, Horng-Ren; Thorat, Ashok; Gesakis, Kanellos; Li, Ping-Chun; Kiranantawat, Kidakorn; Chen, Hung Chi; Jeng, Long-Bin

    2015-01-01

    Malignant cell seeding in subcutaneous tissues along the needle track and/or percutaneous biliary drainage catheters is rare complication, but pose various technical issues in planning surgical treatment of such patients. If underlying primary hepatic malignancy can be treated, an aggressive resection of subcutaneous tissue bearing cancer cell with subsequent abdominal wall reconstruction has been sporadically reported. But, when hepatic resection is not possible due to underlying advanced cirrhosis, liver transplantation along with abdominal wall resection and subsequent reconstruction remains only feasible option. Herein, we describe our successful experience of living donor liver transplantation for hepatocellular carcinoma with full-thickness abdominal wall resection bearing the tumor seeding followed by reconstruction in single stage surgery. PMID:26722665

  3. Laparoscopic liver resection for hepatocellular carcinoma: korean experiences.

    PubMed

    Han, Ho-Seong; Yoon, Yoo-Seok; Cho, Jai Young; Hwang, Dae Wook

    2013-01-01

    The development of laparoscopic liver resection (LLR) has been slow due to technical difficulties. Therefore, LLR has been limited to easily accessible lesions. Recently, this procedure has been well applied to hepatocellular carcinoma. However, until now, the indications for LLR have been tumors in the peripheral portion of the anterolateral segments of the liver (segments II, III, V and VI and the inferior part of IV according to the classification of Couinaud). Due to the growing interest in LLR, there have been many attempts to apply this technique in difficult locations. The lesions in the posterior or superior part of the liver (segments I, VII, VIII and the superior part of IV), which are considered to be poor indications for LLR, have been reported to be successfully operated on by laparoscopic surgery. Accordingly, this laparoscopic approach has become similar to open surgery in many ways. One of the major advancements of LLR is anatomic liver resection including major and minor resection. Laparoscopic mono- and bisegmentectomies have also become possible with growing experience. There are a variety of monosegmentectomies and bisegmentectomies. The common representatives of bisegmentectomies are left lateral sectionectomy, right anterior sectionectomy and right posterior sectionectomy. The common operative types of monosegmentectomies are S4, S5, and S6 monosegmentectomies, etc. Central bi-sectionectomy will also be discussed. The Glissonian approach has been useful for these types of anatomic liver resection. The difficulty of controlling hemorrhage has been overcome by performing meticulous surgical techniques with newly developed instruments, and intraoperative sonography has been used to locate the lesions and guide the resection plane even for deep-seated or invisible lesions. Further accumulation of experience and technical refinements will make theses challenging procedures more reproducible and safer.

  4. Proteoglycans in liver cancer

    PubMed Central

    Baghy, Kornélia; Tátrai, Péter; Regős, Eszter; Kovalszky, Ilona

    2016-01-01

    Proteoglycans are a group of molecules that contain at least one glycosaminoglycan chain, such as a heparan, dermatan, chondroitin, or keratan sulfate, covalently attached to the protein core. These molecules are categorized based on their structure, localization, and function, and can be found in the extracellular matrix, on the cell surface, and in the cytoplasm. Cell-surface heparan sulfate proteoglycans, such as syndecans, are the primary type present in healthy liver tissue. However, deterioration of the liver results in overproduction of other proteoglycan types. The purpose of this article is to provide a current summary of the most relevant data implicating proteoglycans in the development and progression of human and experimental liver cancer. A review of our work and other studies in the literature indicate that deterioration of liver function is accompanied by an increase in the amount of chondroitin sulfate proteoglycans. The alteration of proteoglycan composition interferes with the physiologic function of the liver on several levels. This article details and discusses the roles of syndecan-1, glypicans, agrin, perlecan, collagen XVIII/endostatin, endocan, serglycin, decorin, biglycan, asporin, fibromodulin, lumican, and versican in liver function. Specifically, glypicans, agrin, and versican play significant roles in the development of liver cancer. Conversely, the presence of decorin could potentially provide protective effects. PMID:26755884

  5. MRI With Gadoxetate Disodium in Measuring Tumors in Patients With Liver Cancer

    ClinicalTrials.gov

    2015-10-14

    Adult Hepatocellular Carcinoma; Advanced Adult Hepatocellular Carcinoma; BCLC Stage 0 Adult Hepatocellular Carcinoma; BCLC Stage A Adult Hepatocellular Carcinoma; BCLC Stage B Adult Hepatocellular Carcinoma; BCLC Stage C Adult Hepatocellular Carcinoma; BCLC Stage D Adult Hepatocellular Carcinoma; Localized Non-Resectable Adult Liver Carcinoma; Localized Resectable Adult Liver Carcinoma

  6. Liver scan

    MedlinePlus

    ... cirrhosis or hepatitis ) Superior vena cava obstruction Splenic infarction (tissue death) Tumors Risks Radiation from any scan ... Hepatitis Liver cancer - hepatocellular carcinoma Liver disease Splenic infarction SVC obstruction Review Date 1/18/2015 Updated ...

  7. The status of zinc in the development of hepatocellular cancer

    PubMed Central

    Costello, Leslie C; Franklin, Renty B

    2014-01-01

    Liver cancer (hepatocellular carcinoma, HCC) is increasing worldwide. About 75% of HCC cases result in death generally within one year. The factors responsible for the initiation and progression of HCC remain largely unknown and speculative, thereby impeding advancements in the development of effective therapeutic agents and biomarkers for early detection of HCC. A consistent marked decrease in zinc in HCC tumors compared with normal liver is an established clinical relationship, which occurs in virtually all cases of HCC. However, this relationship has been largely ignored by the contemporary clinical and research community. Consequently, the factors and mechanisms involved in this relationship have not been addressed. Thus, the opportunity and potential for its employment as biomarkers for early identification of malignancy, and for development of a chemotherapeutic approach have been lacking. This presentation includes a review of the literature and the description of important recent and new data, which provide the basis for a concept of the role of zinc in the development of HCC. The basis is presented for characterizing HCC malignancy as ZIP14-deficient tumors, and its requirement to prevent zinc cytotoxic effects on the malignant cells. The potential for an efficacious zinc treatment approach for HCC is described. The involvement of zinc in the predisposition for HCC by chronic liver disease/cirrhosis is presented. Hopefully, this presentation will raise the awareness, interest, and support for the much needed research in the implications of zinc in the development and progression of HCC. PMID:24448510

  8. Molecular profiles suggest two types of liver cancer should be treated as one | Center for Cancer Research

    Cancer.gov

    A comprehensive molecular analysis of two types of liver cancer, hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), has identified common molecular subtypes that can be found among patients with either disease. Although HCC and ICC are considered separate diseases, the finding suggests that a unified clinical approach could benefit patients with both types of liver cancer.  Read more...

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

    SciTech Connect

    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%.

  10. Giant ectopic liver, hepatocellular carcinoma and pachydermia-a rare genetic syndrome?

    PubMed

    Dettmer, Matthias; Itin, Peter; Miny, Peter; Gandhi, Manoj; Cathomas, Gieri; Willi, Niels

    2011-08-10

    Ectopic liver is a very uncommon developmental anomaly that predisposes to the development of hepatocellular carcinoma. We describe the second documented case of a hepatocellular carcinoma developing in the primary liver of a patient with a rare and uncharacterized genetic symptom complex. Also present was the largest ectopic liver ever reported, measuring 12 cm in diameter which contained a solitary focus of metastatic hepatocellular carcinoma. The primary hepatocellular carcinoma is believed to have arisen in the native liver from a hepatic adenoma that was diagnosed 15 years earlier. The patient's uncharacterised condition featured prominent thick, yellow skin over the dorsum of the fingers, and was associated with follicular hyperkeratosis, abnormal plantar creases, digital clubbing, misshaped ears, a lingua plicata and an angioleiomyolipoma of the right kidney. This unique case of hepatocellular carcinoma arising from liver cell adenoma in a patient with an uncharacterised condition featuring a large ectopic liver invites discussion of the role of local factors in carcinogenesis in the parent liver but not the ectopic liver. It also underlines the imperative ongoing need for clinical autopsies.

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

    PubMed

    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

  12. Different survival of Barcelona clinic liver cancer stage C hepatocellular carcinoma patients by the extent of portal vein invasion and the type of extrahepatic spread.

    PubMed

    Sinn, Dong Hyun; Cho, Ju-Yeon; Gwak, Geum-Youn; Paik, Yong-Han; Choi, Moon Seok; Lee, Joon Hyeok; Koh, Kwang Cheol; Paik, Seung Woon; Yoo, Byung Chul

    2015-01-01

    Portal vein invasion (PVI) and extrahepatic spread (ES) are two tumor-related factors that define advanced stage in the Barcelona Clinic Liver Cancer (BCLC) staging system (BCLC stage C), and the recommended first line therapy in this stage is sorafenib. However, the extent of PVI and the type of ES may affect patient prognosis as well as treatment outcome. This study analyzed survival of BCLC stage C HCC patients in order to see whether sub-classification of BCLC stage C is necessary. A total of 582 treatment naïve, BCLC stage C HCC patients [age: 54.3 ± 10.8 years, males = 494 (84.9%), hepatitis B virus (458, 78.7%)], defined by PVI and/or ES, were analyzed. Extent of PVI was divided into none, type I-segmental/sectoral branches, type II-left and/or right portal vein, and type III-main portal vein trunk. Type of ES was divided into nodal and distant metastasis. The extent of PVI and type of ES were independent factors for survival. When patients were sub-classified according to the extent of PVI and type of ES, the median survival was significantly different [11.7 months, 5.7 months, 4.9 months and 2.3 months for C1 (PVI-O/I without distant ES), C2 (PVI-II/III without distant ES), C3 (PVI-0/I with distant ES), and C4 (PVI-II/III with distant ES), respectively, P = 0.01]. Patients' survival was different according to the treatment modality in each sub-stage. Sub-classification of BCLC stage C according to the extent of PVI and type of ES resulted in a better prediction of survival. Also, different outcome was observed by treatment modalities in each sub-stage. Sub-classification of BCLC stage C is required to minimize heterogeneity within the same tumor stage, that will help better predict survival and to select optimal treatment strategies.

  13. Different Survival of Barcelona Clinic Liver Cancer Stage C Hepatocellular Carcinoma Patients by the Extent of Portal Vein Invasion and the Type of Extrahepatic Spread

    PubMed Central

    Gwak, Geum-Youn; Paik, Yong-Han; Choi, Moon Seok; Lee, Joon Hyeok; Koh, Kwang Cheol; Paik, Seung Woon; Yoo, Byung Chul

    2015-01-01

    Portal vein invasion (PVI) and extrahepatic spread (ES) are two tumor-related factors that define advanced stage in the Barcelona Clinic Liver Cancer (BCLC) staging system (BCLC stage C), and the recommended first line therapy in this stage is sorafenib. However, the extent of PVI and the type of ES may affect patient prognosis as well as treatment outcome. This study analyzed survival of BCLC stage C HCC patients in order to see whether sub-classification of BCLC stage C is necessary. A total of 582 treatment naïve, BCLC stage C HCC patients [age: 54.3 ± 10.8 years, males = 494 (84.9%), hepatitis B virus (458, 78.7%)], defined by PVI and/or ES, were analyzed. Extent of PVI was divided into none, type I-segmental/sectoral branches, type II-left and/or right portal vein, and type III-main portal vein trunk. Type of ES was divided into nodal and distant metastasis. The extent of PVI and type of ES were independent factors for survival. When patients were sub-classified according to the extent of PVI and type of ES, the median survival was significantly different [11.7 months, 5.7 months, 4.9 months and 2.3 months for C1 (PVI-O/I without distant ES), C2 (PVI-II/III without distant ES), C3 (PVI-0/I with distant ES), and C4 (PVI-II/III with distant ES), respectively, P = 0.01]. Patients’ survival was different according to the treatment modality in each sub-stage. Sub-classification of BCLC stage C according to the extent of PVI and type of ES resulted in a better prediction of survival. Also, different outcome was observed by treatment modalities in each sub-stage. Sub-classification of BCLC stage C is required to minimize heterogeneity within the same tumor stage, that will help better predict survival and to select optimal treatment strategies. PMID:25923439

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

    PubMed

    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 p<0.0001). No significant impact was observed for leptin on HCC survival regardless of liver transplantation status. Higher levels of plasma adiponectin may predict poor HCC survival among patients without liver transplantation. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  15. Cancer Stem Cells in Primary Liver Cancers: Pathological Concepts and Imaging Findings

    PubMed Central

    Joo, Ijin; Kim, Haeryoung

    2015-01-01

    There is accumulating evidence that cancer stem cells (CSCs) play an integral role in the initiation of hepatocarcinogenesis and the maintaining of tumor growth. Liver CSCs derived from hepatic stem/progenitor cells have the potential to differentiate into either hepatocytes or cholangiocytes. Primary liver cancers originating from CSCs constitute a heterogeneous histopathologic spectrum, including hepatocellular carcinoma, combined hepatocellular-cholangiocarcinoma, and intrahepatic cholangiocarcinoma with various radiologic manifestations. In this article, we reviewed the recent concepts of CSCs in the development of primary liver cancers, focusing on their pathological and radiological findings. Awareness of the pathological concepts and imaging findings of primary liver cancers with features of CSCs is critical for accurate diagnosis, prediction of outcome, and appropriate treatment options for patients. PMID:25598674

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

    PubMed Central

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

    PubMed Central

    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 < 0.001, sensitivity: 96.0%, specificity: 96.5%). BIRC5 (P = 0.021) and CCNE1 (P = 0.027) were associated with poor prognosis, while CDKN2A (P = 0.066) and E2F1 (P = 0.088) demonstrated no statistically significant differences. Discussion The study illustrates liver hepatocellular carcinoma gene signatures, related pathways and networks from the perspective of 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

  18. Hepatocellular carcinoma.

    PubMed

    Macdonald, G A

    1999-05-01

    Hepatitis C infection is associated with the development of hepatocellular carcinoma, and progress has been made in a number of areas. Transgenic mice lines expressing the hepatitis C core protein develop hepatic steatosis, adenomas, and hepatocellular carcinomas, with no significant hepatitis or fibrosis. This implies that hepatitis C can lead directly to malignant transformation. A new lesion, irregular regeneration, has been described in chronic hepatitis C infection and is associated with a 15-fold increase in the relative risk of developing hepatocellular carcinoma. A minority of patients with hepatitis C-related hepatocellular carcinoma have intense lymphocytic infiltration of the cancer, a feature associated with a better prognosis. Several studies have confirmed the association between large cell dysplasia and hepatocellular carcinoma. However, large cell dysplasia may not be a premalignant lesion and instead may be a marker for premalignant alterations elsewhere in the liver. Oral contraceptives previously have been linked to an increased risk of hepatocellular carcinoma. A large multicenter European case-control study has shown minimal increased risk of hepatocellular carcinoma with use of steroidal contraception. Tamoxifen had shown promise in the management of advanced hepatocellular carcinoma. However, a randomized placebo-controlled study of 477 patients with hepatocellular carcinoma found no benefit from tamoxifen. In a preliminary study, however, octreotide has shown improved survival and quality of life in patients with advanced hepatocellular carcinoma. Finally, interferon treatment continues to be linked to a reduced risk of hepatocellular carcinoma in patients with hepatitis C. These studies generally are not randomized, and a randomized prospective study is required to address this issue.

  19. Analysis of Genomes and Transcriptomes of Hepatocellular Carcinomas Identifies Mutations and Gene Expression Changes in the Transforming Growth Factor beta Pathway Short title: Prognostic significance of TGF-β signature in liver cancer.

    PubMed

    Chen, Jian; Zaidi, Sobia; Rao, Shuyun; Chen, Jiun-Sheng; Phan, Liem; Farci, Patrizia; Su, Xiaoping; Shetty, Kirti; White, Jon; Zamboni, Fausto; Wu, Xifeng; Rashid, Asif; Pattabiraman, Nagarajan; Mazumder, Raja; Horvath, Anelia; Wu, Ray-Chang; Li, Shulin; Xiao, Cuiying; Deng, Chu-Xia; Wheeler, David A; Mishra, Bibhuti; Akbani, Rehan; Mishra, Lopa

    2017-09-14

    Development of hepatocellular carcinoma (HCC) is associated with alterations in the transforming growth factor beta (TGFβ) signaling pathway, which regulates liver inflammation and can have tumor suppressor or promoter activities. Little is known about the roles of specific members of this pathway at specific of HCC development. We took an integrated approach to identify and validate the effects of changes in this pathway in HCC and identify therapeutic targets. We performed transcriptome analyses for a total of 488 HCCs that include data from The Cancer Genome Atlas. We also screened 301 HCCs reported in the Catalogue of Somatic Mutations in Cancer and 202 from Cancer Genome Atlas for mutations in genome sequences. We expressed mutant forms of spectrin beta, non-erythrocytic 1 (SPTBN1) in HepG2, SNU398, and SNU475 cells and measured phosphorylation, nuclear translocation, and transcriptional activity of SMAD family member 3 (SMAD3). We found somatic mutations in at least 1 gene whose product is a member of TGFβ signaling pathway in 38% of HCC samples. SPTBN1 was mutated in the largest proportion of samples (12/202, 6%). Unsupervised clustering of transcriptome data identified a group of HCCs with activation of the TGFβ signaling pathway (increased transcription of genes in the pathway) and a group of HCCs with inactivation of TGFβ signaling (reduced expression of genes in this pathway). Patients with tumors with inactivation of TGFβ signaling had shorter survival times than patients with tumors with activation of TGFβ signaling (P=.0129). Patterns of TGFβ signaling correlated with activation of the DNA damage response and sirtuin signaling pathways. HepG2, SNU398, SNU475 cells that expressed the D1089Y mutant or with knockdown of SPTBN1 had increased sensitivity to DNA crosslinking agents and reduced survival compared to cells that expressed normal SPTBN1 (controls). In genome and transcriptome analyses of HCC samples, we found mutations in genes in the

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

    PubMed Central

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

    2016-01-01

    Background For recipients of liver transplants for hepatocellular carcinoma (HCC), HCC recurrence after transplantation remains a major concern. Sirolimus, an immunosuppressant with anti-carcinogenic properties, may reduce HCC recurrence and improve survival. Methods The U.S. 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 sirolimus 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 IL-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. Results Among the 3,936 included HCC liver transplants, 234 (6%) were sirolimus users. In total, there were 242 recurrences and 879 deaths, including 261 cancer-related deaths. All-cause mortality was similar in sirolimus users and non-users (adjusted hazard ratio [HR] =1.01, 95%CI=0.73–1.39). HCC recurrence and cancer-specific mortality rates appeared lower in sirolimus users, but associations were not statistically significant (recurrence HR=0.86, 95%CI=0.45–1.65; cancer-specific mortality HR=0.80, 95%CI=0.43–1.50). Among recipients >55 years old, associations were suggestive of better outcomes for sirolimus users (all-cause mortality HR=0.62, 95%CI=0.38–1.01; recurrence HR=0.52, 95%CI=0.19–1.44; cancer-specific mortality HR=0.34, 95%CI=0.11–1.09), while among recipients ≤55 years old, sirolimus users had worse outcomes (all-cause mortality HR=1.76, 95%CI=1.12–2.75; recurrence HR=1.49, 95%CI=0.62–3.61; cancer-specific mortality HR=1.54, 95%CI=0.71–3.32). Conclusions Among HCC liver recipients overall

  1. Drugs Approved for Liver Cancer

    Cancer.gov

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for liver cancer. The list includes generic names and brand names. The drug names link to NCI’s Cancer Drug Information summaries.

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

    PubMed

    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.

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

    PubMed Central

    Byrne, Thomas J; Rakela, Jorge

    2016-01-01

    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. PMID:27358775

  4. Living donor liver transplantation for hepatocellular carcinoma achieves better outcomes

    PubMed Central

    Lin, Chih-Che

    2016-01-01

    Liver transplantation (LT) for hepatocellular carcinoma (HCC) at Kaohsiung Chang Gung Memorial Hospital mainly relies on live donor LT (LDLT). Owing to taking the risk of LD, we are obligated to adopt strict selection criteria for HCC patients and optimize the pre-transplant conditions to ensure a high disease-free survival similar to those without HCC, even better than deceased donor LT (DDLT). Better outcomes are attributed to excellent surgical results and optimal patient selection. The hospital mortality of primary and salvage LDLT are lower than 2% in our center. Although Taiwan Health Insurance Policy extended the Milan to University of California, San Francisco (UCSF) criteria in 2006, selection criteria will not be consolidated to take into account only by the morphologic size/number of tumors but also by their biology. The criteria are divided into modifiable image morphology, alpha fetoprotein (AFP), and positron emission tomography (PET) scan with standard uptake value (SUV) and unmodifiable unfavorable pathology such as HCC combined with cholangiocarcinoma (CC), sarcomatoid type, and poor differentiation. Downstaging therapy is necessary for HCC patients beyond criteria to fit all modifiable standards. The upper limit of downstaging treatment seems to be extended by more effective drug eluting transarterial chemoembolization in cases without absolute contraindications. In contrast, the pitfall of unmodifiable tumor pathology should be excluded by the findings of pretransplant core biopsy/resection if possible. More recently, achieving complete tumor necrosis in explanted liver could almost predict no recurrence after transplant. Necrotizing therapy is advised if possible before transplant even the tumor status within criteria to minimize the possibility of tumor recurrence. LDLT with low surgical mortality in experienced centers provides the opportunities of optimizing the pre-transplant tumor conditions and timing of transplant to achieve better

  5. Establishment of Hepatocellular Cancer Induced Pluripotent Stem Cells Using a Reprogramming Technique

    PubMed Central

    Kim, Han Joon; Jeong, Jaemin; Park, Sunhoo; Jin, Young-Woo; Lee, Seung-Sook; Lee, Seung Bum; Choi, Dongho

    2017-01-01

    Background/Aims Cancer is known to be a disease by many factors. However, specific results of reprogramming by pluripotency-related transcription factors remain to be scarcely reported. Here, we verified potential effects of pluripotent-related genes in hepatocellular carcinoma cancer cells. Methods To better understand reprogramming of cancer cells in different genetic backgrounds, we used four liver cancer cell lines representing different states of p53 (HepG2, Hep3B, Huh7 and PLC). Retroviral-mediated introduction of reprogramming related genes (KLF4, Oct4, Sox2, and Myc) was used to induce the expression of proteins related to a pluripotent status in liver cancer cells. Results Hep3B cells (null p53) exhibited a higher efficiency of reprogramming in comparison to the other liver cancer cell lines. The reprogrammed Hep3B cells acquired similar characteristics to pluripotent stem cells. However, loss of stemness in Hep3B-iPCs was detected during continual passage. Conclusions We demonstrated that reprogramming was achieved in tumor cells through retroviral induction of genes associated with reprogramming. Interestingly, the reprogrammed pluripotent cancer cells (iPCs) were very different from original cancer cells in terms of colony shape and expressed markers. The induction of pluripotency of liver cancer cells correlated with the status of p53, suggesting that different expression level of p53 in cancer cells may affect their reprogramming. PMID:27728962

  6. Dietary effects on liver tumor burden in mice treated with the hepatocellular carcinogen diethylnitrosamine.

    PubMed

    Healy, Marin E; Chow, Jenny D Y; Byrne, Frances L; Breen, David S; Leitinger, Norbert; Li, Chien; Lackner, Carolin; Caldwell, Stephen H; Hoehn, Kyle L

    2015-03-01

    Mice exposed to the hepatocellular carcinogen diethylnitrosamine at 2 weeks of age have a high risk of developing primary liver tumors later in life. Previous studies have demonstrated that diethylnitrosamine-treated mice have increased tumor burden when fed an obesigenic "Western" diet rich in lard fat and sugar. However, the role of dietary fats vs. sugars in the promotion of liver cancer is poorly understood. The aim of this study was to determine how altering dietary fats vs. sugars affects tumor burden in the diethylnitrosamine model. C57BL/6N mice were treated with diethylnitrosamine at 2 weeks of age and, from 6 to 32 weeks of age, fed one of five diets that differed in fat and sugar content, including normal chow, ketogenic, and Western diets. Mice fed sugar-rich diets had the greatest tumor burden irrespective of dietary fat content. In contrast, mice fed a high-fat low-sugar diet had the least tumor burden despite obesity and glucose intolerance. When evaluated as independent variables, tumor burden was positively correlated with hepatic fat accumulation, postprandial insulin, and liver IL-6, and inversely correlated with serum adiponectin. In contrast, tumor burden did not correlate with adiposity, fasting insulin, or glucose intolerance. Furthermore, mice fed high sugar diets had lower liver expression of p21 and cleaved caspase-3 compared to mice fed low sugar diets. These data indicate that dietary sugar intake contributes to liver tumor burden independent of excess adiposity or insulin resistance in mice treated with diethylnitrosamine. Copyright © 2014 European Association for the Study of the Liver. All rights reserved.

  7. Epigenetic Events in Liver Cancer Resulting From Alcoholic Liver Disease

    PubMed Central

    French, Samuel W.

    2013-01-01

    Epigenetic mechanisms play an extensive role in the development of liver cancer (i.e., hepatocellular carcinoma [HCC]) associated with alcoholic liver disease (ALD) as well as in liver disease associated with other conditions. For example, epigenetic mechanisms, such as changes in the methylation and/or acetylation pattern of certain DNA regions or of the histone proteins around which the DNA is wrapped, contribute to the reversion of normal liver cells into progenitor and stem cells that can develop into HCC. Chronic exposure to beverage alcohol (i.e., ethanol) can induce all of these epigenetic changes. Thus, ethanol metabolism results in the formation of compounds that can cause changes in DNA methylation and interfere with other components of the normal processes regulating DNA methylation. Alcohol exposure also can alter histone acetylation/deacetylation and methylation patterns through a variety of mechanisms and signaling pathways. Alcohol also acts indirectly on another molecule called toll-like receptor 4 (TLR4) that is a key component in a crucial regulatory pathway in the cells and whose dysregulation is involved in the development of HCC. Finally, alcohol use regulates an epigenetic mechanism involving small molecules called miRNAs that control transcriptional events and the expression of genes important to ALD. PMID:24313165

  8. Epigenetic events in liver cancer resulting from alcoholic liver disease.

    PubMed

    French, Samuel W

    2013-01-01

    Epigenetic mechanisms play an extensive role in the development of liver cancer (i.e., hepatocellular carcinoma [HCC]) associated with alcoholic liver disease (ALD) as well as in liver disease associated with other conditions. For example, epigenetic mechanisms, such as changes in the methylation and/or acetylation pattern of certain DNA regions or of the histone proteins around which the DNA is wrapped, contribute to the reversion of normal liver cells into progenitor and stem cells that can develop into HCC. Chronic exposure to beverage alcohol (i.e., ethanol) can induce all of these epigenetic changes. Thus, ethanol metabolism results in the formation of compounds that can cause changes in DNA methylation and interfere with other components of the normal processes regulating DNA methylation. Alcohol exposure also can alter histone acetylation/deacetylation and methylation patterns through a variety of mechanisms and signaling pathways. Alcohol also acts indirectly on another molecule called toll-like receptor 4 (TLR4) that is a key component in a crucial regulatory pathway in the cells and whose dysregulation is involved in the development of HCC. Finally, alcohol use regulates an epigenetic mechanism involving small molecules called miRNAs that control transcriptional events and the expression of genes important to ALD.

  9. Recent advances in immunotherapy for hepatocellular cancer.

    PubMed

    Butterfield, Lisa H

    2007-02-10

    There is a continuing need for innovative, alternative therapies for hepatocellular carcinoma (HCC). Immunotherapy of cancer is attractive because of the exquisite specificity of the immune response. Activation of an HCC-specific response can be accomplished by strategies targeting tumour-associated antigens (for example: alpha fetoprotein (AFP)) or viral antigens in those patients infected with hepatitis B or C. Uncharacterised and mutated antigens can also be targeted with whole tumour cell or tumour lysate-based immunisation strategies. Viral vectors coding for genes which make the patient's tumour immunogenic can allow the immune system to naturally evolve specificity against immunogenic target antigens. Strategies which have been tested in human clinical trials include adoptive transfer of lymphocytes, cytokine injections, autologous tumour-pulsed dendritic cells (DC) as well as AFP-derived peptides in adjuvant and pulsed onto autologous DC. These trials, testing novel immune-based interventions in HCC subjects, have resulted in immunological responses and some have impacted recurrence and survival of HCC subjects.

  10. Wnt Inactivation for Liver Cancer Therapy | Center for Cancer Research

    Cancer.gov

    Hepatocellular carcinoma (HCC) is the fifth most common and third most deadly type of cancer in the world. The majority of cases occur in Asia and Africa, resulting in most cases being diagnosed only at advanced stages of the disease when drug resistance is high. HCC typically follows damage to the liver such as cirrhosis, making radiation and chemotherapy a more challenging prospect. Surgery is also not a very viable option because less than one in four carcinomas can be completely removed. The limitations in these treatment modalities create the need for alternative therapeutic approaches.

  11. Gender differences in the livers of patients with hepatocellular carcinoma and chronic hepatitis C infection.

    PubMed

    Nishida, Naoshi; Arizumi, Tadaaki; Hayaishi, Sosuke; Takita, Masahiro; Kitai, Satoshi; Yada, Norihisa; Hagiwara, Satoru; Inoue, Tatsuo; Minami, Yasunori; Ueshima, Kazuomi; Sakurai, Toshiharu; Ikai, Iwao; Kudo, Masatoshi

    2012-01-01

    A unique causative aspect of hepatocellular carcinoma (HCC) is a gender difference in its incidence. To determine the specific factors that contribute to a male predominance, we analyzed the clinicopathological factors, and genetic and epigenetic alterations of HCCs in male and female patients. We retrospectively analyzed three cohorts of patients: the first cohort consisted of 547 patients identified with the first event of HCC, the second cohort included 176 HCC patients, and the third 127 patients with chronic hepatitis C (CHC). Male patients were found to have HCC more frequently than female patients in cases of non-cirrhotic liver (p = 0.0030 by the χ(2) test), especially in hepatitis C-positive cases. However, there were no gender-specific differences in the genetic and epigenetic alterations of cancer-related genes. Deposition of iron was more severe in male CHC patients than in female patients. Male patients with CHC develop HCC more frequently when they have a non-cirrhotic liver than do female patients. This gender difference could be, at least partially, attributed to a different degree of iron deposition, which contributes to the development of HCC in the absence of liver cirrhosis in men with CHC. Copyright © 2012 S. Karger AG, Basel.

  12. Oncogenic role of the Notch pathway in primary liver cancer

    PubMed Central

    LU, JIE; XIA, YUJING; CHEN, KAN; ZHENG, YUANYUAN; WANG, JIANRONG; LU, WENXIA; YIN, QIN; WANG, FAN; ZHOU, YINGQUN; GUO, CHUANYONG

    2016-01-01

    Primary liver cancer, which includes hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC) and fibrolamellar HCC, is one of the most common malignancies and the third leading cause of cancer-associated mortality, worldwide. Despite the development of novel therapies, the prognosis of liver cancer patients remains extremely poor. Thus, investigation of the genetic background and molecular mechanisms underlying the development and progression of this disease has gained significant attention. The Notch signaling pathway is a crucial determinant of cell fate during development and disease in several organs. In the liver, Notch signaling is involved in biliary tree development and tubulogenesis, and is also significant in the development of HCC and ICC. These findings suggest that the modulation of Notch pathway activity may have therapeutic relevance. The present review summarizes Notch signaling during HCC and ICC development and discusses the findings of recent studies regarding Notch expression, which reveal novel insights into its function in liver cancer progression. PMID:27347091

  13. Hepatocellular Cancer: New Kids on the Block

    PubMed Central

    Hoffmann, Andreas-Claudius; Gerken, Guido G.H.

    2014-01-01

    Background With over 600,000 newly diagnosed hepatocellular cancer (HCC) patients worldwide every year and ongoing clinical research, it is surprising that many of the new molecular entities have not yet resulted in significant prolongation of progression-free or overall survival. Nevertheless, there are a number of promising agents currently under investigation. Given the unique tumor biology and heterogeneous clinical manifestations of HCC, the application of molecular and cellular markers could also benefit patient selection, disease prognosis and trial design. Summary This paper provides an overview of the current therapeutic strategies for HCC in the curative and palliative settings. Furthermore, we introduce some of the promising small molecules and antibodies that may find their way into clinical practice, with a focus on substances that are currently in phase III testing. Finally, we summarize the role of promising biomarkers, such as circulating tumor or cancer stem cells. Key Message Despite the rising prevalence of HCC and active clinical research, few therapeutic options besides sorafenib have been established. This review discusses the new therapeutic agents in the pipeline. Practical Implications Although many promising preclinical studies have resulted in phase I-II trials on HCC, so far only the tyrosine and Raf kinase inhibitor sorafenib has made its way into the hands of physicians. This multikinase inhibitor is the only approved option for systemic treatment of advanced HCC. Currently, the development of promising approaches for disease management is guided by biomarkers such as molecular markers or cellular characteristics. The use of biomarkers may facilitate early diagnosis in high-risk groups and therefore enhance outcomes by detecting patients whose disease is still curable. PMID:26676221

  14. Supportive therapies for prevention of hepatocellular carcinoma recurrence and preservation of liver function.

    PubMed

    Takami, Taro; Yamasaki, Takahiro; Saeki, Issei; Matsumoto, Toshihiko; Suehiro, Yutaka; Sakaida, Isao

    2016-08-28

    Hepatocellular carcinoma (HCC) is one of the deadliest cancers in the world and is associated with a high risk of recurrence. The development of a wide range of new therapies is therefore essential. In this study, from the perspective of supportive therapy for the prevention of HCC recurrence and preservation of liver function in HCC patients, we surveyed a variety of different therapeutic agents. We show that branched chain amino acids (BCAA) supplementation and late evening snack with BCAA, strategies that address issues of protein-energy malnutrition, are important for liver cirrhotic patients with HCC. For chemoprevention of HCC recurrence, we show that viral control after radical treatment is important. We also reviewed the therapeutic potential of antiviral drugs, sorafenib, peretinoin, iron chelators. Sorafenib is a kinase inhibitor and a standard therapy in the treatment of advanced HCC. Peretinoin is a vitamin A-like molecule that targets the retinoid nuclear receptor to induce apoptosis and inhibit tumor growth in HCC cells. Iron chelators, such as deferoxamine and deferasirox, act to prevent cancer cell growth. These chelators may have potential as combination therapies in conjunction with peretinoin. Finally, we review the potential inhibitory effect of bone marrow cells on hepatocarcinogenesis.

  15. Prognostic factors for prediction of survival of hepatocellular cancer patients after selective internal radiation therapy.

    PubMed

    Soydal, Cigdem; Keskin, Onur; Kucuk, Ozlem N; Ozkan, Elgin; Bilgic, Sadik; Idilman, Ramazan; Kir, Metin K

    2015-06-01

    In this study, it was aimed to explore the prognostic factors in patients who received selective internal radiation therapy for hepatocellular cancer. A retrospective evaluation was made of 28 (24 male, 4 female, mean age 65.4 ± 6.8 years) hepatocellular cancer patients who received selective internal radiation therapy with Y-90 resin microspheres. Using Cox proportional hazards regression analysis, the relationship between age, gender, MELD score, serum albumin and AFP levels, number of liver lesions, size of the largest lesion, absence of (18)F-FDG uptake, maximum standardized uptake value and overall survival times was analyzed. Treatment was applied to the right lobe in 22 and both in 6 patients. Mean treatment dose was 1.5 ± 0.2 GBq. Number of liver lesions were 1, <5 and multiple in 16, 5 and 7 patients, respectively, and the mean size of the largest lesion was 41.5 mm (min-max 15-160 mm). While (18)F-FDG uptake was seen in 24 patients, liver lesions were hypometabolic in 4 patients. Mean SUVmax of liver lesions was calculated as 5.3 ± 0.3. During the mean 17.8 (min-max 2-39) months follow-up period, 19 patients died. Median survival time was computed as 18 ± 5 months (95% CI 8.1-27.8). Age (p = 0.04), serum AFP level (p = 0.03) and size of the largest lesion (p = 0.02) had a significant negative effect on survival according to the Cox proportional hazards regression analysis. Age, serum AFP level and the size of the largest liver lesion have a negative significant effect on survival of hepatocellular cancer patients who received selective internal radiation therapy.

  16. Initial experience of surgical microwave tissue precoagulation in liver resection for hepatocellular carcinoma in cirrhotic liver.

    PubMed

    Abdelraouf, A; Hamdy, H; El Erian, A M; Elsebae, M; Taha, S; Elshafey, H E; Ismail, S; Hassany, M

    2014-08-01

    Surgical hepatic resection has been considered as the first-line treatment which is most effective and radical treatment for HCC, however, HCC is usually associated with poor liver function owing to chronic hepatitis or liver cirrhosis. Techniques that can eradicate the tumor and also preserve liver function are needed. Moreover, hepatic resection, in the presence of cirrhosis, raises special problem of high risk as hemorrhage and liver failure, thus, good clinical results can only be achieved by minimizing operative blood loss, time of the intervention as well as the hepatic reserve. The tremendous progress in microwave technology has recently attracted considerable attention. This study evaluated the feasibility of this new liver transection technique demonstrating the high performance of this procedure, the accuracy in terms of squeeze effect on veins and portal branch and in terms of reducing the intra operative blood loss, and minimizing the operative time for safe hepatectomy. Twenty-six consecutive patients a first-time diagnosis of hepatocellular carcinoma (HCC) on top of liver cirrhosis were recruited for the study, from August 2011 to January 2013. All patients were subjected to full clinical examination, laboratory investigations, abdomen ultrasound (U/S), triphasic computed tomographic liver scan (CT) and dynamic magnetic resonance imaging (MRI) in some doubtful cases. Inclusion requirements were presence of resectable disease without vascular invasion or extrahepatic spread at imaging, Child-Pugh class A & B (Score 7) liver cirrhosis, (INR) < 1.6 or platelet count) 60 000/mm3 with no previous treatment. Patients were treated by applying pre-coagulation of the liver transection lines using microwave probe positioned in parallel to the line of resection by open approach after intra-operative U/S assessment for localization of the tumor and line of resection. The procedures were performed under general anesthesia. Mobilization of the liver was not

  17. Hepatocellular carcinoma associated with liver-gender disruption in male mice.

    PubMed

    Rogers, Arlin B; Theve, Elizabeth J; Feng, Yan; Fry, Rebecca C; Taghizadeh, Koli; Clapp, Kristen M; Boussahmain, Chakib; Cormier, Kathleen S; Fox, James G

    2007-12-15

    Hepatocellular carcinoma (HCC) is a male-predominant cancer associated with chronic hepatitis. Like human viral hepatitis, murine Helicobacter hepaticus infection produces inflammation and HCC with a masculine bias. We used this model to identify potential mechanisms of male HCC predisposition. Male weanling A/JCr mice (n = 67) were gavaged with H. hepaticus or vehicle. At 1 year, mice were distributed into four groups: surgical castration, chemical castration, castration followed by dihydrotestosterone supplementation, or sexually intact controls. Responses to infection were compared with IFN-gamma challenge alone. At 21 months, there was no significant difference in hepatitis between groups. Neither castration nor androgen receptor agonism altered tumor incidence. Infected mice with severe, but not mild, disease exhibited a mosaic of alterations to sexually dimorphic genes and microsomal long-chain fatty acids. By microarray, tumorigenic hepatitis was strongly associated with liver-gender disruption, defined as the loss of a gender-identifying hepatic molecular signature. IFN-gamma alone produced similar changes, demonstrating a role for proinflammatory cytokines in this process. In conclusion, hepatocarcinogenesis in male mice with chronic hepatitis is maturationally imprinted and androgen-independent. Proinflammatory cytokines may promote HCC in a male-predominant fashion due to high sensitivity of the masculinized liver to loss of sex-specific transcriptional balance. Liver-gender disruption has pleiotropic implications for hepatic enzyme activity, lipid processing, nuclear receptor activation, apoptosis, and proliferation. We propose a multistep model linking chronic hepatitis to liver cancer through cytokine-mediated derangement of gender-specific cellular metabolism. This model introduces a novel mechanism of inflammation-associated carcinogenesis consistent with male-predominant HCC risk.

  18. Tobacco carcinogen (NNK) induces both lung cancer and non-alcoholic steatohepatitis and hepatocellular carcinomas in ferrets which can be attenuated by lycopene supplementation

    USDA-ARS?s Scientific Manuscript database

    Early epidemiologic studies have reported that tobacco smoking, which is causally associated with liver cancer, is an independent risk factor for non-alcoholic fatty liver diseases (NAFLD). Lycopene from tomatoes has been shown to be a potential preventive agent against NAFLD and hepatocellular carc...

  19. Dietary effects on liver tumor burden in mice treated with the hepatocellular carcinogen diethylnitrosamine

    PubMed Central

    Healy, Marin E.; Chow, Jenny D.Y.; Byrne, Frances L.; Breen, David S.; Leitinger, Norbert; Li, Chien; Lackner, Carolin; Caldwell, Stephen H.; Hoehn, Kyle L.

    2014-01-01

    Background & Aims Mice exposed to the hepatocellular carcinogen diethylnitrosamine at 2 weeks of age have a high risk of developing primary liver tumors later in life. Previous studies have demonstrated that diethylnitrosamine-treated mice have increased tumor burden when fed an obesigenic “Western” diet rich in lard fat and sugar. However, the role of dietary fats versus sugars in the promotion of liver cancer is poorly understood. The aim of this study was to determine how altering dietary fats versus sugars affects tumor burden in the diethylnitrosamine model. Methods C57BL/6N mice were treated with diethylnitrosamine at 2 weeks of age and, from 6 to 32 weeks of age, fed one of five diets that differed in fat and sugar content including normal chow, ketogenic, and Western diets. Results Mice fed sugar-rich diets had the greatest tumor burden irrespective of dietary fat content. In contrast, mice fed a high-fat low-sugar diet had the least tumor burden despite obesity and glucose intolerance. When evaluated as independent variables, tumor burden was positively correlated with hepatic fat accumulation, postprandial insulin, and liver IL-6, and inversely correlated with serum adiponectin. In contrast, tumor burden did not correlate with adiposity, fasting insulin, or glucose intolerance. Furthermore, mice fed high sugar diets had lower liver expression of p21 and cleaved caspase-3 compared to mice fed low sugar diets. Conclusions These data indicate that dietary sugar intake contributes to liver tumor burden independent of excess adiposity or insulin resistance in mice treated with diethylnitrosamine. PMID:25450719

  20. Lipids changes in liver cancer*

    PubMed Central

    Jiang, Jing-ting; Xu, Ning; Zhang, Xiao-ying; Wu, Chang-ping

    2007-01-01

    Liver is one of the most important organs in energy metabolism. Most plasma apolipoproteins and endogenous lipids and lipoproteins are synthesized in the liver. It depends on the integrity of liver cellular function, which ensures homeostasis of lipid and lipoprotein metabolism. When liver cancer occurs, these processes are impaired and the plasma lipid and lipoprotein patterns may be changed. Liver cancer is the fifth common malignant tumor worldwide, and is closely related to the infections of hepatitis B virus (HBV) and hepatitis C virus (HCV). HBV and HCV infections are quite common in China and other Southeast Asian countries. In addition, liver cancer is often followed by a procession of chronic hepatitis or cirrhosis, so that hepatic function is damaged obviously on these bases, which may significantly influence lipid and lipoprotein metabolism in vivo. In this review we summarize the clinical significance of lipid and lipoprotein metabolism under liver cancer. PMID:17565510

  1. Radio Frequency Ablation for Primary Liver Cancer

    PubMed Central

    2004-01-01

    Executive Summary Objective The Medical Advisory Secretariat undertook a review of the evidence on the safety, clinical effectiveness, and cost-effectiveness of radio frequency ablation (RFA) compared with other treatments for unresectable hepatocellular carcinoma (HCC) in Ontario. Background Liver cancer is the fifth most common type of cancer globally, although it is most prevalent in Asia and Africa. The incidence of liver cancer has been increasing in the Western world, primarily because of an increased prevalence of hepatitis B and C. Data from Cancer Care Ontario from 1998 to 2002 suggest that the age-adjusted incidence of liver cancer in men rose slightly from 4.5 cases to 5.4 cases per 100,000 men. For women, the rates declined slightly, from 1.8 cases to 1.4 cases per 100,000 women during the same period. Most people who present with symptoms of liver cancer have a progressive form of the disease. The rates of survival in untreated patients in the early stage of the disease range from 50% to 82% at 1 year and 26% to 32% at 2 years. Patients with more advanced stages have survival rates ranging from 0% to 36% at 3 years. Surgical resection and transplantation are the procedures that have the best prognoses; however, only 15% to 20% of patients presenting with liver cancer are eligible for surgery. Resection is associated with a 50% survival rate at 5 years. The Technology: Radio Frequency Ablation RFA is a relatively new technique for the treatment of small liver cancers that cannot be treated with surgery. This technique applies alternating high-frequency electrical currents to the cancerous tissue. The intense heat leads to thermal coagulation that can kill the tumour. RFA is done under general or local anesthesia and can be done percutaneously (through the skin with a small needle), laparoscopically (microinvasively, using a small video camera), or intraoperatively. Percutaneous RFA is usually a day procedure. Methods The leading international

  2. COMPARATIVE STUDY ON LIVER TRANSPLANTATION WITH AND WITHOUT HEPATOCELLULAR CARCINOMA WITH CIRRHOSIS: ANALYSIS OF MELD, WAITING TIME AND SURVIVAL

    PubMed Central

    de FREITAS, Alexandre Coutinho Teixeira; SHIGUIHARA, Rafael Shinmi; MONTEIRO, Ruan Teles; PAZETO, Thiago Linck; COELHO, Júlio Cezar Uili

    2016-01-01

    Background : Liver transplantation is the usual treatment for hepatocellular carcinoma. Aim: To analyze the MELD score, waiting time and three month and one year survival for liver transplantation in cirrhotic patients affected by hepatocellular carcinoma or not. Methods : This was a retrospective, observational and analytical study of 93 patients submitted to liver transplantation. Results : There were 28 hepatocellular carcinoma and 65 non-hepatocellular carcinoma patients with no differences related to age and sex distribution. The main causes of cirrhosis on hepatocellular carcinoma were hepatitis C virus (57.1%) and hepatitis B virus (28.5%), more frequent than non-hepatocellular carcinoma patients, which presented 27.7% and 4.6% respectively. The physiological and exception MELD score on hepatocellular carcinoma were 11.9 and 22.3 points. On non-hepatocellular carcinoma, it was 19.4 points, higher than the physiological MELD and lower than the exception MELD on hepatocellular carcinoma. The waiting time for transplantation was 96.2 days for neoplasia, shorter than the waiting time for non-neoplasia patients, which was 165.6 days. Three month and one year survival were 85.7% and 78.6% for neoplasia patients, similar to non-neoplasia, which were 77% and 75.4%. Conclusion: Hepatocellular carcinoma patients presented lower physiological MELD score, higher exception MELD score and shorter waiting time for transplantation when compared to non-hepatocellular carcinoma patients. Three month and one year survival were the same between the groups. PMID:27120734

  3. Comprehensive genome sequencing of the liver cancer genome.

    PubMed

    Nakagawa, Hidewaki; Shibata, Tatsuhiro

    2013-11-01

    Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Recently, comprehensive whole genome and exome sequencing analyses for HCC revealed new cancer-associated genes and a variety of genomic alterations. In particular, frequent genetic alterations of the chromatin remodeling genes were observed, suggesting a new potential therapeutic target for HCC. Sequencing analysis has further identified the molecular complexities of multicentric lesions and intratumoral heterogeneity. Detailed analyses of the somatic substitution pattern of the cancer genome and the HBV virus genome integration sites by using whole-genome sequencing will elucidate the molecular basis and diverse etiological factors involved in liver cancer development.

  4. Radioembolization for primary and metastatic liver cancer

    PubMed Central

    Memon, Khairuddin; Lewandowski, Robert J; Kulik, Laura; Riaz, Ahsun; Mulcahy, Mary F; Salem, Riad

    2011-01-01

    The incidence of hepatocellular carcinoma is increasing. Most patients present beyond potentially curative options and are usually affected by underlying cirrhosis. In this scenario, trans-arterial therapies, such as radioembolization, are rapidly gaining acceptance as a potential therapy for hepatocellular carcinoma and liver metastases. Radioembolization is a catheter-based liver-directed therapy that involves injection of micron-sized embolic particles loaded with a radioisotope by use of percutaneous transarterial techniques. Cancer cells are preferentially supplied by arterial blood and normal hepatocytes by portal venous blood; radioembolization therefore specifically targets tumor cells with a high dose of lethal radiation and spares healthy hepatocytes. The antitumor effect mostly comes from radiation rather than embolization. The most commonly used radioisotope is Yttrium-90. The commercially available devices are TheraSphere® (glass-based) and SIR-Sphere® (resin-based). The procedure is performed on outpatient basis. The incidence of complications is generally less than other locoregional therapies and may include nausea, fatigue, abdominal pain, hepatic dysfunction, biliary injury, fibrosis, radiation pneumonitis, gastrointestinal ulcers and vascular injury. However, these can be avoided by meticulous pretreatment assessment, careful patient selection and adequate dosimetry. This article focuses on both the technical and clinical aspects of radioembolization with emphasis on patient selection, uses and complications. PMID:21939859

  5. miR-203 inhibits augmented proliferation and metastasis of hepatocellular carcinoma residual in the promoted regenerating liver.

