Liver Transplantation for Alcoholic Liver Disease and Hepatocellular Carcinoma.

PubMed

Burra, Patrizia; Zanetto, Alberto; Germani, Giacomo

2018-02-09

Hepatocellular carcinoma is one of the main important causes of cancer-related death and its mortality is increasingly worldwide. In Europe, alcohol abuse accounts for approximately half of all liver cancer cases and it will become the leading cause of hepatocellular carcinoma in the next future with the sharp decline of chronic viral hepatitis. The pathophysiology of alcohol-induced carcinogenesis involves acetaldehyde catabolism, oxidative stress and chronic liver inflammation. Genetic background plays also a significant role and specific patterns of gene mutations in alcohol-related hepatocellular carcinoma have been characterized. Survival is higher in patients who undergo specific surveillance programmes than in patients who do not. However, patients with alcohol cirrhosis present a significantly greater risk of liver decompensation than those with cirrhosis due to other aetiologies. Furthermore, the adherence to screening program can be suboptimal. Liver transplant for patients with Milan-in hepatocellular carcinoma represents the best possible treatment in case of tumour recurrence/progression despite loco-regional or surgical treatments. Long-term result after liver transplantation for alcohol related liver disease is good. However, cardiovascular disease and de novo malignancies can significantly hamper patients' survival and should be carefully considered by transplant team. In this review, we have focused on the evolution of alcohol-related hepatocellular carcinoma epidemiology and risk factors as well as on liver transplantation in alcoholic patients with and without hepatocellular carcinoma.

Significance of detecting circulating hepatocellular carcinoma cells in peripheral blood of hepatocellular carcinoma patients by nested reverse transcription-polymerase chain reaction and its clinical value: a retrospective study.

PubMed

Liu, Yang; Wang, Yue-ru; Wang, Long; Song, Rui-mei; Zhou, Bo; Song, Zhen-shun

2014-01-01

hepatocellular carcinoma cells, which might predict hematogenous spreading metastasis in patients with hepatocellular carcinoma and may be a poor prognostic factor for hepatocellular carcinoma patients.

Alpha-1-Antitrypsin in Pathogenesis of Hepatocellular Carcinoma

PubMed Central

Topic, Aleksandra; Ljujic, Mila; Radojkovic, Dragica

2012-01-01

Context Alpha-1-antitrypsin (A1AT) is the most abundant liver-derived, highly polymorphic, glycoprotein in plasma. Hereditary deficiency of alpha-1-antitrypsin in plasma (A1ATD) is a consequence of accumulation of polymers of A1AT mutants in endoplasmic reticulum of hepatocytes and other A1AT-producing cells. One of the clinical manifestations of A1ATD is liver disease in childhood and cirrhosis and/or hepatocellular carcinoma (HCC) in adulthood. Epidemiology and pathophysiology of liver failure in early childhood caused by A1ATD are well known, but the association with hepatocellular carcinoma is not clarified. The aim of this article is to review different aspects of association between A1AT variants and hepatocellular carcinoma, with emphasis on the epidemiology and molecular pathogenesis. The significance of A1AT as a biomarker in the diagnosis of HCC is also discussed. Evidence Acquisitions Search for relevant articles were performed through Pub Med, HighWire, and Science Direct using the keywords “alpha-1-antitrypsin”, “liver diseases”, “hepatocellular carcinoma”, “SERPINA1”. Articles published until 2011 were reviewed. Results Epidemiology studies revealed that severe A1ATD is a significant risk factor for cirrhosis and HCC unrelated to the presence of HBV or HCV infections. However, predisposition to HCC in moderate A1ATD is rare, and probably happens in combination with HBV and/or HCV infections or other unknown risk factors. It is assumed that accumulation of polymers of A1ATD variants in endoplasmic reticulum of hepatocytes leads to damage of hepatocytes by gain-of-function mechanism. Also, increased level of A1AT was recognized as diagnostic and prognostic marker of HCC. Conclusions Clarification of a carcinogenic role for A1ATD and identification of proinflammatory or some still unknown factors that lead to increased susceptibility to HCC associated with A1ATD may contribute to a better understanding of hepatic carcinogenesis and to the

Chromophobe hepatocellular carcinoma with abrupt anaplasia: a proposal for a new subtype of hepatocellular carcinoma with unique morphological and molecular features

PubMed Central

Wood, Laura D; Heaphy, Christopher M; Daniel, Hubert Darius-J; Naini, Bita V; Lassman, Charles R; Arroyo, May R; Kamel, Ihab R; Cosgrove, David P; Boitnott, John K; Meeker, Alan K; Torbenson, Michael S

2014-01-01

Hepatocellular carcinomas exhibit heterogeneous morphologies by routine light microscopy. Although some morphologies represent insignificant variations in growth patterns, others may represent unrecognized subtypes of hepatocellular carcinoma. Identification of these subtypes could lead to separation of hepatocellular carcinomas into discrete groups with unique underlying genetic changes, prognosis, or therapeutic responses. In order to identify potential subtypes, two pathologists independently screened a cohort of 219 unselected hepatocellular carcinoma resection specimens and divided cases into potential subtypes. One of these promising candidate subtypes was further evaluated using histological and molecular techniques. This subtype was characterized by a unique and consistent set of histological features: smooth chromophobic cytoplasm, abrupt focal nuclear anaplasia (small clusters of tumor cells with marked nuclear anaplasia in a background of tumor cells with bland nuclear cytology), and scattered microscopic pseudocysts—we designate this variant as ‘chromophobe hepatocellular carcinoma with abrupt anaplasia’. Thirteen cases were identified (6% of all hepatocellular carcinomas), including 6 men and 7 women with an average age of 61 years. Six cases occurred in cirrhotic livers. Serum AFP was elevated in 6 out of 10 cases. There were a variety of underlying liver diseases, but cases were enrichment for chronic hepatitis B, P = 0.006. Interestingly, at the molecular level, this variant was strongly associated with the alternative lengthening of telomere (ALT) phenotype by telomere FISH. ALT is a telomerase-independent mechanism of telomere maintenance and is found in approximately 8% of unselected hepatocellular carcinomas. In contrast, 11/12 (92%) of the cases of chromophobe hepatocellular carcinoma with abrupt anaplasia were ALT-positive. In summary, we propose that chromophobe hepatocellular carcinoma with abrupt anaplasia represents a new subtype of

Chromophobe hepatocellular carcinoma with abrupt anaplasia: a proposal for a new subtype of hepatocellular carcinoma with unique morphological and molecular features.

PubMed

Wood, Laura D; Heaphy, Christopher M; Daniel, Hubert Darius-J; Naini, Bita V; Lassman, Charles R; Arroyo, May R; Kamel, Ihab R; Cosgrove, David P; Boitnott, John K; Meeker, Alan K; Torbenson, Michael S

2013-12-01

Hepatocellular carcinomas exhibit heterogeneous morphologies by routine light microscopy. Although some morphologies represent insignificant variations in growth patterns, others may represent unrecognized subtypes of hepatocellular carcinoma. Identification of these subtypes could lead to separation of hepatocellular carcinomas into discrete groups with unique underlying genetic changes, prognosis, or therapeutic responses. In order to identify potential subtypes, two pathologists independently screened a cohort of 219 unselected hepatocellular carcinoma resection specimens and divided cases into potential subtypes. One of these promising candidate subtypes was further evaluated using histological and molecular techniques. This subtype was characterized by a unique and consistent set of histological features: smooth chromophobic cytoplasm, abrupt focal nuclear anaplasia (small clusters of tumor cells with marked nuclear anaplasia in a background of tumor cells with bland nuclear cytology), and scattered microscopic pseudocysts--we designate this variant as 'chromophobe hepatocellular carcinoma with abrupt anaplasia'. Thirteen cases were identified (6% of all hepatocellular carcinomas), including 6 men and 7 women with an average age of 61 years. Six cases occurred in cirrhotic livers. Serum AFP was elevated in 6 out of 10 cases. There were a variety of underlying liver diseases, but cases were enrichment for chronic hepatitis B, P=0.006. Interestingly, at the molecular level, this variant was strongly associated with the alternative lengthening of telomere (ALT) phenotype by telomere FISH. ALT is a telomerase-independent mechanism of telomere maintenance and is found in approximately 8% of unselected hepatocellular carcinomas. In contrast, 11/12 (92%) of the cases of chromophobe hepatocellular carcinoma with abrupt anaplasia were ALT-positive. In summary, we propose that chromophobe hepatocellular carcinoma with abrupt anaplasia represents a new subtype of

[Bioinformatics on vascular invasion markers in hepatocellular carcinoma via Big-Data analysis].

PubMed

Chen, Q; Qiu, X Q

2017-04-10

Objective: To investigate the biomarkers in hepatocellular carcinoma and their prognostic value via GEO (Gene Expression Omnibus) and TCGA (The Cancer Genome Atlas) database. Methods: Datasets of hepatocellular carcinoma were downloaded from GEO (GSE67140) and TCGA. MicroRNA in SNU423, SNU449, HepG2, Hep3B, SNU398 cell lines which had low or high invasion capabilities were investigated and verified, in 81 patients with and 91 without vascular invasion hepatocellular carcinoma. The prognostic value of these microRNAs were studied via TCGA database,obtained from 362 patients with hepatocellular carcinoma, through Kaplan-Meier and Multivariate Cox proportional hazard analysis. Target genes were analyzed by GO and KEGG. Results: Expressions of hsa-mir-1180, hsa-mir-149, hsa-mir-744 and hsa-mir-940 were all up regulated in high invasion capable cell lines (SNU423, SNU449) and vascular invasion patients with hepatocellular carcinoma (logFC>1, P <0.05). Results from the Survival analysis showed that hsa-mir-1180 ( HR =1.623, 95 % CI : 1.114-2.365, P =0.012), hsa-mir-149 ( HR =2.400, 95 % CI : 1.639-3.514) and hsa-mir-940 ( HR =1.704, 95 %CI : 1.188-2.443, P =0.004) were independent risk factors on the prognosis of patients with hepatocellular carcinoma ( P <0.05). The mechanism might be related to factors as immune response, focal adhesion and adherence junction signaling pathways. Conclusion: With TCGA and GEO data mining, we found that hsa-mir-1180, hsa-mir-149, hsa-mir-744 and hsa-mir-940 were all highly related to the prognosis of hepatocellular carcinoma, that enabled it to be used to further study the biomarkers related to the prognosis of hepatocellular carcinoma.

[Incidence of hepatocellular carcinoma and consequent lessons for its management in Northeastern Hungary].

PubMed

Papp, Renáta; Papp, Mária; Tornai, István; Vitális, Zsuzsanna

2016-11-01

The increasing incidence and poor prognosis of hepatocellular carcinoma places huge burden on healthcare. After reviewing literature on epidemiological trends, risk factors, diagnosis and management options for hepatocellular carcinoma, the authors investigated results of treatment and survival data of patients in Northeastern Hungary. In a retrospective study, the authors analyzed medical records of 187 patients with hepatocellular carcinoma (etiology, presence of cirrhosis, stage of the tumor, treatment and disease outcome). Seventy-one patients (38%) had known cirrhosis at the diagnosis of hepatocellular carcinoma, while in 52 patients (28%) the presence of cirrhosis was established at the time of the diagnosis of hepatocellular carcinoma. Fifteen patients (8%) had no cirrhosis and in 49 patients (26%) no data were available regarding cirrhosis. Etiological factors were alcohol consumption (52%), viral hepatitis (41%) and metabolic syndrome (44%). In cases of metabolic syndrome, hepatocellular carcinoma frequently occurred without cirrhosis. In 83% of the cases, the tumor was discovered in an advanced stage. Median survival time was significantly associated with tumor stage (Barcelona A stage vs. B/C vs. D: 829 vs. 387 vs. 137 days, respectively p<0.001) but not with disease etiology (virus 282 days, metabolic syndrome 335 days and alcohol 423 days, p = 0.65). High mortality of hepatocellular carcinoma was mainly attributed to the delayed diagnosis of the disease. Screening of patients with cirrhosis could only result in a partial improvement since in a great proportion cirrhosis was diagnosed simultaneously with the tumor. Screening of diabetic and obese patients by ultrasonography should be considered. Management of baseline liver disease is of importance in the care of hepatocellular carcinoma. Orv. Hetil., 2016, 157(45), 1793-1801.

Hepatocellular Carcinoma in the Cirrhotic Liver: Evaluation Using Computed Tomography and Magnetic Resonance Imaging.

PubMed

Coskun, Mehmet

2017-03-01

Hepatocellular carcinoma is the fifth most common tumor in patients worldwide and the third most common cause of cancer-related death, after lung and stomach cancer. Cirrhosis of the liver is the strongest predisposing factor for hepatocellular carcinoma, with approximately 80% of cases of hepatocellular carcinoma developing in a cirrhotic liver. The annual incidence of hepatocellular carcinoma is 2.0% to 6.6% in patients with cirrhosis compared with 0.4% in patients without cirrhosis. The 5-year survival rates of patients undergoing curative therapies for hepatocellular carcinoma, including liver transplant, hepatic resection, and percutaneous ablative techniques, range between 40% and 75%. Orthotropic liver transplant offers the prima facie cure for both hepatocellular carcinoma and liver cirrhosis. In hepatocellular carcinoma confined to the liver without macrovascular invasion, patients with a single tumor ≤ 5 cm or up to 3 tumors ≤ 3 cm each had a 5-year survival rate of 75% and a disease-free survival rate of 83%. In the adult population, liver transplant for hepatocellular carcinoma yields good results for patients whose tumor masses do not exceed the Milan criteria. The diagnosis of hepatocellular carcinoma using imaging tests has had a substantial impact on transplant decisions. Radiologists should be aware of this responsibility and exercise the utmost scrutiny before making a diagnosis of hepatocellular carcinoma. Erroneous diagnosis of hepatocellular carcinoma based on imaging tests could deny deserving patients the opportunity of a life-saving liver transplant and result in unnecessary liver transplants for others. Contrast-enhanced magnetic resonance imaging and helical computed tomography are the best imaging techniques currently available for the noninvasive diagnosis of hepatocellular carcinoma. With technological advances in hardware and software, diffusion-weighted imaging can be readily applied to the liver with resulting improved image

Silencing of karyopherin α2 inhibits cell growth and survival in human hepatocellular carcinoma

PubMed Central

Yang, Yunfeng; Guo, Jian; Hao, Yuxia; Wang, Fuhua; Li, Fengxia; Shuang, Shaomin; Wang, Junping

2017-01-01

Karyopherin α2 (KPNA2), involved in nucleocytoplasmic transport, has been reported to be upregulated in hepatocellular carcinoma and considered as a biomarker for poor prognosis. However, comprehensive studies of KPNA2 functions in hepatocellular carcinogenesis are still lacking. Our study examine the roles and related molecular mechanisms of KPNA2 in hepatocellular carcinoma development. Results show that KPNA2 knockdown inhibited the proliferation and growth of hepatocellular carcinoma cells in vitro and in vivo. KPNA2 knockdown also inhibited colony formation ability, induced cell cycle arrest and cellular apoptosis in two hepatocellular carcinoma cell lines, HepG2 and SMMC-7721. Furthermore, gene expression microarray analysis in HepG2 cells with KPNA2 knockdown revealed that critical signaling pathways involved in cell proliferation and survival were deregulated. In conclusion, this study provided systematic evidence that KPNA2 was an essential factor promoting hepatocellular carcinoma and unraveled potential molecular pathways and networks underlying KPNA2-induced hepatocellular carcinogenesis. PMID:28422734

Silencing of karyopherin α2 inhibits cell growth and survival in human hepatocellular carcinoma.

PubMed

Yang, Yunfeng; Guo, Jian; Hao, Yuxia; Wang, Fuhua; Li, Fengxia; Shuang, Shaomin; Wang, Junping

2017-05-30

Karyopherin α2 (KPNA2), involved in nucleocytoplasmic transport, has been reported to be upregulated in hepatocellular carcinoma and considered as a biomarker for poor prognosis. However, comprehensive studies of KPNA2 functions in hepatocellular carcinogenesis are still lacking. Our study examine the roles and related molecular mechanisms of KPNA2 in hepatocellular carcinoma development. Results show that KPNA2 knockdown inhibited the proliferation and growth of hepatocellular carcinoma cells in vitro and in vivo. KPNA2 knockdown also inhibited colony formation ability, induced cell cycle arrest and cellular apoptosis in two hepatocellular carcinoma cell lines, HepG2 and SMMC-7721. Furthermore, gene expression microarray analysis in HepG2 cells with KPNA2 knockdown revealed that critical signaling pathways involved in cell proliferation and survival were deregulated. In conclusion, this study provided systematic evidence that KPNA2 was an essential factor promoting hepatocellular carcinoma and unraveled potential molecular pathways and networks underlying KPNA2-induced hepatocellular carcinogenesis.

Metastases of Hepatocellular Carcinoma Misdiagnosed as Isolated Hypertrophic Cardiomyopathy.

PubMed

Greco, Assunta; De Masi, Roberto; Orlando, Stefania; Metrangolo, Antonio; Zecca, Vittorio; Morciano, Giancarlo; De Donno, Antonella; Bagordo, Francesco; Piccinni, Giancarlo

At present, cardiac metastasis of hepatocellular carcinoma is rarely mentioned in the literature. We report a hepatocellular carcinoma patient with cardiac metastasis misdiagnosed as hypertrophic cardiomyopathy in 2011. Two years later, on presentation of syncope, an abnormal ventricular septal size was recorded by ultrasound scan, and was subsequently shown by magnetic resonance imaging to be a tumour lesion. A myocardial biopsy confirmed infiltration of hepatocellular carcinoma. This observation underlines the risk of hepatocellular carcinoma cardiac metastasis, manifested in its infiltrative form as hypertrophic cardiomyopathy. In conclusion, we suggest that the ultrasound appearance of hypertrophic cardiomyopathy in hepatocellular carcinoma patients should be seen as a "red flag" and recommend the introduction of magnetic resonance imaging assessment of transplant candidates.

Expression of Fra-1 in human hepatocellular carcinoma and its prognostic significance.

PubMed

Gao, Xiao-Qiang; Ge, Yong-Sheng; Shu, Qing-Hua; Ma, Hua-Xing

2017-06-01

This study aimed to explore the clinical significance and prognostic value of Fra-1 in hepatocellular carcinoma patients after curative resection. Fra-1 expression was investigated using a combination of techniques: immunohistochemistry for 66 samples of hepatocellular carcinoma and quantitative real-time polymerase chain reaction and western blotting assays for 19 matched hepatocellular carcinoma specimens. Fra-1 was present in 38 of 66 (57.6%) tumor tissues, with intense staining in the nuclei. There was also positive staining in 14 of 66 (21.2%) adjacent peritumoral tissues, with weak staining in the cytoplasm. Quantitative real-time polymerase chain reaction and western blotting assays confirmed higher expression of Fra-1 messenger RNA and Fra-1 protein in tumor tissues than adjacent non-tumor tissues for 19 hepatocellular carcinoma samples (p < 0.001). Positive expression of Fra-1 was significantly related to vascular invasion and serum alpha-fetoprotein. Kaplan-Meier survival analysis found that overexpressed Fra-1 was correlated with poor overall survival and disease-free survival. Multivariate analysis identified Fra-1 as an independent prognostic factor. Fra-1 may be involved in the progress of hepatocellular carcinoma and could be a promising molecular candidate in the diagnosis and treatment of hepatocellular carcinoma.

SIRT3 functions as a tumor suppressor in hepatocellular carcinoma.

PubMed

Zeng, Xianchun; Wang, Nanzhu; Zhai, Hui; Wang, Rongpin; Wu, Jiahong; Pu, Wei

2017-03-01

Hepatocellular carcinoma is one of the leading causes for cancer-related mortality worldwide. SIRT3 may function as either oncogene or tumor suppressor in a panel of cancers; however, the role of SIRT3 in hepatocellular carcinoma remains unclear. In this study, we assayed the expression level of SIRT3 in hepatocellular carcinoma tissues by quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry. A loss-of-function approach was used to examine the effects of SIRT3 on biological activity, including cell proliferative activity and invasive potential. The results demonstrated that the expression levels of SIRT3 protein in hepatocellular carcinoma tissues were significantly downregulated compared with those in adjacent non-cancerous tissues. Furthermore, SIRT3 could decrease cell proliferation and inhibit cell migration/invasion in hepatocellular carcinoma cell line. Taken together, these results elucidated the function of SIRT3 in hepatocellular carcinoma development and suggested that SIRT3 might function as tumor suppressor in hepatocellular carcinoma by targeting PI3K/Akt pathway.

Utilisation of hepatocellular carcinoma screening in Australians at risk of hepatitis B virus-related carcinoma and prescribed anti-viral therapy.

PubMed

Sheppard-Law, Suzanne; Zablotska-Manos, Iryna; Kermeen, Melissa; Holdaway, Susan; Lee, Alice; George, Jacob; Zekry, Amany; Maher, Lisa

2018-07-01

To investigate hepatocellular carcinoma screening utilisation and factors associated with utilisation among patients prescribed hepatitis B virus anti-viral therapy and at risk of hepatocellular carcinoma. The incidence of hepatocellular carcinoma has increased in Australia over the past three decades with chronic hepatitis B virus infection a major contributor. hepatocellular carcinoma surveillance programs aim to detect cancers early enabling curative treatment options, longer survival and longer times to recurrence. Multi-site cross-sectional survey. An online study questionnaire was administered to eligible participants attending three Sydney tertiary hospitals. Data were grouped into six mutually exclusive hepatocellular carcinoma risk factor categories as per American Association for the Study of Liver Diseases guidelines. All analyses were undertaken in STATA. Logistic regression was used to assess the associations between covariates and screening utilisation. Multivariate models described were assessed using the Hosmer-Lemeshow goodness of fit. Of the 177 participants, 137 (77.4%) self-reported that US had been performed in the last six months. Awareness that screening should be performed and knowing the correct frequency of US screening were independently associated with screening utilisation. Participants who knew that screening should be undertaken were three times more likely to have had pretreatment education or were prescribed hepatitis B virus anti-viral treatment for >4 years. Participants reporting a family history of hepatocellular carcinoma were less likely to know that screening should be undertaken every 6 months. While utilisation of hepatocellular carcinoma surveillance programs was higher in this study than in previous reports, strategies to further improve surveillance remain necessary. Findings from this research form the basis for proposing strategies to improve utilisation of hepatocellular carcinoma screening, inform hepatitis B virus

The clinical significance and biological function of lncRNA RGMB-AS1 in hepatocellular carcinoma.

PubMed

Sheng, Nan; Li, Yannan; Qian, Ruikun; Li, Yichun

2018-02-01

LncRNA RGMB-AS1 has been suggested to play significant roles in lung cancer progression. However, it remains unknown whether lncRNA RGMB-AS1 is involved in the development and progression of hepatocellular carcinoma. In our results, lncRNA RGMB-AS1 was low-expressed in hepatocellular carcinoma tissues and cell lines, and associated with clinical stage, tumor size and metastasis. Survival analysis indicated that lncRNA RGMB-AS1 high was an independent favorable prognostic factor for hepatocellular carcinoma patients. Gain-of-function studies showed up-regulated lncRNA RGMB-AS1 expression suppressed hepatocellular carcinoma cells proliferation, migration and invasion, and promoted cells apoptosis. There was a positively association between lncRNA RGMB-AS1 and RGMB in hepatocellular carcinoma tissues, and up-regulated lncRNA RGMB-AS1 expression increased RGMB mRNA and protein expressions in hepatocellular carcinoma cells. In conclusion, lncRNA RGMB-AS1 serves an anti-oncogenic role in hepatocellular carcinoma. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Diagnostic Approaches to Metastatic Hepatocellular Carcinoma of the Orbit.

PubMed

Geske, Michael J; Bloomer, Michele M; Kersten, Robert C; Vagefi, M Reza

Orbital metastasis of hepatocellular carcinoma is exceedingly rare and caries a grave prognosis. Three cases of metastatic orbital hepatocellular carcinoma in which the primary tumor was initially unknown and the diagnostic challenges encountered are presented. With hepatocellular carcinoma, open biopsy and palliative tumor debulking has an increased bleeding risk due to the highly vascular nature of the tumor and coagulopathy associated with chronic liver disease. As an alternative, fine needle aspiration biopsy should be considered for hepatocellular carcinoma with a readily accessible mass and the availability of an experienced cytopathologist.

Frequent somatic TERT promoter mutations and CTNNB1 mutations in hepatocellular carcinoma.

PubMed

Lee, Seung Eun; Chang, Seong-Hwan; Kim, Wook Youn; Lim, So Dug; Kim, Wan Seop; Hwang, Tea Sook; Han, Hye Seung

2016-10-25

Genetic alterations of TERT and CTNNB1 have been documented in hepatocellular carcinoma. TERT promoter mutations are the earliest genetic events in the multistep process of hepatocarcinogenesis related to cirrhosis. However, analyses of TERT promoter and CTNNB1 mutations in hepatocellular carcinoma tumor samples have not been performed in the Korean population, where hepatitis B virus-related hepatocellular carcinoma is prevalent. In order to identify the role of TERT promoter and CTNNB1 mutations in the hepatocarcinogenesis and pathogenesis of recurrent hepatocellular carcinoma, we performed the sequence analyses in 140 hepatocellular nodules (including 107 hepatocellular carcinomas), and 8 pairs of matched primary and relapsed hepatocellular carcinomas. TERT promoter and CTNNB1 mutations were only observed in hepatocellular carcinomas but not in precursor lesions. Of 109 patients with hepatocellular carcinoma, 41 (39.0%) and 15 (14.6%) harbored TERT and CTNNB1 mutations, respectively. TERT promotermutations were significantly more frequent in hepatocellular carcinomas related to hepatitis C virus infection (5/6; 83.3%) compared to tumors of other etiologies (P = 0.001). In two cases, discordance in TERT promoter mutation status was observed between the primary and the corresponding recurrent hepatocellular carcinoma. The two patients with discordant cases had early relapses. In conclusion, we identified TERT promoter and CTNNB1 mutations as the most frequent somatic genetic alterations observed in hepatocellular carcinoma, indicating its pivotal role in hepatocarcinogenesis. Furthermore, we suggest the possibility of intratumoral genetic heterogeneity of TERT promoter mutations in hepatocellular carcinoma as indicated by the discordance in TERT promoter mutations between primary and corresponding recurrent hepatocellular carcinoma.

Morphologic Subtypes of Hepatocellular Carcinoma.

PubMed

Torbenson, Michael S

2017-06-01

Hepatocellular carcinomas can be further divided into distinct subtypes that provide important clinical information and biological insights. These subtypes are distinct from growth patterns and are on based on morphologic and molecular findings. There are 12 reasonably well-defined subtypes as well as 6 provisional subtypes, together making up 35% of all hepatocellular carcinomas. These subtypes are discussed, with an emphasis on their definitions and the key morphologic findings. Copyright © 2017 Elsevier Inc. All rights reserved.

A qualitative signature for early diagnosis of hepatocellular carcinoma based on relative expression orderings.

PubMed

Ao, Lu; Zhang, Zimei; Guan, Qingzhou; Guo, Yating; Guo, You; Zhang, Jiahui; Lv, Xingwei; Huang, Haiyan; Zhang, Huarong; Wang, Xianlong; Guo, Zheng

2018-04-23

Currently, using biopsy specimens to confirm suspicious liver lesions of early hepatocellular carcinoma are not entirely reliable because of insufficient sampling amount and inaccurate sampling location. It is necessary to develop a signature to aid early hepatocellular carcinoma diagnosis using biopsy specimens even when the sampling location is inaccurate. Based on the within-sample relative expression orderings of gene pairs, we identified a simple qualitative signature to distinguish both hepatocellular carcinoma and adjacent non-tumour tissues from cirrhosis tissues of non-hepatocellular carcinoma patients. A signature consisting of 19 gene pairs was identified in the training data sets and validated in 2 large collections of samples from biopsy and surgical resection specimens. For biopsy specimens, 95.7% of 141 hepatocellular carcinoma tissues and all (100%) of 108 cirrhosis tissues of non-hepatocellular carcinoma patients were correctly classified. Especially, all (100%) of 60 hepatocellular carcinoma adjacent normal tissues and 77.5% of 80 hepatocellular carcinoma adjacent cirrhosis tissues were classified to hepatocellular carcinoma. For surgical resection specimens, 99.7% of 733 hepatocellular carcinoma specimens were correctly classified to hepatocellular carcinoma, while 96.1% of 254 hepatocellular carcinoma adjacent cirrhosis tissues and 95.9% of 538 hepatocellular carcinoma adjacent normal tissues were classified to hepatocellular carcinoma. In contrast, 17.0% of 47 cirrhosis from non-hepatocellular carcinoma patients waiting for liver transplantation were classified to hepatocellular carcinoma, indicating that some patients with long-lasting cirrhosis could have already gained hepatocellular carcinoma characteristics. The signature can distinguish both hepatocellular carcinoma tissues and tumour-adjacent tissues from cirrhosis tissues of non-hepatocellular carcinoma patients even using inaccurately sampled biopsy specimens, which can aid early

The overexpression and prognostic role of DCAF13 in hepatocellular carcinoma.

PubMed

Cao, Jianzhong; Hou, Pengjiao; Chen, Jiemin; Wang, Penghui; Wang, Wenqin; Liu, Wei; Liu, Changzheng; He, Xiaodong

2017-06-01

DDB1 and CUL4 associated factor 13 (DCAF13) is a protein coding gene located on chromosome 8q22.3, which is a hotspot amplified in various cancers. DCAF13 has been reported to be frequently amplified in breast cancer patients. However, the genetic alteration and potential role of DCAF13 in other cancers, including hepatocellular carcinoma, have not been investigated yet. In this study, we found that DCAF13 was amplified in 14.7% of the cases and its expression was upregulated (p < 0.001) in hepatocellular carcinoma samples in The Cancer Genome Atlas dataset. Increased expression of DCAF13 was also noticed in 40 paired hepatocellular carcinoma and adjacent non-tumor tissues both at messenger RNA and protein levels (p = 0.0002 and 0.0016, respectively). A positive relationship was observed between augmented DCAF13 levels and poorer tumor grade (p = 0.005), and we also found that hepatocellular carcinoma patients with increased DCAF13 expression in their tumors had significantly poorer survival compared with those with decreased DCAF13 expression (median survival time: 45.73 and 70.53 months, respectively). Multivariate Cox regression analysis showed that DCAF13 was an independent prognostic predictor of survival in hepatocellular carcinoma patients. Gene ontology and Kyoto Encyclopedia of Genes and genomes analysis indicated the potential role of DCAF13 as a crucial cell cycle regulator. Collectively, our findings revealed that the overexpression of DCAF13 in hepatocellular carcinoma was significantly associated with poor survival and may participate in the regulation of cell cycle progression.

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. Copyright © 2016 Elsevier Inc. All rights reserved.

Serine/arginine rich splicing factor 2 expression and clinic pathological features indicating a prognostic factor in human hepatocellular carcinoma patients.

PubMed

Wang, Pingan; Guo, Lingyu; Li, Kaipeng; Ning, Shanglei; Shi, Weichen; Liu, Zhaochen; Chen, Yuxin

2018-02-14

This research was aimed to study the expression of Serine/arginine rich splicing factor 2 (SRSF2) in tissues of hepatocellular carcinoma, and explore the relationship between the expression and the clinic pathological and prognosis of human hepatocellular carcinoma (HCC). One hundred and fifty-three pairs HCC tissues and adjacent normal tissue were collected from January 2010 to March 2013. The expression of SRSF2 gene was detected by immunohistochemistry, western blotting and real-time quantitative polymerase chain reaction (PCR), and the relationship between the expression and the clinic pathological and prognosis of HCC being analyzed. In 153 cases of hepatocellular carcinoma, SRSF2 was highly expressed in 93 cases, low expression of 60 cases, immunohistochemistry score (6.50 ± 2.82), which was significantly higher than that in adjacent normal tissues (2.94 ± 1.23) (P< 0.05). The expression of SRSF2 in HCC was not associated with gender (χ2= 0.014, P= 0.906), age (χ2= 0.007, P= 0.931), tumor size (χ2= 3.566, P= 0.059) and T stage (χ2= 2.708, P= 0.100), and was significantly correlated with tumor differentiation (χ2= 9.687, P= 0.007), lymph node metastasis (χ2= 4.827, P= 0.028), distal metastasis (χ2= 9.235, P= 0.002), tumor, node, metastasis (TNM) stage (χ2= 3.978, P= 0.046), portal vein invasion and serum alpha-fetoprotein (χ2= 14.919, P= 0.000). The expression of SRSF2 protein in hepatocellular carcinoma was positively correlated (r = 0.704, P< 0.05) with serum alpha-fetoprotein through Pearson analysis. The survival rates of SRSF2 overexpressing hepatocellular carcinoma were 74.19%, 44.09%, 26.88%, 24.73% and 21.51% at 1 year, 2 years, 3 years, 4 years and 5 years respectively, which were lower than those of SRSF2 low expression group (93.33%, 71.67%, 56.67%, 51.67% and 50.00%). SRSF2 is highly expressed in hepatocellular carcinoma and its expression increases with the degree of tumor differentiation and TNM staging. It is related to lymph node

High MRPS23 expression contributes to hepatocellular carcinoma proliferation and indicates poor survival outcomes.

PubMed

Pu, Meng; Wang, Jianlin; Huang, Qike; Zhao, Ge; Xia, Congcong; Shang, Runze; Zhang, Zhuochao; Bian, Zhenyuan; Yang, Xishegn; Tao, Kaishan

2017-07-01

Hepatocellular carcinoma is one of the most prevalent neoplasms and the leading cause of cancer-related mortality worldwide. Mitochondrial ribosomal protein S23 is encoded by a nuclear gene and participates in mitochondrial protein translation. Mitochondrial ribosomal protein S23 overexpression has been found in many types of cancer. In this study, we explored mitochondrial ribosomal protein S23 expression in primary hepatocellular carcinoma tissues compared with matched adjacent non-tumoral liver tissues using mitochondrial ribosomal protein S23 messenger RNA and protein levels collected from public databases and clinical samples. Immunohistochemistry was performed to analyze the relationship between mitochondrial ribosomal protein S23 and various clinicopathological features. The results indicated that mitochondrial ribosomal protein S23 was significantly overexpressed in hepatocellular carcinoma. High mitochondrial ribosomal protein S23 expression was correlated with the tumor size and tumor-metastasis-node stage. Moreover, patients with high mitochondrial ribosomal protein S23 expression levels presented poorer survival rates. Mitochondrial ribosomal protein S23 was an independent prognostic factor for survival, especially at the early stage of hepatocellular carcinoma. In addition, the downregulation of mitochondrial ribosomal protein S23 decreased the proliferation of hepatocellular carcinoma in vitro and in vivo. In conclusion, we verified for the first time that mitochondrial ribosomal protein S23 expression was upregulated in hepatocellular carcinoma. High mitochondrial ribosomal protein S23 levels can predict poor clinical outcomes in hepatocellular carcinoma, and this protein plays a key role in tumor proliferation. Therefore, mitochondrial ribosomal protein S23 may be a potential therapeutic target for hepatocellular carcinoma.

Synergistic effect of oral corticosteroids use on risk of hepatocellular carcinoma in high risk populations.

PubMed

Lai, Shih-Wei; Lin, Cheng-Li; Liao, Kuan-Fu

2018-06-01

Little evidence is available on the relationship between oral corticosteroids use and hepatocellular carcinoma. The objective of this study was to investigate whether oral corticosteroids use correlates with the risk of hepatocellular carcinoma in high risk populations in Taiwan. Using representative claims database established from the Taiwan National Health Insurance Program with a population coverage rate of 99.6%, we identified 102,182 subjects aged 20-84 years with newly diagnosed hepatocellular carcinoma in 2000-2011 as the cases and 102,182 randomly selected subjects aged 20-84 years without hepatocellular carcinoma as the matched controls. In subjects with any one of comorbidities including alcohol-related disease, chronic liver disease, and diabetes mellitus, the adjusted OR of hepatocellular carcinoma was 29.9 (95% CI 28.7, 31.1) for subjects with never use of oral corticosteroids, and the adjusted OR would increase to 33.7 (95% CI 32.3, 35.3) for those with ever use of oral corticosteroids. The adjusted OR of hepatocellular carcinoma was 1.03 for subjects with increasing cumulative duration of oral corticosteroids use for every one year (95% CI 1.01, 1.06), with a duration-dependent effect. The largest OR occurred in subjects with ever use of oral corticosteroids and concurrently comorbid with alcohol-related disease, chronic liver disease, and diabetes mellitus (adjusted OR 122.7, 95% CI 108.5, 138.8). There is a synergistic effect between oral corticosteroids use and the traditional risk factors on the risk of hepatocellular carcinoma. People with risk factors for hepatocellular carcinoma should receive regular ultrasound surveillance, particularly when they currently use oral corticosteroids. Copyright © 2018 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

Overexpression of Cullin7 is associated with hepatocellular carcinoma progression and pathogenesis.

PubMed

An, Jun; Zhang, Zhigang; Liu, Zhiyong; Wang, Ruizhi; Hui, Dayang; Jin, Yi

2017-12-06

Overexpression of Cullin7 is associated with some types of malignancies. However, the part of Cullin7 in hepatocellular carcinoma remains unclear. The aim of this study was to investigate the role of Cullin7 in pathogenesis and the progression of hepatocellular carcinoma. In the present study, the expression of Cullin7 in hepatocellular carcinoma cell lines and five surgical hepatocellular carcinoma specimens was detected with quantitative reverse transcription PCR and western blotting. In addition, the protein expression of Cullin7 was examined in 162 cases of archived hepatocellular carcinoma using immunohistochemistry. We found elevated expression of both mRNA and protein levels of Cullin7 in hepatocellular carcinoma cell lines, and Cullin7 protein was significantly upregulated in hepatocellular carcinoma compared with paired normal hepatic tissues. The immunohistochemistry analysis revealed that overexpression of Cullin7 occurred in 69.1% of hepatocellular carcinoma samples, which was a significantly higher rate than that in adjacent normal hepatic tissue (P < 0.01). Statistical analysis found that overexpression of Cullin7 was significantly associated with lymph node metastasis, tumor thrombus of the portal vein and advanced clinical stage (P < 0.05). Furthermore, by overexpressing Cullin7 in hepatocellular carcinoma HepG2 cells, we revealed that Cullin7 could significantly enhance cell proliferation, growth, migration and invasion. Conversely, knocking down Cullin7 expression with short hairpin RNAi in hepatocellular carcinoma HepG2 cells inhibited cell proliferation, growth, migration and invasion. Our studies provide evidence that overexpression of Cullin7 plays an important role in the pathogenesis and progression of hepatocellular carcinoma and may be a valuable marker for hepatocellular carcinoma management.

Atypical regulators of Wnt/β-catenin signaling as potential therapeutic targets in Hepatocellular Carcinoma.

PubMed

Chen, Jianxiang; Rajasekaran, Muthukumar; Hui, Kam M

2017-06-01

Hepatocellular carcinoma is one of the most common causes of cancer-related death worldwide. Hepatocellular carcinoma development depends on the inhibition and activation of multiple vital pathways, including the Wnt signaling pathway. The Wnt/β-catenin pathway lies at the center of various signaling pathways that regulate embryonic development, tissue homeostasis and cancers. Activation of the Wnt/β-catenin pathway has been observed frequently in hepatocellular carcinoma. However, activating mutations in β-catenin, Axin and Adenomatous Polyposis Coli only contribute to a portion of the Wnt signaling hyper-activation observed in hepatocellular carcinoma. Therefore, besides mutations in the canonical Wnt components, there must be additional atypical regulation or regulators during Wnt signaling activation that promote liver carcinogenesis. In this mini-review, we have tried to summarize some of these well-established factors and to highlight some recently identified novel factors in the Wnt/β-catenin signaling pathway in hepatocellular carcinoma. Impact statement Early recurrence of human hepatocellular carcinoma (HCC) is a frequent cause of poor survival after potentially curative liver resection. Among the deregulated signaling cascades in HCC, evidence indicates that alterations in the Wnt/β-catenin signaling pathway play key roles in hepatocarcinogenesis. In this review, we summarize the potential molecular mechanisms how the microtubule-associated Protein regulator of cytokinesis 1 (PRC1), a direct Wnt signaling target previously identified in our laboratory to be up-regulated in HCC, in promoting cancer proliferation, stemness, metastasis and tumorigenesis through a complex regulatory circuitry of Wnt3a activities.

Resected Hepatocellular Carcinoma in a Patient with Crohn's Disease on Azathioprine

PubMed Central

Heron, Valérie; Fortinsky, Kyle Joshua; Spiegle, Gillian; Hilzenrat, Nir; Szilagyi, Andrew

2016-01-01

Hepatocellular carcinoma rarely occurs in patients without underlying cirrhosis or liver disease. While inflammatory bowel disease has been linked to certain forms of liver disease, hepatocellular carcinoma is exceedingly rare in these patients. We report the twelfth case of hepatocellular carcinoma in a patient with Crohn's disease. The patient is a 61-year-old with longstanding Crohn's disease who was treated with azathioprine and was found to have elevated liver enzymes and a new 3-cm liver mass on ultrasound. A complete workup for underlying liver disease was unremarkable and liver biopsy revealed hepatocellular carcinoma. The patient underwent a hepatic resection, and there is no evidence of recurrence at the 11-month follow-up. The resection specimen showed no evidence of cancer despite the initial biopsy revealing hepatocellular carcinoma. This case represents the third biopsy-proven complete spontaneous regression of hepatocellular carcinoma. Although large studies have failed to show a definite link between azathioprine and hepatocellular carcinoma, the relationship remains concerning given the multiple case reports suggesting a possible association. Clinicians should exercise a high degree of suspicion in patients with Crohn's disease who present with elevated liver enzymes, especially those on azathioprine therapy. PMID:27403102

Treatment of hepatocellular carcinoma with portal vein tumor thrombus: advances and challenges.

PubMed

Jiang, Jin-Fang; Lao, Yong-Cong; Yuan, Bao-Hong; Yin, Jun; Liu, Xin; Chen, Long; Zhong, Jian-Hong

2017-05-16

Portal vein tumor thrombus is a frequent, challenging complication in hepatocellular carcinoma. Hepatocellular carcinoma patients with portal vein tumor thrombus may show worse liver function, less treatment tolerance and worse prognosis than patients without portal vein tumor thrombus, and they may be at higher risk of comorbidity related to portal hypertension. Western and some Asian guidelines stratify hepatocellular carcinoma with portal vein tumor thrombus together with metastatic hepatocellular carcinoma and therefore recommend only palliative treatment with sorafenib or other systemic agents. In recent years, more treatment options have become available for hepatocellular carcinoma patients with portal vein tumor thrombus, and an evidence-based approach to optimizing disease management and treatment has become more widespread. Nevertheless, consensus policies for managing hepatocellular carcinoma with portal vein tumor thrombus have not been established. This comprehensive literature review, drawing primarily on studies published after 2010, examines currently available management options for patients with hepatocellular carcinoma and portal vein tumor thrombus.

An atypical age-specific pattern of hepatocellular carcinoma in Peru: a threat for Andean populations.

PubMed

Bertani, Stéphane; Pineau, Pascal; Loli, Sebastian; Moura, Julien; Zimic, Mirko; Deharo, Eric; Ruiz, Eloy

2013-01-01

In South America, the highest incidence of primary liver cancer is observed in Peru. However, national estimations on hepatocellular carcinoma incidence and mortality are approximated using aggregated data from surrounding countries. Thus, there is a lack of tangible information from Peru that impairs an accurate description of the local incidence, presentation, and outcomes of hepatocellular carcinoma. The present study attempts to fill this gap and assesses the clinical epidemiology of hepatocellular carcinoma in this country. A retrospective cohort study was conducted by analysing the medical charts of 1,541 patients with hepatocellular carcinoma admitted between 1997 and 2010 at the Peruvian national institute for cancer. The medical records including liver function, serologic status, and tumor pathology and stage were monitored. Statistical analyses were performed in order to characterize tumor presentation according to demographic features, risk factors, and regional origin. Surprisingly, the age distribution of the patient population displayed bimodality corresponding to two distinct age-based subpopulations. While an older group was in keeping with the age range observed for hepatocellular carcinoma around the world, a younger population displayed an abnormally juvenile mean age of 25.5 years old. In addition, each subpopulation displayed age-specific pathophysiological and clinical characteristics. The analysis suggests two different age-specific natural histories of hepatocellular carcinoma in the Peruvian patient population. This otherwise unusual tumor process that is ongoing in younger patients leads to the hypothesis that there may be a Peru-endemic risk factor driving hepatocarcinogenesis in the local population.

Histopathology of hepatocellular carcinoma.

PubMed

Schlageter, Manuel; Terracciano, Luigi Maria; D'Angelo, Salvatore; Sorrentino, Paolo

2014-11-21

Hepatocellular carcinoma (HCC) is currently the sixth most common type of cancer with a high mortality rate and an increasing incidence worldwide. Its etiology is usually linked to environmental, dietary or life-style factors. HCC most commonly arises in a cirrhotic liver but interestingly an increasing proportion of HCCs develop in the non-fibrotic or minimal fibrotic liver and a shift in the underlying etiology can be observed. Although this process is yet to be completely understood, this changing scenario also has impact on the material seen by pathologists, presenting them with new diagnostic dilemmas. Histopathologic criteria for diagnosing classical, progressed HCC are well established and known, but with an increase in detection of small and early HCCs due to routine screening programs, the diagnosis of these small lesions in core needle biopsies poses a difficult challenge. These lesions can be far more difficult to distinguish from one another than progressed HCC, which is usually a clear cut hematoxylin and eosin diagnosis. Furthermore lesions thought to derive from progenitor cells have recently been reclassified in the WHO. This review summarizes recent developments and tries to put new HCC biomarkers in context with the WHOs reclassification. Furthermore it also addresses the group of tumors known as combined hepatocellular-cholangiocellular carcinomas.

Efficacy and Tolerability of ABT-869 Versus Sorafenib in Advanced Hepatocellular Carcinoma (HCC)

ClinicalTrials.gov

2012-09-07

Hepatocellular Carcinoma Non-resectable; Hepatocellular Carcinoma Recurrent; Carcinoma, Hepatocellular; Liver Diseases; Neoplasms by Histologic Type; Digestive System Neoplasms; Carcinoma; Liver Neoplasms; Neoplasms; Neoplasms by Site; Digestive System Diseases; Adenocarcinoma; Neoplasms, Glandular and Epithelial

The evolutionary scenario of hepatocellular carcinoma in Italy: an update.