    PubMed

    Zheng, Xiao-Bo; Chen, Xiao-Bo; Xu, Liang-Liang; Zhang, Ming; Feng, Lei; Yi, Peng-Sheng; Tang, Jian-Wei; Xu, Ming-Qing

    2017-03-01

    Liver resection is still the most commonly used therapeutic treatment for hepatocellular carcinoma (HCC), and liver regeneration promotes HCC growth in the regenerating liver. The high recurrence/metastasis of HCC is the main cause of death for HCC patients after liver resection. However, how the augmented growth and metastasis of residual HCC induced by the promoted liver regeneration following liver resection can be abolished remains unclear. In this study, a rat model with liver cirrhosis and diffused HCC was established by administration of diethylnitrosamine. Recombinant miR-203 adenovirus was administered to induce hepatic miR-203 overexpression and 30% partial hepatectomy (PH) followed. The effect of miR-203 on the proliferation, invasion and metastasis of the residual HCC in the remnant cirrhotic liver with promoted regeneration was investigated. We found that the basic spontaneous regeneration of the non-tumorous liver by 30% PH promoted proliferation, invasion and lung metastasis of the hepatic residual HCC. miR-203 overexpression further promoted the regeneration of the non-tumorous liver by upregulating Ki67 expression and enhancing IL-6/SOCS3/STAT3 pro-proliferative signals. Importantly, miR-203 overexpression markedly inhibited the proliferation, invasion and metastasis of hepatic residual HCC through suppressing expression of Ki67, CAPNS1 and lung metastasis. Moreover, it was found that miR-203 overexpression reversed the epithelial-mesenchymal transition induced by hepatectomy through targeting IL-1β, Snail1 and Twist1. In conclusion, our results suggested that miR-203 overexpression inhibited the augmented proliferation and lung metastasis of the residual HCC induced by the promoted liver regeneration following PH partly by regulating epithelial-mesenchymal transition. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  6. Primary cancer of the liver in Kenyan children.

    PubMed Central

    Cameron, H. M.; Warwick, G. P.

    1977-01-01

    In 9 years in Kenya, 34 examples of primary liver cancer wer diagnosed in patients in the first two decades of life. This represents 4.7% of all liver cancers during this period. The larger proportion (29) were hepatocellular carcinoma. In the second decade, there was a notable association with macronodular cirrhosis. Analogy with experimental work suggests that cells in mitotic cycle may be more vulnerable to the effect of environmental carcinogens. Five examples of hepatoblastoma were identified at ages from 2 months to 14 years; none showed the features of "mixed" tumours. The ratio of hepatoblastoma to hepatocellular carcinoma was the reverse of that found in other large series of juvenile hepatic tumours. The histopathological features of these tumours are described and problems of their classification are discussed. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 PMID:202298

  7. Obesity, autophagy and the pathogenesis of liver and pancreatic cancers.

    PubMed

    Aghajan, Mariam; Li, Ning; Karin, Michael

    2012-03-01

    Liver and pancreatic cancers are both highly lethal diseases with limited to no therapeutic options for patients. Recent studies suggest that deregulated autophagy plays a role in the pathogenesis of these diseases by perturbing cellular homeostasis and laying the foundation for disease development. While accumulation of p62 upon impaired autophagy has been implicated in hepatocellular carcinoma, its role in pancreatic ductal adenocarcinoma remains less clear. This review will focus on recent studies illustrating the role of autophagy in liver and pancreatic cancers. The relationships between autophagy, nuclear factor-κB signaling and obesity in hepatocellular carcinoma will be discussed, as well as the dual role of autophagy in pancreatic ductal adenocarcinoma. © 2012 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.

  8. Factors Influencing Surveillance for Hepatocellular Carcinoma in Patients with Liver Cirrhosis

    PubMed Central

    Ahmed Mohammed, Hager A.; Yang, Ju Dong; Giama, Nasra H.; Choi, Jonggi; Ali, Hawa M.; Mara, Kristin C.; Harmsen, William S.; Wiesner, Russell H.; Leise, Michael D.; Therneau, Terry M.; Roberts, Lewis R.

    2017-01-01

    Objective Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related mortality worldwide, and a rising cause of cancer mortality in the U.S. Liver cirrhosis is the major risk factor for HCC. Surveillance of persons with cirrhosis facilitates early detection and improves outcomes. We assessed the surveillance rate for HCC within a major academic health system and identified factors influencing surveillance. Patients and Methods We examined the surveillance rate for HCC using liver ultrasound, CT, or MRI, and factors influencing surveillance in a cohort of 369 Minnesota residents with cirrhosis seen at the Mayo Clinic between 2007 and 2009. Results Ninety-three percent of cirrhosis patients received at least one surveillance study, but only 14% received the recommended uninterrupted semiannual surveillance. Thirty percent received ≥75% of recommended surveillance, and 59% received ≥50% of recommended surveillance. Factors increasing surveillance included gastroenterology or hepatology specialist visits (p < 0.0001), advanced liver disease as assessed by hepatic encephalopathy (p = 0.0008), and comorbid illness as assessed by diabetes mellitus (p = 0.02). Age, sex, race, residence, cirrhosis etiology, or number of primary care visits did not significantly affect the rate of surveillance. Conclusions While the rate of surveillance in a major academic health system was higher than reported in other studies, surveillance was heavily dependent on visits to a subspecialist. This suggests a major and urgent national need to improve identification of individuals at risk for HCC in the primary care setting and the initiation and maintenance of surveillance by primary care practitioners. PMID:28275579

  9. Survival Benefit of Locoregional Treatment for Hepatocellular Carcinoma with Advanced Liver Cirrhosis

    PubMed Central

    Kitai, Satoshi; Kudo, Masatoshi; Nishida, Naoshi; Izumi, Namiki; Sakamoto, Michiie; Matsuyama, Yutaka; Ichida, Takafumi; Nakashima, Osamu; Matsui, Osamu; Ku, Yonson; Kokudo, Norihiro; Makuuchi, Masatoshi

    2016-01-01

    Background & Aims Hepatocellular carcinoma (HCC) with decompensated liver cirrhosis (LC) is a life-threatening condition, which is amenable to liver transplantation (LT) as the standard first-line treatment. However, the application of LT can be limited due to a shortage of donor livers. This study aimed to clarify the effect of non-surgical therapy on the survival of patients with HCC and decompensated LC. Methods Of the 58,886 patients with HCC registered in the nationwide survey of the Liver Cancer Study Group of Japan (January 2000-December 2005), we included 1,344 patients with primary HCC and Child-Pugh (C-P) grade C for analysis in this retrospective study. Among the patients analyzed, 108 underwent LT, 273 were treated by local ablation therapy (LAT), 370 were treated by transarterial chemoembolization (TACE), and 593 received best supportive care (BSC). The effect of LT, LAT, and TACE on overall survival (OS) was analyzed using multivariate and propensity score analyses. Results Patient characteristics did not differ significantly between each treatment group and the BSC group, after propensity score matching. LAT (hazard ratio [HR]) =0.568; 95% confidence interval [CI], 0.40-0.80) and TACE (HR=0.691; 95% CI, 0.50-0.96) were identified as significant contributors to OS if the C-P score was less than 11 and tumor conditions met the Milan criteria. Conclusions For patients with HCC within the Milan criteria and with a C-P score of 10 or 11, locoregional treatment can be used as a salvage treatment if LT is not feasible. PMID:27493893

  10. Impact of non-oncological factors on tumor recurrence after liver transplantation in hepatocellular carcinoma patients

    PubMed Central

    Gu, Xiang-Qian; Zheng, Wei-Ping; Teng, Da-Hong; Sun, Ji-San; Zheng, Hong

    2016-01-01

    Hepatocellular carcinoma (HCC) is the most common primary neoplasm of the liver and is one of the leading causes of cancer-related death worldwide. Liver transplantation (LT) has become one of the best curative therapeutic options for patients with HCC, although tumor recurrence after LT is a major and unaddressed cause of mortality. Furthermore, the factors that are associated with recurrence are not fully understood, and most previous studies have focused on the biological properties of HCC, such as the number and size of the HCC nodules, the degree of differentiation, the presence of hepatic vascular invasion, elevated serum levels of alpha-fetoprotein, and the tumor stage outside of the Milan criteria. Thus, little attention has been given to factors that are not directly related to HCC (i.e., “non-oncological factors”), which have emerged as predictors of tumor recurrence. This review was performed to assess the effects of non-oncological factors on tumor recurrence after LT. The identification of these factors may provide new research directions and clinical strategies for the prophylaxis and surveillance of tumor recurrence after LT, which can help reduce recurrence and improve patient survival. PMID:26973413

  11. Novel Aspects of the Liver Microenvironment in Hepatocellular Carcinoma Pathogenesis and Development

    PubMed Central

    Tu, Thomas; Budzinska, Magdalena A.; Maczurek, Annette E.; Cheng, Robert; Di Bartolomeo, Anna; Warner, Fiona J.; McCaughan, Geoffrey W.; McLennan, Susan V.; Shackel, Nicholas A.

    2014-01-01

    Hepatocellular carcinoma (HCC) is a prevalent primary liver cancer that is derived from hepatocytes and is characterised by high mortality rate and poor prognosis. While HCC is driven by cumulative changes in the hepatocyte genome, it is increasingly recognised that the liver microenvironment plays a pivotal role in HCC propensity, progression and treatment response. The microenvironmental stimuli that have been recognised as being involved in HCC pathogenesis are diverse and include intrahepatic cell subpopulations, such as immune and stellate cells, pathogens, such as hepatitis viruses, and non-cellular factors, such as abnormal extracellular matrix (ECM) and tissue hypoxia. Recently, a number of novel environmental influences have been shown to have an equally dramatic, but previously unrecognized, role in HCC progression. Novel aspects, including diet, gastrointestinal tract (GIT) microflora and circulating microvesicles, are now being recognized as increasingly important in HCC pathogenesis. This review will outline aspects of the HCC microenvironment, including the potential role of GIT microflora and microvesicles, in providing new insights into tumourigenesis and identifying potential novel targets in the treatment of HCC. PMID:24871369

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

    PubMed

    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

  13. Minimally invasive local therapies for liver cancer

    PubMed Central

    Li, David; Kang, Josephine; Golas, Benjamin J.; Yeung, Vincent W.; Madoff, David C.

    2014-01-01

    Primary and metastatic liver tumors are an increasing global health problem, with hepatocellular carcinoma (HCC) now being the third leading cause of cancer-related mortality worldwide. Systemic treatment options for HCC remain limited, with Sorafenib as the only prospectively validated agent shown to increase overall survival. Surgical resection and/or transplantation, locally ablative therapies and regional or locoregional therapies have filled the gap in liver tumor treatments, providing improved survival outcomes for both primary and metastatic tumors. Minimally invasive local therapies have an increasing role in the treatment of both primary and metastatic liver tumors. For patients with low volume disease, these therapies have now been established into consensus practice guidelines. This review highlights technical aspects and outcomes of commonly utilized, minimally invasive local therapies including laparoscopic liver resection (LLR), radiofrequency ablation (RFA), microwave ablation (MWA), high-intensity focused ultrasound (HIFU), irreversible electroporation (IRE), and stereotactic body radiation therapy (SBRT). In addition, the role of combination treatment strategies utilizing these minimally invasive techniques is reviewed. PMID:25610708

  14. Gender Differences in Adipocyte Metabolism and Liver Cancer Progression.

    PubMed

    Cheung, Otto K-W; Cheng, Alfred S-L

    2016-01-01

    Liver cancer is the third most common cancer type and the second leading cause of deaths in men. Large population studies have demonstrated remarkable gender disparities in the incidence and the cumulative risk of liver cancer. A number of emerging risk factors regarding metabolic alterations associated with obesity, diabetes and dyslipidemia have been ascribed to the progression of non-alcoholic fatty liver diseases (NAFLD) and ultimately liver cancer. The deregulation of fat metabolism derived from excessive insulin, glucose, and lipid promotes cancer-causing inflammatory signaling and oxidative stress, which eventually triggers the uncontrolled hepatocellular proliferation. This review presents the current standing on the gender differences in body fat compositions and their mechanistic linkage with the development of NAFLD-related liver cancer, with an emphasis on genetic, epigenetic and microRNA control. The potential roles of sex hormones in instructing adipocyte metabolic programs may help unravel the mechanisms underlying gender dimorphism in liver cancer and identify the metabolic targets for disease management.

  15. Gender Differences in Adipocyte Metabolism and Liver Cancer Progression

    PubMed Central

    Cheung, Otto K.-W.; Cheng, Alfred S.-L.

    2016-01-01

    Liver cancer is the third most common cancer type and the second leading cause of deaths in men. Large population studies have demonstrated remarkable gender disparities in the incidence and the cumulative risk of liver cancer. A number of emerging risk factors regarding metabolic alterations associated with obesity, diabetes and dyslipidemia have been ascribed to the progression of non-alcoholic fatty liver diseases (NAFLD) and ultimately liver cancer. The deregulation of fat metabolism derived from excessive insulin, glucose, and lipid promotes cancer-causing inflammatory signaling and oxidative stress, which eventually triggers the uncontrolled hepatocellular proliferation. This review presents the current standing on the gender differences in body fat compositions and their mechanistic linkage with the development of NAFLD-related liver cancer, with an emphasis on genetic, epigenetic and microRNA control. The potential roles of sex hormones in instructing adipocyte metabolic programs may help unravel the mechanisms underlying gender dimorphism in liver cancer and identify the metabolic targets for disease management. PMID:27703473

  16. Hepatocellular Carcinoma and Its Precursors in 103 HBV-Related Cirrhotic Explanted Livers: A Study from South Iran

    PubMed Central

    Yazdanpanah, Shahrzad; Geramizadeh, Bita; Nikeghbalian, Saman; Malek-Hosseini, Seyed Ali

    2016-01-01

    Background The most common cause of liver transplantation in Iran is hepatitis B positive cirrhosis, and it also one of the major and important causes of hepatocellular carcinoma (HCC). Most cases with HCC follow a multistep sequence. Morphologic lesions during hepatocarcinogenesis include dysplastic lesions and small cancerous lesions (2 cm in diameter; early HCC). However, insufficient information is available on the incidence of HCC and its precursors in hepatitis B-related cirrhosis. Objectives In this study, we determined the incidence of HCC and its precursors in hepatitis B-related cirrhosis in the largest liver transplant center in Iran. Methods In a two-year study, all explanted livers of patients with hepatitis B virus (HBV)-positive cirrhosis were completely sectioned and examined. Each specimen was investigated grossly and microscopically to determine any abnormal nodule or cellular changes (at least 15 sections from each liver). Results Among all explanted cirrhotic livers (103 livers) during the study period (2014 - 2015), 92 (89.3%) had dysplastic foci with large cell changes (LCC), 57 (55.3%) of which showed small cell changes (SCC) as well. Thirty-nine cases (37.9%) had low-grade dysplastic nodules (LGDN), 38 (36.9%) high-grade dysplastic nodules (HGDN), 19 (18.4%) were early hepatocellular carcinoma (eHCC), and 21 (20.4%) were hepatocellular carcinoma more than 2 cm. All the cases with eHCC and HCC of more than 2 cm also had SCC, LCC, HGDN, and LGDN. Thirteen cases of eHCC were accompanied with HCCs more than 2 cm, and 6 cases of eHCC did not show any HCC (larger than 2 cm). Conclusions SCC, LGDN, and HGDN are common associated findings and precursors of HCC in livers infected with hepatitis B. A strict follow-up and a precise and thorough sampling of livers with SCC and any abnormal dysplastic nodules (DNs), especially those larger than 1 cm, are highly recommended because these DNs are highly associated with malignancy. PMID:27795725

  17. Radiofrequency Ablation for Liver Cancer.

    PubMed

    Jacobs, Amy

    2015-01-01

    Interventional ablative technologies aided by imaging techniques such as ultrasonography, computed tomography, and magnetic resonance imaging have been crucial in managing patients with primary liver cancer and liver metastases over the past 20 years. Several ablative technologies have been used to treat liver cancer; however, radiofrequency ablation (RFA) has emerged as the most common ablative therapy for hepatic lesions, both in the United States and globally. RFA is the treatment of choice for patients who cannot have surgical resection of the liver. This article focuses on the role of imaging in RFA treatment of primary and metastatic hepatic lesions.

  18. Non-viral causes of liver cancer: does obesity led inflammation play a role?

    PubMed

    Alzahrani, Badr; Iseli, Tristan J; Hebbard, Lionel W

    2014-04-10

    Liver cancer is the fifth most common cancer worldwide and the third most common cause of cancer mortality. Hepatocellular carcinoma (HCC) accounts for around 90% of primary liver cancers. Chronic infection with hepatitis B and hepatitis C viruses are two of most common causes of liver cancer. However, there are non-viral factors that are associated with liver cancer development. Numerous population studies have revealed strong links between obesity and the development of liver cancer. Obesity can alter hepatic pathology, metabolism and promote inflammation, leading to nonalcoholic fatty liver disease (NAFLD) and the progression to the more severe form, non-alcoholic steatohepatitis (NASH). NASH is characterised by prominent steatosis and inflammation, and can lead to HCC. Here, we discuss the role of obesity in inflammation and the principal signalling mechanisms involved in HCC formation. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

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

    PubMed Central

    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

  20. Chronic viral hepatitis and its association with liver cancer.

    PubMed

    Tu, Thomas; Bühler, Sandra; Bartenschlager, Ralf

    2017-07-26

    Chronic infection with hepatitis viruses represents the major causative factor for end-stage liver diseases, including liver cirrhosis and primary liver cancer (hepatocellular carcinoma, HCC). In this review, we highlight the current understanding of the molecular mechanisms that drive the hepatocarcinogenesis associated with chronic hepatitis virus infections. While chronic inflammation (associated with a persistent, but impaired anti-viral immune response) plays a major role in HCC initiation and progression, hepatitis viruses can also directly drive liver cancer. The mechanisms by which hepatitis viruses induce HCC include: hepatitis B virus DNA integration into the host cell genome; metabolic reprogramming by virus infection; induction of the cellular stress response pathway by viral gene products; and interference with tumour suppressors. Finally, we summarise the limitations of hepatitis virus-associated HCC model systems and the development of new techniques to circumvent these shortcomings.

  1. The Correlation between NK Cell and Liver Function in Patients with Primary Hepatocellular Carcinoma

    PubMed Central

    Zeng, Xiao-Hui; Min, Lu

    2014-01-01

    Background/Aims This study aimed to detect the expression of natural killer (NK) cell receptor natural killer group 2D (NKG2D) in the peripheral blood of patients with primary hepatocellular carcinoma and to discuss the correlation between NK cell cytotoxicity and liver function. Methods The number of NK cells and the expression of NK cell receptor NKG2D in peripheral blood were determined by flow cytometry in patients with primary hepatocellular carcinoma, hepatitis B cirrhosis, chronic hepatitis B, and healthy controls. Results When compared with patients in the healthy and the chronic hepatitis B groups, the primary hepatocellular carcinoma group showed significant decreases in all parameters, including the cytotoxicity of NK cells on K562 cells, expression rate of NKG2D in NK cells, number of NKG2D+ NK cells, expression level of NKG2D, and number of NK cells (p<0.05). The activity of NK cells showed a positive correlation, whereas the Child-Pugh scores in the primary hepatocellular carcinoma and the hepatitis B cirrhosis groups showed a negative correlation with all parameters detected above. Conclusions The decrease of NK cell activity in patients with primary hepatocellular carcinoma is closely related to their lower expression of NKG2D. Liver function affects the expression of NKG2D and the activity of NK cells. PMID:24827627

  2. The Complex Relationship between Liver Cancer and the Cell Cycle: A Story of Multiple Regulations

    PubMed Central

    Bisteau, Xavier; Caldez, Matias J.; Kaldis, Philipp

    2014-01-01

    The liver acts as a hub for metabolic reactions to keep a homeostatic balance during development and growth. The process of liver cancer development, although poorly understood, is related to different etiologic factors like toxins, alcohol, or viral infection. At the molecular level, liver cancer is characterized by a disruption of cell cycle regulation through many molecular mechanisms. In this review, we focus on the mechanisms underlying the lack of regulation of the cell cycle during liver cancer, focusing mainly on hepatocellular carcinoma (HCC). We also provide a brief summary of novel therapies connected to cell cycle regulation. PMID:24419005

  3. Hepatocellular carcinoma in Japanese patients with nonalcoholic fatty liver disease and alcoholic liver disease: multicenter survey.

    PubMed

    Tokushige, Katsutoshi; Hyogo, Hideyuki; Nakajima, Tomoaki; Ono, Masafumi; Kawaguchi, Takumi; Honda, Koichi; Eguchi, Yuichiro; Nozaki, Yuichi; Kawanaka, Miwa; Tanaka, Saiyu; Imajo, Kento; Sumida, Yoshio; Kamada, Yoshihiro; Fujii, Hideki; Suzuki, Yasuaki; Kogiso, Tomomi; Karino, Yoshiyasu; Munekage, Kensuke; Kuromatsu, Ryoko; Oeda, Satoshi; Yanase, Mikio; Mori, Kohjiro; Ogawa, Yuji; Seko, Yuya; Takehara, Tetsuo; Itoh, Yoshito; Nakajima, Atsushi; Kanemasa, Kazuyuki; Nishino, Ken; Masaki, Naohiko; Takahashi, Hirokazu; Seike, Masataka; Torimura, Takuji; Saibara, Toshiji; Toyota, Joji; Chayama, Kazuaki; Hashimoto, Etsuko

    2016-06-01

    In Japan, the prevalence of hepatocellular carcinoma (HCC) associated with nonviral liver disease, especially with nonalcoholic fatty liver disease (NAFLD-HCC) and alcoholic liver disease (ALD-HCC), has been increasing. Clarification of the clinical features of NAFLD-HCC and ALD-HCC is needed. We performed a large retrospective multicenter survey to clarify the clinical course of these two types of HCC. Clinical characteristics, survival, and recurrence were examined in 532 patients with ALD-HCC and 209 patients with NAFLD-HCC who were diagnosed between January 2000 and December 2013. The ALD-HCC patients were predominantly male and were younger than the patients with NAFLD-HCC. Lifestyle-related diseases were significantly more common in the NAFLD-HCC group, but the prevalence of cirrhosis was significantly higher in the ALD-HCC group. The histological diagnosis of NAFLD-HCC showed a gender difference (F4; 72.7 % in the females vs. 37.6 % in the males). The characteristic features of HCC including histology, survival rate, and recurrence rate were quite similar in the NAFLD-HCC and ALD-HCC groups: 5-year survival rates 49.1 vs. 43.7 %; 5-year recurrence rates 69.6 vs. 65.4 %, respectively. However, the risk factors for recurrence differed between the two groups: des-gamma-carboxy prothrombin was a risk factor in NAFLD-HCC and α-fetoprotein was a risk factor in ALD-HCC. Although the characteristic features underlying these two diseases are different, the two HCC groups showed a similar clinical course. The recurrence rates of the two HCC groups were relatively high. We found that critical tumor markers for recurrence differed between the two diseases.

  4. Apoptosis in human hepatocellular carcinoma and in liver cell dysplasia is correlated with p53 protein immunoreactivity.

    PubMed Central

    Zhao, M; Zimmermann, A

    1997-01-01

    AIMS: To investigate the prevalence of apoptosis in human hepatocellular carcinomas (HCC) of different types and grades and in liver cell dysplasia, and to test whether the apoptotic rate is correlated with the p53 protein status. METHODS: 37 HCC and 66 six liver samples with liver cell dysplasia were analysed for apoptosis using in situ DNA end labelling (ISEL), and for p53 protein expression by immunohistochemistry. In HCCs, proliferative activity was quantitatively assessed using proliferating cell nuclear antigen labelling. RESULTS: The apoptotic index in HCC as based on ISEL ranged from 0.1 to 13.5 per 1000 cells analysed and was not related to type or grade. No nuclear staining was observed in multinuclear tumour cells. There was a significant correlation between the apoptotic rate and both the proliferative activity and p53 protein reactivity. In liver samples containing p53 protein positive liver cell dysplasia cells, there was a significantly higher apoptotic rate of these cells. CONCLUSIONS: Apoptosis is detectable in HCC, and is not related to type and grade. There is a highly significant positive correlation between the apoptotic rate in HCC and both the proliferative activity and p53 protein expression. A similar phenomenon occurs for putative cancer precursors. The findings support the role of p53 in regulating apoptosis in preneoplastic and neoplastic liver lesions. Images PMID:9215122

  5. Existence of cancer stem cells in hepatocellular carcinoma: myth or reality?

    PubMed

    Machida, Keigo

    2017-03-01

    The cancer stem cell (CSC) hypothesis has been disproved in many cancers. CSCs may exist in blood cancer, while many epithelial cancers may not have CSCs but tumor-initiating cells (TICs). Several independent studies have provided strong evidence for existence of CSCs in brain, skin, and colon cancers (Mani et al. in Cell 133:704-715, 2008, Joseph et al. in Cancer Cell 13:129-140, 2008, Reya et al. in Nature 414:105-111, 2001), while the CSC hypothesis remains controversial (Magee et al. in Cancer Cell 21:283-296, 2012). Liver TICs have bipotential to give rise to two different lineage types: hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). In the liver cancer field, the origin of HCC and CC is extensively debated. Several groups have validated that TICs gave rise to HCC and CC. Hepatocytes gave rise to HCC. Several groups have demonstrated that oval cells (or liver progenitor cells) give rise to TICs. However, CSCs may be a myth in gastrointestinal cancer, while many groups have validated liver TICs. The definition of CSCs includes pluripotency, while TICs do not have to have pluripotency and only need to have bi- or multipotential to give rise to diverse tumor types and tumor initiation potential in mouse models. The CSC hypothesis therefore controversial (Magee et al. in Cancer Cell 21:283-296, 2012). Cancer tissues contain subpopulations of cells known as tumor-initiating stem-like cells (TICs, so-called CSCs) that have been identified as key drivers of tumor growth and malignant progression with drug resistance. Stem cells proliferate via self-renewing division in which the two daughter cells differ in proliferative potential, with one displaying differentiated phenotype and the other retaining self-renewing activity.

  6. Real-time confocal laser endomicroscopic evaluation of primary liver cancer based on human liver autofluorescence.

    PubMed

    Maki, Harufumi; Kawaguchi, Yoshikuni; Arita, Junichi; Akamatsu, Nobuhisa; Kaneko, Junichi; Sakamoto, Yoshihiro; Hasegawa, Kiyoshi; Harihara, Yasushi; Kokudo, Norihiro

    2017-02-01

    Confocal laser endomicroscopy (CLE) is available for real-time microscopic examination. This study aims to evaluate the usefulness of intraoperative CLE examination as a modality to evaluate surgical margins in surgery for primary liver cancer. A probe-based CLE system (Cellvizio 100, Mauna Kea Technologies, Paris, France) was used. The subjects comprised seven specimens obtained from six patients with primary liver cancer in November 2015. The probe was manually attached to the surfaces of specimens, and images were collected without external fluorophores. CLE images were compared with hematoxylin and eosin-stained slides. Fluorescence intensity (FI) values of the CLE images were assessed using luminance-analyzing software. CLE examination visualized non-cancerous regions in the background liver as regular structures with high fluorescence because of human liver autofluorescence. Conversely, hepatocellular carcinoma and intrahepatic cholangiocarcinoma were depicted as irregular structures with low fluorescence. The median FI values of the non-cancerous regions and the cancerous regions were 104 (79.8-156) and 74.9 (60.6-106), respectively, and were significantly different (P = 0.031). The probe-based CLE enables real-time differentiation of cancerous regions from non-cancerous tissues in surgical specimens because of human liver autofluorescence. CLE can be used to confirm negative surgical margins in the operating room. J. Surg. Oncol. 2017;115:151-157. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  7. Synchronous primary breast cancer and hepatocellular carcinoma in a male patient: a case report.

    PubMed

    Tian, Fei; Cui, Xiuzheng; Li, Lin; Lu, Haizhen; Rong, Weiqi; Bi, Chao; Wu, Jianxiong

    2015-01-01

    Male breast cancer is a rare malignant disease characterized by hormonal imbalance. Hepatocellular carcinoma (HCC) is the most common neoplasm of the liver, and is generally correlated with hepatitis B or C virus-related cirrhosis. While to our knowledge a case with these two malignant diseases in a same male patient in the concomitant period is an exceptional event, rarely reported in literature. In this report, we present a case in which a Chinese patient with hepatitis B developed a tumor mass that originated from segment V of the liver and presented with right breast nodules at the same time. Synchronous mastectomy and hepatectomy were performed, and standard endocrine therapy and chemotherapy as adjuvant treatment were therefore followed. The diverse histogenesis of the two kinds of cancers highlights the need for us to investigate any common physiopathogenetic elements.

  8. Synchronous primary breast cancer and hepatocellular carcinoma in a male patient: a case report

    PubMed Central

    Tian, Fei; Cui, Xiuzheng; Li, Lin; Lu, Haizhen; Rong, Weiqi; Bi, Chao; Wu, Jianxiong

    2015-01-01

    Male breast cancer is a rare malignant disease characterized by hormonal imbalance. Hepatocellular carcinoma (HCC) is the most common neoplasm of the liver, and is generally correlated with hepatitis B or C virus-related cirrhosis. While to our knowledge a case with these two malignant diseases in a same male patient in the concomitant period is an exceptional event, rarely reported in literature. In this report, we present a case in which a Chinese patient with hepatitis B developed a tumor mass that originated from segment V of the liver and presented with right breast nodules at the same time. Synchronous mastectomy and hepatectomy were performed, and standard endocrine therapy and chemotherapy as adjuvant treatment were therefore followed. The diverse histogenesis of the two kinds of cancers highlights the need for us to investigate any common physiopathogenetic elements. PMID:26617917

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

    PubMed

    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.

  10. Oral contraceptives and liver cancer.

    PubMed

    1997-11-01

    To date, nine case-control studies conducted in developed countries have identified an association between oral contraceptives (OCs) and liver cancer. The most recent population-based data from both developed and developing countries failed to confirm such an association, however. A study conducted by the World Health Organization in eight developing countries (Chile, China, Colombia, Israel, Kenya, Nigeria, Philippines, and Thailand), in which 122 women with liver cancer were matched with 802 controls, found no elevated risk for OC users compared with never-users (relative risk, 0.7; 95% confidence interval, 0.4-1.2). This study is particularly significant since it was conducted in countries where hepatitis B virus infection, an important risk factor for primary liver cancer, is widespread. In addition, population mortality data from the US, UK, Japan, and Sweden have failed to document increases in liver cancer cases coincident with increases in OC use. Given that population statistics can detect changes on the magnitude of a 40-50% decrease in the risk of ovarian and endometrial cancer related to OC use, they should be able to detect increases of two to 20 times the risk of liver cancer. The increased risk of liver cancer found in the case-control studies may reflect bias resulting from the small size of these studies.

  11. Strategies to improve outcome of patients with hepatocellular carcinoma receiving a liver transplantation

    PubMed Central

    Guerrero-Misas, Marta; Rodríguez-Perálvarez, Manuel; De la Mata, Manuel

    2015-01-01

    Liver transplantation is the only therapeutic option which allows to treat both, the hepatocellular carcinoma and the underlying liver disease. Indeed, liver transplantation is considered the standard of care for a subset of patients with cirrhosis and hepatocellular carcinoma. However, tumour recurrence rates are as high as 20%, and once the recurrence is established the therapeutic options are scarce and with little impact on prognosis. Strategies to minimize tumour recurrence and thus to improve outcome may be classified into 3 groups: (1) An adequate selection of candidates for liver transplantation by using the Milan criteria; (2) An optimized management within waiting list including prioritization of patients at high risk of tumour progression, and the implementation of bridging therapies, particularly when the expected length within the waiting list is longer than 6 mo; and (3) Tailored immunosuppression comprising reduced exposure to calcineurin inhibitors, particularly early after liver transplantation, and the addition of mammalian target of rapamycin inhibitors. In the present manuscript the available scientific evidence supporting these strategies is comprehensively reviewed, and future directions are provided for novel research approaches, which may contribute to the final target: to cure more patients with hepatocellular carcinoma and with an improved long term outcome. PMID:25866602

  12. Use of the piggyback hepatectomy technique in liver transplant recipients with hepatocellular carcinoma.

    PubMed

    Mangus, Richard S; Fridell, Jonathan A; Vianna, Rodrigo M; Cooper, Amanda B; Jones, Daniel T; Tector, A Joe

    2008-05-27

    The piggyback hepatectomy technique (PGB) is avoided in liver transplant patients with hepatocellular carcinoma (HCC) to decrease the theoretical risk of a positive vena cava margin or hematologic metastases. This study reports the routine use of PGB in 138 consecutive adult, deceased donor liver transplant recipients with HCC. Piggyback hepatectomy technique was used in 119 subjects, with 19 recipients receiving the conventional bicaval technique (CONV). Median follow-up was 34 months. There were 95 patients (69%) within and 43 patients (31%) outside, Milan criteria at transplant. Hepatocellular carcinoma recurrence rate was 13% and survival was 84.1% (1-year) and 77.4% (2-years). The PGB and CONV study groups did not differ in survival within or outside Milan criteria. Cox proportional hazards modeling of posttransplant survival demonstrated statistically similar survival for PGB and CONV. In conclusion, the presence of HCC in liver transplant patients should not preclude the use of PGB.

  13. Liver Cancer and Hepatitis B

    MedlinePlus

    ... Our Accomplishments Annual Reports Our Videos What Is Hepatitis B? What Is Hepatitis B? The ABCs of Viral Hepatitis Liver Cancer and Hepatitis B Hepatitis Delta Coinfection Hepatitis C Coinfection HIV/AIDS ...

  14. Risk of secondary cancers from scattered radiation during intensity-modulated radiotherapies for hepatocellular carcinoma

    PubMed Central

    2014-01-01

    Purpose To evaluate and compare the risks of secondary cancers from therapeutic doses received by patients with hepatocellular carcinoma (HCC) during intensity-modulated radiotherapy (IMRT), volumetric arc therapy (VMAT), and tomotherapy (TOMO). Methods Treatments for five patients with hepatocellular carcinoma (HCC) were planned using IMRT, VMAT, and TOMO. Based on the Biological Effects of Ionizing Radiation VII method, the excess relative risk (ERR), excess absolute risk (EAR), and lifetime attributable risk (LAR) were evaluated from therapeutic doses, which were measured using radiophotoluminescence glass dosimeters (RPLGDs) for each organ inside a humanoid phantom. Results The average organ equivalent doses (OEDs) of 5 patients were measured as 0.23, 1.18, 0.91, 0.95, 0.97, 0.24, and 0.20 Gy for the thyroid, lung, stomach, liver, small intestine, prostate (or ovary), and rectum, respectively. From the OED measurements, LAR incidence were calculated as 83, 46, 22, 30, 2 and 6 per 104 person for the lung, stomach, normal liver, small intestine, prostate (or ovary), and rectum. Conclusions We estimated the secondary cancer risks at various organs for patients with HCC who received different treatment modalities. We found that HCC treatment is associated with a high secondary cancer risk in the lung and stomach. PMID:24886163

  15. A case of amoxicillin-induced hepatocellular liver injury with bile-duct damage.

    PubMed

    Kim, Ju Seung; Jang, Young Rock; Lee, Ji Won; Kim, Jin Yong; Jung, Young Kul; Chung, Dong Hae; Kwon, Oh Sang; Kim, Yun Soo; Choi, Duck Joo; Kim, Ju Hyun

    2011-09-01

    Amoxicillin, an antibiotic that is widely prescribed for various infections, is associated with a very low rate of drug-induced liver injury; hepatitis and cholestasis are rare complications. Here we present a case of a 39-year-old woman who was diagnosed with abdominal actinomycosis and received amoxicillin treatment. The patient displayed hepatocellular and bile-duct injury, in addition to elevated levels of liver enzymes. The patient was diagnosed with amoxicillin-induced cholestatic hepatitis. When amoxicillin was discontinued, the patient's symptoms improved and her liver enzyme levels reduced to near to the normal range.

  16. Prognostic value of Rho GDP dissociation inhibitors in patients with hepatocellular carcinoma following liver transplantation

    PubMed Central

    Lai, Ming-Chun; Zhu, Qian-Qian; Owusu-Ansah, Kwabena-Gyabaah; Zhu, Yang-Bo; Yang, Zhe; Xie, Hai-Yang; Zhou, Lin; Wu, Li-Ming; Zheng, Shu-Sen

    2017-01-01

    Rho GDP dissociation inhibitors (GDIs) are pivotal regulators of Rho GTPases, which are essential for tumor progression, yet their role in hepatocellular carcinoma (HCC) remains poorly understood. The purpose of the present study was to assess the role of RhoGDIs in the invasiveness and migration of liver cancer, and to determine their clinical prognostic significances in HCC following liver transplantation (LT). In the present study, the expression of RhoGDIs was assessed using reverse transcription-quantitative polymerase chain reaction and confirmed by western-blot analysis and immunohistochemistry. Their prognostic values were also analyzed, and determined in patients treated with LT. In addition, the functions of RhoGDIs in liver cancer cell line were studied in vitro. As a result, the downregulation of RhoGDI1 and RhoGDI2 at mRNA and protein levels were detected in HCC when compared with that of adjacent noncancerous tissues (P<0.05). However, the level of RhoGDI3 was identified to be similar in tumor and para-carcinoma tissues. Additionally, Kaplan-Meier curves demonstrated that patients with lower expression of RhoGDI1 or RhoGDI2 exhibited significantly increased risk of tumor recurrence following LT (P=0.007 and P=0.006, respectively). Cox proportional hazards model analysis revealed that the decreased expression level of RhoGDI2 was an unfavorable independent prognostic factor (hazard ratio, 3.306; P=0.001). In vitro studies involving the silencing of RhoGDI1 or RhoGDI2 demonstrated a significant increase in the migratory and invasive ability of tumor cells upon the silencing of these genes. Results from the present study indicate that RhoGDI dysregulation is a frequent event in human HCC, and that it promotes cancer progression by stimulating cell migration and invasion. RhoGDI2 may be a prognostic biomarker for patients with HCC following LT, and act as a potential therapeutic target. PMID:28789355

  17. Clonal xenobiotic resistance during pollution-induced toxic injury and hepatocellular carcinogenesis in liver of female flounder (Platichthys flesus (L.)).

    PubMed

    Koehler, Angela; Alpermann, Tilmann; Lauritzen, Bjarne; Van Noorden, Cornelis J F

    2004-01-01

    Juvenile and adult female flounder (Platichthys flesus (L.)) were caught either in the estuary of the most polluted European river, the Elbe, or as controls in a reference site to study pollution-induced xenobiotic resistance in their livers in relation to pathological alterations. In juvenile fish, livers displayed reversible and irreversible degenerative toxipathic lesion types but never showed (pre)neoplastic changes. Tumour frequencies up to 70% were found macroscopically in livers of adult female flounder which had progressed to adenomas and carcinomas in the most polluted site. Because male adult flounder show only up to 50% of livers containing early preneoplastic foci but never malignancies, we focussed our study on female individuals. (Pre)neoplastic changes ranged from early eosinophilic foci to basophilic foci, adenomas and hepatocellular carcinomas. Adenomas were generally eosinophilic whereas carcinomas were mainly basophilic. These phenotypical sequential changes strongly resemble those found in chemically-induced liver carcinogenesis in mammals. Characteristic mutations known from mammalian cancers have not been found so far in these flounder livers. Therefore, we investigated whether epigenetic events had induced a metabolic "resistant phenotype" of (pre)malignant cancer cells during hepatocellular carcinogenesis. With a quantitative immunohistochemical approach, we studied expression of P-glycoprotein (P-gp)-mediated multixenobiotic resistance (MXR), cytochrome P4501A1, glutathione-S-transferase-A which are key proteins in xenobiotic metabolism and elimination. Glucose-6-phosphate dehydrogenase (G6PDH) activity, the major source of the reducing power NADPH which is needed for biotransformation, oxyradical scavenging and biosynthesis, was detected as well. We observed upregulation of G6PDH activity already in early preneoplastic eosinophilic foci and subsequent further upregulation in basophilic foci and carcinomas. P-gp started to become

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

    PubMed

    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 < 0.05). Furthermore, the incidence of recurrence of HCC was doubled in the presence of overweight (15%) and obesity (15%) compared with non-obesity (7%) (P < 0.05). Time to recurrence also decreased significantly. Differences in mean ± standard deviation survival in the overweight (45 ± 3 months) and 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.

  19. Malnutrition, liver damage, and cancer.

    PubMed

    Grasso, P

    1981-01-01

    There is no clear indication that malnutrition, per se, is a principal cause of cancer in man, but the prevalence of liver cancer in areas where malnutrition exists supports this hypothesis. Liver damage and liver cancer have been induced in laboratory rats by diets consisting of peanut meal and proteins deficient in some essential amino acids. However, liver damage, but not cancer, was produced when the diets contained no peanut meal but consisted of a mixture of amino acids deficient in methionine and cysteine, so that it is possible that aflatoxin, a contaminant of peanut meal, may have been responsible for the malignancies seen in the earlier experiments. Liver cancer developes in a high proportion of mice allowed to feed ad libitum or given a diet containing a high proportion of fat (groundnut oil) or protein (casein). Dietary restriction reduced the incidences of this cancer. This findings lends some support to current thinking that diet may be a factor in the development of cancer in man.

  20. Role of Sorafenib in Patients With Recurrent Hepatocellular Carcinoma After Liver Transplantation.

    PubMed

    de'Angelis, Nicola; Landi, Filippo; Nencioni, Marco; Palen, Anais; Lahat, Eylon; Salloum, Chady; Compagnon, Philippe; Lim, Chetana; Costentin, Charlotte; Calderaro, Julien; Luciani, Alain; Feray, Cyrille; Azoulay, Daniel

    2016-12-01

    The management of hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) is challenging, especially if it is not treatable by surgery or embolization. The present study aims to compare the survival rates of liver transplanted patients receiving sorafenib or best supportive care (BSC) for HCC recurrence not amenable to curative intent treatments. This is a retrospective comparative study on a prospectively maintained database. Liver transplanted patients with untreatable HCC recurrence receiving BSC (n = 18) until 2007 or sorafenib (n = 15) thereafter were compared. No group difference was observed for demographic characteristics at the time of transplantation and at the time of HCC recurrence. On the explant pathology of the native liver, 81.2% patients were classified within the Milan criteria, and 53.1% presented with microvascular invasion. Hepatocellular carcinoma recurrence was diagnosed 17.8 months (standard deviation: 14.5) after LT, with 17 (53.1%) patients presenting with early recurrence (≤12 months). The 1-year survival from untreatable progression of HCC recurrence was 23.9% for the BSC and 60% for the sorafenib group ( P = .002). The type of treatment (sorafenib vs BSC) was the sole independent predictor of survival (hazard ratio: 2.98; 95% confidence interval: 1.09-8.1; P = .033). In the sorafenib group, 8 (53.3%) patients required dose reduction, and 2 (13.3%) patients discontinued the treatment due to intolerable side effects. Sorafenib improves survival and is superior to the BSC in cases of untreatable posttransplant hepatocellular carcinoma recurrence.

  1. Total tumor volume predicts survival following liver resection in patients with hepatocellular carcinoma.

    PubMed

    Li, Mu-Xing; Zhao, Hong; Bi, Xin-Yu; Li, Zhi-Yu; Huang, Zhen; Han, Yue; Zhou, Jian-Guo; Zhao, Jian-Jun; Zhang, Ye-Fan; Wei, Wen-Qiang; Zhao, Dong-Bin; Cai, Jian-Qiang

    2016-07-01

    Assessing the prognosis of patients with hepatocellular carcinoma (HCC) by the number and size of tumors is sometimes difficult. The main purpose of the study was to evaluate the prognostic value of total tumor volume (TTV), which combines the two factors, in patients with HCC who underwent liver resection. We retrospectively reviewed 521 HCC patients from January 2001 to December 2008 in our center. Patients were categorized using the tertiles of TTV. The prognostic value of TTV was assessed. With a median follow-up of 116 months, the 1-, 3-, and 5-year overall survival (OS) rates of the patients were 93.1 , 69.9, and 46.3 %, respectively. OS was significantly differed by TTV tertile groups, and higher TTV was associated with shorter OS (P < 0.001). Multivariate analysis revealed that TTV was an independent prognostic factor for OS. Larger TTV was significantly associated with higher alpha-fetoprotein level, presence of macrovascular invasion, multiple tumor lesions, larger tumor size, and advanced tumor stages (all P < 0.05). Within the first and second tertiles of TTV (TTV ≤ 73.5 cm(3)), no significant differences in OS were detected in patients within and beyond Milan criteria (P = 0.183). TTV-based Cancer of the Liver Italian Program (CLIP) score gained the lowest Akaike information criterion value, the highest χ (2) value of likelihood ratio test, and the highest C-index among the tested staging systems. Our results suggested that TTV is a good indicator of tumor burden in patients with HCC. Further studies are warranted to validate the prognostic value of TTV.

  2. Human liver carboxylesterase 1 outperforms alpha-fetoprotein as biomarker to discriminate hepatocellular carcinoma from other liver diseases in Korean patients.

    PubMed

    Na, Keun; Jeong, Seul-Ki; Lee, Min Jung; Cho, Sang Yun; Kim, Sun A; Lee, Min-Ji; Song, Si Young; Kim, Hoguen; Kim, Kyung Sik; Lee, Hyun Woong; Paik, Young-Ki

    2013-07-15

    Although alpha-fetoprotein (AFP) is currently the major serologic biomarker for hepatocellular carcinoma (HCC), it cannot efficiently distinguish this cancer from other forms of liver disease in early diagnosis due to its low sensitivity. The aim of this study is to compare sensitivity and specificity of human carboxylesterase 1 (hCE1) and AFP biomarker. Antibody-based assays for hCE1 and AFP were used to test both biomarkers with respect to diagnostic efficiency, Youden's index and the area under the curve (AUC) through receiver operating characteristic (ROC) analysis in plasma from 208 patients with HCC (n=57), liver cirrhosis (n=27), chronic hepatitis (n=37), cholangiocarcinoma (n=22), gastric cancer (n=31) and pancreatic cancer (n=34), along with 52 healthy donors (HDs). The levels of hCE1 were significantly higher in patients with HCC than HDs and the other diseases (p<0.005), further verified by AUC values and Youden's index. In the set of HCC versus liver cirrhosis the AUC values were 0.744 (AFP), 0.918 (hCE1) and 0.938 (combination of AFP and hCE1), respectively. These results indicate that hCE1 is not only a more potent and specific marker in distinguishing cancer from liver diseases, in particular cirrhosis, but the combination of hCE1 and AFP shows also synergistic potential for greater sensitivity and specificity in early diagnosis. Therefore the antibody-based hCE1 assay appears to have high diagnostic efficiency for discriminating HCC from other forms of liver disease. It is now feasible to further validate this novel plasma-based biomarker in the large cohort we assembled. Copyright © 2013 UICC.

  3. Liver cancer diagnosis by fluorescence spectra of blood and urine

    NASA Astrophysics Data System (ADS)

    AlSalhi, Mohamad Saleh; Al Mehmadi, Abdulaziz Mayuof; Abdoo, Aiman; Masilamani, Vadivel

    2012-03-01

    Liver cancer or hepatocellular carcinoma (HCC) is a serious malady with only 10% survival rate. HCC incidence and mortality both are highest in China. This disease is detected and diagnosed by ultra sound, CT or MRI scans which are quite expensive. Also the discrimination between cirrhosis and HCC are poor by this imaging technique. The conventional tissue biopsy is quite invasive and painful. In this context, in the new diagnostic procedure presented in this paper, all the three liver malfunctions, particularly liver cancer, could be detected and discriminated by the spectral feature of blood and urine with accuracy about 80%. All that we need are 5 ml of blood and 5 ml of urine. Hence this inexpensive non invasive, optical technique will have significant impact in screening, diagnosis and also prognosis of HCC in large segment of people in the populous Asian countries.

  4. Liver cancer diagnosis by fluorescence spectra of blood and urine

    NASA Astrophysics Data System (ADS)

    AlSalhi, Mohamad Saleh; Al Mehmadi, Abdulaziz Mayuof; Abdoo, Aiman; Masilamani, Vadivel

    2011-11-01

    Liver cancer or hepatocellular carcinoma (HCC) is a serious malady with only 10% survival rate. HCC incidence and mortality both are highest in China. This disease is detected and diagnosed by ultra sound, CT or MRI scans which are quite expensive. Also the discrimination between cirrhosis and HCC are poor by this imaging technique. The conventional tissue biopsy is quite invasive and painful. In this context, in the new diagnostic procedure presented in this paper, all the three liver malfunctions, particularly liver cancer, could be detected and discriminated by the spectral feature of blood and urine with accuracy about 80%. All that we need are 5 ml of blood and 5 ml of urine. Hence this inexpensive non invasive, optical technique will have significant impact in screening, diagnosis and also prognosis of HCC in large segment of people in the populous Asian countries.

  5. Liver Cancer Risk Prediction Models

    Cancer.gov

    Developing statistical models that estimate the probability of developing liver cancer over a defined period of time will help clinicians identify individuals at higher risk of specific cancers, allowing for earlier or more frequent screening and counseling of behavioral changes to decrease risk.

  6. Hepatic Stellate Cells Alter Liver Immune Environment to Promote Cancer | Center for Cancer Research

    Cancer.gov

    Hepatocellular carcinoma (HCC) is the most common form of liver cancer, accounting for up to 90 percent of cases, and is the second most common cause of cancer-related deaths worldwide according to the World Health Organization’s 2014 World Cancer Report. Even when caught early, HCC often recurs, either from intra-liver metastases or new primary tumors, and recurrence is the leading cause of death for patients with HCC. The liver microenvironment is an important contributor to HCC initiation and progression and also likely plays a role in tumor recurrence. Xin Wei Wang, Ph.D., of CCR’s Laboratory of Human Carcinogenesis, and his colleagues wondered whether activated hepatic stellate cells (A-HSCs), stromal cells in the liver known to participate in repair following injury and in the development of fibrosis, contribute directly to HCC recurrence.

  7. Multiple Bone Metastases as the First Manifestation of Hepatocellular Carcinoma in Patient with Noncirrhotic Liver

    PubMed Central

    Bae, Soo Ya; Kim, Hyun Jung; Oh, Hyun Ho; Kwon, Min Kwan; Lee, Jong Ho; Park, Moon; Sohn, Byeong Seok

    2015-01-01

    Hepatocellular carcinoma (HCC) generally occurs on the background of chronic liver disease. Chronic hepatitides B and C and alcoholic liver disease are well-known risk factors for HCC, and it is uncommon in noncirrhotic liver. Extrahepatic metastasis seldom occurs in patients with early stage intrahepatic HCC and isolated bone metastases as a first documented extrahepatic metastasis is unusual presentation. In this report, we present a rare case of small solitary HCC (<3 cm) in noncirrhotic liver, presenting isolated bone metastases as a sole manifestation in patient with no well-known risk factors. This case suggests that HCC should be considered as one of differential diagnoses in patient presenting with multiple bone metastases, even in the absence of liver cirrhosis. PMID:26635983

  8. Elevated renin levels in patients with liver cirrhosis and hepatocellular carcinoma.

    PubMed

    Lotfy, Mahmoud; El-Kenawy, Ayman El-Meghawry; Abdel-Aziz, Mohamed M; El-Kady, Ibrahim; Talaat, Ayman

    2010-01-01

    Liver fibrosis is the common consequence of chronic liver injury of any etiology, disrupting the normal architecture,and causing hepatocellular dysfunction and portal hypertension. Since the renin-angiotensin system (RAS) may be involved in chronic liver diseases, in the present study we assayed renin levels using ELISA in groups of Egyptian patients with liver cirrhosis (N=32) and hepatocellular carcinoma (HCC) (N=67), for comparison with twenty five healthy controls. The results showed significant differences between the control and liver cirrhosis patients (P<0.001) and also the controls and HCC patients (P<0.001), without significant variation between the patient groups. Furthermore, in HCC patients, it was found that the renin levels negatively correlated with serum albumin and prothrombin time (P=0.003 for each) and positively with α-fetoprotein (P=0.04). Thus, it is concluded that renin levels are elevated in patients with liver cirrhosis and HCC and suitable medical intervention should be placed for management of such alteration. Moreover, further studies are warranted to explore its prognostic significance.

  9. CT assessment of liver hemodynamics in patients with hepatocellular carcinoma after argon-helium cryoablation.

    PubMed

    Hao, Xue-Jia; Li, Jin-Ping; Jiang, Hui-Jie; Li, Da-Qing; Ling, Zai-Sheng; Xue, Li-Ming; Feng, Guang-Long

    2013-12-01

    Assessment of tumor response after argon-helium cryoablation is critical in guiding future therapy for unresectable hepatocellular carcinoma. This study aimed to evaluate liver hemodynamics in hepatocellular carcinoma after argon-helium cryoablation with computed tomography perfusion. The control group comprised 40 volunteers without liver disease. The experimental group was composed of 15 patients with hepatocellular carcinoma treated with argon-helium cryoablation. Computed tomography perfusion parameters were measured: hepatic blood flow, hepatic blood volume, mean transit time, permeability of capillary vessel surface, hepatic arterial fraction, hepatic arterial perfusion, and hepatic portal perfusion. After treatment, in the tumor foci, permeability of capillary vessel surface was higher, and hepatic blood flow, hepatic blood volume, hepatic arterial fraction, and hepatic arterial perfusion values were lower (P<0.05). In the liver parenchyma surrounding the tumor, hepatic arterial perfusion was significantly lower (P<0.05); however, there was no significant difference in hepatic blood flow, hepatic blood volume, mean transit time, permeability of capillary vessel surface, hepatic arterial fraction, or hepatic portal perfusion (P>0.05). Computed tomography perfusion can evaluate tumor response after argon-helium cryoablation.

  10. Multimodality Therapy and Liver Transplantation for Hepatocellular Carcinoma: A 14-Year Prospective Analysis of Outcomes

    PubMed Central

    Ramanathan, Rajesh; Sharma, Amit; Lee, David D; Behnke, Martha; Bornstein, Karen; Stravitz, R Todd; Sydnor, Malcolm; Fulcher, Ann; Cotterell, Adrian; Posner, Marc P; Fisher, Robert A

    2014-01-01

    Background Hepatocellular carcinoma is a major cause of death among patients with cirrhosis. A standardized approach of multimodality therapy with intent-to-treat by transplantation for all patients with hepatocellular carcinoma was instituted at our transplant center in 1997. Data were prospectively collected to evaluate the impact of multimodality therapy on post-transplant patient survival, tumor recurrence and patient survival without transplantation. Methods All patients with hepatocellular carcinoma were eligible for multimodality therapy. Multimodality therapy consisted of hepatic resection, radiofrequency ablation, transarterial chemoembolization, transarterial chemoinfusion, yttrium-90 microsphere radioembolization and sorafenib. Results 715 patients underwent multimodality therapy. 231 patients were included in the intent-to-treat with transplantation arm and 484 patients were treated with multimodality therapy or palliative therapy due to contraindications for transplantation. A 60.2% transplantation rate was achieved in the intent-to-treat with transplantation arm. Post-transplant survivals at 1- and 5-years were 97.1% and 72.5% respectively. Tumor recurrence rates at 1-, 3- and 5-years were 2.4%, 6.2% and 11.6% respectively. Patients with contraindications to transplant had increased 1- and 5-year survival from diagnosis with multimodality therapy compared to those not treated (73.1% and 46.5% vs. 15.5% and 4.4%, p<0.0001). Conclusions Using multimodality therapy prior to liver transplantation for hepatocellular carcinoma achieved low recurrence rates and post-transplant survival equivalent to patients with primary liver disease without hepatocellular carcinoma. Multimodality therapy may help identify patients with less active tumor biology and result in improved disease-free survival and organ utilization. PMID:24503764

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

    PubMed

    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.

  12. Anatomic versus non-anatomic liver resection for hepatocellular carcinoma: a systematic review.

    PubMed

    Tang, Yun-Hao; Wen, Tian-Fu; Chen, Xi

    2013-01-01

    To evaluate the feasibility and therapeutic effects of anatomic liver resection versus non-anatomic liver resection for hepatocellular carcinoma. Randomized controlled trials and non-randomized trials comparing the clinical effectiveness between anatomic and non-anatomic liver resection for hepatocellular carcinoma were identified by using a predefined search strategy. A meta-analysis was performed to estimate pooled survival and recurrence rate. No Randomized controlled trial was identified. Twelve non-randomized comparative trials (10 in English and 2 in Chinese) including total 1,829 cases, 1,005 cases in anatomic resection group and 824 cases in non-anatomic resection group, were included in this review. Meta-analysis showed that there was no significant difference between anatomic and non-anatomic liver resection in 1-year survival rate (p = 0.98), 3-year survival rate (p = 0.75), 5-year survival rate (p = 0.38) and recurrence rate (p = 0.44). The differences in post-operative morbidity (p = 0.32) and blood loss during operation (p = 0.11) were also not statistically significant. Anatomic liver resection for HCC does not provide significant benefit in 1-year/3-year/5-year survival rate, recurrence rate, post-operative morbidity and blood loss during operation compared with non-anatomic resection.

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

    PubMed

    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.

  14. Catheter-based transarterial therapies for hepatocellular cancer.

    PubMed

    Laroia, Sandeep T; Morales, Steven A; Laroia, Archana T

    2015-12-01

    As the prevalence of liver cancer increases, so does the demand for nonsurgical, minimally invasive alternatives to surgery, since many patients have tumors that cannot be surgically resected. Catheter-based hepatic arterial procedures may be an option in patients with primary and metastatic liver cancer. The authors describe four catheter-based hepatic arterial procedures and outline the management of potential complications during the immediate postprocedural period.

  15. Neutrophil-lymphocyte ratio predicts the prognosis of patients with hepatocellular carcinoma after liver transplantation

    PubMed Central

    Xiao, Guang-Qin; Liu, Chang; Liu, Da-Li; Yang, Jia-Yin; Yan, Lu-Nan

    2013-01-01

    AIM: To determine whether an elevated neutrophil-lymphocyte ratio (NLR) is negatively associated with tumor recurrence in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after liver transplantation (LT), and to determine the optimal predictive NLR cut-off value. METHODS: The data of HCC patients who had undergone LT came from the China Liver Transplant Registry database. We collected data from 326 liver cancer patients who had undergone LT at our medical center. We divided the patients into groups based on their NLRs (3, 4 or 5). We then compared the clinicopathological data and long-time survival between these groups. Meanwhile, we used receiver operating characteristic analysis to determine the optimal NLR cut-off. RESULTS: Of 280 HCC patients included in this study, 263 were HBV positive. Patients with an NLR < 3 and patients with an NLR ≥ 3 but < 4 showed no significant differences in overall survival (OS) (P = 0.212) or disease-free survival (DFS) (P = 0.601). Patients with an NLR ≥ 4 but < 5 and patients with an NLR ≥ 5 also showed no significant differences in OS (P = 0.208) or DFS (P = 0.618). The 1-, 3- and 5-year OS rates of patients with an NLR < 4 vs an NLR ≥ 4 were 87.8%, 63.8% and 61.5% vs 73.9%, 36.7% and 30.3%, respectively (P < 0.001). The 1-, 3- and 5-year DFS rates of patients with an NLR < 4 vs NLR ≥ 4 were 83.9%, 62.9% and 60.7% vs 64.9%, 30.1% and 30.1%, respectively (P < 0.001). Univariate and multivariate analyses demonstrated that three factors, including NLR ≥ 4 (P = 0.002), were significant predictors of tumor recurrence in HCC patients after LT. CONCLUSION: A preoperative elevated NLR significantly increased the risk for tumor recurrence in HCC patients after LT. PMID:24363533

  16. Distinction between hemangioma of the liver and hepatocellular carcinoma: value of labeled RBC-SPECT scanning

    SciTech Connect

    Kudo, M.; Ikekubo, K.; Yamamoto, K.; Ibuki, Y.; Hino, M.; Tomita, S.; Komori, H.; Orino, A.; Todo, A.

    1989-05-01

    The role of adding single-photon emission CT (SPECT) to /sup 99m/Tc-labeled RBC imaging of the liver was evaluated by specifically focusing on the differentiation between hepatic hemangioma and hepatocellular carcinoma. Planar RBC imaging followed by blood-pool SPECT scanning was performed in 77 patients with a total of 108 hemangiomas and in 29 patients with a total of 46 hepatocellular carcinomas. All lesions were smaller than 5 cm in diameter. Thirty-six (33%) of 108 hemangiomas were detected by planar delayed RBC imaging, whereas 63 (58%) were detected by the delayed RBC-SPECT scan. The smallest hemangioma shown by delayed RBC-SPECT scanning was 1.4 cm in diameter, compared with 1.7 cm by planar RBC scanning. When confined to nodules larger than 1.4 cm in diameter, 42% of hemangiomas (36/85) were detected by planar delayed RBC imaging, whereas 74% (63/85) were detected by delayed RBC-SPECT. Increase in sensitivity was noted in nodules 2.1-4.0 cm in diameter. No hepatocellular carcinomas were shown by delayed RBC planar or SPECT scans. We concluded that with the addition of SPECT, the sensitivity of delayed RBC scans in the detection of small hemangiomas is considerably improved. Delayed RBC-SPECT scanning can be used to distinguish hemangioma from hepatocellular carcinoma.

  17. Prospect of the use of checkpoint inhibitors in hepatocellular cancer treatments

    PubMed Central

    Raufi, Ali; Tirona, Maria Tria

    2017-01-01

    Hepatocellular cancer (HCC) is a very fatal disease due to limited therapeutic options as well as due to its association with underlying chronic liver disease in the majority of cases. The immune evasion in HCC signifies a major barrier to the delivery of effective immunotherapy. Sorafenib is the only Food and Drug Administration-approved drug available with an overall response rate of 2%–3% and overall survival of 2.8 months. Chemotherapy has not been used routinely because of the relative refractoriness of advanced HCC. The introduction of immune checkpoint inhibitors (cytotoxic T-lymphocyte antigen 4, programmed death 1, and programmed death-ligand 1) has opened a new horizon for cancer immunotherapy. Future direction in immunotherapy for HCC is to rationally combine it with other treatment modalities, including surgery, radiofrequency ablation, and cytotoxic agents, to maximize its therapeutic efficacy. PMID:28223846

  18. Some characteristics of Mozambican Shangaans with primary hepatocellular cancer.

    PubMed

    Kew, M C; Marcus, R; Geddes, E W

    1977-03-05

    Certain characteristics of 328 Mozambican male Shangaans with primary hepatocellular cancer (PHC) have been compared with those of 163 Shangaan men with hepatomegaly from causes other than PHC and with those of 122 Black Southern African men with the same tumour but who belonged to tribes other than the Shangaan. Shangaans with PHC were significantly younger than non-Shangaans with the tumour (mean age 33,4 cf. 40,0 years; Pless than 0,001). They also had a significantly higher positivity rate of alpha-fetoprotein by immunodiffusion (71,4%) than the non-Shangaans (16%), although in other respects the tumours appeared to be similar. Cirrhosis of the non-tumorous part of the liver was present at necropsy in 62% of the Shangaans and in 66% of the non-Shangaans. The hepatitis B (surface) antigen (HBsAg) was detected in the serum of 60% of the Shangaans with PHC compared with only 9% of the controls. The antigen was present in 53,4% of the non-Shangaans with PHC (the difference between this fifure and that in the Shangaans was not significant). HBsAg was detected in the serum of 64% of the Shangaans with PHC and cirrhosis, but also in 74% of those with the tumour without associated cirrhosis. The possible role of the hepatitis B verus in the aetiology of PHC is considered in the light both of these findings and of the possibility that the frequency with which the tumour is associated with cirrhosis may be decreasing in Shangaans. Some of the dietary habits of the Shangaans with PHC were compared with those of the controls. Virtually all the patients with PHC, but also almost all the controls, ate groundnuts in large quantities from an early age, as well as cashew nuts in smaller amounts. Cycad pips, mopani leaves and pods, mopani worms and locusts were not eaten by significantly more of the Shangaans with PHC than the controls. The limitations of this type of dietary analysis are discussed.

  19. Hepatocellular cancer: the impact of obesity, type 2 diabetes and a multidisciplinary team.

    PubMed

    Dyson, Jessica; Jaques, Bryan; Chattopadyhay, Dipankar; Lochan, Rajiv; Graham, Janine; Das, Debasish; Aslam, Tahira; Patanwala, Imran; Gaggar, Sameer; Cole, Michael; Sumpter, Kate; Stewart, Stephen; Rose, John; Hudson, Mark; Manas, Derek; Reeves, Helen L

    2014-01-01

    Hepatocellular cancer (HCC) commonly complicates chronic liver disease and increases in incidence have been reported despite falling prevalences of viral hepatitis. Following the introduction of centralised specialist teams to manage patients with cancer in England, we characterised the demographics of patients with HCC referred to the Newcastle-upon-Tyne Hospitals NHS Foundation Trust between 2000 and 2010. Regional HCC mortality data was from Public Health England. HCC related mortality in the region rose 1.8 fold in 10 years, from 2.0 to 3.7 per 100,000. 632 cases were reviewed centrally, with 2-3 fold increases in referrals of patients with associated hepatitis C, alcoholic liver disease or no chronic liver disease and a >10 fold increase in HCC associated with non-alcoholic fatty liver disease (NAFLD). By 2010 NAFLD accounted for 41/118 (34.8%) cases. Irrespective of associated etiologies, metabolic risk factors were present in 78/118 (66.1%) cases in 2010, associated with regional increases in obesity and diabetes. Median overall survival was just 10.7 months. Although patients with NAFLD associated HCC were older (71.3 yr vs. 67.1 yr; p<0.001) and their cancers less often detected by surveillance, their survival was similar to other etiologies. This was attributed to significantly higher incidental presentation (38.2%) and lower prevalence of cirrhosis (77.2%). HCC related mortality is increasing, with typical patients being elderly with metabolic risk factors. The prognosis for most of the cases is poor, but older patients with co-morbidities can do well, managed, within a specialist multidisciplinary team if their cancer is detected pre-symptomatically. Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  20. Familial liver and gall bladder cancer: a nationwide epidemiological study from Sweden

    PubMed Central

    Hemminki, K; Li, X

    2003-01-01

    Background and aims: Familial risks in liver and biliary cancers have been assessed in small case control studies, usually based on reported, but not medically verified, cancers in family members. Thus the degree of familial clustering for these cancers remains to be established. Methods: The nationwide Swedish Family-Cancer Database was used, covering 10.2 million individuals for the years 1961–1998 from the Swedish Cancer Registry. Liver and biliary tract cancers were identified from 1121 offspring between the ages of 0 and 66 years and 17 131 parents. Standardised incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated for cancers in family members. Results: All cancers in the liver and biliary system showed a familial SIR of 1.65 (95% CI 1.05–2.46). This was mainly explained by a high risk for familial gall bladder cancer (SIR 5.21 (95% CI 2.07–10.80)) and for familial primary liver cancer with hepatocellular carcinoma histology (SIR 4.69 (95% CI 1.48–11.04)). For gall bladder and hepatocellular cancer, maternal transmission appeared to be favoured. Gall bladder cancer was associated with pancreatic cancer (SIR 2.39 (95% CI 1.23–4.18)). Primary liver cancer was associated with cervical, urinary bladder, and endocrine gland tumours. Cancer in extrahepatic bile ducts was associated with ovarian cancer and that in ampulla of Vater with thyroid cancer; however, these associations may have been fortuitous. Conclusions: This study has provided the first data on familial clustering of liver and gall bladder cancers, based on medically confirmed records. The risks were so high that heritable factors were likely to contribute, possibly modified by environmental factors. The demonstration of candidate genes would help to further characterise the familial risks. PMID:12631675

  1. Familial liver and gall bladder cancer: a nationwide epidemiological study from Sweden.

    PubMed

    Hemminki, K; Li, X

    2003-04-01

    Familial risks in liver and biliary cancers have been assessed in small case control studies, usually based on reported, but not medically verified, cancers in family members. Thus the degree of familial clustering for these cancers remains to be established. The nationwide Swedish Family-Cancer Database was used, covering 10.2 million individuals for the years 1961-1998 from the Swedish Cancer Registry. Liver and biliary tract cancers were identified from 1121 offspring between the ages of 0 and 66 years and 17 131 parents. Standardised incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated for cancers in family members. All cancers in the liver and biliary system showed a familial SIR of 1.65 (95% CI 1.05-2.46). This was mainly explained by a high risk for familial gall bladder cancer (SIR 5.21 (95% CI 2.07-10.80)) and for familial primary liver cancer with hepatocellular carcinoma histology (SIR 4.69 (95% CI 1.48-11.04)). For gall bladder and hepatocellular cancer, maternal transmission appeared to be favoured. Gall bladder cancer was associated with pancreatic cancer (SIR 2.39 (95% CI 1.23-4.18)). Primary liver cancer was associated with cervical, urinary bladder, and endocrine gland tumours. Cancer in extrahepatic bile ducts was associated with ovarian cancer and that in ampulla of Vater with thyroid cancer; however, these associations may have been fortuitous. This study has provided the first data on familial clustering of liver and gall bladder cancers, based on medically confirmed records. The risks were so high that heritable factors were likely to contribute, possibly modified by environmental factors. The demonstration of candidate genes would help to further characterise the familial risks.

  2. Prognosis of Hepatocellular Carcinoma after Liver Transplantation: Comparative Analysis with Partial Hepatectomy

    PubMed Central

    Lee, Kyuho; Lee, Kyoung-Bun; Yi, Nam-Joon; Suh, Kyung-Suk; Jang, Ja-June

    2017-01-01

    Background Liver transplantation (LT) is the treatment of choice for hepatocellular carcinoma (HCC). The aim of this study was to investigate the recurrence rate of HCC after LT and prognostic factors for recurrence by comparing LT with non-transplanted resection. Methods The participants were 338 patients who underwent LT between 1996 and 2012 at Seoul National University Hospital (LT group) and 520 HCC patients who underwent partial hepatectomy between 1995 and 2006 (control group, non-LT group). Results In the LT group, 68 of 338 patients (19.8%) showed relapse, and the recurrence rate was lower than that in the non-LT group (64.9%, 357/520, p < .001). Stratification analysis by American Joint Committee on Cancer (AJCC) stage showed that the stage I-II LT group had a lower recurrence rate than the non-LT group. Univariate comparative analysis demonstrated that multiplicity of tumor, tumor size, gross type, Edmondson- Steiner (ES) nuclear grade, extent of tumor, angioinvasion, AJCC stage, Milan criteria, University of California at San Francisco criteria on explant pathology (all p < .001), positive expression of cytokeratin 19 (p = .002), and preoperative α-fetoprotein (AFP) (p < .001) were predictors of tumor recurrence. In multivariate analysis, LT, preoperative AFP, multiplicity of tumor, extent of tumor, size of tumor, and ES nuclear grade were independent prognostic factors. Conclusions LT might have a protective effect against the late recurrence of stage I-II HCC compared to non-LT, and the prognostic factors for recurrence were similar to previously well-known prognostic factors for HCC. PMID:28013531

  3. Timing of Antiviral Therapy in Candidates for Liver Transplant for Hepatitis C and Hepatocellular Carcinoma.

    PubMed

    Saab, Sammy; Jimenez, Melissa; Fong, Tiffany; Wu, Crystal; El Kabany, Mohamed; Tong, Myron J

    2016-02-01

    Hepatitis C virus infection is the most common underlying reason for hepatocellular carcinoma and indication for liver transplant. The increased availability of non-interferon-based therapy has expanded the number of treatment-eligible patients. We used a decision analysis model to compare 2 strategies of treating hepatitis C virus. Included patients were followed for 1 year after liver transplant. The probabilities and costs were obtained from a literature review, an expert panel, and our institution's experience. Sensitivity analyses were performed on all variables. Our model demonstrated that it would be less costly to treat patients after liver transplant than to treat patients while they wait for transplant. When we compared baseline values, the cost difference between the 2 strategies was $25,011 per patient and $41,535 per sustained viral response. Overall survival was 60.1% for both strategies. Our model was robust across most of the variables tested in the sensitivity analysis. Our results indicated that there is no substantial pharmacoeconomic or survival advantage of treating hepatitis C virus in patients with compensated cirrhosis and hepatocellular carcinoma before liver transplant versus after transplant.

  4. Specific patterns of PIWI-interacting small noncoding RNA expression in dysplastic liver nodules and hepatocellular carcinoma

    PubMed Central

    Marchese, Giovanna; Coviello, Elena; Sellitto, Assunta; Cordella, Angela; Giurato, Giorgio; Nassa, Giovanni; Ravo, Maria; Tarallo, Roberta; Milanesi, Luciano; Destro, Anna; Torzilli, Guido; Roncalli, Massimo; Di Tommaso, Luca; Weisz, Alessandro

    2016-01-01

    Hepatocellular carcinoma (HCC) is the result of a stepwise process, often beginning with development within a cirrhotic liver of premalignant lesions, morphologically characterized by low- (LGDN) and high-grade (HGDN) dysplastic nodules. PIWI-interacting RNAs (piRNAs) are small noncoding RNAs (sncRNAs), 23–35 nucleotide-long, exerting epigenetic and post-transcriptional regulation of gene expression. Recently the PIWI-piRNA pathway, best characterized in germline cells, has been identified also in somatic tissues, including stem and cancer cells, where it influences key cellular processes. Small RNA sequencing was applied to search for liver piRNAs and to profile their expression patterns in cirrhotic nodules (CNs), LGDN, HGDN, early HCC and progressed HCC (pHCC), analyzing 55 samples (14 CN, 9 LGDN, 6 HGDN, 6 eHCC and 20 pHCC) from 17 patients, aiming at identifying possible relationships between these sncRNAs and liver carcinogenesis. We identified a 125 piRNA expression signature that characterize HCC from matched CNs, correlating also to microvascular invasion in HCC. Functional analysis of the predicted RNA targets of deregulated piRNAs indicates that these can target key signaling pathways involved in hepatocarcinogenesis and HCC progression, thereby affecting their activity. Interestingly, 24 piRNAs showed specific expression patterns in dysplastic nodules, respect to cirrhotic liver and/or pHCC. The results demonstrate that the PIWI-piRNA pathway is active in human liver, where it represents a new player in the molecular events that characterize hepatocarcinogenesis, from early stages to pHCC. Furthermore, they suggest that piRNAs might be new disease biomarkers, useful for differential diagnosis of dysplastic and neoplastic liver lesions. PMID:27429044

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

    SciTech Connect

    Choi, W; Wang, J; Lu, W; Kang, M

    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.

  6. Value of the 8-oxodG/dG ratio in chronic liver inflammation of patients with hepatocellular carcinoma

    PubMed Central

    Li, Pengcheng; Ramm, Grant A; Macdonald, Graeme A

    2016-01-01

    The aim of this study was to examine the role of oxidative DNA damage in chronic liver inflammation in the evolution of hepatocellular carcinoma. The accumulated data demonstrated that oxidative DNA damage and chronic liver inflammation are involved in the transformation of normal hepatocytes and their evolution towards hepatocellular carcinoma. However, the levels of 8-oxy-2′-deoxy-guanosine (8-oxodG), a biomarker of oxidative DNA damage, were overestimated and underestimated in previous reports due to various technical limitations. The current techniques are not suitable to analyze the 8-oxodG levels in the non-malignant liver tissues and tumors of hepatocellular carcinoma patients unless they are modified. Therefore, in this study, the protocols for extraction and hydrolysis of DNA were optimized using 54 samples from hepatocellular carcinoma patients with various risk factors, and the 8-oxodG and 2′-deoxyguanosine (dG) levels were measured. The patients enrolled in the study include 23 from The Princess Alexandra Hospital and The Royal Brisbane and Women's Hospitals, Brisbane, Australia, and 31 from South Africa. This study revealed that the 8-oxodG/dG ratios tended to be higher in most non-malignant liver tissues compared to hepatocellular carcinoma tissue (p=0.2887). It also appeared that the ratio was higher in non-malignant liver tissue from Southern African patients (p=0.0479), but there was no difference in the 8-oxodG/dG ratios between non-malignant liver tissues and tumors of Australian hepatocellular carcinoma patients (p=0.7722). Additionally, this study also revealed a trend for a higher 8-oxodG/dG ratio in non-malignant liver tissues compared to tumoural tissues of patients with HBV. Significant differences were not observed in the 8-oxodG/dG ratios between non-cirrhotic and cirrhotic non-malignant liver tissues. PMID:26890046

  7. Predictive Models of Liver Cancer

    EPA Science Inventory

    Predictive models of chemical-induced liver cancer face the challenge of bridging causative molecular mechanisms to adverse clinical outcomes. The latent sequence of intervening events from chemical insult to toxicity are poorly understood because they span multiple levels of bio...

  8. Predictive Models of Liver Cancer

    EPA Science Inventory

    Predictive models of chemical-induced liver cancer face the challenge of bridging causative molecular mechanisms to adverse clinical outcomes. The latent sequence of intervening events from chemical insult to toxicity are poorly understood because they span multiple levels of bio...

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

    PubMed Central

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

    2017-01-01

    Background and aims 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. Methods 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. Results 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. Conclusions Whereas resection is the standard therapy of HCC in healthy liver, a standard regarding the indication for LR and transplantation for HCC in

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

    PubMed

    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

  11. Trends in the incidence of primary liver cancer in Central Uganda, 1960–1980 and 1991–2005

    PubMed Central

    Ocama, P; Nambooze, S; Opio, C K; Shiels, M S; Wabinga, H R; Kirk, G D

    2009-01-01

    Primary liver cancer (PLC) incidence trends from Africa are unknown. Using Kampala Cancer Registry data from 1960 to 1980 and 1991 to 2005, we identified 771 PLCs. Although rates were stable among men, PLC incidence among women increased >50%. Investigations of viral hepatitis, aflatoxin, obesity, and human immunodeficiency virus (HIV) may help to explain the increasing incidence of hepatocellular carcinomas (HCCs). PMID:19174820

  12. Mitigation of autophagy ameliorates hepatocellular damage following ischemia-reperfusion injury in murine steatotic liver

    PubMed Central

    Kolachala, Vasantha L.; Jiang, Rong; Abramowsky, Carlos; Shenoi, Asha; Kosters, Astrid; Pavuluri, Haritha; Anania, Frank; Kirk, Allan D.

    2014-01-01

    Ischemia-reperfusion injury (IRI) is a common clinical consequence of hepatic surgery, cardiogenic shock, and liver transplantation. A steatotic liver is particularly vulnerable to IRI, responding with extensive hepatocellular injury. Autophagy, a lysosomal pathway balancing cell survival and cell death, is engaged in IRI, although its role in IRI of a steatotic liver is unclear. The role of autophagy was investigated in high-fat diet (HFD)-fed mice exposed to IRI in vivo and in steatotic hepatocytes exposed to hypoxic IRI (HIRI) in vitro. Two inhibitors of autophagy, 3-methyladenine and bafilomycin A1, protected the steatotic hepatocytes from HIRI. Exendin 4 (Ex4), a glucagon-like peptide 1 analog, also led to suppression of autophagy, as evidenced by decreased autophagy-associated proteins [microtubule-associated protein 1A/1B-light chain 3 (LC3) II, p62, high-mobility group protein B1, beclin-1, and autophagy-related protein 7], reduced hepatocellular damage, and improved mitochondrial structure and function in HFD-fed mice exposed to IRI. Decreased autophagy was further demonstrated by reversal of a punctate pattern of LC3 and decreased autophagic flux after IRI in HFD-fed mice. Under the same conditions, the effects of Ex4 were reversed by the competitive antagonist exendin 9-39. The present study suggests that, in IRI of hepatic steatosis, treatment of hepatocytes with Ex4 mitigates autophagy, ameliorates hepatocellular injury, and preserves mitochondrial integrity. These data suggest that therapies targeting autophagy, by Ex4 treatment in particular, may ameliorate the effects of IRI in highly prevalent steatotic liver. PMID:25258410

  13. [A case of double cancer of gastric and hepatocellular carcinoma associated with cirrhosis treated by hepatic resection after intra-hepatic arterial infusion chemotherapy].

    PubMed

    Une, Y; Nagabuchi, E; Ogasawara, K; Kamiyama, T; Sato, Y; Kawamukai, Y; Sato, N; Nakajima, Y; Uchino, J

    1990-08-01

    A case of double cancer, early gastric cancer and hepatocellular carcinoma, was reported. The patient was diabetic and had liver cirrhosis. After gastrectomy for gastric cancer which was hemorrhagic, he was treated by intra-hepatic arterial infusion chemotherapy followed by hepatic resection. Histopathologically, about half of the main tumor showed necrosis, but very viable new cancer cell nests were seen around the main nodule. The patient is in good condition without recurrence of hepatic lesion 1 year after resection. The usefulness of arterial infusion chemotherapy was demonstrated in the case of double cancer, in which it is difficult to resect both cancers simultaneously.

  14. Protection against Acute Hepatocellular Injury Afforded by Liver Fibrosis Is Independent of T Lymphocytes

    PubMed Central

    Lacoste, Benoit; Raymond, Valérie-Ann; Lapierre, Pascal; Bilodeau, Marc

    2016-01-01

    Collagen produced during the process of liver fibrosis can induce a hepatocellular protective response through ERK1 signalling. However, the influence of T cells and associated cytokine production on this protection is unknown. In addition, athymic mice are frequently used in hepatocellular carcinoma xenograft experiments but current methods limit our ability to study the impact of liver fibrosis in this setting due to high mortality. Therefore, a mouse model of liver fibrosis lacking T cells was developed using Foxn1 nu/nu mice and progressive oral administration of thioacetamide (TAA) [0.01–0.02%] in drinking water. Fibrosis developed over a period of 16 weeks (alpha-SMA positive area: 20.0 ± 2.2%, preCol1a1 mRNA expression: 11.7 ± 4.1 fold changes, hydroxyproline content: 1041.2 ± 77μg/g of liver) at levels comparable to that of BALB/c mice that received intraperitoneal TAA injections [200 μg/g of body weight (bw)] (alpha-SMA positive area: 20.9 ± 2.9%, preCol1a1 mRNA expression: 13.1 ± 2.3 fold changes, hydroxyproline content: 931.6 ± 14.8μg/g of liver). No mortality was observed. Athymic mice showed phosphorylation of ERK1/2 during fibrogenesis (control 0.03 ± 0.01 vs 16 weeks 0.22 ± 0.06AU; P<0.05). The fibrosis-induced hepatoprotection against cytotoxic agents, as assessed histologically and by serum AST levels, was not affected by the absence of circulating T cells (anti-Fas JO2 [0.5μg/g bw] for 6h (fibrotic 4665 ± 2596 vs non-fibrotic 13953 ± 2260 U/L; P<0.05), APAP [750 mg/kg bw] for 6 hours (fibrotic 292 ± 66 U/L vs non-fibrotic 4086 ± 2205; P<0.01) and CCl4 [0.5mL/Kg bw] for 24h (fibrotic 888 ± 268 vs non-fibrotic 15673 ± 2782 U/L; P<0.001)). In conclusion, liver fibrosis can be induced in athymic Foxn1 nu/nu mice without early mortality. Liver fibrosis leads to ERK1/2 phosphorylation. Finally, circulating T lymphocytes and associated cytokines are not involved in the hepatocellular protection afforded by liver fibrosis. PMID

  15. Incidence, Characteristics, and Prognosis of Incidentally Discovered Hepatocellular Carcinoma after Liver Transplantation

    PubMed Central

    El Moghazy, Walid; Kashkoush, Samy; Meeberg, Glenda; Kneteman, Norman

    2016-01-01

    Background. We aimed to assess incidentally discovered hepatocellular carcinoma (iHCC) over time and to compare outcome to preoperatively diagnosed hepatocellular carcinoma (pdHCC) and nontumor liver transplants. Methods. We studied adults transplanted with a follow-up of at least one year. Patients were divided into 3 groups according to diagnosis of hepatocellular carcinoma. Results. Between 1990 and 2010, 887 adults were transplanted. Among them, 121 patients (13.6%) had pdHCC and 32 patients (3.6%) had iHCC; frequency of iHCC decreased markedly over years, in parallel with significant increase in pdHCC. Between 1990 and 1995, 120 patients had liver transplants, 4 (3.3%) of them had iHCC, and only 3 (2.5%) had pdHCC, while in the last 5 years, 263 patients were transplanted, 7 (0.03%) of them had iHCC, and 66 (25.1%) had pdHCC (P < 0.001). There was no significant difference between groups regarding patient survival; 5-year survival was 74%, 75.5%, and 77.3% in iHCC, pdHCC, and non-HCC groups, respectively (P = 0.702). Patients with iHCC had no recurrences after transplant, while pdHCC patients experienced 17 recurrences (15.3%) (P = 0.016). Conclusions. iHCC has significantly decreased despite steady increase in number of transplants for hepatocellular carcinoma. Patients with iHCC had excellent outcomes with no tumor recurrence and survival comparable to pdHCC. PMID:27403337

  16. Temsirolimus and Bevacizumab in Treating Patients With Advanced Endometrial, Ovarian, Liver, Carcinoid, or Islet Cell Cancer

    ClinicalTrials.gov

    2017-07-10

    Adult Hepatocellular Carcinoma; Advanced Adult Hepatocellular Carcinoma; Endometrial Serous Adenocarcinoma; Localized Non-Resectable Adult Liver Carcinoma; Lung Carcinoid Tumor; Malignant Pancreatic Gastrinoma; Malignant Pancreatic Glucagonoma; Malignant Pancreatic Insulinoma; Malignant Pancreatic Somatostatinoma; Metastatic Digestive System Neuroendocrine Tumor G1; Ovarian Carcinosarcoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Seromucinous Carcinoma; Ovarian Serous Surface Papillary Adenocarcinoma; Pancreatic Alpha Cell Adenoma; Pancreatic Beta Cell Adenoma; Pancreatic Delta Cell Adenoma; Pancreatic G-Cell Adenoma; Pancreatic Polypeptide Tumor; Recurrent Adult Liver Carcinoma; Recurrent Digestive System Neuroendocrine Tumor G1; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Pancreatic Neuroendocrine Carcinoma; Recurrent Primary Peritoneal Carcinoma; Recurrent Uterine Corpus Carcinoma; Regional Digestive System Neuroendocrine Tumor G1; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIA Uterine Corpus Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIB Uterine Corpus Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Stage IIIC Uterine Corpus Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer; Stage IVA Uterine Corpus Cancer; Stage IVB Uterine Corpus Cancer; Uterine Carcinosarcoma

  17. Adult mouse model of early hepatocellular carcinoma promoted by alcoholic liver disease

    PubMed Central

    Ambade, Aditya; Satishchandran, Abhishek; Gyongyosi, Benedek; Lowe, Patrick; Szabo, Gyongyi

    2016-01-01

    AIM: To establish a mouse model of alcohol-driven hepatocellular carcinoma (HCC) that develops in livers with alcoholic liver disease (ALD). METHODS: Adult C57BL/6 male mice received multiple doses of chemical carcinogen diethyl nitrosamine (DEN) followed by 7 wk of 4% Lieber-DeCarli diet. Serum alanine aminotransferase (ALT), alpha fetoprotein (AFP) and liver Cyp2e1 were assessed. Expression of F4/80, CD68 for macrophages and Ly6G, MPO, E-selectin for neutrophils was measured. Macrophage polarization was determined by IL-1β/iNOS (M1) and Arg-1/IL-10/CD163/CD206 (M2) expression. Liver steatosis and fibrosis were measured by oil-red-O and Sirius red staining respectively. HCC development was monitored by magnetic resonance imaging, confirmed by histology. Cellular proliferation was assessed by proliferating cell nuclear antigen (PCNA). RESULTS: Alcohol-DEN mice showed higher ALTs than pair fed-DEN mice throughout the alcohol feeding without weight gain. Alcohol feeding resulted in increased ALT, liver steatosis and inflammation compared to pair-fed controls. Alcohol-DEN mice had reduced steatosis and increased fibrosis indicating advanced liver disease. Molecular characterization showed highest levels of both neutrophil and macrophage markers in alcohol-DEN livers. Importantly, M2 macrophages were predominantly higher in alcohol-DEN livers. Magnetic resonance imaging revealed increased numbers of intrahepatic cysts and liver histology confirmed the presence of early HCC in alcohol-DEN mice compared to all other groups. This correlated with increased serum alpha-fetoprotein, a marker of HCC, in alcohol-DEN mice. PCNA immunostaining revealed significantly increased hepatocyte proliferation in livers from alcohol-DEN compared to pair fed-DEN or alcohol-fed mice. CONCLUSION: We describe a new 12-wk HCC model in adult mice that develops in livers with alcoholic hepatitis and defines ALD as co-factor in HCC. PMID:27122661

  18. The role of exosomes in hepatitis, liver cirrhosis and hepatocellular carcinoma.

    PubMed

    Shen, Jiliang; Huang, Chiung-Kuei; Yu, Hong; Shen, Bo; Zhang, Yaping; Liang, Yuelong; Li, Zheyong; Feng, Xu; Zhao, Jie; Duan, Lian; Cai, Xiujun

    2017-02-22

    Exosomes are small vesicles that were initially thought to be a mechanism for discarding unneeded membrane proteins from reticulocytes. Their mediation of intercellular communication appears to be associated with several biological functions. Current studies have shown that most mammalian cells undergo the process of exosome formation and utilize exosome-mediated cell communication. Exosomes contain various microRNAs, mRNAs and proteins. They have been reported to mediate multiple functions, such as antigen presentation, immune escape and tumour progression. This concise review highlights the findings regarding the roles of exosomes in liver diseases, particularly hepatitis B, hepatitis C, liver cirrhosis and hepatocellular carcinoma. However, further elucidation of the contributions of exosomes to intercellular information transmission is needed. The potential medical applications of exosomes in liver diseases seem practical and will depend on the ingenuity of future investigators and their insights into exosome-mediated biological processes.

  19. Dysregulated signaling hubs of liver lipid metabolism reveal hepatocellular carcinoma pathogenesis

    PubMed Central

    Lee, Sunjae; Mardinoglu, Adil; Zhang, Cheng; Lee, Doheon; Nielsen, Jens

    2016-01-01

    Hepatocellular carcinoma (HCC) has a high mortality rate and early detection of HCC is crucial for the application of effective treatment strategies. HCC is typically caused by either viral hepatitis infection or by fatty liver disease. To diagnose and treat HCC it is necessary to elucidate the underlying molecular mechanisms. As a major cause for development of HCC is fatty liver disease, we here investigated anomalies in regulation of lipid metabolism in the liver. We applied a tailored network-based approach to identify signaling hubs associated with regulation of this part of metabolism. Using transcriptomics data of HCC patients, we identified significant dysregulated expressions of lipid-regulated genes, across many different lipid metabolic pathways. Our findings, however, show that viral hepatitis causes HCC by a distinct mechanism, less likely involving lipid anomalies. Based on our analysis we suggest signaling hub genes governing overall catabolic or anabolic pathways, as novel drug targets for treatment of HCC that involves lipid anomalies. PMID:27216817

  20. Radioembolization of hepatocellular carcinoma activates liver regeneration, induces inflammation and endothelial stress and activates coagulation.

    PubMed

    Fernandez-Ros, Nerea; Iñarrairaegui, Mercedes; Paramo, Jose A; Berasain, Carmen; Avila, Matias A; Chopitea, Ana; Varo, Nerea; Sarobe, Pablo; Bilbao, Jose I; Dominguez, Ines; D'Avola, Delia; Herrero, J Ignacio; Quiroga, Jorge; Sangro, Bruno

    2015-05-01

    Radioembolization may rarely induce liver disease resulting in a syndrome that is similar to veno-occlusive disease complicating bone marrow transplantation where inflammation, endothelial cell activation and thrombosis are likely involved. We hypothesized that similar mechanisms could be implicated in radioembolization-induced liver disease (REILD). Moreover, lobar radioembolization may induce hypertrophy of the non-treated hemiliver most probably by inducing liver regeneration. In patients with hepatocellular carcinoma, we prospectively studied serum levels of markers of liver regeneration, oxidative stress, pro-inflammatory pathways, endothelial activation and coagulation parameters over 2 months after radioembolization. Although REILD did not occur among 14 treated patients, a decrease in effective liver blood flow was observed. Radioembolization was followed by a persistent increase in pro-inflammatory (interleukin 6 and 8) and oxidative stress (malondyaldehide) markers, an induction of endothelial injury markers (vW factor and PAI-1) and an activation of the coagulation cascade (factor VIII, PAI-1, D-Dimer) as well as a significant increase in factors related to liver regeneration (FGF-19 and HGF). Radioembolization activates liver regeneration, produces oxidative stress, activates inflammatory cytokines and induces endothelial injury with partial activation of the coagulation cascade. These findings may have implications in the pathogenesis, prevention and therapy of REILD and in the development of new therapies to enhance hypertrophy with a surgical perspective. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  1. Survey of thorotrast-associated liver cancers in Japan

    SciTech Connect

    Yamada, S.; Hosoda, S.; Tateno, H.; Kido, C.; Takahashi, S.

    1983-01-01

    Data on 93 autopsy cases (group A) of thorotrast-associated liver cancers were obtained from the Annual of Pathological Autopsy Cases in Japan from 1958 to 1979, and data on 78 autopsy cases (group B) of thorotrast-associated liver cancers were obtained from the Japanese literature from 1953 to 1980. Cholangiocarcinoma (CLC) constituted 58% of group A and 55% of group B. The curve of the cumulative numbers of patients with CLC versus year in group A was almost linear, showing an increasing risk per surviving patients with advancing time. Angiosarcoma (AGS) occurred in 25% of group A and 24% of group B. The number of patients with AGS increased significantly after 1969 in both groups (P less than 0.05). In group B, age and years after thorotrast injection of patients with AGS were statistically higher than those of patients with CLC (age: P less than 0.05; years after thorotrast injection: P less than 0.0001). Hepatocellular carcinoma (HPC) accounted for 17 and 21% of groups A and B, respectively. When yearly distribution, age, and time after thorotrast injection of patients with HPC were correlated with those of patients with other liver cancers, the only statistically significant difference between patients with HPC and patients with CLC (P less than 0.02) was in the years after thorotrast administration. Since 1977 multiple primary liver cancers including AGS developed in thorotrast-administered patients in both groups.

  2. Helicobacter pylori infection does not promote hepatocellular cancer in a transgenic mouse model of hepatitis C virus pathogenesis

    PubMed Central

    García, Alexis; Feng, Yan; Parry, Nicola MA; McCabe, Amanda; Mobley, Melissa W; Lertpiriyapong, Kvin; Whary, Mark T; Fox, James G

    2013-01-01

    Helicobacter pylori (H. pylori) and hepatitis C virus (HCV) infect millions of people and can induce cancer. We investigated if H. pylori infection promoted HCV-associated liver cancer. Helicobacter-free C3B6F1 wild-type (WT) and C3B6F1-Tg(Alb1-HCVN)35Sml (HT) male and female mice were orally inoculated with H. pylori SS1 or sterile media. Mice were euthanized at ~12 mo postinoculation and samples were collected for analyses. There were no significant differences in hepatocellular tumor promotion between WT and HT mice; however, HT female mice developed significantly larger livers with more hepatic steatosis than WT female mice. H. pylori did not colonize the liver nor promote hepatocellular tumors in WT or HT mice. In the stomach, H. pylori induced more corpus lesions in WT and HT female mice than in WT and HT male mice, respectively. The increased corpus pathology in WT and HT female mice was associated with decreased gastric H. pylori colonization, increased gastric and hepatic interferon gamma expression, and increased serum Th1 immune responses against H. pylori. HT male mice appeared to be protected from H. pylori-induced corpus lesions. Furthermore, during gastric H. pylori infection, HT male mice were protected from gastric antral lesions and hepatic steatosis relative to WT male mice and these effects were associated with increased serum TNF-α. Our findings indicate that H. pylori is a gastric pathogen that does not promote hepatocellular cancer and suggest that the HCV transgene is associated with amelioration of specific liver and gastric lesions observed during concurrent H. pylori infection in mice. PMID:23929035

  3. S-ADENOSYLMETHIONINE IN LIVER HEALTH, INJURY, AND CANCER

    PubMed Central

    Lu, Shelly C.; Mato, José M.