PubMed

Bucci, Laura; Garuti, Francesca; Lenzi, Barbara; Pecorelli, Anna; Farinati, Fabio; Giannini, Edoardo G; Granito, Alessandro; Ciccarese, Francesca; Rapaccini, Gian Lodovico; Di Marco, Maria; Caturelli, Eugenio; Zoli, Marco; Borzio, Franco; Sacco, Rodolfo; Cammà, Calogero; Virdone, Roberto; Marra, Fabio; Felder, Martina; Morisco, Filomena; Benvegnù, Luisa; Gasbarrini, Antonio; Svegliati-Baroni, Gianluca; Foschi, Francesco Giuseppe; Missale, Gabriele; Masotto, Alberto; Nardone, Gerardo; Colecchia, Antonio; Bernardi, Mauro; Trevisani, Franco

2017-02-01

Epidemiology of hepatocellular carcinoma is changing worldwide. This study aimed at evaluating the changing scenario of aetiology, presentation, management and prognosis of hepatocellular carcinoma in Italy during the last 15 years. Retrospective analysis of the ITA.LI.CA (Italian Liver Cancer) database including 5192 hepatocellular carcinoma patients managed in 24 centres from 2000 to 2014. Patients were divided into three groups according to the date of cancer diagnosis (2000-2004, 2005-2009 and 2010-2014). The main results were as follows: (i) progressive patient aging; (ii) progressive expansion of non-viral cases and, namely, of "metabolic" hepatocellular carcinomas; (iii) increasing proportion of hepatocellular carcinoma diagnosed during a correct (semi-annual) surveillance programme; (iv) favourable cancer stage migration; (v) increased use of radiofrequency ablation to the detriment of percutaneous ethanol injection; (vi) improved outcomes of ablative and transarterial treatments; (vii) improved overall survival (adjusted for the lead time in surveyed patients), particularly after 2009, of both viral and non-viral patients presenting with an early- or intermediate-stage hepatocellular carcinoma. During the last 15 years several aetiological and clinical features of hepatocellular carcinoma patients have changed, as their management. The observed improvement of overall survival was owing both to the wider use of semi-annual surveillance, expanding the proportion of tumours that qualified for curative treatments, and to the improved outcome of loco-regional treatments. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The changing epidemiology and aetiology of hepatocellular carcinoma from 1969 through 2013 in Alaska Native people.

PubMed

Connelly, Marc; Bruce, Michael G; Bulkow, Lisa; Snowball, Mary; McMahon, Brian J

2016-12-01

Alaska Native people have an increased rate of hepatocellular carcinoma compared to the United States population. Viral hepatitis is a risk factor for malignancy and the leading cause of hepatocellular carcinoma in Alaska. With the introduction of hepatitis B immunization in 1982, as well as the emergence of hepatitis C virus in this population, the epidemiology and aetiology of hepatocellular carcinoma in Alaska have changed. Using the Alaska Native Tumor Registry, all cases of viral and non-viral hepatocellular carcinoma occurring from 1969 through 2013 were identified and reviewed. Incidence rates per 100 000 population were calculated for hepatocellular carcinoma overall and by aetiological category. One hundred and fifty-two cases of hepatocellular carcinoma were identified in 148 Alaska Native persons. Overall tumour rate was 3.82 per 100 000 and did not change significantly over the study period. Hepatitis B-associated cases decreased significantly over the study period (P = 0.048) and were eliminated in persons under the age of 20. Hepatitis C-associated cases increased significantly (P < 0.001). Undetermined hepatocellular carcinoma rates also decreased (P = 0.034). Overall hepatocellular carcinoma rates in Alaska Native people remained stable over the study period, but the epidemiology and aetiology are changing. Two decades after routine hepatitis B immunization, the hepatocellular carcinoma age distribution has shifted to cases presenting later in life. This is consistent with an ageing hepatitis B-infected population with no new infected young persons' coming into the population, as well as the emergence of hepatitis C in adults. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Protein arginine N-methyltransferase 1 promotes the proliferation and metastasis of hepatocellular carcinoma cells.

PubMed

Gou, Qing; He, ShuJiao; Zhou, ZeJian

2017-02-01

Hepatocellular carcinoma is the most common subtype of liver cancer. Protein arginine N-methyltransferase 1 was shown to be upregulated in various cancers. However, the role of protein arginine N-methyltransferase 1 in hepatocellular carcinoma progression remains incompletely understood. We investigated the clinical and functional significance of protein arginine N-methyltransferase 1 in a series of clinical hepatocellular carcinoma samples and a panel of hepatocellular carcinoma cell lines. We performed suppression analysis of protein arginine N-methyltransferase 1 using small interfering RNA to determine the biological roles of protein arginine N-methyltransferase 1 in hepatocellular carcinoma. In addition, the expression of epithelial-mesenchymal transition indicators was verified by western blotting in hepatocellular carcinoma cell lines after small interfering RNA treatment. Protein arginine N-methyltransferase 1 expression was found to be significantly upregulated in hepatocellular carcinoma cell lines and clinical tissues. Moreover, downregulation of protein arginine N-methyltransferase 1 in hepatocellular carcinoma cells by small interfering RNA could inhibit cell proliferation, migration, and invasion in vitro. These results indicate that protein arginine N-methyltransferase 1 may contribute to hepatocellular carcinoma progression and serves as a promising target for the treatment of hepatocellular carcinoma patients.

Long non-coding RNA CASC2 regulates cell biological behaviour through the MAPK signalling pathway in hepatocellular carcinoma.

PubMed

Gan, Yuanyuan; Han, Nana; He, Xiaoqin; Yu, Jiajun; Zhang, Meixia; Zhou, Yujie; Liang, Huiling; Deng, Junjian; Zheng, Yongfa; Ge, Wei; Long, Zhixiong; Xu, Ximing

2017-06-01

Long non-coding RNAs have previously been demonstrated to play important roles in regulating human diseases, especially cancer. However, the biological functions and molecular mechanisms of long non-coding RNAs in hepatocellular carcinoma have not been extensively studied. The long non-coding RNA CASC2 (cancer susceptibility candidate 2) has been characterised as a tumour suppressor in endometrial cancer and gliomas. However, the role and function of CASC2 in hepatocellular carcinoma remain unknown. In this study, using quantitative real-time polymerase chain reaction, we confirmed that CASC2 expression was downregulated in 50 hepatocellular carcinoma cases (62%) and in hepatocellular carcinoma cell lines compared with the paired adjacent tissues and normal liver cells. In vitro experiments further demonstrated that overexpressed CASC2 decreased hepatocellular carcinoma cell proliferation, migration and invasion as well as promoted apoptosis via inactivating the mitogen-activated protein kinase signalling pathway. Our findings demonstrate that CASC2 could be a useful tumour suppressor factor and a promising therapeutic target for hepatocellular carcinoma.

An Atypical Age-Specific Pattern of Hepatocellular Carcinoma in Peru: A Threat for Andean Populations

PubMed Central

Loli, Sebastian; Moura, Julien; Zimic, Mirko; Deharo, Eric; Ruiz, Eloy

2013-01-01

Background In South America, the highest incidence of primary liver cancer is observed in Peru. However, national estimations on hepatocellular carcinoma incidence and mortality are approximated using aggregated data from surrounding countries. Thus, there is a lack of tangible information from Peru that impairs an accurate description of the local incidence, presentation, and outcomes of hepatocellular carcinoma. The present study attempts to fill this gap and assesses the clinical epidemiology of hepatocellular carcinoma in this country. Methods A retrospective cohort study was conducted by analysing the medical charts of 1,541 patients with hepatocellular carcinoma admitted between 1997 and 2010 at the Peruvian national institute for cancer. The medical records including liver function, serologic status, and tumor pathology and stage were monitored. Statistical analyses were performed in order to characterize tumor presentation according to demographic features, risk factors, and regional origin. Results Surprisingly, the age distribution of the patient population displayed bimodality corresponding to two distinct age-based subpopulations. While an older group was in keeping with the age range observed for hepatocellular carcinoma around the world, a younger population displayed an abnormally juvenile mean age of 25.5 years old. In addition, each subpopulation displayed age-specific pathophysiological and clinical characteristics. Conclusions The analysis suggests two different age-specific natural histories of hepatocellular carcinoma in the Peruvian patient population. This otherwise unusual tumor process that is ongoing in younger patients leads to the hypothesis that there may be a Peru-endemic risk factor driving hepatocarcinogenesis in the local population. PMID:23840771

Transforming Growth Factor-β Drives the Transendothelial Migration of Hepatocellular Carcinoma Cells.

PubMed

Koudelkova, Petra; Costina, Victor; Weber, Gerhard; Dooley, Steven; Findeisen, Peter; Winter, Peter; Agarwal, Rahul; Schlangen, Karin; Mikulits, Wolfgang

2017-10-10

The entry of malignant hepatocytes into blood vessels is a key step in the dissemination and metastasis of hepatocellular carcinoma (HCC). The identification of molecular mechanisms involved in the transmigration of malignant hepatocytes through the endothelial barrier is of high relevance for therapeutic intervention and metastasis prevention. In this study, we employed a model of hepatocellular transmigration that mimics vascular invasion using hepatic sinusoidal endothelial cells and malignant hepatocytes evincing a mesenchymal-like, invasive phenotype by transforming growth factor (TGF)-β. Labelling of respective cell populations with various stable isotopes and subsequent mass spectrometry analyses allowed the "real-time" detection of molecular changes in both transmigrating hepatocytes and endothelial cells. Interestingly, the proteome profiling revealed 36 and 559 regulated proteins in hepatocytes and endothelial cells, respectively, indicating significant changes during active transmigration that mostly depends on cell-cell interaction rather than on TGF-β alone. Importantly, matching these in vitro findings with HCC patient data revealed a panel of common molecular alterations including peroxiredoxin-3, epoxide hydrolase, transgelin-2 and collectin 12 that are clinically relevant for the patient's survival. We conclude that hepatocellular plasticity induced by TGF-β is crucially involved in blood vessel invasion of HCC cells.

Expanded Criteria for Hepatocellular Carcinoma in Liver Transplant.

PubMed

Haberal, Mehmet; Akdur, Aydıncan; Moray, Gökhan; Arslan, Gülnaz; Özçay, Figen; Selçuk, Haldun; Özdemir, Handan

2017-03-01

Hepatocellular carcinoma is the sixth most common cancer worldwide and is the third highest cause of malignancy-related death. Because of its typically late diagnosis, median survival is approximately 6 to 20 months, with 5-year survival of < 12%. Hepatocellular carcinoma typically arises in the background of cirrhosis, with liver transplant regarded as the optimal therapy for selected patients. Initially, orthotopic liver transplant was limited to patients with extensive unresectable tumors, resulting in uniformly dismal outcomes due to high tumor recurrence rates. Here, we evaluated our long-term results with expanded-criteria liver transplant. From December 1988 to January 2017, we performed 552 liver transplants at Baskent University. In candidates with hepatocellular carcinoma, our expanded criteria for liver transplant is applied regardless of tumor size and number, includes those without major vascular invasion and without distant metastasis, and those with negative cytology (if the patient has ascites). Since 1994, of 61 liver transplants for hepatocellular carcinoma, 36 patients received transplants according to our expanded criteria. Of 36 expanded-criteria patients, 11 were children and 25 were adults. Sixteen patients (4 pediatric, 12 adult) were within our expanded criteria both radiologically and pathologically before transplant. The other 20 patients (7 pediatric, 13 adult) were within Milan criteria radiologically before transplant; however, after liver transplant, when pathologic specimens were evaluated, patients were found to be within our center's expanded criteria. During follow-up, 9/36 patients (25%) had hepatocellular carcinoma recurrence. In pediatric patients, 5-year and 10-year survival rates were 90%; in adults, 5-year survival was 58.7% and 10-year survival was 49.7%. Overall 5-year and 10-year survival rates were 71.7% and 62.7%. Liver transplant is safe and effective in patients with hepatocellular carcinoma in combination with

Rottlerin upregulates DDX3 expression in hepatocellular carcinoma.

PubMed

Wang, Zhong; Shen, Gen-Hai; Xie, Jia-Ming; Li, Bin; Gao, Quan-Gen

2018-01-01

Rottlerin has been reported to exert its anti-tumor activity in various types of human cancers. However, the underlying molecular mechanism has not been fully elucidated. In the current study, we explored whether rottlerin exhibits its tumor suppressive function in hepatocellular carcinoma cells. Our MTT assay results showed that rottlerin inhibited cell growth in hepatocellular carcinoma cells. Moreover, we found that rottlerin induced cell apoptosis and caused cell cycle arrest at G1 phase. Furthermore, our wound healing assay result demonstrated that rottlerin retarded cell migration in hepatocellular carcinoma cells. Additionally, rottlerin suppressed cell migration and invasion. Notably, we found that rottlerin upregulated DDX3 expression and subsequently downregulated Cyclin D1 expression and increased p21 level. Importantly, down-regulation of DDX3 abrogated the rottlerin-mediated tumor suppressive function, whereas overexpression of DDX3 promoted the anti-tumor activity of rottlerin. Our study suggests that rottlerin exhibits its anti-cancer activity partly due to upregulation of DDX3 in hepatocellular carcinoma cells. Copyright © 2017 Elsevier Inc. All rights reserved.

SERUM LEPTIN LEVENS AND HEPATOCELLULAR CARCINOMA: REVIEW ARTICLE.

PubMed

Andrighetto, Luiza Vitelo; Poziomyck, Aline Kirjner

2016-01-01

Hepatocellular carcinoma is one of the most frequent types of malignant tumors in the world. There is growing evidence of the relationship between it development and obesity. The mechanism that links obesity to cancer is still not fully understood; however, it is essential to the understanding the adipose tissue in metabolic changes related to obesity and hepatocellular carcinoma. To review the influence of serum leptin levels in patients with hepatocelular carcinoma. Systematic review of the literature based on the methodology of the Cochrane Institute. The search for articles was in the database: Science Direct, Scielo, Medline, Lilacs e Pubmed. The key words used were hepatocellular carcinoma, leptin, adipokine. After evaluation of individual studies, were selected seven studies. The results previously studied are still inconsistent and contradictory, and leptin can be effectively involved in the occurrence and development of hepatocellular carcinoma. Therefore, it is necessary to develop prospective, well-designed and conducted focusing on the role and specific mechanisms of this hormone in patients with hepatocellular carcinoma, so that new correlations can be properly supported. O carcinoma hepatocelular é um dos tipos mais frequentes de tumores malignos no mundo. Há crescentes evidências da relação entre o seu desenvolvimento e a obesidade. O mecanismo que os relaciona ainda não é completamente entendido. Entretanto é essencial a compreensão do tecido adiposo nas alterações metabólicas relacionadas à obesidade e ao câncer. Revisar a influência dos níveis séricos de leptina em pacientes com carcinoma hepatocelular. Trata-se de revisão bibliográfica baseada na metodologia do Instituto Cochrane; a busca de dados foi realizada na base de dados Science Direct, Scielo, Medline, Lilacs e Pubmed, empregando as seguintes descritores: hepatocellular carcinoma, leptin, adipokine. Após avaliação individual dos artigos selecionaram-se sete estudos

Androgen associated hepatocellular carcinoma with an aggressive course.

PubMed Central

Gleeson, D; Newbould, M J; Taylor, P; McMahon, R F; Leahy, B C; Warnes, T W

1991-01-01

The hepatocellular carcinomas that develop in patients treated with androgens have previously been associated with a benign clinical outcome. We describe a man who developed a hepatocellular carcinoma after 24 years of androgen treatment, whose tumour initially showed partial regression after withdrawal of androgens but subsequently pursued an aggressive and fatal course. Images Figure 1 Figure 2 PMID:1655591

Linc-POU3F3 is overexpressed in hepatocellular carcinoma and regulates cell proliferation, migration and invasion.

PubMed

Li, Yichun; Li, Yannan; Wang, Dan; Meng, Qingdong

2018-06-12

Linc-POU3F3 showed an up-regulated tendency and functioned as tumor promoter in glioma, esophageal cancer and colorectal cancer. There was no report about the expression pattern and clinical value of linc-POU3F3 in hepatocellular carcinoma. Thus, the purpose of our study is to explore the clinical significance and biological role of linc-POU3F3 in hepatocellular carcinoma. Our results suggested that levels of linc-POU3F3 were dramatically increased in hepatocellular carcinoma tissues and cell lines compared with paired normal hepatic tissues and normal hepatic cell line, respectively. Levels of linc-POU3F3 were positively correlated with clinical stage, tumor size, vascular invasion and metastasis. Moreover, high-expression of linc-POU3F3 was an independent prognostic factor for hepatocellular carcinoma patients. The gain- and loss-of-function experiments showed that linc-POU3F3 expression significantly promoted tumor cell proliferation, migration and invasion. In addition, linc-POU3F3 expression was negatively correlated with POU3F3 mRNA and protein expressions in hepatocellular carcinoma tissues, and negatively regulated POU3F3 mRNA and protein expressions in hepatocellular carcinoma cells. In conclusion, our study supports the first evidence that linc-POU3F3 plays an oncogenic role in hepatocellular carcinoma, and represents a potential therapeutic strategy for hepatocellular carcinoma patients. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Metformin confers risk reduction for developing hepatocellular carcinoma recurrence after liver resection.

PubMed

Chan, Kun-Ming; Kuo, Chang-Fu; Hsu, Jun-Te; Chiou, Meng-Jiun; Wang, Yu-Chao; Wu, Tsung-Han; Lee, Chen-Fang; Wu, Ting-Jung; Chou, Hong-Shiue; Lee, Wei-Chen

2017-03-01

Hepatocellular carcinoma recurrence following liver resection remains a great concern. The study aims to examine the chemopreventive effect of metformin in patients undergoing liver resection for hepatocellular carcinoma from a population-based study. All patients registered as having hepatocellular carcinoma between January 1995 and December 2011 in a nationwide database were retrospectively analysed. Outcomes related to liver resection and the presence of diabetes mellitus were assessed. Prognosis in terms of the use of metformin was further explored, in which only patients in the long-term follow-up starting at 2 years were included for analysis. Patients with diabetes mellitus had a significantly poorer outcome than patients without diabetes mellitus. Among diabetes mellitus patients, metformin users had significantly better survival curves in both recurrence-free survival (P<.0001) and overall survival (P<.0001) after liver resection. The hazard ratio of metformin use in hepatocellular carcinoma patients with diabetes mellitus was 0.65 (P<.05, 95% CI=0.60-0.72) for hepatocellular carcinoma recurrence and 0.79 (P<.05, 95% CI=0.72-0.88) for overall survival after liver resection. The risk reduction in hepatocellular carcinoma recurrence after liver resection was significantly associated with a dose/duration dependent of accumulated metformin usage. Diabetes mellitus has an adverse effect on patients with hepatocellular carcinoma regardless of treatment modality. The use of metformin significantly reduces the risk of hepatocellular carcinoma recurrence and improves the overall outcome of patients after liver resection if patients survives the initial 2 years. Nonetheless, a prospective controlled study is recommended for validating the metformin use on preventing postoperative hepatocellular carcinoma recurrence. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

An Ecological Study of the Association between Air Pollution and Hepatocellular Carcinoma Incidence in Texas.

PubMed

Cicalese, Luca; Raun, Loren; Shirafkan, Ali; Campos, Laura; Zorzi, Daria; Montalbano, Mauro; Rhoads, Colin; Gazis, Valia; Ensor, Katherine; Rastellini, Cristiana

2017-11-01

Primary liver cancer is a significant cause of cancer-related death in both the United States and the world at large. Hepatocellular carcinoma comprises 90% of these primary liver cancers and has numerous known etiologies. Evaluation of these identified etiologies and other traditional risk factors cannot explain the high incidence rates of hepatocellular carcinoma in Texas. Texas is home to the second largest petrochemical industry and agricultural industry in the nation; industrial activity and exposure to pathogenic chemicals have never been assessed as potential links to the state's increased incidence rate of hepatocellular carcinoma. The association between the county-level concentrations of 4 air pollutants known to be linked to liver cancer, vinyl chloride, arsenic, benzene, and 1,3-butadiene, and hepatocellular carcinoma rates was evaluated using nonparametric generalized additive logistic regression and gamma regression models. Hepatocellular carcinoma incidence rates for 2000-2013 were evaluated in comparison to 1996 and 1999 pollution concentrations and hepatocellular carcinoma rates for the subset of 2006-2013 were evaluated in comparison to 2002 and 2005 pollution concentrations, respectively. The analysis indicates that the relationship between the incidence of liver cancer and air pollution and risk factors is nonlinear. There is a consistent significant positive association between the incidence of liver cancer and hepatitis C prevalence rates (gamma all years, p < 0.05) and vinyl chloride concentrations (logistic 2002 and 2005, p < 0.0001; gamma 2002 and 2005, p < 0.05). This study suggests that vinyl chloride is a significant contributor to the incidence of liver cancer in Texas. The relationship is notably nonlinear. Further, the study supports the association between incidence of liver cancer and prevalence of hepatitis B.

[Expression and clinical significance of KIAA1199 in primary hepatocellular carcinoma].

PubMed

Gu, C J; Ni, Q C; Ni, K; Zhang, S; Qian, H X

2018-05-29

Objective: To investigate the expression and clinical significance of KIAA1199 in primary hepatocellular carcinoma. Methods: A total of 136 cases of primary hepatocellular carcinoma tissues and paired adjacent tissues were collected. Immunohistochemistry and Western blot were used to detect the expression of KIAA1199 in primary hepatocellular carcinoma tissues and paired adjacent tissues. The relationship between KIAA1199 and clinicopathological parameter of primary hepatocellular carcinoma was analyzed. Results: The positive rate of KIAA1199 in primary hepatocellular carcinoma was 82.3% (112/136), which was higher than that in paired para-cancerous tissues (14.7%, 20/136). High expression of KIAA1199 was significantly correlated with age, cirrhosis history, tumor size, tumor number, degree of differentiation, TNM staging and microvenous invasion (MVI) ( P <0.05), but without gender, drinking alcohol hobby, hepatitis history, family genetic history, tumor location ( P >0.05). The Kaplan-Meier survival curves indicated that high KIAA1199 expression was associated with poor survival ( P <0.01). In addition, Cox proportional hazards model showed that the expression of KIAA1199 was related to age, cirrhosis history, tumor size, tumor number, degree of differentiation, TNM staging and MVI ( P <0.05). Conclusion: The expression of KIAA1199 is up-regulated in primary hepatocellular carcinoma, which is significantly correlated with the clinicopathological features and prognosis, high expression of KIAA1199 increased the risk of death in patients with primary hepatocellular carcinoma.

Intraoperative ultrasound for prediction of hepatocellular carcinoma biological behaviour: Prospective comparison with pathology.

PubMed

Santambrogio, Roberto; Cigala, Claudia; Barabino, Matteo; Maggioni, Marco; Scifo, Giovanna; Bruno, Savino; Bertolini, Emanuela; Opocher, Enrico; Bulfamante, Gaetano

2018-02-01

Preoperative prediction of both microinvasive hepatocellular carcinoma and histological grade of hepatocellular carcinoma is pivotal to treatment planning and prognostication. The aim of this study was to evaluate whether some intraoperative ultrasound features correlate with both the presence of same histological patterns and differentiation grade of hepatocellular carcinoma on the histological features of the primary resected tumour. All patients with single, small hepatocellular carcinoma that underwent hepatic resection were included in this prospective double-blind study: the intraoperative ultrasound patterns of nodule were registered and compared with similar histological features. A total of 179 patients were enclosed in this study: 97 (54%) patients (34% in HCC ≤2 cm) had a microinvasive hepatocellular carcinoma at ultrasound examination, while 82 (46%) patients (41% in HCC ≤2 cm) at histological evaluation. Statistical analysis showed that diameters ≤2 cm, presence of satellites and microinvasive hepatocellular carcinoma at ultrasound examination were the variables with the strongest association with the histological findings. In the multivariate analysis, the vascular microinfiltration and infiltrative hepatocellular carcinoma aspect were independent predictors for grading. In patients with cirrhosis and hepatocellular carcinoma, the prevalence of microinvasive hepatocellular carcinoma is high, even in cases of HCC ≤2 cm. Intraoperative ultrasound findings strongly correlated with histopathological criteria in detecting microinvasive patterns and are useful to predict neoplastic differentiation. The knowledge of these features prior to treatment are highly desired (this can be obtained by an intraoperative ultrasound examination), as they could help in providing optimal management of patients with hepatocellular carcinoma. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Cerebrovascular Accidents Associated with Sorafenib in Hepatocellular Carcinoma

PubMed Central

Saif, Muhammad W.; Isufi, Iris; Peccerillo, Jennifer; Syrigos, Kostas N.

2011-01-01

Sorafenib is an oral angiogenetic multikinase inhibitor approved in the treatment of renal and hepatocellular carcinoma. Bleeding and venous thrombotic events have been described with angiogenetic agents but cerebrovascular accidents are rarely reported. We report two cases of patients with hepatocellular carcinoma who developed a cerebrovascular accident while on sorafenib. Neither patient had any risk factors for the cerebrovascular events apart from gender and age in the second patient. Laboratory data were noncontributory. The head CT scan did not reveal acute abnormalities. No hemodynamically significant stenosis was visible in the carotid ultrasound, and the echocardiogram showed normal size of the heart chambers and normal systolic function of the left ventricle. Sorafenib was discontinued in both cases. Physicians should monitor patients receiving sorafenib for neurologic symptoms, and in the absence of other etiology, prompt discontinuation of this drug should be considered. PMID:21687621

Cerebrovascular accidents associated with sorafenib in hepatocellular carcinoma.

PubMed

Saif, Muhammad W; Isufi, Iris; Peccerillo, Jennifer; Syrigos, Kostas N

2011-01-01

Sorafenib is an oral angiogenetic multikinase inhibitor approved in the treatment of renal and hepatocellular carcinoma. Bleeding and venous thrombotic events have been described with angiogenetic agents but cerebrovascular accidents are rarely reported. We report two cases of patients with hepatocellular carcinoma who developed a cerebrovascular accident while on sorafenib. Neither patient had any risk factors for the cerebrovascular events apart from gender and age in the second patient. Laboratory data were noncontributory. The head CT scan did not reveal acute abnormalities. No hemodynamically significant stenosis was visible in the carotid ultrasound, and the echocardiogram showed normal size of the heart chambers and normal systolic function of the left ventricle. Sorafenib was discontinued in both cases. Physicians should monitor patients receiving sorafenib for neurologic symptoms, and in the absence of other etiology, prompt discontinuation of this drug should be considered.

GPX2 overexpression indicates poor prognosis in patients with hepatocellular carcinoma.

PubMed

Liu, Ting; Kan, Xue-Feng; Ma, Charlie; Chen, Li-Li; Cheng, Tian-Tian; Zou, Zhen-Wei; Li, Yong; Cao, Feng-Jun; Zhang, Wen-Jie; Yao, Jing; Li, Pin-Dong

2017-06-01

Glutathione peroxidase 2 has important role of tumor progression in lots of carcinomas, yet little is known about the prognosis of glutathione peroxidase 2 in hepatocellular carcinoma. Glutathione peroxidase 2 expression was assessed by immunohistochemistry in hepatocellular carcinoma tissues. The association between glutathione peroxidase 2 expression with clinicopathological/prognostic value was examined. Glutathione peroxidase 2 overexpression was correlated with alpha-fetoprotein level, larger tumor, BCLC stage, and tumor recurrence. Kaplan-Meier analysis showed that glutathione peroxidase 2 was an independent predictor for overall survival and time to recurrence. glutathione peroxidase 2 overexpression was correlated with poor prognosis in patient subgroups stratified by tumor size, differentiation, tumor-node-metastasis, and BCLC stage. Moreover, stratified analysis showed that tumor-node-metastasis stage-I patients with high glutathione peroxidase 2 expression had poor prognosis than those with low glutathione peroxidase 2 expression. Additionally, combination of glutathione peroxidase 2 and serum alpha-fetoprotein was correlated with prognosis in hepatocellular carcinoma. In conclusion, glutathione peroxidase 2 overexpression contributes to poor prognosis of hepatocellular carcinoma patients and helps to identify the high-risk hepatocellular carcinoma patients.

Transforming Growth Factor-β Drives the Transendothelial Migration of Hepatocellular Carcinoma Cells

PubMed Central

Koudelkova, Petra; Costina, Victor; Weber, Gerhard; Dooley, Steven; Findeisen, Peter; Winter, Peter; Agarwal, Rahul; Schlangen, Karin

2017-01-01

The entry of malignant hepatocytes into blood vessels is a key step in the dissemination and metastasis of hepatocellular carcinoma (HCC). The identification of molecular mechanisms involved in the transmigration of malignant hepatocytes through the endothelial barrier is of high relevance for therapeutic intervention and metastasis prevention. In this study, we employed a model of hepatocellular transmigration that mimics vascular invasion using hepatic sinusoidal endothelial cells and malignant hepatocytes evincing a mesenchymal-like, invasive phenotype by transforming growth factor (TGF)-β. Labelling of respective cell populations with various stable isotopes and subsequent mass spectrometry analyses allowed the “real-time” detection of molecular changes in both transmigrating hepatocytes and endothelial cells. Interestingly, the proteome profiling revealed 36 and 559 regulated proteins in hepatocytes and endothelial cells, respectively, indicating significant changes during active transmigration that mostly depends on cell–cell interaction rather than on TGF-β alone. Importantly, matching these in vitro findings with HCC patient data revealed a panel of common molecular alterations including peroxiredoxin-3, epoxide hydrolase, transgelin-2 and collectin 12 that are clinically relevant for the patient’s survival. We conclude that hepatocellular plasticity induced by TGF-β is crucially involved in blood vessel invasion of HCC cells. PMID:28994702

Treatment options after sorafenib failure in patients with hepatocellular carcinoma

PubMed Central

Dika, Imane El

2017-01-01

Second line therapy after failure of sorafenib continues to be under study. Prognosis of hepatocellular carcinoma is measured in months, with median overall survival reaching 10.7 months with sorafenib. Because of the modest net benefit sorafenib has contributed, and rising incidence of hepatocellular carcinoma in the world, continued efforts are ongoing to look for efficient upfront, second line, or combination therapies. Herein we review the most relevant to date published literature on treatment options beyond sorafenib, reported studies, ongoing investigational efforts, and possibilities for future studies in advanced hepatocellular carcinoma. PMID:29151326

Decreased Expression of EHD2 Promotes Tumor Metastasis and Indicates Poor Prognosis in Hepatocellular Carcinoma.

PubMed

Liu, Jinxia; Ni, Wenkai; Qu, Lishuai; Cui, Xiaopeng; Lin, Zhipeng; Liu, Qingqing; Zhou, Huiling; Ni, Runzhou

2016-09-01

Metastasis remains the most common cause of lethal outcomes in hepatocellular carcinoma (HCC) after curative resection. Understanding molecular mechanisms that regulate metastasis process is crucial for improving treatment of hepatocellular carcinoma. In this article, we examined whether Eps15 homology domain-containing 2 (EHD2) played a critical role in hepatocellular carcinoma metastasis and explored the possible mechanism. EHD2 and E-cadherin expression levels in hepatocellular carcinoma patients were examined using Western blotting and immunohistochemistry. The cell migration and invasion were evaluated by wound-healing assay and trans-well assay. Epithelial-mesenchymal transition was analyzed by immunofluorescence, and the vital markers were detected by Western blotting. The correlation of EHD2 and E-cadherin was confirmed by co-immunoprecipitation. EHD2 expression, along with the epithelial marker E-cadherin, was markedly reduced in tumor tissues than in adjacent noncancerous tissues. Moreover, EHD2 was positively correlated with E-cadherin, histological grade, tumor metastasis, and microvascular invasion. Kaplan-Meier survival analysis showed that hepatocellular carcinoma patients with decreased EHD2 expression had shorter overall survival times than those with higher EHD2 expression. Knockdown of EHD2 induced an increase in cell invasion and changes characteristic of epithelial-mesenchymal transition, while overexpression of EHD2 inhibited these processes. Molecular data indicated that EHD2 inhibited migration and invasion of hepatocellular carcinoma probably by interacting with E-cadherin and it might be an independent, significant risk factor for survival after curative resection.

Diagnostic performance of tumor markers AFP and PIVKA-II in Chinese hepatocellular carcinoma patients.

PubMed

Huang, Shujing; Jiang, Feifei; Wang, Ying; Yu, Yanhua; Ren, Siqian; Wang, Xiaowei; Yin, Peng; Lou, Jinli

2017-06-01

Alpha-fetoprotein is an effective biomarker as an aid in hepatocellular carcinoma detection in many countries. However, alpha-fetoprotein has its limitations, especially in early hepatocellular carcinoma diagnosis. Protein induced by vitamin K absence or antagonist-II is another biomarker that is used for hepatocellular carcinoma detection. The aim of this study is to compare the diagnostic performance of alpha-fetoprotein and protein induced by vitamin K absence or antagonist-II alone and in combination to explore improving biomarker performance as an aid in early hepatocellular carcinoma detection. In this study a total of 582 serum samples including 132 hepatocellular carcinoma patients, 250 non-hepatocellular carcinoma patients, and 200 healthy volunteers were collected. Alpha-fetoprotein and protein induced by vitamin K absence or antagonist-II levels were measured by both chemiluminescent enzyme immunoassay on LUMIPULSE platform and by chemiluminescent microparticle immunoassay on ARCHITECT platform. Receiver operation characteristic curve analyses were performed for each biomarker and in combination. The results showed that Alpha-fetoprotein and protein induced by vitamin K absence or antagonist-II in combination have shown higher area under the curve compared to alpha-fetoprotein alone for diagnosis in whole patients (0.906 vs 0.870) in hepatocellular carcinoma early-stage patients (0.809 vs 0.77) and in hepatitis B virus-related hepatocellular carcinoma patients (0.851 vs 0.788) with ARCHITECT platform. Protein induced by vitamin K absence or antagonist-II showed higher area under the curve than alpha-fetoprotein for diagnosis of hepatitis B virus-related hepatocellular carcinoma patients (0.901 vs 0.788).We conclude that Combining alpha-fetoprotein and protein induced by vitamin K absence or antagonist-II may improve the diagnostic value for early detection of hepatocellular carcinoma. Protein induced by vitamin K absence or antagonist-II performs better

Critical reappraisal of risk factors for occurrence of hepatocellular carcinoma in patients with hepatitis C virus

PubMed Central

Bruno, Savino; Savojardo, Daniela; Almasio, Piero L; Mondelli, Mario U

2011-01-01

More than one and half of current cases of hepatocellular carcinoma in the US, Europe, and Japan are attributable to hepatitis C virus (HCV) infection. HCV is also the primary cause of death in patients with HCV-related cirrhosis, with annual incidences of 0.5%–5% in Europe and 4%–10% in Asia. Screening is based on serum alpha-fetoprotein determination and liver ultrasound scan, but the sensitivity of the former is far less than optimal, and screening intervals are still poorly defined for the latter. Risk factors related to the host or environment, or both, appear to be more relevant than viral factors, such as HCV genotype, in determining disease progression to cirrhosis and cancer, and include age, male gender, severity of liver disease at presentation, coinfection with hepatitis B virus or human immunodeficiency virus, and alcohol abuse. Early liver transplantation in selected cases can be curative, but most patients are not eligible for liver grafting and are treated with locoregional ablative therapies, after which recurrence is common. Recently, orally available inhibitors of the vascular endothelial growth factor receptor have shown a significant, albeit modest, increment of survival in patients with advanced hepatocellular carcinoma, thus paving the way for modern molecular approaches to treatment of this highly malignant tumor. PMID:24367218

PGK1 Drives Hepatocellular Carcinoma Metastasis by Enhancing Metabolic Process.

PubMed

Xie, Huijun; Tong, Guihui; Zhang, Yupei; Liang, Shu; Tang, Kairui; Yang, Qinhe

2017-07-27

During the proliferation and metastasis, the tumor cells prefer glycolysis (Warburg effect), but its exact mechanism remains largely unknown. In this study, we demonstrated that phosphoglycerate kinase 1 (PGK1) is an important enzyme in the pathway of metabolic glycolysis. We observed a significant overexpression of PGK1 in hepatocellular carcinoma tissues, and a correlation between PGK1 expression and poor survival of hepatocellular carcinoma patients. Also, the depletion of PGK1 dramatically reduced cancer cell proliferation and metastasis, indicating an oncogenic role of PGK1 in liver cancer progression. Further experiments showed that PGK1 played an important role in MYC -induced metabolic reprogramming, which led to an enhanced Warburg effect. Our results revealed a new effect of PGK1, which can provide a new treatment strategy for hepatocellular carcinoma, as PGK1 is used to indicate the prognosis of hepatocellular carcinoma (HCC).

The overexpression of Rabl3 is associated with pathogenesis and clinicopathologic variables in hepatocellular carcinoma.

PubMed

Pan, Yuhang; Liu, Zhiyong; Feng, Zhiying; Hui, Dayang; Huang, Xiangqi; Tong, Dayue; Jin, Yi

2017-04-01

Overexpression of Rabl3 is associated with some malignancies. However, their relationship with hepatocellular carcinoma remains unclear. In this study, the expression of Rabl3 in hepatocellular carcinoma cell lines, and four pairs of matched hepatocellular carcinoma tissues and their adjacent normal hepatic tissues were detected by quantitative reverse transcription polymerase chain reaction and western blot. In addition, the protein expression of Rabl3 was examined in 162 cases of hepatocellular carcinoma by immunohistochemistry. Rabl3 in hepatocellular carcinoma cell lines was elevated at both messenger RNA and protein levels, and the Rabl3 protein was significantly upregulated by upto 3.3-fold in hepatocellular carcinoma compared with the paired normal hepatic tissues. Immunohistochemical analysis revealed that overexpressions of Rabl3 were 80.2% in hepatocellular carcinoma. Rabl3 is expressed at significantly higher rates in hepatocellular carcinoma compared with adjacent normal hepatic tissue (p < 0.01). Statistical analysis suggested the upregulation of Rabl3 was significantly associated with lymph node metastasis, tumor thrombus of the portal vein, and advanced clinical stage (p < 0.05). Furthermore, we found that overexpression of Rabl3 in hepatocellular carcinoma cells could significantly enhance cell proliferation and growth ability. Conversely, silencing Rabl3 by small hairpin RNA interference caused an inhibition of cell proliferation and growth. Our studies suggest that the Rabl3 is a valuable marker of hepatocellular carcinoma progression and that the overexpression of Rabl3 plays an important role in the development and pathogenesis of hepatocellular carcinoma.

Enhanced circulating transforming growth factor beta 1 is causally associated with an increased risk of hepatocellular carcinoma: a mendelian randomization meta-analysis.

PubMed

Lu, Wei-Qun; Qiu, Ji-Liang; Huang, Zhi-Liang; Liu, Hai-Ying

2016-12-20

The aim of this study was to test the causal association between circulating transforming growth factor beta 1 (protein: TGF-β1 and coding gene: TGFB1) and hepatocellular carcinoma by choosing TGFB1 gene C-509T polymorphism as an instrument in a Mendelian randomization (MR) meta-analysis. Ten English articles were identified for analysis. Two authors independently assessed each article and abstracted relevant data. Odds ratio (OR) and weighted mean difference (WMD) with 95% confidence interval (CI) were synthesized under a random-effects model. Overall, the association of C-509T polymorphism with hepatocellular carcinoma was negative, but its association with circulating TGF-β1 was statistically significant, with a higher concentration observed in carriers of the -509TT genotype (WMD, 95% CI, P: 1.72, 0.67-2.78, 0.001) and -509TT/-509TC genotypes (WMD, 95% CI, P: 0.98, 0.43-1.53, < 0.001). In subgroup analysis, C-509T polymorphism was significantly associated with hepatocellular carcinoma in population-based studies under homozygous-genotype (OR, 95% CI, P: 1.74, 1.08-2.80, 0.023) and dominant (OR, 95% CI, P: 1.48, 1.01-2.17, 0.047) models. Further MR analysis indicated that per unit increase in circulating TGF-β1 was significantly associated with a 38% (95% CI: 1.03-4.65) and 49% (95% CI: 1.01-6.06) increased risk of hepatocellular carcinoma under homozygous-genotype and dominant models, respectively. Conclusively, based on a MR meta-analysis, our findings suggest that enhanced circulating TGF-β1 is causally associated with an increased risk of hepatocellular carcinoma.

Changing incidence patterns of hepatocellular carcinoma among age groups in Taiwan.

PubMed

Hung, Giun-Yi; Horng, Jiun-Lin; Yen, Hsiu-Ju; Lee, Chih-Ying; Lin, Li-Yih

2015-12-01

This study examined and compared the incidence patterns of hepatocellular carcinoma among age groups in Taiwan, 30 years after a universal hepatitis B virus immunization program was launched. Data for hepatocellular carcinoma diagnosed in 2003-2011 were collected from the population-based Taiwan Cancer Registry. Age-standardized incidence rates were calculated to analyze and compare the changes in incidence rates and trends. More specific analyses were performed on four age groups separated by sex. A total of 82,856 patients were diagnosed with hepatocellular carcinoma in 2003-2011 in Taiwan, yielding an age-standardized incidence rate of 32.97 per 100,000 person-years. Hepatocellular carcinoma was predominantly diagnosed in middle-aged adults (50.1%) and elderly people (49.1%), in contrast to the low incidences in children (0.04%) and adolescents and young adults (0.8%). Striking variations in trends were found for children (annual percent change: -16.6%, 2003-2010) and adolescents and young adults (annual percent change: -7.9%, 2003-2011). The incidence rate of hepatocellular carcinoma in children decreased to zero in 2011; only a slight decline in trends occurred for the middle-aged group (annual percent change: -2%, 2003-2011), and a slight upward trend was observed for elderly people (1.3%), specifically in women (1.7%). In Taiwan, hepatitis B virus-related hepatocellular carcinoma was nearly eradicated in children in 2011. The findings on age-specific incidence patterns and trends of hepatocellular carcinoma suggest that different control strategies for treating this devastating disease in the future be made according to age. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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

MiR-590-3p suppresses hepatocellular carcinoma growth by targeting TEAD1.

PubMed

Ge, Xin; Gong, Liansheng

2017-03-01

MicroRNA signature is altered in different disease states including cancer, and some microRNAs act as oncogenes or tumor suppressors. MiR-590-3p has been shown to be involved in human cancer progression. However, its role in hepatocellular carcinoma remains unknown. In this study, miR-590-3p level was measured, and clinicopathological features were determined in hepatocellular carcinoma tissues. The function of miR-590-3p was examined in vitro and in vivo. Real-time reverse transcription polymerase chain reaction analysis demonstrated downregulation of miR-590-3p in hepatocellular carcinoma tissues, and its downregulation was associated with a poor overall survival of hepatocellular carcinoma patients. Ectopic expression of miR-590-3p promoted growth of hepatocellular carcinoma cells, whereas its depletion inhibited cell growth. Transcriptional enhancer activator domain 1 was identified as a validated miR-590-3p target. Upregulation of transcriptional enhancer activator domain 1 was found in hepatocellular carcinoma tissues and inversely correlated with miR-590-3p. Our results indicate a tumor suppressor role of miR-590-3p in hepatocellular carcinoma through targeting transcriptional enhancer activator domain 1 and suggest its use in the diagnosis and prognosis of liver cancer.

Evaluating hepatocellular carcinoma cell lines for tumour samples using within-sample relative expression orderings of genes.

PubMed

Ao, Lu; Guo, You; Song, Xuekun; Guan, Qingzhou; Zheng, Weicheng; Zhang, Jiahui; Huang, Haiyan; Zou, Yi; Guo, Zheng; Wang, Xianlong

2017-11-01

Concerns are raised about the representativeness of cell lines for tumours due to the culture environment and misidentification. Liver is a major metastatic destination of many cancers, which might further confuse the origin of hepatocellular carcinoma cell lines. Therefore, it is of crucial importance to understand how well they can represent hepatocellular carcinoma. The HCC-specific gene pairs with highly stable relative expression orderings in more than 99% of hepatocellular carcinoma but with reversed relative expression orderings in at least 99% of one of the six types of cancer, colorectal carcinoma, breast carcinoma, non-small-cell lung cancer, gastric carcinoma, pancreatic carcinoma and ovarian carcinoma, were identified. With the simple majority rule, the HCC-specific relative expression orderings from comparisons with colorectal carcinoma and breast carcinoma could exactly discriminate primary hepatocellular carcinoma samples from both primary colorectal carcinoma and breast carcinoma samples. Especially, they correctly classified more than 90% of liver metastatic samples from colorectal carcinoma and breast carcinoma to their original tumours. Finally, using these HCC-specific relative expression orderings from comparisons with six cancer types, we identified eight of 24 hepatocellular carcinoma cell lines in the Cancer Cell Line Encyclopedia (Huh-7, Huh-1, HepG2, Hep3B, JHH-5, JHH-7, C3A and Alexander cells) that are highly representative of hepatocellular carcinoma. Evaluated with a REOs-based prognostic signature for hepatocellular carcinoma, all these eight cell lines showed the same metastatic properties of the high-risk metastatic hepatocellular carcinoma tissues. Caution should be taken for using hepatocellular carcinoma cell lines. Our results should be helpful to select proper hepatocellular carcinoma cell lines for biological experiments. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Congenital extrahepatic portosystemic shunt complicated by the development of hepatocellular carcinoma.

PubMed

Sharma, Ruchi; Suddle, Abid; Quaglia, Alberto; Peddu, Praveen; Karani, John; Satyadas, Thomas; Heaton, Nigel

2015-10-01

Congenital extrahepatic portosystemic shunt, also known as Abernethy malformation, is a rare congenital malformation. It causes shunting of blood through a communication between the portal and systemic veins such as a patent ductus venous. We report 3 cases of Abernethy malformation complicated by the development of hepatocellular carcinoma. Additionally, we comprehensively reviewed all previously reported cases and highlighted common features that may help in early diagnosis and appropriate management. Patients with Abernethy malformation may have an increased propensity to develop hepatocellular carcinoma. All 5 previously reported cases, plus the three of our patients, have a type 1 (complete) shunt suggesting a role for absent portal blood flow in the pathogenesis of hepatocellular carcinoma. Congenital extrahepatic portosystemic shunt should be sought for in cases with raised serum ammonia, hepatic encephalopathy or hepatocellular carcinoma in the absence of cirrhosis.

Large hepatocellular carcinoma in a non-cirrhotic liver with peritoneal and omental metastasis in a healthy man: a case report.

PubMed

Herath, H M M T B; Kulatunga, Aruna

2017-02-08

Liver cancer is the second leading cause of cancer death in men worldwide. Hepatocellular carcinoma usually develops in the setting of cirrhosis or chronic inflammation. Major risk factors for developing hepatocellular carcinoma are chronic hepatitis B or C virus infection, alcoholic cirrhosis, and nonalcoholic fatty liver disease. The most frequent locations for hepatocellular carcinoma to metastasize are the lungs, portal vein, bones, and regional lymph nodes. A 41-year-old Sri Lankan man presented with progressive abdominal distension and on examination was found to have a palpable irregular mass in the left lobe of his liver with moderate ascites. His ascitic fluid was an exudate without malignant cells. An ultrasound scan and contrast-enhanced computed tomography of his abdomen showed a large contrast-enhancing lesion in the left lobe of his liver without features of cirrhosis. Laparoscopic assessment revealed peritoneal and omental deposits. Histology of the biopsies taken from the liver lesion, omental deposits, and peritoneal deposits supported a diagnosis of hepatocellular carcinoma. His liver biochemistry was normal and hepatitis serology was negative. He is abstinent from alcohol and did not have metabolic syndrome. It is rare for a young patient to develop hepatocellular carcinoma with a normal liver without chronic hepatitis B or C infection, or any other risk factors. Intraperitoneal metastasis of non-ruptured hepatocellular carcinoma is also very rare. Here we report a rare case of a 41-year-old man with a large hepatocellular carcinoma in a non-cirrhotic liver without chronic hepatitis who presented with peritoneal and omental metastasis.

Worldwide incidence of hepatocellular carcinoma cases attributable to major risk factors.