    2013-01-01

    S-adenosylmethionine (AdoMet, also known as SAM and SAMe) is the principal biological methyl donor synthesized in all mammalian cells but most abundantly in the liver. Biosynthesis of AdoMet requires the enzyme methionine adenosyltransferase (MAT). In mammals, two genes, MAT1A that is largely expressed by normal liver and MAT2A that is expressed by all extrahepatic tissues, encode MAT. Patients with chronic liver disease have reduced MAT activity and AdoMet levels. Mice lacking Mat1a have reduced hepatic AdoMet levels and develop oxidative stress, steatohepatitis, and hepatocellular carcinoma (HCC). In these mice, several signaling pathways are abnormal that can contribute to HCC formation. However, injury and HCC also occur if hepatic AdoMet level is excessive chronically. This can result from inactive mutation of the enzyme glycine N-methyltransferase (GNMT). Children with GNMT mutation have elevated liver transaminases, and Gnmt knockout mice develop liver injury, fibrosis, and HCC. Thus a normal hepatic AdoMet level is necessary to maintain liver health and prevent injury and HCC. AdoMet is effective in cholestasis of pregnancy, and its role in other human liver diseases remains to be better defined. In experimental models, it is effective as a chemopreventive agent in HCC and perhaps other forms of cancer as well. PMID:23073625

  4. High risk of primary liver cancer in a cohort of 179 patients with Acute Hepatic Porphyria.

    PubMed

    Sardh, Eliane; Wahlin, Staffan; Björnstedt, Mikael; Harper, Pauline; Andersson, Dan E H

    2013-11-01

    Previous studies have indicated a high risk of hepatocellular carcinoma in acute hepatic porphyrias. In this retrospective study we present the incidence of primary liver cancer and clinical characteristics in a cohort of 179 acute porphyria patients above the age of 50 years. Twenty-three cases with primary liver cancer were found either by a surveillance program or due to clinical suspicion. Standardized rate ratio was used to estimate the relative risk of primary liver cancer after indirect standardization. Survival data were calculated using the Kaplan-Meier method. The mean age at diagnosis was 69 years. Hepatocellular carcinoma was found in 19 patients while four patients had cholangiocarcinoma or a combination of the two. Four patients had underlying cirrhosis. Mean tumour size was 4.3 cm in the surveillance group and 10.3 cm in the non-surveillance group (p = 0.01). The overall relative risk of primary liver cancer was 86 above the age of 50: 150 for women and 37 for men. Mean survival time was 5.7 years. Acute hepatic porphyria carries a high risk of primary liver cancer above the age of 50 which warrants ultrasound surveillance. Sex distribution and frequency of cirrhosis differs from more common aetiologies of primary liver cancer.

  5. Stabilization of LKB1 and Akt by neddylation regulates energy metabolism in liver cancer

    PubMed Central

    Barbier-Torres, Lucía; Delgado, Teresa C.; García-Rodríguez, Juan L.; Zubiete-Franco, Imanol; Fernández-Ramos, David; Buqué, Xabier; Cano, Ainara; Juan, Virginia Gutiérrez-de; Fernández-Domínguez, Itziar; Lopitz-Otsoa, Fernando; Fernández-Tussy, Pablo; Boix, Loreto; Bruix, Jordi; Villa, Erica; Castro, Azucena; Lu, Shelly C.; Aspichueta, Patricia; Xirodimas, Dimitris; Varela-Rey, Marta; Mato, José M.; Beraza, Naiara; Martínez-Chantar, María L.

    2015-01-01

    The current view of cancer progression highlights that cancer cells must undergo through a post-translational regulation and metabolic reprogramming to progress in an unfriendly environment. In here, the importance of neddylation modification in liver cancer was investigated. We found that hepatic neddylation was specifically enriched in liver cancer patients with bad prognosis. In addition, the treatment with the neddylation inhibitor MLN4924 in Phb1-KO mice, an animal model of hepatocellular carcinoma showing elevated neddylation, reverted the malignant phenotype. Tumor cell death in vivo translating into liver tumor regression was associated with augmented phosphatidylcholine synthesis by the PEMT pathway, known as a liver-specific tumor suppressor, and restored mitochondrial function and TCA cycle flux. Otherwise, in protumoral hepatocytes, neddylation inhibition resulted in metabolic reprogramming rendering a decrease in oxidative phosphorylation and concomitant tumor cell apoptosis. Moreover, Akt and LKB1, hallmarks of proliferative metabolism, were altered in liver cancer being new targets of neddylation. Importantly, we show that neddylation-induced metabolic reprogramming and apoptosis were dependent on LKB1 and Akt stabilization. Overall, our results implicate neddylation/signaling/metabolism, partly mediated by LKB1 and Akt, in the development of liver cancer, paving the way for novel therapeutic approaches targeting neddylation in hepatocellular carcinoma. PMID:25650664

  6. Stabilization of LKB1 and Akt by neddylation regulates energy metabolism in liver cancer.

    PubMed

    Barbier-Torres, Lucía; Delgado, Teresa C; García-Rodríguez, Juan L; Zubiete-Franco, Imanol; Fernández-Ramos, David; Buqué, Xabier; Cano, Ainara; Gutiérrez-de Juan, Virginia; Fernández-Domínguez, Itziar; Lopitz-Otsoa, Fernando; Fernández-Tussy, Pablo; Boix, Loreto; Bruix, Jordi; Villa, Erica; Castro, Azucena; Lu, Shelly C; Aspichueta, Patricia; Xirodimas, Dimitris; Varela-Rey, Marta; Mato, José M; Beraza, Naiara; Martínez-Chantar, María L

    2015-02-10

    The current view of cancer progression highlights that cancer cells must undergo through a post-translational regulation and metabolic reprogramming to progress in an unfriendly environment. In here, the importance of neddylation modification in liver cancer was investigated. We found that hepatic neddylation was specifically enriched in liver cancer patients with bad prognosis. In addition, the treatment with the neddylation inhibitor MLN4924 in Phb1-KO mice, an animal model of hepatocellular carcinoma showing elevated neddylation, reverted the malignant phenotype. Tumor cell death in vivo translating into liver tumor regression was associated with augmented phosphatidylcholine synthesis by the PEMT pathway, known as a liver-specific tumor suppressor, and restored mitochondrial function and TCA cycle flux. Otherwise, in protumoral hepatocytes, neddylation inhibition resulted in metabolic reprogramming rendering a decrease in oxidative phosphorylation and concomitant tumor cell apoptosis. Moreover, Akt and LKB1, hallmarks of proliferative metabolism, were altered in liver cancer being new targets of neddylation. Importantly, we show that neddylation-induced metabolic reprogramming and apoptosis were dependent on LKB1 and Akt stabilization. Overall, our results implicate neddylation/signaling/metabolism, partly mediated by LKB1 and Akt, in the development of liver cancer, paving the way for novel therapeutic approaches targeting neddylation in hepatocellular carcinoma.

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

    PubMed

    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

  8. Dithiothreitol abrogates the effect of arsenic trioxide on normal rat liver mitochondria and human hepatocellular carcinoma cells

    SciTech Connect

    Paul, Manash K. Kumar, Rajinder; Mukhopadhyay, Anup K.

    2008-01-15

    Arsenic trioxide (ATO) is a known environmental toxicant and a potent chemotherapeutic agent. Significant correlation has been reported between consumption of arsenic-contaminated water and occurrence of liver cancer; moreover, ATO-treated leukemia patients also suffers from liver toxicity. Hence, modulation of ATO action may help to prevent populations suffering from arsenic toxicity as well as help reduce the drug-related side effects. Dithiothreitol (DTT) is a well-known dithiol agent reported to modulate the action of ATO. Controversial reports exist regarding the effect of DTT on ATO-induced apoptosis in leukemia cells. To the best of our knowledge, no report illustrates the modulatory effect of DTT on ATO-induced liver toxicity, the prime target for arsenic. Mitochondria serve as the doorway to apoptosis and have been implicated in ATO-induced cell death. Hence, we attempted to study the modulatory effect of DTT on ATO-induced dysfunction of mammalian liver mitochondria and human hepatocellular carcinoma cell line (Hep3B). We, for the first time, report that ATO produces complex I-mediated electron transfer inhibition, reactive oxygen species (ROS) generation, respiration inhibition, and ATO-induced ROS-mediated mitochondrial permeability transition (MPT) opening. DTT at low concentration (100 {mu}M and less) prevents the effect of ATO-induced complex I-malfunctions. DTT protects mitochondria from ATO-mediated opening of MPT and membrane potential depolarization. DTT also prevented ATO-induced Hep3B cell death. Thus, at low concentrations DTT abrogates the effect of ATO on rat liver mitochondria and Hep3B cell line. Therefore, the present result suggests, that use of low concentration of dithiols as food supplement may prevent arsenic toxicity in affected population.

  9. Acetylation of MAT IIα represses tumour cell growth and is decreased in human hepatocellular cancer

    PubMed Central

    Yang, Hong-Bin; Xu, Ying-Ying; Zhao, Xiang-Ning; Zou, Shao-Wu; Zhang, Ye; Zhang, Min; Li, Jin-Tao; Ren, Feng; Wang, Li-Ying; Lei, Qun-Ying

    2015-01-01

    Metabolic alteration is a hallmark of cancer. Dysregulation of methionine metabolism is implicated in human liver cancer. Methionine adenosyltransferase IIα (MAT IIα) is a key enzyme in the methionine cycle, catalysing the production of S-adenosylmethionine (SAM), a key methyl donor in cellular processes, and is associated with uncontrolled cell proliferation in cancer. Here we show that P300 acetylates MAT IIα at lysine residue 81 and destabilizes MAT IIα by promoting its ubiquitylation and subsequent proteasomal degradation. Conversely, histone deacetylase-3 deacetylates and stabilizes MAT IIα by preventing its proteasomal degradation. Folate deprivation upregulates K81 acetylation and destabilizes MAT IIα to moderate cell proliferation, whereas a single mutation at K81 reverses the proliferative disadvantage of cancer cells upon folate deprivation. Moreover, MAT IIα K81 acetylation is decreased in human hepatocellular cancer. Collectively, our study reveals a novel mechanism of MAT IIα regulation by acetylation and ubiquitylation, and a direct functional link of this regulation to cancer development. PMID:25925782

  10. Particulate matter air pollution and liver cancer survival.

    PubMed

    Deng, Huiyu; Eckel, Sandrah P; Liu, Lihua; Lurmann, Frederick W; Cockburn, Myles G; Gilliland, Frank D

    2017-08-15

    Particulate matter (PM) air pollution exposure has been associated with cancer incidence and mortality especially with lung cancer. The liver is another organ possibly affected by PM due to its role in detoxifying xenobiotics absorbed from PM. Various studies have investigated the mechanistic pathways between inhaled pollutants and liver damage, cancer incidence, and tumor progression. However, little is known about the effects of PM on liver cancer survival. Twenty thousand, two hundred and twenty-one California Cancer Registry patients with hepatocellular carcinoma (HCC) diagnosed between 2000 and 2009 were used to examine the effect of exposure to ambient PM with diameter <2.5 μm (PM2.5 ) on HCC survival. Cox proportional hazards models were used to estimate hazard ratios (HRs) relating PM2.5 to all-cause and liver cancer-specific mortality linearly and nonlinearly-overall and stratified by stage at diagnosis (local, regional and distant)-adjusting for potential individual and geospatial confounders.PM2.5 exposure after diagnosis was statistically significantly associated with HCC survival. After adjustment for potential confounders, the all-cause mortality HR associated with a 1 standard deviation (5.0 µg/m(3) ) increase in PM2.5 was 1.18 (95% CI: 1.16-1.20); 1.31 (95% CI:1.26-1.35) for local stage, 1.19 (95% CI:1.14-1.23) for regional stage, and 1.05 (95% CI:1.01-1.10) for distant stage. These associations were nonlinear, with substantially larger HRs at higher exposures. The associations between liver cancer-specific mortality and PM2.5 were slightly attenuated compared to all-cause mortality, but with the same patterns.Exposure to elevated PM2.5 after the diagnosis of HCC may shorten survival, with larger effects at higher concentrations. © 2017 UICC.

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

    PubMed

    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.

  12. Histological changes in nontumoral liver secondary to radioembolization of hepatocellular carcinoma with yttrium 90-impregnated microspheres: report of two cases.

    PubMed

    Dhingra, Sadhna; Schwartz, Myron; Kim, Edward; Mabel Ko, Huaibin; Ward, Stephen C; Fiel, M Isabel; Thung, Swan N

    2014-11-01

    Transarterial radioembolization (TARE) with yttrium-90 is a minimally invasive locoregional therapy for hepatocellular carcinoma (HCC), and involves selective delivery of glass or resin microspheres impregnated with radioactive yttrium-90 into small arteries preferentially supplying the tumor for tumoricidal effect thus sparing the nontumoral liver, or into lobar artery to induce atrophy and contralateral hypertrophy. Clinically, post-TARE a small proportion of cases develop radioembolization-induced liver disease. Histological changes of TARE on nontumoral liver parenchyma have not been well characterized. Herein, we report two cases of liver resections for HCC post-TARE, and describe the histological changes in nontumoral liver parenchyma.

  13. Enhanced colorectal cancer metastases in the alcohol-injured liver.

    PubMed

    Mohr, Ashley M; Gould, John J; Kubik, Jacy L; Talmon, Geoffrey A; Casey, Carol A; Thomas, Peter; Tuma, Dean J; McVicker, Benita L

    2017-02-01

    Metastatic liver disease is a major cause of mortality in colorectal cancer (CRC) patients. Alcohol consumption is a noted risk factor for secondary cancers yet the role of alcoholic liver disease (ALD) in colorectal liver metastases (CRLM) is not defined. This work evaluated tumor cell colonization in the alcoholic host liver using a novel preclinical model of human CRC liver metastases. Immunocompromised Rag1-deficient mice were fed either ethanol (E) or isocaloric control (C) diets for 4 weeks prior to intrasplenic injection of LS174T human CRC cells. ALD and CRLM were evaluated 3 or 5 weeks post-LS174T cell injection with continued C/E diet administration. ALD was confirmed by increased serum transaminases, hepatic steatosis and expression of cytochrome P4502E1, a major ethanol-metabolizing enzyme. Alcohol-mediated liver dysfunction was validated by impaired endocytosis of asialoorosomucoid and carcinoembryonic antigen (CEA), indicators of hepatocellular injury and progressive CRC disease, respectively. Strikingly, the rate and burden of CRLM was distinctly enhanced in alcoholic livers with metastases observed earlier and more severely in E-fed mice. Further, alcohol-related increases (1.5-3.0 fold) were observed in the expression of hepatic cytokines (TNF-α, IL-1 beta, IL-6, IL-10) and other factors noted to be involved in the colonization of CRC cells including ICAM-1, CCL-2, CCL-7, MMP-2, and MMP-9. Also, alcoholic liver injury was associated with altered hepatic localization as well as increased circulating levels of CEA released from CRC cells. Altogether, these findings indicate that the alcoholic liver provides a permissive environment for the establishment of CRLM, possibly through CEA-related inflammatory mechanisms.

  14. Liquid biopsy in liver cancer.

    PubMed

    Labgaa, Ismail; Villanueva, Augusto

    2015-04-01

    Liver cancer has become the second cause of cancer-related death worldwide. Most patients are still diagnosed at intermediate or advanced stage, where potentially curative treatment options are not recommended. Unlike other solid tumors, there are no validated oncogenic addiction loops and the only systemic agent to improve survival in advanced disease is sorafenib. All phase 3 clinical trials testing molecular therapies after sorafenib have been negative, none of which selected patients based on predictive biomarkers of response. Theoretically, analysis of circulating cancer byproducts (e.g., circulating tumor cells, cell-free nucleic acids), namely "liquid biopsy," could provide easy access to molecular tumor information, improve patients' stratification and allow to assess tumor dynamics over time. Recent technical developments and preliminary data from other malignancies indicate that liquid biopsy might have a role in the future management of cancer patients.

  15. What's New in Liver Cancer Research and Treatment?

    MedlinePlus

    ... Cancer Research? Liver Cancer About Liver Cancer What's New in Liver Cancer Research? Because there are only ... being made in treating chronic hepatitis. Screening Several new blood tests are being studied to see if ...

  16. Liver cancer mortality rate model in Thailand

    NASA Astrophysics Data System (ADS)

    Sriwattanapongse, Wattanavadee; Prasitwattanaseree, Sukon

    2013-09-01

    Liver Cancer has been a leading cause of death in Thailand. The purpose of this study was to model and forecast liver cancer mortality rate in Thailand using death certificate reports. A retrospective analysis of the liver cancer mortality rate was conducted. Numbering of 123,280 liver cancer causes of death cases were obtained from the national vital registration database for the 10-year period from 2000 to 2009, provided by the Ministry of Interior and coded as cause-of-death using ICD-10 by the Ministry of Public Health. Multivariate regression model was used for modeling and forecasting age-specific liver cancer mortality rates in Thailand. Liver cancer mortality increased with increasing age for each sex and was also higher in the North East provinces. The trends of liver cancer mortality remained stable in most age groups with increases during ten-year period (2000 to 2009) in the Northern and Southern. Liver cancer mortality was higher in males and increase with increasing age. There is need of liver cancer control measures to remain on a sustained and long-term basis for the high liver cancer burden rate of Thailand.

  17. Isolated port-site metastasis of hepatocellular carcinoma after laparoscopic liver resection.

    PubMed

    Kihara, Kyoichi; Endo, Kanenori; Suzuki, Kazunori; Nakamura, Seiichi; Sawata, Takashi; Shimizu, Tetsu; Ikeguchi, Masahide; Tokuyasu, Yusuke; Nakamoto, Shu

    2016-10-17

    Port-site metastasis of hepatocellular carcinoma (HCC) is extremely rare, and only one case has been reported in the English-language literature. Contamination with malignant cells along the needle tract during percutaneous biopsy or radiofrequency ablation is a well-recognized cause of HCC recurrence. Here, we describe a case of port-site metastasis after laparoscopic liver resection of HCC. The patient, who had undergone laparoscopic partial resection of the left lateral segment of the liver 18 months earlier, was diagnosed with HCC. CT showed a nodule in the abdominal wall where the laparoscopic port had been inserted during resection. Local excision was performed, and histological examination revealed HCC consistent with recurrence after laparoscopic resection. The experience described in this report highlights the risk of port-site metastasis of HCC. Imaging for oncologic surveillance after laparoscopic resection must include all port sites.

  18. Liver transplantation for hepatocellular carcinoma after yttrium therapy: a case report.

    PubMed

    Sotiropoulos, G C; Hilgard, P; Antoch, G; Nowak, K M; Ertl, J; Fouzas, I; Molmenti, E P; Sgourakis, G; Beckebaum, S; Paul, A; Broelsch, C E; Lang, H

    2008-12-01

    Yttrium-90 microspheres constitute one of the most recent treatment options for hepatocellular carcinoma (HCC) in the setting of cirrhosis. As such, their spectrum of indication is not yet fully established. Herein, we have reported the case of a patient with HCC beyond the listing criteria for liver transplantation (OLT) who was treated preoperatively with selective transarterial chemoembolization and yttrium-90 microspheres. He was subsequently transplanted with a liver from an 81-year-old donor allocated through Eurotransplant as a "rescue offer." The posttransplant course was uneventful. Pathologic examination revealed a multifocal, well-differentiated pT2 tumor with no vascular invasion. The patient is currently alive and in good condition at 14 months posttransplant, with no evidence of tumor recurrence by a current computed tomography scan. This report provided encouraging information on the potential of yttrium-90 microspheres as a bridging option before OLT for multifocal HCC.

  19. Transarterial chemo-embolisation of hepatocellular carcinoma: impact of liver function and vascular invasion

    PubMed Central

    Waked, Imam; Berhane, Sarah; Toyoda, Hidenori; Chan, Stephen L; Stern, Nicholas; Palmer, Daniel; Tada, Toshifumi; Yeo, Winnie; Mo, Frankie; Bettinger, Dominik; Kirstein, Martha M; Iñarrairaegui, Mercedes; Gomaa, Asmaa; Vogel, Arndt; Meyer, Tim; Sangro, Bruno; Lai, Paul; Kumada, Takashi; Johnson, Philip J

    2017-01-01

    Background: Transarterial chemo-embolisation (TACE) is recommended for patients with BCLC intermediate stage hepatocellular carcinoma (stage B), particularly in patients with good underlying liver function and minimal symptoms. The hepatoma arterial embolisation prognostic (HAP) score combines measures of liver function and tumour-related factors to offer a simple prognostic scoring system. The Albumin-Bilirubin (ALBI) grade permits assessment of the impact of liver function on survival. We aimed to investigate these two models and vascular invasion (VI). Methods: In an international cohort of 3030 patients undergoing TACE, we examined the impact of liver function as assessed by the ALBI score, the HAP score and VI on survival. Results: Classification according to ALBI grade resulted in non-overlapping survival curves in the overall data set and all regional cohorts. The HAP score was also validated. Tumour number, aetiology and VI were identified as additional independent prognostic risk factors not currently included in the HAP score. Survival was particularly poor for patients with VI. Conclusions: The ALBI grade categorised patients receiving TACE into three clear prognostic groups, thereby emphasising the importance of underlying liver function in the outcome of TACE. The HAP score has been validated internationally and the serious adverse impact of VI is clearly shown. PMID:28125820

  20. Automatic segmentation of hepatocellular structure from HE-stained liver tissue

    NASA Astrophysics Data System (ADS)

    Ishikawa, Masahiro; Ahi, Sercan Taha; Murakami, Yuri; Kimura, Fumikazu; Yamaguchi, Masahiro; Abe, Tokiya; Hashiguchi, Akinori; Sakamoto, Michiie

    2013-03-01

    The analysis of hepatic tissue structure is required for quantitative assessment of liver histology. Especially, a cord-like structure of liver cells, called trabecura, has important information in the diagnosis of hepatocellular carcinoma (HCC). However, the extraction of trabeculae is thought to be difficult because liver cells take on various colors and appearances depending on tissue conditions. In this paper, we propose an approach to extract trabeculae from images of hematoxyline and eosin stained liver tissue slide by extracting the rest of trabeculae: sinusoids and stromal area. The sinusoids are simply extracted based on the color information, where the image is corrected by an orientation selective filtering before segmentaion. The stromal area mainly consists of fiber, and often includes lymphocytes densely. Therefore, in the proposed method, fiber region and lymphocytes are extracted separately, then, stromal region is determined based on the extracted results. The determination of stroma is performed based on superpixels, to obtain precise boundaries. Once the regions of sinusoids and stroma are obtained, trabeculae can be segmented as the remaining region. The proposed method was applied to 10 test images of normal and HCC liver tissues, and the results were evaluated based on the manual segmentation. As a result, we confirmed that both sensitivity and specificity of the extraction of trabeculae reach around 90%.

  1. MicroRNAs as Biomarkers for Liver Disease and Hepatocellular Carcinoma

    PubMed Central

    Hayes, C. Nelson; Chayama, Kazuaki

    2016-01-01

    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. PMID:26927063

  2. 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

    PubMed Central

    Seydi, Enayatollah; Motallebi, Abbasali; Dastbaz, Maryam; Dehghan, Sahar; Salimi, Ahmad; Nazemi, Melika; Pourahmad, Jalal

    2015-01-01

    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

  3. Impact of myeloid-derived suppressor cell on Kupffer cells from mouse livers with hepatocellular carcinoma

    PubMed Central

    Lacotte, Stéphanie; Slits, Florence; Orci, Lorenzo A.; Meyer, Jeremy; Oldani, Graziano; Gonelle-Gispert, Carmen; Morel, Philippe; Toso, Christian

    2016-01-01

    ABSTRACT Kupffer cells represent the first line of defense against tumor cells in the liver. Myeloid-derived suppressor cells (MDSC) have recently been observed in the liver parenchyma of tumor-bearing animals. The present study investigates the function of the MDSC subsets, and their impact on Kupffer cell phenotype and function. RIL-175 mouse hepatocellular carcinoma (HCC) cells were injected into the median liver lobe of C57BL/6 mice. Three weeks later, the median lobe hosting the tumor nodule was removed, and Kupffer cells and MDSCs were sorted from the remaining liver. Mouse livers devoid of HCC served as control. Kupffer cells expressed less co-stimulatory CD86 and MHCII and more co-inhibitory CD274 molecules in HCC-bearing livers than in control livers. Corresponding to this phenotype, Kupffer cells from HCC-bearing mice were less efficient in their function as antigen-presenting cells. Three CD11b+ cell populations were identified and sorted from HCC-bearing mice. These cells had various phenotypes with different levels of MDSC-specific surface markers (Ly6Ghigh cells, Gr1high cells, and Ly6Clow cells), and may be considered as bonafide MDSCs given their suppression of antigen-specific T cell proliferation. Primary isolated Kupffer cells in co-culture with the three MDSC subsets showed a decrease in CCL2 and IL-18 secretion, and an increase in IL-10 and IL-1β secretion, and an increased expression of CD86, CD274, and MHCII. In conclusion, these data demonstrated the existence of three MDSC subsets in HCC-bearing animals. These cells altered Kupffer cell function and may decrease the migration and activation of anticancer effector cells in the liver. PMID:27999748

  4. S-Adenosylmethionine in cell growth, apoptosis and liver cancer.

    PubMed

    Lu, Shelly C; Mato, José M

    2008-03-01

    S-Adenosylmethionine (SAMe), the principal biological methyl donor, is synthesized from methionine and ATP in a reaction catalyzed by methionine adenosyltransferase (MAT). In mammals, two genes (MAT1A and MAT2A), encode for two homologous MAT catalytic subunits, while a third gene MAT2beta, encodes for the beta-subunit that regulates MAT2A-encoded isoenzyme. Normal liver expresses MAT1A, whereas extrahepatic tissues express MAT2A. MAT2A and MAT2 beta are induced in human hepatocellular carcinoma (HCC), which facilitate cancer cell growth. Patients with cirrhosis of various etiologies, including alcohol, have decreased hepatic MAT activity and SAMe biosynthesis. Consequences of hepatic SAMe deficiency as illustrated by the Mat1a knock-out mouse model include increased susceptibility to steatosis and oxidative liver injury, spontaneous development of steatohepatitis and HCC. Predisposition to HCC can be partly explained by the effect of SAMe on growth. Thus, SAMe inhibits the mitogenic effect of growth factors such as hepatocyte growth factor and, following partial hepatectomy, a fall in SAMe level is required for the liver to regenerate. During liver regeneration, the fall in hepatic SAMe is transient. If the fall were to persist, it would favor a proliferative phenotype and, ultimately, development of HCC. Not only does SAMe control liver growth, it also regulates apoptosis. Interestingly, SAMe is anti-apoptotic in normal hepatocytes but pro-apoptotic in liver cancer cells. In liver cancer cells but not in normal human hepatocytes, SAMe can selectively induce Bcl-x(S), an alternatively spliced isoform of Bcl-x(L) that promotes apoptosis. This should make SAMe an attractive agent for both chemoprevention and treatment of HCC.

  5. Dietary factors can protect against liver cancer development

    PubMed Central

    Koumbi, Lemonica

    2017-01-01

    Liver cancer is the third leading cause of cancer mortality worldwide with hepatocellular carcinoma (HCC) representing more than 90% of primary liver cancers. Most HCC patients are also suffering from chronic liver disease (CLD). Evidence is emerging that the composition of diet plays an important role in HCC and CLD development and may also have a chemoprotective role. In contrast to other types of cancer, there are few studies investigating the role of diet in hepatocarcinogenesis. From the available data it is evident that high intakes of red meat and dietary sugar positively correlate with HCC occurrence. On the contrary, high consumption of white meat, fish, vegetables, fruits and cereals are inversely associated with HCC risk. This letter discusses the potential role of dietary interventions in the prevention of hepatocarcinogenesis. The increasing HCC incidence and its high fatality are making HCC prevention an urgent matter. Dietary modifications are found to offer protection against HCC, however, new studies from well-designed and large prospective trials are required to confirm these results. PMID:28217247

  6. Studying liver cancer metastasis by in vivo imaging and flow cytometer

    NASA Astrophysics Data System (ADS)

    Wang, Chen; Gu, Zhengqin; Guo, Jin; Li, Yan; Liu, Guangda; Wei, Xunbin

    2009-11-01

    Primary liver cancer (hepatocellular carcinoma, or HCC) is associated with liver cirrhosis 60-80% of the time. Liver cancer is one of the most common malignancies in the world, with approximately 1,000,000 cases reported every year. About 80% of people with primary liver cancer are male. Although two-thirds of people have advanced liver disease when they seek medical help, one third of the patients have cancer that has not progressed beyond the liver. HCC may metastasize to the lung, bones, kidney, and many other organs. Surgical resection, liver transplantation, chemotherapy and radiation therapy are the foundation of current HCC therapies. However the outcomes are poor: the survival rate is almost zero for metastatic HCC patients. Molecular mechanisms of HCC metastasis need to be understood better and new therapies must be developed to selectively target to unique characteristics of HCC cell growth and metastasis. We have developed the "in vivo microscopy" to study the mechanisms that govern liver tumor cell spread through the microenvironment in vivo with real-time confocal near-infrared fluorescence imaging. A recently developed "in vivo flow cytometer" and optical imaging are used to assess liver tumor cell spreading and the circulation kinetics of liver tumor cells. A real- time quantitative monitoring of circulating liver tumor cells by the in vivo flow cytometer will be useful to assess the effectiveness of the potential therapeutic interventions.

  7. Clinical characteristics and time trends in etiology of hepatocellular cancer in Germany.

    PubMed

    Schütte, Kerstin; Kipper, Matthias; Kahl, Stefan; Bornschein, Jan; Götze, Tobias; Adolf, Daniela; Arend, Jörg; Seidensticker, Ricarda; Lippert, Hans; Ricke, Jens; Malfertheiner, Peter

    2013-01-01

    The incidence of hepatocellular cancer (HCC) continues to rise in Europe with a shift of the primary cause towards alcoholic and non-alcoholic fatty liver disease. Metabolic factors like diabetes mellitus and overweight have been identified as significant risk factors for HCC development. A retrospective analysis in a large single-center cohort of 650 patients diagnosed with HCC was performed. Demographic characteristics, risk factors, tumor stage at diagnosis and survival were evaluated. Among 650 patients (aged 17-87 years, with a male: female ratio of 4:1), 80.8% had underlying liver cirrhosis. Alcohol abuse was identified as the only risk factor for liver cirrhosis in 52.2% of patients. Viral infection with hepatitis C and hepatitis B was present in 13.7 and 3.6% of patients, respectively. 66.1% of patients with HCC were overweight with a body mass index exceeding 25, 25.5% even exceeding 30; 52% of patients had diabetes mellitus. Strategies aiming at prevention and surveillance of patients at risk to develop HCC in the future need to widen the focus from patients with chronic viral hepatitis and a history of alcohol abuse to patients with metabolic risk factors. Copyright © 2013 S. Karger AG, Basel.

  8. Prospective comparison of computed tomography and magnetic resonance imaging for liver cancer delineation using deformable image registration

    SciTech Connect

    Voroney, Jon-Paul; Brock, Kristy K.; Eccles, Cynthia; Haider, Masoom; Dawson, Laura A. . E-mail: laura.dawson@rmp.uhn.on.ca

    2006-11-01

    Purpose: The aim of this study was to compare magnetic resonance imaging (MRI) with computed tomography (CT) for liver cancer tumor definition for high-precision radiotherapy planning. Methods and Materials: Diagnostic quality MRI scans and triphasic CT scans, with the liver immobilized in exhale, were obtained at the time of radiation planning for 26 patients with unresectable liver metastases (n = 8), hepatocellular carcinoma (n = 10), and cholangiocarcinoma (n = 8). On the CT and MRI series best demonstrating the tumor, the liver and gross tumor volumes (GTVs) were contoured, and intrahepatic anatomic reference points were identified. Deformable registration was used to register the liver from the CT with that from the MRI. Results: A difference in the number of tumor foci was seen on CT vs. MRI in 5 patients with hepatocellular carcinoma: MRI showed more foci in 3 patients, CT in 2. After deformable registration of the livers, the population median of the average distance between the CT tumor surface and MRI tumor surface was 3.7 mm (2.2-21.3 mm). The median percentage of tumor surface area that differed by {>=}5 mm was 26% (1-86%). Median percentage concordance volumes were 81% (77-86%) in metastases, 77% (60-88%) in hepatocellular carcinoma and 64% (25-85%) in cholangiocarcinoma. Conclusion: Differences between MRI-defined liver cancer GTVs and CT-defined GTVs can be substantial and are more common in primary liver cancer.

  9. Evaluation of the anti-neoplastic effect of sorafenib on liver cancer through bioluminescence tomography

    NASA Astrophysics Data System (ADS)

    Liang, Qian; Ye, Jinzuo; Du, Yang; Chi, Chongwei; Tian, Jie

    2017-03-01

    Hepatocellular carcinoma (HCC) is one of the most important leading causes of cancer-related deaths worldwide. In this study, we evaluated the efficacy of sorafenib on hepatocellular carcinoma through bioluminescence tomography (BLT) based on Micro-CT/BLT multi-modal system. Initially, the human hepatocellular carcinoma cell line HepG2-Red-FLuc, which was transfected with luciferase gene, was cultured. And then, the orthotopic liver tumor mouse model was established on 4 5 weeks old athymic male Balb/c nude mice by inoculating the HepG2-Red-FLuc cell suspension into the liver lobe under isoflurane anesthesia. 15 20 days after tumor cells implantation, the mice were divided into two groups including the sorafenib treatment group and the control group. The mice in the treatment group were treated with sorafenib with dosage of 62 mg/kg/day by oral gavage for continuous 14 days, and the mice in the control group were treated with sterile water at equal volume. The tumor growth and drug treatment efficacy were dynamically monitored through BLT. The results in this study showed that the growth of liver cancer can be dynamically monitored from very early stage, and also the sorafenib treatment efficacy can be reliably and objectively assessed using BLT imaging method. Our experimental result demonstrated sorafenib can inhibit the tumor growth effectively. BLT enabled the non-invasive and reliable assessment of anti-neoplastic drug efficacy on liver cancer.

  10. Combining Angiogenesis-Targeted Treatments for Liver Cancer

    Cancer.gov

    In this trial, patients with unresectable hepatocellular carcinoma who are ineligible for a liver transplant or other local therapies will be given oral sorafenib at the standard approved dose and intravenous TRC105.

  11. Several microRNAs could predict survival in patients with hepatitis B-related liver cancer

    PubMed Central

    Zhen, Ye; Xinghui, Zhao; Chao, Wu; Yi, Zhao; Jinwen, Chen; Ruifang, Gao; Chao, Zhang; Min, Zhao; Chunlei, Guo; Yan, Fang; Lingfang, Du; Long, Shen; Wenzhi, Shen; Xiaohe, Luo; Rong, Xiang

    2017-01-01

    MicroRNAs as biomarkers play an important role in the tumorigenesis process, including hepatocellular carcinomas (HCCs). In this paper, we used The Cancer Genome Atlas (TCGA) database to mine hepatitis B-related liver cancer microRNAs that could predict survival in patients with hepatitis B-related liver cancer. There were 93 cases of HBV-HCC and 49 cases of adjacent normal controls included in the study. Kaplan–Meier survival analysis of a liver cancer group versus a normal control group of differentially expressed genes identified eight genes with statistical significance. Compared with the normal liver cell line, hepatocellular carcinoma cell lines had high expression of 8 microRNAs, albeit at different levels. A Cox proportional hazards regression model for multivariate analysis showed that four genes had a significant difference. We established classification models to distinguish short survival time and long survival time of liver cancers. Eight genes (mir9-3, mir10b, mir31, mir519c, mir522, mir3660, mir4784, and mir6883) were identified could predict survival in patients with HBV-HCC. There was a significant correlation between mir10b and mir31 and clinical stages (p < 0.05). A random forests model effectively estimated patient survival times. PMID:28322348

  12. Oxidative Stress and Liver Cancer: Etiology and Therapeutic Targets

    PubMed Central

    Wang, Zhanpeng; Li, Zhuonan; Ye, Yanshuo; Xie, Lijuan

    2016-01-01

    Accumulating evidence has indicated that oxidative stress (OS) is associated with the development of hepatocellular carcinoma (HCC). However, the mechanisms remain largely unknown. Normally, OS occurs when the body receives any danger signal—from either an internal or external source—and further induces DNA oxidative damage and abnormal protein expression, placing the body into a state of vulnerability to the development of various diseases such as cancer. There are many factors involved in liver carcinogenesis, including hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, alcohol abuse, and nonalcoholic fatty liver disease (NAFLD). The relationship between OS and HCC has recently been attracting increasing attention. Therefore, elucidation of the impact of OS on the development of liver carcinogenesis is very important for the prevention and treatment of liver cancer. This review focuses mainly on the relationship between OS and the development of HCC from the perspective of cellular and molecular mechanisms and the etiology and therapeutic targets of HCC. PMID:27957239

  13. Can living donor liver transplantation offer similar outcomes to deceased donor liver transplantation using expanded selection criteria for hepatocellular carcinoma?

    PubMed

    Chen, Li-Ping; Li, Chuan; Wen, Tian-Fu; Yan, Lu-Nan; Li, Bo; Yang, Jia-Yin

    2015-01-01

    To compare the outcomes of living donor liver transplantation (LDLT) versus deceased donor liver transplantation (DDLT) for patients with hepatocellular carcinoma (HCC) in different selection criteria. Data of patients with HCC who underwent liver transplantation between 2005 and 2013 at our center were reviewed. Clinical data of LDLT recipients and DDLT recipients were compared. The postoperative recurrence-free survival (RFS) rate and overall survival (OS) rate after LDLT versus DDLT were compared in the Milan recipients, the University of California, San Francisco (UCSF) recipients, the up-to-seven recipients, the Hangzhou recipients and the Chengdu recipients. Data of 255 patients were retrospectively reviewed in this study. Seventeen DDLT recipient and 9 LDLT recipients died during the perioperative period. Among the remaining 229 recipients (NLDLT=66, NDDLT=163), 96 patients met the Milan criteria, 123 recipients met the UCSF criteria, 135 patients met the up-to-seven criteria, 216 patients met the Hangzhou criteria, and 229 recipients met the Chengdu criteria. The overall RFS and OS rates of the Milan recipients, the UCSF recipients, the up-to-seven recipients, the Hangzhou recipients and the Chengdu recipients after LDLT and DDLT were all similar. Using well-studied selection criteria, LDLT offers similar outcomes to DDLT for patient with HCC, even using expanded selection criteria.

  14. Lack of correlation between hepatitis B virus infection and the increasing incidence of primary liver cancer in Sweden.

    PubMed

    Kaczynski, J; Hansson, G; Norkrans, G; Wallerstedt, S

    1991-01-01

    The incidence of primary carcinoma of the liver in Sweden has been reported to increase. In order to study the role of chronic hepatitis B virus (HBV) infection for liver cancer development 40 cases with hepatocellular carcinoma (HCC) were examined for the presence of HBV surface antigen and HBV core antigen in the cancer and in the surrounding non-neoplastic liver tissue. It was not possible to demonstrate a single case with tissue HBV antigen, indicating that HBV plays a minor role in the etiology of HCC in Sweden and thus does not seem to be responsible for the increasing incidence of this cancer.

  15. Granulin-epithelin precursor and ATP-dependent binding cassette (ABC)B5 regulate liver cancer cell chemoresistance.

    PubMed

    Cheung, Siu Tim; Cheung, Phyllis F Y; Cheng, Christine K C; Wong, Nicholas C L; Fan, Sheung Tat

    2011-01-01

    Chemotherapy is used to treat unresectable liver cancer with marginal efficacy; this might result from hepatic cancer cells with stem cell and chemoresistant features. Gene expression profiling studies have shown that hepatic cancer cells express granulin-epithelin precursor (GEP); we investigated its role in hepatic cancer stem cell functions and chemoresistance. The effects of GEP and drug transporter signaling on chemoresistance were investigated in hepatic cancer stem cells. We analyzed the expression patterns of 142 clinical samples from liver tumors, adjacent nontumorous liver tissue, and liver tissue from patients who did not have cancer. GEP regulated the expression of the adenosine triphosphate-dependent binding cassette (ABC)B5 drug transporter in liver cancer cells. Chemoresistant cells that expressed GEP had increased levels of ABCB5; suppression of ABCB5 sensitized the cells to doxorubicin uptake and apoptosis. Most cells that expressed GEP and ABCB5 also expressed the hepatic cancer stem cell markers CD133 and EpCAM; blocking ABCB5 reduced their expression. Expression levels of GEP and ABCB5 were correlated in human liver tumor samples. ABCB5 levels were increased in liver cancer cells compared with nontumor liver tissue from patients with cirrhosis or hepatitis, or normal liver tissue. ABCB5 expression was associated with the recurrence of hepatocellular carcinoma after partial hepatectomy. Expression of GEP and ABCB5 in liver cancer stem cells is associated with chemoresistance and reduced survival times of patients with hepatocellular carcinoma. Reagents designed to target these proteins might be developed as therapeutics and given in combination with chemotherapy to patients with liver cancer. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

  16. Glypican-3 antibodies: a new therapeutic target for liver cancer

    PubMed Central

    Ho, Mingqian Feng, Mitchell

    2013-01-01

    Glypican-3 (GPC3) is an emerging therapeutic target in hepatocellular carcinoma (HCC), even though the biological function of GPC3 remains elusive. Currently human (MDX-1414 and HN3) and humanized mouse (GC33 and YP7) antibodies that target GPC3 for HCC treatment are under different stages of preclinical or clinical development. Humanized mouse antibody GC33 is being evaluated in a phase II clinical trial. Human antibodies MDX-1414 and HN3 are under different stages of preclinical evaluation. Here, we summarize current evidence for GPC3 as a new target in liver cancer, discuss both its oncogenic function and its mode of actions for current antibodies, and evaluate potential challenges for GPC3-targeted anti-cancer therapies. PMID:24140348

  17. Pseudolesion of the liver observed on gadoxetate disodium-enhanced magnetic resonance imaging obtained shortly after transarterial chemoembolization for hepatocellular carcinoma.

    PubMed

    Shinagawa, Yoshinobu; Sakamoto, Keiko; Fujimitsu, Ritsuko; Ida, Mikiko; Urakawa, Hiroshi; Kora, Shin-Ichi; Higashihara, Hideyuki; Takano, Kouichi; Yoshimitsu, Kengo

    2010-07-01

    The purpose of this report was to describe pseudolesions of the liver that mimicked residual hypervascular hepatocellular carcinoma (HCC), as observed on gadoxetate disodium-enhanced magnetic resonance imaging (EOB-MRI) obtained shortly after transarterial chemoembolization (TACE). Between June 2008 and December 2008, three patients underwent MRI within 12 days after TACE to rule out remaining viable cancerous tissue or to assess the treatment effect. In all three patients, nontumorous liver tissue adjacent to the treated HCC exhibited focal arterial enhancement on dynamic phase and subsequent diminished uptake of gadoxetate disodium on hepatocellular phase images, which mimicked residual HCC. All three patients had mild postembolization syndrome at the time of EOB-MRI and showed no evidence of residual or recurrent tumors on follow-up. The findings of these areas may represent transient focal hyperemia and damage to the liver cell function caused by TACE. Radiologists should be aware that EOB-MRI obtained shortly after TACE may show pseudolesions around the treated tumors and should not mistake them for residual or recurrent tumors.

  18. Living donor liver transplantation for hepatocellular carcinoma at the University of Tokyo Hospital

    PubMed Central

    Togashi, Junichi; Akamastu, Nobuhisa; Kokudo, Norihiro

    2016-01-01

    Background Living donor liver transplantation (LDLT) is an established treatment not only for those with end-stage liver disease but for those with hepatocellular carcinoma (HCC) developing in cirrhotic liver. The aim of this study was to present a single-center experience of LDLT for HCC at the University of Tokyo Hospital, Japan. Methods Among 573 liver transplant recipients from January 1996 until the end of 2015, 139 patients have been indicated LDLT for the treatment of HCC, and were the subjects of the present study. We use the expanded criteria for HCC as follows; the number of tumor should be five or less, and the maximum diameter of the tumor should be 5 cm or less, without the distant metastasis nor the vascular invasion (Tokyo criteria, 5-5 rule). We also focused on the identification of the incidental intrahepatic cholangiocarcinoma (ICC) and combined hepatocellular carcinoma/cholangiocarcinoma (cHCC-CC) in liver explants. Results The overall 1-, 5-, and 10-year recurrence-free and patient survival rates were 95%, 91%, and 91%, 91%, and 80%, 78%, respectively. The 1-, 3-, and 5-year cumulative recurrence rate was 5%, 6%, and 6% for within Milan, 0%, 8%, and 8% for beyond Milan/within Tokyo, and 33%, 50%, and 50% for beyond Tokyo, respectively, demonstrating the significantly impaired outcome of those beyond Tokyo criteria (P<0.001). The high alpha-fetoprotein (AFP) value (≥400 ng/mL), the high des-gamma-carboxy prothrombin (DCP) value (≥200 mAU/mL) and beyond the Tokyo criteria were proved to be significant predictors for the HCC recurrence, but the size or the type of the partial graft was not associated. Incidental ICC and cHCC-CC were found in one and two patients, respectively, with the size of less than 2 cm in all cases. ICC was not detected in preoperative evaluation but cHCC-CCs were misdiagnosed as HCC preoperatively. All three patients were alive without recurrence with a follow-up period of 2 to 14 years. Conclusions The present results

  19. Sox9 regulates self-renewal and tumorigenicity by promoting symmetrical cell division of cancer stem cells in hepatocellular carcinoma.

    PubMed

    Liu, Chungang; Liu, Limei; Chen, Xuejiao; Cheng, Jiamin; Zhang, Heng; Shen, Junjie; Shan, Juanjuan; Xu, Yanmin; Yang, Zhi; Lai, Maode; Qian, Cheng

    2016-07-01

    Hepatocellular carcinoma (HCC) is a highly aggressive liver tumor containing cancer stem cells (CSCs) that participate in tumor propagation, resistance to conventional therapy, and promotion of tumor recurrence, causing poor patient outcomes. The protein SRY (sex determining region Y)-box 9 (Sox9) is a transcription factor expressed in some solid tumors, including HCC. However, the molecular mechanisms underlying Sox9 function in liver CSCs remain unclear. Here, we show that Sox9 is highly expressed in liver CSCs and that high levels of Sox9 predict a decreased probability of survival in HCC patients. We demonstrate that Sox9 is required for maintaining proliferation, self-renewal, and tumorigenicity in liver CSCs. Overexpression of exogenous Sox9 in liver non-CSCs restored self-renewal capacity. Additionally, a reduction in the asymmetrical cell division of spheroid-cultured liver CSCs was observed when compared with differentiated cancer cells or liver CSCs with inhibited Notch signaling. Furthermore, we demonstrate that Sox9 is responsible for the asymmetrical-to-symmetrical cell division switch in liver CSCs. Sox9 also negatively regulates Numb expression, contributing to a feedback circuit that maintains Notch activity and directs symmetrical cell division. Clinical analyses revealed that the Sox9(High) Numb(Low) profile is associated with poor prognosis in human HCC patients. We demonstrate that Sox9 plays a critical role in self-renewal and tumor propagation of liver CSCs and identify the molecular mechanisms regulated by Sox9 that link tumor initiation and cell division. (Hepatology 2016;64:117-129). © 2016 by the American Association for the Study of Liver Diseases.

  20. Association of early age at establishment of chronic hepatitis B infection with persistent viral replication, liver cirrhosis and hepatocellular carcinoma: a systematic review.

    PubMed

    Shimakawa, Yusuke; Yan, Hong-Jing; Tsuchiya, Naho; Bottomley, Christian; Hall, Andrew J

    2013-01-01

    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.

  1. [Studies on telomerase reverse transcriptase components and liver cancer].

    PubMed

    Cai, J J; Guo, X L

    2016-07-20

    Telomeres are DNA tandem repeats at the ends of chromosomes in eukaryotic cells and play important roles in maintaining the stability and integrity of chromosomes. Telomeres are gradually shortened with cell proliferation, and when they are shortened to a certain length, the cells experience senescence and apoptosis. However, a small number of cells can maintain the length of telomeres and restore their function through related mechanisms (activation of telomerase or other mechanisms), and some cells may even be immortalized. Therefore, telomere and telomerase are thought to be closely associated with tumor development and progression. It has been confirmed that telomerase activation is an early event in the development of primary liver cancer, especially the important component of telomerase telomerase reverse transcriptase (TERT), which plays an important role in this process. Here this article reviews the latest research advances in the function and regulation mechanisms of telomerase and the role of TERT in the development, progression, and treatment of primary liver cancer, especially hepatocellular carcinoma, so as to provide a molecular genetic basis for intervention of liver cancer and related targeted therapy.

  2. Glypican-3 Targeting Immunotoxins for the Treatment of Liver Cancer

    PubMed Central

    Fleming, Bryan D.; Ho, Mitchell

    2016-01-01

    Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, yet no effective therapeutics exist. This review provides an overview of the recent development of recombinant immunotoxins for the treatment of glypican-3 (GPC3) expressing HCC. GPC3 is a cell surface heparan sulfate proteoglycan that is overexpressed in HCC, but is absent from normal adult human tissues. Treatment of HCC with anti-GPC3 immunotoxins represents a new therapeutic option. Using phage display and hybridoma technologies, three high affinity antibodies (HN3, HS20 and YP7) have been generated against GPC3. Two of these antibodies (HN3 and HS20) have demonstrated the ability to inhibit Wnt/Yap signaling, leading to a reduction in liver cancer cell proliferation. By combining the HN3 antibody capable of inhibiting Wnt/Yap signaling with the protein synthesis inhibitory domain of the Pseudomonas exotoxin, a recombinant immunotoxin that exhibits a dual inhibitory mechanism was generated. This immunotoxin was found to be highly effective in the treatment of human HCCs in mouse xenograft models. Engineering of the toxin fragment to reduce the level of immunogenicity is currently being explored. The development of immunotoxins provides opportunities for novel liver cancer therapies. PMID:27669301

  3. Rising Rates of Hepatocellular Carcinoma Leading to Liver Transplantation in Baby Boomer Generation with Chronic Hepatitis C, Alcohol Liver Disease, and Nonalcoholic Steatohepatitis-Related Liver Disease.