PubMed

Baecker, Aileen; Liu, Xing; La Vecchia, Carlo; Zhang, Zuo-Feng

2018-05-01

To facilitate regionally specific liver cancer prevention and control, this study estimates the fraction of hepatocellular carcinoma (HCC) cases attributable to five major liver cancer risk factors by geographic region. Prevalence estimates of major HCC risk factors, including chronic infection with hepatitis B and hepatitis C, alcohol drinking, tobacco smoking, obesity, and diabetes, were extracted for each country from the literature, along with recent incidence and risk estimate data, to calculate regionally specific population attributable fractions. Overall, 44% of HCC cases worldwide were attributable to chronic hepatitis B infection, with the majority of cases occurring in Asia. Hepatitis C was responsible for 21% of cases. Lifestyle risk factors such as alcohol drinking and obesity were responsible for a larger percentage of cases in North America and Western, Central, and Eastern Europe. In addition, strong sex disparities were observed when looking at lifestyle risk factors, particularly tobacco smoking, in Asia and Africa. Prominent risk factors for HCC vary depending on the region. Our findings provide useful data for developing regionally specific guidelines for liver cancer prevention and control worldwide.

A Hepatocellular Carcinoma Case in a Patient Who had Immunity to Hepatitis B Virus Earlier.

PubMed

Ates, Ihsan; Kaplan, Mustafa; Demirci, Selim; Altiparmak, Emin

2016-01-01

Hepatocellular carcinoma (HCC) is the most common malignant tumor of the liver. Hepatitis B virus infection is one of the most important etilogical factors of HCC. In this case report, a patient with HCC previously infected and having ongoing immunity against hepatitis B virus will be discussed. Ates I, Kaplan M, Demirci S, Altiparmak E. A Hepatocellular Carcinoma Case in a Patient Who had Immunity to Hepatitis B Virus Earlier. Euroasian J Hepato-Gastroenterol 2016;6(1):82-83.

Molecular pathogenesis of hepatocellular carcinoma and impact of therapeutic advances

PubMed Central

Dhanasekaran, Renumathy; Bandoh, Salome; Roberts, Lewis R.

2016-01-01

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality and has an increasing incidence worldwide. HCC can be induced by multiple etiologies, is influenced by many risk factors, and has a complex pathogenesis. Furthermore, HCCs exhibit substantial heterogeneity, which compounds the difficulties in developing effective therapies against this highly lethal cancer. With advances in cancer biology and molecular and genetic profiling, a number of different mechanisms involved in the development and progression of HCC have been identified. Despite the advances in this area, the molecular pathogenesis of hepatocellular carcinoma is still not completely understood. This review aims to elaborate our current understanding of the most relevant genetic alterations and molecular pathways involved in the development and progression of HCC, and anticipate the potential impact of future advances on therapeutic drug development. PMID:27239288

ESTABLISHMENT AND EVALUATION OF ORTHOTOPIC HEPATOCELLULAR CARCINOMA AND DRUG-INDUCED HEPATOCELLULAR CARCINOMA IN MICE WITH SPLEEN-DEFICIENCY SYNDROME IN TRADITIONAL CHINESE MEDICINE.

PubMed

Luo, Haoxuan; Chen, Yan; Sun, Baoguo; Xiang, Ting; Zhang, Shijun

2017-01-01

Spleen-deficiency syndrome (SDS) in Traditional Chinese Medicine (TCM) played pivotal roles on the development of hepatocellular carcinoma (HCC). This study was performed to establish and evaluate HCC model in mice with SDS in TCM. A total of 90 C57BL/6 mice were randomized in six groups (n=15 for each group): A, Control group; B, SDS group; C, orthotopic HCC (OHCC) group; D, OHCC based on SDS (SDS-OHCC) group; E, Drug-induced HCC (DHCC) group; F, DHCC based on SDS (SDS-DHCC) group. The SDS model were established by subcutaneous injection of reserpine, followed by the OHCC or DHCC model establishment. The SDS scores, tumor formation rate and survival time were recorded and calculated, as well as the histochemical stain was performed. The SDS scores of mice in Group B, D, F were 17.57±4.86 (P<0.05 vs. Group A), 18.13±4.53 (P<0.05 vs. Group A and C) and 23.32±4.94 (P<0.05 vs. Group A and E) respectively. The tumor formation rate of mice in Group C, D, E and F were 73.33%, 100%, 60% and 80% respectively. The survival time of mice in Group C, D, E and F were 26.42±5.27, 17.33±4.76 (P<0.05 vs. Group C), 35.77±6.12 and 22.61±5.05 (P<0.05 vs. Group E) respectively. The SDS-oriented HCC mice models were simple and easily-operated models for further studies on SDS oriented tumor. Meanwhile, SDS was a pivotal factor for low outcome of hepatic tumor. Abbreviations: HCC, Hepatocellular carcinoma; OHCC, Orthotopic hepatocellular carcinoma; DHCC, Drug-induced hepatocellular carcinoma; SDS, Spleen-deficiency syndrome; TCM, Traditional Chinese Medicine; SPF, Specific pathogen-free; DEN, Diethylnitrosamine; CCl4, Carbon tetrachloride; HE, Hematoxylin-eosin; IACUC, Institutional Animal Care and Use Committee.

Hepatocellular carcinoma with neuroendocrine differentiation: a case report.

PubMed

Lu, Jiajie G; Farukhi, M Aabid; Mayeda, Donna; French, Samuel W

2017-10-01

Hepatocellular carcinoma with neuroendocrine differentiation, where tumor cells stain for both hepatocellular and neuroendocrine markers, is extremely rare. We report a case of a 65-year-old man who presented with a 14-cm rapidly growing mass in the right lobe of his liver with local extension into the gallbladder and portal vein. Serum AFP was 4625ng/mL. Liver biopsy showed a poorly differentiated neoplasm with cells showing nuclear pleomorphism, high nuclear/cytoplasmic ratio, and numerous mitoses. The tumor cells stain for AFP, glutamine synthase, arginase, and glypican-3. The same tumor regions also stain positively for synaptophysin, chromogranin, and CD56. Given this histological pattern, this tumor was ultimately diagnosed as hepatocellular carcinoma with neuroendocrine differentiation. Published by Elsevier Inc.

Plasma Level of Interleukin-35 as an Independent Prognostic Indicator in Hepatocellular Carcinoma.

PubMed

Qiu, Xiangting; Wang, Xinhua; Song, Yucui; Chen, Lingling

2016-12-01

Hepatocellular carcinoma is a major type of liver cancer with poor prognosis. The aim of the study was to determine the prognostic significance of plasma interleukin-35 level in hepatocellular carcinoma. A total of 153 hepatocellular carcinoma patients and 153 healthy controls were enrolled. Blood samples were obtained at admission. Plasma interleukin-35 level was analyzed by enzyme-linked immunosorbent assay. Distribution of T cell subset and expression of Fas/FasL protein were detected by flow cytometry. The patients were followed up for 2 years. Poor prognosis was defined as death of hepatocellular carcinoma. The plasma levels of interleukin-35 were significantly higher in the patients than the controls (25.1 ± 13.1, 9.3 ± 6.3 pg/mL, P < 0.001). After adjusted for multiple confounding factors, the multivariate logistic regression analyses reported that high level of interleukin-35 (≥25.0 pg/mL) was associated with the poor prognosis in the patients (OR 6.63, 95 % CI 3.27-13.47). Compared with the patients with low level of interleukin-35 (<25.0 pg/mL), the patients with high level of interleukin-35 showed higher frequencies of CD4+CD25+FoxP3+ and CD3+Foxp3+ regulatory T cells (P < 0.001 and P < 0.001) and also showed higher apoptosis levels of CD8+ T cells (P < 0.001). Circulating interleukin-35 concentration might be an independent prognostic indicator in hepatocellular carcinoma. Such prognostic significance could be partly involved in the activation of regulatory T cell and the apoptosis of CD8+ T cell.

Complete necrosis of hepatocellular carcinoma after preoperative portal vein embolization: a case report.

PubMed

El Bacha, H; Salihoun, M; Kabbaj, N; Benkabbou, A

2017-01-04

Hepatocellular carcinoma has a poor prognosis; few patients can undergo surgical curative treatment according to Barcelona Clinic Liver Cancer guidelines. Progress in surgical techniques has led to operations for more patients outside these guidelines. Our case shows a patient with intermediate stage hepatocellular carcinoma presenting a good outcome after curative treatment. We report the case of an 80-year-old Moroccan man, who was positive for hepatitis c virus, presenting an intermediate stage hepatocellular carcinoma (three lesions between 20 and 60 mm). He presented a complete tumor necrosis after portal vein embolization and achieved 24-month disease-free survival after surgery. Perioperative care in liver surgery and multidisciplinary discussion can help to extend indications for liver resection for hepatocellular carcinoma outside European Association for the Study of the Liver/American Association for the Study of Liver Diseases recommendations and offer a curative approach to selected patients with intermediate and advanced stage hepatocellular carcinoma.

Mitochondrial fission promotes cell migration by Ca2+ /CaMKII/ERK/FAK pathway in hepatocellular carcinoma.

PubMed

Sun, Xiacheng; Cao, Haiyan; Zhan, Lei; Yin, Chun; Wang, Gang; Liang, Ping; Li, Jibin; Wang, Zhe; Liu, Bingrong; Huang, Qichao; Xing, Jinliang

2018-07-01

Mitochondrial dynamics of fission and fusion plays critical roles in a diverse range of important cellular functions, and its deregulation has been increasingly implicated in human diseases. Previous studies have shown that increased mitochondrial fission significantly promoted the proliferation of hepatocellular carcinoma (HCC) cells. However, how they influence the migration of tumour cells remained largely unknown. In the present study, we further investigated the effect of mitochondrial fission on the migration and metastasis of hepatocellular carcinoma cells. Moreover, the underlying molecular mechanisms and therapeutic application were explored. Our data showed that dynamin-1-like protein expression was strongly increased in distant metastasis of hepatocellular carcinoma when compared to primary hepatocellular carcinoma. In contrast, the mitochondrial fusion protein mitofusin 1 showed an opposite trend. Moreover, the expression of dynamin-1-like protein and mitofusin 1 was significantly associated with the disease-free survival of hepatocellular carcinoma patients. In addition, our data further showed that mitochondrial fission significantly promoted the reprogramming of focal-adhesion dynamics and lamellipodia formation in hepatocellular carcinoma cells mainly by activating typical Ca 2+ /CaMKII/ERK/FAK pathway. Importantly, treatment with mitochondrial division inhibitor-1 significantly decreased calcium signalling in hepatocellular carcinoma cells and had a potential treatment effect for hepatocellular carcinoma metastasis in vivo. Taken together, our findings demonstrate that mitochondrial fission plays a critical role in the regulation of hepatocellular carcinoma cell migration, which provides strong evidence for this process as a drug target in hepatocellular carcinoma metastasis treatment. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The Safety and Efficacy of Irreversible Electroporation for Large Hepatocellular Carcinoma.

PubMed

Zeng, Jianying; Liu, Guifeng; Li, Zhong-Hai; Yang, Yi; Fang, Gang; Li, Rong-Rong; Xu, Ke-Cheng; Niu, Lizhi

2017-02-01

This study aimed to investigate the safety and effectiveness of irreversible electroporation ablation for unresectable large liver cancer. Fourteen patients were enrolled: 8 with large hepatocellular carcinoma (tumor diameter: 5.1-11.5 cm) and 6 with medium hepatocellular carcinoma (tumor diameter: 3.0-4.1 cm). All patients received percutaneous irreversible electroporation ablation. Ablation time and the incidence of complications were assessed by a t test. Post-irreversible electroporation and regular contrast-enhanced computerized tomography scans were performed to investigate the effect of tumor size (large vs medium) on irreversible electroporation treatment efficacy; 4-table data were assessed using a Fisher exact test. The 14 patients completed irreversible electroporation ablation successfully. In the large hepatocellular carcinoma group, no major complications occurred in the perioperative period. Minor complications comprised bloating, hypokalemia, edema, low white blood cells, and blood clotting abnormalities. All complications were mild and improved after symptomatic treatment. The frequency of minor complications was not significantly different ( P > .05) compared with the medium hepatocellular carcinoma group. The average follow-up time was 2.8 ± 2.1 months and complete ablation was achieved in 25% (2/8; residual = 75%). For the patients with medium hepatocellular carcinoma, the mean follow-up time was 4.3 ± 3.2 months; the rate of complete ablation was 66.6% (4/6; residual rate = 33.3%). The complete ablation rate was not statistically different between the 2 groups ( P > .05). Irreversible electroporation ablation for unresectable large hepatocellular carcinoma is safe, with no major complications. Short-term efficacy is relatively good; however, long-term efficacy remains to be explored.

A Hepatocellular Carcinoma Case in a Patient Who had Immunity to Hepatitis B Virus Earlier

PubMed Central

Kaplan, Mustafa; Demirci, Selim; Altiparmak, Emin

2016-01-01

ABSTRACT Hepatocellular carcinoma (HCC) is the most common malignant tumor of the liver. Hepatitis B virus infection is one of the most important etilogical factors of HCC. In this case report, a patient with HCC previously infected and having ongoing immunity against hepatitis B virus will be discussed. How to cite this article Ates I, Kaplan M, Demirci S, Altiparmak E. A Hepatocellular Carcinoma Case in a Patient Who had Immunity to Hepatitis B Virus Earlier. Euroasian J Hepato-Gastroenterol 2016;6(1):82-83. PMID:29201732

Case-Control Study Examining the Association between Selective Serotonin Reuptake Inhibitors Use and Hepatocellular Carcinoma.

PubMed

Lai, Shih-Wei; Liao, Kuan-Fu; Lin, Cheng-Li; Lin, Hsien-Feng

2017-01-01

Objectives: The purpose of the study was to assess the relationship between selective serotonin reuptake inhibitors use and hepatocellular carcinoma in Taiwan. Methods: Using the database of the Taiwan National Health Insurance Program, we conducted a case-control study to identify 4901 subjects aged 20 years and more with newly diagnosed hepatocellular carcinoma in 2000-2013 as the cases. We randomly selected 19604 subjects aged 20 years and more without hepatocellular carcinoma as the controls. Both cases and controls were matched with sex and age. Ever use of selective serotonin reuptake inhibitors was defined as a subject who had at least a prescription for selective serotonin reuptake inhibitors before index date. Never use was defined as a subject who never had a prescription for selective serotonin reuptake inhibitors before index date. The odds ratio (OR) and 95% confidence interval (CI) for hepatocellular carcinoma associated with selective serotonin reuptake inhibitors use was estimated by the multivariable logistic regression model. Results: Among subjects with any one of the comorbid conditions associated with hepatocellular carcinoma, the adjusted OR of hepatocellular carcinoma was 0.89 (95% CI 0.75, 1.06) for subjects with ever use of selective serotonin reuptake inhibitors, comparing with never use. Conclusion: The findings indicate that among subjects with any one of the comorbid conditions associated with hepatocellular carcinoma, no significant association can be detected between selective serotonin reuptake inhibitors use and hepatocellular carcinoma.

Relatively Long Survival in Hepatocellular Carcinoma Presenting With Carcinoid Syndrome

PubMed Central

Nwokediuko, Sylvester Chuks; Uchenna, Ijoma; Esther, Ofoegbu; Okechukwu, Okafor; Augustine, Onuh; Charity, Ajuyah

2010-01-01

Hepatocelluar carcinoma is one of the commonest cancers in Nigeria. Some patients may manifest a variety of paraneoplastic syndromes. Carcinoid syndrome is an extremely rare presentation of hepatocellular carcinoma. A 57-year old man presented with recurrent facial flushing and diarrhea, tricuspid regurgitation, and very high level of urinary hydroxyindoleacetic acid (HIAA) as the first manifestation of a multicentric hepatic lesion which proved histologically to be hepatocellular carcinoma. The lesions also exhibited arterial hypervascularization on contrast enhanced computerized tomography. The patient is still alive after 6 years of symptoms. PMID:27956985

Hepatocellular Carcinoma: An Unusual Complication of Longstanding Wilson Disease.

PubMed

Gunjan, Deepak; Shalimar; Nadda, Neeti; Kedia, Saurabh; Nayak, Baibaswata; Paul, Shashi B; Gamanagatti, Shivanand Ramachandra; Acharya, Subrat K

2017-06-01

Wilson disease is caused by the accumulation of copper in the liver, brain or other organs, due to the mutation in ATP7B gene, which encodes protein that helps in excretion of copper in the bile canaliculus. Clinical presentation varies from asymptomatic elevation of transaminases to cirrhosis with decompensation. Hepatocellular carcinoma is a known complication of cirrhosis, but a rare occurrence in Wilson disease. We present a case of neurological Wilson disease, who later developed decompensated cirrhosis and hepatocellular carcinoma.

Dysregulation of serum microRNA-574-3p and its clinical significance in hepatocellular carcinoma.

PubMed

Shen, Xianjuan; Xue, Yajing; Cong, Hui; Wang, Xudong; Ju, Shaoqing

2018-07-01

Objectives To explore microRNA-574-3p expression in serum of patients with hepatocellular carcinoma and investigate correlations between serum microRNA-574-3p expression and the development and prognosis of hepatocellular carcinoma. Design and methods Serum samples were collected from 70 patients with primary hepatocellular carcinoma, 40 patients with cirrhosis and 45 healthy controls. Serum microRNA-574-3p expression levels were detected by real-time quantitative polymerase chain reaction. The linearity, specificity and reproducibility were evaluated. In addition, the diagnostic value of microRNA-574-3p and its correlations with clinicopathologic features were assessed. Results The relative expression of microRNA-574-3p in hepatocellular carcinoma patients, cirrhosis patients and healthy controls was 2.306 (1.801-3.130), 1.362 (0.994-1.665) and 1.263 (0.765-1.723), respectively, indicating that it was significantly higher in hepatocellular carcinoma patients than that in the other two groups ( U = 439.5, 514.5, both P < 0.0001) and was significantly correlated with hepatitis B virus DNA copies ( U = 383.0, P = 0.018). In hepatitis B virus-positive hepatocellular carcinoma patients, the relative expression of microRNA-574-3p was significantly correlated with hepatitis B virus DNA concentration ( r = 0.348, P = 0.022). Compared with healthy control group, AUC ROC of serum microRNA-574-3p in hepatocellular carcinoma group was 0.837 with 95% CI: 0.763-0.910. Combining microRNA-574-3p, AFU and alpha-fetoprotein together, the sensitivity was highest compared with other markers alone or combined. Conclusions The relative expression of serum microRNA-574-3p in hepatocellular carcinoma patients was significantly higher than that in cirrhosis patients and healthy controls, and it may be an important biomarker in the auxiliary diagnosis of hepatocellular carcinoma.

Multifunctional Effects of a Small-Molecule STAT3 Inhibitor on NASH and Hepatocellular Carcinoma in Mice.

PubMed

Jung, Kwang Hwa; Yoo, Wonbeak; Stevenson, Heather L; Deshpande, Dipti; Shen, Hong; Gagea, Mihai; Yoo, Suk-Young; Wang, Jing; Eckols, T Kris; Bharadwaj, Uddalak; Tweardy, David J; Beretta, Laura

2017-09-15

Purpose: The incidence of hepatocellular carcinoma is increasing in the United States, and liver cancer is the second leading cause of cancer-related mortality worldwide. Nonalcoholic steatohepatitis (NASH) is becoming an important risk for hepatocellular carcinoma, and most patients with hepatocellular carcinoma have underlying liver cirrhosis and compromised liver function, which limit treatment options. Thus, novel therapeutic strategies to prevent or treat hepatocellular carcinoma in the context of NASH and cirrhosis are urgently needed. Experimental Design: Constitutive activation of STAT3 is frequently detected in hepatocellular carcinoma tumors. STAT3 signaling plays a pivotal role in hepatocellular carcinoma survival, growth, angiogenesis, and metastasis. We identified C188-9, a novel small-molecule STAT3 inhibitor using computer-aided rational drug design. In this study, we evaluated the therapeutic potential of C188-9 for hepatocellular carcinoma treatment and prevention. Results: C188-9 showed antitumor activity in vitro in three hepatocellular carcinoma cell lines. In mice with hepatocyte-specific deletion of Pten (Hep Pten - mice), C188-9 treatment blocked hepatocellular carcinoma tumor growth, reduced tumor development, and reduced liver steatosis, inflammation, and bile ductular reactions, resulting in improvement of the pathological lesions of NASH. Remarkably, C188-9 also greatly reduced liver injury in these mice as measured by serum aspartate aminotransferase and alanine transaminase levels. Analysis of gene expression showed that C188-9 treatment of Hep Pten - mice resulted in inhibition of signaling pathways downstream of STAT3, STAT1, TREM-1, and Toll-like receptors. In contrast, C188-9 treatment increased liver specification and differentiation gene pathways. Conclusions: Our results suggest that C188-9 should be evaluated further for the treatment and/or prevention of hepatocellular carcinoma. Clin Cancer Res; 23(18); 5537-46. ©2017 AACR

Hepatocellular carcinoma: clinicopathological profile and challenges of management in a resource-limited setting.

PubMed

Jaka, Hyasinta; Mshana, Stephen E; Rambau, Peter F; Masalu, Nestory; Chalya, Phillipo L; Kalluvya, Samuel E

2014-08-02

Hepatocellular carcinoma is one of the most common cancers worldwide and its incidence is reported to be increasing in resource-limited countries. There is a paucity of published data regarding hepatocellular carcinoma in Tanzania, and the study area in particular. This study describes the clinicopathological profile of hepatocellular carcinoma in our local setting and highlights the challenging problems in the management of this disease. This was a retrospective study of histopathologically confirmed cases of hepatocellular carcinoma seen at Bugando Medical Center between March 2009 and February 2013. A total of 142 patients (M: F = 2.2: 1) were studied representing 4.6% of all malignancies. The median age of patients was 45 years. Hepatitis B virus infection (66.2%) and heavy alcohol consumption (60.6%) were the most frequently identified risk factors for hepatocellular carcinoma. The majority of patients (88.0%) presented late with advanced stages. HBsAg was positive in 66.2% of the patients and Hepatitis C Virus antibody in 16.9%. Thirteen (9.2%) patients tested positive for HIV infection. Most patients (52.8%) had both right and left lobe involvement. The trabecular pattern (47.9%) was the most frequent histopathological type. None of patients had curative therapy because of the advanced nature of the disease. Coagulopathy (45.7%) was the most common complications. The overall mortality rate was 46.5% and it was significantly associated with comorbidity, HIV positivity, CD4+ count <200 cells/μl, high histological grade, advanced stage of the tumor, presence of distant metastases at the time of diagnosis, and associated complications (P < 0.001). The overall median duration of hospital stay was 14 days. The majority of patients (71.1%) were lost to follow-up at the end of the follow-up period. Hepatocellular carcinoma patients in this region are relatively young at diagnosis and the majority of them present late with an advanced stage and high rate

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

Hepatocellular carcinoma in urban born blacks: frequency and relation to hepatitis B virus infection.

PubMed Central

Kew, M C; Kassianides, C; Hodkinson, J; Coppin, A; Paterson, A C

1986-01-01

Chronic hepatitis B virus infection is far less common in urban born than in rural born southern African blacks, who also have a high incidence of hepatocellular carcinoma. A case-control study was carried out to determine the relative frequency of hepatocellular carcinoma and its relation to hepatitis B virus infection in urban born blacks. Three hundred and ninety two black patients with hepatocellular carcinoma and matched controls seen at two city hospitals were classified by questioning as urban born or rural born. The ratio of rural born to urban born blacks among the controls was 1.1:1.0 (207/185), whereas in the patients with cancer the ratio was 4.8:1.0 (324/68) (p less than 0.0001). Analysis of the prevalence of hepatitis B markers in 62 urban born and matched rural born blacks with hepatocellular carcinoma showed no differences in the frequency of current or past hepatitis B virus infection. It is concluded that urban born blacks are less likely than rural born blacks to develop hepatocellular carcinoma, but when they do the tumour is equally likely to be related to infection with hepatitis B virus. The findings lend further support to an important role for chronic hepatitis B virus infection in the aetiology of hepatocellular carcinoma. PMID:3024771

Non-infective occupational risk factors for hepatocellular carcinoma: A review

PubMed Central

Ledda, Caterina; Loreto, Carla; Zammit, Christian; Marconi, Andrea; Fago, Lucrezia; Matera, Serena; Costanzo, Valentina; Sanzà, Giovanni Fuccio; Palmucci, Stefano; Ferrante, Margherita; Costa, Chiara; Fenga, Concettina; Biondi, Antonio; Pomara, Cristoforo; Rapisarda, Venerando

2017-01-01

Liver cancer is the second leading worldwide cause of cancer-associated mortalities. Hepatocellular carcinoma, which accounts for the majority of liver tumors, ranks fifth among types of human cancer. Well-established risk factors for liver cancer include the hepatitis B and C viruses, aflatoxins, alcohol consumption, and oral contraceptives. Tobacco smoking, androgenic steroids, and diabetes mellitus are suspected risk factors. Current knowledge regarding non-infective occupational risk factors for liver cancer is inconclusive. The relevance of liver disorders to occupational medicine lies in the fact that the majority of chemicals are metabolized in the liver, and toxic metabolites generated via metabolism are the predominant cause of liver damage. However, their non-specific clinical manifestations that are similar in a number of liver diseases make diagnosis difficult. Furthermore, concomitant conditions, such as viral hepatitis and alcohol or drug abuse, may mask liver disorders that result from occupational hepatotoxic agents and block the demonstration of an occupational cause. The identification of environmental agents that result in human cancer is a long and often difficult process. The purpose of the present review is to summarize current knowledge regarding the association of non-infective occupational risk exposure and HCC, to encourage further research and draw attention to this global occupational public health problem. PMID:28000892

Role of surveillance in prevention of hepatocellular carcinoma.

PubMed

Panda, Dipanjan

2014-08-01

Hepatocellular carcinoma is a common malignancy and one of the important public health problems in India. The surveillance of hepatocellular carcinoma (HCC) is an established approach to detect early cancers in patients with defined risks. However, there are still controversies and issues to be addressed regarding the optimal surveillance methods and interval. The current level of awareness among physicians in India about surveillance is low and the need and most cost effective surveillance strategy in developing country like ours is unclear. This article has tried to discuss these issues in their appropriate perspective. To address this complicated issue, a multicenter randomized prospective study however may be required.

Hepatocellular carcinoma: Advances in diagnostic imaging.

PubMed

Sun, Haoran; Song, Tianqiang

2015-10-01

Thanks to the growing knowledge on biological behaviors of hepatocellular carcinomas (HCC), as well as continuous improvement in imaging techniques and experienced interpretation of imaging features of the nodules in cirrhotic liver, the detection and characterization of HCC has improved in the past decade. A number of practice guidelines for imaging diagnosis have been developed to reduce interpretation variability and standardize management of HCC, and they are constantly updated with advances in imaging techniques and evidence based data from clinical series. In this article, we strive to review the imaging techniques and the characteristic features of hepatocellular carcinoma associated with cirrhotic liver, with emphasis on the diagnostic value of advanced magnetic resonance imaging (MRI) techniques and utilization of hepatocyte-specific MRI contrast agents. We also briefly describe the concept of liver imaging reporting and data systems and discuss the consensus and controversy of major practice guidelines.

Radiofrequency ablation of hepatocellular carcinoma: Mono or multipolar?

PubMed

Cartier, Victoire; Boursier, Jérôme; Lebigot, Jérôme; Oberti, Frédéric; Fouchard-Hubert, Isabelle; Aubé, Christophe

2016-03-01

Thermo-ablation by radiofrequency is recognized as a curative treatment for early-stage hepatocellular carcinoma. However, local recurrence may occur because of incomplete peripheral tumor destruction. Multipolar radiofrequency has been developed to increase the size of the maximal ablation zone. We aimed to compare the efficacy of monopolar and multipolar radiofrequency for the treatment of hepatocellular carcinoma and determine factors predicting failure. A total of 171 consecutive patients with 214 hepatocellular carcinomas were retrospectively included. One hundred fifty-eight tumors were treated with an expandable monopolar electrode and 56 with a multipolar technique using several linear bipolar electrodes. Imaging studies at 6 weeks after treatment, then every 3 months, assessed local effectiveness. Radiofrequency failure was defined as persistent residual tumor after two sessions (primary radiofrequency failure) or local tumor recurrence during follow-up. This study received institutional review board approval (number 2014/77). Imaging showed complete tumor ablation in 207 of 214 lesions after the first session of radiofrequency. After a second session, only two cases of residual viable tumor were observed. During follow-up, there were 46 local tumor recurrences. Thus, radiofrequency failure occurred in 48/214 (22.4%) cases. By multivariate analysis, technique (P < 0.001) and tumor size (P = 0.023) were independent predictors of radiofrequency failure. Failure rate was lower with the multipolar technique for tumors < 25 mm (P = 0.023) and for tumors between 25 and 45 mm (P = 0.082). There was no difference for tumors ≥ 45 mm (P = 0.552). Compared to monopolar radiofrequency, multipolar radiofrequency improves tumor ablation with a subsequent lower rate of local tumor recurrence. © 2015 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Can non-selective beta-blockers prevent hepatocellular carcinoma in patients with cirrhosis?

PubMed

Thiele, Maja; Wiest, Reiner; Gluud, Lise Lotte; Albillos, Agustín; Krag, Aleksander

2013-11-01

Hepatocellular carcinoma is the main liver-related cause of death in patients with compensated cirrhosis. The early phases are asymptomatic and the prognosis is poor, which makes prevention essential. We propose that non-selective beta-blockers decrease the incidence and growth of hepatocellular carcinoma via a reduction of the inflammatory load from the gut to the liver and inhibition of angiogenesis. Due to their effect on the portal pressure, non-selective beta-blockers are used for prevention of esophageal variceal bleeding. Recently, non-hemodynamic effects of beta-blockers have received increasing attention. Blockage of β-adrenoceptors in the intestinal mucosa and gut lymphatic tissue together with changes in type and virulence of the intestinal microbiota lead to reduced bacterial translocation and a subsequent decrease in the portal load of pathogen-associated molecular patterns. This may reduce hepatic inflammation. Blockage of β-adrenoceptors also decrease angiogenesis by inhibition of vascular endothelial growth factors. Because gut-derived inflammation and neo-angiogenesis are important in hepatic carcinogenesis, non-selective beta-blockers can potentially reduce the development and growth of hepatocellular carcinoma. Rodent and in vitro studies support the hypothesis, but clinical verification is needed. Different study designs may be considered. The feasibility of a randomized controlled trial is limited due to the necessary large number of patients and long follow-up. Observational studies carry a high risk of bias. The meta-analytic approach may be used if the incidence and mortality of hepatocellular carcinoma can be extracted from trials on variceal bleeding and if the combined sample size and follow up is sufficient. Copyright © 2013 Elsevier Ltd. All rights reserved.

Pituitary metastasis of hepatocellular carcinoma presenting with panhypopituitarism: a case report.

PubMed

Tanaka, Tomoko; Hiramatsu, Katsushi; Nosaka, Takuto; Saito, Yasushi; Naito, Tatsushi; Takahashi, Kazuto; Ofuji, Kazuya; Matsuda, Hidetaka; Ohtani, Masahiro; Nemoto, Tomoyuki; Suto, Hiroyuki; Yamamoto, Tatsuya; Kimura, Hirohiko; Nakamoto, Yasunari

2015-11-06

Metastasis to the pituitary gland is extremely rare and is often detected incidentally by symptoms associated with endocrine dysfunction. Breast and lung cancer are the most common primary metastasizing to pituitary gland. Metastasis from hepatocellular carcinoma to the pituitary gland is extremely rare, with only 10 cases having been previously reported. We present here the first case of pituitary metastasis of hepatocellular carcinoma presenting with panhypopituitarism diagnosed by magnetic resonance imaging. We report the case of an 80-year-old Japanese woman who presented with the sudden onset of hypotension and bradycardia after having previously been diagnosed with hepatocellular carcinoma. Based on low levels of pituitary hormones, she was diagnosed with panhypopituitarism caused by metastasis of the hepatocellular carcinoma to the pituitary gland. Magnetic resonance imaging with arterial spin-labeling was effective in the differential diagnosis of the intrasellar tumor. The patient died despite hormone replacement therapy because of hypovolemic shock. Metastasis to the pituitary gland causes various non-specific symptoms, so it is difficult to diagnose. The present case emphasizes the importance of diagnostic imaging in identifying these metastases. Clinicians should consider the possibility of pituitary metastasis in patients with malignant tumors who demonstrate hypopituitarism.

[Care pathway of patients with hepatocellular carcinoma in France: State of play in 2017].

PubMed

Costentin, Charlotte; Ganne-Carrié, Nathalie; Rousseau, Benoit; Gérolami, René; Barbare, Jean-Claude

2017-09-01

Hepatocellular carcinoma is a major public health problem with one of the highest overall mortality compared to other cancers. The median overall survival in France in a hospital population with hepatocellular carcinoma is 9.4 months. Several publications reported a positive impact of hepatocellular carcinoma screening on diagnosis at an early-stage, eligibility for curative treatment and overall survival. However, the identification of patients to be included in a hepatocellular carcinoma screening program and the application of screening recommendations are not optimal. Other studies suggest a potentially negative impact of delayed diagnosis or treatment initiation on the patient's prognosis. Finally, marked variations between French regions and departments have been described in terms of access to curative treatment and overall survival. In this review article, we propose a state of play of the hepatocellular carcinoma patient's care pathway in France with the aim of identifying potential breaking points with negative impact on prognosis and of developing proposals for improvement. Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Caturelli, Eugenio; Biasini, Elisabetta; Bartolucci, Francesca

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 yieldedmore » 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)« less

Knockdown of long noncoding RNA linc-ITGB1 suppresses migration, invasion of hepatocellular carcinoma via regulating ZEB1.

PubMed

Yu, W-W; Wang, K; Liao, G-J

2017-11-01

This research focuses on the influence of linc-ITGB1 on the metastasis of hepatocellular carcinoma and further explores its underlying mechanism. A total of 70 hepatocellular carcinoma patients were chosen for our study. RT-qPCR was used for detecting the expression level of linc-ITGB1 in their cancer tissues. Moreover, the expression level of linc-ITGB1 was also detected in hepatocellular carcinoma cell lines. Furthermore, whether linc-ITGB1 could affect the migrated and invaded ability of hepatocellular carcinoma cells was determined by wound healing assay and transwell assay. We further explored the potential mechanism by RT-qPCR and Western blot assay. Linc-ITGB1 expression level in hepatocellular carcinoma tissues was remarkably higher than that in adjacent tissues. Moreover, migrated and invaded ability of hepatocellular carcinoma cells was inhibited through knockdown of linc-ITGB1. Further study revealed that silenced linc-ITGB1 inhibited the expression of ZEB1 and then suppressed epithelial to mesenchymal transition (EMT), which was important during the metastasis of hepatocellular carcinoma. Moreover, the inhibition of cell invasion by silenced linc-ITGB1 could be rescued through overexpression of ZEB1 in hepatocellular carcinoma. The results indicate that linc-ITGB1, a novel oncogene in tumorigenesis, could promote the metastasis and EMT via ZEB1, which may offer a possible therapeutic target in hepatocellular carcinoma.

Genome-wide differences in hepatitis C- vs alcoholism-associated hepatocellular carcinoma

PubMed Central

Derambure, Céline; Coulouarn, Cédric; Caillot, Frédérique; Daveau, Romain; Hiron, Martine; Scotte, Michel; François, Arnaud; Duclos, Celia; Goria, Odile; Gueudin, Marie; Cavard, Catherine; Terris, Benoit; Daveau, Maryvonne; Salier, Jean-Philippe

2008-01-01

AIM: To look at a comprehensive picture of etiology-dependent gene abnormalities in hepatocellular carcinoma in Western Europe. METHODS: With a liver-oriented microarray, transcript levels were compared in nodules and cirrhosis from a training set of patients with hepatocellular carcinoma (alcoholism, 12; hepatitis C, 10) and 5 controls. Loose or tight selection of informative transcripts with an abnormal abundance was statistically valid and the tightly selected transcripts were next quantified by qRTPCR in the nodules from our training set (12 + 10) and a test set (6 + 7). RESULTS: A selection of 475 transcripts pointed to significant gene over-representation on chromosome 8 (alcoholism) or -2 (hepatitis C) and ontology indicated a predominant inflammatory response (alcoholism) or changes in cell cycle regulation, transcription factors and interferon responsiveness (hepatitis C). A stringent selection of 23 transcripts whose differences between etiologies were significant in nodules but not in cirrhotic tissue indicated that the above dysregulations take place in tumor but not in the surrounding cirrhosis. These 23 transcripts separated our test set according to etiologies. The inflammation-associated transcripts pointed to limited alterations of free iron metabolism in alcoholic vs hepatitis C tumors. CONCLUSION: Etiology-specific abnormalities (chromosome preference; differences in transcriptomes and related functions) have been identified in hepatocellular carcinoma driven by alcoholism or hepatitis C. This may open novel avenues for differential therapies in this disease. PMID:18350606

Role of microRNA-7 and selenoprotein P in hepatocellular carcinoma.

PubMed

Tarek, Marwa; Louka, Manal Louis; Khairy, Eman; Ali-Labib, Randa; Zakaria Zaky, Doaa; Montasser, Iman F

2017-05-01

There is an obvious need to diagnose hepatocellular carcinoma using novel non-invasive and sensitive biomarkers. In this regard, the aim of this study was to evaluate and correlate both relative quantification of microRNA-7 using quantitative real time polymerase chain reaction and quantitative analysis of selenoprotein P using enzyme-linked immunosorbent assay in sera of hepatocellular carcinoma patients, chronic liver disease patients, as well as normal healthy subjects in order to establish a new diagnostic biomarker with a valid non-invasive technique. In addition, this study aimed to investigate whether changes in selenium supply affect microRNA-7 expression and selenoprotein P levels in human hepatocarcinoma cell line (HepG2). The results showed a highly significant decrease in serum microRNA-7 relative quantification values and selenoprotein P levels in malignant group in comparison with benign and control groups. The best cutoff for serum microRNA-7 and selenoprotein P to discriminate hepatocellular carcinoma group from benign and control groups was 0.06 and 4.30 mg/L, respectively. Furthermore, this study showed that changes in selenium supply to HepG2 cell line can alter the microRNA-7 profile and are paralleled by changes in the concentration of its target protein (selenoprotein P). Hence, serum microRNA-7 and selenoprotein P appear to be potential non-invasive diagnostic markers for hepatocellular carcinoma. Moreover, the results suggest that selenium could be used as an anticancer therapy for hepatocellular carcinoma by affecting both microRNA-7 and selenoprotein P.

Gastric and hepatocellular carcinomas do not overexpress the same ribosomal protein messenger RNAs as colonic carcinoma.

PubMed

Barnard, G F; Staniunas, R J; Mori, M; Puder, M; Jessup, M J; Steele, G D; Chen, L B

1993-09-01

The levels of a number of ribosomal protein mRNAs are reported to be increased in human colon cancer. We have assessed whether selected ribosomal protein mRNAs are overexpressed in other gastrointestinal malignancies, namely gastric and hepatocellular carcinomas. Subtracted complementary DNA libraries were generated from paired samples of human (a) colorectal carcinoma minus adjacent normal colonic mucosa and (b) hepatocellular carcinoma minus adjacent normal liver. Screening of approximately 3% of these library clones determined that ribosomal protein mRNAs encoding L18 and L37 (not previously reported) and P0 and S6 were overexpressed in one or the other library. Their complementary DNA inserts were then used as probes to evaluate their expression in a larger number of paired tumor/normal surgical samples of human colonic, gastric, and hepatocellular carcinomas, by Northern hybridization. The mRNA signal was greater in the colonic carcinoma than in paired adjacent normal colonic mucosa in 38 of 42 cases for P0 [tumor/normal (T/N) ratio = 3.0 +/- 0.3, mean +/- SE, P < 0.001] (G. F. Barnard, R. J. Staniunas, S. Bao, K. Mafune, J. L. Gollan, G. D. Steele, Jr., and L. B. Chen, Cancer Res., 52: 3067-3072, 1992), in 25 of 28 cases for L18 (T/N ratio = 3.7 +/- 0.5, P < 0.001), in 27 of 28 cases for L37 (T/N ratio = 5.3 +/- 0.4, P < 0.001), and in 24 of 28 cases for S6 (T/N ratio = 3.1 +/- 0.5, P < 0.01). The level of mRNA overexpression of L18 and S6 did not correlate with the Dukes' stage of disease. In hepatocellular carcinoma samples, using the same four ribosomal protein complementary DNA probes, only P0 mRNA was significantly increased (T/N ratio = 2.8 +/- 0.4, n = 6, P = 0.047). In gastric carcinoma samples, none of these mRNAs was increased (mean T/N ratios = 0.9-1.2, n = 6). Therefore, gastric and hepatocellular carcinomas do not overexpress the same ribosomal protein mRNAs as do colonic carcinoma.

Assessment of the Clinical Utility of Glypican 3 as a Serum Marker for the Diagnosis of Hepatocellular Carcinoma.

PubMed

Jia, Xiaobo; Gao, Yingtang; Zhai, Daokuan; Liu, Jiao; Cai, Junjun; Wang, Yajie; Jing, Li; Du, Zhi

2016-12-01

Glypican-3 has been reported to be one of the most promising serum markers for hepatocellular carcinoma. This study aimed to assess the clinical utility of serum glypican 3 for the diagnosis of hepatocellular carcinoma. We recruited consecutive patients on a large scale, 283 with hepatocellular carcinoma, 445 with chronic hepatic diseases, and 162 normal controls, to assess the diagnostic accuracy of serum glypican 3 for hepatocellular carcinoma by enzyme-linked immunosorbent assay. In addition, we further analyzed the relationship between the serum levels of α-fetoprotein and glypican-3 in patients with hepatocellular carcinoma. The results indicated that serum glypican 3 was elevated in patients with hepatocellular carcinoma (0 ng/mL, range = 0-14.0 ng/mL, P = .033) and liver cirrhosis (0 ng/mL, range = 0-12.5 ng/mL, P = .001) compared to the levels in normal control (0 ng/mL, range = 0-4.3 ng/mL), but there was no difference between hepatocellular carcinoma and liver cirrhosis (P = .097). The area under the curve of the receiver-operating characteristics curve for hepatocellular carcinoma versus all controls was 0.519, with a sensitivity of 39.9%, a specificity of 60.6%, and an optimal cutoff value of 0.002 ng/mL. The positive and negative predictive values were 32.0% and 68.3%, respectively. No significant correlation in serum levels was observed between glypican 3 and α-fetoprotein (P > .05). The diagnostic sensitivity for hepatocellular carcinoma increased to 72.8% (206 of the 283) when glypican 3 was combined with α-fetoprotein. Glypican 3 was not a promising serum maker for the diagnosis of hepatocellular carcinoma alone, but it could be complementary to α-fetoprotein and elevate the sensitivity of hepatocellular carcinoma diagnosis. © The Author(s) 2015.

[Localization of hepatocellular carcinoma with monoclonal antibodies].

PubMed

Liu, Y

1991-07-01

We prepared monoclonal antibodies (MAbs) against hepatocellular carcinoma using cell suspensions isolated from surgical fresh hepatoma specimens as antigen. Totally we got 6 strains of hybridoma cell lines stably secreting MAbs for more than 2 years. Immunocytochemically they stained positively most of the paraffin embedded hepatoma tissues (63.1 to 91.1%) without reaction to the normal liver tissues. Localization of human hepatoma with 125I or 131I labelled MAbs in nude mice was done by IV injection, which showed clear tumor image by ECT radioimmunodetection and autoradiography of tissues. The T/N ratios of different MAbs were 3.1, 3.6, 5.15 and that of HAb 18-F (ab')2 was 14.4. Among 15 patients suspected to have hepatoma and given the labelled MAb, 13 proved pathologically to be hepatocellular carcinoma.

Bacoside A downregulates matrix metalloproteinases 2 and 9 in DEN-induced hepatocellular carcinoma.

PubMed

Janani, Panneerselvam; Sivakumari, Kanakarajan; Geetha, Arumugam; Yuvaraj, Sambandam; Parthasarathy, Chandrakesan

2010-03-01

Cancer metastasis is a complex multi-step process, responsible for a majority of cancer-related deaths by affecting the critical organs and causing complications in therapies. Hepatocellular carcinoma is a multi-factorial disease and is the third most common cause of cancer related mortality worldwide. Clinical and experimental studies have shown that MMP-2 and MMP-9 are involved in tumor invasion and metastases and their elevated expression has been associated with poor prognosis. Our recent studies showed a strong anti-oxidant and hepatoprotective effects of bacoside A (BA) against carcinogen. Nevertheless the effect of BA on the activities and expression of MMP-2 and MMP-9 during hepatocellular carcinoma is not yet recognized. Therefore, the present study was designed to assess the same. Results of gelatin zymography study showed that BA co-treatment significantly decreased the activities of MMP-2 and MMP-9, which is increased during hepatocellular carcinoma. Further immunoblot analysis showed decreased expression of MMP-2 and MMP-9 in rats co-treated with BA compared to DEN-induced hepatocellular carcinoma. Our results reveal that BA exerts its anti-metastatic effect against DEN-induced hepatocellular carcinoma by inhibiting the activities and expressions of MMP-2 and MMP-9. 2010 John Wiley & Sons, Ltd.

Aflatoxins, hepatocellular carcinoma and public health.

PubMed

Magnussen, Arvin; Parsi, Mansour A

2013-03-14

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer deaths worldwide, primarily affecting populations in the developing countries. Aflatoxin, a food contaminant produced by the fungi Aspergillus flavus and Aspergillus parasiticus, is a known human carcinogen that has been shown to be a causative agent in the pathogenesis of HCC. Aflatoxin can affect a wide range of food commodities including corns, oilseeds, spices, and tree nuts as well as milk, meat, and dried fruit. Many factors affect the growth of Aspergillus fungi and the level of aflatoxin contamination in food. Drought stress is one of the factors that increase susceptibility of plants to Aspergillus and thus aflatoxin contamination. A recent drought is thought to be responsible for finding of trace amounts of aflatoxin in some of the corn harvested in the United States. Although it's too soon to know whether aflatoxin will be a significant problem, since United States is the world's largest corn producer and exporter, this has raised alarm bells. Strict regulations and testing of finished foods and feeds in the United States should prevent a major health scare, and prevent human exposure to deleterious levels of aflatoxin. Unfortunately, such regulations and testing are not in place in many countries. The purpose of this editorial is to summarize the current knowledge on association of aflatoxin and HCC, encourage future research and draw attention to this global public health issue.

Environmental Exposures and Hepatocellular Carcinoma

PubMed Central

Wu, Hui-Chen

2013-01-01

Infection with hepatitis B and/or hepatitis C virus is a well-established risk factor for the development of hepatocellular carcinoma (HCC). However, it is now clear that certain occupational, environmental, and lifestyle factors also play a role in cancer development. Among these factors are smoking, alcohol consumption, workplace exposure to vinyl chloride, and exposure to polycylic aromatic hydrocarbons and aflatoxins. There is also evidence that several other chemical and infectious agents have a role in inducing HCC in humans. Epidemiologic studies and the use of biomarkers have provided essential data to demonstrate the importance of some of these factors in human risk, while animal studies have suggested that other chemicals may also play a role. Although immunization against hepatitis B virus infection remains the primary method of preventing HCC in regions of the world where this virus is a primary etiologic agent, there is currently no vaccine for hepatitis C virus. Thus, limiting exposure to other known risk factors remains an important mechanism in preventing HCC. PMID:26357611

Do occupational exposures to vinyl chloride cause hepatocellular carcinoma and cirrhosis?

PubMed

Lotti, Marcello

2017-05-01

Controversy exists about the association between occupational exposures to vinyl chloride and hepatocellular carcinoma and cirrhosis. Two large multicentre mortality cohort studies, one American and another European, reported higher mortality for primary cancer of liver and biliary tract. However, the American study was not able to rule out misclassification, because based on death certificates and under the heading primary liver cancers, some angiosarcomas, the typical neoplasia associated with vinyl chloride, may have been included. The American study does not report on cirrhosis mortality. The European study also reports higher mortality of primary liver cancer, but contrary to the American study in a further analysis based on 10 verified cases of hepatocellular carcinoma, an exposure-response trend with duration of employment and with cumulative exposure to vinyl chloride was detected. A smaller cohort belonging to this multicentre cohort confirmed these results. Meta-analyses based on the two large cohorts concluded for a small excess of primary liver cancer, although misclassification could not be ruled out. Excess risk of cirrhosis was reported in the European cohort, in a subcohort and in a cross-sectional study. However, a meta-analysis did not confirm this excess. Several critical appraisals of the literature reached antithetical conclusions about hepatocellular carcinoma, cirrhosis and occupational exposures to vinyl chloride. For both hepatocellular carcinoma and cirrhosis, a study suggests an additive and multiplicative effect of vinyl chloride exposure with viral hepatitis and alcohol consumption respectively. Pathology reports seem to indicate a possible development of hepatocellular carcinoma but not of cirrhosis after high exposures to vinyl chloride. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Diagnostic and prognostic potential of serum miR-132/212 cluster in patients with hepatocellular carcinoma.

PubMed

Wang, Feng; Wang, Jun; Ju, Linlin; Chen, Lin; Cai, Weihua; Yang, Jialin

2018-01-01

Background It has been reported that both of the miR-132/212 (micro-RNA) cluster members, miR-132 and miR-212, are downregulated in hepatocellular carcinoma. Nevertheless, the expression pattern and clinical utility of serum miR-132/212 in hepatocellular carcinoma are still unknown. Methods In this study, serum concentrations of miR-132 and miR-212 were measured in 80 hepatocellular carcinoma patients, 51 controls with chronic liver diseases and 42 healthy volunteers by using quantitative real-time polymerase chain reaction. Results In hepatocellular carcinoma patients, serum concentrations of miR-132 and miR-212 were significantly reduced and strongly correlated (r = 0.603, p < 0.001). Receiver operator characteristic analyses showed that serum miR-132 and miR-212 might have a potential role in the diagnosis of hepatocellular carcinoma. Moreover, the combination of serum miR-132, miR-212 and alpha-fetoprotein improved the diagnostic efficiency for hepatocellular carcinoma, especially in sensitivity and negative predictive value. Serum miR-132 was associated with tumour differentiation degree ( p = 0.021) and tumour-node-metastasis stage ( p = 0.002); serum miR-212 correlated with tumour size ( p = 0.023) and tumour-node-metastasis stage ( p = 0.007). Kaplan-Meier analyses indicated poorer overall survival in hepatocellular carcinoma patients with lower serum concentrations of miR-132 ( p < 0.001) and miR-212 ( p = 0.005). Conclusions Our results suggest that both components of the miR-132/212 cluster have potential roles as non-invasive serum biomarkers for diagnosis and prognosis of hepatocellular carcinoma.

The application of proteomics in different aspects of hepatocellular carcinoma research.

PubMed

Xing, Xiaohua; Liang, Dong; Huang, Yao; Zeng, Yongyi; Han, Xiao; Liu, Xiaolong; Liu, Jingfeng

2016-08-11

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors, which is causing the second leading cancer-related death worldwide. With the significant advances of high-throughput protein analysis techniques, the proteomics offered an extremely useful and versatile analytical platform for biomedical researches. In recent years, different proteomic strategies have been widely applied in the various aspects of HCC studies, ranging from screening the early diagnostic and prognostic biomarkers to in-depth investigating the underlying molecular mechanisms. In this review, we would like to systematically summarize the current applications of proteomics in hepatocellular carcinoma study, and discuss the challenges of applying proteomics in study clinical samples, as well as discuss the possible application of proteomics in precision medicine. In this review, we have systematically summarized the current applications of proteomics in hepatocellular carcinoma study, ranging from screening biomarkers to in-depth investigating the underlying molecular mechanisms. In addition, we have discussed the challenges of applying proteomics in study clinical samples, as well as the possible applications of proteomics in precision medicine. We believe that this review would help readers to be better familiar with the recent progresses of clinical proteomics, especially in the field of hepatocellular carcinoma research. Copyright © 2016 Elsevier B.V. All rights reserved.

Impact factors on development of cirrhosis and subsequent hepatocellular carcinoma.

PubMed

Holmes-McNary, M

2001-07-01

Hepatocellular carcinoma (HCC), on the rise in many countries, is of multifactorial etiology. Its etiological associations differ between populations at high and low risk. Africans and Chinese have the highest incidence of HCC, but other affected groups include African Americans, Japanese, and Native Americans. Chronic infections by hepatitis B and hepatitis C viruses are major risk factors worldwide, although mechanisms through which the infections cause liver cancer are yet to be explained. Other documented risk factors have been postulated and include dietary exposure, cigarette smoking, alcohol consumption, diabetes, oral infection, and oral contraceptive use. In addition, many naturally occurring and synthetic chemicals to which humans are exposed via accidental contamination of food or water are shown to induce liver cancer in experimental animals. Consequently, assessment of possible human liver cancer risk associated with such exposures is complex. Early diagnosis and transplantation are the best treatments presently, although transplantation is not widely available due to donor shortage. Every effort should be directed toward the prevention of HCC, through the treatment and prevention of hepatitis and oral infections, prevention of chronic hepatitis progressing to cirrhosis, and prevention of the cirrhotic liver from developing HCC through chemopreventive modalities. However, at present, very few such studies exist.

Hepatocellular carcinoma and evidence-based surgery

PubMed Central

Braillon, Alain

2009-01-01

Transplantation cannot be considered the most important therapeutic procedure for hepatocellular carcinoma (HCC). In France, no more than 2% of patients with HCC undergo a transplantation. Randomized controlled trial must assess the benefit to risk ratio of various potentially “curative” treatment procedures (transplantation, resection, radio-frequency ablation). PMID:19908350

Overexpression of Rabl3 and Cullin7 is associated with pathogenesis and poor prognosis in hepatocellular carcinoma.

PubMed

An, Jun; Liu, Zhiyong; Liang, Qiong; Pan, Yuhang; Li, Haifeng; Wang, Ruizhi; Jin, Yi

2017-09-01

The expression of Rabl3 and Cullin7 is relevant to the carcinogenesis of certain cancers. However, the relationship of this expression with hepatocellular carcinoma remains unclear. To study the protein expression of Rabl3 and Cullin7 and to evaluate their role in hepatocarcinogenesis, in 162 cases of hepatocellular carcinoma, we used immunohistochemistry to investigate the expression of Rabl3 and Cullin7 in both the cancer tissues and the normal hepatic tissues around the hepatocellular carcinoma. The results demonstrated that the rates of positive Rabl3 and Cullin7 expression were 80.2% and 69.1%, respectively, in hepatocellular carcinoma tissues. However, the rates of positive Rabl3 and Cullin7 expression were 31.5% and 29.0%, respectively, in adjacent normal hepatic tissues. Rabl3 and Cullin7 were expressed at significantly higher rates in hepatocellular carcinoma compared with adjacent normal hepatic tissues (P<.01). The rates of positive Rabl3 and Cullin7 expression were higher in the hepatocellular carcinoma tissues of patients with lymph node metastasis, tumor thrombi in the portal vein and an advanced clinical stage (P<.05). A positive correlation between the expression of Rabl3 and the expression of Cullin7 (r=0.27, P<.001) was also observed in our hepatocellular carcinoma cohort. Moreover, patients with positive expression for both Rabl3 and Cullin7 had a remarkably shorter survival time compared with patients with negative expression for both proteins (P<.05). Therefore, the expression of the Rabl3 and Cullin7 proteins may play an important role in the pathogenesis and progression of hepatocellular carcinoma and could be used as a prognostic indicator in patients with hepatocellular carcinoma. Copyright © 2017 Elsevier Inc. All rights reserved.

Contemporary management of fibrolamellar hepatocellular carcinoma: diagnosis, treatment, outcome, prognostic factors, and recent developments.

PubMed

Kassahun, Woubet Tefera

2016-05-23

Fibrolamellar hepatocellular carcinoma (FL-HCC) is a malignant liver tumor which is thought to be a variant of conventional hepatocellular carcinoma (HCC). It accounts for a small proportion of HCC cases and occurs in a distinctly different group of patients which are young and usually not in the setting of chronic liver disease. The diagnosis of FL-HCC requires the integration of clinical information, imaging studies, and histology. In terms of the treatment options, the only potentially curative treatment option for patients who have resectable disease is surgery either liver resection (LR) or liver transplantation (LT). When performed in a context of aggressive therapy, long-term outcomes after surgery, particularly liver resection for FL-HCC, were favorable. The clinical outcome of patients with unresectable disease is suboptimal with median survival of less than 12 months. The aim of this review is to update the available evidence on diagnosis, treatment options, outcome predictors, and recent developments of patients with this rare disease and to provide a summarized overview of the available literature.

Frequent alteration of the protein synthesis of enzymes for glucose metabolism in hepatocellular carcinomas.

PubMed

Shimizu, Takayuki; Inoue, Ken-ichi; Hachiya, Hiroyuki; Shibuya, Norisuke; Shimoda, Mitsugi; Kubota, Keiichi

2014-09-01

Cancer cells show enhanced glycolysis and inhibition of oxidative phosphorylation, even in the presence of sufficient oxygen (aerobic glycolysis). Glycolysis is much less efficient for energy production than oxidative phosphorylation, and the reason why cancer cells selectively use glycolysis remains unclear. Biospecimens were collected from 45 hepatocellular carcinoma patients. Protein samples were prepared through subcellular localization or whole-cell lysis. Protein synthesis was measured by SDS-PAGE and immunoblotting. mRNA transcription was measured using quantitative RT-PCR. Statistical correlation among immunoblotting data and clinicolaboratory factors were analyzed using SPSS. Enzymes for oxidative phosphorylation (SDHA and SDHB) were frequently decreased (56 and 48 % of patients, respectively) in hepatocellular carcinomas. The lowered amount of the SDH protein complex was rarely accompanied by stabilization of HIF1α and subsequent activation of the hypoxia response. On the other hand, protein synthesis of G6PD and TKT, enzymes critical for pentose phosphate pathway (PPP), was increased (in 45 and 55 % of patients, respectively), while that of ALDOA, an enzyme for mainstream glycolysis, was eliminated (in 55 % of patients). Alteration of protein synthesis was correlated with gene expression for G6PD and TKT, but not for TKTL1, ALDOA, SDHA or SDHB. Augmented transcription and synthesis of PPP enzymes were accompanied by nuclear accumulation of NRF2. Hepatocellular carcinomas divert glucose metabolism to the anabolic shunt by activating transcription factor NRF2.

High-intensity focused ultrasound ablation induced apoptosis in human hepatocellular carcinoma.

PubMed

Yi, Jiang; Wu, Liguo; Liu, Zhou; Zou, Haibo; Li, Ning; Chen, Heping; Liu, Jinheng; Li, Tao; Zhang, Gang

2014-01-01

To evaluate the effect of high-intensity ultrasound (HIFU) ablation on human hepatocellular carcinoma tissues and apoptotic proteins (bcl-2 and p-53). Patients with hepatocellular carcinoma at stage B were treated with HIFU ablation. Levels of bcl-2 and p53 protein and the apoptosis rate were evaluated both in the pre-treatment and post-treatment tissue specimens using immunochemistry and TUNEL methods, respectively. After HIFU ablation, p53 protein levels were significantly increased around the coagulation necrosis area, whereas, the level of bcl-2 was significantly decreased. More apoptosis cells were found post ablation compared with those in the pretreatment tissues. Additionally, no significant correlation was found between p53/bcl-2 levels and apoptotic index. HIFU ablation may exert promote the apoptosis of hepatocellular carcinoma cells and the effect has a closely association with the change of p53 and bcl-2 expression.

Interstitial Fluid Flow Increases Hepatocellular Carcinoma Cell Invasion through CXCR4/CXCL12 and MEK/ERK Signaling

PubMed Central

2015-01-01

Hepatocellular carcinoma (HCC) is the most common form of liver cancer (~80%), and it is one of the few cancer types with rising incidence in the United States. This highly invasive cancer is very difficult to detect until its later stages, resulting in limited treatment options and low survival rates. There is a dearth of knowledge regarding the mechanisms associated with the effects of biomechanical forces such as interstitial fluid flow (IFF) on hepatocellular carcinoma invasion. We hypothesized that interstitial fluid flow enhanced hepatocellular carcinoma cell invasion through chemokine-mediated autologous chemotaxis. Utilizing a 3D in vitro invasion assay, we demonstrated that interstitial fluid flow promoted invasion of hepatocellular carcinoma derived cell lines. Furthermore, we showed that autologous chemotaxis influences this interstitial fluid flow-induced invasion of hepatocellular carcinoma derived cell lines via the C-X-C chemokine receptor type 4 (CXCR4)/C-X-C motif chemokine 12 (CXCL12) signaling axis. We also demonstrated that mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling affects interstitial fluid flow-induced invasion; however, this pathway was separate from CXCR4/CXCL12 signaling. This study demonstrates, for the first time, the potential role of interstitial fluid flow in hepatocellular carcinoma invasion. Uncovering the mechanisms that control hepatocellular carcinoma invasion will aid in enhancing current liver cancer therapies and provide better treatment options for patients. PMID:26560447

Hepatocellular carcinoma and the risk of occupational exposure

PubMed Central

Rapisarda, Venerando; Loreto, Carla; Malaguarnera, Michele; Ardiri, Annalisa; Proiti, Maria; Rigano, Giuseppe; Frazzetto, Evelise; Ruggeri, Maria Irene; Malaguarnera, Giulia; Bertino, Nicoletta; Malaguarnera, Mariano; Catania, Vito Emanuele; Di Carlo, Isidoro; Toro, Adriana; Bertino, Emanuele; Mangano, Dario; Bertino, Gaetano

2016-01-01

Hepatocellular carcinoma (HCC) is the most common type of liver cancer. The main risk factors for HCC are alcoholism, hepatitis B virus, hepatitis C virus, nonalcoholic steatohepatitis, obesity, type 2 diabetes, cirrhosis, aflatoxin, hemochromatosis, Wilson’s disease and hemophilia. Occupational exposure to chemicals is another risk factor for HCC. Often the relationship between occupational risk and HCC is unclear and the reports are fragmented and inconsistent. This review aims to summarize the current knowledge regarding the association of infective and non-infective occupational risk exposure and HCC in order to encourage further research and draw attention to this global occupational public health problem. PMID:27168870

Prognostic Impact of Indocyanine Green Plasma Disappearance Rate in Hepatocellular Carcinoma Patients after Radiofrequency Ablation: A Prognostic Nomogram Study

PubMed Central

Azumi, Motoi; Suda, Takeshi; Terai, Shuji; Akazawa, Kouhei

2017-01-01

Objective Radiofrequency ablation has been used widely for the local ablation of hepatocellular carcinoma, particularly in its early stages. The study aim was to identify significant prognostic factors and develop a predictive nomogram for patients with hepatocellular carcinoma who have undergone radiofrequency ablation. We also developed the formula to predict the probability of 3- and 5-year overall survival based on clinical variables. Methods We retrospectively studied 96 consecutive patients with hepatocellular carcinoma who had undergone radiofrequency ablation as a first-line treatment. Independent and significant factors affecting the overall survival were selected using a Cox proportional hazards model, and a prognostic nomogram was developed based on these factors. The predictive accuracy of the nomogram was determined by Harrell's concordance index and compared with the Cancer of the Liver Italian Program score and Japan Integrated Staging score. Results A multivariate analysis revealed that age, indocyanine green plasma disappearance rate, and log(des-gamma-carboxy prothrombin) level were independent and significant factors influencing the overall survival. The nomogram was based on these three factors. The mean concordance index of the nomogram was 0.74±0.08, which was significantly better than that of conventional staging systems using the Cancer of the Liver Italian Program score (0.54±0.03) and Japan Integrated Staging score (0.59±0.07). Conclusion This study suggested that the indocyanine green plasma disappearance rate and age at radiofrequency ablation (RFA) and des-gamma-carboxy-prothrombin (DCP) are good predictors of the prognosis in hepatocellular carcinoma patients after radiofrequency ablation. We successfully developed a nomogram using obtainable variables before treatment. PMID:28458303

Prognostic Impact of Indocyanine Green Plasma Disappearance Rate in Hepatocellular Carcinoma Patients after Radiofrequency Ablation: A Prognostic Nomogram Study.

PubMed

Azumi, Motoi; Suda, Takeshi; Terai, Shuji; Akazawa, Kouhei

2017-01-01

Objective Radiofrequency ablation has been used widely for the local ablation of hepatocellular carcinoma, particularly in its early stages. The study aim was to identify significant prognostic factors and develop a predictive nomogram for patients with hepatocellular carcinoma who have undergone radiofrequency ablation. We also developed the formula to predict the probability of 3- and 5-year overall survival based on clinical variables. Methods We retrospectively studied 96 consecutive patients with hepatocellular carcinoma who had undergone radiofrequency ablation as a first-line treatment. Independent and significant factors affecting the overall survival were selected using a Cox proportional hazards model, and a prognostic nomogram was developed based on these factors. The predictive accuracy of the nomogram was determined by Harrell's concordance index and compared with the Cancer of the Liver Italian Program score and Japan Integrated Staging score. Results A multivariate analysis revealed that age, indocyanine green plasma disappearance rate, and log (des-gamma-carboxy prothrombin) level were independent and significant factors influencing the overall survival. The nomogram was based on these three factors. The mean concordance index of the nomogram was 0.74±0.08, which was significantly better than that of conventional staging systems using the Cancer of the Liver Italian Program score (0.54±0.03) and Japan Integrated Staging score (0.59±0.07). Conclusion This study suggested that the indocyanine green plasma disappearance rate and age at radiofrequency ablation (RFA) and des-gamma-carboxy-prothrombin (DCP) are good predictors of the prognosis in hepatocellular carcinoma patients after radiofrequency ablation. We successfully developed a nomogram using obtainable variables before treatment.

SGK2 promotes hepatocellular carcinoma progression and mediates GSK-3β/β-catenin signaling in HCC cells.

PubMed

Liu, Junying; Zhang, Guangdong; Lv, Yanping; Zhang, Xiaoyang; Ying, Cui; Yang, Suocheng; Kong, Xin; Yu, Yanzhang

2017-06-01

The phosphoinositide 3-kinase pathway is one of the most commonly altered pathways in human cancers. The serum/glucocorticoid-regulated kinase (SGK) family of serine/threonine kinases consists of three isoforms, SGK1, SGK2, and SGK3. This family of kinases is highly homologous to the AKT kinase family, sharing similar upstream activators and downstream targets. Few studies have investigated the role of SGK2 in hepatocellular carcinoma. Here, we report that SGK2 expression levels were upregulated in hepatocellular carcinoma tissues and human hepatoma cell lines compared to the adjacent normal liver tissues and a normal hepatocyte line, respectively. We found that downregulated SGK2 inhibits cell migration and invasive potential of hepatocellular carcinoma cell lines (SMMC-7721 and Huh-7).We also found that downregulated SGK2 suppressed the expression level of unphosphorylated (activated) glycogen synthase kinase 3 beta. In addition, SGK2 downregulation decreased the dephosphorylation (activation) of β-catenin by preventing its proteasomal degradation in the hepatocellular carcinoma cell lines. These findings suggest that SGK2 promotes hepatocellular carcinoma progression and mediates glycogen synthase kinase 3 beta/β-catenin signaling in hepatocellular carcinoma cells.

Synergistic growth inhibition by sorafenib and vitamin K2 in human hepatocellular carcinoma cells.

PubMed

Zhang, Yafei; Zhang, Bicheng; Zhang, Anran; Zhao, Yong; Zhao, Jie; Liu, Jian; Gao, Jianfei; Fang, Dianchun; Rao, Zhiguo

2012-09-01

Sorafenib is an oral multikinase inhibitor that has been proven effective as a single-agent therapy in hepatocellular carcinoma, and there is a strong rationale for investigating its use in combination with other agents. Vitamin K2 is nearly non-toxic to humans and has been shown to inhibit the growth of hepatocellular carcinoma. In this study, we evaluated the effects of a combination of sorafenib and vitamin K2 on the growth of hepatocellular carcinoma cells. Flow cytometry, 3-(4,5-dimethyl-2-thiazolyl-2,5-diphenyl-2H-tetrazolium bromide) and nude mouse xenograft assays were used to examine the effects of sorafenib and vitamin K2 on the growth of hepatocellular carcinoma cells. Western blotting was used to elucidate the possible mechanisms underlying these effects. Assays for 3-(4,5-dimethyl-2-thiazolyl-2,5-diphenyl-2H-tetrazolium bromide) revealed a strong synergistic growth-inhibitory effect between sorafenib and vitamin K2. Flow cytometry showed an increase in cell cycle arrest and apoptosis after treatment with a combination of these two drugs at low concentrations. Sorafenib-mediated inhibition of extracellular signal-regulated kinase phosphorylation was promoted by vitamin K2, and downregulation of Mcl-1, which is required for sorafenib-induced apoptosis, was observed after combined treatment. Vitamin K2 also attenuated the downregulation of p21 expression induced by sorafenib, which may represent the mechanism by which vitamin K2 promotes the inhibitory effects of sorafenib on cell proliferation. Moreover, the combination of sorafenib and vitamin K2 significantly inhibited the growth of hepatocellular carcinoma xenografts in nude mice. Our results determined that combined treatment with sorafenib and vitamin K2 can work synergistically to inhibit the growth of hepatocellular carcinoma cells. This finding raises the possibility that this combined treatment strategy might be promising as a new therapy against hepatocellular carcinoma, especially for patients

Curcumin inhibits vasculogenic mimicry through the downregulation of erythropoietin-producing hepatocellular carcinoma-A2, phosphoinositide 3-kinase and matrix metalloproteinase-2

PubMed Central

LIANG, YIMING; HUANG, MIN; LI, JIANWEN; SUN, XINLIN; JIANG, XIAODAN; LI, LIANGPING; KE, YIQUAN

2014-01-01

Glioblastomas (GBMs) are the most common and aggressive malignant primary brain tumors found in humans. In high-grade gliomas, vasculogenic mimicry (VM) is often detected. VM is the formation of de novo vascular networks by highly invasive tumor cells, instead of endothelial cells. An understanding of the mechanisms of VM formation will contribute to the targeted therapy of GBMs. In the present study, the efficacy of curcumin (CCM) on VM formation and its mechanisms were investigated. It was found that CCM inhibits the VM formation, proliferation, migration and invasion of human glioma U251 cells in a dose-dependent manner. Furthermore, CCM downregulated the protein and mRNA expression of erythropoietin-producing hepatocellular carcinoma-A2, phosphoinositide 3-kinase and matrix metalloproteinase-2, indicating that CCM may function through these factors for the inhibition of VM formation. These data provide novel insights into the use of CCM to antagonize VM, and may contribute to the angiogenesis-targeted therapy of malignant glioma. PMID:25202424

A multi-target protein of hTERTR-FAM96A presents significant anticancer potent in the treatment of hepatocellular carcinoma.

PubMed

Zhang, Meng-Yu; Wang, Jie-Ping

2017-04-01

The abilities to escape apoptosis induced by anticancer drugs are an essential factor of carcinogenesis and a hallmark of resistance to cancer therapy. In this study, we identified hTERTR-FAM96A (human telomerase reverse transcriptase-family with sequence similarity 96 member A) as a new efficient agent for apoptosome-activating and anti-tumor protein and investigated the potential tumor suppressor function in hepatocellular carcinoma. The hTERTR-FAM96A fusion protein was constructed by genetic engineering and its anticancer function of hTERTR-FAM96A was explored in vitro and in vivo by investigating the possible preclinical outcomes. Effects of hTERTR-FAM96A on improvement of apoptotic sensitivity and inhibition of migration and invasion were examined in cancer cells and tumors. Our results showed that the therapeutic effects of hTERTR-FAM96A were highly effective for inhibiting tumor growth and inducing apoptosis of hepatocellular carcinoma cells in H22-bearing nude mice. The hTERTR-FAM96A fusion protein could specifically bind with Apaf-1 and hTERT, which further induced apoptosis of hepatocellular carcinoma cells and improved apoptosis sensitivity. Our results indicated that hTERTR-FAM96A treatment enhanced cytotoxic effects by upregulation of cytotoxic T lymphocyte responses, interferon-γ release, and T lymphocyte infiltration. In addition, hTERTR-FAM96A led to tumor-specific immunologic cytotoxicity through increasing apoptotic body on hepatocellular tumors. Furthermore, hTERTR-FAM96A dramatically inhibited tumor growth, reduced death rate, and prolonged mice survival in hepatocellular carcinoma mice derived from three independent hepatocellular carcinoma mice cohorts compared to control groups. In summary, our data suggest that hTERTR-FAM96A may serve as an efficient anti-tumor agent for the treatment of hepatocellular carcinoma.

Hepatocellular Carcinoma Screening Associated with Early Tumor Detection and Improved Survival Among Patients with Cirrhosis in the US.

PubMed

Singal, Amit G; Mittal, Sahil; Yerokun, Olutola A; Ahn, Chul; Marrero, Jorge A; Yopp, Adam C; Parikh, Neehar D; Scaglione, Steve J

2017-09-01

Professional societies recommend hepatocellular carcinoma screening in patients with cirrhosis, but high-quality data evaluating its effectiveness to improve early tumor detection and survival in "real world" clinical practice are needed. We aim to characterize the association between hepatocellular carcinoma screening and early tumor detection, curative treatment, and overall survival among patients with cirrhosis. We performed a retrospective cohort study of patients diagnosed with hepatocellular carcinoma between June 2012 and May 2013 at 4 health systems in the US. Patients were categorized in the screening group if hepatocellular carcinoma was detected by imaging performed for screening purposes. Generalized linear models and multivariate Cox regression with frailty adjustment were used to compare early detection, curative treatment, and survival between screen-detected and non-screen-detected patients. Among 374 hepatocellular carcinoma patients, 42% (n = 157) were detected by screening. Screen-detected patients had a significantly higher proportion of early tumors (Barcelona Clinic Liver Cancer stage A 63.1% vs 36.4%, P <.001) and were more likely to undergo curative treatment (31% vs 13%, P = .02). Hepatocellular carcinoma screening was significantly associated with improved survival in multivariate analysis (hazards ratio 0.41; 95% confidence interval, 0.26-0.65) after adjusting for patient demographics, Child-Pugh class, and performance status. Median survival of screen-detected patients was 14.6 months, compared with 6.0 months for non-screen-detected patients, with the difference remaining significant after adjusting for lead-time bias (hazards ratio 0.59, 95% confidence interval, 0.37-0.93). Hepatocellular carcinoma screening is associated with increased early tumor detection and improved survival; however, a minority of hepatocellular carcinoma patients are detected by screening. Interventions to increase screening use in patients with cirrhosis may

Anticancer effects of deproteinized asparagus polysaccharide on hepatocellular carcinoma in vitro and in vivo.

PubMed

Xiang, Jianfeng; Xiang, Yanjie; Lin, Shengming; Xin, Dongwei; Liu, Xiaoyu; Weng, Lingling; Chen, Tao; Zhang, Minguang

2014-04-01

Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies in the world whose chemoprevention became increasingly important in HCC treatment. Although the anticancer effects of asparagus constituents have been investigated in several cancers, its effects on hepatocellular carcinoma have not been fully studied. In this study, we investigated the anticancer effects of the deproteinized asparagus polysaccharide on the hepatocellular carcinoma cells using the in vitro and in vivo experimental model. Our data showed that deproteinized asparagus polysaccharide might act as an effective inhibitor on cell growth in vitro and in vivo and exert potent selective cytotoxicity against human hepatocellular carcinoma Hep3B and HepG2 cells. Further study showed that it could potently induce cell apoptosis and G2/M cell cycle arrest in the more sensitive Hep3B and HepG2 cell lines. Moreover, deproteinized asparagus polysaccharide potentiated the effects of mitomycin both in vitro and in vivo. Mechanistic studies revealed that deproteinized asparagus polysaccharide might exert its activity through an apoptosis-associated pathway by modulating the expression of Bax, Bcl-2, and caspase-3. In conclusion, deproteinized asparagus polysaccharide exhibited significant anticancer activity against hepatocellular carcinoma cells and could sensitize the tumoricidal effects of mitomycin, indicating that it is a potential therapeutic agent (or chemosensitizer) for liver cancer therapy.

The correlation between NK cell and liver function in patients with primary hepatocellular carcinoma.

PubMed

Sha, Wei Hong; Zeng, Xiao Hui; Min, Lu

2014-05-01

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. 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. 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. 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.

Lipid nanocapsules loaded with rhenium-188 reduce tumor progression in a rat hepatocellular carcinoma model.

PubMed

Vanpouille-Box, Claire; Lacoeuille, Franck; Roux, Jérôme; Aubé, Christophe; Garcion, Emmanuel; Lepareur, Nicolas; Oberti, Frédéric; Bouchet, Francis; Noiret, Nicolas; Garin, Etienne; Benoît, Jean-Pierre; Couturier, Olivier; Hindré, François

2011-03-07

Due to their nanometric scale (50 nm) along with their biomimetic properties, lipid nanocapsules loaded with Rhenium-188 (LNC(188)Re-SSS) constitute a promising radiopharmaceutical carrier for hepatocellular carcinoma treatment as its size may improve tumor penetration in comparison with microspheres devices. This study was conducted to confirm the feasibility and to assess the efficacy of internal radiation with LNC(188)Re-SSS in a chemically induced hepatocellular carcinoma rat model. Animals were treated with an injection of LNC(188)Re-SSS (80 MBq or 120 MBq). The treated animals (80 MBq, n = 12; 120 MBq, n = 11) were compared with sham (n = 12), blank LNC (n = 7) and (188)Re-perrhenate (n = 4) animals. The evaluation criteria included rat survival, tumor volume assessment, and vascular endothelial growth factor quantification. Following treatment with LNC(188)Re-SSS (80 MBq) therapeutic efficiency was demonstrated by an increase in the median survival from 54 to 107% compared with control groups with up to 7 long-term survivors in the LNC(188)Re-SSS group. Decreased vascular endothelial growth factor expression in the treated rats could indicate alterations in the angiogenesis process. Overall, these results demonstrate that internal radiation with LNC(188)Re-SSS is a promising new strategy for hepatocellular carcinoma treatment.

Lipid Nanocapsules Loaded with Rhenium-188 Reduce Tumor Progression in a Rat Hepatocellular Carcinoma Model

PubMed Central

Vanpouille-Box, Claire; Lacoeuille, Franck; Roux, Jérôme; Aubé, Christophe; Garcion, Emmanuel; Lepareur, Nicolas; Oberti, Frédéric; Bouchet, Francis; Noiret, Nicolas; Garin, Etienne; Benoît, Jean-Pierre; Couturier, Olivier; Hindré, François

2011-01-01

Background Due to their nanometric scale (50 nm) along with their biomimetic properties, lipid nanocapsules loaded with Rhenium-188 (LNC188Re-SSS) constitute a promising radiopharmaceutical carrier for hepatocellular carcinoma treatment as its size may improve tumor penetration in comparison with microspheres devices. This study was conducted to confirm the feasibility and to assess the efficacy of internal radiation with LNC188Re-SSS in a chemically induced hepatocellular carcinoma rat model. Methodology/Principal Findings Animals were treated with an injection of LNC188Re-SSS (80 MBq or 120 MBq). The treated animals (80 MBq, n = 12; 120 MBq, n = 11) were compared with sham (n = 12), blank LNC (n = 7) and 188Re-perrhenate (n = 4) animals. The evaluation criteria included rat survival, tumor volume assessment, and vascular endothelial growth factor quantification. Following treatment with LNC188Re-SSS (80 MBq) therapeutic efficiency was demonstrated by an increase in the median survival from 54 to 107% compared with control groups with up to 7 long-term survivors in the LNC188Re-SSS group. Decreased vascular endothelial growth factor expression in the treated rats could indicate alterations in the angiogenesis process. Conclusions/Significance Overall, these results demonstrate that internal radiation with LNC188Re-SSS is a promising new strategy for hepatocellular carcinoma treatment. PMID:21408224

Occult hepatitis B virus and hepatocellular carcinoma

PubMed Central

Pollicino, Teresa; Saitta, Carlo

2014-01-01

Occult hepatitis B virus (HBV) infection (OBI) is a challenging pathobiological and clinical issue that has been widely debated for several decades. By definition, OBI is characterized by the persistence of HBV DNA in the liver tissue (and in some cases also in the serum) in the absence of circulating HBV surface antigen (HBsAg). Many epidemiological and molecular studies have indicated that OBI is an important risk factor for hepatocellular carcinoma (HCC) development. OBI may exert direct pro-oncogenic effects through the activation of the same oncogenic mechanisms that are activated in the course of an HBsAg-positive infection. Indeed, in OBI as in HBV-positive infection, HBV DNA can persist in the hepatocytes both integrated into the host genome as well as free episome, and may maintain the capacity to produce proteins-mainly X protein and truncated preS-S protein - provided with potential transforming properties. Furthermore, OBI may indirectly favor HCC development. It has been shown that the persistence of very low viral replicative activity during OBI may induce mild liver necro-inflammation continuing for life, and substantial clinical evidence indicates that OBI can accelerate the progression of liver disease towards cirrhosis that is considered the most important risk factor for HCC development. PMID:24876718

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

PubMed

Sugihara, Fumie; Murata, Satoru; Ueda, Tatsuo; Yasui, Daisuke; Yamaguchi, Hidenori; Miki, Izumi; Kawamoto, Chiaki; Uchida, Eiji; Kumita, Shin-Ichiro

2017-06-01

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

Anti-tumor effect of evodiamine by inducing Akt-mediated apoptosis in hepatocellular carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, Fan; Shi, Le; Liang, Tao

Background: Evodiamine is an alkaloid extracted from Euodia rutaecarpa (Juss.) Benth. There is little information about the mechanisms of evodiamine on the apoptosis of hepatocellular carcinoma (HCC). Materials and methods: A xenograft model and CCK8 assay were used to investigate the anti-HCC effect of evodiamine. The effect of evodiamine on apoptosis was evaluated by DAPI staining and flow cytometry. Western blot analyses and immunohistochemistry were processed to assess the protein expressions of Akt and apoptotic proteins. Results: Evodiamine suppressed tumor growth, improved the expression of cleaved-caspase3 and decreased tumor specific growth factor (TSGF) and alpha fetoprotein (AFP) activities. Furthermore, evodiaminemore » inhibited cell viability and induced cell cycle arrest. DAPI staining revealed nuclear condensation in evodiamine-treated groups. Meanwhile, evodiamine increased the number of apoptotic cells. Furthermore, evodiamine suppressed Akt and regulated apoptotic proteins in HepG2 cells. Evodiamine decreased p-Akt levels activated by SC79, which led to the increase of bax/bcl-2 and cleaved-caspase3. Conclusions: Our findings suggested that evodiamine could exert anti-HCC effect through inducing Akt-mediated apoptosis. Evodiamine has the potential to be a therapeutic medicine for HCCs. - Highlights: • Anti-tumor effect of evodiamine in hepatocellular carcinoma. • Evodiamine induces apoptosis in hepatocellular carcinoma. • The correlation between induction of apoptosis and Akt expression.« less

Hepatocellular Carcinoma (HCC)

NASA Astrophysics Data System (ADS)

Helmberger, Thomas K.

Hepatocellular carcinoma (HCC) is considered to be one of the most common malignancies worldwide, and the most common one in Africa and Asia. Over the last decade, a rising incidence of up to 10-15/100,000 per population has been seen in the Western world, with an estimate of 250,000 deaths and more than a million worldwide per year. By the year 2010, the World Health Organization expects that HCC will be the leading cause of cancer mortality surpassing lung cancer. This increasing incidence is most likely related to an increasing prevalence of chronic hepatitis C (HC) and B (HB) virus infections and other diseases inducing chronic inflammation (Befeler and Di Bisceglie 2002; Llovet et al. 2003).

Downstaging therapy followed by liver transplantation for hepatocellular carcinoma beyond Milan criteria.

PubMed

Kim, Young; Stahl, Christopher C; Makramalla, Abouelmagd; Olowokure, Olugbenga O; Ristagno, Ross L; Dhar, Vikrom K; Schoech, Michael R; Chadalavada, Seetharam; Latif, Tahir; Kharofa, Jordan; Bari, Khurram; Shah, Shimul A

2017-12-01

Orthotopic liver transplantation is a curative treatment for hepatocellular carcinoma within Milan criteria, but these criteria preclude many patients from transplant candidacy. Recent studies have demonstrated that downstaging therapy can reduce tumor burden to meet conventional criteria. The present study reports a single-center experience with tumor downstaging and its effects on post-orthotopic liver transplantation outcomes. All patients with hepatocellular carcinoma who were evaluated by our multidisciplinary liver services team from 2012 to 2016 were identified (N = 214). Orthotopic liver transplantation candidates presenting outside of Milan criteria at initial radiographic diagnosis and/or an initial alpha-fetoprotein >400 ng/mL were categorized as at high risk for tumor recurrence and post-transplant mortality. Of the 214 patients newly diagnosed with hepatocellular carcinoma, 73 (34.1%) eventually underwent orthotopic liver transplantation. The majority of patients who did not undergo orthotopic liver transplantation were deceased or lost to follow-up (47.5%), with 14 of 141 (9.9%) currently listed for transplantation. Among transplanted patients, 21 of 73 (28.8%) were considered high-risk candidates. All 21 patients were downstaged to within Milan criteria with an alpha-fetoprotein <400 ng/mL before orthotopic liver transplantation, through locoregional therapies. Recurrence of hepatocellular carcinoma was higher but acceptable between downstaged high-risk and traditional candidates (9.5% vs 1.9%; P > .05) at a median follow-up period of 17 months. Downstaged high-risk candidates had a similar overall survival compared with those transplanted within Milan criteria (log-rank P > .05). In highly selected cases, patients with hepatocellular carcinoma outside of traditional criteria for orthotopic liver transplantation may undergo downstaging therapy in a multidisciplinary fashion with excellent post-transplant outcomes. These data support an

Direct-acting antiviral therapy decreases hepatocellular carcinoma recurrence rate in cirrhotic patients with chronic hepatitis C.

PubMed

Virlogeux, Victor; Pradat, Pierre; Hartig-Lavie, Kerstin; Bailly, François; Maynard, Marianne; Ouziel, Guillaume; Poinsot, Domitille; Lebossé, Fanny; Ecochard, Marie; Radenne, Sylvie; Benmakhlouf, Samir; Koffi, Joseph; Lack, Philippe; Scholtes, Caroline; Uhres, Anne-Claire; Ducerf, Christian; Mabrut, Jean-Yves; Rode, Agnès; Levrero, Massimo; Combet, Christophe; Merle, Philippe; Zoulim, Fabien

2017-08-01

Arrival of direct-acting antiviral agents against hepatitis C virus with high-sustained virological response rates and very few side effects has drastically changed the management of hepatitis C virus infection. The impact of direct-acting antiviral exposure on hepatocellular carcinoma recurrence after a first remission in patients with advanced fibrosis remains to be clarified. 68 consecutive hepatitis C virus patients with a first hepatocellular carcinoma diagnosis and under remission, subsequently treated or not with a direct-acting antiviral combination, were included. Clinical, biological and virological data were collected at first hepatocellular carcinoma diagnosis, at remission and during the surveillance period. All patients were cirrhotic. Median age was 62 years and 76% of patients were male. Twenty-three patients (34%) were treated with direct-acting antivirals and 96% of them achieved sustained virological response. Median time between hepatocellular carcinoma remission and direct-acting antivirals initiation was 7.2 months (IQR: 3.6-13.5; range: 0.3-71.4) and median time between direct-acting antivirals start and hepatocellular carcinoma recurrence was 13.0 months (IQR: 9.2-19.6; range: 3.0-24.7). Recurrence rate was 1.7/100 person-months among treated patients vs 4.2/100 person-months among untreated patients (P=.008). In multivariate survival analysis, the hazard ratio for hepatocellular carcinoma recurrence after direct-acting antivirals exposure was 0.24 (95% confidence interval: 0.10-0.55; P<.001). Hepatocellular carcinoma recurrence rate was significantly lower among patients treated with direct-acting antivirals compared with untreated patients. Given the potential impact of our observation, large-scale prospective cohort studies are needed to confirm these results. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Upregulation of MiR-212 Inhibits Migration and Tumorigenicity and Inactivates Wnt/β-Catenin Signaling in Human Hepatocellular Carcinoma.

PubMed

Jia, Pengbo; Wei, Guangbing; Zhou, Cancan; Gao, Qi; Wu, Yunhua; Sun, Xuejun; Li, Xuqi

2018-01-01

MicroRNAs are involved in hepatocellular carcinoma metastasis, a principal cause of hepatocellular carcinoma-related death in patients worldwide. MiR-212 is a microRNA that has been identified in several types of cancers and is postulated to influence cell signaling and subsequent malignant pathogenesis. Despite emerging reports suggesting that miR-212 plays a significant role in the onset, progression, and migration of these types of malignant tumors, its involvement in the development of hepatocellular carcinoma has not been fully elucidated. Quantitative reverse transcription polymerase chain reaction, wound healing, transwell migration and invasion assays, Western blotting, and xenograft tumor growth models were performed to test the expression levels and functions of miR-212 in hepatocellular carcinoma. Luciferase reporter assay, quantitative reverse transcription polymerase chain reaction, Western blotting, and immunohistochemistry were used to identify and verify the target of miR-212. In this study, we identify significant repression of miR-212 in hepatocellular carcinoma and demonstrate that overexpression of miR-212 inhibits the migration of hepatocellular carcinoma cells in vitro and in vivo. Furthermore, we identify forkhead box M1, whose expression is inversely related to that of miR-212, as a direct target of miR-212. Additionally, reexpression of forkhead box M1 rescues the miR-212-mediated inhibition of cell migration. We observed that inhibition of miR-212 activates forkhead box M1 but inhibits the Wnt/β-catenin pathway by suppressing Wnt, LEF-1, c-Myc, and nuclear β-catenin. Finally, in vivo studies confirmed the inhibitory effect of miR-212 on hepatocellular carcinoma growth. Our present findings indicate that miR-212 is a potential prognostic biomarker of hepatocellular carcinoma and that the miR-212/forkhead box M1 regulatory axis may represent a new therapeutic objective for hepatocellular carcinoma treatment.

[A single metastasis in the carpal bones as the first clinical manifestation of a hepatocellular carcinoma].

PubMed

Corrales Pinzón, R; Alonso Sánchez, J M; de la Mano González, S; El Karzazi Tarazona, K

2014-01-01

Hepatocellular carcinoma is the most common primary tumor of the liver. Spreading outside the liver usually takes place in advanced stages of the disease, and bone is the third most common site of metastases. We present a case of hepatocellular carcinoma in which the first clinical manifestation was a single metastasis to the carpal bones. The interest of this case lies in the way this hepatocellular carcinoma manifested as well as in the unusual site of the metastasis. Copyright © 2012 SERAM. Published by Elsevier Espana. All rights reserved.

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

PubMed

Liang, Yingjian; Yin, Dalong; Hou, Limin; Zheng, Tongsen; Wang, Jiabei; Meng, Xianzhi; Lu, Zhaoyang; Song, Xuan; Pan, Shangha; Jiang, Hongchi; Liu, Lianxin

2011-01-01

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

Diphenyl Difluoroketone: A Potent Chemotherapy Candidate for Human Hepatocellular Carcinoma

PubMed Central

Hou, Limin; Zheng, Tongsen; Wang, Jiabei; Meng, Xianzhi; Lu, Zhaoyang; Song, Xuan; Pan, Shangha; Jiang, Hongchi; Liu, Lianxin

2011-01-01

Diphenyl difluoroketone (EF24), a molecule having structural similarity to curcumin, was recently reported to inhibit proliferation of various cancer cells significantly. Here we try to determine the effect and mechanism of EF24 on hepatocellular carcinoma. 2 µM EF24 was found to inhibit the proliferation of PLC/PRF/5, Hep3B, HepG2, SK-HEP-1 and Huh 7 cell lines. However, even 8 µM EF24 treatment did not affect the proliferation of normal liver LO2 cells. Accordingly, 20 mg/kg/d EF24 inhibited the growth of the tumor xenografts conspicuously while causing no apparent change in liver, spleen or body weight. In addition, significant apoptosis and G2/M phase cell cycle arrest were found using flow cytometry. Besides, caspases and PARP activation and features typical of apoptosis including fragmented nuclei with condensed chromatin were also observed. Furthermore, the mechanism was targeted at the reduction of nuclear factor kappa b (NF-κB) pathway and the NF-κB–regulated gene products Bcl-2, COX-2, Cyclin B1. Our study has offered a strategy that EF24 being a therapeutic agent for hepatocellular carcinoma. PMID:21901145

Cerebral Lipiodol Embolism: A Complication of Transcatheter Arterial Chemoembolization for Hepatocellular Carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Matsumoto, Koichi, E-mail: matsumk2@cc.saga-u.ac.jp; Nojiri, Junichi; Takase, Yukinori

2007-06-15

We report a case of cerebral lipiodol embolism following transcatheter chemoembolization (TACE) for hepatocellular carcinoma. A 70-year-old woman with a large unresectable hepatocellular carcinoma underwent TACE. Her level of consciousness deteriorated after the procedure, and magnetic resonance imaging and non-contrast computed tomography revealed a cerebral lipiodol embolism. Despite intensive care, the patient died 2 weeks later. The complication might have been due to systemic-pulmonary shunts caused by previous surgeries and/or direct invasion of the recurrent tumor.

Loss of tumor suppressor miR-126 contributes to the development of hepatitis B virus-related hepatocellular carcinoma metastasis through the upregulation of ADAM9.