    PubMed

    Cholankeril, George; Yoo, Eric R; Perumpail, Ryan B; Liu, Andy; Sandhu, Jeevin S; Nair, Satheesh; Hu, Menghan; Ahmed, Aijaz

    2017-09-26

    We aim to study the impact of the baby boomer (BB) generation, a birth-specific cohort (born 1945-1965) on hepatocellular carcinoma (HCC)-related liver transplantation (LT) in patients with chronic hepatitis C virus (HCV), alcoholic liver disease (ALD), and non-alcoholic steatohepatitis (NASH). We performed a retrospective analysis using the United Network for Organ Sharing (UNOS)/Organ Procurement Transplant Network (OPTN) database from 2003 to 2014 to compare HCC-related liver transplant surgery trends between two cohorts-the BB and non-BB-with a secondary diagnosis of HCV, ALD, or NASH. From 2003-2014, there were a total of 8313 liver transplant recipients for the indication of HCC secondary to HCV, ALD, or NASH. Of the total, 6658 (80.1%) HCC-related liver transplant recipients were BB. The number of liver transplant surgeries for the indication of HCC increased significantly in NASH (+1327%), HCV (+382%), and ALD (+286%) during the study period. The proportion of BB who underwent LT for HCC was the highest in HCV (84.7%), followed by NASH (70.3%) and ALD (64.7%). The recommendations for birth-cohort specific HCV screening stemmed from a greater understanding of the high prevalence of chronic HCV and HCV-related HCC within BB. The rising number of HCC-related LT among BB with ALD and NASH suggests the need for increased awareness and improved preventative screening/surveillance measures within NASH and ALD cohorts as well.

  4. Successful surgical resection of solitary plasmacytoma of the liver mimicking hepatocellular carcinoma. A case report.

    PubMed

    Mirarchi, Mariateresa; De Raffele, Emilio; Bacci, Francesco; Cuicchi, Dajana; Lecce, Ferdinando; Cola, Bruno

    Solitary extramedullary plasmacitomas (SEMP) of the liver are very rare. We report the case of an elderly woman with a huge symptomatic SEMP of the liver mimicking hepatocellular carcinoma (HCC). The patient was a 89-year-old woman who presented with severe abdominal pain and a huge solid mass in the right hypochondrium. The laboratory data on admission revealed normal liver function tests. A multiphasic computed tomography (CT) showed a huge solid mass of the left hemiliver, hypoattenuating on noncontrast images, dishomogeneously hyperenhancing in the late arterial phase, with washout in the portal venous and equilibrium phases. A 18F-FDG positron emission tomography (18F-FDG PET)-CT scan documented a marked FDG uptake within the lesion, without evidence of extrahepatic metastases. We considered the clinical and radiologic findings consistent with the diagnosis of high-grade HCC with areas of intratumoral necrosis preluding to possible tumour rupture. Surgical resection was ultimately considered feasible with a reasonable risk and the patient underwent left hepatectomy with diaphragmatic resection. Pathological examination exhibited an extramedullary plasmacytoma. At immunohistochemical analysis neoplastic cells were positive for CD45, CD38, IRF4, HTPD52, kappa-chain, but negative for lambda- chain; Mib-1 proliferation index was 50%. Subsequent clinical evaluation excluded any sign of multiple myeloma, so that a diagnosis of truly localized SEMP of the liver was finally established. To our knowledge, this is the first case of a solitary extramedullary plasmacitoma of the liver undergoing successful radical liver resection. The patient is alive and well 5 years after surgery without evidence of local recurrence and of systemic disease.

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

    PubMed Central

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

    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/mL could be an exclusion criterion, whereas values of < 15 ng/mL 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. PMID:27478538

  6. Living donor liver transplantation does not increase tumor recurrence of hepatocellular carcinoma compared to deceased donor transplantation

    PubMed Central

    Xiao, Guang-Qin; Song, Jiu-Lin; Shen, Shu; Yang, Jia-Yin; Yan, Lu-Nan

    2014-01-01

    AIM: To compare the recurrence-free survival (RFS) and overall survival (OS) of hepatitis B virus (HBV)-positive hepatocellular carcinoma (HCC) after living donor liver transplantation (LDLT) and deceased donor liver transplantation (DDLT). METHODS: We retrospectively collected clinical data from 408 liver cancer patients from February 1999 to September 2012. We used the chi-squared test or Fisher’s exact test to analyze the characteristics of LDLT and DDLT. Kaplan-Meier analysis was used to compare the RFS and OS in HCC. RESULTS: Three hundred sixty HBV-positive patients (276 DDLT and 84 LDLT) were included in this study. The mean follow-up time was 27.1 mo (range 1.1-130.8 mo). One hundred eighty-five (51.2%) patients died during follow-up. The 1-, 3-, and 5-year RFS rates for LDLT were 85.2%, 55.7%, and 52.9%, respectively; for DDLT, the RFS rates were 73.2%, 49.1%, and 45.3% (P = 0.115). The OS rates were similar between the LDLT and DDLT recipients, with 1-, 3-, and 5-year survival rates of 81.8%, 49.5%, and 43.0% vs 69.5%, 43.0%, and 38.3%, respectively (P = 0.30). The outcomes of HCC according to the Milan criteria after LDLT and DDLT were not significantly different (for LDLT: 1-, 3-, and 5-year RFS: 94.7%, 78.7%, and 78.7% vs 89.2%, 77.5%, and 74.5%, P = 0.50; for DDLT: 86.1%, 68.8%, and 68.8% vs 80.5%, 62.2%, and 59.8% P = 0.53). CONCLUSION: The outcomes of LDLT for HCC are not worse compared to the outcomes of DDLT. LDLT does not increase tumor recurrence of HCC compared to DDLT. PMID:25152599

  7. Epigenetic regulation of hepatocellular carcinoma in non-alcoholic fatty liver disease.

    PubMed

    Tian, Yuan; Wong, Vincent Wai-Sun; Chan, Henry Lik-Yuen; Cheng, Alfred Sze-Lok

    2013-12-01

    Emerging evidence that epigenetics converts alterations in nutrient and metabolism into heritable pattern of gene expression has profound implications in understanding human physiology and diseases. Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome including obesity and diabetes which elevate the risk of hepatocellular carcinoma (HCC) especially in male. This review focuses on the molecular connections between metabolic dysfunction and aberrant epigenetic alterations in the development of HCC in NAFLD. The metabolites derived from excessive insulin, glucose and lipid may perturb epigenetic gene regulation through DNA methylation, histone modifications, and RNA interference, leading to activation of pro-inflammatory signaling and deregulation of metabolic pathways. The interplay and crosstalk of chromatin-modifying enzymes, microRNAs, signaling pathways and the downstream transcription factors result in epigenomic reprogramming that drives hepatocellular transformation. The interactions between sex hormone pathways and the epigenetic machineries that influence chromatin states in NAFLD provide potential molecular mechanisms of gender disparity in HCC. A deeper understanding of these connections and comprehensive molecular catalog of hepatocarcinogenesis may shed light in the identification of druggable epigenetic targets for the prevention and treatment of HCC in obese or diabetic patients.

  8. The Notch pathway promotes the cancer stem cell characteristics of CD90+ cells in hepatocellular carcinoma.

    PubMed

    Luo, Jing; Wang, Peng; Wang, Ronghua; Wang, Jinlin; Liu, Man; Xiong, Si; Li, Yawen; Cheng, Bin

    2016-02-23

    CD90 has been identified as a marker for liver cancer stem cells (CSCs) that are responsible for tumorigenic activity, but it is not known how CD90+ cells contribute to tumor initiation and progression. Our data demonstrated that high expression of CD90 in Hepatocellular Carcinoma (HCC) tissues correlated with venous filtration in HCC patients. CD90+ cells isolated from HCC cell lines exhibited increased tumorigenicity, chemoresistance, tumor invasion and metastasis. Notch pathway was activated in CD90+ cells and we found that inhibition of Notch pathway in CD90+ CSCs decreased tumorigenicity, cell invasion, migration and expression of stem cell related genes. Activation of Notch pathway in CD90- cells induced self-renewal, invasion and migration. Furthermore, we observed that cancer stem cell features were facilitated by stimulating G1-S transition in the cell cycle phase and inhibiting apoptosis mediated by Notch pathway. Our findings suggested CD90 could be used as a potential biomarker for HCC CSCs, and that cancer stem cell activity was elevated through up activated Notch pathway in CD90+ CSCs.

  9. Cancer-Associated Fibroblasts from Hepatocellular Carcinoma Promote Malignant Cell Proliferation by HGF Secretion

    PubMed Central

    Fu, Bin-Sheng; Hua, XueFeng; Wang, Guo-Ying; Li, Tuan-Jie; Li, Xing; Wu, Xiang-Yuan; Tai, Yan; Zhou, Jie; Chen, Gui-Hua; Zhang, Qi

    2013-01-01

    Cancer-associated fibroblasts (CAFs) are reported to support tumorigenesis by stimulating angiogenesis, cancer cell proliferation, and invasion in most solid tumors. However, the roles of CAFs in the liver cancer microenvironment have not been thoroughly studied. In our previous study, we successfully isolated CAFs from hepatocellular carcinoma (HCC) (H-CAFs) and proved that H-CAFs suppressed the activation of NK cells and thereby created favorable conditions for HCC progression. In our present study, we found that the proliferation of MHCC97L and Hep3B cells was significantly promoted by treatment with conditioned medium from H-CAFs. Pathological analysis also revealed that H-CAFs increased the proportion of Ki-67 (+) malignant cells and prevented them from undergoing necrosis. Moreover, the concentration of hepatocyte growth factor (HGF) cytokine in the conditioned medium of H-CAFs was higher than conditioned medium from normal skin fibroblasts (NSFs). Anti-HGF significantly reduced the proliferation-promoting capability of H-CAFs. In addition, we found that the abundance of H-CAFs correlated positively with tumor size. These results indicate that H-CAFs are an important factor for promoting the growth of HCC in vitro and in vivo, and that HGF plays a key role in HCC proliferation induced by H-CAFs. PMID:23667593

  10. Novel metronomic chemotherapy and cancer vaccine combinatorial strategy for hepatocellular carcinoma in a mouse model.

    PubMed

    Tagliamonte, Maria; Petrizzo, Annacarmen; Napolitano, Maria; Luciano, Antonio; Arra, Claudio; Maiolino, Piera; Izzo, Francesco; Tornesello, Maria Lina; Aurisicchio, Luigi; Ciliberto, Gennaro; Buonaguro, Franco M; Buonaguro, Luigi

    2015-10-01

    Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer and represents the third and the fifth leading cause of cancer-related death worldwide in men and women, respectively. Hepatitis B virus (HBV) and hepatitis C virus (HCV) chronic infections account for pathogenesis of more than 80 % of primary HCC. HCC prognosis greatly varies according to stage at beginning of treatment, but the overall 5-year survival rate is approximately 5-6 %. Given the limited number of effective therapeutic strategies available, immunotherapies and therapeutic cancer vaccines may help in improving the clinical outcome for HCC patients. However, the few clinical trials conducted to date have shown contrasting results, indicating the need for improvements. In the present study, a novel combinatorial strategy, based on metronomic chemotherapy plus vaccine, is evaluated in a mouse model. The chemotherapy is a multi-drug cocktail including taxanes and alkylating agents, which is administered in a metronomic-like fashion. The vaccine is a multi-peptide cocktail including HCV as well as universal tumor antigen TERT epitopes. The combinatorial strategy designed and evaluated in the present study induces an enhanced specific T cell response, when compared to vaccine alone, which correlates to a reduced Treg frequency. Such results are highly promising and may pave way to relevant improvements in immunotherapeutic strategies for HCC and beyond.

  11. Immunotoxin Targeting Glypican-3 Effective against Liver Tumors | Center for Cancer Research

    Cancer.gov

    Worldwide, liver cancer is the fifth most common malignancy, and hepatocellular carcinoma (HCC) makes up about two-thirds of those cases. Unfortunately, surgery is still the most effective treatment for HCC but is only available to patients diagnosed at early stages. HCC is known for being particularly drug resistant, sorafenib being the only FDA-approved chemotherapy currently available. Thus, new strategies for treating the disease are urgently needed.

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

    PubMed Central

    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

  13. Trametinib or Combination Chemotherapy in Treating Patients With Refractory or Advanced Biliary or Gallbladder Cancer or That Cannot Be Removed by Surgery

    ClinicalTrials.gov

    2017-08-11

    Adult Cholangiocarcinoma; Advanced Adult Hepatocellular Carcinoma; BCLC Stage C Adult Hepatocellular Carcinoma; BCLC Stage D Adult Hepatocellular Carcinoma; Hilar Cholangiocarcinoma; Localized Non-Resectable Adult Liver Carcinoma; Recurrent Adult Liver Carcinoma; Recurrent Childhood Liver Cancer; Recurrent Extrahepatic Bile Duct Carcinoma; Recurrent Gallbladder Carcinoma; Stage II Gallbladder Cancer; Stage III Childhood Hepatocellular Carcinoma; Stage IIIA Gallbladder Cancer; Stage IIIB Gallbladder Cancer; Stage IV Childhood Hepatocellular Carcinoma; Stage IV Distal Bile Duct Cancer; Stage IVA Gallbladder Cancer; Stage IVB Gallbladder Cancer; Unresectable Extrahepatic Bile Duct Carcinoma

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

    PubMed

    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.

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

    SciTech Connect

    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.

  16. Detection of hepatocellular carcinoma and liver metastases with BR14: a multicenter phase IIA study.

    PubMed

    Hohmann, Joachim; Müller, Anja; Skrok, Jan; Wolf, Karl-Jürgen; Martegani, Alberto; Dietrich, Christoph F; Albrecht, Thomas

    2012-03-01

    The study was designed primarily to find the optimal dosage range of BR14 contrast-enhanced ultrasonography (CEUS) to detect malignant focal liver lesions. Secondary objectives were the evaluation of the safety profile and comparison with contrast-enhanced MRI (CE MRI). We studied 25 patients (9 females, 16 males, mean age, 66 years) with known hepatocellular carcinoma or liver metastases at 3 centers over a 3-month period. Each patient underwent a baseline examination and at least 3 CEUS examinations with ascending dose levels (0.25 mL; 1.0 mL; 4.0 mL) of BR14. CE MRI was performed 4 weeks before or after the CEUS examination. Dedicated liver maps were used to record the location, size, and type of detected lesions. Examination quality was documented and safety parameters were assessed. The number of lesions detected by BR14 CEUS increased with dosage, whereas the number of missed lesions and the lesion sizes decreased. Despite the increasing contrast enhancement, substantial differences among dosages were not seen for other image quality parameters. No significant changes were noted in safety parameters and no serious adverse events were reported. We conclude that the recommended dose level of BR14 is between 1 mL and 4 mL; at this dosage, lesion detection is comparable to that of CE MRI.

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

    PubMed

    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.

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

    PubMed Central

    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

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

    PubMed Central

    Takada, Yasutsugu

    2016-01-01

    With the scarcity of deceased donor liver grafts, living donor liver transplantation (LDLT) is gaining popularity as an alternative to deceased donor liver transplantation (DDLT) for patients with hepatocellular carcinoma (HCC). However, as the evidence of cases of LDLT accumulates, several authors have reported higher HCC recurrence rates after LDLT. The suggested reasons for the higher recurrence rates following LDLT are related to the small-for-size graft in LDLT, surgical procedures that are specific to LDLT, and the fast-track to LDLT. Fast-tracking to LDLT may not allow sufficient time for evaluation of the biological aggressiveness of tumors, which may result in high recurrence rates due to inclusion of patients with more inherently aggressive tumors. Actually, some studies that reported higher recurrence rates with LDLT included a larger number of cases of HCC with microvascular invasion or poorly differentiated HCC. In order to exclude biologically aggressive HCC preoperatively, selection criteria incorporating tumor markers, such as alpha-fetoprotein (AFP) and des-gamma-carboxyprothrombin (DCP), as well as morphological tumor number and size have been proposed. With more reliable selection criteria incorporating biological markers to eliminate biologically aggressive HCC, LDLT can be a viable treatment option for patients with HCC, providing similar recurrence rates as those achieved with DDLT. PMID:28138602

  20. An orthotopic mouse model of hepatocellular carcinoma with underlying liver cirrhosis

    PubMed Central

    Reiberger, Thomas; Chen, Yunching; Ramjiawan, Rakesh R; Hato, Tai; Fan, Christopher; Samuel, Rekha; Roberge, Sylvie; Huang, Peigen; Lauwers, Gregory Y; Zhu, Andrew X; Bardeesy, Nabeel; Jain, Rakesh K; Duda, Dan G

    2016-01-01

    Subcutaneous xenografts have been used for decades to study hepatocellular carcinoma (HCC). These models do not reproduce the specific pathophysiological features of HCCs, which occur in cirrhotic livers that show pronounced necroinflammation, abnormal angiogenesis and extensive fibrosis. As these features are crucial for studying the role of the pathologic host microenvironment in tumor initiation, progression and treatment response, alternative HCC models are desirable. Here we describe a syngeneic orthotopic HCC model in immunocompetent mice with liver cirrhosis induced by carbon tetrachloride (CCl4) that recapitulates key features of human HCC. Induction of substantial hepatic fibrosis requires 12 weeks of CCl4 administration. Intrahepatic implantation of mouse HCC cell lines requires 30 min per mouse. Tumor growth varies by tumor cell line and mouse strain used. Alternatively, tumors can be induced in a genetically engineered mouse model. In this setting, CCl4 is administered for 12 weeks after tail-vein injection of Cre-expressing adenovirus (adeno-Cre) in Stk4−/−Stk3F/− (also known as Mst1−/−Mst2F/−; F indicates a floxed allele) mice, and it results in the development of HCC tumors (hepatocarcinogenesis) concomitantly with liver cirrhosis. PMID:26203823

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

    PubMed

    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.

  2. Neo-adjuvant therapy for hepatocellular carcinoma before liver transplantation: Where do we stand?

    PubMed Central

    Fujiki, Masato; Aucejo, Federico; Choi, Minsig; Kim, Richard

    2014-01-01

    Liver transplantation (LT) for hepatocellular carcinoma (HCC) within Milan criteria is a widely accepted optimal therapy. Neo-adjuvant therapy before transplantation has been used as a bridging therapy to prevent dropout during the waiting period and as a down-staging method for the patient with intermediate HCC to qualify for liver transplantation. Transarterial chemoembolization and radiofrequency ablation are the most commonly used method for locoregional therapy. The data associated with newer modalities including drug-eluting beads, radioembolization with Y90, stereotactic radiation therapy and sorafenib will be discussed as a tool for converting advanced HCC to LT candidates. The concept “ablate and wait” has gained the popularity where mandated observation period after neo-adjuvant therapy allows for tumor biology to become apparent, thus has been recommended after down-staging. The role of neo-adjuvant therapy with conjunction of “ablate and wait” in living donor liver transplantation for intermediate stage HCC is also discussed in the paper. PMID:24833861

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

    PubMed Central

    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

  4. Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report.

    PubMed

    Clavien, Pierre-Alain; Lesurtel, Mickael; Bossuyt, Patrick M M; Gores, Gregory J; Langer, Bernard; Perrier, Arnaud

    2012-01-01

    Although liver transplantation is a widely accepted treatment for hepatocellular carcinoma (HCC), much controversy remains and there is no generally accepted set of guidelines. An international consensus conference was held on Dec 2-4, 2010, in Zurich, Switzerland, with the aim of reviewing current practice regarding liver transplantation in patients with HCC and to develop internationally accepted statements and guidelines. The format of the conference was based on the Danish model. 19 working groups of experts prepared evidence-based reviews according to the Oxford classification, and drafted recommendations answering 19 specific questions. An independent jury of nine members was appointed to review these submissions and make final recommendations, after debates with the experts and audience at the conference. This report presents the final 37 statements and recommendations, covering assessment of candidates for liver transplantation, criteria for listing in cirrhotic and non-cirrhotic patients, role of tumour downstaging, management of patients on the waiting list, role of living donation, and post-transplant management.

  5. N-Nitrosodiethylamine-Induced Pig Liver Hepatocellular Carcinoma Model: Radiological and Histopathological Studies

    SciTech Connect

    Li Xiao; Zhou Xiangping Guan Yongsong; Wang, Yi-Xiang J.; Scutt, Diane; Gong Qiyong

    2006-06-15

    Experimental research involving animal models plays a critical role in the development and improvement of minimally invasive therapies for hepatocellular carcinoma (HCC). As a large animal, the pig is commonly used for surgery and interventional radiology research. In this study, liver multicentric HCC with cirrhosis was induced in six China Taihu pigs by intraperitoneal injection of 10 mg/kg of N-nitrosodiethylamine once a week for 3 months, followed by a period of 10-12 months without N-nitrosodiethylamine treatment. All pigs were in generally good health until the end of the study. The tumor nodules appeared hyperattenuating in the arterial phase of a dynamic computed tomography (CT) scan. Digital subtraction angiography (DSA) and CT angiography demonstrated that the tumors derived their blood supply mainly from the hepatic artery system. Lipiodol-CT showed Lipiodol retention in tumor areas. The histology and electron microscopic ultrastructure of the chemically induced liver HCC in this study resembled human HCC with a cirrhosis background. An immunohistochemistry study confirmed that the tumors were of hepatocyte origin. All highly, moderately, and poorly differentiated HCC tumors were identified in this study. Cholangiocarcinoma was not seen in any of the animals. Due to its comparable size to human anatomy, the pig liver HCC model would give a better scope for interventional and surgical manipulations than small animal models.

  6. Evaluation of Liver Function After Proton Beam Therapy for Hepatocellular Carcinoma

    SciTech Connect

    Mizumoto, Masashi; Okumura, Toshiyuki; Hashimoto, Takayuki; Fukuda, Kuniaki; Oshiro, Yoshiko; Fukumitsu, Nobuyoshi; Abei, Masato; Kawaguchi, Atsushi; Hayashi, Yasutaka; Ohkawa, Ayako; Hashii, Haruko; Kanemoto, Ayae; Moritake, Takashi; Tohno, Eriko; Tsuboi, Koji; Sakae, Takeji; Sakurai, Hideyuki

    2012-03-01

    Purpose: Our previous results for treatment of hepatocellular carcinoma with proton beam therapy (PBT) revealed excellent local control. In this study, we focused on the impact of PBT on normal liver function. Methods and Materials: The subjects were 259 patients treated with PBT at University of Tsukuba between January 2001 and December 2007. We evaluated the Child-Pugh score pretreatment, on the final day of PBT, and 6, 12, and 24 months after treatment with PBT. Patients who had disease progression or who died with tumor progression at each evaluation point were excluded from the analysis to rule out an effect of tumor progression. An increase in the Child-Pugh score of 1 or more was defined as an adverse event. Results: Of the 259 patients, 241 had no disease progression on the final day of PBT, and 91 had no progression within 12 months after PBT. In univariate analysis, the percentage volumes of normal liver receiving at least 0, 10, 20, and 30 GyE in PBT (V0, 10, 20, and 30) were significantly associated with an increase of Child-Pugh score at 12 months after PBT. Of the 91 patients evaluated at 12 months, 66 had no increase of Child-Pugh score, 15 had a 1-point increase, and 10 had an increase of {>=}2 points. For the Youden index, the optimal cut-offs for V0, V10, V20, and V30 were 30%, 20%, 26%, and 18%, respectively. Conclusion: Our findings indicate that liver function after PBT is significantly related to the percentage volume of normal liver that is not irradiated. This suggests that further study of the relationship between liver function and PBT is required.

  7. Chemoembolization Decreases Drop-Off Risk of Hepatocellular Carcinoma Patients on the Liver Transplant List

    SciTech Connect

    Frangakis, Constantine; Geschwind, Jean-Francois; Kim, Daniel; Chen, Yong; Koteish, Ayman; Hong, Kelvin; Liapi, Eleni; Georgiades, Christos S.

    2011-12-15

    Introduction: The drop-off risk for patients awaiting liver transplantation for hepatocellular carcinoma (HCC) is 22%. Transplant liver availability is expected to worsen, resulting in longer waiting times and increased drop-off rates. Our aim was to determine whether chemoembolization can decrease this risk. Patients and Methods: Eighty-seven consecutive HCC patients listed for liver transplant (Milan criteria) underwent statistical comparability adjustments using the propensity score (Wilcoxon, Fisher's, and chi-square tests). Forty-three nonchemoembolization patients and 22 chemoembolization patients were comparable for Child-Pugh and Model for End-Stage Liver Disease scores, tumor size and number, alpha fetoprotein (AFP) levels, and cause of cirrhosis. We calculated the risk of dropping off the transplant list by assigning a transplant time to those who dropped off (equal probability with patients who were on the list longer than the patient in question). The significance level was obtained by calculating the simulation distribution of the difference compared with the permutations of chemoembolization versus nonchemoembolization assignment of the patients. Kaplan-Meier estimators (log-rank test) were used to determine survival rates. Results: Median follow-up was 187 {+-} 110 weeks (range 38 to 435, date of diagnosis). The chemoembolization group had an 80% drop-off risk decrease (15% nonchemoembolization versus 3% chemoembolization, p = 0.04). Although survival was better for the chemoembolization group, it did not reach statistical significance. Two-year survival for the nonchemoembolization and chemoembolization group was 57.3% {+-} 7.1% and 76.0% {+-} 7.9%, respectively (p = 0.078). Conclusions: Chemoembolization appears to result in a significant decrease in the risk of dropping off liver transplant list for patients with HCC and results in a tendency toward longer survival.

  8. Modification of Acid-Base Balance in Cirrhotic Patients Undergoing Liver Resection for Hepatocellular Carcinoma

    PubMed Central

    Cucchetti, Alessandro; Siniscalchi, Antonio; Ercolani, Giorgio; Vivarelli, Marco; Cescon, Matteo; Grazi, Gian Luca; Faenza, Stefano; Pinna, Antonio Daniele

    2007-01-01

    Objective: To examine modifications of acid-base balance of cirrhotic patients undergoing hepatectomy for hepatocellular carcinoma (HCC). Summary Background Data: Acid-base disorders are frequently observed in cirrhotics; however, modifications during hepatectomy and their impact on prognosis have never been investigated. Methods: Two hundred and two hepatectomies for HCC on cirrhosis were reviewed. Arterial blood samples were collected immediately before and at the end of resection. Preresection and postresection acid-base parameters were compared and related to patient characteristics and postoperative course. The accuracy of acid-base parameters in predicting postoperative liver failure, defined as an impairment of liver function after surgery that led to patient death or required transplantation, was assessed using receiver operating characteristic analysis (ROC). Results: All patients showed a significant reduction in pH, bicarbonate, and base excess at the end of hepatectomy (P < 0.001 in all cases), worsened by intraoperative blood loss (P < 0.010) and preoperative Model for end-stage liver disease score ≥11 (P < 0.010). ROC curve analysis identifies patients with postresection bicarbonate <19.4 mmol/L at high risk for liver failure (50.0%) whereas levels >22.1 mmol/L did not lead to the event (0%; P < 0.001). Postoperative prolongation of prothrombin time and increases in bilirubin, creatinine, and morbidity were also more frequent in patients with lower postresection bicarbonate, resulting in a longer in-hospital stay. Conclusion: In cirrhotic patients, a trend toward a relative acidosis can be expected during surgery and is worsened by the severity of the underlying liver disease and intraoperative blood loss. Postresection bicarbonate level lower than 19.4 mmol/L is an adverse prognostic factor. PMID:17522516

  9. Aflatoxin-induced TP53 R249S mutation in hepatocellular carcinoma in Thailand: association with tumors developing in the absence of liver cirrhosis.

    PubMed

    Villar, Stephanie; Ortiz-Cuaran, Sandra; Abedi-Ardekani, Behnoush; Gouas, Doriane; Nogueira da Costa, Andre; Plymoth, Amelie; Khuhaprema, Thiravud; Kalalak, Anant; Sangrajrang, Suleeporn; Friesen, Marlin D; Groopman, John D; Hainaut, Pierre

    2012-01-01

    Primary Liver Cancer (PLC) is the leading cause of death by cancer among males in Thailand and the 3(rd) among females. Most cases are hepatocellular carcinoma (HCC) but cholangiocarcinomas represent between 4 and 80% of liver cancers depending upon geographic area. Most HCC are associated with chronic infection by Hepatitis B Virus while a G → T mutation at codon 249 of the TP53 gene, R249S, specific for exposure to aflatoxin, is detected in tumors for up to 30% of cases. We have used Short Oligonucleotide Mass Analysis (SOMA) to quantify free circulating R249S-mutated DNA in plasma using blood specimens collected in a hospital case:control study. Plasma R249S-mutated DNA was detectable at low concentrations (≥ 67 copies/mL) in 53 to 64% of patients with primary liver cancer or chronic liver disease and in 19% of controls. 44% of patients with HCC and no evidence of cirrhosis had plasma concentrations of R249S-mutated DNA ≥ 150 copies/mL, compared to 21% in patients with both HCC and cirrhosis, 22% in patients with cholangiocarcinoma, 12% in patients with non-cancer chronic liver disease and 3% of subjects in the reference group. Thus, plasma concentrations of R249S-mutated DNA ≥ 150 copies/mL tended to be more common in patients with HCC developing without pre-existing cirrhosis (p = 0.027). Overall, these results support the preferential occurrence of R249S-mutated DNA in HCC developing in the absence of cirrhosis in a context of HBV chronic infection.

  10. Differential effects of targeting Notch receptors in a mouse model of liver cancer.

    PubMed

    Huntzicker, Erik G; Hötzel, Kathy; Choy, Lisa; Che, Li; Ross, Jed; Pau, Gregoire; Sharma, Neeraj; Siebel, Christian W; Chen, Xin; French, Dorothy M

    2015-03-01

    Primary liver cancer encompasses both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). The Notch signaling pathway, known to be important for the proper development of liver architecture, is also a potential driver of primary liver cancer. However, with four known Notch receptors and several Notch ligands, it is not clear which Notch pathway members play the predominant role in liver cancer. To address this question, we utilized antibodies to specifically target Notch1, Notch2, Notch3, or jagged1 (Jag1) in a mouse model of primary liver cancer driven by v-akt murine thymoma viral oncogene homolog and neuroblastoma RAS viral oncogene homolog (NRas). We show that inhibition of Notch2 reduces tumor burden by eliminating highly malignant HCC- and CCA-like tumors. Inhibition of the Notch ligand, Jag1, had a similar effect, consistent with Jag1 acting in cooperation with Notch2. This effect was specific to Notch2, because Notch3 inhibition did not decrease tumor burden. Unexpectedly, Notch1 inhibition altered the relative proportion of tumor types, reducing HCC-like tumors but dramatically increasing CC-like tumors. Finally, we show that Notch2 and Jag1 are expressed in, and Notch2 signaling is activated in, a subset of human HCC samples. These findings underscore the distinct roles of different Notch receptors in the liver and suggest that inhibition of Notch2 signaling represents a novel therapeutic option in the treatment of liver cancer. © 2014 by the American Association for the Study of Liver Diseases.

  11. Response Evaluation Criteria in Solid Tumors (RECIST) criteria are superior to European Association for Study of the Liver (EASL) criteria at 1 month follow-up for predicting long-term survival in patients treated with transarterial chemoembolization before liver transplantation for hepatocellular cancer.

    PubMed

    Shuster, Anatoly; Huynh, Thien J; Rajan, Dheeraj K; Marquez, Max A; Grant, David R; Huynh, Dan C; Jaskolka, Jeffrey D

    2013-06-01

    To determine whether response to transarterial chemoembolization can predict survival in patients with hepatocellular carcinoma (HCC) who are candidates for orthotopic liver transplantation (LT) and if either European Association for Study of the Liver (EASL) criteria or Response Evaluation Criteria in Solid Tumors (RECIST) criteria are more accurate for this purpose. A retrospective review of all patients who underwent LT after transarterial chemoembolization between January 2005 and June 2011 was performed. Follow-up imaging with multiphasic computed tomography or magnetic resonance imaging was performed 1 month after transarterial chemoembolization and every 3 months thereafter until LT. Treatment response was evaluated at each imaging time point using RECIST criteria and EASL criteria. The relationship between survival and objective response (OR), time to response (TTR), time to progression (TTP), and time interval between transarterial chemoembolization and LT was assessed. A median of one transarterial chemoembolization procedure was performed before LT in 58 patients (52 men, 6 women; mean age, 57 y). OR was shown by 28 (48%) patients and 51 (88%) patients at 1 month by EASL criteria and RECIST criteria, respectively. OR at 1-month follow-up using RECIST criteria was associated with increased survival compared with patients with no response (NR) (P = .03). Using RECIST criteria, 5-year survival in the OR group was 66.7% versus 0% in the NR group (P = .015). There was no significant difference in survival in patients who showed OR at 1 month using EASL criteria. There was poor agreement between RECIST and EASL response assessments (κ = 0.23). There was no significant association between survival and TTR, TTP, or time interval between transarterial chemoembolization and LT. Patients with objective response to transarterial chemoembolization at 1 month using RECIST criteria showed improved survival over nonresponders. RECIST criteria demonstrated better

  12. [Examination of percutaneous microwave coagulation and radiofrequency ablation therapy for metastatic liver cancer].

    PubMed

    Ohkawa, Shinichi; Hirokawa, Satoru; Masaki, Takahiro; Miyakawa, Kaoru; Tarao, Kazuo; Akaike, Makoto; Sugimasa, Yukio; Takemiya, Shoji; Sairenji, Motonori; Motohashi, Hisahiko

    2002-11-01

    Percutaneous microwave coagulation therapy (PMCT) and radio frequency ablation therapy (RFA) as treatments for metastatic liver cancer were examined. PMCT or RFA was administered for 18 metastatic liver cancer lesions (primary lesion: 11 colon rectal cancer, one esophagus cancer, one thyroid cancer, one pancreatic cancer, one pheochromocytoma) in 16 patients from July 1999 to March 2002. RFA was performed 1 time for 12 minutes in principle, using a Cool-tip RF system from Radionics. Patients had a mean age of 58.8 years and the mean diameter of the neoplasms was about 22 mm. Critical complications were not seen. The rate of partial recurrence was 35.3% as of March, 2002, in an average observation period of 7.3 months. On the other hand, with the medical treatment for the hepatocellular carcinoma provided during this period, the rate of partial recurrence was 14.8%. The treatment of metastatic liver cancer by PMCT and RFA is associated with a high rate of a recurrence as compared with hepatocellular carcinoma, and needs to be examined to discover ways of adaptation and improvement of the technology.

  13. Liver cell cancer--intervention studies.

    PubMed

    Linsell, C A

    1981-01-01

    The field studies leading to possible intervention procedures are reviewed. Currently the most promising form of intervention is the prevention of aflatoxin contamination of foodstuffs. It is essential that these are monitored and their efficacy in lowering the incidence of liver cancer measured. The association of liver cancer with hepatitis B infection may be a confounding factor and the impact of this on the study population must also be considered. The imminent production of vaccines for hepatitis B infection may provide an alternative or additional mode of intervention. The possibilities for intervention in liver cell cancer appear one of the brighter prospects for primary prevention of a cancer.

  14. O-GlcNAcylation of histone deacetylases 1 in hepatocellular carcinoma promotes cancer progression.

    PubMed

    Zhu, Guizhou; Tao, Tao; Zhang, Dongmei; Liu, Xiaojuan; Qiu, Huiyuan; Han, LiJian; Xu, Zhiwei; Xiao, Ying; Cheng, Chun; Shen, Aiguo

    2016-08-01

    Hepatocellular carcinoma (HCC) is a malignant tumor originating in the liver. Previous studies have indicated that O-GlcNAc transferase (OGT) and histone deacetylase-1 (HDAC1) play important roles in the pathogenesis of HCC. In the present study, we investigated the physical link between OGT and HDAC1. The O-GlcNAcylation of HDAC1 is overexpressed in HCC. We found that HDAC1 has two major sites of O-GlcNAcylation in its histone deacetylase domain. HDAC1 O-GlcNAcylation increases the activated phosphorylation of HDAC1, which enhances its enzyme activity. HDAC1 O-GlcNAc mutants promote the p21 transcription regulation through affecting the acetylation levels of histones from chromosome, and then influence the proliferation of HCC cells. We also found that mutants of O-GlcNAcylation site of HDAC1 affect invasion and migration of HepG2 cells. E-cadherin level is highly up-regulated in HDAC1 O-GlcNAc mutant-treated liver cancer cells, which inhibit the occurrence and development of HCC. Our findings suggest that OGT promotes the O-GlcNAc modification of HDAC1in the development of HCC. Therefore, inhibiting O-GlcNAcylation of HDAC1 may repress the progression of HCC.

  15. A study of structural differences between liver cancer cells and normal liver cells using FTIR spectroscopy

    NASA Astrophysics Data System (ADS)

    Sheng, Daping; Xu, Fangcheng; Yu, Qiang; Fang, Tingting; Xia, Junjun; Li, Seruo; Wang, Xin

    2015-11-01

    Since liver cancer seriously threatens human health, it is very urgent to explore an effective method for diagnosing liver cancer early. In this study, we investigated the structure differences of IR spectra between neoplastic liver cells and normal liver cells. The major differences of absorption bands were observed between liver cancer cells and normal liver cells, the values of A2955/A2921, A1744/A1082, A1640/A1535, H1121/H1020 might be potentially useful factors for distinguishing liver cancer cells from normal liver cells. Curve fitting also provided some important information on structural differences between malignant and normal liver cancer cells. Furthermore, IR spectra combined with hierarchical cluster analysis could make a distinction between liver cancer cells and normal liver cells. The present results provided enough cell basis for diagnosis of liver cancer by FTIR spectroscopy, suggesting FTIR spectroscopy may be a potentially useful tool for liver cancer diagnosis.

  16. Prospective and randomized trial of lipiodol-transcatheter arterial chemoembolization for treatment of hepatocellular carcinoma: a comparison of epirubicin and doxorubicin (second cooperative study). The Cooperative Study Group for Liver Cancer Treatment of Japan.

    PubMed

    Kawai, S; Tani, M; Okamura, J; Ogawa, M; Ohashi, Y; Monden, M; Hayashi, S; Inoue, J; Kawarada, Y; Kusano, M; Kubo, Y; Kuroda, C; Sakata, Y; Shimamura, Y; Jinno, K; Takahashi, A; Takayasu, K; Tamura, K; Nagasue, N; Nakanishi, Y; Makino, M; Masuzawa, M; Yumoto, Y; Mori, T; Oda, T

    1997-04-01

    A randomized, controlled clinical trial was conducted to compare the use of epirubicin (EPI) and doxorubicin (DOX) in Lipiodol (Laboratoire Guerbet, Roissy-Charles-de-Gaulle Cedex, France)-transcatheter arterial chemoembolization as a treatment of hepatocellular carcinoma. One hundred ninety-two hospitals participated, and 415 patients were enrolled in the study during the period between October 1989 and December 1990. The patients were randomly allocated to group A (EPI) or group B (DOX) by a centralized telephone registration. The actual doses of EPI and DOX were 72 mg/body and 48 mg/body, respectively. The 1-, 2-, and 3-year survival rates were, respectively, 69%, 44%, and 33% for group A and 73%, 54%, and 37% for group B. There were no statistically significant differences (P = .2296, log-rank test). When each group of patients was classified retrospectively into high-risk and low-risk subgroups based on the severity index calculated by the Cox regression model from the significant prognostic factors (the pretreatment tumor size, the pretreatment serum alpha-fetoprotein level, tumor encroachment, and Child's classification), the survival curve of the low-risk DOX subgroup was significantly superior to that of the low-risk EPI subgroup (P = .0182). However, there was no significant difference between the high-risk subgroups (P = .4606). The change in the serum alpha-fetoprotein level, the extent of Lipiodol accumulation in the tumor, and the extent of tumor reduction after the treatment did not show any significant differences between the groups. The white blood cell count in group B showed a tendency to decrease slightly more than in group A at 3 weeks after Lipiodol-transcatheter arterial chemoembolization. In conclusion, there was no statistically significant difference between the survival curves of the EPI and DOX groups in Lipiodol-transcatheter arterial embolization treatment of hepatocellular carcinoma.

  17. Natural History of Untreated Hepatocellular Carcinoma in a US Cohort and the Role of Cancer Surveillance.

    PubMed

    Khalaf, Natalia; Ying, Jun; Mittal, Sahil; Temple, Sarah; Kanwal, Fasiha; Davila, Jessica; El-Serag, Hashem B

    2017-02-01

    Determining the natural history and predictors of survival in patients with untreated hepatocellular carcinoma (HCC) in the United States is useful to test existing tumor classifications, identify subgroups of patients likely to benefit from treatment, and estimate lead time related to HCC surveillance. We identified a national cohort of 518 veterans diagnosed with HCC from 2004 through 2011, with follow-up ending in 2014, who received no palliative or curative treatment. We examined the association between postdiagnosis survival and patient factors, tumor characteristics, and prediagnosis surveillance. The mean age at HCC diagnosis was 65.7 years and most patients had hepatitis C (60.6%). Almost all patients (99%) died within the observation period; the median overall survival time was 3.6 months and survival times were 13.4, 9.5, 3.4, and 1.6 months for patients of Barcelona Clinic Liver Cancer stages 0/A, B, C, and D, respectively. In addition, model for end-stage liver disease and levels of α-fetoprotein were predictive of survival. Nearly 28% received prediagnosis HCC surveillance, which was associated with detection of disease at an earlier stage (Barcelona Clinic Liver Cancer 0/A/B; 26.4% vs 14.4%; P = .0006) and slightly longer survival than patients with no surveillance overall (5.2 months vs 3.4 months; P = .021); there was no difference in survival times of patients with 0/A stage who did versus did not receive surveillance (10.3 months vs 10.5 months). Patients with HCCs, including those detected through surveillance, survived for short time periods in the absence of treatment, irrespective of their initial stage at diagnosis. Model for end-stage liver disease scores and levels of α-fetoprotein were prognostic factors, independent of Barcelona Clinic Liver Cancer stage. The lead time related to detection by surveillance was modest (<2 months) and therefore unlikely to explain the survival benefit associated with surveillance in previous studies

  18. Surgical treatment of double primary liver cancer

    PubMed Central

    Li, Aijun; Ma, Senlin; Pawlik, Timothy; Wu, Bin; Yang, Xiaoyu; Cui, Longjiu; Wu, Mengchao

    2016-01-01

    Abstract Double primary liver cancer (DPLC) is a special type of clinical situation. As such, a detailed analysis of the surgical management and prognosis of patients with DPLC is lacking. The objective of the current study was to define the management and outcome of patients undergoing surgery for DPLC at a major hepatobiliary center. A total of 87 patients treated by surgical resection at the Eastern Hepatobiliary Surgery Hospital from January 1st, 2007 to October 31st, 2013 who had DPLC demonstrated by final pathological diagnosis were identified. Among these, 50 patients had complete clinical and prognostic data. Demographic and tumor characteristics as well as the prognosis were analyzed. The proportion of hepatitis B surface antigen (HBsAg) (+) and hepatitis B virus e antigen (HBeAg) (+), HBsAg (+), and HBeAg (−) hepatocirrhosis in all patients was 21.84%, 67.82%, and 63.22%, respectively. Incidental findings accounted for 58.62% of patients; among those who had symptoms, the main symptom was abdominal pain (31.03%). Nonanatomic wedge resection was the main operative approach (62.07%). Postoperatively, the main complications included seroperitoneum (11.49%), hypoproteinemia (10.34%), and pleural effusion (8.05%). Factors associated with disease-free survival (DFS) included intrahepatic cholangiocarcinoma (ICC) tumor size (P = 0.002) and use of postoperative prophylactic transcatheter arterial chemoembolization (TACE) treatment (P = 0.015). Meanwhile, hepatocellular carcinoma (HCC) size (P = 0.045), ICC size (P < 0.001), and liver function (including aspartate aminotransferase [P = 0.001] and r-glutamyl transferase [P < 0.001]) were associated with overall survival (OS). Hepatitis B virus (HBV)-related hepatitis or cirrhosis is also an important factor in the pathogenesis of DPLC and surgical treatment is safe for it with low complication rates. In addition, it is effective to prolong DFS that DPLC patients undergo postoperative

  19. Stop feeding cancer: pro-inflammatory role of visceral adiposity in liver cancer.

    PubMed

    Zhao, Jun; Lawless, Matthew W

    2013-12-01

    Liver cancer is the fifth most common cancer in the world with an estimated over half a million new cases diagnosed every year. Due to the difficulty in early diagnosis and lack of treatment options, the prevalence of liver cancer continues to climb with a 5-year survival rate of between 6% and 11%. Coinciding with the rise of liver cancer, the prevalence of obesity has rapidly increased over the past two decades. Evidence from epidemiological studies demonstrates a higher risk of hepatocellular carcinoma (HCC) in obese individuals. Obesity is recognised as a low-grade inflammatory disease, this is of particular relevance as inflammation has been proposed as the seventh hallmark of cancer development with abdominal visceral adiposity considered as an important source of pro-inflammatory stimuli. Emerging evidence points towards the direct role of visceral adipose tissue rather than generalised body fat in carcinogenesis. Cytokines such as IL-6 and TNF-α secreted from visceral adipose tissue have been demonstrated to induce a chronic inflammatory condition predisposing the liver to a protumourigenic milieu. This review focuses on excess visceral adiposity rather than simple obesity; particularly adipokines and their implications for chronic inflammation, lipid accumulation, insulin resistance, Endoplasmic Reticulum (ER) stress and angiogenesis. Evidence of molecular signalling pathways that may give rise to the onset and progression of HCC in this context are depicted. Delineation of the pro-inflammatory role of visceral adiposity in liver cancer and its targeting will provide better rational and therapeutic approaches for HCC prevention and elimination. The concept of a central role for metabolism in cancer is the culmination of an effort that began with one of the 20th century's leading biochemists and Nobel laureate of 1931, Otto Warburg. Copyright © 2013 Elsevier Ltd. All rights reserved.

  20. Frequently mutated genes/pathways and genomic instability as prevention targets in liver cancer.

    PubMed

    Rao, Chinthalapally V; Asch, Adam S; Yamada, Hiroshi Y

    2017-01-01

    The incidence of liver cancer has increased in recent years. Worldwide, liver cancer is common: more than 600000 related deaths are estimated each year. In the USA, about 27170 deaths due to liver cancer are estimated for 2016. Liver cancer is highly resistant to conventional chemotherapy and radiotherapy. For all stages combined, the 5-year survival rate is 15-17%, leaving much to be desired for liver cancer prevention and therapy. Heterogeneity, which can originate from genomic instability, is one reason for poor outcome. About 80-90% of liver cancers are hepatocellular carcinoma (HCC), and recent cancer genome sequencing studies have revealed frequently mutated genes in HCC. In this review, we discuss the cause of the tumor heterogeneity based on the functions of genes that are frequently mutated in HCC. We overview the functions of the genes that are most frequently mutated (e.g. TP53, CTNNB1, AXIN1, ARID1A and WWP1) that portray major pathways leading to HCC and identify the roles of these genes in preventing genomic instability. Notably, the pathway analysis suggested that oxidative stress management may be critical to prevent accumulation of DNA damage and further mutations. We propose that both chromosome instability (CIN) and microsatellite instability (MIN) are integral to the hepatic carcinogenesis process leading to heterogeneity in HCC and that the pathways leading to heterogeneity may be targeted for prognosis, prevention and treatment.

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

    PubMed Central

    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

  2. Dissociation of liver inflammation and hepatocellular damage induced by carbon tetrachloride in myeloid cell-specific STAT3 knockout mice

    PubMed Central

    Horiguchi, Norio; Fouad, Lafdil; Miller, Andrew M.; Park, Ogyi; Wang, Hua; Mohanraj, Rajesh; Mukhopadhyay, Partha; Fu, Xin Yuan; Pacher, Pal; Gao, Bin

    2010-01-01

    Liver injury is associated with inflammation, which is generally believed to accelerate the progression of liver diseases; however, clinical data show that inflammation does not always correlate with hepatocelluar damage in some patients. Investigating the cellular mechanisms underlying these events using an experimental animal model, we show that inflammation may attenuate liver necrosis induced by carbon tetrachloride (CCl4) in myeloid-specific signal transducer and activator of transcription 3 (STAT3) knockout mice. As an important anti-inflammatory signal, conditional deletion of STAT3 in myeloid cells results in markedly enhanced liver inflammation after CCl4 injection. However, these effects are also accompanied by reduced liver necrosis, correlating with elevated serum IL-6 and hepatic STAT3 activation. An additional deletion of STAT3 in hepatocytes in myeloid-specific STAT3 knockout mice restored hepatic necrosis, but decreased liver inflammation. Conclusions: Inflammation-mediated STAT3 activation attenuates hepatocellular injury induced by CCl4 in myeloid-specific STAT3 knockout mice, suggesting that inflammation associated with a predominance of hepatoprotective cytokines that activate hepatic STAT3 may reduce rather than accelerate hepatocellular damage in patients with chronic liver diseases. PMID:20196117

  3. Targeting FGF19 inhibits tumor growth in colon cancer xenograft and FGF19 transgenic hepatocellular carcinoma models.

    PubMed

    Desnoyers, L R; Pai, R; Ferrando, R E; Hötzel, K; Le, T; Ross, J; Carano, R; D'Souza, A; Qing, J; Mohtashemi, I; Ashkenazi, A; French, D M

    2008-01-03

    Although fibroblast growth factor 19 (FGF19) can promote liver carcinogenesis in mice its involvement in human cancer is not well characterized. Here we report that FGF19 and its cognate receptor FGF receptor 4 (FGFR4) are coexpressed in primary human liver, lung and colon tumors and in a subset of human colon cancer cell lines. To test the importance of FGF19 for tumor growth, we developed an anti-FGF19 monoclonal antibody that selectively blocks the interaction of FGF19 with FGFR4. This antibody abolished FGF19-mediated activity in vitro and inhibited growth of colon tumor xenografts in vivo and effectively prevented hepatocellular carcinomas in FGF19 transgenic mice. The efficacy of the antibody in these models was linked to inhibition of FGF19-dependent activation of FGFR4, FRS2, ERK and beta-catenin. These findings suggest that the inactivation of FGF19 could be beneficial for the treatment of colon cancer, liver cancer and other malignancies involving interaction of FGF19 and FGFR4.