PubMed

Xiang, Le-Yang; Ou, Huo-Hui; Liu, Xin-Cheng; Chen, Zhan-Jun; Li, Xiang-Hong; Huang, Yu; Yang, Ding-Hua

2017-06-01

Hepatocellular carcinoma is the most common histological type of primary liver cancer, which represents the second leading cause of cancer-related mortality. MiR-126 was reported to be downregulated in hepatocellular carcinoma tissues, compared with its levels in noncancerous tissues. However, baseline miR-126 expression levels in hepatitis B virus-related hepatocellular carcinoma patients who did not undergo pre-operational treatment remains unknown since hepatitis B virus infection and pre-operational transcatheter arterial chemoembolization were shown to upregulate miR-126 expression. Here, we demonstrated that miR-126 is generally downregulated in a homogeneous population of pre-operational treatment-naïve hepatitis B virus-related hepatocellular carcinoma patients (84.0%, 84/100), and its expression is significantly associated with pre-operational alpha-fetoprotein levels ( p < 0.05), microvascular invasion ( p < 0.05), tumor metastasis ( p < 0.05), as well as early recurrence (12 months after surgery; p < 0.01). Furthermore, the results of our study revealed that miR-126 is negatively correlated with ADAM9 expression in hepatitis B virus-related hepatocellular carcinoma patients. Overexpression of miR-126 was shown to attenuate ADAM9 expression in hepatocellular carcinoma cells, which subsequently inhibits cell migration and invasion in vitro. In addition, Cox proportional hazards regression model analysis showed that ADAM9 levels, tumor number, microvascular invasion, and tumor metastasis rate represent independent prognostic factors for shorter recurrence-free survival. In conclusion, we demonstrated that the loss of tumor suppressor miR-126 in hepatitis B virus-related hepatocellular carcinoma cells contributes to the development of metastases through the upregulated expression of its target gene, ADAM9. MiR-126-ADAM9 pathway-based therapeutic targeting may represent a novel approach for the inhibition of hepatitis B virus

Inhibitor of differentiation 1 transcription factor promotes metabolic reprogramming in hepatocellular carcinoma cells

PubMed Central

Sharma, Bal Krishan; Kolhe, Ravindra; Black, Stephen M.; Keller, Jonathan R.; Mivechi, Nahid F.; Satyanarayana, Ande

2016-01-01

Reprograming of metabolism is one of the central hallmarks of cancer. The majority of cancer cells depend on high rates of glycolysis and glutaminolysis for their growth and survival. A number of oncogenes and tumor suppressors have been connected to the regulation of altered glucose and glutamine metabolism in cancer cells. For example, the oncogene c-Myc plays vital roles in cancer cell metabolic adaptation by directly regulating various genes that participate in aerobic glycolysis and glutaminolysis. Inhibitor of differentiation 1 (Id1) is a helix-loop-helix transcription factor that plays important roles in cell proliferation, differentiation, and cell fate determination. Overexpression of Id1 causes intestinal adenomas and thymic lymphomas in mice, suggesting that Id1 could function as an oncogene. Despite it being an oncogene, whether Id1 plays any prominent role in cancer cell metabolic reprograming is unknown. Here, we demonstrate that Id1 is strongly expressed in human and mouse liver tumors and in hepatocellular carcinoma (HCC) cell lines, whereas its expression is very low or undetectable in normal liver tissues. In HCC cells, Id1 expression is regulated by the MAPK/ERK pathway at the transcriptional level. Knockdown of Id1 suppressed aerobic glycolysis and glutaminolysis, suggesting that Id1 promotes a metabolic shift toward aerobic glycolysis. At the molecular level, Id1 mediates its metabolic effects by regulating the expression levels of c-Myc. Knockdown of Id1 resulted in down-regulation (∼75%) of c-Myc, whereas overexpression of Id1 strongly induced (3-fold) c-Myc levels. Interestingly, knockdown of c-Myc resulted in down-regulation (∼60%) of Id1, suggesting a positive feedback-loop regulatory mechanism between Id1 and c-Myc. Under anaerobic conditions, both Id1 and c-Myc are down-regulated (50–70%), and overexpression of oxygen-insensitive hypoxia-inducible factor 1α (Hif1α) or its downstream target Mxi1 resulted in a significant reduction

Expression of toll-like receptors in hepatic cirrhosis and hepatocellular carcinoma.

PubMed

Sun, L; Dai, J J; Hu, W F; Wang, J

2016-07-14

Toll-like receptors (TLRs) can specifically identify pathogen-associated molecular patterns (PAMPs) by recognizing structural patterns in diverse microbial molecules, and can provide an effective defense against multiple microbial infectious. A variety of TLRs can be expressed on the surface of liver parenchymal as well as nonparenchymal cells. Kupffer cells are a type of hepatic nonparenchymal macrophage, and are positively associated with the severity of liver fibrosis. They play an important role in the synthesis and deposition of the extracellular matrix by upregulating the expression of tissue inhibitor of metalloproteinases and downregulating the activity of matrix metalloproteinases. Cirrhosis, a chronic diffuse lesion usually accompanying extensive liver fibrosis and nodular regeneration, is caused by liver parenchymal cells repeating injury-repair following reconstruction of organizational structure in the hepatic lobules. Hepatocellular carcinoma is caused by repeated and persistent chronic severe liver injury, and partial hepatocytes can eventually transform into hepatoma cells. Multiple TLRs such as TLR2, TLR3, TLR4, and TLR9, as well as other receptors, can be expressed in cirrhosis and hepatocellular carcinoma. About 53 and 85% of hepatocellular carcinoma patients frequently express TLR3 and TLR9, respectively. The chronic and repeated liver injury caused by alcohol, and HBV, HCV, or other pathogens can be recognized by TLRs through the PAMP pathway, which directly increases the risk for hepatic cirrhosis and hepatocellular carcinoma. In this review, we briefly present evidence that the novel cellular molecular mechanisms of TLRs may provide more information about new therapeutics targets of the anti-inflammatory immune response.

Inflammation-Dependent IL18 Signaling Restricts Hepatocellular Carcinoma Growth by Enhancing the Accumulation and Activity of Tumor-Infiltrating Lymphocytes.

PubMed

Markowitz, Geoffrey J; Yang, Pengyuan; Fu, Jing; Michelotti, Gregory A; Chen, Rui; Sui, Jianhua; Yang, Bin; Qin, Wen-Hao; Zhang, Zheng; Wang, Fu-Sheng; Diehl, Anna Mae; Li, Qi-Jing; Wang, Hongyang; Wang, Xiao-Fan

2016-04-15

Chronic inflammation in liver tissue is an underlying cause of hepatocellular carcinoma. High levels of inflammatory cytokine IL18 in the circulation of patients with hepatocellular carcinoma correlates with poor prognosis. However, conflicting results have been reported for IL18 in hepatocellular carcinoma development and progression. In this study, we used tissue specimens from hepatocellular carcinoma patients and clinically relevant mouse models of hepatocellular carcinoma to evaluate IL18 expression and function. In a mouse model of liver fibrosis that recapitulates a tumor-promoting microenvironment, global deletion of the IL18 receptor IL18R1 enhanced tumor growth and burden. Similarly, in a carcinogen-induced model of liver tumorigenesis, IL18R1 deletion increased tumor burden. Mechanistically, we found that IL18 exerted inflammation-dependent tumor-suppressive effects largely by promoting the differentiation, activity, and survival of tumor-infiltrating T cells. Finally, differences in the expression of IL18 in tumor tissue versus nontumor tissue were more predictive of patient outcome than overall tissue expression. Taken together, our findings resolve a long-standing contradiction regarding a tumor-suppressive role for IL18 in established hepatocellular carcinoma and provide a mechanistic explanation for the complex relationship between its expression pattern and hepatocellular carcinoma prognosis. Cancer Res; 76(8); 2394-405. ©2016 AACR. ©2016 American Association for Cancer Research.

Early development of de novo hepatocellular carcinoma after direct-acting agent therapy: Comparison with pegylated interferon-based therapy in chronic hepatitis C patients.

PubMed

Yoo, S H; Kwon, J H; Nam, S W; Kim, H Y; Kim, C W; You, C R; Choi, S W; Cho, S H; Han, J-Y; Song, D S; Chang, U I; Yang, J M; Lee, H L; Lee, S W; Han, N I; Kim, S-H; Song, M J; Hwang, S; Sung, P S; Jang, J W; Bae, S H; Choi, J Y; Yoon, S K

2018-04-16

Patients with chronic hepatitis C who achieve a sustained viral response after pegylated interferon therapy have a reduced risk of hepatocellular carcinoma, but the risk after treatment with direct-acting antivirals is unclear. We compared the rates of early development of hepatocellular carcinoma after direct-acting antivirals and after pegylated interferon therapy. We retrospectively analysed 785 patients with chronic hepatitis C who had no history of hepatocellular carcinoma (211 treated with pegylated interferon, 574 with direct-acting antivirals) and were followed up for at least 24 weeks after antiviral treatment. De novo hepatocellular carcinoma developed in 6 of 574 patients receiving direct-acting antivirals and in 1 of 211 patients receiving pegylated interferon. The cumulative incidence of early hepatocellular carcinoma development did not differ between the treatment groups either for the whole cohort (1.05% vs 0.47%, P = .298) or for those patients with Child-Pugh Class A cirrhosis (3.73% vs 2.94%, P = .827). Multivariate analysis indicated that alpha-fetoprotein level >9.5 ng/mL at the time of end-of-treatment response was the only independent risk factor for early development of hepatocellular carcinoma in all patients (P < .0001, hazard ratio 176.174, 95% confidence interval 10.768-2882.473) and in patients treated with direct-acting agents (P < .0001, hazard ratio 128.402, 95% confidence interval 8.417-1958.680). In conclusion, the rate of early development of hepatocellular carcinoma did not differ between patients treated with pegylated interferon and those treated with direct-acting antivirals and was associated with the serum alpha-fetoprotein level at the time of end-of-treatment response. © 2018 John Wiley & Sons Ltd.

CTP synthase forms the cytoophidium in human hepatocellular carcinoma.

PubMed

Chang, Chia-Chun; Jeng, Yung-Ming; Peng, Min; Keppeke, Gerson Dierley; Sung, Li-Ying; Liu, Ji-Long

2017-12-15

CTP synthase (CTPS) can aggregate into an intracellular macrostructure, the cytoophidium, in various organisms including human cells. Previous studies have shown that assembly of human CTPS cytoophidia may be correlated with the cellular metabolic status, and is able to promote the activity of CTPS. A correlation between the cytoophidium and cancer metabolism has been proposed but not yet been revealed. In the current study we provide clear evidence of the presence of CTPS cytoophidia in various human cancers and some non-cancerous tissues. Moreover, among 203 tissue samples of hepatocellular carcinoma, 56 (28%) samples exhibited many cytoophidia, whereas no cytoophidia were detected in adjacent non-cancerous hepatocytes for all samples. Our findings suggest that the CTPS cytoophidium may participate in the adaptive metabolism of human hepatocellular carcinoma. Copyright © 2017. Published by Elsevier Inc.

Sulforaphane inhibits TGF-β-induced epithelial-mesenchymal transition of hepatocellular carcinoma cells via the reactive oxygen species-dependent pathway.

PubMed

Wu, Jinsheng; Han, Jingli; Hou, Benxin; Deng, Chengwei; Wu, Huanliang; Shen, Liangfang

2016-05-01

Sulforaphane is recognized as a safe antitumor agent derived from various cruciferous vegetables, including broccoli. It has been demonstrated that sulforaphase is a potent antitumor agent in diverse cancers. However, its effect on hepatocellular carcinoma remains largely unknown. Here, we show that sulforaphane inhibits TGF-β-induced epithelial-mesenchymal transition of hepatocellular carcinoma cell via the reactive oxygen species-dependent pathway. We found sulforaphane inhibited hepatocellular carcinoma cell proliferation in a dose- and time-dependent manner. Sulforaphane induced G0/G1 phase cell cycle arrest and promoted cell apoptosis. A set of experiments showed that sulforaphase inhibited hepatocellular carcinoma cell migration and invasion, inhibited the formation of fibroblast like mesenchymal cells and the expression of Vimentin, but increased the expression of E-cadherin, suggesting sulforaphane suppresses epithelial-mesenchymal transition (EMT) process. Cotreatment with N-acetyl-L-cysteine inhibited sulforaphane-inhibited invasion and upregulation of E-cadherin and almost completely abolished the sulforaphane-induced expression of Vimentin. The effect of sulforaphane on the growth of hepatocellular carcinoma cells was confirmed by a xenograft tumor growth model. All our finding indicated that sulforaphane is a promising and safe strategy for treating hepatocellular carcinoma.

Risk factors for hepatocellular carcinoma in Caucasian patients with non-viral cirrhosis: the importance of prior obesity.

PubMed

Archambeaud, Isabelle; Auble, Hélène; Nahon, Pierre; Planche, Lucie; Fallot, Guillaume; Faroux, Roger; Gournay, Jérôme; Samuel, Didier; Kury, Sebastien; Féray, Cyrille

2015-07-01

In patients with cirrhosis, the risk of hepatocellular carcinoma (HCC) depends upon age, gender and the etiology of liver disease. Few studies are available in Caucasian patients with alcoholic or metabolic cirrhosis without viral hepatitis. Cross-sectional clinical data from 905 HCV- and HBV-negative Caucasian patients with alcoholic or metabolic cirrhosis were prospectively collected in four French centres. The risk factors for HCC were identified by logistic regression analysis in the whole population and in a nested case-control study. The etiology of cirrhosis was alcoholic (48%), metabolic (7%) or mixed (45%). Patients were predominantly male (80%), mean age 62 years old and 31% had HCC. Mean body mass index (BMI) was 27 ± 5 and 30% were obese at inclusion. The maximum BMI reached throughout life was 31 ± 6 and 63% had been obese. Ninety percent of the population had daily alcohol consumption, 73% were smokers. Hepatocellular carcinoma was independently related to male gender (P < 0.0001), older age (P < 0.0001), past obesity (P = 0.007), diabetes (P = 0.037), abnormal levels of transaminases (P < 0.0001) and tobacco consumption (P = 0.007). The case-control study (200 HCC cases matched with 400 non-HCC cases for gender, age and Child-Pugh score) confirmed past obesity, tobacco and abnormal levels of transaminases. Beside diabetes, male gender and age, a past history of obesity, but not an existing overweight, as well as exposure to tobacco and elevated transaminases were three risk factors which could improve the strategy for HCC screening in Caucasian cirrhotic patients without hepatitis B or C. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Berberine-loaded Janus nanocarriers for magnetic field-enhanced therapy against hepatocellular carcinoma.

PubMed

Wang, Zheng; Wang, Ying-Shuai; Chang, Zhi-Min; Li, Li; Zhang, Yi; Lu, Meng-Meng; Zheng, Xiao; Li, Mingqiang; Shao, Dan; Li, Jing; Chen, Li; Dong, Wen-Fei

2017-03-01

Berberine, an bioactive isoquinolin alkaloid from traditional Chinese herbs, is considered to be a promising agent based on its remarkable activity against hepatocellular carcinoma. However, the clinical application of this nature compound had been hampered owing to its properties such as poor aqueous solubility, low gastrointestinal absorption, and reduced bioavailability. Therefore, we developed Janus magnetic mesoporous silica nanoparticles (Fe 3 O 4 -mSiO 2 NPs) consisting of a Fe 3 O 4 head for magnetic targeting and a mesoporous SiO 2 body for berberine delivery. A pH-sensitive group was introduced on the surface of mesoporous silica for berberine loading to develop a tumor microenvironment-responsive nanocarrier, which exhibited uniform morphology, good superparamagnetic properties, high drug-loading amounts, superior endocytic ability, and low cytotoxicity. Berberine-loaded Fe 3 O 4 -mSiO 2 NPs exerted extraordinarily high specificity for hepatocellular carcinoma cells, which was due to the pH-responsive berberine release, as well as higher endocytosis capacity in hepatocellular carcinoma cells rather than normal liver cells. More importantly, an external magnetic field could significantly improve antitumor activity of Ber-loaded Fe 3 O 4 -mSiO 2 NPs through enhancing berberine internalization. Taken together, our results suggest that Janus nanocarriers driven by the magnetic field may provide an effective and safe way to facilitate clinical use of berberine against hepatocellular carcinoma. © 2016 John Wiley & Sons A/S.

Current management of hepatocellular carcinoma

PubMed Central

Tabrizian, Parissa; Roayaie, Sasan; Schwartz, Myron E

2014-01-01

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and leading cause of death among patients with cirrhosis. Treatment guidelines are based according to the Barcelona Clinic Liver Cancer staging system. The choice among therapeutic options that include liver resection, liver transplantation, locoregional, and systemic treatments must be individualized for each patient. The aim of this paper is to review the outcomes that can be achieved in the treatment of HCC with the heterogeneous therapeutic options currently available in clinical practice. PMID:25132740

Hepatocellular carcinoma: Will novel targeted drugs really impact the next future?

PubMed

Montella, Liliana; Palmieri, Giovannella; Addeo, Raffaele; Del Prete, Salvatore

2016-07-21

Cancer treatment has been revolutionized by the advent of new molecular targeted and immunotherapeutic agents. Identification of the role of tumor angiogenesis changed the understanding of many tumors. After the unsuccessful results with chemotherapy, sorafenib, by interfering with angiogenic pathways, has become pivotal in the treatment of hepatocellular carcinoma. Sorafenib is the only systemic treatment to show a modest but statistically significant survival benefit. All novel drugs and strategies for treatment of advanced hepatocellular carcinoma must be compared with the results obtained with sorafenib, but no new drug or drug combination has yet achieved better results. In our opinion, the efforts to impact the natural history of the disease will be directed not only to drug development but also to understanding the underlying liver disease (usually hepatitis B virus- or hepatitis C virus-related) and to interrupting the progression of cirrhosis. It will be important to define the role and amount of mutations in the complex pathogenesis of hepatocellular carcinoma and to better integrate locoregional and systemic therapies. It will be important also to optimize the therapeutic strategies with existing chemotherapeutic drugs and new targeted agents.

[A case of synchronous hepatocellular carcinoma successfully treated by S-1 and cisplatin (CDDP) as neoadjuvant chemotherapy for gastric cancer].

PubMed

Oka, Tomo; Onoda, Yuji; Ohashi, Ryuichiro; Izumi, Sadanobu; Suzuka, Ichio; Shiota, Kunihiko

2009-05-01

Combination chemotherapy with S-1 and cisplatin(S-1/CDDP)has become the standard treatment for gastric cancer, but the effect for hepatocellular carcinoma has not become clear. We experienced a case with advanced gastric cancer and hepatocellular carcinoma at the same time. We used S-1/CDDP as neoadjuvant chemotherapy for the case and performed surgical resection of the gastric cancer and hepatocellular carcinoma. From histological examination of the resected specimen, we may be able to prove that the S-1/CDDP chemotherapy for the hepatocellular carcinoma was also effective. A 57-year-old man visited our hospital with epigastralgia. Further examinations revealed a type-3 advanced gastric cancer with bulky N2 and hepatocellular carcinoma at segment 5. The gastric cancer was thought to be too advanced for initial surgery, so we performed S-1/CDDP chemotherapy(S-1 100 mg/body/day, CDDP 20 mg/body twice/week for 2 weeks)as preoperative therapy. After remarkable shrinkage of the gastric cancer was obtained, we performed distal gastrectomy, D2+a lymph node excision, liver S5 segmentectomy and cholecystectomy. The histological examination showed remarkable denaturation and necrosis as grade 2 effectiveness in over two-thirds of the hepatocellular carcinoma area and grade 1b in gastric cancer according to the Japanese classification of gastric carcinoma. This result suggests that S-1/CDDP chemotherapy might therefore be effective as systemic therapy for patients with hepatocellular carcinoma. However, further clinical trials are required.

Preclinical evaluation of transcriptional targeting strategy for human hepatocellular carcinoma in an orthotopic xenograft mouse model.

PubMed

Sia, Kian Chuan; Huynh, Hung; Chung, Alexander Yaw Fui; Ooi, London Lucien Peng Jin; Lim, Kiat Hon; Hui, Kam Man; Lam, Paula Yeng Po

2013-08-01

Gene regulation of many key cell-cycle players in S-, G(2) phase, and mitosis results from transcriptional repression in their respective promoter regions during the G(0) and G(1) phases of cell cycle. Within these promoter regions are phylogenetically conserved sequences known as the cell-cycle-dependent element (CDE) and cell-cycle genes homology regions (CHR) sites. Thus, we hypothesize that transcriptional regulation of cell-cycle regulation via the CDE/CHR region together with liver-specific apolipoprotein E (apoE)-hAAT promoter could bring about a selective transgene expression in proliferating human hepatocellular carcinoma. We show that the newly generated vector AH-6CC-L2C could mediate hepatocyte-targeted luciferase gene expression in tumor cells and freshly isolated short-term hepatocellular carcinoma cultures from patient biopsy. In contrast, normal murine and human hepatocytes infected with AH-6CC-L2C expressed minimal or low luciferase activities. In the presence of prodrug 5-fluorocytosine (5-FC), AH-6CC-L2C effectively suppressed the growth of orthotopic hepatocellular carcinoma patient-derived xenograft mouse model via the expression of yeast cytosine deaminase (yCD) that converts 5-FC to anticancer metabolite 5-fluoruracil. More importantly, we show that combination treatment of AH-6CC-L2C with an EZH2 inhibitor, DZNep, that targets EpCAM-positive hepatocellular carcinoma, can bring about a greater therapeutic efficacy compared with a single treatment of virus or inhibitor. Our study showed that targeting proliferating human hepatocellular carcinoma cells through the transcriptional control of therapeutic gene could represent a feasible approach against hepatocellular carcinoma.

Radioembolization in Advanced Hepatocellular Carcinoma.

PubMed

Riaz, Ahsun; Lewandowski, Robert; Salem, Riad

2018-05-02

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 68-year-old man with a remote history of alcohol abuse presented with vague abdominal pain. A review of systems suggested the patient had an Eastern Cooperative Oncology Group performance status 1 (restriction of strenuous physical activity). There were no physical examination findings of note. Laboratory studies disclosed Child-Pugh A liver status (no ascites; no encephalopathy; total bilirubin, 1 mg/dL; albumin, 3.5 g/dL; and international normalized rato, 1.2). The alpha-fetoprotein was mildly elevated (19.5 ng/mL). Magnetic resonance imaging with contrast disclosed an infiltrative mass with extensive malignant right and left portal vein thrombosis ( Fig 1A ) with cavernous transformation of the portal vein. The infiltrative mass ( Fig 2A ) was biopsied, revealing hepatocellular carcinoma. No distant metastases were found on a bone scintigraphy or computerized tomography scan. Given these features, this patient was classified as Barcelona Clinic for Liver Cancer stage C. The patient was referred for management of advanced hepatocellular carcinoma.

Factors of transforming growth factor beta signalling are co-regulated in human hepatocellular carcinoma.

PubMed

Longerich, Thomas; Breuhahn, Kai; Odenthal, Margarete; Petmecky, Katharina; Schirmacher, Peter

2004-12-01

Transforming growth factor beta (TGFbeta) is a central mitoinhibitory factor for epithelial cells, and alterations of TGFbeta signalling have been demonstrated in many different human cancers. We have analysed human hepatocellular carcinomas (HCCs) for potential pro-tumourigenic alterations in regard to expression of Smad4 and mutations and expression changes of the pro-oncogenic transcriptional co-repressors Ski and SnoN, as well as mRNA levels of matrix metalloproteinase-2 (MMP2), which is transcriptionally regulated by TGFbeta. Smad4 mRNA was detected in all HCCs; while, using immunohistology, loss of Smad4 expression was found in 10% of HCCs. Neither mutations in the transformation-relevant sequences nor significant pro-tumourigenic expression changes of the Ski and SnoN genes were detected. In HCC cell lines, expression of both genes was regulated, potentially involving phosphorylation. Ski showed a distinct nuclear speckled pattern, indicating recruitment to active transcription complexes. MMP2 mRNA levels were increased in 19% of HCCs, whereas MMP2 mRNA was not detectable in HCC cell lines, suggesting that MMP2 was derived only from tumour stroma cells. Transcript levels of Smad4, Ski, SnoN and MMP2 correlated well. These data argue against a significant role of Ski and SnoN in human hepatocarcinogenesis and suggest that, in the majority of HCCs, the analysed factors are co-regulated by an upstream mechanism, potentially by TGFbeta itself.

Remission of Psoriasis in a Patient with Hepatocellular Carcinoma Treated with Sorafenib.

PubMed

Antoniou, Efstathios A; Koutsounas, Ioannis; Damaskos, Christos; Koutsounas, Sotiris

Psoriasis is a chronic, immune-mediated and angiogenesis-dependent disease. Activated keratinocytes in psoriatic lesions produce pro-angiogenic cytokines, including vascular endothelial growth factor (VEGF), which binds to vascular endothelial growth factor receptor (VEGFR) and promotes cell proliferation and angiogenesis. Sorafenib (BAY 43-9006) is a molecular multikinase inhibitor of RAF kinase, platelet-derived growth factor (PDGF), VEGFR-1, -2, -3, platelet-derived growth factor receptor (PDGFR)-β and c-Kit. This molecule inhibits tumor cell proliferation and angiogenesis and it is currently approved for the treatment of hepatocellular carcinoma (HCC). We present the complete remission of resistant psoriasis in a hepatitis C virus (HCV)-infected cirrhotic patient who was treated with sorafenib, for recurrent HCC. Several targeted therapies have demonstrated efficacy against psoriasis. More research and well-designed studies, both in novel drugs and those already marketed for other indications, are needed to determine their value as potential novel therapies for psoriasis. Copyright © 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Association between hepatitis B virus/hepatitis C virus infection and primary hepatocellular carcinoma risk: A meta-analysis based on Chinese population.

PubMed

Li, Libo; Lan, Xiaolin

2016-12-01

To assess the relationship between hepatitis B virus (HBV), hepatitis C virus (HCV), and HBV/HCV double infection and hepatocellular carcinoma risk in Chinese population. The databases of PubMed and CNKI were electronic searched by reviewers according to the searching words of HBV, HCV, and hepatocellular carcinoma. The related case-control studies or cohort studies were included. The association between virus infection and hepatocellular carcinoma risk was demonstrated by odds ratio (OR) and 95% confidence interval (95% CI). The data were pooled by fixed or random effects model according to the statistical heterogeneity. The publication bias was assessed by Begg's funnel plot and Egger's linear regression test. Finally, 13 publications were included in this meta-analysis. For significant statistical heterogeneity (I2 = 99.8%,P = 0.00), the OR was pooled by random effects model. The pooled results showed that HBV infection can significantly increase the risk of developing hepatocellular carcinoma (OR = 58.01, 95% CI: 44.27-71.75); statistical heterogeneity analysis showed that significant heterogeneity existed in evaluation of HCV infection and hepatocellular carcinoma risk across the included 13 studies I2 = 77.78%, P = 0.00). The OR was pooled by random effects model. The pooled results showed that HCV infection can significantly increase the risk of developing hepatocellular carcinoma (OR = 2.34, 95% CI: 1.20-3.47); significant heterogeneity did not exist in evaluation HBV/HCV double infection and hepatocellular carcinoma risk for the included 13 studies (I2 = 0.00%,P = 0.80). The OR was pooled by fixed effects model. The pooled results showed that HBV/HCV double infection can significantly increase the risk of developing hepatocellular carcinoma (OR = 11.39, 95% CI: 4.58-18.20). No publication bias was found in the aspects of HBV, HCV, and HBV/HCV double infection and hepatocellular carcinoma. For Chinese population, HBV, HCV or HBV/HCV double infection can

Glycyrrhetinic acid-functionalized mesoporous silica nanoparticles as hepatocellular carcinoma-targeted drug carrier.

PubMed

Lv, Yongjiu; Li, Jingjing; Chen, Huali; Bai, Yan; Zhang, Liangke

2017-01-01

In this study, a glycyrrhetinic acid-functionalized mesoporous silica nanoparticle (MSN-GA) was prepared for active tumor targeting. MSN-GA exhibited satisfactory loading capacity for insoluble drugs, uniform size distribution, and specific tumor cell targeting. Glycyrrhetinic acid, a hepatocellular carcinoma-targeting group, was covalently decorated on the surface of MSN via an amido bond. The successful synthesis of MSN-GA was validated by the results of Fourier transform infrared spectroscopy, transmission electron microscopy (TEM), and zeta potential measurement. TEM images revealed the spherical morphology and uniform size distribution of the naked MSN and MSN-GA. Curcumin (CUR), an insoluble model drug, was loaded into MSN-GA (denoted as MSN-GA-CUR) with a high-loading capacity (8.78%±1.24%). The results of the in vitro cellular experiment demonstrated that MSN-GA-CUR significantly enhanced cytotoxicity and cellular uptake toward hepatocellular carcinoma (HepG2) cells via a specific GA receptor-mediated endocytosis mechanism. The results of this study provide a promising nanoplatform for the targeting of hepatocellular carcinoma.

Glycyrrhetinic acid-functionalized mesoporous silica nanoparticles as hepatocellular carcinoma-targeted drug carrier

PubMed Central

Lv, Yongjiu; Li, Jingjing; Chen, Huali; Bai, Yan; Zhang, Liangke

2017-01-01

In this study, a glycyrrhetinic acid-functionalized mesoporous silica nanoparticle (MSN-GA) was prepared for active tumor targeting. MSN-GA exhibited satisfactory loading capacity for insoluble drugs, uniform size distribution, and specific tumor cell targeting. Glycyrrhetinic acid, a hepatocellular carcinoma-targeting group, was covalently decorated on the surface of MSN via an amido bond. The successful synthesis of MSN-GA was validated by the results of Fourier transform infrared spectroscopy, transmission electron microscopy (TEM), and zeta potential measurement. TEM images revealed the spherical morphology and uniform size distribution of the naked MSN and MSN-GA. Curcumin (CUR), an insoluble model drug, was loaded into MSN-GA (denoted as MSN-GA-CUR) with a high-loading capacity (8.78%±1.24%). The results of the in vitro cellular experiment demonstrated that MSN-GA-CUR significantly enhanced cytotoxicity and cellular uptake toward hepatocellular carcinoma (HepG2) cells via a specific GA receptor-mediated endocytosis mechanism. The results of this study provide a promising nanoplatform for the targeting of hepatocellular carcinoma. PMID:28652738

Cationic poly(amidoamine) dendrimers induced cyto-protective autophagy in hepatocellular carcinoma cells

NASA Astrophysics Data System (ADS)

Li, Yubin; Wang, Shaofei; Wang, Ziyu; Qian, Xiaolu; Fan, Jiajun; Zeng, Xian; Sun, Yun; Song, Ping; Feng, Meiqing; Ju, Dianwen

2014-09-01

Poly(amidoamine) (PAMAM) dendrimers are proposed as one of the most promising nanomaterials for biomedical applications because of their unique tree-like structure, monodispersity and tunable properties. In this study, we found that PAMAM dendrimers could induce the formation of autophagosomes and the conversion of microtubule-associated protein 1 light chain 3 (LC3) in hepatocellular carcinoma HepG2 cells, while the inhibition of the Akt/mTOR and activation of the Erk 1/2 signaling pathways were involved in autophagy-induced by PAMAM dendrimers. We also investigated the suppression of autophagy with the obviously enhanced cytotoxicity of PAMAM dendrimers. Moreover, the blockage of a reactive oxygen species (ROS) could enhance the growth inhibition and apoptosis of hepatocellular carcinoma cells, induced by PAMAM dendrimers through reducing autophagic effects. Taken together, these findings explored the role and mechanism of autophagy induced by PAMAM dendrimers in HepG2 cells, provided new insight into the effect of autophagy on drug delivery nanomaterials and tumor cells and contributed to the use of a drug delivery vehicle for hepatocellular carcinoma treatment.

High-intensity focused ultrasound ablation for treatment of hepatocellular carcinoma and hypersplenism: preliminary study.

PubMed

Zhu, Jing; Zhu, Hui; Mei, Zhechuan; Jin, Chengbing; Ran, Lifeng; Zhou, Kun; Yang, Wei; Zhang, Lian; She, Chaokun

2013-10-01

The purpose of this work was to preliminarily investigate the efficacy and safety of high-intensity focused ultrasound treatment of hepatocellular carcinoma and hypersplenism. Nine patients with hepatocellular carcinoma complicated by hypersplenism (5 male and 4 female; median age, 56 years; range, 51-66 years) were treated with ultrasound-guided high-intensity focused ultrasound. Complications were recorded. Laboratory examination and magnetic resonance imaging were used to evaluate the efficacy. After high-intensity focused ultrasound treatment, mean spleen ablation ± SD of 28.76% ± 6.1% was discovered; meanwhile, the white blood cell count, platelet count, and liver function of the patients were substantially improved during the follow-up period. In addition, symptoms such as epistaxis and gingival bleeding were ameliorated or even eliminated, and the quality of life was improved. Follow-up imaging showed a nonperfused volume in the spleen and an absence of a tumor blood supply at the treated lesions in the liver. For the first time to our knowledge, high-intensity focused ultrasound ablation was used to treat hepatocellular carcinoma complicated by hypersplenism. High-intensity focused ultrasound may be an effective and safe alternative for treatment of hepatocellular carcinoma complicated by hypersplenism, but further studies are necessary to clarify the mechanisms.

A qRT-PCR and Gene Functional Enrichment Study Focused on Downregulation of miR-141-3p in Hepatocellular Carcinoma and Its Clinicopathological Significance.

PubMed

Liu, Cui-Zhen; Ye, Zhi-Hua; Ma, Jie; He, Rong-Quan; Liang, Hai-Wei; Peng, Zhi-Gang; Chen, Gang

2017-01-01

The clinical significance of miR-141-3p in hepatocellular carcinoma has not been verified. Therefore, we conducted this study to examine miR-141-3p expression and its clinical significance in hepatocellular carcinoma and to investigate the functions of its potential targets. The Cancer Genome Atlas database and the Gene Expression Omnibus database were used to explore the aberrant expression of miR-141-3p in hepatocellular carcinoma. Furthermore, we assessed the miR-141-3p levels in 95 hepatocellular carcinoma tissues with 95 matched adjacent tissues using real-time quantitative polymerase chain reaction. Moreover, a target gene prediction analysis of miR-141-3p, a natural language processing analysis for hepatocellular carcinoma using PubMed, and a gene functional enrichment analysis were conducted to search the potential function of miR-141-3p in the pathogenesis of hepatocellular carcinoma. Regarding The Cancer Genome Atlas data, miR-141-3p levels were markedly downregulated in hepatocellular carcinoma tissue compared to para- or nontumor tissue (4.6112 [1.7096] vs 5.3053 [1.4254], P = .045). MiR-141-3p expression was reduced in patients with hepatocellular carcinoma with a low pathologic T stage ( P = .006), a low grade ( P = .01), elderly hepatocellular carcinoma patients ( P = .001), and male patients with hepatocellular carcinoma ( P = .01) compared with that in patients with hepatocellular carcinoma with high pathologic T stages, high grades, young patients with hepatocellular carcinoma, and female patients with hepatocellular carcinoma. However, according to the Gene Expression Omnibus database, no significant differences in the expression of miR-141-3p were observed between hepatocellular carcinoma tissue and normal liver tissue ( P = .984). Real-time quantitative polymerase chain reaction confirmed a similar trend of decreased miR-141-3p in hepatocellular carcinoma tissue (1.7542 [0.8663] vs 2.5562 [1.7913], P = .001) as observed in The Cancer Genome

The Combination of Periostin Overexpression and Microvascular Invasion Is Related to a Poor Prognosis for Hepatocellular Carcinoma.

PubMed

Jang, Se Young; Park, Soo Young; Lee, Hye Won; Choi, Yeon-Kyung; Park, Keun-Gyu; Yoon, Ghil Suk; Tak, Won Young; Kweon, Young Oh; Hur, Keun; Lee, Won Kee

2016-11-15

Periostin is an extracellular matrix protein and is known to be related to the metastatic potential and prognosis of cancer. However, few studies have investigated the expression level of periostin and its association with prognoses in hepatocellular carcinoma. Therefore, we analyzed periostin overexpression in hepatocellular carcinoma and its implication for prognoses. We evaluated 149 patients who underwent surgical resection between 2006 and 2010. Tissue microarrays were constructed from hepatocellular carcinoma tissue and adjacent nontumor tissue, and immunohistochemistry was performed. A high periostin level was observed more frequently in cases of multiple tumors (odds ratio [OR], 2.826; 95% confidence interval [CI], 1.224 to 6.527; p=0.013), positive microvascular invasion (OR, 2.974; 95% CI, 1.431 to 6.181; p=0.003), and advanced stage disease (OR, 3.032; 95% CI, 1.424 to 6.452; p=0.003). Patients with high periostin expression had significantly (p=0.002) lower overall survival rates than those with low periostin expression (90.3%, 66.1%, and 56.2% vs 97.7%, 85.1%, and 77.5% at 1, 3, and 5 years). We found that a combination of periostin overexpression and microvascular invasion in hepatocellular carcinoma was correlated with a poor prognosis and can be a good prognostic marker for hepatocellular carcinoma.

Immune repertoire: A potential biomarker and therapeutic for hepatocellular carcinoma.

PubMed

Han, Yingxin; Li, Hongmei; Guan, Yanfang; Huang, Jian

2016-09-01

The immune repertoire (IR) refers to the sum of B cells and T cells with functional diversity in the circulatory system of one individual at any given time. Immune cells, which reside within microenvironments and are responsible for protecting the human body, include T cells, B cells, macrophages, and dendritic cells. These dedicated immune cells have a characteristic structure and function. T and B cells are the main lymphocytes and are responsible for cellular immunity and humoral immunity, respectively. The T cell receptor (TCR) and B cell receptor (BCR) are composed of multiple peptide chains with antigen specificity. The amino acid composition and sequence order are more diverse in the complementarity-determining regions (including CDR1, CDR2 and CDR3) of each peptide chain, allowing a vast library of TCRs and BCRs. IR research is becoming increasingly focused on the study of CDR3 diversity. Deep profiling of CDR3s using high-throughput sequencing is a powerful approach for elucidating the composition and distribution of the CDR3s in a given sample, with in-depth information at the sequence level. Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world. To identify novel biomarkers for diagnosis and drug targets for therapeutic interventions, several groups attempted to describe immune repertoire characteristics of the liver in the physiological environment or/and pathological conditions. This paper reviews the recent progress in IR research on human diseases, including hepatocellular carcinoma, attempting to depict the relationships between hepatocellular carcinogenesis and the IR, and discusses the possibility of IR as a potential biomarker and therapeutic for hepatocellular carcinoma. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

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

DNA damage induces down-regulation of Prp19 via impairing Prp19 stability in hepatocellular carcinoma cells.

PubMed

Yin, Jie; Zhang, Yi-An; Liu, Tao-Tao; Zhu, Ji-Min; Shen, Xi-Zhong

2014-01-01

Pre-mRNA processing factor 19 (Prp19) activates pre-mRNA spliceosome and also mediates DNA damage response. Prp19 overexpression in cells with functional p53 leads to decreased apoptosis and increases cell survival after DNA damage. Here we showed that in hepatocellular carcinoma (HCC) cells with inactive p53 or functional p53, Prp19 was down-regulated due to the impaired stability under chemotherapeutic drug treatment. Silencing Prp19 expression enhanced apoptosis of HCC cells with or without chemotherapeutic drug treatment. Furthermore high level of Prp19 may inhibit chemotherapeutic drugs induced apoptosis in hepatocellular carcinoma cells through modulating myeloid leukemia cell differentiation 1 expression. These results indicated that targeting Prp19 may potentiate pro-apoptotic effect of chemotherapeutic agents on HCC.

Persistence of hepatocellular carcinoma risk in hepatitis C patients with a response to IFN and cirrhosis regression.

PubMed

D'Ambrosio, Roberta; Aghemo, Alessio; Rumi, Maria Grazia; Degasperi, Elisabetta; Sangiovanni, Angelo; Maggioni, Marco; Fraquelli, Mirella; Perbellini, Riccardo; Rosenberg, William; Bedossa, Pierre; Colombo, Massimo; Lampertico, Pietro

2018-01-27

In patients with HCV-related cirrhosis, a sustained virological response may lead to cirrhosis regression. Whether histological changes translate into prevention of long-term complications, particularly hepatocellular carcinoma is still unknown. This was investigated in a cohort of histological cirrhotics who had been prospectively followed-up for 10 years after the achievement of a sustained virological response to IFN. In all, 38 sustained virological response cirrhotics who underwent a liver biopsy 5 years post-SVR were prospectively followed to assess the impact of cirrhosis regression on clinical endpoints. During a follow-up of 86 (30-96) months from liver biopsy, no patients developed clinical decompensation, whilst 5 (13%) developed hepatocellular carcinoma after 79 (7-88) months. The 8-year cumulative probability of hepatocellular carcinoma was 17%, without differences between patients with or without cirrhosis regression (19% [95% CI 6%-50%] vs 14% [95% CI 4%-44%], P = .88). Patients who developed or did not an hepatocellular carcinoma had similar rates of residual cirrhosis (P = 1.0), collagen content (P = .48), METAVIR activity (P = .34), portal inflammation (P = .06) and steatosis (P = .17). At baseline, patients who developed an hepatocellular carcinoma had higher γGT (HR 1.03, 95% CI 1.00-1.06; P = .014) and glucose (HR 1.02, 95% CI 1.00-1.02; P = .012) values; moreover, they had increased Forns Score (HR 12.8, 95% CI 1.14-143.9; P = .039), Lok Index (HR 6.24, 95% CI 1.03-37.6; P = .046) and PLF (HR 19.3, 95% CI 1.72-217.6; P = .016) values. One regressor died of lung cancer. The 8-year cumulative survival probability was 97%, independently on cirrhosis regression (96% vs 100%, P = 1.0) or hepatocellular carcinoma (100% vs 97%, P = 1.0). Post-SVR cirrhosis regression does not prevent hepatocellular carcinoma occurrence. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Intravenous miR-144 inhibits tumor growth in diethylnitrosamine-induced hepatocellular carcinoma in mice.

PubMed

He, Quan; Wang, Fangfei; Honda, Takashi; Lindquist, Diana M; Dillman, Jonathan R; Timchenko, Nikolai A; Redington, Andrew N

2017-10-01

Previous in vitro studies have demonstrated that miR-144 inhibits hepatocellular carcinoma cell proliferation, invasion, and migration. We have shown that miR-144, injected intravenously, is taken up by the liver and induces endogenous hepatic synthesis of miR-144. We hypothesized that administered miR-144 has tumor-suppressive effects on liver tumor development in vivo. The effects of miR-144 on tumorigenesis and tumor growth were tested in a diethylnitrosamine-induced hepatocellular carcinoma mouse model. MiR-144 injection had no effect on body weight but significantly reduced diethylnitrosamine-induced liver enlargement compared with scrambled microRNA. MiR-144 had no effect on diethylnitrosamine-induced liver tumor number but reduced the tumor size above 50%, as evaluated by magnetic resonance imaging (scrambled microRNA 23.07 ± 5.67 vs miR-144 10.38 ± 2.62, p < 0.05) and histological analysis (scrambled microRNA 30.75 ± 5.41 vs miR-144 15.20 ± 3.41, p < 0.05). The levels of miR-144 was suppressed in tumor tissue compared with non-tumor tissue in all treatment groups (diethylnitrosamine-phosphate-buffered saline non-tumor 1.05 ± 0.09 vs tumor 0.54 ± 0.08, p < 0.01; diethylnitrosamine-scrambled microRNA non-tumor 1.23 ± 0.33 vs tumor 0.44 ± 0.10, p < 0.05; diethylnitrosamine-miR-144 non-tumor 54.72 ± 11.80 vs tumor 11.66 ± 2.75, p < 0.01), but injection of miR-144 greatly increased miR-144 levels both in tumor and non-tumor tissues. Mechanistic studies showed that miR-144 targets epidermal growth factor receptor and inhibits the downstream Src/AKT signaling pathway which has previously been implicated in hepatocellular carcinoma tumorigenesis. Exogenously delivered miR-144 may be a therapeutic strategy to suppress tumor growth in hepatocellular carcinoma.

Dopamine-induced SULT1A3/4 promotes EMT and cancer stemness in hepatocellular carcinoma.

PubMed

Zou, Juan; Li, Hong; Huang, Qianling; Liu, Xiaomin; Qi, Xiaoxiao; Wang, Ying; Lu, Linlin; Liu, Zhongqiu

2017-10-01

Hepatocellular carcinoma has the second highest incidence rate among malignant cancers in China. Hepatocellular carcinoma development is complex because of the metabolism disequilibrium involving SULT1A3/4, a predominant sulfotransferase that metabolizes sulfonic xenobiotics and endogenous catecholamines. However, the correlation between SULT1A3/4 and hepatocellular carcinoma progression is unclear. By utilizing immunofluorescence and immunohistochemical analysis, we found that in nine hepatocellular carcinoma clinical specimens, SULT1A3/4 was abundantly expressed in tumor tissues compared to that in the adjacent tissues. Moreover, liver cancer cells (HepG2, MHCC97-L, and MHCC97-H) had higher basal expression of SULT1A3/4 than immortalized liver cells (L02 and Chang liver). Ultra-high-pressure liquid chromatography-tandem mass spectrometry assay results further revealed that the concentration of dopamine (a substrate of SULT1A3/4) was negatively correlated with SULT1A3/4 protein expression. As a transcriptional regulator of SULT1A3/4 in turn, dopamine was used to induce SULT1A3/4 in vitro. Interestingly, dopamine significantly induced SULT1A3/4 expression in liver cancer HepG2 cells, while decreased that in L02 cells. More importantly, the expression levels of epithelial-mesenchymal transition biomarkers (N-cadherin and vimentin) and cell stemness biomarkers (nanog, sox2, and oct3/4) considerably increased in HepG2 with dopamine-induced SULT1A3/4, whereas in L02, epithelial-mesenchymal transition and cancer stem cell-associated proteins were contrarily decreased. Furthermore, invasion and migration assays further revealed that dopamine-induced SULT1A3/4 dramatically stimulated the metastatic capacity of HepG2 cells. Our results implied that SULT1A3/4 exhibited bidirectional effect on tumor and normal hepatocytes and may thus provide a novel strategy for hepatocellular carcinoma clinical targeting. In addition, SULT1A3/4 re-expression could serve as a biomarker for

[Primary study on fluro [ 19F] berberine derivative for human hepatocellular carcinoma targetting in vitro].

PubMed

Zhang, Tong; Wu, Xiaoai; Cai, Huawei; Liang, Meng; Fan, Chengzhong

2017-04-01

[ 18 F]HX-01, a Fluorine-18 labeled berberine derivative, is a potential positron emission tomography (PET) tumor imaging agent, while [ 19 F]HX-01 is a nonradioactive reference substance with different energy state and has the same physical and chemical properties. In order to collect data for further study of [ 18 F]HX-01 PET imaging of hepatocellular carcinoma in vivo , this study compared the uptake of [ 19 F]HX-01 by human hepatocellular carcinoma and normal hepatocytes in vitro . The target compound, [ 19 F]HX-01, was synthesized in one step using berberrubine and 3-fluoropropyl 4-methylbenzenesulfonate. Cellular uptake and localization of [ 19 F]HX-01 were performed by a fluorescence microscope in human hepatocellular carcinoma HepG2, SMMC-7721 and human normal hepatocyte HL-7702. Cellular proliferation inhibition and cell cytotoxicity assay of the [ 19 F]HX-01 were conducted using cell counting kit-8 (CCK-8) on HepG2, SMMC-7721 and HL-7702 cells. Fluorescent microscopy showed that the combining ability of [ 19 F]HX-01 to the carcinoma SMMC-7721 and HepG2 was higher than that to the normal HL-7702. Cellular proliferation inhibition assay demonstrated that [ 19 F]HX-01 leaded to a dose-dependent inhibition on SMMC-7721, HepG2, and HL-7702 proliferation. Cell cytotoxicity assay presented that the cytotoxicity of [ 19 F]HX-01 to SMMC-7721 and HepG2 was obviously higher than that to HL-7702. This in vitro study showed that [ 19 F]HX-01 had a higher selectivity on human hepatocellular carcinoma cells (SMMC-7721, HepG2) but has less toxicity to normal hepatocytes (HL-7702). This could set up the idea that the radioactive reference substance [ 18 F]HX-01 may be worthy of further development as a potential molecular probe targeting human hepatocellular carcinoma using PET.

High-resolution characterization of a hepatocellular carcinoma genome.

PubMed

Totoki, Yasushi; Tatsuno, Kenji; Yamamoto, Shogo; Arai, Yasuhito; Hosoda, Fumie; Ishikawa, Shumpei; Tsutsumi, Shuichi; Sonoda, Kohtaro; Totsuka, Hirohiko; Shirakihara, Takuya; Sakamoto, Hiromi; Wang, Linghua; Ojima, Hidenori; Shimada, Kazuaki; Kosuge, Tomoo; Okusaka, Takuji; Kato, Kazuto; Kusuda, Jun; Yoshida, Teruhiko; Aburatani, Hiroyuki; Shibata, Tatsuhiro

2011-05-01

Hepatocellular carcinoma, one of the most common virus-associated cancers, is the third most frequent cause of cancer-related death worldwide. By massively parallel sequencing of a primary hepatitis C virus-positive hepatocellular carcinoma (36× coverage) and matched lymphocytes (>28× coverage) from the same individual, we identified more than 11,000 somatic substitutions of the tumor genome that showed predominance of T>C/A>G transition and a decrease of the T>C substitution on the transcribed strand, suggesting preferential DNA repair. Gene annotation enrichment analysis of 63 validated non-synonymous substitutions revealed enrichment of phosphoproteins. We further validated 22 chromosomal rearrangements, generating four fusion transcripts that had altered transcriptional regulation (BCORL1-ELF4) or promoter activity. Whole-exome sequencing at a higher sequence depth (>76× coverage) revealed a TSC1 nonsense substitution in a subpopulation of the tumor cells. This first high-resolution characterization of a virus-associated cancer genome identified previously uncharacterized mutation patterns, intra-chromosomal rearrangements and fusion genes, as well as genetic heterogeneity within the tumor.

Clinical outcome after pulmonary metastasectomy from primary hepatocellular carcinoma: Analysis of prognostic factors

PubMed Central

Kwon, Jong-Bum; Park, Khun; Kim, Young-Du; Seo, Jong-Hee; Moon, Seok-Whan; Cho, Deog-Gon; Kim, Yong-Whan; Kim, Dong-Goo; Yoon, Seung-Kew; Lim, Hyeon-Woo

2008-01-01

AIM: To review the surgical outcomes in terms of the surgical indications and relevant prognostic factors. METHODS: Sixteen patients underwent therapeutic lung surgery between March 1999 and May 2006. The observation period was terminated on May 31, 2007. The surgical outcomes and the clinicopathological factors were compared. RESULTS: There was no mortality or major morbidity encountered in this study. The mean follow-up period after metastasectomy was 26.7 ± 28.2 (range: 1-99 mo), and the median survival time was 20 mo. The 1- and 5-year survival rates were 56% and 26%, respectively. At the end of the follow-up, 1 patient died from hepatic failure without recurrence, 6 died from hepatic failure with a recurrent hepatocellular carcinoma (HCC), and 4 died from recurrent HCC with cachexia. Among several clinical factors, Kaplan-Meier analysis revealed that liver transplantation as a treatment for the primary lesion, grade of cell differentiation, and negative evidence HBV infection were independent predictive factors. On Cox’s proportional hazard model, there were no significant factors affecting survival after pulmonary metastasectomy in patients with HCC. CONCLUSION: A metastasectomy should be performed before other treatments in selected patients. Although not significant, patients with liver transplantation of a primary HCC survived longer. Liver transplantation might be the most beneficial modality that can offer patients better survival. A multi-institutional and collaborative study would be needed for identifying clinical prognostic factors predicting survival in patients with HCC and lung metastasis. PMID:18837090

PARP-1 serves as a novel molecular marker for hepatocellular carcinoma in a Southern Chinese Zhuang population.

PubMed

Li, Jiatong; Dou, Dongwei; Li, Ping; Luo, Wenqi; Lv, Wenxin; Zhang, Chengdong; Song, Xiaowei; Yang, Yuan; Zhang, Yuening; Xu, Yanzhen; Xiao, Feifan; Wei, Yan; Qin, Jian; Li, Hongtao; Yang, Xiaoli

2017-07-01

PARP-1 (poly(ADP-ribose) polymerase-1) plays an important role in tumorigenesis. Since its effects on different populations are varied, this study investigated the impact of PARP-1 on primary hepatocellular carcinoma in a Southern Chinese Zhuang population. We assessed the global PARP-1 messenger RNA expression in patients with hepatocellular carcinoma using The Cancer Genome Atlas dataset. Increased PARP-1 expression, related to alpha-fetoprotein level, was observed. The area under the receiver operating characteristic curve value was 0.833. Kaplan-Meier survival curves indicated that higher PARP-1 expression was not correlated with poorer overall survival and recurrence-free survival. In a Zhuang population, PARP-1 messenger RNA and protein levels were increased in the hepatocellular carcinoma tissue and its adjacent liver tissues as assessed by quantitative polymerase chain reaction, immunohistochemistry, and western blotting. Higher PARP-1 level was associated with a higher tumor stage (p < 0.05), without correlation with age, gender, smoking, drinking, tumor size, serum alpha-fetoprotein level, hepatitis B virus infection, metastasis, and invasion (p > 0.05). Further analysis suggested that H2AX, a PARP-1 protein interaction partner, was coordinated with PARP-1 in hepatocellular carcinoma tumorigenesis. Overall, some new characteristics of PARP-1 expression were noted in the Zhuang population. PARP-1 is a novel promising diagnostic marker for hepatocellular carcinoma in the Southern Chinese Zhuang population.

A discussion of serum albumin level in advanced-stage hepatocellular carcinoma: a medical oncologist's perspective.

PubMed

Tanriverdi, Ozgur

2014-11-01

Hepatocellular carcinoma is the most common primary malignant tumor of the liver, and it is particularly prevalent in East and Southeast Asia. With surgical and/or local interventional treatment methods, survival rates for early-stage hepatocellular cancers have increased. However, it is not yet clear which staging systems are more applicable in hepatocellular carcinoma. Serum albumin level is already being used as a criterion in most staging systems. Albumin is an important serum protein in human bodily functions, but only 5 % of the daily amount needed is synthesized by the liver. The serum albumin level is affected by multifactorial situations, including capillary permeability, drugs, liver insufficiency, inflammation and/or infections, dehydration or overhydration, protein loosing disorders, and decreased nutrition intake in anorexia-malnutrition syndrome and cancer cachexia. Because of this complex situation, serum albumin level may affect many staging systems for hepatocellular carcinoma by leading to false-negative results. In this paper, the statuses of current staging systems are reviewed, and possible negative events regarding the serum albumin levels found in these staging systems are discussed.

Differences in health-related quality of life between European and Asian patients with hepatocellular carcinoma.

PubMed

Chie, Wei-Chu; Blazeby, Jane M; Hsiao, Chin-Fu; Chiu, Herng-Chia; Poon, Ronnie T; Mikoshiba, Naoko; Al-Kadhim, Gillian; Heaton, Nigel; Calara, Jozer; Collins, Peter; Caddick, Katharine; Costantini, Anna; Vilgrain, Valerie

2017-10-01

The aim of this study is to explore the possible effects of clinical and cultural characteristics of hepatocellular carcinoma on patients' health-related quality of life (HRQoL). Patients with hepatocellular carcinoma from Asian and European countries completed the EORTC QLQ-C30 and the EORTC QLQ-HCC18. Comparisons were made using Student's t-test and Wilcoxon rank-sum test with method of false discovery to correct multiple comparisons. Multiway analysis of variance and model selection were used to assess the effects of clinical characteristics and geographic areas. Two hundred and twenty-seven patients with hepatocellular carcinoma completed questionnaires. After adjusting for demographic and clinical characteristics, Asian patients still had significantly better HRQoL scores in emotional functioning, insomnia, (QLQ-C30) and in sexual interest (QLQ-HCC18). We also found an interaction in physical functioning (QLQ-C30) and fatigue (QLQ-HCC18) between geographic region and marital status, married European had worse HRQoL scores than Asian singles. Both clinical characteristics and geographic areas affected the HRQoL in with hepatocellular carcinoma. Cultural differences and clinical differences in the pattern of disease due to active surveillance of Asian countries may explain the results. © 2016 John Wiley & Sons Australia, Ltd.

Development of models to predict early post-transplant recurrence of hepatocellular carcinoma that also integrate the quality and characteristics of the liver graft: A national registry study in China.

PubMed

Ling, Qi; Liu, Jimin; Zhuo, Jianyong; Zhuang, Runzhou; Huang, Haitao; He, Xiangxiang; Xu, Xiao; Zheng, Shusen

2018-04-27

Donor characteristics and graft quality were recently reported to play an important role in the recurrence of hepatocellular carcinoma after liver transplantation. Our aim was to establish a prognostic model by using both donor and recipient variables. Data of 1,010 adult patients (training/validation: 2/1) undergoing primary liver transplantation for hepatocellular carcinoma were extracted from the China Liver Transplant Registry database and analyzed retrospectively. A multivariate competing risk regression model was developed and used to generate a nomogram predicting the likelihood of post-transplant hepatocellular carcinoma recurrence. Of 673 patients in the training cohort, 70 (10.4%) had hepatocellular carcinoma recurrence with a median recurrence time of 6 months (interquartile range: 4-25 months). Cold ischemia time was the only independent donor prognostic factor for predicting hepatocellular carcinoma recurrence (hazard ratio = 2.234, P = .007). The optimal cutoff value was 12 hours when patients were grouped according to cold ischemia time at 2-hour intervals. Integrating cold ischemia time into the Milan criteria (liver transplantation candidate selection criteria) improved the accuracy for predicting hepatocellular carcinoma recurrence in both training and validation sets (P < .05). A nomogram composed of cold ischemia time, tumor burden, differentiation, and α-fetoprotein level proved to be accurate and reliable in predicting the likelihood of 1-year hepatocellular carcinoma recurrence after liver transplantation. Additionally, donor anti-hepatitis B core antibody positivity, prolonged cold ischemia time, and anhepatic time were linked to the intrahepatic recurrence, whereas older donor age, prolonged donor warm ischemia time, cold ischemia time, and ABO incompatibility were relevant to the extrahepatic recurrence. The graft quality integrated models exhibited considerable predictive accuracy in early hepatocellular carcinoma recurrence risk

Factors associated with tumor size of hepatocellular carcinoma

NASA Astrophysics Data System (ADS)

Siregar, G. A.; Buulolo, B. A.

2018-03-01

Determining the association of age and laboratory parameters with tumor size of hepatocellular carcinoma (HCC). The study was at Adam Malik Hospital Medan from June- December 2016. 100 HCC patients were enrolled; those with excluding liver metastatic. Baseline characteristics of gender, age, obtaining etiology of HCC. Liver function tests, viral marker, and INR were done. Based on tumor size from abdomen CT, patients were three groups: tumor size below 3 cm, 3-5 cm, and above 5 cm size. Patients were also divided based on Child-Pugh class. Correlation of age and laboratory results with tumor size of HCC patients were analyzed. Age have negative correlation with tumor size in HCC patients (r=-0.297, p=0.032) while AFP have positive correlation with tumor size (r0.446, p=<0.001). Total bilirubin, AST, and ALT have negative correlation but non-significant (r=-0.045, -0.078, - 0.126 respectively). Albumin and INR have positive correlation but non-significant (r=0.021, 0.112 respectively). Our study suggests that older age correlates with smaller tumor size, while AFP level has a significant correlation with tumor size in HCC patients. AFP level may be a useful marker for determining the prognosis of HCC patients.

Significance of estrogen receptor 1 (ESR-1) gene imbalances in colon and hepatocellular carcinomas based on tissue microarrays analysis.

PubMed

Tsiambas, Evangelos; Georgiannos, Stavros N; Salemis, Nikolaos; Alexopoulou, Despoina; Lambropoulou, Sofia; Dimo, Blerta; Ioannidis, Ioannis; Kravvaritis, Christos; Karameris, Andreas; Patsouris, Efstratios; Dourakis, Spyridon

2011-12-01

Estrogen receptor alpha-encoded by ESR1 gene-overexpression correlates with prognosis and response to specific chemotherapy in breast adenocarcinoma cases. Mechanisms of ESR-1 deregulation in carcinomas remain under investigation. To analyze ESR1 in carcinomas of different histogenesis. Using tissue microarray technology, 172 primary carcinomas including breast ductal adenocarcinomas (n=60), hepatocellular carcinomas (n=52), and colon adenocarcinomas (n=60) were cored and re-embedded in three paraffin blocks. Initial diagnosis was based on liquid based cytology (LiquiPrep/ThinPrep). Immunohistochemistry and fluorescence in situ hybridization were performed. Quantitative evaluation of ER-a protein levels was assessed by applying digital image analysis. ER-a overexpression was observed in 41/60 (68.3%), 23/52 (44.2%) and 4/60 (6.6%) cases, respectively. ESR1 gene multiple copies were confirmed in 13/60 (21.6%) breast adenocarcinomas, but high amplification only in 8/13 (62.8%). Allelic absence was identified in 3/52 (5.7%) hepatocellular carcinomas, whereas colon adenocarcinomas demonstrated gene gains in 5/60 (8.3%) cases referred to chr 6 aneuploidy and not to amplification. ER-a overall expression was associated strongly to ESR1 gene copies only in breast carcinoma (P=0.036). ESR-1 gene overexpression happens frequently in breast cancer, but only a subset of them are high amplified cases correlated to increased response rates in hormonal therapy (tamoxifen). Absence of this mechanism in hepatocellular and colon carcinomas maybe is a negative factor for applying this therapy. This is a pattern of histo-genetic depended targeted therapeutic strategy.

Sorafenib Combined With Transarterial Chemoembolization in Treating HBV-infected Patients With Intermediate Hepatocellular Carcinoma

ClinicalTrials.gov

2012-04-24

PHENYTOIN/SORAFENIB [VA Drug Interaction]; Liver Neoplasms; Carcinoma, Hepatocellular; Digestive System Neoplasms; Neoplasms by Site; Liver Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; DOXORUBICIN/TRASTUZUMAB [VA Drug Interaction]; HBV

Notch Inhibitor PF-03084014 Inhibits Hepatocellular Carcinoma Growth and Metastasis via Suppression of Cancer Stemness due to Reduced Activation of Notch1-Stat3.

PubMed

Wu, Chuan Xing; Xu, Aimin; Zhang, Cathy C; Olson, Peter; Chen, Lin; Lee, Terence K; Cheung, Tan To; Lo, Chung Mau; Wang, Xiao Qi

2017-08-01

Aberrant activation of the Notch signaling pathway is implicated in many solid tumors, including hepatocellular carcinoma, indicating a potential use of Notch inhibitors for treatment. In this study, we investigated the antitumor and antimetastasis efficacy of the novel Notch inhibitor (γ-secretase inhibitor) PF-03084014 in hepatocellular carcinoma. Hepatocellular carcinoma spherical cells (stem-like cancer cells), a sphere-derived orthotopic tumor model and one patient-derived xenograft (PDX) model were used in our experiment. We demonstrated that PF-03084014 inhibited the self-renewal and proliferation of cancer stem cells. PF-03084014 reduced the hepatocellular carcinoma sphere-derived orthotopic tumor and blocked the hepatocellular carcinoma tumor liver to lung metastasis. We further tested the PF-03084014 in PDX models and confirmed the inhibition tumor growth effect. In addition, a low dose of PF-03084014 induced hepatocellular carcinoma sphere differentiation, resulting in chemosensitization. Antitumor activity was associated with PF-03084014-induced suppression of Notch1 activity, decreased Stat3 activation and phosphorylation of the Akt signaling pathway, and reduced epithelial-mesenchymal transition. These are the key contributors to the maintenance of cancer stemness and the promotion of cancer metastasis. Moreover, the Notch-Stat3 association was implicated in the clinical hepatocellular carcinoma prognosis. Collectively, PF-03084014 revealed antitumor and antimetastatic effects in hepatocellular carcinoma, providing evidence for the potential use of gamma-secretase inhibitors as a therapeutic option for the treatment of hepatocellular carcinoma. Mol Cancer Ther; 16(8); 1531-43. ©2017 AACR . ©2017 American Association for Cancer Research.

Simple sugar intake and hepatocellular carcinoma: epidemiological and mechanistic insight.

PubMed

Laguna, Juan Carlos; Alegret, Marta; Roglans, Núria

2014-12-22

Sugar intake has dramatically increased during the last few decades. Specifically, there has been a clear trend towards higher consumption of fructose and high fructose corn syrup, which are the most common added sugars in processed food, soft drinks and other sweetened beverages. Although still controversial, this rising trend in simple sugar consumption has been positively associated with weight gain and obesity, insulin resistance and type 2 diabetes mellitus and non-alcoholic fatty liver disease. Interestingly, all of these metabolic alterations have also been related to the development of hepatocellular carcinoma. The purpose of this review is to discuss the evidence coming from epidemiological studies and data from animal models relating the consumption of simple sugars, and specifically fructose, with an increased risk of hepatocellular carcinoma and to gain insight into the putative molecular mechanisms involved.

CASC2/miR-24/miR-221 modulates the TRAIL resistance of hepatocellular carcinoma cell through caspase-8/caspase-3.

PubMed

Jin, Xiaoxin; Cai, Lifeng; Wang, Changfa; Deng, Xiaofeng; Yi, Shengen; Lei, Zhao; Xiao, Qiangsheng; Xu, Hongbo; Luo, Hongwu; Sun, Jichun

2018-02-23

Hepatocellular carcinoma is one of the most common solid tumors in the digestive system. The prognosis of patients with hepatocellular carcinoma is still poor due to the acquisition of multi-drug resistance. TNF Related Apoptosis Inducing Ligand (TRAIL), an attractive anticancer agent, exerts its effect of selectively inducing apoptosis in tumor cells through death receptors and the formation of the downstream death-inducing signaling complex, which activates apical caspases 3/8 and leads to apoptosis. However, hepatocellular carcinoma cells are resistant to TRAIL. Non-coding RNAs, including long non-coding RNAs (lncRNAs) and miRNAs have been regarded as major regulators of normal development and diseases, including cancers. Moreover, lncRNAs and miRNAs have been reported to be associated with multi-drug resistance. In the present study, we investigated the mechanism by which TRAIL resistance of hepatocellular carcinoma is affected from the view of non-coding RNA regulation. We selected and validated candidate miRNAs, miR-24 and miR-221, that regulated caspase 3/8 expression through direct targeting, and thereby affecting TRAIL-induced tumor cell apoptosis TRAIL resistance of hepatocellular carcinoma. In addition, we revealed that CASC2, a well-established tumor suppressive long non-coding RNA, could serve as a "Sponge" of miR-24 and miR-221, thus modulating TRAIL-induced tumor cell apoptosis TRAIL resistance of hepatocellular carcinoma. Taken together, we demonstrated a CASC2/miR-24/miR-221 axis, which can affect the TRAIL resistance of hepatocellular carcinoma through regulating caspase 3/8; through acting as a "Sponge" of miR-24 and miR-221, CASC2 may contribute to improving hepatocellular carcinoma TRAIL resistance, and finally promoting the treatment efficiency of TRAIL-based therapies.

Hepatitis B virus X promotes hepatocellular carcinoma development via nuclear protein 1 pathway.

PubMed

Bak, Yesol; Shin, Hye-jun; Bak, In seon; Yoon, Do-young; Yu, Dae-Yeul

2015-10-30

Hepatocellular carcinoma (HCC) is one of the most common malignancies and chronic hepatitis B virus (HBV) infection is a major risk factor for HCC. Hepatitis B virus X (HBx) protein relates to trigger oncogenesis. HBx has oncogenic properties with a hyperproliferative response to HCC. Nuclear protein 1 (NUPR1) is a stress-response protein, frequently upregulated in several cancers. Recent data revealed that NUPR1 is involved in tumor progression, but its function in HCC is not revealed yet. Here we report HBx can induce NUPR1 in patients, mice, and HCC cell lines. In an HBx transgenic mouse model, we found that HBx overexpression upregulates NUPR1 expression consistently with tumor progression. Further, in cultured HBV positive cells, HBx knockdown induces downregulation of NUPR1. Smad4 is a representative transcription factor, regulated by HBx, and we showed that HBx upregulates NUPR1 by Smad4 dependent way. We found that NUPR1 can inhibit cell death and induce vasculogenic mimicry in HCC cell lines. Moreover, NUPR1 silencing in HepG2-HBx showed reduced cell motility. These results suggest that HBx can modulate NUPR1 expression through the Smad4 pathway and NUPR1 has a role in hepatocellular carcinoma progression. Copyright © 2015 Elsevier Inc. All rights reserved.

Characteristics, management, and outcomes of patients with hepatocellular carcinoma in Africa: a multicountry observational study from the Africa Liver Cancer Consortium.

PubMed

Yang, Ju Dong; Mohamed, Essa A; Aziz, Ashraf O Abdel; Shousha, Hend I; Hashem, Mohamed B; Nabeel, Mohamed M; Abdelmaksoud, Ahmed H; Elbaz, Tamer M; Afihene, Mary Y; Duduyemi, Babatunde M; Ayawin, Joshua P; Gyedu, Adam; Lohouès-Kouacou, Marie-Jeanne; Ndam, Antonin W Ndjitoyap; Moustafa, Ehab F; Hassany, Sahar M; Moussa, Abdelmajeed M; Ugiagbe, Rose A; Omuemu, Casimir E; Anthony, Richard; Palmer, Dennis; Nyanga, Albert F; Malu, Abraham O; Obekpa, Solomon; Abdo, Abdelmounem E; Siddig, Awatif I; Mudawi, Hatim M Y; Okonkwo, Uchenna; Kooffreh-Ada, Mbang; Awuku, Yaw A; Nartey, Yvonne A; Abbew, Elizabeth T; Awuku, Nana A; Otegbayo, Jesse A; Akande, Kolawole O; Desalegn, Hailemichael M; Omonisi, Abidemi E; Ajayi, Akande O; Okeke, Edith N; Duguru, Mary J; Davwar, Pantong M; Okorie, Michael C; Mustapha, Shettima; Debes, Jose D; Ocama, Ponsiano; Lesi, Olufunmilayo A; Odeghe, Emuobor; Bello, Ruth; Onyekwere, Charles; Ekere, Francis; Igetei, Rufina; Mah'moud, Mitchell A; Addissie, Benyam; Ali, Hawa M; Gores, Gregory J; Topazian, Mark D; Roberts, Lewis R

2017-02-01

Hepatocellular carcinoma is a leading cause of cancer-related death in Africa, but there is still no comprehensive description of the current status of its epidemiology in Africa. We therefore initiated an African hepatocellular carcinoma consortium aiming to describe the clinical presentation, management, and outcomes of patients with hepatocellular carcinoma in Africa. We did a multicentre, multicountry, retrospective observational cohort study, inviting investigators from the African Network for Gastrointestinal and Liver Diseases to participate in the consortium to develop hepatocellular carcinoma research databases and biospecimen repositories. Participating institutions were from Cameroon, Egypt, Ethiopia, Ghana, Ivory Coast, Nigeria, Sudan, Tanzania, and Uganda. Clinical information-demographic characteristics, cause of disease, liver-related blood tests, tumour characteristics, treatments, last follow-up date, and survival status-for patients diagnosed with hepatocellular carcinoma between Aug 1, 2006, and April 1, 2016, were extracted from medical records by participating investigators. Because patients from Egypt showed differences in characteristics compared with patients from the other countries, we divided patients into two groups for analysis; Egypt versus other African countries. We undertook a multifactorial analysis using the Cox proportional hazards model to identify factors affecting survival (assessed from the time of diagnosis to last known follow-up or death). We obtained information for 2566 patients at 21 tertiary referral centres (two in Egypt, nine in Nigeria, four in Ghana, and one each in the Ivory Coast, Cameroon, Sudan, Ethiopia, Tanzania, and Uganda). 1251 patients were from Egypt and 1315 were from the other African countries (491 from Ghana, 363 from Nigeria, 277 from Ivory Coast, 59 from Cameroon, 51 from Sudan, 33 from Ethiopia, 21 from Tanzania, and 20 from Uganda). The median age at which hepatocellular carcinoma was diagnosed

Autophagy‑mediated adaptation of hepatocellular carcinoma cells to hypoxia‑mimicking conditions constitutes an attractive therapeutic target.

PubMed

Owada, Satoshi; Endo, Hitoshi; Shida, Yukari; Okada, Chisa; Ito, Kanako; Nezu, Takahiro; Tatemichi, Masayuki

2018-04-01

Hepatocellular carcinoma has extremely poor prognosis. In cancerous liver tissues, aberrant proliferation of cancer cells leads to the creation of an area where an immature vascular network is formed. Since oxygen is supplied to cancer tissues through the bloodstream, a part of the tumor is exposed to hypoxic conditions. As hypoxia is known to severely reduce the effectiveness of existing anticancer agents, novel valid therapeutic targets must be identified for the treatment of hepatocellular carcinoma. Generally, autophagy has been reported to play an important role in the adaptation of cancer cells to hypoxia. However, the exact role and significance of this process vary depending on the cancer type, requiring detailed analysis in individual primary tumors and cell lines. In the present study, we examined autophagy induced by cobalt chloride, a hypoxia‑mimicking agent, in hepatocellular carcinoma cells with the aim to evaluate the validity of this process as a potential therapeutic target. We observed that treatment with cobalt chloride induced autophagy, including the intracellular quality control mechanism, in an AMPK‑dependent manner. Furthermore, treatment with autophagy inhibitors (bafilomycin and LY294002) resulted in significant, highly‑selective cytotoxicity and apoptosis activation under hypoxia‑mimicking conditions. The knockdown of AMPK also revealed significant cytotoxicity in hypoxia‑mimicking conditions. These results clearly demonstrated that autophagy, especially mitophagy, was induced by the AMPK pathway when hepatocellular carcinoma cells were subjected to hypoxic conditions and played an important role in the adaptation of these cells to such conditions. Thus, autophagy may constitute an attractive therapeutic target for the treatment of hepatocellular carcinoma.

[Echo-guided radiofrequency percutaneous ablation of hepatocellular carcinoma in cirrhosis using a cooled needle].

PubMed

Marone, G; Francica, G; D'Angelo, V; Iodice, G; Pastore, P; Altamura, G; Cusati, B; Siani, A

1998-06-01

Radiofrequency hyperthermia using the newly-developed "cooled-tip" needle is one of the latest US-guided percutaneous treatments of hepatocellular carcinoma arising in cirrhosis. The continuous cooling of the needle tip allows tissue heating and necrosis far from the electrode without tissue charring, which was the major drawback of the old monopolar technique. Herein we report our preliminary results on feasibility and effectiveness of the thermoablation of mono- or paucifocal hepatocellular carcinoma with the cooled-tip needle. November, 1996, to January, 1998, we treated thirteen cirrhotic patients (mean age 69.5 yrs, 10 men, 12 HCV-positive; 11 in Child's Class A and 2 in Class B) with 19 hepatocellular carcinoma nodules (mean diameter: 27 mm; range: 10-41 mm; 6 with diameter > 3 cm). None of the patients had portal thrombosis and/or extrahepatic spread. We used a radiofrequency generator (100 W power) connected to an 18 G perfusion electrode needle with an exposed tip of 2-3 cm. The circuit is closed through a dispersive electrode positioned under the patient's thighs. A peristaltic pump infuses a chilled (2-5 degrees C) saline solution to guarantee the continuous cooling of the needle tip. The needle was placed into target lesions under US guidance. The interventional procedure was carried out under general anesthesia using Propofol without intubation. Dynamic CT (more recently with the helical technique) was carried out 15-20 days after thermoablation to assess treatment efficacy. In all, 31 thermal injuries (at 1000-1200 mA for 10-15 minutes) were caused in 21 sessions in the 19 hepatocellular carcinoma nodules (mean: 1.5 lesions per nodule and 1.6 sessions per patient). Complete necrosis as assessed at dynamic CT (no enhancement during the arteriographic phase) was achieved in 16 of 19 nodules (84%). No side-effects occurred. During the follow-up (median: 11 months) no death occurred and five patients had recurrent hepatocellular carcinoma appearing either

In vivo fluorescence imaging of hepatocellular carcinoma xenograft using near-infrared labeled epidermal growth factor receptor (EGFR) peptide

PubMed Central

Li, Z.; Zhou, Q.; Zhou, J.; Duan, X.; Zhu, J.; Wang, T. D.

2016-01-01

Minimally-invasive surgery of hepatocellular carcinoma (HCC) can be limited by poor tumor visualization with white light. We demonstrate systemic administration of a Cy5.5-labeled peptide specific for epidermal growth factor receptor (EGFR) to target HCC in vivo in a mouse xenograft model. We attached a compact imaging module to the proximal end of a medical laparoscope to collect near-infrared fluorescence and reflectance images concurrently at 15 frames/sec. We measured a mean target-to-background ratio of 2.99 ± 0.22 from 13 surgically exposed subcutaneous human HCC tumors in vivo in 5 mice. This integrated imaging methodology is promising to guide laparoscopic resection of HCC. PMID:27699089

Hepatocellular carcinoma in patients with autoimmune liver diseases: two case reports and literature review.

PubMed

Meza-Junco, Judith; Montaño-Loza, Aldo J; Martínez-Benitez, Braulio; Kimura-Hayama, Eric

2007-01-01

Hepatocellular carcinoma has been reported as a rare complication of autoimmune liver diseases. We describe herein two patients with this neoplasia associated with autoimmune hepatitis and primary biliary cirrhosis, and we also review the literature. The first case corresponds to a 49-year-old woman presented for evaluation of right upper abdominal pain. She had been diagnosed with autoimmune hepatitis 4 years before. Alpha-fetoprotein was markedly elevated and an abdominal MRI showed a 10 cm x 9.0 cm mass. She received transarterial chemoembolization, and currently the disease has progressed to the lungs and bones, and she is on supportive care. The second case corresponds to a 68-year-old woman presented for evaluation of a liver mass found in a screening ultrasound. She had been diagnosed with primary biliary cirrhosis 5 years previously. At admission alpha-fetoprotein was 1000 ng/mL and an abdominal MRI revealed a 4 cm x 3 cm liver tumor. She was treated with percutaneous radiofrequency ablation getting complete response, and currently she has no evidence of neoplastic disease. These two patients constitute the only cases of hepatocellular carcinoma associated to autoimmune liver diseases that have been attended in our Institute. These cases highlight that hepatocellular carcinoma secondary to autoimmune hepatitis and primary biliary cirrhosis, although rare, can occur in the absence of coexistent viral hepatitis, or excessive alcohol consumption. The utility of screening for hepatocellular carcinoma in autoimmune liver diseases is still not defined.

Targeting Phosphatidylinositide3-Kinase/Akt pathway by BKM120 for radiosensitization in hepatocellular carcinoma

PubMed Central

Liu, Wei-Lin; Gao, Ming; Tzen, Kai-Yuan; Tsai, Chiao-Ling; Hsu, Feng-Ming; Cheng, Ann-Lii; Cheng, Jason Chia-Hsien

2014-01-01

Tumor control of hepatocellular carcinoma by radiotherapy remains unsatisfactory. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway plays a critical role in inhibiting cancer cell death. Elevated PI3K/Akt activity is associated with increased cellular resistance to irradiation. Our aim was to determine whether the inhibition of PI3K/Akt activity by a PI3K inhibitor, BKM120, contributes to the increased sensitivity of liver cancer cells to irradiation. The hepatocellular carcinoma cell lines (Huh7 and BNL) were used to evaluate the in vitro synergism between BKM120 and irradiation. Balb/c mice bearing ectopic BNL xenografts were treated with BKM120 and/or radiotherapy to assess the in vivo response. BKM120 increased cell killing by radiation, increased the expression of apoptotic markers, and suppressed the repair of radiation-induced DNA double-strand breaks. BKM120 pretreatment inhibited radiation-induced Akt phosphorylation and enhanced the tumor-suppressive effect and radiation-induced tumor cell apoptosis in ectopic xenografts. Inhibition of mTOR phosphorylation by rapamycin enhanced the radiosensitivity of BKM120-treated hepatocellular carcinoma cells. The synergism between BKM120 and irradiation likely inhibits the activation of Akt by radiation, leading to increased cell apoptosis and suppression of DNA-double-strand breaks repair in hepatocellular carcinoma cells. These data suggest that the BKM120/radiation combination may be a strategy worthy of clinical trials. PMID:25004403

Stratified aspartate aminotransferase-to-platelet ratio index accurately predicts survival in hepatocellular carcinoma patients undergoing curative liver resection.

PubMed

Yang, Hao-Jie; Jiang, Jing-Hang; Yang, Yu-Ting; Guo, Zhe; Li, Ji-Jia; Liu, Xuan-Han; Lu, Fei; Zeng, Feng-Hua; Ye, Jin-Song; Zhang, Ke-Lan; Chen, Neng-Zhi; Xiang, Bang-De; Li, Le-Qun

2017-03-01

The aspartate aminotransferase-to-platelet ratio index has been reported to predict prognosis of patients with hepatocellular carcinoma. This study examined the prognostic potential of stratified aspartate aminotransferase-to-platelet ratio index for hepatocellular carcinoma patients undergoing curative liver resection. A total of 661 hepatocellular carcinoma patients were retrieved and the associations between aspartate aminotransferase-to-platelet ratio index and clinicopathological variables and survivals (overall survival and disease-free survival) were analyzed. Higher aspartate aminotransferase-to-platelet ratio index quartiles were significantly associated with poorer overall survival (p = 0.002) and disease-free survival (p = 0.001). Multivariate analysis showed aspartate aminotransferase-to-platelet ratio index to be an independent risk factor for overall survival (p = 0.018) and disease-free survival (p = 0.01). Patients in the highest aspartate aminotransferase-to-platelet ratio index quartile were at 44% greater risk of death than patients in the first quartile (hazard ratio = 1.445, 95% confidence interval = 1.081 - 1.931, p = 0.013), as well as 49% greater risk of recurrence (hazard ratio = 1.49, 95% confidence interval = 1.112-1.998, p = 0.008). Subgroup analysis also showed aspartate aminotransferase-to-platelet ratio index to be an independent predictor of poor overall survival and disease-free survival in patients positive for hepatitis B surface antigen or with cirrhosis (both p < 0.05). Similar results were obtained when aspartate aminotransferase-to-platelet ratio index was analyzed as a dichotomous variable with cutoff values of 0.25 and 0.62. Elevated preoperative aspartate aminotransferase-to-platelet ratio index may be independently associated with poor overall survival and disease-free survival in hepatocellular carcinoma patients following curative resection.

Surgical resection versus liver transplantation for hepatocellular carcinoma within the Hangzhou criteria: a preoperative nomogram-guided treatment strategy.

PubMed

Li, Yang; Ruan, Dan-Yun; Jia, Chang-Chang; Zhao, Hui; Wang, Guo-Ying; Yang, Yang; Jiang, Nan

2017-10-15

With the expansion of surgical criteria, the comparative efficacy between surgical resection (SR) and liver transplantation (LT) for hepatocellular carcinoma is inconclusive. This study aimed to develop a prognostic nomogram for predicting recurrence-free survival of hepatocellular carcinoma patients after resection and explored the possibility of using nomogram as treatment algorithm reference. From 2003 to 2012, 310 hepatocellular carcinoma patients within Hangzhou criteria undergoing resection or liver transplantation were included. Total tumor volume, albumin level, HBV DNA copies and portal hypertension were included for constructing the nomogram. The resection patients were stratified into low- and high-risk groups by the median nomogram score of 116. Independent risk factors were identified and a visually orientated nomogram was constructed using a Cox proportional hazards model to predict the recurrence risk for SR patients. The low-risk SR group had better outcomes compared with the high-risk SR group (3-year recurrence-free survival rate, 71.1% vs 35.9%; 3-year overall survival rate, 89.8% vs 78.9%, both P<0.001). The high-risk SR group was associated with a worse recurrence-free survival rate but similar overall survival rate compared with the transplantation group (3-year recurrence-free survival rate, 35.9% vs 74.1%, P<0.001; 3-year overall survival rate, 78.9% vs 79.6%, P>0.05). This nomogram offers individualized recurrence risk evaluation for hepatocellular carcinoma patients within Hangzhou criteria receiving resection. Transplantation should be considered the first-line treatment for high-risk patients. Copyright © 2017 The Editorial Board of Hepatobiliary & Pancreatic Diseases International. Published by Elsevier B.V. All rights reserved.

Fusion with stem cell makes the hepatocellular carcinoma cells similar to liver tumor-initiating cells.

PubMed

Wang, Ran; Chen, Shuxun; Li, Changxian; Ng, Kevin Tak Pan; Kong, Chi-wing; Cheng, Jinping; Cheng, Shuk Han; Li, Ronald A; Lo, Chung Mau; Man, Kwan; Sun, Dong

2016-02-04

Cell fusion is a fast and highly efficient technique for cells to acquire new properties. The fusion of somatic cells with stem cells can reprogram somatic cells to a pluripotent state. Our research on the fusion of stem cells and cancer cells demonstrates that the fused cells can exhibit stemness and cancer cell-like characteristics. Thus, tumor-initiating cell-like cells are generated. We employed laser-induced single-cell fusion technique to fuse the hepatocellular carcinoma cells and human embryonic stem cells (hESC). Real-time RT-PCR, flow cytometry and in vivo tumorigenicity assay were adopted to identify the gene expression difference. We successfully produced a fused cell line that coalesces the gene expression information of hepatocellular carcinoma cells and stem cells. Experimental results showed that the fused cells expressed cancer and stemness markers as well as exhibited increased resistance to drug treatment and enhanced tumorigenesis. Fusion with stem cells transforms liver cancer cells into tumor initiating-like cells. Results indicate that fusion between cancer cell and stem cell may generate tumor initiating-like cells.

TMEM88, CCL14 and CLEC3B as prognostic biomarkers for prognosis and palindromia of human hepatocellular carcinoma.

PubMed

Zhang, Xin; Wan, Jin-Xiang; Ke, Zun-Ping; Wang, Feng; Chai, Hai-Xia; Liu, Jia-Qiang

2017-07-01

Hepatocellular carcinoma is one of the most mortal and prevalent cancers with increasing incidence worldwide. Elucidating genetic driver genes for prognosis and palindromia of hepatocellular carcinoma helps managing clinical decisions for patients. In this study, the high-throughput RNA sequencing data on platform IlluminaHiSeq of hepatocellular carcinoma were downloaded from The Cancer Genome Atlas with 330 primary hepatocellular carcinoma patient samples. Stable key genes with differential expressions were identified with which Kaplan-Meier survival analysis was performed using Cox proportional hazards test in R language. Driver genes influencing the prognosis of this disease were determined using clustering analysis. Functional analysis of driver genes was performed by literature search and Gene Set Enrichment Analysis. Finally, the selected driver genes were verified using external dataset GSE40873. A total of 5781 stable key genes were identified, including 156 genes definitely related to prognoses of hepatocellular carcinoma. Based on the significant key genes, samples were grouped into five clusters which were further integrated into high- and low-risk classes based on clinical features. TMEM88, CCL14, and CLEC3B were selected as driver genes which clustered high-/low-risk patients successfully (generally, p = 0.0005124445). Finally, survival analysis of the high-/low-risk samples from external database illustrated significant difference with p value 0.0198. In conclusion, TMEM88, CCL14, and CLEC3B genes were stable and available in predicting the survival and palindromia time of hepatocellular carcinoma. These genes could function as potential prognostic genes contributing to improve patients' outcomes and survival.

Chlorogenic acid inhibits hepatocellular carcinoma in vitro and in vivo.

PubMed

Yan, Yuan; Liu, Na; Hou, Ni; Dong, Lei; Li, Jie

2017-08-01

Curative treatment of patients with hepatocellular carcinoma (HCC) is poor. There is an urgent need to develop more effective strategies for the chemoprevention of HCC. Chlorogenic acid (CGA), a type of polyphenol present in the diet, especially from coffee, has many biological activities. Patients with viral hepatitis who drank coffee everyday experienced a reduction in the incidence of HCC. In the present study, we evaluated the effects of CGA on HCC. CGA inhibited the proliferation of HepG2 cells in vitro and the progression of HepG2 xenograft in vivo. CGA induced the inactivation of ERK1/2 and suppressed the expression of MMP-2 and MMP-9 in HepG2 xenograft tissue. These data demonstrate that CGA can prevent the progression of HCC through multiple pathways. CGA appears to be an effective chemopreventive agent for hepatocellular carcinoma. Copyright © 2017 Elsevier Inc. All rights reserved.

Circulating predictive and diagnostic biomarkers for hepatitis B virus-associated hepatocellular carcinoma

PubMed Central

Van Hees, Stijn; Michielsen, Peter; Vanwolleghem, Thomas

2016-01-01

Chronic hepatitis B virus (HBV) infected patients have an almost 100-fold increased risk to develop hepatocellular carcinoma (HCC). HCC is the fifth most common and third most deadly cancer worldwide. Up to 50% of newly diagnosed HCC cases are attributed to HBV infection. Early detection improves survival and can be achieved through regular screening. Six-monthly abdominal ultrasound, either alone or in combination with alpha-fetoprotein serum levels, has been widely endorsed for this purpose. Both techniques however yield limited diagnostic accuracy, which is not improved when they are combined. Alternative circulating or histological markers to predict or diagnose HCC are therefore urgently needed. Recent advances in systems biology technologies have enabled the identification of several new putative circulating biomarkers. Although results from studies assessing combinations of these biomarkers are promising, evidence for their clinical utility remains low. In addition, most of the studies conducted so far show limitations in design. Attention must be paid for instance to different ethnicities and different etiologies when studying biomarkers for hepatocellular carcinoma. This review provides an overview on the current understandings and recent progress in the field of diagnostic and predictive circulating biomarkers for hepatocellular carcinoma in chronically infected HBV patients and discusses the future prospects. PMID:27729734

Silencing the Girdin gene enhances radio-sensitivity of hepatocellular carcinoma via suppression of glycolytic metabolism.

PubMed

Yu, Li; Sun, Yifan; Li, Jingjing; Wang, Yan; Zhu, Yuxing; Shi, Yong; Fan, Xiaojun; Zhou, Jianda; Bao, Ying; Xiao, Jie; Cao, Ke; Cao, Peiguo

2017-08-15

Radiotherapy has been used increasingly to treat primary hepatocellular carcinoma. Clinically, the main cause of radiotherapy failure is cellular radioresistance, conferred via glycolytic metabolism. Our previous study demonstrated that Girdin is upregulated in primary hepatocellular carcinoma and promotes the invasion and metastasis of tumor cells. However, whether Girdin underlies the radio-sensitivity of hepatocellular carcinoma remains unclear. A short hairpin RNA (shRNA) was used to silence CCDC88A (encoding Girdin), and real-time PCR was performed to determine CCDC88A mRNA expression. Then, cell proliferation, colony formation, flow cytometric, scratch, and transwell assays were to examine the influence of Girdin silencing on cellular radiosensitivity. Glycolysis assays were conducted to exam cell glycolysis process. Western blotting was performed to explore the signaling pathway downstream of Girdin. Finally, animal experiments were performed to demonstrate the effect of CCDC88A silencing on the radiosensitivity of hepatoma in vivo. shRNA-induced Girdin silencing suppressed glycolysis and enhanced the radio-sensitivity of hepatic cell lines, HepG2 and Huh-7. Furthermore, silencing of Girdin inhibited the PI3K/AKT/HIF-1α signaling pathway, which is a central regulator of glycolysis. Girdin can regulate glycolysis in hepatocellular carcinoma cells through the PI3K/AKT/HIF-1α signaling pathway, which decreases the sensitivity of tumor cells to radiotherapy.

[Hepatocellular carcinoma arising in the normal liver. A clinical study and long-term prognosis after surgical resection in 12 patients].

PubMed

Fekete, F; Belghiti, J; Flejou, J F; Panis, Y; Molas, G

1990-01-01

Hepatocellular carcinoma mainly affects patients with cirrhosis or with various degrees of fibrosis. From 1979 to 1990, among 87 patients who underwent hepatic resection for non fibrolamellar hepatocellular carcinoma, 12 (14%) had a non fibrolamellar hepatocellular carcinoma developed in a normal liver. There were 8 men and 4 women, aged 29 to 74 years. In 7 patients (58%) hepatocellular carcinoma was associated with clinical manifestations. Serum hepatitis B surface antigen were absent in all patients. Serum alphafetoprotein level was less than 100 ng/ml in 10 (83%), size of the tumor was greater than or equal to 5 cm in 10 (83%) and capsule was present in 10 (83%). Resections included removal of 2 segments or more in 11 (91%). One patient died postoperatively. Actuarial survival rate at 3 and 5 years were respectively 57% and 38%. Intra or extrahepatic recurrence was recognized in 8 (67%), 2 patients were alive respectively 28 and 16 months after treatment of their intrahepatic recurrence (resection in one and intraarterial embolisation in one). In conclusion, our results suggest that aggressive surgical efforts are justified in non fibrolamellar hepatocellular carcinoma arising in normal liver.

Targeting hepatocellular carcinoma with aptamer-functionalized PLGA/PLA-PEG nanoparticles

NASA Astrophysics Data System (ADS)

Weigum, Shannon E.; Sutton, Melissa; Barnes, Eugenia; Miller, Sarah; Betancourt, Tania

2014-08-01

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide, particularly in regions where chronic Hepatitis B and C infections are common. Nanoparticle assemblies that incorporate high-affinity aptamers which specifically bind malignant hepatocellular carcinoma cells could be useful for targeted drug delivery or enhancing contrast with existing ablation therapies. The in vitro interactions of a tumor-specific aptamer, TLS11a, were characterized in a hepatoma cell line via live-cell fluorescence imaging, SDS-PAGE and Western Blotting techniques. Cell surface binding of the aptamer-AlexaFluor®546 conjugate was found to occur within 20 minutes of initial exposure, followed by internalization and localization to late endosomes or lysosomes using a pH-sensitive LysoSensor™ Green dye and confocal microscopy. Aptamer-functionalized polymer nanoparticles containing poly(lactic-co-glycolic acid) (PLGA) and poly(lactide)-b-poly(ethylene glycol) (PLA-PEG) were then prepared by nanoprecipitation and passively loaded with the chemotherapeutic agent, doxorubicin, yielding spherical nanoparticles approximately 50 nm in diameter. Targeted drug delivery and cytotoxicity was assessed using live/dead fluorescent dyes and a MTT colorimetric viability assay with elevated levels of cell death found in cultures treated with either the aptamer-coated and uncoated polymer nanoparticles. Identification and characterization of the cell surface protein epitope(s) recognized by the TLS11a aptamer are ongoing along with nanoparticle optimization, but these preliminary studies support continued investigation of this aptamer and functionalized nanoparticle conjugates for targeted labeling and drug delivery within malignant hepatocellular carcinomas.

Fibrolamellar hepatocellular carcinoma with ovarian metastasis - an unusual presentation.