  4. Percutaneous radiofrequency thermal ablation of hepatocellular carcinoma: a safe and effective bridge to liver transplantation.

    PubMed

    Fontana, Robert J; Hamidullah, Halimi; Nghiem, Hanh; Greenson, Joel K; Hussain, Hero; Marrero, Jorge; Rudich, Steve; McClure, Leslie A; Arenas, Juan

    2002-12-01

    The incidence of hepatocellular carcinoma (HCC) is increasing in the United States. Although liver transplantation is an effective means of treating selected patients, pretransplantation tumor progression may preclude some patients from undergoing transplantation. The aim of this study is to determine the safety and efficacy of percutaneous radiofrequency thermal ablation (RFA) in 33 consecutive patients with nonresectable HCC and advanced cirrhosis. Mean subject age was 57.2 +/- 10.6 years, mean Child-Turcotte-Pugh score was 7.0 +/- 1.4, and mean maximal tumor diameter was 3.6 +/- 1.1 cm. Using contrast-enhanced computed tomography and magnetic resonance imaging, 22 patients (66%) had a complete radiological response at 3 months post-RFA, whereas 11 patients (33%) had an incomplete radiological response. During follow-up, 18 patients (54%) experienced tumor progression and 9 subjects underwent repeated ablation for either residual disease or tumor progression. The overall actuarial patient survival rate of the 33 patients was 58% at 2 years, whereas the transplantation-free patient survival rate was 34% at 2 years. Fifteen of 23 transplant candidates were successfully bridged to liver transplantation after a mean post-RFA follow-up of 7.9 +/- 6.7 months. The extent of tumor necrosis in the explant varied, but no subjects had evidence of tumor seeding on post-RFA imaging, at liver transplantation, or in the explant. The 3-year actuarial posttransplantation patient survival rate was 85%. Two patients have developed posttransplantation recurrence, and both had microscopic vascular invasion in their explants. In summary, our data show that RFA is a safe and effective treatment modality for patients with advanced cirrhosis and nonresectable HCC. Although the ability of RFA to prevent or delay tumor progression requires further prospective study, its favorable safety profile and promising efficacy make it an attractive treatment option for liver transplant candidates

  5. Liver Transplantation for the Treatment of Moderately or Well-Differentiated Hepatocellular Carcinoma

    PubMed Central

    Cillo, Umberto; Vitale, Alessandro; Bassanello, Marco; Boccagni, Patrizia; Brolese, Alberto; Zanus, Giacomo; Burra, Patrizia; Fagiuoli, Stefano; Farinati, Fabio; Rugge, Massimo; D'Amico, Davide Francesco

    2004-01-01

    Objective: To determine the long-term results of liver transplantation for well- or moderately differentiated hepatocellular carcinoma (HCC). Summary Background Data: HCC patient selection for liver transplantation remains controversial, and deciding exclusively on the strength of criteria such as number and size of nodules appears prognostically inaccurate. Methods: Since 1991, preoperative tumor grading has been used at our center to establish whether a patient with HCC is fit for transplantation. Poorly differentiated HCC cases were excluded, while size and number of nodules were not considered as absolute selection criteria. Thirty-three patients with moderately or well-differentiated HCC were prospectively studied after liver transplantation. A group of 15 patients with incidental HCC transplanted during the same period were also evaluated and compared with the 33 patients with preoperatively diagnosed HCC. Results: On histologic examination, 38% of the entire group of 48 patients did not meet the “Milan criteria” and 42% were pTNM stages III and IV. The median follow-up was 44 months. The 5-year actuarial survival rate was 75% and recurrence-free survival was 92%. HCC recurred in only 3 patients (6%). The only histomorphologic variable differing significantly between incidental and nonincidental HCC was nodule size. The timing of diagnosis (incidental vs. nonincidental HCC), the Milan criteria, and the TNM stage revealed no statistically significant impact on overall and recurrence-free survival rates. Conclusions: The routine pre-orthotopic liver transplantation tumor grading may represent a valid tool in the selection of unresectable HCC patients for transplantation. PMID:14745321

  6. Stereotactic Body Radiation Therapy as a Bridge to Transplantation and for Recurrent Disease in the Transplanted Liver of a Patient with Hepatocellular Carcinoma

    PubMed Central

    Mazloom, Ali; Hezel, Aram F.; Katz, Alan W.

    2014-01-01

    Hepatocellular carcinoma (HCC) is one of the most common causes of cancer mortality worldwide. Despite orthotopic liver transplantation (OLT), recurrent HCC is a major cause of morbidity. In this case report, we evaluate the efficacy of stereotactic body radiation therapy (SBRT) as a bridge to OLT and for recurrence in the transplanted liver of a patient with HCC. A 52-year-old male with a history of chronic hepatitis C presented with a 1.7-cm liver lesion radiographically consistent with HCC, which was subsequently treated with a course of SBRT to 50 Gy in 5 fractions followed by OLT in 2009. The patient had a 2.2-cm recurrence in the transplanted liver in 2012, which was treated with SBRT to 62.5 Gy in 5 fractions. He tolerated the course of radiotherapy well with no significant radiation-related toxicity and remains in complete remission approximately 1 year after SBRT. SBRT is a safe and effective modality for the treatment of recurrent HCC in the transplanted liver of the same patient initially treated with SBRT as a bridge to OLT. PMID:24575010

  7. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) procedure for hepatocellular carcinoma with chronic liver disease: a case report and review of literature

    PubMed Central

    Pizanias, Michail; Yip, Vincent; Prassas, Evangellos; Prachalias, Andreas; Quaglia, Alberto; Peddu, Praveen; Heaton, Nigel; Srinivasan, Parthi

    2016-01-01

    The incidence of complications after liver resection is closely related to functional future liver remnant (FLR). The standard approach to augment FLR is surgical or radiological occlusion of the artery or portal vein on the tumor side. Associated liver partition and portal vein ligation for staged hepatectomy (ALLPS) has been introduced as an alternative method to augment FLR. It offers rapid and effective hypertrophy for resecting liver metastases. However, data regarding its application in patients with hepatocellular carcinoma (HCC) with a background of chronic liver disease are limited. Here we describe the use of ALPPS procedure to manage a large solitary HCC with a background of chronic liver disease. The rising incidence of HCC has increased the number of surgical resections in patients with advanced stage liver disease not considered for liver transplantation. We reviewed reported experience of ALPPS in established chronic liver disease and current therapeutic modalities for HCC on a background of chronic liver disease in patients with potential liver insufficiency where tumor burden is beyond liver transplant criteria. PMID:27212995

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

    PubMed

    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.

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

    PubMed Central

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

    2016-01-01

    Aim: In the current study, we analysised only the articles that investigate serum proteome profile of cirrhosis patients or HCC patients versus healthy controls. Background: 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. Methods: 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. Results: 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. Conclusion: 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

  10. EASL HCC summit: liver cancer management.

    PubMed

    Sacco, Rodolfo; Gadaleta-Caldarola, Gennaro; Galati, Giovanni; Lombardi, Giuseppe; Mazza, GianCarlo; Cabibbo, Giuseppe

    2014-05-01

    EASL HCC Summit, Geneva, Switzerland, 13-16 February 2014. The European Association for the Study of the Liver (EASL) organized the 2014 EASL HCC Summit in Geneva, Switzerland. We discuss here the most interesting and provocative contents from the clinical program of the summit. The objective of this segment was to provide an in-depth review on the different management issues related to early detection, diagnosis and treatment of hepatocellular carcinoma, and, in addition, to highlight the ways of dealing with such an important and rapidly involving field.

  11. CRISPR/Cas9 Engineering of Adult Mouse Liver Demonstrates That the Dnajb1-Prkaca Gene Fusion is Sufficient to Induce Tumors Resembling Fibrolamellar Hepatocellular Carcinoma.

    PubMed

    Engelholm, Lars H; Riaz, Anjum; Serra, Denise; Dagnæs-Hansen, Frederik; Johansen, Jens V; Santoni-Rugiu, Eric; Hansen, Steen H; Niola, Francesco; Frödin, Morten

    2017-09-15

    Fibrolamellar hepatocellular carcinoma (FL-HCC) is a primary liver cancer that predominantly affects young adults with no underlying liver disease. A somatic, 400 Kb deletion on chromosome 19 that fuses part of the DnaJ heat shock protein family (Hsp40) member B1 gene (DNAJB1) to the protein kinase cAMP-activated catalytic subunit alpha gene (PRKACA) has been repeatedly identified in patients with FL-HCC. However, the DNAJB1-PRKACA gene fusion has not been shown to induce liver tumorigenesis. We used the CRISPR/Cas9 technique to delete in mice the syntenic region on chromosome 8 to create a Dnajb1-Prkaca fusion and monitored the mice for liver tumor development. We delivered CRISPR/Cas9 vectors designed to juxtapose exon 1 of Dnajb1 with exon 2 of Prkaca to create the Dnajb1-Prkaca gene fusion associated with FL-HCC, or control Cas9 vector, via hydrodynamic tail vein injection to livers of 8 week-old female FVB/N mice. These mice did not have any other engineered genetic alterations and were not exposed to liver toxins or carcinogens. Liver tissues were collected 14 months after delivery; genomic DNA was analyzed by PCR to detect the Dnajb1-Prkaca fusion, and tissues were characterized by histology, immunohistochemistry, RNA sequencing, and whole-exome sequencing. Livers from 12 of the 15 mice given the vectors to induce the Dnajb1-Prkaca gene fusion, but none of the 11 mice given the control vector, developed neoplasms. The tumors contained the Dnajb1-Prkaca gene fusion and had histologic and cytologic features of human FL-HCCs: large polygonal cells with granular, eosinophilic, and mitochondria-rich cytoplasm, prominent nucleoli, and markers of hepatocytes and cholangiocytes. In comparing expression levels of genes between the mouse tumor and non-tumor liver cells, we identified changes similar to those detected in human FL-HCC, which included genes that affect cell cycle and mitosis regulation. Genomic analysis of mouse neoplasms induced by the Dnajb1-Prkaca

  12. Model of fibrolamellar hepatocellular carcinomas reveals striking enrichment in cancer stem cells

    PubMed Central

    Oikawa, Tsunekazu; Wauthier, Eliane; Dinh, Timothy A.; Selitsky, Sara R.; Reyna-Neyra, Andrea; Carpino, Guido; Levine, Ronald; Cardinale, Vincenzo; Klimstra, David; Gaudio, Eugenio; Alvaro, Domenico; Carrasco, Nancy; Sethupathy, Praveen; Reid, Lola M.

    2015-01-01

    The aetiology of human fibrolamellar hepatocellular carcinomas (hFL-HCCs), cancers occurring increasingly in children to young adults, is poorly understood. We present a transplantable tumour line, maintained in immune-compromised mice, and validate it as a bona fide model of hFL-HCCs by multiple methods. RNA-seq analysis confirms the presence of a fusion transcript (DNAJB1-PRKACA) characteristic of hFL-HCC tumours. The hFL-HCC tumour line is highly enriched for cancer stem cells as indicated by limited dilution tumourigenicity assays, spheroid formation and flow cytometry. Immunohistochemistry on the hFL-HCC model, with parallel studies on 27 primary hFL-HCC tumours, provides robust evidence for expression of endodermal stem cell traits. Transcriptomic analyses of the tumour line and of multiple, normal hepatic lineage stages reveal a gene signature for hFL-HCCs closely resembling that of biliary tree stem cells—newly discovered precursors for liver and pancreas. This model offers unprecedented opportunities to investigate mechanisms underlying hFL-HCCs pathogenesis and potential therapies. PMID:26437858

  13. Diagnosis of Hepatocellular Carcinoma Complicating Liver Cirrhosis: Utility of Repeat Ultrasound-Guided Biopsy after Unsuccessful First Sampling

    SciTech Connect

    Caturelli, Eugenio; Biasini, Elisabetta; Bartolucci, Francesca; Facciorusso, Domenico; Decembrino, Francesco; Attino, Vito; Bisceglia, Michele

    2002-08-15

    Purpose: To evaluate the utility of a second ultrasound-guided fine-needle biopsy of liver nodules thought to be hepatocellular carcinoma when the original biopsy has failed to provide a reliable diagnosis. Methods: Thirty-seven cirrhotic patients underwent ultrasound-guided fine-needle biopsy of liver nodules that were subsequently diagnosed as hepatocellular carcinoma. Each biopsy involved a single puncture with a 20 G cutting needle, which yielded pathologic material used both for cytologic and histologic studies. In 23 cases (mean diameter of nodules 48 mm) the biopsy furnished exclusively necrotic material (non-diagnostic subgroup); in the other 14 cases (mean diameter 26 mm) the biopsy yielded no neoplastic elements (false-negative subgroup). All 37 nodules were subjected to repeat biopsies performed in the same manner. Results: The repeat biopsies provided a diagnosis of hepatocellular carcinoma in six of the 23 patients from the non-diagnostic subgroup and in seven of the 14 in the false-negative subgroup. Overall, repeat biopsy produced a diagnostic gain of 35.1%. Conclusion: The chance of success with repeat biopsy of hepatocellular carcinoma is limited and may depend to some extent on the characteristics of the lesions (i.e., areas of necrosis in large nodules, well-differentiated cellular populations in small ones)

  14. A novel prognostic nomogram accurately predicts hepatocellular carcinoma recurrence after liver transplantation: analysis of 865 consecutive liver transplant recipients.

    PubMed

    Agopian, Vatche G; Harlander-Locke, Michael; Zarrinpar, Ali; Kaldas, Fady M; Farmer, Douglas G; Yersiz, Hasan; Finn, Richard S; Tong, Myron; Hiatt, Jonathan R; Busuttil, Ronald W

    2015-04-01

    Although radiologic size criteria (Milan/University of California, San Francisco [UCSF]) have led to improved outcomes after liver transplantation (LT) for hepatocellular carcinoma (HCC), recurrence remains a significant challenge. We analyzed our 30-year experience with LT for HCC to identify predictors of recurrence. A novel clinicopathologic risk score and prognostic nomogram predicting post-transplant HCC recurrence was developed from a multivariate competing-risk Cox regression analysis of 865 LT recipients with HCC between 1984 and 2013. Overall patient and recurrence-free survivals were 83%, 68%, 60% and 79%, 63%, and 56% at 1-, 3-, and 5-years, respectively. Hepatocellular carcinoma recurred in 117 recipients, with a median time to recurrence of 15 months, involving the lungs (59%), abdomen/pelvis (38%), liver (35%), bone (28%), pleura/mediastinum (12%), and brain (5%). Multivariate predictors of recurrence included tumor grade/differentiation (G4/poor diff hazard ratio [HR] 8.86; G2-3/mod-poor diff HR 2.56), macrovascular (HR 7.82) and microvascular (HR 2.42) invasion, nondownstaged tumors outside Milan criteria (HR 3.02), nonincidental tumors with radiographic maximum diameter ≥ 5 cm (HR 2.71) and <5 cm (HR 1.55), and pretransplant neutrophil-to-lymphocyte ratio (HR 1.77 per log unit), maximum alpha fetoprotein (HR 1.21 per log unit), and total cholesterol (HR 1.14 per SD). A pretransplantation model incorporating only known radiographic and laboratory parameters had improved accuracy in predicting HCC recurrence (C statistic 0.79) compared with both Milan (C statistic 0.64) and UCSF (C statistic 0.64) criteria alone. A novel clinicopathologic prognostic nomogram included explant pathology and had an excellent ability to predict post-transplant recurrence (C statistic 0.85). In the largest single-institution experience with LT for HCC, excellent long-term survival was achieved. Incorporation of routine pretransplantation biomarkers to existing

  15. HCV-related hepatocellular carcinoma: From chronic inflammation to cancer.

    PubMed

    Castello, Giuseppe; Scala, Stefania; Palmieri, Giuseppe; Curley, Steven A; Izzo, Francesco

    2010-03-01

    Hepatitis C virus (HCV) infection is a worldwide health problem because of its incidence and pathogenicity. It might evolve into chronic disease, cirrhosis, and/or hepatocellular carcinoma (HCC) and the outcome is mainly determined by the host immune response. For viral clearance, combined innate and adaptive immune responses are required; resolution requires a vigorous, durable, polyclonal CD4(+) and CD8(+) T-cell response, with an increase in virus-specific CD8(+) T cells or cytotoxic T lymphocytes. Failure of efficient immune response can lead to chronic inflammation, tissue remodeling through cell growth, apoptosis and/or necrosis and induction of oxidative stress. Development of fibrosis and/or cirrhosis plus a microenvironment conducive to genomic instability mutations will promote neoplastic transformation. System governance derives from cellular (regulatory cells) and humoral (cytokines and chemokines) immune networks. Therefore, HCC pathogenesis may be a model to study the disease progression from chronic inflammation to cancer allowing design of new strategies targeting the immune response, thereby modifying disease outcome.

  16. The changing characteristics of hepatocellular cancer in Hawaii over time.

    PubMed

    Wong, Linda L; Ogihara, Makoto; Ji, Junfang; Tsai, Naoky

    2015-07-01

    The incidence of hepatocellular cancer (HCC) is increasing, and we sought to characterize the differences and trends in HCC over 2 decades in Hawaii. This retrospective study of 821 HCC cases analyzed risk factors, diabetes, alpha-fetoprotein (AFP), tumor characteristics, and treatment, comparing 5-year eras (1993 to 2012). With succeeding eras, there were fewer Asians, immigrants, and hepatitis B-related HCC. Hepatitis C, diabetes, hyperlipidemia, and body mass index have increased. Over time, more patients had normal AFP, and normal AFP was seen more often in nonviral HCC (49.6% vs 33.2%, P = .007). Over time, the proportion of patients who underwent resection or transplant was stable, but fewer patients underwent no therapy. Characteristics of HCC are changing, and diagnosis may be more difficult as metabolic factors are becoming more important than viral factors. AFP seems to be a less important biomarker, and clearly, better diagnostic tools will be necessary to identify HCC in the future. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Liver metastases

    MedlinePlus

    Metastases to the liver; Metastatic liver cancer; Liver cancer - metastatic; Colorectal cancer - liver metastases; Colon cancer - liver metastases; Esophageal cancer - liver metastases; Lung cancer - liver metastases; Melanoma - liver metastases

  18. Bridging and downstaging treatments for hepatocellular carcinoma in patients on the waiting list for liver transplantation

    PubMed Central

    Pompili, Maurizio; Francica, Giampiero; Ponziani, Francesca Romana; Iezzi, Roberto; Avolio, Alfonso Wolfango

    2013-01-01

    Several therapeutic procedures have been proposed as bridging treatments for patients with hepatocellular carcinoma (HCC) awaiting liver transplantation (LT). The most used treatments include transarterial chemoembolization and radiofrequency ablation. Surgical resection has also been successfully used as a bridging procedure, and LT should be considered a rescue treatment in patients with previous HCC resection who experience tumor recurrence or post-treatment severe decompensation of liver function. The aims of bridging treatments include decreasing the waiting list dropout rate before transplantation, reducing HCC recurrence after transplantation, and improving post-transplant overall survival. To date, no data from prospective randomized studies are available; however, for HCC patients listed for LT within the Milan criteria, prolonging the waiting time over 6-12 mo is a risk factor for tumor spread. Bridging treatments are useful in containing tumor progression and decreasing dropout. Furthermore, the response to pre-LT treatments may represent a surrogate marker of tumor biological aggressiveness and could therefore be evaluated to prioritize HCC candidates for LT. Lastly, although a definitive conclusion can not be reached, the experiences reported to date suggest a positive impact of these treatments on both tumor recurrence and post-transplant patient survival. Advanced HCC may be downstaged to achieve and maintain the current conventional criteria for inclusion in the waiting list for LT. Recent studies have demonstrated that successfully downstaged patients can achieve a 5-year survival rate comparable to that of patients meeting the conventional criteria without requiring downstaging. PMID:24282343

  19. Hepatocellular carcinoma in patients with non-alcoholic fatty liver disease

    PubMed Central

    Wong, Carrie R; Nguyen, Mindie H; Lim, Joseph K

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the United States and represents an increasingly important etiology of hepatocellular carcinoma (HCC) with annual cumulative incidence rates ranging from 2% to 12% in cohorts of NAFLD cirrhosis. While the risk of progression of NAFLD to HCC remains higher among patients with fibrosis or cirrhosis, an increasing amount of literature describes NAFLD-HCC as a disease that can occur in the absence of cirrhosis. Efforts to characterize the pathogenesis of NAFLD-HCC have suggested mechanisms that strongly associate with states of hyperinsulinemia and chronic inflammation, cellular mechanisms including adaptive immune responses and hepatic progenitor cell populations, and genetic polymorphisms including mutations of PNPLA3. Current literature describes NAFLD-HCC mostly as a disease of late presentation with lower rates of receipt of curative therapy and worse prognosis. However, a growing body of evidence has reported comparable and potentially more favorable disease-free and overall survival rates among patients with NAFLD-HCC after receipt of curative treatment. This review summarizes current evidence of epidemiology, pathophysiology, disease presentation, demand and receipt of curative therapy, post-treatment outcomes, and overall survival of NAFLD-associated HCC. PMID:27729736

  20. High circulating D-dimers are associated with ascites and hepatocellular carcinoma in liver cirrhosis

    PubMed Central

    Spadaro, Aldo; Tortorella, Vincenza; Morace, Carmela; Fortiguerra, Agostino; Composto, Paola; Bonfiglio, Caterina; Alibrandi, Angela; Luigiano, Carmelo; Caro, Giuseppe De; Ajello, Antonino; Ferraù, Oscar; Freni, Maria Antonietta

    2008-01-01

    AIM: To measure plasma D-dimer levels in cirrhotic patients with and without ascites, assessing the effect of ascites resolution in D-dimer concentration. METHODS: Seventy consecutive cirrhotic patients (M = 44, F = 26, mean age 65 years, SD ± 13), observed from October 2005 to March 2006 were enrolled. Circulating D-dimer levels were measured using a latex-enhanced, immunoturbidimetric test. In patients with ascites (n = 42) the test was repeated after ascites resolution. RESULTS: Ascites was present in 42 patients (group A) and absent in 28 (group B). Group A patients had more advanced liver disease. Hepatocellular carcinoma (HCC) was diagnosed in 14 patients and was more frequent in group B. Above normal range D-dimers were found in 45/70 patients. High D-dimers were more frequent in group A than in group B (P = 0.001). High D-dimers were associated with presence of HCC (P = 0.048) only in group B. After ascites resolution, obtained in all patients, mean D-dimer values decreased in those 34 patients with high basal levels (P = 0.007), returning to normal in 17. CONCLUSION: In patients with liver cirrhosis, ascites and HCC are the main factors associated with increased fibrinolytic activity. PMID:18330946

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

    PubMed

    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 < or =4 or microscopic venous invasion was absent, there was no significant difference in overall survival (OS) between the LT and 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 < or =4, HR remains the initial treatment of choice.

  2. Hepatocellular Carcinoma in Alcoholic Liver Disease: Current Management and Recent Advances.

    PubMed

    Galati, Giovanni; Dell'Unto, Chiara; Vespasiani-Gentilucci, Umberto; Vincentis, Antonio De; Gallo, Paolo; Guidi, Alessandro; Picardi, Antonio

    2016-01-01

    Hepatocellular Carcinoma (HCC) is a major healthcare problem. Almost ninety percent of HCCs develops on cirrhosis due to chronic viral hepatitis, Non-Alcoholic Steatohepatitis (NASH) and alcohol abuse. Alcohol itself is defined a strong human carcinogenic agent. Some genetic polymorphisms in alcohol-metabolizing systems and more recently, some sequence variations within the genes coding for patatin-like phospholipase encoding 3 (PNPLA3) and Transmembrane 6 superfamily 2 (TM6SF2), have been found to promote liver fibrosis in alcohol abuse, until HCC development. The current management of HCC is related to tumor burden and liver function and it does not differ in alcoholics, although in alcoholics the surveillance for HCC could be less effective because socioeconomic context, such as the recall policy, the stage at the diagnosis and the prognosis are not different compared to viral HCCs. On regards of loco-regional treatment options, there have not been significant advances in the last few years, though an increasing role will be probably reserved to radio embolization and irreversible electroporation in the next future. Sorafenib (SOR) is still the only drug approved as systemic therapy in patients with HCC, whereas immunotherapy represents a promising approach for the treatment of HCC.

  3. Hierarchical and selective roles of galectins in hepatocarcinogenesis, liver fibrosis and inflammation of hepatocellular carcinoma.

    PubMed

    Bacigalupo, María L; Manzi, Malena; Rabinovich, Gabriel A; Troncoso, María F

    2013-12-21

    Hepatocellular carcinoma (HCC) represents a global health problem. Infections with hepatitis B or C virus, non-alcoholic steatohepatitis disease, alcohol abuse, or dietary exposure to aflatoxin are the major risk factors to the development of this tumor. Regardless of the carcinogenic insult, HCC usually develops in a context of cirrhosis due to chronic inflammation and advanced fibrosis. Galectins are a family of evolutionarily-conserved proteins defined by at least one carbohydrate recognition domain with affinity for β-galactosides and conserved sequence motifs. Here, we summarize the current literature implicating galectins in the pathogenesis of HCC. Expression of "proto-type" galectin-1, "chimera-type" galectin-3 and "tandem repeat-type" galectin-4 is up-regulated in HCC cells compared to their normal counterparts. On the other hand, the "tandem-repeat-type" lectins galectin-8 and galectin-9 are down-regulated in tumor hepatocytes. The abnormal expression of these galectins correlates with tumor growth, HCC cell migration and invasion, tumor aggressiveness, metastasis, postoperative recurrence and poor prognosis. Moreover, these galectins have important roles in other pathological conditions of the liver, where chronic inflammation and/or fibrosis take place. Galectin-based therapies have been proposed to attenuate liver pathologies. Further functional studies are required to delineate the precise molecular mechanisms through which galectins contribute to HCC.

  4. Hierarchical and selective roles of galectins in hepatocarcinogenesis, liver fibrosis and inflammation of hepatocellular carcinoma

    PubMed Central

    Bacigalupo, María L; Manzi, Malena; Rabinovich, Gabriel A; Troncoso, María F

    2013-01-01

    Hepatocellular carcinoma (HCC) represents a global health problem. Infections with hepatitis B or C virus, non-alcoholic steatohepatitis disease, alcohol abuse, or dietary exposure to aflatoxin are the major risk factors to the development of this tumor. Regardless of the carcinogenic insult, HCC usually develops in a context of cirrhosis due to chronic inflammation and advanced fibrosis. Galectins are a family of evolutionarily-conserved proteins defined by at least one carbohydrate recognition domain with affinity for β-galactosides and conserved sequence motifs. Here, we summarize the current literature implicating galectins in the pathogenesis of HCC. Expression of “proto-type” galectin-1, “chimera-type” galectin-3 and “tandem repeat-type” galectin-4 is up-regulated in HCC cells compared to their normal counterparts. On the other hand, the “tandem-repeat-type” lectins galectin-8 and galectin-9 are down-regulated in tumor hepatocytes. The abnormal expression of these galectins correlates with tumor growth, HCC cell migration and invasion, tumor aggressiveness, metastasis, postoperative recurrence and poor prognosis. Moreover, these galectins have important roles in other pathological conditions of the liver, where chronic inflammation and/or fibrosis take place. Galectin-based therapies have been proposed to attenuate liver pathologies. Further functional studies are required to delineate the precise molecular mechanisms through which galectins contribute to HCC. PMID:24379606

  5. Can sorafenib increase survival for recurrent hepatocellular carcinoma after liver transplantation? A pilot study.

    PubMed

    Alsina, Angel E; Makris, Alexia; Nenos, Vasilios; Sucre, Eduardo; Arrobas, Jade; Franco, Edson; Kemmer, Nyingi

    2014-07-01

    Recurrence of hepatocellular carcinoma (HCC) remains a main detriment to long-term survival in liver transplants (LTx) for HCC. The study aims to review the use of sorafenib in recurrent HCC LTx in the Model End Stage Liver Disease era. Two hundred forty-seven patients with HCC LTx from 2002 to 2013 were included. Survival was calculated by the Kaplan-Meier (KM) method and Cox multivariate model. Twenty-two patients recurred (11%). By KM, overall survival was 27 months (standard deviation [SD], 3.2 months; median, 28.4 months). Mean time to recurrence was 16.9 months (SD, 2.8 months; median, 12 months). Nine patients were treated with sorafenib after recurrence. Median survival for sorafenib-treated patients was 42 months compared with a median of 16.2 months without sorafenib (-2 log likelihood ratio, P = 0.0582). By Cox, only sorafenib (P = 0.0233; hazard ratio, 8.528) and pathologic stage had a significant impact on survival. The recurrence rates of HCC LTx remain acceptable considering understaging and expansion of beyond Stage A. This pilot study of sorafenib in recurrent HCC demonstrates improved survival over historic controls. Many other factors affecting improved survival are explained. However, treatment remains palliative. Quality-of-life years and cost analysis need to be performed in this population.

  6. Liver transplantation for hepatocellular carcinoma beyond the Milan criteria: A review

    PubMed Central

    Xu, Dong-Wei; Wan, Ping; Xia, Qiang

    2016-01-01

    Liver transplantation (LT) has been accepted as an effective therapy for hepatocellular carcinoma (HCC). The Milan criteria (MC) are widely used across the world to select LT candidates in HCC patients. However, the MC may be too strict because a substantial subset of patients who have HCC exceed the MC and who would benefit from LT may be unnecessarily excluded from the waiting list. In recent years, many extended criteria beyond the MC were raised, which were proved to be able to yield similar outcomes compared with those patients meeting the MC. Because the simple use of tumor size and number was insufficient to indicate HCC biological features and to predict the risk of tumor recurrence, some biological markers such as Alpha-fetoprotein, Des-Gamma-carboxy prothrombin and the neutrophil-to-lymphocyte ratio were useful in selecting LT candidates in HCC patients beyond the MC. For patients with advanced HCC, downstaging therapy is an effective way to reduce the tumor stage to fulfill the MC by using liver-directed therapy such as transarterial chemoembolization, radiofrequency ablation and percutaneous ethanol injection. This article reviews the recent advances in LT for HCC beyond the MC. PMID:27022214

  7. The progressive elevation of alpha fetoprotein for the diagnosis of hepatocellular carcinoma in patients with liver cirrhosis

    PubMed Central

    Arrieta, Oscar; Cacho, Bernardo; Morales-Espinosa, Daniela; Ruelas-Villavicencio, Ana; Flores-Estrada, Diana; Hernández-Pedro, Norma

    2007-01-01

    Background Hepatocellular carcinoma is the most common cause of primary liver neoplasms and is one of the main causes of death in patients with liver cirrhosis. High Alpha fetoprotein serum levels have been found in 60–70% of patients with Hepatocellular carcinoma; nevertheless, there are other causes that increase this protein. Alpha fetoprotein levels ≥200 and 400 ng/mL in patients with an identifiable liver mass by imaging techniques are diagnostic of hepatocellular carcinoma with high specificity. Methods We analysed the sensitivity and specificity of the progressive increase of the levels of alpha fetoprotein for the detection of hepatocellular carcinoma in patients with liver cirrhosis. Seventy-four patients with cirrhosis without hepatocellular carcinoma and 193 with hepatic lesions diagnosed by biopsy and shown by image scans were included. Sensitivity and specificity of transversal determination of alpha fetoprotein ≥ 200 and 400 ng/mL and monthly progressive elevation of alpha fetoprotein were analysed. Areas under the ROC curves were compared. Positive and negative predictive values adjusted to a 5 and 10% prevalence were calculated. Results For an elevation of alpha fetoprotein ≥ 200 and 400 ng/mL the specificity is of 100% in both cases, with a sensitivity of 36.3 and 20.2%, respectively. For an alpha fetoprotein elevation rate ≥7 ng/mL/month, sensitivity was of 71.4% and specificity of 100%. The area under the ROC curve of the progressive elevation was significantly greater than that of the transversal determination of alpha fetoprotein. The positive and negative predictive values modified to a 10% prevalence are of: 98.8% and 96.92%, respectively; while for a prevalence of 5% they were of 97.4% and 98.52%, respectively. Conclusion The progressive elevation of alpha fetoprotein ≥7 ng/mL/month in patients with liver cirrhosis is useful for the diagnosis of hepatocellular carcinoma in patients that do not reach αFP levels ≥200 ng

  8. Comparison of anamnestic history, alcohol intake and smoking, nutritional status, and liver dysfunction between thorotrast patients who developed primary liver cancer and those who did not

    SciTech Connect

    Kiyosawa, K.; Imai, H.; Sodeyama, T.; Franca, S.T.; Yousuf, M.; Furuta, S.; Fujisawa, K.; Kido, C. )

    1989-08-01

    In order to clarify the differences in past history, nutritional condition and, consumption of alcohol and tobacco, and liver dysfunction between the thorotrast patients who developed primary liver cancer and those who did not, 103 persons who had no primary liver cancer in January 1980 were studied. All subjects were military men who had undergone angiography with thorotrast between 1943 and 1946. Twenty persons developed hepatocellular carcinoma and 16 developed intrahepatic bile duct carcinoma by April 1987, whereas 67 are still alive without any cancer. There was no difference in age or period after thorotrast infusion between those two groups of patients in January 1980. A difference in history of hepatitis and/or jaundice and presence of hepatic dysfunction was found between the subjects who developed primary liver cancers and those who did not. These findings suggest that an anamnestic history of hepatitis and liver dysfunction are risks for development of thorotrast-induced liver cancer. On the basis of the above findings, early detection of liver dysfunction offers a possibility of early diagnosis of primary liver cancer.

  9. Ganetespib radiosensitization for liver cancer therapy

    PubMed Central

    Chettiar, Sivarajan T.; Malek, Reem; Annadanam, Anvesh; Nugent, Katriana M.; Kato, Yoshinori; Wang, Hailun; Cades, Jessica A.; Taparra, Kekoa; Belcaid, Zineb; Ballew, Matthew; Manmiller, Sarah; Proia, David; Lim, Michael; Anders, Robert A.; Herman, Joseph M.; Tran, Phuoc T.

    2016-01-01

    ABSTRACT Therapies for liver cancer particularly those including radiation are still inadequate. Inhibiting the stress response machinery is an appealing anti-cancer and radiosensitizing therapeutic strategy. Heat-shock-protein-90 (HSP90) is a molecular chaperone that is a prominent effector of the stress response machinery and is overexpressed in liver cancer cells. HSP90 client proteins include critical components of pathways implicated in liver cancer cell survival and radioresistance. The effects of a novel non-geldanamycin HSP90 inhibitor, ganetespib, combined with radiation were examined on 3 liver cancer cell lines, Hep3b, HepG2 and HUH7, using in vitro assays for clonogenic survival, apoptosis, cell cycle distribution, γH2AX foci kinetics and client protein expression in pathways important for liver cancer survival and radioresistance. We then evaluated tumor growth delay and effects of the combined ganetespib-radiation treatment on tumor cell proliferation in a HepG2 hind-flank tumor graft model. Nanomolar levels of ganetespib alone exhibited liver cancer cell anti-cancer activity in vitro as shown by decreased clonogenic survival that was associated with increased apoptotic cell death, prominent G2-M arrest and marked changes in PI3K/AKT/mTOR and RAS/MAPK client protein activity. Ganetespib caused a supra-additive radiosensitization in all liver cancer cell lines at low nanomolar doses with enhancement ratios between 1.33–1.78. These results were confirmed in vivo, where the ganetespib-radiation combination therapy produced supra-additive tumor growth delay compared with either therapy by itself in HepG2 tumor grafts. Our data suggest that combined ganetespib-radiation therapy exhibits promising activity against liver cancer cells, which should be investigated in clinical studies. PMID:26980196

  10. Ganetespib radiosensitization for liver cancer therapy.

    PubMed

    Chettiar, Sivarajan T; Malek, Reem; Annadanam, Anvesh; Nugent, Katriana M; Kato, Yoshinori; Wang, Hailun; Cades, Jessica A; Taparra, Kekoa; Belcaid, Zineb; Ballew, Matthew; Manmiller, Sarah; Proia, David; Lim, Michael; Anders, Robert A; Herman, Joseph M; Tran, Phuoc T

    2016-04-02

    Therapies for liver cancer particularly those including radiation are still inadequate. Inhibiting the stress response machinery is an appealing anti-cancer and radiosensitizing therapeutic strategy. Heat-shock-protein-90 (HSP90) is a molecular chaperone that is a prominent effector of the stress response machinery and is overexpressed in liver cancer cells. HSP90 client proteins include critical components of pathways implicated in liver cancer cell survival and radioresistance. The effects of a novel non-geldanamycin HSP90 inhibitor, ganetespib, combined with radiation were examined on 3 liver cancer cell lines, Hep3b, HepG2 and HUH7, using in vitro assays for clonogenic survival, apoptosis, cell cycle distribution, γH2AX foci kinetics and client protein expression in pathways important for liver cancer survival and radioresistance. We then evaluated tumor growth delay and effects of the combined ganetespib-radiation treatment on tumor cell proliferation in a HepG2 hind-flank tumor graft model. Nanomolar levels of ganetespib alone exhibited liver cancer cell anti-cancer activity in vitro as shown by decreased clonogenic survival that was associated with increased apoptotic cell death, prominent G2-M arrest and marked changes in PI3K/AKT/mTOR and RAS/MAPK client protein activity. Ganetespib caused a supra-additive radiosensitization in all liver cancer cell lines at low nanomolar doses with enhancement ratios between 1.33-1.78. These results were confirmed in vivo, where the ganetespib-radiation combination therapy produced supra-additive tumor growth delay compared with either therapy by itself in HepG2 tumor grafts. Our data suggest that combined ganetespib-radiation therapy exhibits promising activity against liver cancer cells, which should be investigated in clinical studies.

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

    PubMed

    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. Hepatocellular carcinoma and focal nodular hyperplasia of the liver: differentiation with CT spectral imaging.

    PubMed

    Yu, Yixing; Lin, Xiaozhu; Chen, Kemin; Chai, Weimin; Hu, Shudong; Tang, Rongbiao; Zhang, Jing; Cao, Lixiu; Yan, Fuhua

    2013-06-01

    To investigate the value of CT spectral imaging in differentiating hepatocellular carcinoma (HCC) from focal nodular hyperplasia (FNH) during the arterial phase (AP) and portal venous phase (PP). Fifty-eight patients with 42 HCCs and 16 FNHs underwent spectral CT during AP and PP. The lesion-liver contrast-to-noise ratio (CNR) at different energy levels, normalised iodine concentrations (NIC) and the lesion-normal parenchyma iodine concentration ratio (LNR) were calculated. The two-sample t test compared quantitative parameters. Two readers qualitatively assessed lesion types according to imaging features. Sensitivity and specificity of the qualitative and quantitative studies were compared. In general, CNRs at low energy levels (40-70 keV) were higher than those at high energy levels (80-140 keV). NICs and LNRs for HCC differed significantly from those of FNH: mean NICs were 0.25 mg/mL ± 0.08 versus 0.42 mg/mL ± 0.12 in AP and 0.52 mg/mL ± 0.14 versus 0.86 mg/mL ± 0.18 in PP. Mean LNRs were 2.97 ± 0.50 versus 6.15 ± 0.62 in AP and 0.99 ± 0.12 versus 1.22 ± 0.26 in PP. NICs and LNRs for HCC were lower than those of FNH. LNR in AP had the highest sensitivity and specificity in differentiating HCC from FNH. CT spectral imaging may help to increase detectability of lesions and accuracy of differentiating HCC from FNH. • CT spectral imaging may help to detect hepatocellular carcinoma (HCC). • CT spectral imaging may help differentiate HCC from focal nodular hyperplasia. • Quantitative analysis of iodine concentration provides greater diagnostic confidence. • Treatment can be given with greater confidence.

  13. Serum Markers of Epithelial Mesenchymal Transition as Predictors of HCV-induced Liver Fibrosis, Cirrhosis and Hepatocellular Carcinoma

    PubMed Central

    Zoheiry, Mona M; Hasan, Shaimaa AA; El-Ahwany, Eman; Nagy, Faten M; Taleb, Hoda Abu; Nosseir, Mona; Magdy, Mona; Meshaal, Safa; EL-Talkawy, Mohamed Darwish; Raafat, Inas

    2015-01-01

    Introduction Hepatitis C virus (HCV) is a major cause of chronic liver disease in Egypt, leading to hepatic fibrosis, liver cirrhosis (LC), and hepatocellular carcinoma (HCC). Liver fibrosis is characterized by excessive deposition of extracellular matrix (ECM). Newly-recognized pathogenic mechanisms point to the epithelial-mesenchymal transition (EMT) of hepatocytes to matrix synthesizing (myo-) fibroblasts. Transforming growth factor-beta (TGF-β1), bone morphogenic protein (BMP)-7, and connective tissue growth factor (CTGF) are biomarkers reflecting the EMT process. YKL-40 is a glycoprotein member of ECM and plays a role in cancer cell proliferation. The purpose of this study was to determine the serum biomarkers of EMT and its impact on the fibrogenic process and tumorigenesis in HCV-genotype 4 patients. Methods In this case-control study that was conducted in 2013–2014, 97 HCV-infected patients were subjected to clinical examination, laboratory investigations, and liver biopsy. According to the histopathologic examination, they were classified to F0 (14 cases), F1 (17 cases), F2 (15 cases), F3 (18 cases), F4 (22 cases), and HCC (11 cases). Fifteen age- and gender-matched subjects were included as normal controls. Serum levels of TGF-β1, BMP-7, CTGF, YKL-40 were assessed, and the TGF-β1/BMP-7 ratios were calculated. The data were analyzed by plotting the receiver operating characteristic curve (ROC), Pearson product-moment correlation coefficient, and Spearman’s rank correlation coefficient (Spearman’s rho). Results Serum levels of TGF-β1, BMP-7, CTGF, and YKL-40 were significantly increased in all patient groups compared to controls (p < 0.001). LC exhibited the highest CTGF level and YKL-40 was highest in HCC. The TGF-β1/ BMP-7 ratios reflected the progression of EMT from CHC to LC, however, there was no significant difference between LC and HCC. TGF-β1/ BMP-7 ratio is considered to reflect positive correlation with CTGF in LC group (r = 0.629; p

  14. Cancer chemoprevention by an adenosine derivative in a model of cirrhosis-hepatocellular carcinoma induced by diethylnitrosamine in rats.

    PubMed

    Velasco-Loyden, Gabriela; Pérez-Martínez, Lidia; Vidrio-Gómez, Susana; Pérez-Carreón, Julio Isael; Chagoya de Sánchez, Victoria

    2017-02-01

    Hepatocellular carcinoma is one of the most common cancers, and approximately 80% develop from cirrhotic livers. We have previously shown that the aspartate salt of adenosine prevents and reverses carbon tetrachloride-induced liver fibrosis in rats. Considering the hepatoprotective role of this adenosine derivative in fibrogenesis, we were interested in evaluating its effect in a hepatocarcinogenesis model induced by diethylnitrosamine in rats, where multinodular cancer is preceded by cirrhosis. Rats were injected with diethylnitrosamine for 12 weeks to induce cirrhosis and for 16 weeks to induce hepatocarcinogenesis. Groups of rats were treated with aspartate salt of adenosine from the beginning of carcinogen administration for 12 or 18 weeks total, and another group received the compound from weeks 12 to 18. Fibrogenesis was estimated and the proportion of preneoplastic nodules and tumors was measured. The apoptotic and proliferation rates in liver tissues were evaluated, as well as the expression of cell signaling and cell cycle proteins participating in hepatocarcinogenesis. The adenosine derivative treatment reduced diethylnitrosamine-induced collagen expression and decreased the proportion of nodules positive for the tumor marker γ-glutamyl transferase. This compound down-regulated the expression of thymidylate synthase and hepatocyte growth factor, and augmented the protein level of the cell cycle inhibitor p27; these effects could be part of its chemopreventive mechanism. These findings suggest a hepatoprotective role of aspartate salt of adenosine that could be used as a therapeutic compound in the prevention of liver tumorigenesis as described earlier for hepatic fibrosis.

  15. Cancer stem cells in hepatocellular carcinoma - an immunohistochemical study with histopathological association

    PubMed Central

    Matthai, Smita Mary; Ramakrishna, Banumathi

    2015-01-01

    Background & objectives: Cancer stem cells (CSCs) may be responsible for tumour recurrence and resistance to chemotherapy in hepatocellular carcinoma (HCC). This study was carried out to evaluate the association between histological parameters and liver CSCs (LCSC) in HCC, and to compare distribution of liver CSCs in HCC associated with and without hepatitis B virus (HBV) infection. Methods: Seventy nine tumours (49 surgical resections from 46 patients, and 30 from autopsy) were reviewed. Immunohistochemical staining for the LCSC marker EpCAM (epithelial cell adhesion molecule), liver progenitor cell (LPC) markers CK19 (cytokeratin 19) and neural cell adhesion molecule (NCAM) were performed and were associated with histological features of tumour behaviour. Results: Thirty three tumours (41.8%) showed positive staining for EpCAM. CK19 and NCAM expression were seen in 26 (32.9%) and four (5.1%) tumours, respectively. The expression of EpCAM and CK19 was significantly associated with each other (P<0.001). EpCAM expression was significantly associated with clinical and histological features indicating aggressive tumour behaviour, including younger age of onset, higher serum alpha foetoprotein (AFP) levels, tumour cell dedifferentiation, increased mitotic activity, and vascular invasiveness. There was no significant difference in expression of EpCAM, CK19 and NCAM between HBV positive and negative HCC. Interpretation & conclusions: The LCSC marker EpCAM was expressed in less than half of HCC, was independent of HBV aetiology, and was strongly associated with clinical and histological features of aggressive tumour behaviour. Positive staining for CK19 suggests a possible LPC origin of the EpCAM positive HCCs. PMID:26609030

  16. Chemical or genetic Pin1 inhibition exerts potent anticancer activity against hepatocellular carcinoma by blocking multiple cancer-driving pathways

    PubMed Central

    Liao, Xin-Hua; Zhang, Arina Li; Zheng, Min; Li, Mei-Qing; Chen, Champ Peng; Xu, Huijuan; Chu, Qing-Song; Yang, Dayun; Lu, Wenxian; Tsai, Ting-Fen; Liu, Hekun; Zhou, Xiao Zhen; Lu, Kun Ping

    2017-01-01

    Hepatocellular carcinoma (HCC) is one of the most prevalent and malignant cancers with high inter- and intra-tumor heterogeneity. A central common signaling mechanism in cancer is proline-directed phosphorylation, which is further regulated by the unique proline isomerase Pin1. Pin1 is prevalently overexpressed in human cancers including ~70% of HCC, and promotes tumorigenesis by activating multiple cancer-driving pathways. However, it was challenging to evaluate the significance of targeting Pin1 in cancer treatment until the recent identification of all-trans retinoic acid (ATRA) as a Pin1 inhibitor. Here we systematically investigate functions of Pin1 and its inhibitor ATRA in the development and treatment of HCC. Pin1 knockdown potently inhibited HCC cell proliferation and tumor growth in mice. ATRA-induced Pin1 degradation inhibited the growth of HCC cells, although at a higher IC50 as compared with breast cancer cells, likely due to more active ATRA metabolism in liver cells. Indeed, inhibition of ATRA metabolism enhanced the sensitivity of HCC cells to ATRA. Moreover, slow-releasing ATRA potently and dose-dependently inhibited HCC growth in mice. Finally, chemical or genetic Pin1 ablation blocked multiple cancer-driving pathways simultaneously in HCC cells. Thus, targeting Pin1 offers a promising therapeutic approach to simultaneously stop multiple cancer-driving pathways in HCC. PMID:28262728

  17. Allicin induces p53-mediated autophagy in Hep G2 human liver cancer cells.

    PubMed

    Chu, Yung-Lin; Ho, Chi-Tang; Chung, Jing-Gung; Rajasekaran, Raghu; Sheen, Lee-Yan

    2012-08-29

    Garlic has been used throughout history for both culinary and medicinal purpose. Allicin is a major component of crushed garlic. Although it is sensitive to heat and light and easily metabolized into various compounds such as diallyl disulfide, diallyl trisulfide, and diallyl sulfide, allicin is still a major bioactive compound of crushed garlic. The mortality of hepatocellular carcinoma is quite high and ranks among the top 10 cancer-related deaths in Taiwan. Although numerous studies have shown the cancer-preventive properties of garlic and its components, there is no study on the effect of allicin on the growth of human liver cancer cells. In this study, we focused on allicin-induced autophagic cell death in human liver cancer Hep G2 cells. Our results indicated that allicin induced p53-mediated autophagy and inhibited the viability of human hepatocellular carcinoma cell lines. Using Western blotting, we observed that allicin decreased the level of cytoplasmic p53, the PI3K/mTOR signaling pathway, and the level of Bcl-2 and increased the expression of AMPK/TSC2 and Beclin-1 signaling pathways in Hep G2 cells. In addition, the colocalization of LC3-II with MitoTracker-Red (labeling mitochondria), resulting in allicin-induced degradation of mitochondria, could be observed by confocal laser microscopy. In conclusion, allicin of garlic shows great potential as a novel chemopreventive agent for the prevention of liver cancer.