PubMed

Ciurea, Silviu Horia; Matei, Emil; Stănescu, CodruŢ Silvian; Lupescu, Ioana Gabriela; Boroş, Mirela; Herlea, Vlad; Luca, Niculina Ioana; DorobanŢu, Bogdan Mihail

2017-01-01

Fibrolamellar carcinoma (FLC) has been considered a distinct clinical entity vs. hepatocellular carcinoma, with respect to its epidemiology, etiology, and prognosis. We describe the unusual case of a 23-year-old female patient with FLC and ovarian (Krukenberg) and peritoneal metastases, clinically mimicking an ovarian carcinoma. Multiple recurrences occurred despite initial R0 resection and chemotherapy, requiring surgical treatment. The patient survived five years and died from generalized disease. The particularities of our case are discussed by comparison with the other two similar cases and other date from the literature. To our knowledge, the ovarian involvement encountered in our case is the third case published in literature, being explained by the superficial location of the liver tumor.

Mycotoxins are conventional and novel risk biomarkers for hepatocellular carcinoma

PubMed Central

Matsuda, Yasunobu; Wakai, Toshifumi; Kubota, Masayuki; Osawa, Mami; Sanpei, Ayumi; Fujimaki, Shun

2013-01-01

Hepatocellular carcinoma (HCC) is a common malignant disease with poor prognosis. To improve the clinical outcome, early diagnosis of HCC arising from nonviral agents and hepatitis virus is important. Among several etiological factors, mycotoxins defined as carcinogens by the International Agency for Research in Cancer might be one of the critical risk factors for nonviral HCC. Aflatoxin B1 is the most well-known carcinogenic mycotoxin for HCC, but the role of the other types of mycotoxin remains unclear. Several studies have reported that a chromatographic separation technique based on high-performance liquid chromatography can successfully detect the concentration of mycotoxins in plasma. In this article, we review recent studies of mycotoxin, and discuss its possible significance as a biomarker of HCC. PMID:23674865

Metastatic breast cancer to the liver with hepatoid features and Hep Par 1 antibody positive mimicking hepatocellular carcinoma.

PubMed

Affleck, Authur; Lyman, William B; Jacobs, W Carl; Livasy, Chad A; Martinie, John B; Iannitti, David A; Vrochides, Dionisios

2018-05-09

The hepatocyte paraffin 1 antibody (Hep Par 1) has a high positive predictive value for differentiating hepatocellular carcinoma from cholangiocarcinoma and metastatic carcinoma. 1 We report a case of metastatic breast cancer to the liver with hepatoid histology and strong positive staining for Hep Par 1 mimicking hepatocellular carcinoma. To our knowledge, primary breast carcinoma staining Hep Par 1 positive has not been reported in the setting of hepatic metastasis. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Histopathology of type C liver disease for determining hepatocellular carcinoma risk factors.

PubMed

Matsumura, Hiroshi; Nirei, Kazushige; Nakamura, Hitomi; Higuchi, Teruhisa; Arakawa, Yasuo; Ogawa, Masahiro; Tanaka, Naohide; Moriyama, Mitsuhiko

2013-08-14

To evaluate the histopathological findings of type C liver disease to determine risk factors for development of hepatocellular carcinoma (HCC). We studied 232 patients, who underwent liver biopsy for type C chronic liver disease between 1992 and 2009, with sustained virological response (SVR) after interferon therapy. The patients were divided into two groups according to the F stage 0 + 1 + 2 group (n = 182) and F3 + 4 group (n = 50). We prospectively observed and compared the incidence of HCC of the patients with SVR in the F0 + 1 + 2 and F3 + 4 groups. Then, the background factors and liver histopathological findings, including the degree of fibrosis, F stage, inflammation, necrosis, bile duct obstruction, fat deposition, and degree of irregular regeneration (IR) of hepatocytes, were correlated with the risk of developing HCC. HCC developed in three of 182 (1.6%) patients in the F0 + 1 + 2 group, and four of 50 (8.0%) in the F3 + 4 group. The cumulative incidence of HCC in the former group was found to be significantly lower than in the F3 + 4 group (log rank test P = 0.0224). The presence of atypical hepatocytes among IR of hepatocytes in the F3 + 4 group resulted in a higher cumulative incidence of HCC, and was significantly correlated with risk of HCC development (RR = 20.748, 95%CI: 1.335-322.5, P = 0.0303). Atypical hepatocytes among the histopathological findings of type C liver disease may be an important risk factor for HCC development along with progression of liver fibrosis.

Controversies in imaging of hepatocellular carcinoma: multidetector CT (MDCT)

PubMed Central

Silverman, Paul M; Szklaruk, Janio

2005-01-01

Primary hepatocellular carcinoma (HCC) is a significant tumor worldwide and represents the most common primary hepatic neoplasm. Staging criteria are important for appreciation of timely work up of these neoplasms in contradiction with surgical colleagues. This article demonstrates the appearance of HCC on multiphasic, multidetector CT (MDCT) and relates these findings to current staging criteria. The variable appearance on different planes of contrast is critical to appreciate in staging this neoplasm. The hypervascular nature of the primary tumor makes MDCT and three-phase imaging a critical feature in the detection and characterization of this tumor. This is especially critical in the patients who are candidates for surgical resection. Additionally, MDCT has allowed arterial phase imaging to define the vascular supply of the tumor. An accurate representation of the size and number of lesions is critical in not only the initial staging but also the follow-up of hepatocellular carcinoma. The post-treatment features including the appearance post-surgically and after radiofrequency ablation can be well appreciated on MDCT. PMID:16361147

Inhibitory effect of dimeric beta peptide on the recurrence and metastasis of hepatocellular carcinoma in vitro and in mice.

PubMed

Wang, Song-Mei; Zhu, Jun; Pan, Luan-Feng; Liu, Yin-Kun

2008-05-21

To block the adhesion of tumor cells to the extracellular matrix, and prevent tumor metastasis and recurrence, the dimer of the beta peptide (DLYYLMDLSYSMKGGDLYYLMDLSYSMK, beta2) was designed and synthesized and its anti-adhesion and anti-invasion effects on hepatocellular carcinoma cells were assessed. Additionally, its influence on the metastasis and recurrence of mouse hepatocellular carcinoma was measured. The anti-adhesion effect of beta2 on the highly metastatic hepatocellular carcinoma cell line HCCLM6 cells and fibronectin (FN) was assayed by the MTT assay. The inhibition of invasion of HCCLM6 cells by beta2 was observed using a Transwell (modified Boyden chamber) and matrigel. Using the hepatocellular carcinoma metastasis model and LCI-D20 nude mice, the influence of beta2 on the metastasis and recurrence of hepatocellular carcinoma after early resection was investigated. HCCLM6 cells co-incubated with 100 mumol/L, 50 micromol/L, 20 micromol/L or 10 micromol/L beta2 for 3 h showed an obvious decrease in adhesion to FN. The adhesion inhibition ratios were 11.8%, 21.7%, 29.6% and 48.7%, respectively. Additionally, HCCLM6 cells cultured with 100 mumol/L beta2 had a dramatic decrease in cell invasion. beta2 was also observed to inhibit the incisal edge recurrence and the distant metastasis of nude mice hepatocellular carcinoma after early resection (P < 0.05). The beta2 peptide can specifically block the adhesion and invasion of HCCLM6 cells, and can inhibit HCC recurrence and metastasis of LCI-D20 model posthepatectomy in vivo. Thus, beta2 should be further studied as a new anti-tumor drug.

The long non-coding RNA MALAT1 promotes the migration and invasion of hepatocellular carcinoma by sponging miR-204 and releasing SIRT1.

PubMed

Hou, Zhouhua; Xu, Xuwen; Zhou, Ledu; Fu, Xiaoyu; Tao, Shuhui; Zhou, Jiebin; Tan, Deming; Liu, Shuiping

2017-07-01

Increasing evidence supports the significance of long non-coding RNA in cancer development. Several recent studies suggest the oncogenic activity of long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in hepatocellular carcinoma. In this study, we explored the molecular mechanisms by which MALAT1 modulates hepatocellular carcinoma biological behaviors. We found that microRNA-204 was significantly downregulated in sh-MALAT1 HepG2 cell and 15 hepatocellular carcinoma tissues by quantitative real-time polymerase chain reaction analysis. Through bioinformatic screening, luciferase reporter assay, RNA-binding protein immunoprecipitation, and RNA pull-down assay, we identified microRNA-204 as a potential interacting partner for MALAT1. Functionally, wound-healing and transwell assays revealed that microRNA-204 significantly inhibited the migration and invasion of hepatocellular carcinoma cells. Notably, sirtuin 1 was recognized as a direct downstream target of microRNA-204 in HepG2 cells. Moreover, si-SIRT1 significantly inhibited cell invasion and migration process. These data elucidated, by sponging and competitive binding to microRNA-204, MALAT1 releases the suppression on sirtuin 1, which in turn promotes hepatocellular carcinoma migration and invasion. This study reveals a novel mechanism by which MALAT1 stimulates hepatocellular carcinoma progression and justifies targeting metastasis-associated lung adenocarcinoma transcript 1 as a potential therapy for hepatocellular carcinoma.

Liver transplantation for hepatocellular carcinoma: a proposal of a prognostic scoring system.

PubMed

Iwatsuki, S; Dvorchik, I; Marsh, J W; Madariaga, J R; Carr, B; Fung, J J; Starzl, T E

2000-10-01

The current staging system of hepatocellular carcinoma established by the International Union Against Cancer and the American Joint Committee on Cancer does not necessarily predict the outcomes after hepatic resection or transplantation. Various clinical and pathologic risk factors for tumor recurrence were examined on 344 consecutive patients who received hepatic transplantation in the presence of nonfibrolamellar hepatocellular carcinoma to establish a reliable risk scoring system. Multivariate analysis identified three factors as independently significant poor prognosticators: 1) bilobarly distributed tumors, 2) size of the greatest tumor (2 to 5 cm and > 5 cm), and 3) vascular invasion (microscopic and macroscopic). Prognostic risk score (PRS) of each patient was calculated from the relative risks of multivariate analysis. The patients were grouped into five grades of tumor recurrence risk: grade 1: PRS = 0 to < 7.5; grade 2: PRS = 7.5 to < or = 11.0; grade 3: PRS > 11.0 to 15.0; grade 4: PRS > or = 15.0; and grade 5: positive node, metastasis, or margin. The proposed PRS system correlated extremely well with tumor-free survival after liver transplantation (100%, 61%, 40%, 5%, and 0%, from grades 1 to 5, respectively, at 5 years), but current pTNM staging did not. 1) Patients with grades 1 and 2 are effectively treated with liver transplantation, 2) patients with grades 4 and 5 are poor candidates for liver transplantation, and 3) patients with grade 1 do not benefit from adjuvant chemotherapy.

Repeated courses of transarterial embolization with polyvinyl alcohol particles: 'long life elixir' in a cirrhotic patient with unresectable hepatocellular carcinoma.

PubMed

Marelli, Laura; Shusang, Vibhakorn; Senzolo, Marco; Cholongitas, Evangelos; Goode, Antony; Yu, Dominic; Patch, David W; Burroughs, Andrew K

2007-04-01

Chemoembolization improves survival in selected cirrhotic patients with hepatocellular carcinoma, but prolonged survival is unusual. In this study, a 70-year-old cirrhotic patient, who had a histologically proven hepatocellular carcinoma of 5 cm diameter, embolization with polyvinyl alcohol particles alone, without chemotherapeutic agent, has resulted in continued survival, of 5 years to date, with virtual elimination of residual hypervascularity following 10 sessions of embolization, and with continued patency of the injected branch of the hepatic artery. Provided liver function is maintained, embolization alone appears a feasible long term and effective therapy for unresectable hepatocellular carcinoma.

Inhibition of Regulatory Volume Decrease Enhances the Cytocidal Effect of Hypotonic Shock in Hepatocellular Carcinoma.

PubMed

Kudou, Michihiro; Shiozaki, Atsushi; Kosuga, Toshiyuki; Ichikawa, Daisuke; Konishi, Hirotaka; Morimura, Ryo; Komatsu, Shuhei; Ikoma, Hisashi; Fujiwara, Hitoshi; Okamoto, Kazuma; Hosogi, Shigekuni; Nakahari, Takashi; Marunaka, Yoshinori; Otsuji, Eigo

2016-01-01

Background : Hypotonic shock induces cytocidal effects through cell rupture, and cancer therapy based on this mechanism has been clinically administered to hepatocellular carcinoma patients. We herein investigated the effectiveness of hypotonic shock combined with the inhibition of regulatory volume decrease as cancer therapy for hepatocellular carcinoma. Methods : Morphological changes in human hepatocellular carcinoma cell lines were observed under a differential interference contrast microscope connected to a high-speed digital video camera. Cell volume changes under hypotonic shock with or without chloride, potassium, or water channel blockers were observed using a high-resolution flow cytometer. In order to investigate cytocidal effects, the number of surviving cells was compared after exposure to hypotonic solution with and without each channel blocker (re-incubation experiment). Results : Video recordings showed that cells exposed to distilled water rapidly swelled and then ruptured. Cell volume measurements revealed regulatory volume decrease under mild hypotonic shock, whereas severe hypotonic shock increased the number of broken fragments as a result of cell rupture. Moreover, regulatory volume decrease was inhibited in cells treated with each channel blocker. Re-incubation experiments showed the cytocidal effects of hypotonic shock in cells exposed to hypotonic solution, and additional treatments with each channel blocker enhanced these effects. Conclusion : The inhibition of regulatory volume decrease with chloride, potassium, or water channel blockers may enhance the cytocidal effects of hypotonic shock in hepatocellular carcinoma. Hypotonic shock combined with the inhibition of regulatory volume decrease was a more effective therapy than hypotonic shock alone.

Exposure to bacterial products lipopolysaccharide and flagellin and hepatocellular carcinoma: a nested case-control study.

PubMed

Fedirko, Veronika; Tran, Hao Quang; Gewirtz, Andrew T; Stepien, Magdalena; Trichopoulou, Antonia; Aleksandrova, Krasimira; Olsen, Anja; Tjønneland, Anne; Overvad, Kim; Carbonnel, Franck; Boutron-Ruault, Marie-Christine; Severi, Gianluca; Kühn, Tilman; Kaaks, Rudolf; Boeing, Heiner; Bamia, Christina; Lagiou, Pagona; Grioni, Sara; Panico, Salvatore; Palli, Domenico; Tumino, Rosario; Naccarati, Alessio; Peeters, Petra H; Bueno-de-Mesquita, H B; Weiderpass, Elisabete; Castaño, José María Huerta; Barricarte, Aurelio; Sánchez, María-José; Dorronsoro, Miren; Quirós, J Ramón; Agudo, Antonio; Sjöberg, Klas; Ohlsson, Bodil; Hemmingsson, Oskar; Werner, Mårten; Bradbury, Kathryn E; Khaw, Kay-Tee; Wareham, Nick; Tsilidis, Konstantinos K; Aune, Dagfinn; Scalbert, Augustin; Romieu, Isabelle; Riboli, Elio; Jenab, Mazda

2017-04-04

Leakage of bacterial products across the gut barrier may play a role in liver diseases which often precede the development of liver cancer. However, human studies, particularly from prospective settings, are lacking. We used a case-control study design nested within a large prospective cohort to assess the association between circulating levels of anti-lipopolysaccharide (LPS) and anti-flagellin immunoglobulin A (IgA) and G (IgG) (reflecting long-term exposures to LPS and flagellin, respectively) and risk of hepatocellular carcinoma. A total of 139 men and women diagnosed with hepatocellular carcinoma between 1992 and 2010 were matched to 139 control subjects. Multivariable rate ratios (RRs), including adjustment for potential confounders, hepatitis B/C positivity, and degree of liver dysfunction, were calculated with conditional logistic regression. Antibody response to LPS and flagellin was associated with a statistically significant increase in the risk of hepatocellular carcinoma (highest vs. lowest quartile: RR = 11.76, 95% confidence interval = 1.70-81.40; P trend  = 0.021). This finding did not vary substantially by time from enrollment to diagnosis, and did not change after adjustment for chronic infection with hepatitis B and C viruses. These novel findings, based on exposures up to several years prior to diagnosis, support a role for gut-derived bacterial products in hepatocellular carcinoma development. Further study into the role of gut barrier failure and exposure to bacterial products in liver diseases is warranted.

Peroxisome proliferator-activated receptor gamma coactivator-1 alpha acts as a tumor suppressor in hepatocellular carcinoma.

PubMed

Liu, Rui; Zhang, Haiyang; Zhang, Yan; Li, Shuang; Wang, Xinyi; Wang, Xia; Wang, Cheng; Liu, Bin; Zen, Ke; Zhang, Chen-Yu; Zhang, Chunni; Ba, Yi

2017-04-01

Peroxisome proliferator-activated receptor gamma coactivator-1 alpha plays a crucial role in regulating the biosynthesis of mitochondria, which is closely linked to the energy metabolism in various tumors. This study investigated the regulatory role of peroxisome proliferator-activated receptor gamma coactivator-1 alpha in the pathogenesis of hepatocellular carcinoma. In this study, the changes of peroxisome proliferator-activated receptor gamma coactivator-1 alpha messenger RNA levels between normal human liver and hepatocellular carcinoma tissue were examined by quantitative reverse transcription polymerase chain reaction. Knockdown of peroxisome proliferator-activated receptor gamma coactivator-1 alpha was conducted by RNA interference in the human liver cell line L02, while overexpression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha was conducted by adenovirus encoding peroxisome proliferator-activated receptor gamma coactivator-1 alpha complementary DNA in the human hepatocarcinoma cell line HepG2. Cellular morphological changes were observed via optical and electron microscopy. Cellular apoptosis was determined by Hoechst 33258 staining. In addition, the expression levels of 21,400 genes in tissues and cells were detected by microarray. It was shown that peroxisome proliferator-activated receptor gamma coactivator-1 alpha expression was significantly downregulated in hepatocellular carcinoma compared with normal liver tissues. After knockdown of peroxisome proliferator-activated receptor gamma coactivator-1 alpha expression in L02 cells, cells reverted to immature and dedifferentiated morphology exhibiting cancerous tendency. Apoptosis occurred in the HepG2 cells after transfection by adenovirus encoding peroxisome proliferator-activated receptor gamma coactivator-1 alpha. Microarray analysis showed consistent results. The results suggest that peroxisome proliferator-activated receptor gamma coactivator-1 alpha acts as a tumor

The silencing of Pokemon attenuates the proliferation of hepatocellular carcinoma cells in vitro and in vivo by inhibiting the PI3K/Akt pathway.

PubMed

Lin, Chan-Chan; Zhou, Jing-Ping; Liu, Yun-Peng; Liu, Jing-Jing; Yang, Xiao-Ning; Jazag, Amarsanaa; Zhang, Zhi-Ping; Guleng, Bayasi; Ren, Jian-Lin

2012-01-01

Pokemon (POK erythroid myeloid ontogenic factor), which belongs to the POK protein family, is also called LRF, OCZF and FBI-1. As a transcriptional repressor, Pokemon assumes a critical function in cellular differentiation and oncogenesis. Our study identified an oncogenic role for Pokemon in human hepatocellular carcinoma (HCC). We successfully established human HepG2 and Huh-7 cell lines in which Pokemon was stably knocked down. We demonstrated that Pokemon silencing inhibited cell proliferation and migration. Pokemon knockdown inhibited the PI3K/Akt and c-Raf/MEK/ERK pathways and modulated the expression of various cell cycle regulators in HepG2 and Huh-7 cells. Therefore, Pokemon may also be involved in cell cycle progression in these cells. We confirmed that Pokemon silencing suppresses hepatocellular carcinoma growth in tumor xenograft mice. These results suggest that Pokemon promotes cell proliferation and migration in hepatocellular carcinoma and accelerates tumor development in an Akt- and ERK-signaling-dependent manner.

The Silencing of Pokemon Attenuates the Proliferation of Hepatocellular Carcinoma Cells In Vitro and In Vivo by Inhibiting the PI3K/Akt Pathway

PubMed Central

Liu, Yun-Peng; Liu, Jing-Jing; Yang, Xiao-Ning; Jazag, Amarsanaa; Zhang, Zhi-Ping; Guleng, Bayasi; Ren, Jian-Lin

2012-01-01

Pokemon (POK erythroid myeloid ontogenic factor), which belongs to the POK protein family, is also called LRF, OCZF and FBI-1. As a transcriptional repressor, Pokemon assumes a critical function in cellular differentiation and oncogenesis. Our study identified an oncogenic role for Pokemon in human hepatocellular carcinoma (HCC). We successfully established human HepG2 and Huh-7 cell lines in which Pokemon was stably knocked down. We demonstrated that Pokemon silencing inhibited cell proliferation and migration. Pokemon knockdown inhibited the PI3K/Akt and c-Raf/MEK/ERK pathways and modulated the expression of various cell cycle regulators in HepG2 and Huh-7 cells. Therefore, Pokemon may also be involved in cell cycle progression in these cells. We confirmed that Pokemon silencing suppresses hepatocellular carcinoma growth in tumor xenograft mice. These results suggest that Pokemon promotes cell proliferation and migration in hepatocellular carcinoma and accelerates tumor development in an Akt- and ERK-signaling-dependent manner. PMID:23300578

Evolution of hepatocellular carcinoma epidemiology in Côte d'Ivoire.

PubMed

Didi-Kouko Coulibaly, Judith; Yeboua, Mireille; Kouassi Mbengue, Alphonsine; Kouadio, Emile Allah; Anzouan-Kacou Kissi, Henriette; Binan, Allah Yves-Omer; Lohoues Kouacou, Marie-Jeanne; Attia, Alain; Yao, Dowlo N'dri Athanase; Toutou, Toussaint; Adoubi, Innocent; Pineau, Pascal

2017-11-01

Hepatocellular carcinoma is a major concern for Public health in West Africa. In Côte d'Ivoire, the bulk of our knowledge stems from studies conducted decades ago. Our aim was, thus, to assess whether the epidemiological features of this tumor changed recently. Records from 863 patients diagnosed between 2007 and 2014 were analyzed. We observed major drifts concerning hepatocellular carcinoma with regards to the 1970-1980 period. Age at presentation is substantially delayed (49.4±14.1 years) whereas sex ratio decreased substantially (M:F=2.6). Patients seropositive for hepatitis B surface antigen and anti-hepatitis C virus represented 65% and 25% of cases whereas alcohol intake was reported in 36%. AFP level was above 400ng/mL in 36% of cases and tumors were already multinodular and/or metastatic at diagnosis in 77% and 26% of patients. Geographical and anthropological variations were observed with excesses of female cases affecting regions (Lagunes) or linguisitic groups (Kru). North-Mande speakers were more often identified as nonBnonC than others. Ivorian epidemiology of hepatocellular carcinoma was reshaped during the last decades. These changes, most likely due to the spread of hepatitis C virus, resulted in an older and feminized population of patients. We fear that the current and future prevalence of anti-HCV cases might thwart the expected benefits of anti-hepatitis B immunization. Appropriate measures should be taken to prevent further transmission of hepatitis C in the country. Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

Circular RNA cSMARCA5 inhibits growth and metastasis in hepatocellular carcinoma.

PubMed

Yu, Jian; Xu, Qing-Guo; Wang, Zhen-Guang; Yang, Yuan; Zhang, Ling; Ma, Jin-Zhao; Sun, Shu-Han; Yang, Fu; Zhou, Wei-Ping

2018-06-01

In recent years, circular RNAs (circRNAs) have been shown to have critical regulatory roles in cancer biology. However, the contributions of circRNAs to hepatocellular carcinoma (HCC) remain largely unknown. cSMARCA5 (a circRNA derived from exons 15 and 16 of the SMARCA5 gene, hsa_circ_0001445) was identified by RNA-sequencing and validated by quantitative reverse transcription PCR. The role of cSMARCA5 in HCC progression was assessed both in vitro and in vivo. circRNAs in vivo precipitation, luciferase reporter assay, biotin-coupled microRNA capture and fluorescence in situ hybridization were conducted to evaluate the interaction between cSMARCA5 and miR-17-3p/miR-181b-5p. The expression of cSMARCA5 was lower in HCC tissues, because of the regulation of DExH-Box Helicase 9, an abundant nuclear RNA helicase. The downregulation of cSMARCA5 in HCC was significantly correlated with aggressive characteristics and served as an independent risk factor for overall survival and recurrence-free survival in patients with HCC after hepatectomy. Our in vivo and in vitro data indicated that cSMARCA5 inhibits the proliferation and migration of HCC cells. Mechanistically, we found that cSMARCA5 could promote the expression of TIMP3, a well-known tumor suppressor, by sponging miR-17-3p and miR-181b-5p. These results reveal an important role of cSMARCA5 in the growth and metastasis of HCC and provide a fresh perspective on circRNAs in HCC progression. Herein, we studied the role of cSMARCA5, a circular RNA, in hepatocellular carcinoma. Our in vitro and in vivo data showed that cSMARCA5 inhibits the growth and migration of hepatocellular carcinoma cells, making it a potential therapeutic target. Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

The association of six non-synonymous variants in three DNA repair genes with hepatocellular carcinoma risk: a meta-analysis.

PubMed

Shi, Yan-Hui; Wang, Bin; Xu, Bai-Ping; Jiang, Dan-Na; Zhao, Dong-Mei; Ji, Man-Ru; Zhou, Li; Li, Xue; Lu, Chang-Zhu

2016-11-01

Hepatocellular carcinoma is a complex polygenic disease. Despite the huge advances in genetic epidemiology, it still remains a challenge to unveil the genetic architecture of hepatocellular carcinoma. We, therefore, decided to meta-analytically assess the association of six non-synonymous coding variants from XRCC1, XRCC3 and XPD genes with hepatocellular carcinoma risk by pooling the results of 20 English articles. This meta-analysis was conducted according to the PRISMA statement, and data collection was independently completed in duplicate. In overall analyses, the minor alleles of four variants, Arg280His (odds ratio, 95% confidence interval, P: 1.37, 1.13-1.66, 0.001), Thr241Met (1.93, 1.17-3.20, 0.011), Asp312Asn (1.22, 1.08-1.38, 0.001) and Lys751Gln (1.42, 1.02-1.97, 0.038), were associated with the significant risk for hepatocellular carcinoma. There were low probabilities of publication bias for all variants. Subgroup analyses revealed significant association of XRCC1 gene Arg399Gln with hepatocellular carcinoma in Chinese especially from south China (odds ratio, 95% confidence interval, P: 1.57, 1.16-2.14, 0.004), in larger studies (1.48, 1.11-1.98, 0.007) and in studies with population-based controls (1.33, 1.06-1.68, 0.016). Taken together, our findings demonstrated that XPD gene Asp312Asn and XRCC1 gene Arg399Gln might be candidate susceptibility loci for hepatocellular carcinoma. Considering the ubiquity of genetic heterogeneity, further validation in a broad range of ethnic populations is warranted. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Replication and Oncolytic Activity of an Avian Orthoreovirus in Human Hepatocellular Carcinoma Cells

PubMed Central

Kozak, Robert A.; Hattin, Larissa; Biondi, Mia J.; Corredor, Juan C.; Walsh, Scott; Xue-Zhong, Max; Manuel, Justin; McGilvray, Ian D.; Morgenstern, Jason; Lusty, Evan; Cherepanov, Vera; McBey, Betty-Anne; Leishman, David; Feld, Jordan J.; Bridle, Byram; Nagy, Éva

2017-01-01

Oncolytic viruses are cancer therapeutics with promising outcomes in pre-clinical and clinical settings. Animal viruses have the possibility to avoid pre-existing immunity in humans, while being safe and immunostimulatory. We isolated an avian orthoreovirus (ARV-PB1), and tested it against a panel of hepatocellular carcinoma cells. We found that ARV-PB1 replicated well and induced strong cytopathic effects. It was determined that one mechanism of cell death was through syncytia formation, resulting in apoptosis and induction of interferon stimulated genes (ISGs). As hepatitis C virus (HCV) is a major cause of hepatocellular carcinoma worldwide, we investigated the effect of ARV-PB1 against cells already infected with this virus. Both HCV replicon-containing and infected cells supported ARV-PB1 replication and underwent cytolysis. Finally, we generated in silico models to compare the structures of human reovirus- and ARV-PB1-derived S1 proteins, which are the primary targets of neutralizing antibodies. Tertiary alignments confirmed that ARV-PB1 differs from its human homolog, suggesting that immunity to human reoviruses would not be a barrier to its use. Therefore, ARV-PB1 can potentially expand the repertoire of oncolytic viruses for treatment of human hepatocellular carcinoma and other malignancies. PMID:28441762

Particle radiotherapy, a novel external radiation therapy, versus liver resection for hepatocellular carcinoma accompanied with inferior vena cava tumor thrombus: A matched-pair analysis.

PubMed

Komatsu, Shohei; Kido, Masahiro; Asari, Sadaki; Toyama, Hirochika; Ajiki, Tetsuo; Demizu, Yusuke; Terashima, Kazuki; Okimoto, Tomoaki; Sasaki, Ryohei; Fukumoto, Takumi

2017-12-01

Hepatocellular carcinoma accompanied with inferior vena cava tumor thrombus carries a dismal prognosis, and the feasibility of local treatment has remained controversial. The present study aimed to compare the outcomes of particle radiotherapy and liver resection in patients with hepatocellular carcinoma with inferior vena cava tumor thrombus. Thirty-one and 19 patients, respectively, underwent particle radiotherapy and liver resection for hepatocellular carcinoma with inferior vena cava tumor thrombus. A matched-pair analysis was undertaken to compare the short- and long-term outcomes according to tumor stage determined using the tumor-node-metastasis classification. Both stages IIIB and IV (IVA and IVB) patients were well-matched for 12 factors, including treatment policy and patient and tumor characteristics. The median survival time of matched patients with stage IIIB tumors in the particle radiotherapy group was greater than that in the liver resection group (748 vs 272 days, P = .029), whereas no significant difference was observed in the median survival times of patients with stage IV tumors (239 vs 311 days, respectively). There were significantly fewer treatment-related complications of grade 3 or greater in the particle radiotherapy group (0%) than in the liver resection group (26%). Particle radiotherapy is potentially preferable in hepatocellular carcinoma patients with stage IIIB inferior vena cava tumor thrombus and at least equal in efficiency to liver resection in those with stage IV disease, while causing significantly fewer complications. Considering the relatively high survival and low invasiveness of particle radiotherapy when compared to liver resection, this approach may represent a novel treatment modality for hepatocellular carcinoma with inferior vena cava tumor thrombus. Copyright © 2017 Elsevier Inc. All rights reserved.

Dual energy spectral CT imaging for the evaluation of small hepatocellular carcinoma microvascular invasion.

PubMed

Yang, Chuang-Bo; Zhang, Shuang; Jia, Yong-Jun; Yu, Yong; Duan, Hai-Feng; Zhang, Xi-Rong; Ma, Guang-Ming; Ren, Chenglong; Yu, Nan

2017-10-01

To study the clinical value of dual-energy spectral CT in the quantitative assessment of microvascular invasion of small hepatocellular carcinoma. This study was approved by our ethics committee. 50 patients with small hepatocellular carcinoma who underwent contrast enhanced spectral CT in arterial phase (AP) and portal venous phase (VP) were enrolled. Tumour CT value and iodine concentration (IC) were measured from spectral CT images. The slope of spectral curve, normalized iodine concentration (NIC, to abdominal aorta) and ratio of IC difference between AP and VP (RIC AP-VP : [RIC AP-VP =(IC AP -IC VP )/IC AP ]) were calculated. Tumours were identified as either with or without microvascular invasion based on pathological results. Measurements were statistically compared using independent samples t test. The receiver operating characteristic (ROC) analysis was used to evaluate the diagnostic performance of tumours microvascular invasion assessment. The 70keV images were used to simulate the results of conventional CT scans for comparison. 56 small hepatocellular carcinomas were detected with 37 lesions (Group A) with microvascular invasion and 19 (Group B) without. There were significant differences in IC, NIC and slope in AP and RIC AP-VP between Group A (2.48±0.70mg/ml, 0.23±0.05, 3.39±1.01 and 0.28±0.16) and Group B (1.65±0.47mg/ml, 0.15±0.05, 2.22±0.64 and 0.03±0.24) (all p<0.05). Using 0.188 as the threshold for NIC, one could obtain an area-under-curve (AUC) of 0.87 in ROC to differentiate between tumours with and without microvascular invasion. AUC was 0.71 with CT value at 70keV and improved to 0.81 at 40keV. Dual-energy Spectral CT provides additional quantitative parameters than conventional CT to improve the differentiation between small hepatocellular carcinoma with and without microvascular invasion. Quantitative iodine concentration measurement in spectral CT may be used to provide a new method to improve the evaluation for small

Living-Donor Liver Transplant for Fibrolamellar Hepatocellular Carcinoma With Hilar Lymph Node Metastasis: A Case Report.

PubMed

Ince, Volkan; Isik, Burak; Ozdemir, Fatih; Ozgor, Dincer; Ara, Cengiz; Yilmaz, Sezai

2018-04-09

Fibrolamellar hepatocellular carcinoma is a rare primary malignant liver neoplasm. Benefits from liver transplant for patients with fibrolamellar hepatocellular carcinoma have not yet been reported. Here, we report a 19-year-old female patient who presented with abdominal pain. A computed tomography scan revealed bilobar and multiple solid lesions with the largest measuring 15 cm in diameter on the right lobe of her liver. Her blood alpha-fetoprotein level and viral hepatitis markers were normal. A fine-needle biopsy of the largest lesion detected fibrolamellar heptocellular carcinoma. Because no distant metastasis was evident and the carcinoma was unresectable, a right lobe living-donor liver transplant with hilar lymph node dissection was performed. A pathology report revealed poorly differentiated fibrolamellar hepatocellular carcinoma, and further testing indicated microvascular invasion and hilar lymph node metastasis. The largest tumor measured 12 cm. She was discharged on postoperative day 14. During postoperative month 22, multiple vertebral metastases were detected, and she died with diffuse metastasis during postoperative month 26. Our patient, with poor prognostic criteria such as hilar lymph node metastasis, microvascular invasion, and poor differentiation, had 22 months of tumor-free survival and 26 months of overall survival after having undergone living-donor liver transplant.

Electrochemotherapy as treatment option for hepatocellular carcinoma, a prospective pilot study.

PubMed

Djokic, Mihajlo; Cemazar, Maja; Popovic, Peter; Kos, Bor; Dezman, Rok; Bosnjak, Masa; Zakelj, Martina Niksic; Miklavcic, Damijan; Potrc, Stojan; Stabuc, Borut; Tomazic, Ales; Sersa, Gregor; Trotovsek, Blaz

2018-05-01

Electrochemotherapy provides non-thermal ablation of cutaneous as well as deep seated tumors. Based on positive results of the treatment of colorectal liver metastases, we conducted a prospective pilot study on hepatocellular carcinomas with the aim of testing the feasibility, safety and effectiveness of electrochemotherapy. Electrochemotherapy with bleomycin was performed on 17 hepatocellular carcinomas in 10 patients using a previously established protocol. The procedure was performed during open surgery and the patients were followed for median 20.5 months. Electrochemotherapy was feasible for all 17 lesions, and no treatment-related adverse events or major post-operative complications were observed. The median size of the treated lesions was 24 mm (range 8-41 mm), located either centrally, i.e., near the major hepatic vessels, or peripherally. The complete response rate at 3-6 months was 80% per patient and 88% per treated lesion. Electrochemotherapy of hepatocellular carcinoma proved to be a feasible and safe treatment in all 10 patients included in this study. To evaluate the effectiveness of this method, longer observation period is needed; however the results at medium observation time of 20.5 months after treatment are encouraging, in 15 out of 17 lesions complete response was obtained. Electrochemotherapy is predominantly applicable in patients with impaired liver function due to liver cirrhosis and/or with lesions where a high-risk operation is needed to achieve curative intent, given the intra/perioperative risk for high morbidity and mortality. Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Risk Factors for Hepatocellular Carcinoma in Cirrhotic Patients with Chronic Hepatitis B.

PubMed

Zhang, Yuan-Qing; Peng, Li-Jun; Cao, Yi-Rong; Zeng, Zhi-Ping; Wu, Yu-Jing; Shi, Hong; Cheng, Shi-Yao; Wang, Ji-Yao; Friedman, Scott L; Sninsky, John J; Guo, Jin-Sheng

2016-09-01

To investigate the clinical and genetic risk factors associated with hepatocellular carcinoma (HCC) in cirrhotic patients with chronic hepatitis B (CHB). Nine hundred forty-nine Chinese Han patients with CHB were studied, including noncirrhotic patients without HCC (N = 234), cirrhotic patients without (N = 281) and with HCC (N = 434). Patients were genotyped for 10 candidate single nucleotide polymorphisms (SNPs) by the polymerase chain reaction (PCR)-ligase detection reaction (LDR) method. By multivariate logistic regression analysis adjusted for Child-Pugh scores, noneffective antiviral treatment, drinking history, family history of HCC, and age ≥50 years old were associated with HCC risk (odds ratio [OR] = 5.923, 2.456, 2.241, 1.955, respectively). Sixty-two of 170 cirrhotic patients who achieved sustained virological suppression by antiviral treatment developed HCC, with fatty liver disease, family history of HCC, and family history of hepatitis B virus (HBV) infection as the risk factors (OR = 11.646, 3.339, 2.537, respectively). The SNPs associated with HCC risk in patients with cirrhosis and CHB were rs11536889 in TLR4 and rs2853744 in SPP1. Polymorphisms of TLR4 rs2149356, AP3S2 rs2290351, STXBP5L rs2169302, MLEC rs7976497, and SOCS3 rs4969168 were associated with HCC risk in specific stratified analyses with gender, age, and drinking history in the cirrhotic patients. Inadequate antiviral treatment, family history of HCC, drinking history, and age ≥50 years old are risk factors for HCC. Sustained suppression of HBV does not eliminate the risk of HCC. Specific host genetic factors may impact HCC development in Han Chinese cirrhotic patients with CHB, including SNPs in TLR4, SPP1, AP3S2, STXBP5L, MLEC, and SOCS3, which warrant further validation in additional cohorts.

Proteomic Studies of Cholangiocarcinoma and Hepatocellular Carcinoma Cell Secretomes

PubMed Central

Srisomsap, Chantragan; Sawangareetrakul, Phannee; Subhasitanont, Pantipa; Chokchaichamnankit, Daranee; Chiablaem, Khajeelak; Bhudhisawasdi, Vaharabhongsa; Wongkham, Sopit; Svasti, Jisnuson

2010-01-01

Cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC) occur with relatively high incidence in Thailand. The secretome, proteins secreted from cancer cells, are potentially useful as biomarkers of the diseases. Proteomic analysis was performed on the secreted proteins of cholangiocarcinoma (HuCCA-1) and hepatocellular carcinoma (HCC-S102, HepG2, SK-Hep-1, and Alexander) cell lines. The secretomes of the five cancer cell lines were analyzed by SDS-PAGE combined with LC/MS/MS. Sixty-eight proteins were found to be expressed only in HuCCA-1. Examples include neutrophil gelatinase-associated lipocalin (lipocalin 2), laminin 5 beta 3, cathepsin D precursor, desmoplakin, annexin IV variant, and annexin A5. Immunoblotting was used to confirm the presence of lipocalin 2 in conditioned media and cell lysate of 5 cell lines. The results showed that lipocalin 2 was a secreted protein which is expressed only in the conditioned media of the cholangiocarcinoma cell line. Study of lipocalin 2 expression in different types of cancer and normal tissues from cholangiocarcinoma patients showed that lipocalin 2 was expressed only in the cancer tissues. We suggest that lipocalin 2 may be a potential biomarker for cholangiocarcinoma. PMID:20069059

Hepatocellular Carcinoma Supplied From the Short Gastric Artery: Treatment With Chemoembolization

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jeon, Ung Bae, E-mail: junwb73@pnuyh.co.kr; Lee, Jun Woo, E-mail: jwlee@pusan.ac.kr; Baik, Seung Kug, E-mail: skbaik9@gmail.com

2012-12-15

We report a case of transcatheter arterial chemoembolization (TACE) to treat hepatocellular carcinoma (HCC) that was supplied by the short gastric artery. A 67-year-old woman with two nodular HCCs underwent repeated TACE. One of the nodules was supplied by the short gastric artery.

Histologic study of the effects of chemoembolization with preloaded doxorubicin beads in patients with hepatocellular carcinoma.

PubMed

Zurera, L J; Espejo, J J; Lombardo, S; Marchal, T; Muñoz, M C; Canis, M; Montero, J L

2015-01-01

To determine the degree of tumor necrosis in surgical specimens of hepatocellular carcinomas treated with microspheres preloaded with doxorubicin and to analyze the relationship between the degree of necrosis and a) morphologic factors and b) imaging biomarkers. We studied the livers of 21 patients who had undergone selective arterial chemoembolization with DC beads (Biocompatibles, UK) before receiving liver transplants. Imaging techniques detected 43 nodules (mean size, 25 mm). Angiography showed 25 hypervascularized nodules, 12 slightly vascularized nodules, and 6 avascular nodules. A total of 81 hepatocellular carcinomas (mean size, 15 mm) were detected in the specimens: two were capsular and two had vascular infiltration. The mean degree of necrosis after chemoembolization was 39%; necrosis was greater than 60% in 28 hepatocellular carcinomas and less than 60% in 52. The degree of necrosis correlated significantly with the time elapsed between the last chemoembolization treatment and liver transplantation (the degree of necrosis decreased as time increased), with the number of nodules in the specimen, and with capsular infiltration. When imaging techniques detected 1 or 2 nodules, there was a greater probability of achieving greater than 90% necrosis. No relation with the degree of necrosis achieved was found for the size of the nodules detected at imaging, the enhancement pattern, or the number of chemoembolization treatments. The degree of necrosis achieved depends on the time spent on the waiting list, on the number of nodules in the specimen, and on whether capsular infiltration is present. Copyright © 2014 SERAM. Published by Elsevier España, S.L.U. All rights reserved.

Inhibition of Regulatory Volume Decrease Enhances the Cytocidal Effect of Hypotonic Shock in Hepatocellular Carcinoma

PubMed Central

Kudou, Michihiro; Shiozaki, Atsushi; Kosuga, Toshiyuki; Ichikawa, Daisuke; Konishi, Hirotaka; Morimura, Ryo; Komatsu, Shuhei; Ikoma, Hisashi; Fujiwara, Hitoshi; Okamoto, Kazuma; Hosogi, Shigekuni; Nakahari, Takashi; Marunaka, Yoshinori; Otsuji, Eigo

2016-01-01

Background: Hypotonic shock induces cytocidal effects through cell rupture, and cancer therapy based on this mechanism has been clinically administered to hepatocellular carcinoma patients. We herein investigated the effectiveness of hypotonic shock combined with the inhibition of regulatory volume decrease as cancer therapy for hepatocellular carcinoma. Methods: Morphological changes in human hepatocellular carcinoma cell lines were observed under a differential interference contrast microscope connected to a high-speed digital video camera. Cell volume changes under hypotonic shock with or without chloride, potassium, or water channel blockers were observed using a high-resolution flow cytometer. In order to investigate cytocidal effects, the number of surviving cells was compared after exposure to hypotonic solution with and without each channel blocker (re-incubation experiment). Results: Video recordings showed that cells exposed to distilled water rapidly swelled and then ruptured. Cell volume measurements revealed regulatory volume decrease under mild hypotonic shock, whereas severe hypotonic shock increased the number of broken fragments as a result of cell rupture. Moreover, regulatory volume decrease was inhibited in cells treated with each channel blocker. Re-incubation experiments showed the cytocidal effects of hypotonic shock in cells exposed to hypotonic solution, and additional treatments with each channel blocker enhanced these effects. Conclusion: The inhibition of regulatory volume decrease with chloride, potassium, or water channel blockers may enhance the cytocidal effects of hypotonic shock in hepatocellular carcinoma. Hypotonic shock combined with the inhibition of regulatory volume decrease was a more effective therapy than hypotonic shock alone. PMID:27471568

Long non-coding RNA XIST promotes cell growth by regulating miR-139-5p/PDK1/AKT axis in hepatocellular carcinoma.

PubMed

Mo, Yichao; Lu, Yaoyong; Wang, Peng; Huang, Simin; He, Longguang; Li, Dasheng; Li, Fuliang; Huang, Junwei; Lin, Xiaoxia; Li, Xueru; Che, Siyao; Chen, Qinshou

2017-02-01

Abnormal expression of long non-coding RNA often contributes to unrestricted growth of cancer cells. Long non-coding RNA XIST expression is upregulated in several cancers; however, its modulatory mechanisms have not been reported in hepatocellular carcinoma. In this study, we found that XIST expression was significantly increased in hepatocellular carcinoma tissues and cell lines. XIST promoted cell cycle progression from the G1 phase to the S phase and protected cells from apoptosis, which contributed to hepatocellular carcinoma cell growth. In addition, we revealed that there was reciprocal repression between XIST and miR-139-5p. PDK1 was identified as a direct target of miR-139-5p. We proposed that XIST was responsible for hepatocellular carcinoma cell proliferation, and XIST exerted its function through the miR-139-5p/PDK1 axis.

Evaluation of prognostic factors on recurrence after curative resections for hepatocellular carcinoma.

PubMed

Han, Jae Hyun; Kim, Dong Goo; Na, Gun Hyung; Kim, Eun Young; Lee, Soo Ho; Hong, Tae Ho; You, Young Kyoung

2014-12-07

To select appropriate patients before surgical resection for hepatocellular carcinoma (HCC), especially those with advanced tumors. From January 2000 to December 2012, we retrospectively analyzed the medical records of 298 patients who had undergone surgical resections for HCC with curative intent at our hospital. We evaluated preoperative prognostic factors associated with histologic grade of tumor, recurrence and survival, especially the findings of pre-operative imaging studies such as positron emission tomography-computed tomography (PET-CT) and magnetic resonance imaging (MRI). And then, we established a scoring system to predict recurrence and survival after surgery dividing the patients into two groups based on a tumor size of 5 cm. Of the 298 patients, 129 (43.3%) developed recurrence during the follow-up period. The 5 year disease free survival and overall survival were 47.0% and 58.7% respectively. In multivariate analysis, a serum alpha-fetoprotein (AFP) level of > 100 ng/mL and a standardized uptake value (SUV) of PET-CT of > 3.5 were predictive factors for histologic grade of tumor, recurrence, and survival. Tumor size of > 5 cm and a relative enhancement ratio (RER) calculated from preoperative MRI were also significantly associated with prognosis in univariate analysis. We established a scoring system to predict prognosis using AFP, SUV, and RER. In those with tumors of > 5 cm, it showed predicted both recurrence (P = 0.005) and survival (P = 0.001). The AFP, tumor size, SUV and RER are useful for prognosis preoperatively. An accurate prediction of prognosis is possible using our scoring system in large size tumors.

Survival and prognostic factors for hepatocellular carcinoma: an Egyptian multidisciplinary clinic experience.