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

    PubMed

    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, 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.

  19. Surgical outcomes of laparoscopic versus open liver resection for hepatocellular carcinoma for various resection extent

    PubMed Central

    Chen, Junhua; Li, Hongyu; Liu, Fei; Li, Bo; Wei, Yonggang

    2017-01-01

    Abstract Although the number of laparoscopic liver resections (LRRs) has increased, studies of surgical outcomes in comparison with the conventional open approach are limited. The purpose of this study was to analyze the surgical outcomes (safety and efficacy) of LLR versus open liver resection (OLR) for hepatocellular carcinoma (HCC). We collected data on all patients who received liver resection for HCC between April 2015 and September 2016 in our institution, and retrospectively investigated the demographic and perioperative data, and also surgical outcomes. Laparoscopic liver resection was performed in 225 patients and OLR in 291. In patients who underwent minor hepatectomy, LLR associated with a shorter duration of operation time (200 vs 220 minutes; P < 0.001), less blood loss (100 vs 225 mL; P < 0.001), lower transfusion rate (3.0% vs 12.0%; P = 0.012), and shorter postoperative hospital stay (6 vs 7 days; P < 0.001) compared with OLR. Dietary recovery was relatively fast in the group of LLR, but there were no significant differences in hepatic inflow occlusion rate, complication rate, and transfusion volume. Patients who received major hepatectomy had a longer duration of operation (240 vs 230 minutes; P < 0.001), less blood loss (200 vs 400 mL; P < 0.001), lower transfusion rate (4.8% vs 16.5%; P = 0.002), lower hepatic inflow occlusion rate (68.3% vs 91.7%; P < 0.001), and shorter postoperative hospital stay (6 vs 8 days; P < 0.001). Complication rate (P = 0.366) and transfusion volume (P = 0.308) did not differ between groups. Laparoscopic liver resection is a feasible and safe alternative to OLR for HCC when performed by a surgeon experienced with the relevant surgical techniques, associated with less blood loss, lower transfusion rate, a rapid return to a normal diet, and shorter postoperative hospital stay with no compromise in complications. Further, long-term follow-up should be acquired for

  20. SRC-2-mediated coactivation of anti-tumorigenic target genes suppresses MYC-induced liver cancer

    PubMed Central

    Zhou, Xiaorong; Comerford, Sarah A.; York, Brian; O’Donnell, Kathryn A.

    2017-01-01

    Hepatocellular carcinoma (HCC) is the fifth most common solid tumor in the world and the third leading cause of cancer-associated deaths. A Sleeping Beauty-mediated transposon mutagenesis screen previously identified mutations that cooperate with MYC to accelerate liver tumorigenesis. This revealed a tumor suppressor role for Steroid Receptor Coactivator 2/Nuclear Receptor Coactivator 2 (Src-2/Ncoa2) in liver cancer. In contrast, SRC-2 promotes survival and metastasis in prostate cancer cells, suggesting a tissue-specific and context-dependent role for SRC-2 in tumorigenesis. To determine if genetic loss of SRC-2 is sufficient to accelerate MYC-mediated liver tumorigenesis, we bred Src-2-/- mice with a MYC-induced liver tumor model and observed a significant increase in liver tumor burden. RNA sequencing of liver tumors and in vivo chromatin immunoprecipitation assays revealed a set of direct target genes that are bound by SRC-2 and exhibit downregulated expression in Src-2-/- liver tumors. We demonstrate that activation of SHP (Small Heterodimer Partner), DKK4 (Dickkopf-4), and CADM4 (Cell Adhesion Molecule 4) by SRC-2 suppresses tumorigenesis in vitro and in vivo. These studies suggest that SRC-2 may exhibit oncogenic or tumor suppressor activity depending on the target genes and nuclear receptors that are expressed in distinct tissues and illuminate the mechanisms of tumor suppression by SRC-2 in liver. PMID:28273073

  1. Bridging and downstaging therapy in patients suffering from hepatocellular carcinoma waiting on the list of liver transplantation

    PubMed Central

    She, Wong Hoi

    2016-01-01

    Hepatocellular carcinoma (HCC) is a common primary malignancy worldwide especially in the patients with the background of chronic liver disease. Liver transplantation (LT) is the only curative treatment effective for both malignancy as well as the cirrhosis and portal hypertension. Unfortunately, living donor is not always possible and the deceased graft is scarce. Neoadjuvant therapies, therefore, have been developed as a downstaging treatment to try to downstage the tumor within the transplant criteria, or as a bridging therapy to control the tumor growth in patients while waiting in the transplant list. This paper reviewed the common modalities used as bridging and downstaging therapies for patients suffering from HCC before undergoing LT. PMID:28138601

  2. The Synthetic Triterpenoid RTA 405 (CDDO-EA) Halts Progression of Liver Fibrosis and Reduces Hepatocellular Carcinoma Size Resulting in Increased Survival in an Experimental Model of Chronic Liver Injury

    PubMed Central

    Getachew, Yonas; Cusimano, Frank A.; Gopal, Purva; Reisman, Scott A.; Shay, Jerry W.

    2016-01-01

    Patients with cirrhosis have an increased risk of developing liver cancer and a higher rate of mortality. Cirrhosis currently has no known cure, and patients may benefit from new agents aimed at alleviating their complications and slowing down the rate of disease progression. Therefore, the effects of the orally bioavailable synthetic triterpenoid 2-cyano-3,12-dioxooleana- 1,9(11)-dien-28-oate-ethyl amide (CDDO-EA, RTA 405), which has potent antioxidative and antiinflammatory properties, was evaluated in a chronic carbon tetrachloride (CCl4)-induced model of liver cirrhosis and hepatocellular carcinoma (HCC). Mice were injected with CCl4 (to induce fibrosis and cirrhosis) or placebo biweekly for 12 weeks followed by CDDO-EA in the diet for 18 weeks with continued biweekly injections of CCl4. Chronic CCl4 administration resulted in cirrhosis, ascites, and HCC formation, associated with increased serum transforming growth factor-β1, hepatic hydroxyproline content, and increased serum bilirubin. CDDO-EA, whose administration commenced after establishment of liver fibrosis, decreased liver fibrosis progression, serum bilirubin, ascites, and HCC formation and markedly increased overall survival. CDDO-EA also attenuated -TNFα (tumor necrosis factor-α), α-SMA (alpha smooth muscle actin), augmented -IL-10 levels, and improved histologic and serologic markers of fibrosis. Conclusions: CDDO-EA mitigates the progression of liver fibrosis induced by chronic CCl4 administration, which is associated with the induction of antifibrogenic genes and suppression of profibrogenic genes. PMID:26443840

  3. Liver cancer: descriptive epidemiology and risk factors other than HBV and HCV infection.

    PubMed

    Chuang, Shu-Chun; La Vecchia, Carlo; Boffetta, Paolo

    2009-12-01

    The incidence of liver cancer is high in all low-resource regions of the world, with the exception of Northern Africa and Western Asia. The estimated worldwide number of new cases of liver cancer in 2002 is 600,000, of which 82% are from developing countries. Given the poor survival from this disease, the estimated number of deaths is similar to that of new cases. Hepatocellular carcinoma (HCC) is the main form of liver cancer. A part from chronic infections with Hepatitis B and Hepatitis C viruses, which are the main causes of HCC, contamination of foodstuff with aflatoxins, a group of mycotoxins produced by the fungi Aspergillus flavus and Aspergillus parasiticus, is an important contributor to HCC burden in many low-income country. Alcoholic cirrhosis is an important risk factor for HCC in populations with low prevalence of HBV and HCV infection, and the association between tobacco smoking and HCC is now established. Diabetes is also related to an excess risk of HCC and the increased prevalence of overweight and obesity likely contributes to it. The second most important type of liver cancer is cholangiocarcinoma, whose main known cause is infestation with the liver flukes, Opistorchis viverrini and Clonorchis sinensis, which is frequent in some areas in South-East Asia. Angiosarcoma is a rare form of liver cancer whose occurence is linked to occupational exposure to vinyl chloride.

  4. Macro- and micro-environmental factors in clinical hepatocellular cancer.

    PubMed

    Pancoska, Petr; Carr, Brian I

    2014-04-01

    We previously developed a network phenotyping strategy (NPS), a graph theory-based transformation of clinical practice data, for recognition of two primary subgroups of hepatocellular cancer (HCC), called S and L, which differed significantly in their tumor masses. In the current study, we have independently validated this result on 641 HCC patients from another continent. We identified the same HCC subgroups with mean tumor masses 9 cm x n (S) and 22 cm x n (L), P<10(-14). The means of survival distribution (not available previously) for this new cohort were also significantly different (S was 12 months, L was 7 months, P<10(-5)). We characterized nine unique reference patterns of interactions between tumor and clinical environment factors, identifying four subtypes for S and five subtypes for L phenotypes, respectively. In L phenotype, all reference patterns were portal vein thrombosis (PVT)-positive, all platelet/alpha fetoprotein (AFP) levels were high, and all were chronic alcohol consumers. L had phenotype landmarks with worst survival. S phenotype interaction patterns were PVT-negative, with low platelet/AFP levels. We demonstrated that tumor-clinical environment interaction patterns explained how a given parameter level can have a different significance within a different overall context. Thus, baseline bilirubin is low in S1 and S4, but high in S2 and S3, yet all are S subtype patterns, with better prognosis than in L. Gender and age, representing macro-environmental factors, and bilirubin, prothrombin time, and AST levels representing micro-environmental factors, had a major impact on subtype characterization. Clinically important HCC phenotypes are therefore represented by complete parameter relationship patterns and cannot be replaced by individual parameter levels. Copyright © 2014 Elsevier Inc. All rights reserved.

  5. What Should You Ask Your Doctor about Liver Cancer?

    MedlinePlus

    ... Cancer Early Detection, Diagnosis, and Staging What Should You Ask Your Health Care Team About Liver Cancer? ... add others as you think of them. When you’re told you have liver cancer What kind ...

  6. Monocyte-induced recovery of inflammation-associated hepatocellular dysfunction in a biochip-based human liver model

    PubMed Central

    Gröger, Marko; Rennert, Knut; Giszas, Benjamin; Weiß, Elisabeth; Dinger, Julia; Funke, Harald; Kiehntopf, Michael; Peters, Frank T.; Lupp, Amelie; Bauer, Michael; Claus, Ralf A.; Huber, Otmar; Mosig, Alexander S.

    2016-01-01

    Liver dysfunction is an early event in sepsis-related multi-organ failure. We here report the establishment and characterization of a microfluidically supported in vitro organoid model of the human liver sinusoid. The liver organoid is composed of vascular and hepatocyte cell layers integrating non-parenchymal cells closely reflecting tissue architecture and enables physiological cross-communication in a bio-inspired fashion. Inflammation-associated liver dysfunction was mimicked by stimulation with various agonists of toll-like receptors. TLR-stimulation induced the release of pro- and anti-inflammatory cytokines and diminished expression of endothelial VE-cadherin, hepatic MRP-2 transporter and apolipoprotein B (ApoB), resulting in an inflammation-related endothelial barrier disruption and hepatocellular dysfunction in the liver organoid. However, interaction of the liver organoid with human monocytes attenuated inflammation-related cell responses and restored MRP-2 transporter activity, ApoB expression and albumin/urea production. The cellular events observed in the liver organoid closely resembled pathophysiological responses in the well-established sepsis model of peritoneal contamination and infection (PCI) in mice and clinical observations in human sepsis. We therefore conclude that this human liver organoid model is a valuable tool to investigate sepsis-related liver dysfunction and subsequent immune cell-related tissue repair/remodeling processes. PMID:26902749

  7. Discrete nature of EpCAM+ and CD90+ cancer stem cells in human hepatocellular carcinoma.

    PubMed

    Yamashita, Taro; Honda, Masao; Nakamoto, Yasunari; Baba, Masayo; Nio, Kouki; Hara, Yasumasa; Zeng, Sha Sha; Hayashi, Takehiro; Kondo, Mitsumasa; Takatori, Hajime; Yamashita, Tatsuya; Mizukoshi, Eishiro; Ikeda, Hiroko; Zen, Yoh; Takamura, Hiroyuki; Wang, Xin Wei; Kaneko, Shuichi

    2013-04-01

    Recent evidence suggests that hepatocellular carcinoma (HCC) is organized by a subset of cells with stem cell features (cancer stem cells; CSCs). CSCs are considered a pivotal target for the eradication of cancer, and liver CSCs have been identified by the use of various stem cell markers. However, little information is known about the expression patterns and characteristics of marker-positive CSCs, hampering the development of personalized CSC-targeted therapy. Here, we show that CSC markers EpCAM and CD90 are independently expressed in liver cancer. In primary HCC, EpCAM+ and CD90+ cells resided distinctively, and gene-expression analysis of sorted cells suggested that EpCAM+ cells had features of epithelial cells, whereas CD90+ cells had those of vascular endothelial cells. Clinicopathological analysis indicated that the presence of EpCAM+ cells was associated with poorly differentiated morphology and high serum alpha-fetoprotein (AFP), whereas the presence of CD90+ cells was associated with a high incidence of distant organ metastasis. Serial xenotransplantation of EpCAM+ /CD90+ cells from primary HCCs in immune-deficient mice revealed rapid growth of EpCAM+ cells in the subcutaneous lesion and a highly metastatic capacity of CD90+ cells in the lung. In cell lines, CD90+ cells showed abundant expression of c-Kit and in vitro chemosensitivity to imatinib mesylate. Furthermore, CD90+ cells enhanced the motility of EpCAM+ cells when cocultured in vitro through the activation of transforming growth factor beta (TGF-β) signaling, whereas imatinib mesylate suppressed TGFB1 expression in CD90+ cells as well as CD90+ cell-induced motility of EpCAM+ cells. Our data suggest the discrete nature and potential interaction of EpCAM+ and CD90+ CSCs with specific gene-expression patterns and chemosensitivity to molecular targeted therapy. The presence of distinct CSCs may determine the clinical outcome of HCC. Copyright © 2012 American Association for the Study of Liver

  8. Highly tumorigenic hepatocellular carcinoma cell line with cancer stem cell-like properties

    PubMed Central

    Cassim, Shamir; Lapierre, Pascal; Bilodeau, Marc

    2017-01-01

    There are limited numbers of models to study hepatocellular carcinoma (HCC) in vivo in immunocompetent hosts. In an effort to develop a cell line with improved tumorigenicity, we derived a new cell line from Hepa1-6 cells through an in vivo passage in C57BL/6 mice. The resulting Dt81Hepa1-6 cell line showed enhanced tumorigenicity compared to Hepa1-6 with more frequent (28±12 vs. 0±0 lesions at 21 days) and more rapid tumor development (21 (100%) vs. 70 days (10%)) in C57BL/6 mice. The minimal Dt81Hepa1-6 cell number required to obtain visible tumors was 100,000 cells. The Dt81Hepa1-6 cell line showed high hepatotropism with subcutaneous injection leading to liver tumors without development of tumors in lungs or spleen. In vitro, Dt81Hepa1-6 cells showed increased anchorage-independent growth (34.7±6.8 vs. 12.3±3.3 colonies; P<0.05) and increased EpCAM (8.7±1.1 folds; P<0.01) and β-catenin (5.4±1.0 folds; P<0.01) expression. A significant proportion of Dt81Hepa1-6 cells expressed EpCAM compared to Hepa1-6 (34.8±1.1% vs 0.9±0.13%; P<0.001). Enriched EpCAM+ Dt81Hepa1-6 cells led to higher tumor load than EpCAM- Dt81Hepa1-6 cells (1093±74 vs 473±100 tumors; P<0.01). The in vivo selected Dt81Hepa1-6 cell line shows high liver specificity and increased tumorigenicity compared to Hepa1-6 cells. These properties are associated with increased expression of EpCAM and β-catenin confirming that EpCAM+ HCC cells comprise a subset with characteristics of tumor-initiating cells with stem/progenitor cell features. The Dt81Hepa1-6 cell line with its cancer stem cell-like properties will be a useful tool for the study of hepatocellular carcinoma in vivo. PMID:28152020

  9. Impact of time to surgery in the outcome of patients with liver resection for BCLC 0-A stage hepatocellular carcinoma.

    PubMed

    Lim, Chetana; Bhangui, Prashant; Salloum, Chady; Gavara, Concepción Gómez; Lahat, Eylon; Luciani, Alain; Compagnon, Philippe; Calderaro, Julien; Feray, Cyrille; Azoulay, Daniel

    2017-10-05

    The Barcelona Clinic Liver Cancer (BCLC) guidelines recommend resection for very early and early single hepatocellular carcinoma (HCC) patients. It is not known whether a delay in resection from the time of diagnosis (the time-to-surgery (TTS), i.e., the elapsed time from diagnosis to surgery) affects outcomes. We aim to evaluate the impact of TTS on the recurrence and survival outcomes. All patients resected for BCLC stage 0-A single HCC from 2006 to 2016 were studied to evaluate the impact of TTS on recurrence rate, recurrence-free survival (RFS), transplantability following recurrence, and intention-to-treat overall survival (ITT-OS). Propensity score matching (PSM) was further performed to ensure comparability. The study population included 100 patients. Surgery was performed between 0.6 and 77 months after diagnosis (median TTS: 3 months; interquartile range: 1.8 - 4.6 months). There was no post-operative mortality. Patients with TTS ≥ 3 months (70% of these patients had TTS 3-6 months) compared to those with TTS < 3 months had a higher post-operative morbidity (36% vs. 16%, p = 0.02), a similar tumor recurrence rate (32% vs. 32%, p = 1.00), RFS (37% vs. 48%, p = 0.42), transplantability following tumor recurrence (63% vs. 50% p = 0.48), and 5-year ITT-OS (82% vs. 80%, p = 0.20). Similar results were observed after PSM. Patients with BCLC stage 0-A single HCC can undergo surgery with TTS ≥ 3 months without impaired oncologic outcomes. An increase in the TTS within a safe range could allow time for proper evaluation before surgery, and ethical testing of new neoadjuvant treatments aiming to reduce the high rate of tumor recurrence despite curative resection. A delay of ≥ 3 months in time to resection after diagnosis in HCC patients meeting the European Association for the Study of Liver Disease/American Association for the Study of Liver Disease criteria for resection does not affect oncological and long-term outcomes compared to those with a delay to

  10. Role of cytosolic liver fatty acid binding protein in hepatocellular oxidative stress: effect of dexamethasone and clofibrate treatment.

    PubMed

    Rajaraman, G; Wang, G Q; Yan, J; Jiang, P; Gong, Y; Burczynski, F J

    2007-01-01

    The presence of cysteine and methionine groups together with an ability to bind long-chain fatty acid (LCFA) oxidation products makes liver fatty acid binding protein (L-FABP) an attractive candidate against hepatocellular oxidative stress. In this report, we show that pharmacological treatment directed at modulating L-FABP level affected hepatocellular oxidant status. L-FABP expressing 1548-hepatoma cells, treated with dexamethasone or clofibrate, decreased and increased intracellular L-FABP levels, respectively. Oxidative stress was induced by H2O2 incubation or hypoxia-reoxygenation. The fluorescent marker, dichlorofluorescein (DCF), was employed to measure intracellular reactive oxygen species (ROS). Hepatocellular damage was assessed by lactate dehydrogenase (LDH) level. Dexamethasone treatment resulted in a significant increase in DCF fluorescence with higher LDH release compared to control cells. Clofibrate treatment, however, resulted in a significant decrease in both parameters (p<0.05). Drug treatments did not affect cytosolic activities of glutathione peroxidase (GPx), superoxide dismutase (SOD), or catalase suggesting that the differences between treated and control cells may likely be associated with varying L-FABP levels. We conclude that L-FABP may act as an effective endogenous cytoprotectant against hepatocellular oxidative stress.

  11. Downregulation of esophageal cancer-related gene 4 promotes proliferation and migration of hepatocellular carcinoma.

    PubMed

    Ge, Shujian; Xu, Yali; Wang, Hongliang; Sun, Yaxin; Tian, Xiangguo; Cao, Zhixin; Lin, Xiaoyan; Xu, Jiawen; Wang, Qiangxiu

    2017-09-01

    Esophageal cancer-related gene 4 (ECRG4) is a candidate tumor suppressor gene, which is involved in cell apoptosis, migration, infection and inflammation responsiveness; however, its expression level and clinical significance in hepatocellular carcinoma (HCC) remains unclear. In the present study, the authors aim to evaluate the clinical significance and potential role of ECRG4 in HCC. Level of ECRG4 protein expression in HCC and peripheral tissues was investigated in tissue specimens obtained from 56 consecutive HCC patients by immunohistochemistry. Cell proliferation, cell migration and invasion regulations were examined by MTT curves, flow cytometry, Transwell assays and western blotting. ECRG4 expression was weak positive in normal liver cells but was downregulated in HCC cells in vivo or in vitro. A decreased expression of ECRG4 was associated with the age of the patients, metastasis and Ki-67 proliferation index. However, decreased ECRG4 expression was not associated with differentiation, tumor size, the presence of portal vein tumor thrombosis, satellite lesions, tumor relapse or mortality. Further investigations revealed that ectopic expression of ECRG4 inhibited cell proliferation, migration and invasion and promoted cell apoptosis in SMMC-7721 cells, which was mediated by the regulation of BAX and B cell lymphoma-2, in addition to the upregulation of epithelial-mesenchymal transition markers. In conclusion, the results of the present study indicated that ECRG4 was downregulated in HCC and served important roles in promoting cell proliferation and migration.

  12. Characteristics of patients with liver cancer in the BioBank Japan project.

    PubMed

    Ukawa, Shigekazu; Okada, Emiko; Nakamura, Koshi; Hirata, Makoto; Nagai, Akiko; Matsuda, Koichi; Yamagata, Zentaro; Kamatani, Yoichiro; Ninomiya, Toshiharu; Kiyohara, Yutaka; Muto, Kaori; Kubo, Michiaki; Nakamura, Yusuke; Tamakoshi, Akiko

    2017-03-01

    Liver cancer is the fifth cause of cancer-related deaths in Japan. The BioBank Japan (BBJ) project included 200,000 patients with 47 diseases and samples; their clinical information can be used for further studies. Patients diagnosed with liver cancer (n = 1733; 1316 men, 417 women) were included. Histology, patient characteristics, clinical characteristics, and causes of death were collected. Cumulative and relative survival rates for liver cancer were calculated. Of the 1354 patients with available liver cancer histology, 91.9% had hepatocellular carcinoma (HCC). Compared with the National Health and Nutrition Examination Survey, greater proportions of the male patients in this cohort were daily alcohol consumers (26%), and a greater proportion of the men was overweight/obesity (22%). Although Japan is the only Asian country with a predominance of hepatitis C virus (HCV)-related HCC, the prevalence of HCV infection (44%) was lower than that in a previous study. The 3-, 5-, and 10-year cumulative survival rates were 57%, 47%, and 25% in men, respectively, and 49%, 41%, and 27% in women, respectively. The present results provide an overview of the patients with liver cancer in the BBJ project. We are planning further analyses combined with various high-throughput 'omics' technologies. Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

  13. Human immunodeficiency virus infection does not worsen prognosis of liver transplantation for hepatocellular carcinoma.

    PubMed

    Agüero, Fernando; Forner, Alejandro; Manzardo, Christian; Valdivieso, Andres; Blanes, Marino; Barcena, Rafael; Rafecas, Antoni; Castells, Lluis; Abradelo, Manuel; Torre-Cisneros, Julian; Gonzalez-Dieguez, Luisa; Salcedo, Magdalena; Serrano, Trinidad; Jimenez-Perez, Miguel; Herrero, Jose Ignacio; Gastaca, Mikel; Aguilera, Victoria; Fabregat, Juan; Del Campo, Santos; Bilbao, Itxarone; Romero, Carlos Jimenez; Moreno, Asuncion; Rimola, Antoni; Miro, Jose M

    2016-02-01

    The impact of human immunodeficiency virus (HIV) infection on patients undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC) is uncertain. This study aimed to assess the outcome of a prospective Spanish nationwide cohort of HIV-infected patients undergoing LT for HCC (2002-2014). These patients were matched (age, gender, year of LT, center, and hepatitis C virus (HCV) or hepatitis B virus infection) with non-HIV-infected controls (1:3 ratio). Patients with incidental HCC were excluded. Seventy-four HIV-infected patients and 222 non-HIV-infected patients were included. All patients had cirrhosis, mostly due to HCV infection (92%). HIV-infected patients were younger (47 versus 51 years) and had undetectable HCV RNA at LT (19% versus 9%) more frequently than non-HIV-infected patients. No significant differences were detected between HIV-infected and non-HIV-infected recipients in the radiological characteristics of HCC at enlisting or in the histopathological findings for HCC in the explanted liver. Survival at 1, 3, and 5 years for HIV-infected versus non-HIV-infected patients was 88% versus 90%, 78% versus 78%, and 67% versus 73% (P = 0.779), respectively. HCV infection (hazard ratio = 7.90, 95% confidence interval 1.07-56.82) and maximum nodule diameter >3 cm in the explanted liver (hazard ratio = 1.72, 95% confidence interval 1.02-2.89) were independently associated with mortality in the whole series. HCC recurred in 12 HIV-infected patients (16%) and 32 non-HIV-infected patients (14%), with a probability of 4% versus 5% at 1 year, 18% versus 12% at 3 years, and 20% versus 19% at 5 years (P = 0.904). Microscopic vascular invasion (hazard ratio = 3.40, 95% confidence interval 1.34-8.64) was the only factor independently associated with HCC recurrence. HIV infection had no impact on recurrence of HCC or survival after LT. Our results support the indication of LT in HIV-infected patients with HCC. © 2015 by the American Association for the Study

  14. AP-2α inhibits hepatocellular carcinoma cell growth and migration.

    PubMed

    Huang, Wenhuan; Chen, Cheng; Liang, Zhongheng; Qiu, Junlu; Li, Xinxin; Hu, Xiang; Xiang, Shuanglin; Ding, Xiaofeng; Zhang, Jian

    2016-03-01

    Transcription factor AP-2α is involved in many types of human cancers, but its role in hepatocellular carcinogenesis is largely unknown. In this study, we found that expression of AP-2α was low in 40% of human hepatocellular cancers compared with adjacent normal tissues by immunohistochemical analysis. Moreover, AP-2α expression was low or absent in hepatocellular cancer cell lines (HepG2, Hep3B, SMMC-7721 and MHHC 97-H). Human liver cancer cell lines SMMC-7721 and Hep3B stably overexpressing AP-2α were established by lentiviral infection and puromycin screening, and the ectopic expression of AP-2α was able to inhibit hepatocellular cancer cell growth and proliferation by cell viability, MTT assay and liquid colony formation in vitro and in vivo. Furthermore, AP-2α overexpression decreased liver cancer cell migration and invasion as assessed by wound healing and Transwell assays, increasing the sensitivity of liver cancer cells to cisplatin analyzed by MTT assays. Also AP-2α overexpression suppressed the sphere formation and renewed the ability of cancer stem cells. Finally, we found that AP-2α is epigenetically modified and modulates the levels of phosphorylated extracellular signal-regulated protein kinase (ERK), β-catenin, p53, EMT, and CD133 expression in liver cancer cell lines. These results suggested that AP-2α expression is low in human hepatocellular cancers by regulating multiple signaling to affect hepatocellular cancer cell growth and migration. Therefore, AP-2α might represent a novel potential target in human hepatocellular cancer therapy.

  15. Analysis of serum haptoglobin fucosylation in hepatocellular carcinoma and liver cirrhosis of different etiologies.

    PubMed

    Zhu, Jianhui; Lin, Zhenxin; Wu, Jing; Yin, Haidi; Dai, Jianliang; Feng, Ziding; Marrero, Jorge; Lubman, David M

    2014-06-06

    We have developed herein a quantitative mass spectrometry-based approach to analyze the etiology-related alterations in fucosylation degree of serum haptoglobin in patients with liver cirrhosis and hepatocellular carcinoma (HCC). The three most common etiologies, including infection with hepatitis B virus (HBV), infection with hepatitis C virus (HCV), and heavy alcohol consumption (ALC), were investigated. Only 10 μL of serum was used in this assay in which haptoglobin was immunoprecipitated using a monoclonal antibody. The N-glycans of haptoglobin were released with PNGase F, desialylated, and permethylated prior to MALDI-QIT-TOF MS analysis. In total, N-glycan profiles derived from 104 individual patient samples were quantified (14 healthy controls, 40 cirrhosis, and 50 HCCs). A unique pattern of bifucosylated tetra-antennary glycan, with both core and antennary fucosylation, was identified in HCC patients. Quantitative analysis indicated that the increased fucosylation degree was highly associated with HBV- and ALC-related HCC patients compared to that of the corresponding cirrhosis patients. Notably, the bifucosylation degree was distinctly increased in HCC patients versus that in cirrhosis of all etiologies. The elevated bifucosylation degree of haptoglobin can discriminate early stage HCC patients from cirrhosis in each etiologic category, which may be used to provide a potential marker for early detection and to predict HCC in patients with cirrhosis.

  16. Managements of recurrent hepatocellular carcinoma after liver transplantation: A systematic review

    PubMed Central

    de’Angelis, Nicola; Landi, Filippo; Carra, Maria Clotilde; Azoulay, Daniel

    2015-01-01

    AIM: To investigate the efficacy (survival) and safety of treatments for recurrent hepatocellular carcinoma (HCC) in liver transplantation (LT) patients. METHODS: Literature search was performed on available online databases without a time limit until January 2015. Clinical studies describing survival after HCC recurrence in LT patients were retrieved for a full-text evaluation. A total of 61 studies were selected: 13 case reports, 41 retrospective case series, and 7 retrospective comparative studies. RESULTS: Based on all included studies, the mean HCC recurrence rate was 16% of all LTs for HCC. A total of 1021 LT patients experienced HCC recurrence. The median time from LT to HCC recurrence was 13 mo (range 2-132 mo). The majority of patients (67%) presented with HCC extra-hepatic recurrences, involving lung, bone, adrenal gland, peritoneal lymph nodes, and rarely the brain. Overall survival after HCC recurrence was 12.97 mo. Surgical resection of localized HCC recurrence and Sorafenib for controlling systemic spread of HCC recurrence were associated with the higher survival rates (42 and 18 mo, respectively). However, Sorafenib, especially when combined with mTOR, was frequently associated with severe side effects that required dose reduction or discontinuation CONCLUSION: Management of recurrent HCC in LT patients is challenging and associated with poor prognosis independently of the type of treatment. PMID:26494973

  17. Characteristics of hepatocellular carcinoma in cirrhotic and non-cirrhotic non-alcoholic fatty liver disease

    PubMed Central

    Leung, Christopher; Yeoh, Sern Wei; Patrick, Desmond; Ket, Shara; Marion, Kaye; Gow, Paul; Angus, Peter W

    2015-01-01

    AIM: To determine characteristics and prognostic predictors of patients with hepatocellular carcinoma (HCC) in association with non-alcoholic fatty liver disease (NAFLD). METHODS: We reviewed the records of all patients with NAFLD associated HCC between 2000 and 2012. Data collected included demographics; histology; presence or absence of cirrhosis, size and number of HCC, alpha-fetoprotein, body mass index (BMI), and the presence of diabetes, hypertension, or dyslipidaemia. RESULTS: Fifty-four patients with NAFLD associated HCC were identified. Mean age was 64 years with 87% male. Fifteen percent (8/54) were not cirrhotic. 11%, 24% and 50% had a BMI of < 25 kg/m2, 25-29 kg/m2 and ≥ 30 kg/m2 respectively. Fifty-nine percent were diabetic, 44% hypertensive and 26% hyperlipidaemic. Thirty-four percent of the patients had ≤ 1 of these risk factors. Non-cirrhotics had a significantly larger mean tumour diameter at diagnosis than cirrhotics (P = 0.041). Multivariate analysis did not identify any other patient characteristics that predicted the size or number of HCC. CONCLUSION: HCC can develop in NAFLD without cirrhosis. At diagnosis such tumours are larger than those in cirrhotics, conferring a poorer prognosis. PMID:25632192

  18. Effect of Sarcopenic Obesity on Outcomes of Living-Donor Liver Transplantation for Hepatocellular Carcinoma.

    PubMed

    Itoh, Shinji; Yoshizumi, Tomoharu; Kimura, Koichi; Okabe, Hirohisa; Harimoto, Norifumi; Ikegami, Toru; Uchiyama, Hideaki; Shirabe, Ken; Nishie, Akihiro; Maehara, Yoshihiko

    2016-06-01

    We aimed to evaluate the effect of body composition on the outcome of living-donor liver transplantation (LDLT) in patients with hepatocellular carcinoma (HCC). We performed LDLT in 153 patients with HCC and divided the patients into two groups based on skeletal muscle mass-to-visceral fat area ratio (SVR), as assessed by computed tomography (CT) measurement, namely a low-SVR group (n=38) and a not-low SVR group (n=112). We compared surgical outcomes between the two groups. A low SVR was significantly correlated with a higher body mass index and male sex. No differences were found between the two groups in terms of other factors. The patients in the low-SVR group had a significantly poorer prognosis than those in the not-low SVR group in terms of recurrence-free (p=0.01) and overall (p=0.03) survival. The results of the multivariate analysis showed low SVR to be an independent and prognostic indicator for patients with HCC who had undergone LDLT. Pre-transplant body composition measured by CT is a major determinant of prognosis in LDLT for HCC in Japan. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  19. Obesity and hepatocellular carcinoma: targeting obesity-related inflammation for chemoprevention of liver carcinogenesis.

    PubMed

    Shimizu, Masahito; Tanaka, Takuji; Moriwaki, Hisataka

    2013-03-01

    Obesity and related metabolic abnormalities, including a state of chronic inflammation, increase the risk of hepatocellular carcinoma (HCC). Adipose tissue constitutively expresses the proinflammatory cytokine tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), which are important tumor promoters in inflammation-related carcinogenesis. Dysregulation of TNF-α and IL-6 is associated with the development of steatosis and inflammation within the liver. These cytokines also lie at the core of the association between obesity and insulin resistance, which is a key factor in the development of obesity-related HCC. Here we present a detailed review of the relationship between metabolic abnormalities and the development of HCC, focusing on the role played by inflammation. Drawing from our basic and clinical research, the present report also reviews evidence that targeting metabolic abnormalities, such as attenuation of chronic inflammation and improvement of insulin resistance by either pharmaceutical or nutritional intervention, may be an effective strategy in preventing the development of HCC in obese individuals.

  20. Managements of recurrent hepatocellular carcinoma after liver transplantation: A systematic review.

    PubMed

    de'Angelis, Nicola; Landi, Filippo; Carra, Maria Clotilde; Azoulay, Daniel

    2015-10-21

    To investigate the efficacy (survival) and safety of treatments for recurrent hepatocellular carcinoma (HCC) in liver transplantation (LT) patients. Literature search was performed on available online databases without a time limit until January 2015. Clinical studies describing survival after HCC recurrence in LT patients were retrieved for a full-text evaluation. A total of 61 studies were selected: 13 case reports, 41 retrospective case series, and 7 retrospective comparative studies. Based on all included studies, the mean HCC recurrence rate was 16% of all LTs for HCC. A total of 1021 LT patients experienced HCC recurrence. The median time from LT to HCC recurrence was 13 mo (range 2-132 mo). The majority of patients (67%) presented with HCC extra-hepatic recurrences, involving lung, bone, adrenal gland, peritoneal lymph nodes, and rarely the brain. Overall survival after HCC recurrence was 12.97 mo. Surgical resection of localized HCC recurrence and Sorafenib for controlling systemic spread of HCC recurrence were associated with the higher survival rates (42 and 18 mo, respectively). However, Sorafenib, especially when combined with mTOR, was frequently associated with severe side effects that required dose reduction or discontinuation Management of recurrent HCC in LT patients is challenging and associated with poor prognosis independently of the type of treatment.

  1. Prediction of hepatocellular carcinoma biological behavior in patient selection for liver transplantation

    PubMed Central

    Cillo, Umberto; Giuliani, Tommaso; Polacco, Marina; Herrero Manley, Luz Maria; Crivellari, Gino; Vitale, Alessandro

    2016-01-01

    Morphological criteria have always been considered the benchmark for selecting hepatocellular carcinoma (HCC) patients for liver transplantation (LT). These criteria, which are often inappropriate to express the tumor’s biological behavior and aggressiveness, offer only a static view of the disease burden and are frequently unable to correctly stratify the tumor recurrence risk after LT. Alpha-fetoprotein (AFP) and its progression as well as AFP-mRNA, AFP-L3%, des-γ-carboxyprothrombin, inflammatory markers and other serological tests appear to be correlated with post-transplant outcomes. Several other markers for patient selection including functional imaging studies such as 18F-FDG-PET imaging, histological evaluation of tumor grade, tissue-specific biomarkers, and molecular signatures have been outlined in the literature. HCC growth rate and response to pre-transplant therapies can further contribute to the transplant evaluation process of HCC patients. While AFP, its progression, and HCC response to pre-transplant therapy have already been used as a part of an integrated prognostic model for selecting patients, the utility of other markers in the transplant setting is still under investigation. This article intends to review the data in the literature concerning predictors that could be included in an integrated LT selection model and to evaluate the importance of biological aggressiveness in the evaluation process of these patients. PMID:26755873

  2. Studies on the incidence of hepatocellular carcinoma in heavy drinkers with liver cirrhosis.

    PubMed

    Suzuki, M; Suzuki, H; Mizuno, H; Tominaga, T; Kono, M; Kato, Y; Sato, A; Okabe, K

    1993-01-01

    The incidence of hepatocellular carcinoma (HCC) in heavy drinkers who drank more than 130 g per day for more than 10 years, and non-drinkers with cirrhosis who were positive or negative hepatitis C virus (HCV) markers, was analyzed in order to evaluate the effect of a large amount of alcohol on the development of HCC. A parallel study was also conducted in some patients from the aspect of HCV genotypes. Among 57 heavy drinkers with liver cirrhosis, HCV marker was positive in 36 patients (C+Al group) and negative in 21 patients (Al-alone group). Eighty-one patients with liver cirrhosis of non-drinkers were positive for HCV markers (C-alone group). HCV infection was involved in 63% of heavy drinkers with cirrhosis and 44% of patients with HCC. The majority of HCC patients in the C+Al group was infected with HCV through routes other than blood transfusion. HCC developed at a younger age in patients of the C+Al group than in patients of the C-alone group without relation to history of blood transfusion. In more than a third of patients who had tattoos or used stimulants in the C+Al group, HCC developed without a history of blood transfusion. These results suggest that heavy drinking enhances the development of HCC. The HCV genotypes in patients with HCC were all type II, except for one case of type III and one unclassified. The mixed type of HCV was often found in patients who had a blood transfusion or tattoo, suggesting that there may be some correlation between the routes of HCV infection and the diversity of genotypes.

  3. Liver focal lesions and hepatocellular carcinoma in cirrhotic patients: from screening to diagnosis.

    PubMed

    Zardi, E M; Uwechie, V; Picardi, A; Costantino, S

    2001-01-01

    This short review aims at pointing out the role of ultrasonography (US) as a valuable means for an early detection of liver focal lesions in cirrhotic patients. Among these lesions which may be benign and malignant, hepatocellular carcinoma (HCC) finds its place with an incidence in cirrhotic patients becoming higher as the time passes from the onset of cirrhosis. US is of fundamental importance in the regular screening of subjects with viral cirrhosis because of its sensitivity in evaluating focal lesions (79-82%); however, it is not yet the most valuable method for the diagnosis of HCC for which other diagnostic techniques are needed such as CT (Computerized Tomography), MR (Magnetic Resonance) and the US-guided fine-needle biopsy. In fact, the echo-structure of HCC varies with its dimensions and may mimic that of one of many other liver focal lesions. Lately, some new sonographic techniques have become available that can allow a more accurate investigation of HCC. Among them, the "Tissue Harmonic" and the "Pulse Inversion Imaging" techniques provide a better definition of the grey-scale image thus improving the conspicuity of focal lesions. Color and Power Doppler techniques, while allowing an accurate observation of the lesion vascularization, integrate the sonographic appearance of HCC. The enhancement of the US color Doppler signal obtainable by using echographic contrast agents, represents a further progress for a detailed observation of the focal lesions' micro-vascularization and, thus, for the HCC identification. Further advancements in terms of improvement of the image quality and characterization of the focal lesion are to be expected from the use of "Tissue Harmonic" and "Pulse Inversion Imaging" techniques associated with echographic contrast agents. However, the diagnosis of HCC still rests on the incontrovertible histological evidence obtained by echo-guided fine-needle biopsy.

  4. Conditional disease-free survival after liver transplantation for hepatocellular carcinoma

    PubMed Central

    Dong, Jian; Zhu, Ying; Ma, Feng; Ren, Yifang; Lu, Jianwen; Wang, Zhengxin; Qin, Lunxiu; Wu, Rongqian; Lv, Yi

    2016-01-01

    Abstract Traditionally, survival estimates following liver transplantation (LT) of hepatocellular carcinoma (HCC) patients were calculated as survival from the surgery date, but future survival probabilities can change over time and conditional disease-free survival (CDFS) may provide patients and clinicians with more accurate prognostic information. This study aimed to assess CDFS in HCC patients after LT. Three hundred eighty-four HCC patients who underwent LT were included. Disease-free survival (DFS) was calculated using the Kaplan–Meier analysis. The 3-year CDFS, which represents the probability of remaining disease free for an additional 3 years, was calculated. 1-, 3-, and 5-year DFS rates after LT were 69.9%, 45.8%, and 39.0 %, respectively. Based on the concept of CDFS, the probability of surviving an additional 3 years given that the patient was disease free at 1 year, 3 years, and 5 years were 58.4%, 76.9%, and 83.1%, respectively. Multivariate analysis indicated that larger tumor size (hazard ratio [HR], 1.509; 95% CI, 1.146–1.985; P = 0.003) was associated with poorer DFS. Patients with worse prognostic features at baseline demonstrated the greater increase in CDFS over time. Survival estimates following liver transplantation of HCC patients change according to survival time accrued since surgery. CDFS estimates improved dramatically over time especially among patients with worse prognostic features at the time of surgery. CDFS may be a useful tool in counseling patients with HCC, as it is a more accurate assessment of future survival for those patients who have already survived a certain amount of time. PMID:27495049

  5. Liver Transplantation for Hepatocellular Carcinoma: A Single Center Resume Overlooking Four Decades of Experience

    PubMed Central

    Emmanouilidis, Nikos; Peters, Rickmer; Ringe, Bastian P.; Güner, Zeynep; Ramackers, Wolf; Bektas, Hüseyin; Lehner, Frank; Manns, Michael; Klempnauer, Jürgen; Schrem, Harald

    2016-01-01

    Background. This is a single center oncological resume overlooking four decades of experience with liver transplantation (LT) for hepatocellular carcinoma (HCC). Methods. All 319 LT for HCC that were performed between 1975 and 2011 were included. Predictors for HCC recurrence (HCCR) and survival were identified by Cox regression, Kaplan-Meier analysis, Log Rank, and χ2-tests where appropriate. Results. HCCR was the single strongest hazard for survival (exp⁡(B) = 10.156). Hazards for HCCR were tumor staging beyond the histologic MILAN (exp⁡(B) = 3.645), bilateral tumor spreading (exp⁡(B) = 14.505), tumor grading beyond G2 (exp⁡(B) = 8.668), and vascular infiltration of small or large vessels (exp⁡(B) = 11.612, exp⁡(B) = 18.324, resp.). Grading beyond G2 (exp⁡(B) = 10.498) as well as small and large vascular infiltrations (exp⁡(B) = 13.337, exp⁡(B) = 16.737, resp.) was associated with higher hazard ratios for long-term survival as compared to liver transplantation beyond histological MILAN (exp⁡(B) = 4.533). Tumor dedifferentiation significantly correlated with vascular infiltration (χ2p = 0.006) and intrahepatic tumor spreading (χ2p = 0.016). Conclusion. LT enables survival from HCC. HCC dedifferentiation is associated with vascular infiltration and intrahepatic tumor spreading and is a strong hazard for HCCR and survival. Pretransplant tumor staging should include grading by biopsy, because grading is a reliable and easily accessible predictor of HCCR and survival. Detection of dedifferentiation should speed up the allocation process. PMID:27057348

  6. Nonalcoholic fatty liver disease, metabolic risk factors, and hepatocellular carcinoma: an open question.

    PubMed

    Streba, Letiția Adela Maria; Vere, Cristin Constantin; Rogoveanu, Ion; Streba, Costin Teodor

    2015-04-14

    Non-alcoholic liver disease (NAFLD) defines liver abnormalities ranging from simple steatosis to nonalcoholic steatohepatitis with or without cirrhosis development, occurring in the absence of significant alcohol consumption, use of teratogenic medication, or hereditary disorders. The association between NAFLD and metabolic syndrome is well documented and widely recognized. Obesity, type 2 diabetes mellitus (T2DM), and dyslipidemia are the most common metabolic risk factors associated with NAFLD. Among the components of metabolic syndrome, current evidence strongly indicates obesity and diabetes as hepatocellular carcinoma (HCC) risk factors. There is also growing evidence that suggests an increased risk of HCC in NAFLD patients, even surpassing other etiologies in some high-income countries. Epidemiologic data demonstrate a parallel rise in prevalence of obesity, diabetes, NAFLD, and HCC. As obesity and its related diseases have steadily afflicted larger populations, HCC incidence is expected to increase in the future. Pathophysiologic mechanisms that underlie NAFLD development and subsequent progression to nonalcoholic steatohepatitis and cirrhosis (insulin resistance and hyperinsulinemia, oxidative stress, hepatic stellate cell activation, cytokine/adipocytokine signaling pathways, and genetic and environmental factors) appear to play a significant role in the development of NAFLD-related HCC. However, a comprehensive view of molecular mechanisms linking obesity, T2DM, and NAFLD-related HCC, as well as the exact sequence of molecular events, is still not understood in its entirety. Good-quality data are still necessary, and efforts should continue towards better understanding the underlying carcinogenic mechanisms of NAFLD-related HCC. In this paper, we aimed to centralize the most important links supporting these relationships, focusing on obesity, T2DM, and NAFLD-related HCC, as well as point out the major gaps in knowledge regarding the underlying molecular

  7. Fasting inhibits hepatic stellate cells activation and potentiates anti-cancer activity of Sorafenib in hepatocellular cancer cells.

    PubMed

    Lo Re, Oriana; Panebianco, Concetta; Porto, Stefania; Cervi, Carlo; Rappa, Francesca; Di Biase, Stefano; Caraglia, Michele; Pazienza, Valerio; Vinciguerra, Manlio

    2017-05-04

    Hepatocellular carcinoma (HCC) has a poor outcome. Most HCCs develop in the context of liver fibrosis and cirrhosis caused by chronic inflammation. Short-term fasting approaches enhance the activity of chemotherapy in preclinical cancer models, other than HCC. Multi-tyrosine kinase inhibitor Sorafenib is the mainstay of treatment in HCC. However, its benefit is frequently short-lived. Whether fasting can alleviate liver fibrosis and whether combining fasting with Sorafenib is beneficial remains unknown. A 24 hr fasting (2% serum, 0.1% glucose)-induced changes on human hepatic stellate cells (HSC) LX-2 proliferation/viability/cell cycle were assessed by MTT and flow cytometry. Expression of lypolysaccharide (LPS)-induced activation markers (vimentin, αSMA) was evaluated by qPCR and immunoblotting. Liver fibrosis and inflammation were evaluated in a mouse model of steatohepatitis exposed to cycles of fasting, by histological and biochemical analyses. A 24 hr fasting-induced changes were also analyzed on the proliferation/viability/glucose uptake of human HCC cells exposed to Sorafenib. An expression panel of genes involved in survival, inflammation, and metabolism was examined by qPCR in HCC cells exposed to fasting and/or Sorafenib. Fasting decreased the proliferation and the activation of HSC. Repeated cycles of short term starvation were safe in mice but did not improve fibrosis. Fasting synergized with Sorafenib in hampering HCC cell growth and glucose uptake. Finally, fasting normalized the expression levels of genes which are commonly altered by Sorafenib in HCC cells. Fasting or fasting-mimicking diet diets should be evaluated in preclinical studies as a mean to potentiate the activity of Sorafenib in clinical use. © 2017 Wiley Periodicals, Inc.

  8. Plasma microRNA might as a potential biomarker for hepatocellular carcinoma and chronic liver disease screening.

    PubMed

    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

  9. Hepatocellular carcinoma development in non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Is it going to be the "Plague" of the 21st century? A literature review focusing on pathogenesis, prevention and treatment.

    PubMed

    Argyrou, Chrysoula; Moris, Demetrios; Vernadakis, Spiridon

    2017-01-01

    Liver carcinogenesis in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is a subject of intense research nowadays, since NAFLD is the most common chronic liver disease, affecting a great percentage of the population worldwide, while hepatocellular carcinoma (HCC), which represents the most common primary liver malignancy, is the third leading cause of cancer-related mortality. The underlying pathogenic pathways of both NAFLD and HCC are not completely understood, but there is growing evidence that they share many common pathophysiologic mechanisms and risk factors. Due to lack of solid evidence, though, the ultimate goal of designing effective diagnostic tools, treatment options and screening policies remain unmet for the time being. This review article aims to present recent data available regarding pathogenesis, diagnosis and management of HCC and NAFLD, as well as to highlight the importance of the development of HCC in the setting of NAFLD and NASH.

  10. International trends in liver cancer incidence, overall and by histologic subtype, 1978-2007.

    PubMed

    Petrick, Jessica L; Braunlin, Megan; Laversanne, Mathieu; Valery, Patricia C; Bray, Freddie; McGlynn, Katherine A

    2016-10-01

    Primary liver cancer, the most common histologic types of which are hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), is the second leading cause of cancer death worldwide. While rising incidence of liver cancer in low-risk areas and decreasing incidence in some high-risk areas has been reported, trends have not been thoroughly explored by country or by histologic type. We examined liver cancer incidence overall and by histology by calendar time and birth cohort for selected countries between 1978 and 2007. For each successive 5-year period, age-standardized incidence rates were calculated from volumes V-IX of the Cancer Incidence in Five Continents electronic database (CI5plus) and the newly released CI5X (volume X) database. Wide global variations persist in liver cancer incidence. Rates of liver cancer remain highest in Asian countries, specifically Eastern and South-Eastern Asian countries. While rates in most of these high-risk countries have been decreasing in recent years, rates in India and several low-risk countries of Africa, Europe, the Americas, and Oceania have been on the rise. Liver cancer rates by histologic type tend to convey a similar temporal profile. However, in Thailand, France, and Italy, ICC rates have increased while HCC rates have declined. We expect rates in high-risk countries to continue to decrease, as the population seroprevalence of hepatitis B virus (HBV) continues to decline. In low-risk countries, targeted screening and treatment of the hepatitis C virus (HCV), treatment of diabetes and primary prevention of obesity, will be key in reducing future liver cancer incidence. © 2016 UICC.

  11. Death receptor-independent FADD signalling triggers hepatitis and hepatocellular carcinoma in mice with liver parenchymal cell-specific NEMO knockout.

    PubMed

    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

  12. Mechanisms of HCV-induced liver cancer: What did we learn from in vitro and animal studies?

    PubMed Central

    Rusyn, Ivan; Lemon, Stanley M.

    2013-01-01

    Hepatitis C virus (HCV) is a cause of liver diseases that range from steatohepatitis, to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The challenge of understanding the pathogenesis of HCV-associated liver cancer is difficult as most standard animal models used in biomedical research are not permissive to HCV infection. Herein, we provide an overview of a number of creative in vivo, mostly in the mouse, and in vitro models that have been developed to advance our understanding of the molecular and cellular effects of HCV on the liver, specifically with their relevance to HCC. PMID:23871966

  13. Evaluation of tumour markers as differential diagnostic tool in patients with suspicion of liver metastases from breast cancer.

    PubMed

    Liska, Vaclav; Holubec, Lubos; Treska, Vladislav; Vrzalova, Jindra; Skalicky, Tomas; Sutnar, Alan; Kormunda, Stanislav; Bruha, Jan; Vycital, Ondrej; Finek, Jindrich; Pesta, Martin; Pecen, Ladislav; Topolcan, Ondrej

    2011-04-01

    The liver is the site of breast cancer metastasis in 50% of patients with advanced disease. Tumour markers have been demonstrated as being useful in follow-up of patients with breast cancer, in early detection of recurrence of breast cancer after radical surgical treatments, and in assessing oncologic therapy effect, but no study has been carried out on their usefullness in distinguishing benign liver lesions from breast cancer metastases. The aim of this study was therefore to evaluate the importance of tumour markers carcinoembryonic antigen (CEA), carbohydrate antigen CA19-9 (CA19-9), thymidine kinase (TK), tissue polypeptide antigen (TPA), tissue polypeptide-specific antigen (TPS) and cytokeratin 19 fragment (CYFRA 21-1) in differential diagnosis between benign liver lesions and liver metastases of breast cancer. The study includes 3 groups: 22 patients with liver metastases of breast cancer; 39 patients with benign liver lesions (hemangioma, focal nodular hyperplasia, liver cyst, hepatocellular adenoma); and 21 patients without any liver disease or lesion that were operated on for benign extrahepatic diseases (groin hernia, varices of lower limbs) as a control group. The serum levels of tumour markers were assessed by means of immunoanalytical methods. Preoperative serum levels of CYFRA 21-1, TPA, TPS and CEA were significantly higher in patients with liver metastases of breast cancer in contrast to healthy controls and patients with benign liver lesions (p-value<0.05). Serum levels of CA19-9 and TK were higher in patients with malignancy in comparison with benign liver disease and healthy controls but these differences were not statistically significant. Tumour markers CEA, CYFRA 21-1, TPA and TPS can be recommended as a good tool for differential diagnosis between liver metastases of breast cancer and benign liver lesions.

  14. Hepatocellular carcinoma surgery outcomes in the developing world: A 20-year retrospective cohort study at the National Cancer Institute of Peru.

    PubMed

    Ruiz, Eloy; Rojas Rojas, Teresa; Berrospi, Francisco; Chávez, Ivan; Luque, Carlos; Cano, Luis; Doimi, Franco; Pineau, Pascal; Deharo, Eric; Bertani, Stéphane

    2016-01-01

    In the developing world, most patients with hepatocellular carcinoma present with advanced-stage disease, considered to be incurable based on current therapeutic algorithms. Here, we demonstrate that curative liver resection is achievable in a portion of Peruvian patients not addressed by these treatment algorithms. We conducted a retrospective cohort study of 253 hepatocellular carcinoma patients that underwent a curative hepatectomy between 1991 and 2011 at the National Cancer Institute of Peru. The median age of the cohort was 36 years, and merely 15.4% of the patients displayed cirrhosis. The average tumor size was over 14 cm in diameter, resulting in 76.3% of major hepatectomies performed. The 5- and 10-year survival probability estimates were 37.5% and 26.2%, respectively. Age (>44 vs. ≤44 years old; P = 0.005), tumor size (>10 cm vs. ≤10 cm in diameter; P = 0.009), cirrhosis (P < 0.001), satellite lesions (P < 0.001), macroscopic vascular invasion (P < 0.001), allogeneic blood transfusion (P = 0.011), and spontaneous rupture of the tumor (P = 0.006) were independent predictive factors for prognosis. Hepatocellular carcinomas in Peru are characterized by a distinct clinical presentation with notable features compared with those typically described throughout relevant literature. Despite a large number of advanced-stage hepatocellular carcinomas, the outcomes of liver resection observed in the present study were in good standing with the results previously described in other series. It thus appears that staging systems and associated therapeutic algorithms designed for use in the developed world remain inadequate in certain populations, especially in the context of Peruvian patients. Our findings suggest that clinicians in the developing world should reconsider management guidelines pertaining to hepatocellular carcinoma. Indeed, we hypothesize that, in developing countries, a strict adherence to these therapeutic algorithms might create a selection bias

  15. [Primary cancer of the liver].

    PubMed

    Orozco, H; Mercado, M A

    1997-01-01

    The epidemiologic and pathogenic aspects of primary hepatic malignancies are discussed. The role of viruses in the etiology of the disease is stressed. Imageology methods have a preponderant role for diagnosis and treatment options. Liver resection has a one years survival between 60 and 80% and a five years survival of 20 to 40%. A good surgical results is expected for tumors with no more than 5 cm in diameter, encapsulated and without vascular invasion non-cirrhotic livers, large tumors can also be removed. Surgical resection margin should be of 1 cm. For cirrhotic livers, a good liver function is needed (Child A-B) and no safe major resection can be done. History of bleeding portal hypertension has a negative role in the outcome. Liver transplantation should be limited to selected case, in which the tumors are small and asymptomatic (incidental). For larger tumors, long term results are not good with invariable recurrency of the tumor.

  16. Selection of patients with hepatocellular carcinoma for liver transplantation: Past and future

    PubMed Central

    Soriano, Arturo; Varona, Aranzazu; Gianchandani, Rajesh; Moneva, Modesto Enrique; Arranz, Javier; Gonzalez, Antonio; Barrera, Manuel

    2016-01-01

    The aim of liver transplantation (LT) for hepatocellular carcinoma (HCC) is to ensure a rate of disease-free survival similar to that of patients transplanted due to benign disease. Therefore, we are forced to adopt strict criteria when selecting candidates for LT and prioritizing patients on the waiting list (WL), to have clarified indications for bridging therapy for groups at risk for progression or recurrence, and to establish certain limits for downstaging therapies. Although the Milan criteria (MC) remain the standard and most employed criteria for indication of HCC patients for LT by far, in the coming years, criteria will be consolidated that take into account not only data regarding the size/volume and number of tumors but also their biology. This criteria will mainly include the alpha fetoprotein (AFP) values and, in view of their wide variability, any of the published logarithmic models for the selection of candidates for LT. Bridging therapy is necessary for HCC patients on the WL who meet the MC and have the possibility of experiencing a delay for LT greater than 6 mo or any of the known risk factors for recurrence. It is difficult to define single AFP values that would indicate bridging therapy (200, 300 or 400 ng/mL); therefore, it is preferable to rely on the criteria of a French AFP model score > 2. Other single indications for bridging therapy include a tumor diameter greater than 3 cm, more than one tumor, and having an AFP slope greater than 15 ng/mL per month or > 50 ng/mL for three months during strict monitoring while on the WL. When considering the inclusion of patients on the WL who do not meet the MC, it is mandatory to determine their eligibility for downstaging therapy prior to inclusion. The upper limit for this therapy could be one lesion up to 8 cm, 2-3 lesions with a total tumor diameter up to 8 cm, or a total tumor volume of 115 cm3. Lastly, liver allocation and the prioritization of patients with HCC on the WL should take into

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

    PubMed

    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

  18. Ultrasound-guided interventional PDT of liver cancer

    NASA Astrophysics Data System (ADS)

    Zeng, Chaoying; Yang, Dong; Huang, Ping; Zhang, Huijuan; Huang, Muyin; Chen, Ji; Lu, Guorong

    1996-09-01

    Thirty patients with advanced liver cancer were treated by interstitial photodynamic therapy (PDT). These included 28 hepatocellular carcinoma and two adenocarcinoma, 19 primary tumors and 11 recurred follow other treatments. The diameter of tumors were 7-10cm in 13 cases and 10-16cm in 17 cases. In this study, an argon laser pumped dye laser system was used to give a CW laser beam at 630 nm which was split and coupled into there optical fibers. The patients were injected intravenously with photosensitizer hematoporphyrin derivative at a dose of 5mg/kg body weight 48 hours before PDT. Then the fibers were inserted into tumor by ultrasound- guided percutaneous puncture. The inserted irradiation points were spaced in entire tumor with the light release power 300mW and the irradiation time 12 minutes per point. Total 52 treatments were performed in 30 patients. Among them, 14 cases were treated only one time and 16 cases via 2-3 times. The follow-up was carried out in 25 cases for 12- 24 months. The results show that significant remission was 22 percent in those patients by only one treatment and 62 percent in those via 2 to 3 treatments. The shrink rate of tumor size was over 90 percent in five of six cases after treatment 3. The survival time has been over one year in 12 cases. No obvious change to be found for all patients in liver function test, renal function test and blood routine examination. The level of AFP indicated a descending trend after PDT. This work indicate that PDT is effective and safe for the treatment of large liver cancers including those recurred follow hepatic resection and those failed in hepatic artery infusion embolic chemotherapy.

  19. Immunohistochemical detection of HCV infection in patients with hepatocellular carcinoma and other liver diseases

    PubMed Central

    Zhang, Li-Fa; Peng, Wen-Wei; Yao, Ji-Lu; Tang, Yong-Huang

    1998-01-01

    AIM: To detect HCV infection in patients with HCC and other liver diseases by the immunohistochemical method. METHODS: The expression of HCV antigen was identified by means of LSAB (labelled streptavidin-biotin) method using anti-NS3 monoclonal antibody. RESULTS: The positive rates of HCV antigen in the three groups of HCC, liver cirrhosis and hepatitis were 13.5% (7/52), 12.5% (2/16), and 10% (4/40) respectively, while in the samples from patients with constitutional jaundice and normal liver samples, no HCV antigen was found. HCV antigen could be seen in the nuclei and/or cytoplasms of carcinoma cells and/or pericancerous hepatocytes. In HCC, HCV antigen was more often seen in nuclei than in cytoplasms. The positive rate of HCV antigen in pericancerous tissues was higher than that in cancerous tissues. CONCLUSION: HCV is associated with HCC, and HCV infection enhances the development of liver diseases. HCV affects the initiative period of HCC and induces the malignant phenotypic alteration of hepatocytes. PMID:11819235

  20. Tobacco carcinogen induces both lung cancer and non-alcoholic steatohepatitis and hepatocellular carcinomas in ferrets which can be attenuated by lycopene supplementation.

    PubMed

    Aizawa, Koichi; Liu, Chun; Tang, Sanyuan; Veeramachaneni, Sudipta; Hu, Kang-Quan; Smith, Donald E; Wang, Xiang-Dong

    2016-09-01

    Early epidemiologic studies have reported that tobacco smoking, which is causally associated with liver cancer, is an independent risk factor for non-alcoholic fatty liver diseases (NAFLD). Lycopene from tomatoes has been shown to be a potential preventive agent against NAFLD and hepatocellular carcinoma (HCC). In the present study, we investigated whether the tobacco carcinogen 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces lesions in both lungs and livers of ferrets with or without lycopene intervention. Male ferrets (6 groups, n = 8-10) were treated either with NNK (50 mg/kg BW, i.p., once a month for four consecutive months) or saline with or without dietary lycopene supplementation (2.2 and 6.6 mg/kg BW/day, respectively) for 26 weeks. Results demonstrate that NNK exposure results in higher incidences of lung tumors, HCC and steatohepatitis (which is characterized by severe inflammatory cell infiltration with concurrent fat accumulation in liver, hepatocellular ballooning degeneration and increased NF-κB expression), as well as elevations in bilirubin and AST levels in ferrets. Lycopene supplementation at two doses prevented NNK-induced expressions of α7 nicotinic acetylcholine receptor in the lung and NF-κB and CYP2E1 in the liver and attenuated the NNK-induced mortality and pathological lesions in both the lungs and livers of ferrets. The present study provided strong experimental evidence that the tobacco carcinogen NNK can induce both HCC and steatohepatitis in the ferrets and can be a useful model for studying tobacco carcinogen-associated NAFLD and liver cancer. Furthermore, lycopene could provide potential benefits against smoke carcinogen-induced pulmonary and hepatic injury. © 2016 UICC.

  1. The nanomechanical signature of liver cancer tissues and its molecular origin

    NASA Astrophysics Data System (ADS)

    Tian, Mengxin; Li, Yiran; Liu, Weiren; Jin, Lei; Jiang, Xifei; Wang, Xinyan; Ding, Zhenbin; Peng, Yuanfei; Zhou, Jian; Fan, Jia; Cao, Yi; Wang, Wei; Shi, Yinghong

    2015-07-01

    Patients with cirrhosis are at higher risk of developing hepatocellular carcinoma (HCC), the second most frequent cause of cancer-related deaths. Although HCC diagnosis based on conventional morphological characteristics serves as the ``gold standard'' in the clinic, there is a high demand for more convenient and effective diagnostic methods that employ new biophysical perspectives. Here, we show that the nanomechanical signature of liver tissue is directly correlated with the development of HCC. Using indentation-type atomic force microscopy (IT-AFM), we demonstrate that the lowest elasticity peak (LEP) in the Young's modulus distribution of surgically removed liver cancer tissues can serve as a mechanical fingerprint to evaluate the malignancy of liver cancer. Cirrhotic tissues shared the same LEP as normal tissues. However, a noticeable downward shift in the LEP was detected when the cirrhotic tissues progressed to a malignant state, making the tumor tissues more prone to microvascular invasion. Cell-level mechanistic studies revealed that the expression level of a Rho-family effector (mDia1) was consistent with the mechanical trend exhibited by the tissue. Our findings indicate that the mechanical profiles of liver cancer tissues directly varied with tumor progression, providing an additional platform for the future diagnosis of HCC.Patients with cirrhosis are at higher risk of developing hepatocellular carcinoma (HCC), the second most frequent cause of cancer-related deaths. Although HCC diagnosis based on conventional morphological characteristics serves as the ``gold standard'' in the clinic, there is a high demand for more convenient and effective diagnostic methods that employ new biophysical perspectives. Here, we show that the nanomechanical signature of liver tissue is directly correlated with the development of HCC. Using indentation-type atomic force microscopy (IT-AFM), we demonstrate that the lowest elasticity peak (LEP) in the Young's modulus

  2. MK2206 in Treating Patients With Advanced Refractory Biliary Cancer That Cannot Be Removed by Surgery

    ClinicalTrials.gov

    2016-05-16

    Advanced Adult Hepatocellular Carcinoma; Localized Non-Resectable Adult Liver Carcinoma; Recurrent Adult Liver Carcinoma; Recurrent Gallbladder Carcinoma; Stage IV Distal Bile Duct Cancer; Stage IV Gallbladder Cancer; Unresectable Extrahepatic Bile Duct Carcinoma; Unresectable Gallbladder Carcinoma

  3. An integrated genomic and epigenomic approach predicts therapeutic response to zebularine in human liver cancer.

    PubMed

    Andersen, Jesper B; Factor, Valentina M; Marquardt, Jens U; Raggi, Chiara; Lee, Yun-Han; Seo, Daekwan; Conner, Elizabeth A; Thorgeirsson, Snorri S

    2010-10-20

    Epigenomic changes such as aberrant hypermethylation and subsequent atypical gene silencing are characteristic features of human cancer. Here, we report a comprehensive characterization of epigenomic modulation caused by zebularine, an effective DNA methylation inhibitor, in human liver cancer. Using transcriptomic and epigenomic profiling, we identified a zebularine response signature that classified liver cancer cell lines into two major subtypes with different drug responses. In drug-sensitive cell lines, zebularine caused inhibition of proliferation coupled with increased apoptosis, whereas drug-resistant cell lines showed up-regulation of oncogenic networks (for example, E2F1, MYC, and TNF) that drive liver cancer growth in vitro and in preclinical mouse models. Assessment of zebularine-based therapy in xenograft mouse models demonstrated potent therapeutic effects against tumors established from zebularine-sensitive but not zebularine-resistant liver cancer cells, leading to increased survival and decreased pulmonary metastasis. Integration of the zebularine gene expression and demethylation response signatures allowed differentiation of patients with hepatocellular carcinoma according to their survival and disease recurrence. This integrated signature identified a subclass of patients within the poor-survivor group that is likely to benefit from therapeutic agents that target the cancer epigenome.

  4. Elastin Fiber Accumulation in Liver Correlates with the Development of Hepatocellular Carcinoma

    PubMed Central

    Kurosaki, Masayuki; Higuchi, Mayu; Komiyama, Yasuyuki; Yoshida, Tsubasa; Hayashi, Tsuguru; Kuwabara, Konomi; Takaura, Kenta; Nakakuki, Natsuko; Takada, Hitomi; Tamaki, Nobuharu; Suzuki, Shoko; Nakanishi, Hiroyuki; Tsuchiya, Kaoru; Itakura, Jun; Takahashi, Yuka; Hashiguchi, Akinori; Sakamoto, Michiie; Izumi, Namiki

    2016-01-01

    Background & Aims The fibrosis stage, which is evaluated by the distribution pattern of collagen fibers, is a major predictor for the development of hepatocellular carcinoma (HCC) for patients with hepatitis C. Meanwhile, the role of elastin fibers has not yet been elucidated. The present study was conducted to determine the significance of quantifying both collagen and elastin fibers. Methods We enrolled 189 consecutive patients with hepatitis C and advanced fibrosis. Using Elastica van Gieson-stained whole-slide images of pretreatment liver biopsies, collagen and elastin fibers were evaluated pixel by pixel (0.46 μm/pixel) using an automated computational method. Consequently, fiber amount and cumulative incidences of HCC within 3 years were analyzed. Results There was a significant correlation between collagen and elastin fibers, whereas variation in elastin fiber was greater than in collagen fiber. Both collagen fiber (p = 0.008) and elastin fiber (p < 0.001) were significantly correlated with F stage. In total, 30 patients developed HCC during follow-up. Patients who have higher elastin fiber (p = 0.002) in addition to higher collagen fiber (p = 0.05) showed significantly higher incidences of HCC. With regard to elastin fiber, this difference remained significant in F3 patients. Furthermore, for patients with a higher collagen fiber amount, higher elastin was a significant predictor for HCC development (p = 0.02). Conclusions Computational analysis is a novel technique for quantification of fibers with the added value of conventional staging. Elastin fiber is a predictor for the development of HCC independently of collagen fiber and F stage. PMID:27128435

  5. Stages of Childhood Liver Cancer

    MedlinePlus

    ... Events Scientific Meetings & Lectures Conferences Advisory Board Meetings Social Media Events Cancer Currents Blog All Press Releases 2017 ... Events Scientific Meetings & Lectures Conferences Advisory Board Meetings Social Media Cancer Currents Blog About NCI NCI Overview History ...

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

    PubMed Central

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

    2015-01-01

    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. PMID:26658617

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

    NASA Astrophysics Data System (ADS)

    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.

  8. Genetic diversity of hepatitis B virus and mutations associated to hepatocellular carcinoma in patients from Venezuela, with different stages of liver disease.

    PubMed

    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.

  9. Liver Fluke-Associated Biliary Tract Cancer.

    PubMed

    Prueksapanich, Piyapan; Piyachaturawat, Panida; Aumpansub, Prapimphan; Ridtitid, Wiriyaporn; Chaiteerakij, Roongruedee; Rerknimitr, Rungsun

    2017-08-09

    Cholangiocarcinoma (CCA) is an aggressive cancer arising from epithelial cells of the bile duct. Most patients with CCA have an unresectable tumor at the time of diagnosis. In Western countries, the risk of CCA increases in patients with primary sclerosing cholangitis, whereas liver fluke infection appears to be the major risk factor for CCA in Asian countries. A diagnosis of liver fluke infection often relies on stool samples, including microscopic examination, polymerase chain reaction-based assays, and fluke antigen detection. Tests of serum, saliva and urine samples are also potentially diagnostic. The presence of liver fluke along with exogenous carcinogens magnifies the risk of CCA in people living in endemic areas. The "liver fluke-cholangiocarcinoma" carcinogenesis pathways consist of mechanical damage to the bile duct epithelium, immunopathologic and cellular reactions to the liver fluke's antigens and excretory/secretory products, liver fluke-induced changes in the biliary tract microbiome and the effects of repeated treatment for liver fluke. A vaccine and novel biomarkers are needed for the primary and secondary prevention of CCA in endemic areas. Importantly, climate change exerts an effect on vector-borne parasitic diseases, and awareness of liver fluke should be enhanced in potentially migrated habitat areas.

  10. Non-alcoholic fatty liver disease and hepatocellular carcinoma in a 7-year-old obese boy: coincidence or comorbidity?

    PubMed

    Nobili, V; Alisi, A; Grimaldi, C; Liccardo, D; Francalanci, P; Monti, L; Castellano, A; de Ville de Goyet, J

    2014-10-01

    Hepatocellular carcinoma (HCC) may develop from non-alcoholic fatty liver disease (NAFLD) either in the presence or in the absence of established cirrhosis. Non-cirrhotic patients with NAFLD-related HCC are usually adult, male and obese. However, this association has not been reported yet in younger age groups. Objectives In the present study, the clinical case of a 7-yaer-old obese boy with steatosis and HCC is presented. A 7-year-old boy, with no evidence of chronic liver disease, was admitted for assessment of a liver mass. Preliminary assessment was suggestive of a combined and severe liver steatosis together with a malignant disease. A biopsy confirmed the suspected diagnosis of HCC; interestingly, the non-neoplastic liver was surrounded and characterized by the presence of steatosis and ballooning, and being absent of lobular inflammation and fibrosis. Chemotherapy and diet changes were conducted successfully with ultrasound characteristics suggesting improvements on both aspects: conventional liver mass resection could take place. This case report suggests that HCC might develop in paediatric age patients with obesity-related NAFLD, even in the absence of fibrosis. © 2013 The Authors. Pediatric Obesity © 2013 International Association for the Study of Obesity.

  11. Lymphoepithelioma-Like Carcinoma in Liver.

    PubMed

    Labgaa, Ismail; Stueck, Ashley; Ward, Stephen C

    2017-07-01

    Liver cancer, primarily encompassing hepatocellular carcinoma and intrahepatic cholangiocarcinoma, has become the second leading cause of worldwide cancer-related death during the past two decades. Lymphoepithelioma-like carcinomas (LELCs) are defined as tumors composed of undifferentiated epithelial cells with a prominent lymphoid infiltrate, and can arise in the liver as hepatocellular or cholangiocarcinoma forms. Patients with liver LELC display distinctive demographics and tumor characteristics. LELCs also appear to be associated with strikingly better outcomes compared to typical liver cancers, with 5-year survival rates of 57% to 100% versus 12% to 68%, respectively. Liver LELCs represent a unique model of immune response in liver cancer. Data on LELCs of the liver remain limited, and future comprehensive studies are needed to further elucidate this disease, which could ultimately offer precious insights for immunotherapeutic strategies in liver cancer. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  12. Pseudolesion of the liver on gadoxetate disodium-enhanced MR images obtained after transarterial chemoembolization for hepatocellular carcinoma: clinicoradiologic correlation.

    PubMed

    Shinagawa, Yoshinobu; Sakamoto, Keiko; Fujimitsu, Ritsuko; Shimakura, Mikiko; Kora, Shin-ichi; Takano, Koichi; Yoshimitsu, Kengo

    2012-11-01

    The purpose of this study was to elucidate the clinicoradiologic characteristics of pseudolesions of the liver in patients with hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE) as observed on gadoxetate disodium-enhanced MR images. A particular interest was correlation between the pseudolesion characteristics and TACE-MRI interval, during which sequential changes in pseudolesions may be revealed after TACE. Forty-eight patients with HCC who underwent gadoxetate disodium-enhanced MRI after TACE were retrospectively recruited. Pseudolesions were defined as areas of decreased signal intensity in treated areas on hepatocellular phase images that were confirmed to be nontumorous areas at follow-up. The prevalence and MRI features of pseudolesions were correlated with various clinical parameters, including TACE-MRI interval. Pseudolesions were found in 14 patients (29%). Within 1 month of TACE, the prevalence of pseudolesions was 83%. All of the pseudolesions had arterial enhancement, mimicking residual HCC. After 1 month, the prevalence of pseudolesions decreased, and these pseudolesions tended to exhibit no abnormality in any sequence other than the hepatocellular phase. Results of multivariate analysis suggested that size of HCC (p < 0.0001), duration of postembolization syndrome (p = 0.012), and TACE-MRI interval (p = 0.038) are independent indicators of the presence of pseudolesions. The prevalence and appearance of pseudolesions differ at different intervals from TACE. Radiologists need to recognize the clinicoradiologic characteristics to differentiate pseudolesions from true residual or recurrent HCC.

  13. Advances in non-surgical management of primary liver cancer

    PubMed Central

    Chen, Xiao; Liu, Hai-Peng; Li, Mei; Qiao, Liang

    2014-01-01

    Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer-related death worldwide. There have been great improvements in the diagnosis and treatment of HCC in recent years, but the problems, including difficult diagnosis at early stage, quick progression, and poor prognosis remain unsolved. Surgical resection is the mainstay of the treatment for HCC. However, 70%-80% of HCC patients are diagnosed at an advanced stage when most are ineligible for potentially curative therapies such as surgical resection and liver transplantation. In recent years, non-surgical management for unrespectable HCC, such as percutaneous ethanol injection, percutaneous microwave coagulation therapy, percutaneous radiofrequency ablation, transcatheter arterial chemoembolization, radiotherapy, chemotherapy, biotherapy, and hormonal therapy have been developed. These therapeutic options, either alone or in combination, have been shown to control tumor growth, prolong survival time, and improve quality of life to some extent. This review covers the current status and progress of non-surgical management for HCC. PMID:25469032

  14. Effective Dose from Stray Radiation for a Patient Receiving Proton Therapy for Liver Cancer

    NASA Astrophysics Data System (ADS)

    Taddei, Phillip J.; Krishnan, Sunil; Mirkovic, Dragan; Yepes, Pablo; Newhauser, Wayne D.

    2009-03-01

    Because of its advantageous depth-dose relationship, proton radiotherapy is an emerging treatment modality for patients with liver cancer. Although the proton dose distribution conforms to the target, healthy tissues throughout the body receive low doses of stray radiation, particularly neutrons that originate in the treatment unit or in the patient. The aim of this study was to calculate the effective dose from stray radiation and estimate the corresponding risk of second cancer fatality for a patient receiving proton beam therapy for liver cancer. Effective dose from stray radiation was calculated using detailed Monte Carlo simulations of a double-scattering proton therapy treatment unit and a voxelized human phantom. The treatment plan and phantom were based on CT images of an actual adult patient diagnosed with primary hepatocellular carcinoma. For a prescribed dose of 60 Gy to the clinical target volume, the effective dose from stray radiation was 370 mSv; 61% of this dose was from neutrons originating outside of the patient while the remaining 39% was from neutrons originating within the patient. The excess lifetime risk of fatal second cancer corresponding to the total effective dose from stray radiation was 1.2%. The results of this study establish a baseline estimate of the stray radiation dose and corresponding risk for an adult patient undergoing proton radiotherapy for liver cancer and provide new evidence to corroborate the suitability of proton beam therapy for the treatment of liver tumors.

  15. Differential expression of laminin receptors in human hepatocellular carcinoma

    PubMed Central

    Ozaki, I; Yamamoto, K; Mizuta, T; Kajihara, S; Fukushima, N; Setoguchi, Y; Morito, F; Sakai, T

    1998-01-01

    Background—Laminin receptors are involved in cell-extracellular matrix interactions in malignant cells that show invasion and metastasis. Hepatocellular carcinoma frequently shows early invasion into blood vessels, and intrahepatic and extrahepatic metastases. However, the role of laminin receptors in hepatocellular carcinoma is unknown. 
Aims—To examine the expression of mRNA for laminin receptors and their isoforms in hepatocellular carcinoma. 
Methods—The expression of several laminin receptors, including α1 integrin, α6 integrin and its isoforms α6A and α6B, β1 integrin and its isoforms β1A and β1B, and 32kD/67kDa laminin binding protein was examined in human hepatocellular carcinomas and non-cancerous liver tissues using the reverse transcription polymerase chain reaction. 
Results—α6 Integrin, β1 integrin, and laminin binding protein showed notably increased expression in hepatocellular carcinoma, compared with non-cancerous liver tissue, although the α1 integrin did not show a significant change. Furthermore, β1B integrin, a splicing variant of β1 integrin, was overexpressed in hepatocellular carcinoma while the β1A integrin isoform did not show significant changes between hepatocellular carcinoma and surrounding non-cancerous liver tissue. 
Conclusions—The differential upregulation of laminin receptors and their splicing isoforms was shown in hepatocellular carcinoma, suggesting that certain laminin receptors and their isoforms may be involved in the development and progression of hepatocellular carcinoma. 

 Keywords: laminin receptor; integrin α6β1; hepatocellular carcinoma PMID:9824613

  16. Gene Expression Patterns in Human Liver Cancers

    PubMed Central

    Chen, Xin; Cheung, Siu Tim; So, Samuel; Fan, Sheung Tat; Barry, Christopher; Higgins, John; Lai, Kin-Man; Ji, Jiafu; Dudoit, Sandrine; Ng, Irene O.L.; van de Rijn, Matt; Botstein, David; Brown, Patrick O.

    2002-01-01

    Hepatocellular carcinoma (HCC) is a leading cause of death worldwide. Using cDNA microarrays to characterize patterns of gene expression in HCC, we found consistent differences between the expression patterns in HCC compared with those seen in nontumor liver tissues. The expression patterns in HCC were also readily distinguished from those associated with tumors metastatic to liver. The global gene expression patterns intrinsic to each tumor were sufficiently distinctive that multiple tumor nodules from the same patient could usually be recognized and distinguished from all the others in the large sample set on the basis of their gene expression patterns alone. The distinctive gene expression patterns are characteristic of the tumors and not the patient; the expression programs seen in clonally independent tumor nodules in the same patient were no more similar than those in tumors from different patients. Moreover, clonally related tumor masses that showed distinct expression profiles were also distinguished by genotypic differences. Some features of the gene expression patterns were associated with specific phenotypic and genotypic characteristics of the tumors, including growth rate, vascular invasion, and p53 overexpression. PMID:12058060

  17. Aflatoxin, hepatitis and worldwide liver cancer risks.

    PubMed

    Henry, Sara H; Bosch, F Xavier; Bowers, J C

    2002-01-01

    Aflatoxins are among the most potent mutagenic and carcinogenic substances known. Differential potency of aflatoxin among species can be partially attributed to differences in metabolism; however, current information on competing aspects of metabolic activation and detoxification of aflatoxin in various species does not identify an adequate animal model for humans. Risk of liver cancer is influenced by a number of factors, most notably carriage of hepatitis B virus as determined by the presence in serum of the hepatitis B surface antigen (HBsAg+ or HBsAg-). About 50 to 100% of liver cancer cases are estimated to be associated with persistent infection of hepatitis B (or C) virus. The potency of aflatoxin in HBsAg+ individuals is substantially higher (about a factor of 30) than the potency in HBsAg- individuals. Thus, reduction of the intake of aflatoxins in populations with a high prevalence of HBsAg+ individuals will have greater impact on reducing liver cancer rates than reductions in populations with a low prevalence of HbsAg+ individuals. The present analysis suggests that vaccination against hepatitis B (or protection against hepatits C), which reduces prevalence of carriers, would reduce the potency of the aflatoxins in vaccinated populations and reduce liver cancer risk.

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

    PubMed Central

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

    2013-01-01

    AIM: To assess the role of contrast enhanced ultrasonography in evaluation of hepatocellular carcinoma (HCC) at the first Indian tertiary liver center. METHODS: 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. RESULTS: 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

  19. Biomarkers for Hepatocellular Carcinoma

    PubMed Central

    Behne, Tara; Copur, M. Sitki

    2012-01-01

    The hepatocellular carcinoma (HCC) is one of the most common malignant tumors and carries a poor survival rate. The management of patients at risk for developing HCC remains challenging. Increased understanding of cancer biology and technological advances have enabled identification of a multitude of pathological, genetic, and molecular events that drive hepatocarcinogenesis leading to discovery of numerous potential biomarkers in this disease. They are currently being aggressively evaluated to establish their value in early diagnosis, optimization of therapy, reducing the emergence of new tumors, and preventing the recurrence after surgical resection or liver transplantation. These markers not only help in prediction of prognosis or recurrence but may also assist in deciding appropriate modality of therapy and may represent novel potential targets for therapeutic interventions. In this paper, a summary of most relevant available data from published papers reporting various tissue and serum biomarkers involved in hepatocellular carcinoma was presented. PMID:22655201

  20. An Outcome-Based Approach to Assign MELD Exception Points for Patients With Hepatocellular Cancer.

    PubMed

    Kensinger, Clark D; Feurer, Irene D; Karp, Seth J

    2017-09-01

    Current Model for End-Stage Liver Disease (MELD) exception points provided to patients with hepatocellular cancer (HCC) are not based on outcome data and advantage these patients compared to those listed based on laboratory values (LABMELD). We sought to develop a data-based assignment for exception points for patients with HCC that equalizes outcomes among HCC and LABMELD patients. We used Scientific Registry of Transplant Recipients data to compare patients listed with HCC who received exception points versus patients listed with LABMELD. Nation- and region-specific data were examined for (1) a composite outcome for adverse events of death, delisting, or becoming ineligible for transplant; and (2) transplant rate. We also determined MELD progression rates for LABMELD patients. Candidates listed with LABMELD scores were compared with those listed with 22 exception points for HCC (HCC22) to determine the LABMELD for which statistical parity was achieved for our composite outcome. HCC22 candidates time to adverse event were comparable to LABMELD scores of 16 (LABMELD16) candidates (range, 15-19), whereas time to transplant was comparable to LABMELD22 candidates (range, 21-23). LABMELD22 candidates had 2.1 times greater risk of adverse event compared with HCC22 (95% confidence interval, 1.9-2.4; range, 1.5-2.4). Progression among LABMELD16 candidates whose scores did not improve was similar across regions and averaged 0.94 points/month (95% confidence interval, 0.88-0.99, range 0.80-1.04). To equalize the occurrence of an adverse outcome, the proper listing MELD for patients with HCC is 16, with approximately 1 additional point/month. These results provide a data-driven algorithm to increase fairness in listing priority.

  1. Chinese herbal medicine-derived compounds for cancer therapy: a focus on hepatocellular carcinoma.

    PubMed

    Hu, Yangyang; Wang, Shengpeng; Wu, Xu; Zhang, Jinming; Chen, Ruie; Chen, Meiwan; Wang, Yitao

    2013-10-07

    Hepatocellular carcinoma (HCC) as the major histological subtype of primary liver cancer remains one of the most common malignancies worldwide. Due to the complicated molecular pathogenesis of HCC, the option for effective systemic treatment is quite limited. There exists a critical need to explore and evaluate possible alternative strategies for effective control of HCC. With a long history of clinical use, Chinese herbal medicine (CHM) is emerging as a noticeable choice for its multi-level, multi-target and coordinated intervention effects against HCC. With the aids of phytochemistry and molecular biological approaches, in the past decades many CHM-derived compounds have been carefully studied through both preclinical and clinical researches and have shown great potential in novel anti-HCC natural product development. The present review aimed at providing the most recent developments on anti-HCC compounds derived from CHM, especially their underlying pharmacological mechanisms. A systematic search of anti-HCC compounds from CHM was carried out focusing on literatures published both in English (PubMed, Scopus, Web of Science and Medline) and in Chinese academic databases (Wanfang and CNKI database). In this review, we tried to give a timely and comprehensive update about the anti-HCC effects and targets of several representative CHM-derived compounds, namely curcumin, resveratrol, silibinin, berberine, quercetin, tanshinone II-A and celastrol. Their mechanisms of anti-HCC behaviors, potential side effects or toxicity and future research directions were discussed. Herbal compounds derived from CHM are of much significance in devising new drugs and providing unique ideas for the war against HCC. We propose that these breakthrough findings may have important implications for targeted-HCC therapy and modernization of CHM. Copyright © 2013. Published by Elsevier Ireland Ltd.

  2. The role of hepatic resection in the treatment of hepatocellular cancer.

    PubMed

    Roayaie, Sasan; Jibara, Ghalib; Tabrizian, Parissa; Park, Joong-Won; Yang, Jijin; Yan, Lunan; Schwartz, Myron; Han, Guohong; Izzo, Francesco; Chen, Mishan; Blanc, Jean-Frédéric; Johnson, Philip; Kudo, Masatoshi; Roberts, Lewis R; Sherman, Morris

    2015-08-01

    Current guidelines recommend surgical resection as the primary treatment for a single hepatocellular cancer (HCC) with Child's A cirrhosis, normal serum bilirubin, and no clinically significant portal hypertension. We determined how frequently guidelines were followed and whether straying from them impacted survival. BRIDGE is a multiregional cohort study including HCC patients diagnosed between January 1, 2005 and June 30, 2011. A total of 8,656 patients from 20 sites were classified into four groups: (A) 718 ideal resection candidates who were resected; (B) 144 ideal resection candidates who were not resected; (C) 1,624 nonideal resection candidates who were resected; and (D) 6,170 nonideal resection candidates who were not resected. Median follow-up was 27 months. Log-rank and Cox's regression analyses were conducted to determine differences between groups and variables associated with survival. Multivariate analysis of all ideal candidates for resection (A+B) revealed a higher risk of mortality with treatments other than resection. For all resected patients (A+C), portal hypertension and bilirubin >1 mg/dL were not associated with mortality. For all patients who were not ideal candidates for resection (C+D), resection was associated with better survival, compared to embolization and "other" treatments, but was inferior to ablation and transplantation. The majority of patients undergoing resection would not be considered ideal candidates based on current guidelines. Not resecting ideal candidates was associated with higher mortality. The study suggests that selection criteria for resection may be modestly expanded without compromising outcomes, and that some nonideal candidates may still potentially benefit from resection over other treatment modalities. © 2015 by the American Association for the Study of Liver Diseases.

  3. Sorafenib for the Treatment of Advanced Hepatocellular Cancer - a UK Audit.

    PubMed

    King, J; Palmer, D H; Johnson, P; Ross, P; Hubner, R A; Sumpter, K; Darby, S; Braconi, C; Iwuji, C; Swinson, D; Collins, P; Patel, K; Nobes, J; Muazzam, I; Blesing, C; Kirkwood, A; Nash, S; Meyer, T

    2017-04-01

    Sorafenib is the current standard treatment for advanced hepatocellular carcinoma. We carried out a national audit of UK patients treated with sorafenib as standard-of-care and those treated with systemic therapy in first-line trials. Sorafenib-treated and trial-treated patients were identified via the Cancer Drugs Fund and local databases. Data were collected retrospectively from medical records according to a standard case report form. The primary outcome measure was overall survival, estimated by the Kaplan-Meier method. Data were obtained for 448 sorafenib-treated patients from 15 hospitals. The median age was 68 years (range 17-89) and 75% had performance status ≤ 1. At baseline, 77% were Child-Pugh A and 16.1% Child-Pugh B; 38% were albumin-bilirubin grade 1 (ALBI-1) and 48% ALBI-2; 23% were Barcelona Clinic Liver Classification B (BCLC-B) and 72% BCLC-C. The median time on sorafenib was 3.6 months, with a mean daily dose of 590 mg. The median overall survival for 448 evaluable sorafenib-treated patients was 8.5 months. There were significant differences in overall survival comparing Child-Pugh A versus Child-Pugh B (9.5 versus 4.6 months), ALBI-1 versus ALBI-2 (12.9 versus 5.9 months) and BCLC-B versus BCLC-C (13.0 versus 8.3 months). For trial-treated patients (n=109), the median overall survival was 8.1 months and this was not significantly different from the sorafenib-treated patients. For Child-Pugh A patients with good performance status, survival outcomes were similar to those reported in global randomised controlled trials. Patients with ALBI grade > 1, Child-Pugh B or poor performance status seem to derive limited benefit from sorafenib treatment. Copyright © 2016 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

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

    PubMed

    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.

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

    PubMed Central

    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. PMID:27458508

  6. The Evolution of the Use of Serum Alpha-fetoprotein in Clinical Liver Cancer Surveillance

    PubMed Central

    Kelly, Sarah-Louise; Bird, Thomas G

    2017-01-01

    Liver cancer is the 6th most common cancer and 2nd leading cause of cancer-related mortality. In order to improve patient survival early tumor detection is required and this necessitates accurate screening of at risk individuals. In this article we concisely review the methodologies employed for Hepatocellular Carcinoma (HCC) surveillance and how their use has evolved over the last three decades. We focus attention to serum biomarkers, particularly alpha-fetoprotein. We propose that by using an increasingly sophisticated approach to assess dynamic rates of change in biomarkers tailored to individual patients that screening accuracy may be improved. Additional improvements may also be possible by the incorporation of patient clinical data into such personalised screening assessments. These possibilities may hold the promise of improving cancer detection and early curative therapy for the increasing worldwide population at risk of HCC development. PMID:28133640

  7. Fighting liver cancer with combination immunotherapies | Center for Cancer Research

    Cancer.gov

    A new clinical trial testing the effectiveness of immunotherapy treatment combinations against liver cancer is enrolling patients at the NIH Clinical Center in Bethesda, Maryland. Individually, immunotherapy drugs harness the power of the human immune system to better identify and kill cancer cells. Now, researchers at the NIH’s Center for Cancer Research have begun to find evidence that the drugs may work far more effectively when taken in combination with other therapies and with each other than when taken alone.

  8. Biallelic inactivation of protoporphyrinogen oxidase and hydroxymethylbilane synthase is associated with liver cancer in acute porphyrias.

    PubMed

    Schneider-Yin, Xiaoye; van Tuyll van Serooskerken, Anne-Moon; Siegesmund, Marko; Went, Philip; Barman-Aksözen, Jasmin; Bladergroen, Reno S; Komminoth, Paul; Cloots, Roy H E; Winnepenninckx, Véronique J; zur Hausen, Axel; Weber, Markus; Driessen, Ann; Poblete-Gutiérrez, Pamela; Bauer, Peter; Schroeder, Christopher; van Geel, Michel; Minder, Elisabeth I; Frank, Jorge

    2015-03-01

    Variegate porphyria (VP) and acute intermittent porphyria (AIP), the two most common types of acute porphyrias (AHPs), result from a partial deficiency of protoporphyrinogen oxidase (PPOX) and hydroxymethylbilane synthase (HMBS), respectively. A rare but serious complication in the AHPs is hepatocellular carcinoma (HCC). However, the underlying pathomechanisms are yet unknown. We performed DNA sequence analysis in cancerous and non-cancerous liver tissue of a VP and an AIP patient, both with HCC. In samples of both cancerous and non-cancerous liver tissues from the patients, we identified the underlying PPOX and HMBS germline mutations, c.1082dupC and p.G111R, respectively. Additionally, we detected a second somatic mutation, only in the cancer tissue i.e., p.L416X in the PPOX gene of the VP patient and p.L220X in the HMBS gene of the AIP patient, both located in trans to the respective germline mutations. Both somatic mutations were not detected in 10 non-porphyria-associated HCCs. Our data demonstrate that in the hepatic cancer tissue of AHP patients, somatic second-hit mutations result in nearly complete inactivation of the enzymes catalyzing major steps in the heme biosynthetic pathway. Both PPOX and HMBS, which might act as tumor suppressors, play a crucial role in the development of HCC in these individuals. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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

    PubMed Central

    Hänsler, Johannes; Wissniowski, Thaddäus Till; Schuppan, Detlef; Witte, Astrid; Bernatik, Thomas; Hahn, Eckhart Georg; Strobel, Deike

    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. PMID:16773688

  10. Evaluation of Bufadienolides as the Main Antitumor Components in Cinobufacin Injection for Liver and Gastric Cancer Therapy

    PubMed Central

    Zhang, Yuefei; Zhao, Haiyu; Yang, Jian; Wang, Hongjie; Wang, Lianmei; Han, Linyu; Bian, Baolin

    2017-01-01

    Background Cinobufacin injection, also known as huachansu, is a preparation form of Cinobufacini made from Cinobufacin extract liquid. Despite that Cinobufacin injection is shown to shrink liver and gastric tumors, improving patient survival and life quality, the effective components in Cinobufacin remain elusive. In this study, we aim to screen antitumor components from Cinobufacin injection to elucidate the most effective antitumor components for treatment of liver and gastric cancers. Materials and Methods High performance liquid chromatography (HPLC) and LC-MS/MS analysis were used to separate and determine the components in Cinobufacin injection. Inhibition rates of various components in Cinobufacin injection on liver and gastric cancer cells were determined with MTT assay; Hepatocellular carcinoma and gastric cancer models were used to assess the antitumor effect of the compounds in vivo. Results The major constituents in Cinobufacin injection include peptides, nucleic acids, tryptamines and bufotalins. MTT assay revealed that bufadienolides had the best antitumor activity, with peptides being the second most effective components. Bufadienolides showed significant inhibition rates on gastric and hepatocellular tumour growth in vivo. Conclusion Bufadienolides are the most effective components in Cinobufacini injection for the treatment of liver and gastric cancers. This discovery can greatly facilitate further research in improving the therapeutic effects of Cinobufacin injection, meanwhile reducing its adverse reaction. PMID:28081155