PubMed

Abdelaziz, Ashraf Omar; Elbaz, Tamer Mahmoud; Shousha, Hend Ibrahim; Ibrahim, Mostafa Mohamed; Rahman El-Shazli, Mostafa Abdel; Abdelmaksoud, Ahmed Hosni; Aziz, Omar Abdel; Zaki, Hisham Atef; Elattar, Inas Anwar; Nabeel, Mohamed Mahmoud

2014-01-01

Hepatocellular carcinoma (HCC) is a dismal tumor with a high incidence, prevalence and poor prognosis and survival. Management of HCC necessitates multidisciplinary clinics due to the wide heterogeneity in its presentation, different therapeutic options, variable biologic behavior and background presence of chronic liver disease. We studied the different prognostic factors that affected survival of our patients to improve future HCC management and patient survival. This study is performed in a specialized multidisciplinary clinic for HCC in Kasr El Eini Hospital, Cairo University, Egypt. We retrospectively analyzed the different patient and tumor characteristics and the primary mode of management applied to our patients. Further analysis was performed using univariate and multivariate statistics. During the period February 2009 till February 2013, 290 HCC patients presented to our multidisciplinary clinic. They were predominantly males and the mean age was 56.5 ± 7.7 years. All cases developed HCC on top of cirrhosis that was mainly due to HCV (71%). Most of our patients were Child-Pugh A (50%) or B (36.9%) and commonly presented with small single lesions. Transarterial chemoembolization was the most common line of treatment used (32.4%). The overall survival was 79.9% at 6 months, 54.5% at 1 year and 22.4% at 2 years. Serum bilirubin, site of the tumor and type of treatment were the significant independent prognostic factors for survival. Our main prognostic variables are the bilirubin level, the bilobar hepatic affection and the application of specific treatment (either curative or palliative). Multidisciplinary clinics enhance better HCC management.

Factors predicting outcomes of microwave ablation of small hepatocellular carcinoma.

PubMed

Ierardi, Anna Maria; Giorlando, Francesca; Piacentino, Filippo; Fontana, Federico; Novario, Raffaele; Angileri, Salvatore Alessio; Duka, Ejona; Carrafiello, Gianpaolo

2017-02-01

The aim of our study was to evaluate factors influencing effectiveness of percutaneous microwave ablation (MWA) in patients with small hepatocellular carcinoma (HCC) (<3 cm). Between December 2007 and August 2015, 49 patients with 65 previously histological typed HCC were treated in a total of 61 sessions. Tumours were subdivided into central (>3 cm from the capsule) (n = 22) and peripheral (<3 cm from the capsule) (n = 43). Imaging follow-up was performed at 1, 3, 6, and 12 months after treatment, then annually. Mean follow-up period was 18 months (range 1-55). Location of the lesion, age, sex, and underlying disease of the patients was analyzed and related with efficacy. Technical success was obtained in all cases. Residual disease was registered in 21 lesions (32.3 %): 13 were peripheral and 8 were central. Twelve of them were retreated with percutaneous MWA. Local recurrence was recorded in 8 lesions (12.3 %): 5 were retreated with MWA. No significant difference in terms of effectiveness was observed in lesions located in a central position and those situated in the peripheral position. Age, sex, and underlying disease not influenced results. Only one major complication was observed. The rate of minor complications was 24.5 %. Mortality at 30 days was 0 %. Our results encourage the role of MWA in the treatment of small HCC. More numerous series and randomized studies are necessary to state the role of MWA and to select cases in which MWA may be more effective and safer than RFA.

Bioinformatics prediction and experimental validation of microRNA-20a targeting Cyclin D1 in hepatocellular carcinoma.

PubMed

Karimkhanloo, Hamzeh; Mohammadi-Yeganeh, Samira; Ahsani, Zeinab; Paryan, Mahdi

2017-04-01

Hepatocellular carcinoma is the major form of primary liver cancer, which is the second and sixth leading cause of cancer-related death in men and women, respectively. Extensive research indicates that Wnt/β-catenin signaling pathway, which plays a pivotal role in growth, development, and differentiation of hepatocellular carcinoma, is one of the major signaling pathways that is dysregulated in hepatocellular carcinoma. Cyclin D1 is a proto-oncogene and is one of the major regulators of Wnt signaling pathway, and its overexpression has been detected in various types of cancers including hepatocellular carcinoma. Using several validated bioinformatic databases, we predicted that the microRNAs are capable of targeting 3'-untranslated region of Cyclin D1 messenger RNA. According to the results, miR-20a was selected as the highest ranking microRNA targeting Cyclin D1 messenger RNA. Luciferase assay was recruited to confirm bioinformatic prediction results. Cyclin D1 expression was first assessed by quantitative real-time polymerase chain reaction in HepG2 cell line. Afterward, HepG2 cells were transduced by lentiviruses containing miR-20a. Then, the expression of miR-20a and Cyclin D1 was evaluated. The results of luciferase assay demonstrated targeting of 3'-untranslated region of Cyclin D1 messenger RNA by miR-20a. Furthermore, 238-fold decline in Cyclin D1 expression was observed after lentiviral induction of miR-20a in HepG2 cells. The results highlighted a considerable effect of miRNA-20a induction on the down-regulation of Cyclin D1 gene. Our results suggest that miR-20a can be used as a novel candidate for therapeutic purposes and a biomarker for hepatocellular carcinoma diagnosis.

The role of p21-activated kinases in hepatocellular carcinoma metastasis.

PubMed

Tse, Edith Yuk Ting; Ching, Yick Pang

2014-01-01

The p21-activated kinases (PAKs) are downstream effectors of the Rho family small GTPases as well as a wide variety of mitogenic factors and have been implicated in cancer formation, development and metastasis. PAKs phosphorylate a wide spectrum of substrates to mediate extracellular signals and regulate cytoskeletal remodeling, cell motility and survival. In this review, we aim to summarize the findings regarding the oncogenic role and the underlying mechanisms of PAKs signaling in various cancers, and in particular highlight the prime importance of PAKs in hepatocellular carcinoma (HCC) progression and metastasis. Recent studies exploring the potential therapeutic application of PAK inhibitors will also be discussed.

TRB3 reverses chemotherapy resistance and mediates crosstalk between endoplasmic reticulum stress and AKT signaling pathways in MHCC97H human hepatocellular carcinoma cells.

PubMed

Li, Yang; Zhu, Danxi; Hou, Lidan; Hu, Bin; Xu, Min; Meng, Xiangjun

2018-01-01

Tribbles homolog 3 (TRB3), a type of pseudokinase that contains a consensus serine/threonine kinase catalytic core structure, is upregulated in hepatocellular carcinoma. However, the effect of TRB3 expression in hepatocellular carcinoma and the molecular mechanisms underlying TRB3-mediated effects on tumorigenesis in hepatocellular carcinoma have not been fully elucidated. The present study focused on the effect of TRB3 expression in MHCC97H hepatocellular carcinoma cells and investigated the underlying molecular mechanisms in MHCC97H cells. In the present study, it was revealed that TRB3 was significantly overexpressed in the MHCC97H hepatocellular carcinoma cell compared with L-02 normal hepatic cells. Under endoplasmic reticulum (ER) stress induced by thapsigargin and tunicamycin, the levels of TRB3, CCAAT/enhancer binding protein homologous protein (CHOP), protein kinase B (AKT) and phosphorylated (p)AKT expression were upregulated. Furthermore, when the expression of TRB3 was silenced by short hairpin (sh)RNA, the survival of MHCC97H hepatocellular carcinoma cells was increased. Notably, following transduction with lentiviral containing TRB3-shRNA, cell survival also increased after treatment with chemotherapy drug cisplatin. The present study demonstrated that knockdown of CHOP by shRNA was able to reduce TRB3 expression, and the knockdown of TRB3 markedly increased the level of pAKT. TRB3 was overexpressed in MHCC97H hepatocellular carcinoma cells, particularly under endoplasmic reticulum stress. Knockdown of TRB3 was able to increase cell survival. Therefore, TRB3 expression may induce apoptosis and reverse resistance to chemotherapy in MHCC97H hepatic carcinoma cells. The present study suggests that TRB3 is a key molecule that mediates the crosstalk between ER stress and AKT signal pathways. Furthermore, the present study may provide further insight into the cancer biology of hepatocellular carcinoma and the development of anticancer drugs targeting the ER

Anti cancerous efficacy of Ayurvedic milk extract of Semecarpus anacardium nuts on hepatocellular carcinoma in Wistar rats.

PubMed

Joseph, Joice P; Raval, Sunant K; Sadariya, Kamlesh A; Jhala, Mayur; Kumar, Pranay

2013-01-01

The objective of the study was to determine the anticancerous efficacy of Ayurvedic preparation made of Semecarpus anacardium (SA) nuts. Five groups of rats were used for the study. Group I served as water control. Hepatocellular carcinoma (HCC) was induced in groups II, III and IV animals using N-nitrosodiethylamine as inducing agent followed by phenobarbitone as promoter for 13 weeks. Group-II animals were kept untreated as hepatocellular carcinoma control. Group-III animals were treated with Ayurvedic milk extract of Semecarpus anacardium nuts at dose mentioned in Ashtangahridaya, an authentic book of Ayurveda for 49 days and group-IV animals were treated with doxorubicin as reference drug at dose of 1mg/kg twice a week for 7 weeks. Group V animals were kept as drug (SA nut milk extract) control for studying the effect of nut milk extract on normal rats. After 154 days of experiment, all animals were subjected to screening for HCC by estimation of liver enzymes, HCC marker (alpha-2 macroglobulin) and histopathology. Both liver enzymes and HCC marker were increased in hepatocellular carcinoma control along with neoplastic changes in liver and were decreased in Semecarpus anacardium nut milk extract treated group. The Ayurvedic drug showed positive correlation with the action of doxorubicin. This study demonstrated the efficacy of Semecarpus anacardium nut milk extract for the treatment of hepatocellular carcinoma either alone or along with chemotherapy.

Current status of liver diseases in Korea: hepatocellular carcinoma.

PubMed

Song, Il Han; Kim, Kyung Sik

2009-12-01

Primary liver cancer, most of which is hepatocellular carcinoma (HCC), is the third common leading cancer in Korea. During the last two decades, the incidence rate of primary liver cancer has shown a modest decrease, but its mortality rate has slightly increased. The incidence of HCC, according to age, peaks in the late sixth decade in men and in the early seventh decade in women. Hepatitis B virus (HBV) is the most important risk factor, which represents approximately 70% of all HCC, and hepatitis C virus (HCV) and alcohol are the next in order of major risk factors for the development of HCC in Korea. HBV-associated HCC occurs 10 years earlier than HCV-associated HCC due to a more prolonged exposure to HBV, which is vertically transmitted almost from HBsAg-positive mother in HBV-endemic area. National Cancer Control Institute, which was reorganized in 2005, is now working for several national projects such as National Cancer Registration Program, National R&D Program for Cancer Control and National Cancer Screening Program. International collaboration for the clinico-epidemiologic research would be needed to provide the specific measures for managing HCC in diverse etiologic situations. Finally, the mechanisms of hepatitis virus-associated hepatocellular carcinogenesis might be clarified to provide insights into the advanced therapeutic and preventive approaches for HCC in Korea, where the majority of HCC originate from chronic HBV and HCV infections.

Defeating EpCAM(+) liver cancer stem cells by targeting chromatin remodeling enzyme CHD4 in human hepatocellular carcinoma.

PubMed

Nio, Kouki; Yamashita, Taro; Okada, Hikari; Kondo, Mitsumasa; Hayashi, Takehiro; Hara, Yasumasa; Nomura, Yoshimoto; Zeng, Sha Sha; Yoshida, Mariko; Hayashi, Tomoyuki; Sunagozaka, Hajime; Oishi, Naoki; Honda, Masao; Kaneko, Shuichi

2015-11-01

Hepatocellular carcinoma is composed of a subset of cells with enhanced tumorigenicity and chemoresistance that are called cancer stem (or stem-like) cells. We explored the role of chromodomain-helicase-DNA-binding protein 4, which is encoded by the CHD4 gene and is known to epigenetically control gene regulation and DNA damage responses in EpCAM(+) liver cancer stem cells. Gene and protein expression profiles were determined by microarray and immunohistochemistry in 245 and 144 hepatocellular carcinoma patients, respectively. The relationship between gene/protein expression and prognosis was examined. The functional role of CHD4 was evaluated in primary hepatocellular carcinoma cells and in cell lines in vitro and in vivo. CHD4 was abundantly expressed in EpCAM(+) hepatocellular carcinoma with expression of hepatic stem cell markers and poor prognosis in two independent cohorts. In cell lines, CHD4 knockdown increased chemosensitivity and CHD4 overexpression induced epirubicin chemoresistance. To inhibit the functions of CHD4 that are mediated through histone deacetylase and poly (ADP-ribose) polymerase, we evaluated the effect of the histone deacetylase inhibitor suberohydroxamic acid and the poly (ADP-ribose) polymerase inhibitor AG-014699. Treatment with either suberohydroxamic acid or AG-014699 reduced the number of EpCAM(+) liver cancer stem cells in vitro, and suberohydroxamic acid and AG-014699 in combination successfully inhibited tumor growth in a mouse xenograft model. CHD4 plays a pivotal role in chemoresistance and the maintenance of stemness in liver cancer stem cells and is therefore a good target for the eradication of hepatocellular carcinoma. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Diagnostic and therapeutic management of hepatocellular carcinoma

PubMed Central

Bellissimo, Francesco; Pinzone, Marilia Rita; Cacopardo, Bruno; Nunnari, Giuseppe

2015-01-01

Hepatocellular carcinoma (HCC) is an increasing health problem, representing the second cause of cancer-related mortality worldwide. The major risk factor for HCC is cirrhosis. In developing countries, viral hepatitis represent the major risk factor, whereas in developed countries, the epidemic of obesity, diabetes and nonalcoholic steatohepatitis contribute to the observed increase in HCC incidence. Cirrhotic patients are recommended to undergo HCC surveillance by abdominal ultrasounds at 6-mo intervals. The current diagnostic algorithms for HCC rely on typical radiological hallmarks in dynamic contrast-enhanced imaging, while the use of α-fetoprotein as an independent tool for HCC surveillance is not recommended by current guidelines due to its low sensitivity and specificity. Early diagnosis is crucial for curative treatments. Surgical resection, radiofrequency ablation and liver transplantation are considered the cornerstones of curative therapy, while for patients with more advanced HCC recommended options include sorafenib and trans-arterial chemo-embolization. A multidisciplinary team, consisting of hepatologists, surgeons, radiologists, oncologists and pathologists, is fundamental for a correct management. In this paper, we review the diagnostic and therapeutic management of HCC, with a focus on the most recent evidences and recommendations from guidelines. PMID:26576088

CD4+CD25+ Treg derived from hepatocellular carcinoma mice inhibits tumor immunity.

PubMed

Chen, Xin; Du, Yong; Huang, Zhiming

2012-01-01

CD4+CD25+ regulatory T cells (Tregs) play an essential role in the establishment and persistence of tumor immune suppression. Tregs can prevent anti-tumor-specific T cells from clearing the tumor, making Tregs a significant barrier for effective immunotherapy. An increase in the number of Tregs has been detected in the peripheral blood and tumor infiltrating lymphocytes of patients with hepatocellular carcinoma. Dendritic cells (DCs) are antigen-presenting cells that play a pivotal role in the initiation of immune responses. The evidence for their ability to act as natural adjuvant in the stimulation of specific anti-tumor cytotoxic T lymphocytes and in the induction of protective and therapeutic anti-tumor immunity is now overwhelming. The aim of our study was to investigate the variation of Tregs in hepatocellular carcinoma mice and how Tregs derived from the tumor mice affect DCs' function. We found that Tregs derived from the tumor mice down-regulated the expression of costimulatory molecules CD80/CD86 on DCs and inhibited the production of TNF-α and IL-12 from DCs. The suppressive function of Tregs was mediated by cell-to-cell contact, CTLA-4 expression and IL-10 secretion. In conclusion, these mechanisms acting in hepatocellular carcinoma may be necessary to better understand the immunosuppression of Tregs and helpful to the tumor immunotherapy. Copyright © 2012 Elsevier B.V. All rights reserved.

Hepatocellular carcinoma treatment: a comparative review of emerging growth factor receptor antagonists.

PubMed

Lee, Su Jin; Lim, Ho Yeong

2017-06-01

Hepatocellular carcinoma (HCC) is a leading cause of death worldwide. Over the last decade, sorafenib has been the only available therapeutic option for advanced HCC, although regorafenib recently showed a survival benefit compared with placebo in a second-line setting. Areas covered: This review discusses key published and ongoing studies with targeted agents in HCC, molecular targets of HCC, the mechanism of resistance to sorafenib, and the role of biomarker-enriched clinical trials. Expert opinion: The multiplicity of drivers and the existence of substantial molecular heterogeneity limit the benefits of targeted therapies in HCC. Based on molecular biology developments, a few biomarker-enriched clinical trials that target candidate driver genes are ongoing, and the outcomes of these are highly anticipated. Poor availability of tumor tissue and tumor heterogeneity in patients with HCC make liquid biopsy a very attractive option, although this technique remains to be validated.

Upregulation of heat shock factor 1 transcription activity is associated with hepatocellular carcinoma progression.

PubMed

Li, Shulian; Ma, Wanli; Fei, Teng; Lou, Qiang; Zhang, Yaqin; Cui, Xiukun; Qin, Xiaoming; Zhang, Jun; Liu, Guangchao; Dong, Zheng; Ma, Yuanfang; Song, Zhengshun; Hu, Yanzhong

2014-11-01

Heat shock factor 1 (HSF1) is associated with tissue‑specific tumorigenesis in a number of mouse models, and has been used a as prognostic marker of cancer types, including breast and prostatic cancer. However, its role in human hepatocellular carcinoma (HCC) is not well understood. Using immunoblotting and immunohistochemical staining, it was identified that HSF1 and its serine (S) 326 phosphorylation, a biomarker of HSF1 activation, are significantly upregulated in human HCC tissues and HCC cell lines compared with their normal counterparts. Cohort analyses indicated that upregulation of the expression of HSF1 and its phospho‑S326 is significantly correlated with HCC progression, invasion and patient survival prognosis (P<0.001); however, not in the presence of a hepatitis B virus infection and the expression of alpha-fetoprotein and carcinoembryonic antigen. Knockdown of HSF1 with shRNA induced the protein expression of tumor suppressor retinoblastoma protein, resulting in attenuated plc/prf5 cell growth and colony formation in vitro. Taken together, these data markedly support that HSF1 is a potential prognostic marker and therapeutic target for the treatment of HCC.

Down-regulation of connective tissue growth factor by inhibition of transforming growth factor beta blocks the tumor-stroma cross-talk and tumor progression in hepatocellular carcinoma.

PubMed

Mazzocca, Antonio; Fransvea, Emilia; Dituri, Francesco; Lupo, Luigi; Antonaci, Salvatore; Giannelli, Gianluigi

2010-02-01

Tumor-stroma interactions in hepatocellular carcinoma (HCC) are of key importance to tumor progression. In this study, we show that HCC invasive cells produce high levels of connective tissue growth factor (CTGF) and generate tumors with a high stromal component in a xenograft model. A transforming growth factor beta (TGF-beta) receptor inhibitor, LY2109761, inhibited the synthesis and release of CTGF, as well as reducing the stromal component of the tumors. In addition, the TGF-beta-dependent down-regulation of CTGF diminished tumor growth, intravasation, and metastatic dissemination of HCC cells by inhibiting cancer-associated fibroblast proliferation. By contrast, noninvasive HCC cells were found to produce low levels of CTGF. Upon TGF-beta1 stimulation, noninvasive HCC cells form tumors with a high stromal content and CTGF expression, which is inhibited by treatment with LY2109761. In addition, the acquired intravasation and metastatic spread of noninvasive HCC cells after TGF-beta1 stimulation was blocked by LY2109761. LY2109761 interrupts the cross-talk between cancer cells and cancer-associated fibroblasts, leading to a significant reduction of HCC growth and dissemination. Interestingly, patients with high CTGF expression had poor prognosis, suggesting that treatment aimed at reducing TGF-beta-dependent CTGF expression may offer clinical benefits. Taken together, our preclinical results indicate that LY2109761 targets the cross-talk between HCC and the stroma and provide a rationale for future clinical trials.

Chitosan nanoparticles from marine squid protect liver cells against N-diethylnitrosoamine-induced hepatocellular carcinoma.

PubMed

Subhapradha, Namasivayam; Shanmugam, Vairamani; Shanmugam, Annaian

2017-09-01

Rationale of this study was framed to investigate the protective effect and anti-cancer property of nanoparticles based on chitosan isolated from squid, Sepioteuthis lessoniana, on hepatic cells in N-Nitrosodiethylamine-induced hepatocellular carcinoma in rats. The results conferred that the chitosan nanoparticle supplementation had a protective effect on liver cells by reducing the levels of marker enzymes and bilirubin and thus increasing the albumin levels. The level of reduced glutathione, ascorbic acid and α-tocopherol significantly increased in both post- and pre-treatment with chitosan nanoparticles. The levels of antioxidant enzymes were enhanced and lipid peroxidation products were diminished while treating nitrosodiethylamine-induced hepatocellular carcinoma with chitosan nanoparticles. Supplementation of chitosan nanoparticles had potent anti-hyperlipidemic property that was evidenced by monitoring the serum lipid levels and its components. Animals pre-treated with chitosan nanoparticles along with nitrosodiethylamine showed a significant reduction in the total cholesterol and triglycerides levels with increase in the levels of phospholipids and free fatty acids. Chitosan nanoparticles treated rats showed significant increment in high-density lipoprotein cholesterol and reduction in low-density lipoprotein and very low-density lipoprotein cholesterol when compared with levels in nitrosodiethylamine-induced hepatocellular carcinoma. Nitrosodiethylamine-induced carcinoma changes on circulation and hepatic antioxidant defense mechanism were regulated by chitosan nanoparticles, concluding that the chitosan nanoparticles have a potent protective effect on liver cells which might be due to its robust antioxidant and anti-lipidemic property. Copyright © 2017 Elsevier Ltd. All rights reserved.

Review of hepatocellular carcinoma: Epidemiology, etiology, and carcinogenesis.

PubMed

Ghouri, Yezaz Ahmed; Mian, Idrees; Rowe, Julie H

2017-01-01

Since the 1970s, the epidemic of hepatocellular carcinoma (HCC) has spread beyond the Eastern Asian predominance and has been increasing in Northern hemisphere, especially in the United States (US) and Western Europe. It occurs more commonly in males in the fourth and fifth decades of life. Among all cancers, HCC is one of the fastest growing causes of death in the US and poses a significant economic burden on healthcare. Chronic liver disease due to hepatitis B virus or hepatitis C virus and alcohol accounts for the majority of HCC cases. Incidence of nonalcoholic fatty liver disease has been on the risem and it has also been associated with the development of HCC. Its pathogenesis varies based on the underlying etiological factor although majority of cases develop in the setting of background cirrhosis. Carcinogenesis of HCC includes angiogenesis, chronic inflammation, and tumor macroenvironment and microenvironment. There is a significant role of both intrinsic genetic risk factors and extrinsic influences such as alcohol or viral infections that lead to the development of HCC. Understanding its etiopathogenesis helps select appropriate diagnostic tests and treatments.

High-powered microwave ablation of larger hepatocellular carcinoma: evaluation of recurrence rate and factors related to recurrence.

PubMed

Zhang, N N; Lu, W; Cheng, X J; Liu, J Y; Zhou, Y H; Li, F

2015-11-01

To evaluate the safety and efficacy of high-powered (80-100 W) percutaneous microwave ablation (MWA) at a frequency of 2450±10 MHz for treating larger hepatocellular carcinoma (HCC) and to predict the risk factors of local recurrence after high-powered MWA. The study was approved by the Institutional Review Board, and informed consent was waived because of the retrospective study design. Forty-five patients with a total of 60 lesions received high-power (80-100 W) MWA at a frequency of 2450±10 MHz through a percutaneous approach that was guided by ultrasound. Of the 60 lesions with a maximum tumour measuring 3-8 cm, 46 lesions were 3-5 cm and 14 were 5-8 cm. The complete ablation rates, local recurrence rates, complications, and short-term survival were analysed. Ten possible risk factors for local recurrence were analysed. The complete ablation rates were 82.61% for the first ablation and 100% for the second ablation for 3-5 cm lesions. The complete ablation rates were 64.29% (82.61% versus 64.29%, p=0.037) for the first ablation and 85.71% (100% versus 85.71%, p=0.055) for the second ablation for 5-8 cm lesions. Local recurrence was observed in 11 out of the 45 (24.44%) successfully treated patients. The 1-year and 2-year survival rates were 95.56% (43/45) and 86.67% (39/45), respectively. No procedure-related mortality was observed and no major bleeding, liver rupture, or liver abscesses occurred. Univariate analysis showed that a positive correlation existed between the number of lesions (p=0.022), proximity to the risk area (p=0.001), pre-ablation alpha-fetoprotein (AFP) levels (p=0.025), hepatitis B virus (HBV)-DNA replication (p=0.027) and local recurrence. Multivariate analysis identified HBV-DNA (p=0.031) and proximity to the risk area (p=0.039) as the independent prognosis factors causing postoperative HCC local recurrence. High-powered MWA of larger hepatocellular carcinomas appears to be a safe and effective treatment. HBV-DNA and proximity

Can the Contrast-Enhanced Ultrasound Washout Rate Be Used to Predict Microvascular Invasion in Hepatocellular Carcinoma?

PubMed

Zhu, Wei; Qing, Xiachuan; Yan, Feng; Luo, Yan; Li, Yongzhong; Zhou, Xiang

2017-08-01

The objective of this study was to investigate use of the washout rate of hepatocellular carcinoma on contrast-enhanced ultrasound (CEUS) for pre-operative determination of the presence of microvascular invasion. The study included 271 patients who underwent liver resection for hepatocellular carcinoma between April 2008 and December 2012, and were examined with contrast-enhanced ultrasound before surgery. Patients were followed up at 3-mo intervals for 3 y. Four washout patterns were classified according to the start time of washout: rapid, portal, delayed and slow. Rapid washout, presence of two or more tumors and tumor size ≥5 cm were identified as independent pre-operative predictors of microvascular invasion on multivariate analysis. Recurrence rates for patients with none, one, two or three predictors were 22.6%, 34.7%, 57.6% and 75.0%, respectively. In combination with tumor number and tumor size, contrast-enhanced ultrasound washout rate may have a role in identifying hepatocellular carcinoma patients with microvascular invasion. Copyright © 2017 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Therapeutic and scintigraphic applications of polymeric micelles: combination of chemotherapy and radiotherapy in hepatocellular carcinoma

PubMed Central

Shih, Ying-Hsia; Peng, Cheng-Liang; Chiang, Ping-Fang; Lin, Wuu-Jyh; Luo, Tsai-Yueh; Shieh, Ming-Jium

2015-01-01

This study evaluated a multifunctional micelle simultaneously loaded with doxorubicin (Dox) and labeled with radionuclide rhenium-188 (188Re) as a combined radiotherapy and chemotherapy treatment for hepatocellular carcinoma. We investigated the single photon emission computed tomography, biodistribution, antitumor efficacy, and pathology of 188Re-Dox micelles in a murine orthotopic luciferase-transfected BNL tumor cells hepatocellular carcinoma model. The single photon emission computed tomography and computed tomography images showed high radioactivity in the liver and tumor, which was in agreement with the biodistribution measured by γ-counting. In vivo bioluminescence images showed the smallest size tumor (P<0.05) in mice treated with the combined micelles throughout the experimental period. In addition, the combined 188Re-Dox micelles group had significantly longer survival compared with the control, 188ReO4 alone (P<0.005), and Dox micelles alone (P<0.01) groups. Pathohistological analysis revealed that tumors treated with 188Re-Dox micelles had more necrotic features and decreased cell proliferation. Therefore, 188Re-Dox micelles may enable combined radiotherapy and chemotherapy to maximize the effectiveness of treatment for hepatocellular carcinoma. PMID:26719687

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

PubMed

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

2012-12-21

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

Branched-chain amino acids to tyrosine ratio value as a potential prognostic factor for hepatocellular carcinoma.

PubMed

Ishikawa, Toru

2012-05-07

The prognosis of hepatocellular carcinoma (HCC) depends on tumor extension as well as hepatic function. Hepatic functional reserve is recognized as a factor affecting survival in the treatment of HCC; the Child-Pugh classification system is the most extensively used method for assessing hepatic functional reserve in patients with chronic liver disease, using serum albumin level to achieve accurate assessment of the status of protein metabolism. However, insufficient attention has been given to the status of amino acid (AA) metabolism in chronic liver disease and HCC. Fischer's ratio is the molar ratio of branched-chain AAs (BCAAs: leucine, valine, isoleucine) to aromatic AAs (phenylalanine, tyrosine) and is important for assessing liver metabolism, hepatic functional reserve and the severity of liver dysfunction. Although this ratio is difficult to determine in clinical situations, BCAAs/tyrosine molar concentration ratio (BTR) has been proposed as a simpler substitute. BTR correlates with various liver function examinations, including markers of hepatic fibrosis, hepatic blood flow and hepatocyte function, and can thus be considered as reflecting the degree of hepatic impairment. This manuscript examines the literature to clarify whether BTR can serve as a prognostic factor for treatment of HCC.

Prediction of posthepatectomy liver failure using transient elastography in patients with hepatitis B related hepatocellular carcinoma.

PubMed

Lei, Jie-Wen; Ji, Xiao-Yu; Hong, Jun-Feng; Li, Wan-Bin; Chen, Yan; Pan, Yan; Guo, Jia

2017-12-29

It is essential to accurately predict Postoperative liver failure (PHLF) which is a life-threatening complication. Liver hardness measurement (LSM) is widely used in non-invasive assessment of liver fibrosis. The aims of this study were to explore the application of preoperative liver stiffness measurements (LSM) by transient elastography in predicting postoperative liver failure (PHLF) in patients with hepatitis B related hepatocellular carcinoma. The study included 247 consecutive patients with hepatitis B related hepatocellular carcinoma who underwent hepatectomy between May 2015 and September 2015. Detailed preoperative examinations including LSM were performed before hepatectomy. The endpoint was the development of PHLF. All of the patients had chronic hepatitis B defined as the presence of hepatitis B surface antigen (HBsAg) for more than 6 months and 76 (30.8%) had cirrhosis. PHLF occurred in 37 (14.98%) patients. Preoperative LSM (odds ratio, OR, 1.21; 95% confidence interval, 95% CI: 1.13-1.29; P < 0.001) and international normalized ratio (INR) (OR, 1.07; 95% CI: 1.01-1.12; P < 0.05) were revealed to be independent risk factors for PHLF, and a new model was defined as LSM-INR index (LSM-INR index = 0.191*LSM + 6.317*INR-11.154). The optimal cutoff values of LSM and LSM-INR index for predicting PHLF were 14 kPa (AUC 0.86, 95% CI: 0.811-0.901, P < 0.001) and -1.92 (AUC 0.87, 95% CI: 0.822-0.909, P < 0.001), respectively. LSM can be helpful for surgeons to make therapeutic decisions in patients with hepatitis B related hepatocellular carcinoma.

Newly diagnosed hepatocellular carcinoma in patients with advanced hepatitis C treated with DAAs: A prospective population study.

PubMed

Romano, Antonietta; Angeli, Paolo; Piovesan, Sara; Noventa, Franco; Anastassopoulos, Georgios; Chemello, Liliana; Cavalletto, Luisa; Gambato, Martina; Russo, Francesco Paolo; Burra, Patrizia; Vincenzi, Valter; Scotton, Pier Giorgio; Panese, Sandro; Tempesta, Diego; Bertin, Tosca; Carrara, Maurizio; Carlotto, Antonio; Capra, Franco; Carolo, Giada; Scroccaro, Giovanna; Alberti, Alfredo

2018-03-16

Direct-acting antiviral agents (DAAs) are safe and effective in patients with hepatitis C. Conflicting data were reported on the risk of hepatocellular carcinoma (HCC) during/after therapy with DAAs. The aim of this study was to evaluate the incidence of newly diagnosed HCC and associated risk factors in patients with advanced hepatitis C treated with DAAs. The study is based on the NAVIGATORE platform, a prospectively recording database of all patients with hepatitis C receiving DAAs in the Veneto region of Italy. The inclusion criteria were: fibrosis stage ≥F3. The exclusion criteria were: Child-Turcotte-Pugh (CTP)-C, liver transplantation before DAAs, history or presence of HCC, follow-up <4 weeks after starting DAAs. A total of 3,917 out of 4,234 consecutive patients were included, with a mean follow-up of 536.2 ± 197.6 days. Overall, HCC was diagnosed in 55 patients. During the first year, HCC incidence was 0.46% (95% CI 0.12-1.17) in F3, 1.49% (1.03-2.08) in CTP-A and 3.61% (1.86-6.31) in CTP-B cirrhotics; in the second year, HCC incidences were 0%, 0.2%, and 0.69%, respectively. By multivariate analysis, HCC was significantly associated with an aspartate aminotransferase to platelet ratio ≥2.5 (hazard ratio [HR] 2.03; 95% CI 1.14-3.61; p = 0.016) and hepatitis B virus infection (HR 3.99; 1.24-12.91; p = 0.021). Failure to achieve a sustained virological response was strongly associated with development of HCC (HR 9.09; 5.2-16.1; p = 0.0001). A total of 29% of patients with HCC had an aggressive tumor, often seen in the early phase of treatment. These data, obtained in a large, prospective, population-based study, indicate that in patients with advanced hepatitis C receiving DAAs, the risk of "de novo" hepatocarcinoma during the first year is not higher, and might be lower, than that of untreated patients. The risk further declines thereafter. Early hepatocarcinoma appearance may reflect pre-existing, microscopic, undetectable tumors

Recent advances in hepatocellular carcinoma therapy☆

PubMed Central

Dutta, Rinku; Mahato, Ram I.

2017-01-01

Hepatocellular carcinoma (HCC), also called malignant hepatoma, is one of the deadliest cancers due to its complexities, reoccurrence after surgical resection, metastasis and heterogeneity. Incidence and mortality of HCC are increasing in Western countries and are expected to rise as a consequence of the obesity epidemic. Multiple factors trigger the initiation and progression of HCC including chronic alcohol consumption, viral hepatitis B and C infection, metabolic disorders and age. Although Sorafenib is the only FDA approved drug for the treatment of HCC, numerous treatment modalities such as transcatheter arterial chemoembolization/transarterial chemoembolization (TACE), radiotherapy, locoregional therapy and chemotherapy have been tested in the clinics. Polymeric nanoparticles, liposomes, and micelles carrying small molecules, proteins, peptides and nucleic acids have attracted great attention for the treatment of various cancers including HCC. Herein, we discuss the pathogenesis of HCC in relation to its various recent treatment methodologies using nanodelivery of monoclonal antibodies (mAbs), small molecules, miRNAs and peptides. Synopsis of recent clinical trials of mAbs and peptide drugs has been presented with a broad overview of the pathogenesis of the disease and treatment efficacy. PMID:28174094

Long-term survival after liver transplant for recurrent hepatocellular carcinoma with bile duct tumor thrombus: case report.

PubMed

Liu, Chao; Wang, Jie

2012-12-01

Hepatocellular carcinoma with bile duct tumor thrombus is considered an aggressive malignancy, and the prognosis of liver transplant for it remains obscure. A 42-year-old man with recurrent hepatocellular carcinoma and a history of surgical resection was admitted to our hospital with a 10-day history of yellowish urine and itchy skin. There were 3 lesions in the right lobe with the diameter of 2 cm each. A mass was found in the upper part of common bile duct, and the intrahepatic bile duct was dilated. His serum alpha-fetoprotein level was 2476 μg/L, total bilirubin level was 327 μmol/L, direct bilirubin level was 261 μmol/L, and alanine aminotransferase was 714 U/L. There was no main portal vein thrombus or extrahepatic metastases. Because of his poor liver function, he was listed for a liver transplant. During the wait (30 d), he underwent 9 episodes of plasmapheresis to decrease the serum level of bilirubin. He had an orthotopic liver transplant with the graft from a deceased donor. After the liver transplant, he received 5 cycles of chemotherapy with the regimen of oxaliplatin and 5-fluorouracil. This patient has survived without recurrence of hepatocellular carcinoma for more than 82 months and remains in good condition. Liver transplant may have a favorable result for hepatocellular carcinoma patient with a bile duct tumor thrombus, within the Milan criteria.

Evaluation of prognostic factors on recurrence after curative resections for hepatocellular carcinoma

PubMed Central

Han, Jae Hyun; Kim, Dong Goo; Na, Gun Hyung; Kim, Eun Young; Lee, Soo Ho; Hong, Tae Ho; You, Young Kyoung

2014-01-01

AIM: To select appropriate patients before surgical resection for hepatocellular carcinoma (HCC), especially those with advanced tumors. METHODS: From January 2000 to December 2012, we retrospectively analyzed the medical records of 298 patients who had undergone surgical resections for HCC with curative intent at our hospital. We evaluated preoperative prognostic factors associated with histologic grade of tumor, recurrence and survival, especially the findings of pre-operative imaging studies such as positron emission tomography-computed tomography (PET-CT) and magnetic resonance imaging (MRI). And then, we established a scoring system to predict recurrence and survival after surgery dividing the patients into two groups based on a tumor size of 5 cm. RESULTS: Of the 298 patients, 129 (43.3%) developed recurrence during the follow-up period. The 5 year disease free survival and overall survival were 47.0% and 58.7% respectively. In multivariate analysis, a serum alpha-fetoprotein (AFP) level of > 100 ng/mL and a standardized uptake value (SUV) of PET-CT of > 3.5 were predictive factors for histologic grade of tumor, recurrence, and survival. Tumor size of > 5 cm and a relative enhancement ratio (RER) calculated from preoperative MRI were also significantly associated with prognosis in univariate analysis. We established a scoring system to predict prognosis using AFP, SUV, and RER. In those with tumors of > 5 cm, it showed predicted both recurrence (P = 0.005) and survival (P = 0.001). CONCLUSION: The AFP, tumor size, SUV and RER are useful for prognosis preoperatively. An accurate prediction of prognosis is possible using our scoring system in large size tumors. PMID:25493027

Staging systems of hepatocellular carcinoma: A review of literature

PubMed Central

Maida, Marcello; Orlando, Emanuele; Cammà, Calogero; Cabibbo, Giuseppe

2014-01-01

Hepatocellular carcinoma (HCC) is a major health problem with a high incidence and mortality all over the world. Natural history of HCC is severe and extremely variable, and prognostic factors influencing outcomes are incompletely defined. Over time, many staging and scoring systems have been proposed for the classification and prognosis of patients with HCC. Currently, the non-ideal predictive performance of existing prognostic systems is secondary to their inherent limitations, as well as to a non-universal reproducibility and transportability of the results in different populations. New serological and histological markers are still under evaluation with promising results, but they require further evaluation and external validation. The aim of this review is to highlight the main tools for assessing the prognosis of HCC and the main concerns, pitfalls and warnings regarding its staging systems currently in use. PMID:24764652

A multicenter matched case-control analysis on seven polymorphisms from HMGB1 and RAGE genes in predicting hepatocellular carcinoma risk.

PubMed

Wang, Dan; Qi, Xiaoying; Liu, Fang; Yang, Chuanhua; Jiang, Wenguo; Wei, Xiaodan; Li, Xuri; Mi, Jia; Tian, Geng

2017-07-25

Based on 540 hepatocellular carcinoma patients and 540 age- and gender-matched controls, we tested the hypothesis that high mobility group protein box1 (HMGB1) and the receptor for advanced glycation end products (RAGE) genes are two potential candidate susceptibility genes for hepatocellular carcinoma in a multicenter hospital-based case-control analysis. The genotypes of seven widely-studied polymorphisms were determined, and their distributions respected the Hardy-Weinberg equilibrium. The mutant alleles of two polymorphisms, rs1045411 in HMGB1 gene and rs2070600 in RAGE gene, had significantly higher frequencies in patients than in controls (P < 0.001), with the power to detect this significance of being over 99.9%. Moreover, the above two polymorphisms increased the risk of developing hepatocellular carcinoma significantly, particularly for rs2070600 under the additive (odds ratio [OR] = 1.77; 95% confidence interval [CI]: 1.34-2.32; P < 0.001) and dominant (OR = 1.75; 95% CI: 1.23-2.50; P = 0.002) models after adjusting for body mass index, smoking and drinking. Haplotype analysis showed that the T-C-T haplotype (rs1045411-rs2249825-rs1415125) in HMGB1 gene was associated with a 2.47-fold (95% CI: 1.41-4.34; P = 0.002) increased risk of hepatocellular carcinoma compared with the commonest C-C-T haplotype after adjustment. In RAGE gene, the T-T-A-G (rs1800625-rs1800624-rs2070600-rs184003) (adjusted OR; 95% CI; P: 1.75; 1.02-3.03; 0.045) and T-T-A-T (adjusted OR; 95% CI; P: 1.95; 1.01-3.76; 0.048) haplotypes were associated with a marginally increased risk of hepatocellular carcinoma compared with the commonest T-T-G-G haplotype. In summary, we identified two risk-associated polymorphisms (rs1045411 and rs2070600), and more importantly a joint impact of seven polymorphisms from the HMGB1/RAGE axis in susceptibility to hepatocellular carcinoma.

Liver stiffness measurement by transient elastography predicts late posthepatectomy outcomes in patients undergoing resection for hepatocellular carcinoma.

PubMed

Rajakannu, Muthukumarassamy; Cherqui, Daniel; Ciacio, Oriana; Golse, Nicolas; Pittau, Gabriella; Allard, Marc Antoine; Antonini, Teresa Maria; Coilly, Audrey; Sa Cunha, Antonio; Castaing, Denis; Samuel, Didier; Guettier, Catherine; Adam, René; Vibert, Eric

2017-10-01

Postoperative hepatic decompensation is a serious complication of liver resection in patients undergoing hepatectomy for hepatocellular carcinoma. Liver fibrosis and clinical significant portal hypertension are well-known risk factors for hepatic decompensation. Liver stiffness measurement is a noninvasive method of evaluating hepatic venous pressure gradient and functional hepatic reserve by estimating hepatic fibrosis. Effectiveness of liver stiffness measurement in predicting persistent postoperative hepatic decompensation has not been investigated. Consecutive patients with resectable hepatocellular carcinoma were recruited prospectively and liver stiffness measurement of nontumoral liver was measured using FibroScan. Hepatic venous pressure gradient was measured intraoperatively by direct puncture of portal vein and inferior vena cava. Hepatic venous pressure gradient ≥10 mm Hg was defined as clinically significant portal hypertension. Primary outcome was persistent hepatic decompensation defined as the presence of at least one of the following: unresolved ascites, jaundice, and/or encephalopathy >3 months after hepatectomy. One hundred and six hepatectomies, including 22 right hepatectomy (20.8%), 3 central hepatectomy (2.8%), 12 left hepatectomy (11.3%), 11 bisegmentectomy (10.4%), 30 unisegmentectomy (28.3%), and 28 partial hepatectomy (26.4%) were performed in patients for hepatocellular carcinoma (84 men and 22 women with median age of 67.5 years; median model for end-stage liver disease score of 8). Ninety-day mortality was 4.7%. Nine patients (8.5%) developed postoperative hepatic decompensation. Multivariate logistic regression bootstrapped at 1,000 identified liver stiffness measurement (P = .001) as the only preoperative predictor of postoperative hepatic decompensation. Area under receiver operating characteristic curve for liver stiffness measurement and hepatic venous pressure gradient was 0.81 (95% confidence interval, 0.506-0.907) and 0

Venom from Cuban Blue Scorpion has tumor activating effect in hepatocellular carcinoma

PubMed Central

Giovannini, Catia; Baglioni, Michele; Baron Toaldo, Marco; Cescon, Matteo; Bolondi, Luigi; Gramantieri, Laura

2017-01-01

Complementary and alternative medicine (CAM) is the term used to describe many kinds of products, practices, and systems that are not part of conventional medicine. Cancer patients usually do everything they can to combat the disease, manage its symptoms, and cope with the side effects of treatment. Unfortunately, patients who use CAM underestimate the risk of interaction with cancer therapy or worse they omit conventional therapy thus reducing the possibility of cancer remission. Herein we analyzed the effects of Vidatox 30 CH (venom extracted from the Junceus Rhopalurus scorpion) on hepatocellular carcinoma (HCC), the second leading cause of cancer-related deaths. We found out that Vidatox increases HCC proliferation and invasion whereas it does not seem to interact with sorafenib, the orally active multikinase inhibitor approved for the treatment of advanced hepatocellular carcinoma. Our results suggest that the concentration of Vidatox used in the present study has not anti-neoplastic effects and care must be taken in hiring Vidatox in patients with HCC. PMID:28322221

Venom from Cuban Blue Scorpion has tumor activating effect in hepatocellular carcinoma.

PubMed

Giovannini, Catia; Baglioni, Michele; Baron Toaldo, Marco; Cescon, Matteo; Bolondi, Luigi; Gramantieri, Laura

2017-03-21

Complementary and alternative medicine (CAM) is the term used to describe many kinds of products, practices, and systems that are not part of conventional medicine. Cancer patients usually do everything they can to combat the disease, manage its symptoms, and cope with the side effects of treatment. Unfortunately, patients who use CAM underestimate the risk of interaction with cancer therapy or worse they omit conventional therapy thus reducing the possibility of cancer remission. Herein we analyzed the effects of Vidatox 30 CH (venom extracted from the Junceus Rhopalurus scorpion) on hepatocellular carcinoma (HCC), the second leading cause of cancer-related deaths. We found out that Vidatox increases HCC proliferation and invasion whereas it does not seem to interact with sorafenib, the orally active multikinase inhibitor approved for the treatment of advanced hepatocellular carcinoma. Our results suggest that the concentration of Vidatox used in the present study has not anti-neoplastic effects and care must be taken in hiring Vidatox in patients with HCC.

Chemotherapeutic potential of curcumin-bearing microcells against hepatocellular carcinoma in model animals

PubMed Central

Farazuddin, Mohammad; Dua, Bhavyata; Zia, Qamar; Khan, Aijaz Ahmad; Joshi, Beenu; Owais, Mohammad

2014-01-01

Curcumin (diferuloylmethane) is found in large quantities in the roots of Curcuma longa. It possesses strong antioxidant and anti-inflammatory properties, and inhibits chemically-induced carcinogenesis in the skin, forestomach, colon, and liver. Unfortunately, the poor bioavailability and hydrophobicity of curcumin pose a major hurdle to its use as a potent anticancer agent. To circumvent some of these problems, we developed a novel, dual-core microcell formulation of curcumin. The encapsulation of curcumin in microcells increases its solubility and bioavailability, and facilitates slow release kinetics over extended periods. Besides being safe, these formulations do not bear any toxicity constraints, as revealed by in vitro and in vivo studies. Histopathological analysis revealed that curcumin-bearing microcells helped in regression of hepatocellular carcinoma and the maintenance of cellular architecture in liver tissue. Free curcumin had a very mild effect on cancer suppression. Empty (sham) microcells and microparticles failed to inhibit cancer cells. The novel curcumin formulation was found to suppress hepatocellular carcinoma efficiently in Swiss albino mice. PMID:24627632

Exploiting bilosomes for delivering bioactive polysaccharide isolated from Enteromorpha intestinalis for hacking hepatocellular carcinoma.

PubMed

Matloub, Azza Abdelmageed; Salama, Alaa Hamed; Aglan, Hadeer Ahmed; AbouSamra, Mona Mahmoud; ElSouda, Sahar Salah Mohamed; Ahmed, Hanaa Hamdy

2018-04-01

Bile salts containing vesicles (bilosomes) represent a portentous vesicular carrier that showed prosperous results in delivering active moieties in the gastrointestinal tract (GIT). In this study, bilosomes were exploited to deliver sulfated polysaccharide-protein complexes of Enteromorpha intestinalis (EHEM) and enhance its activity against hepatocellular carcinoma as well as resist harsh GIT conditions. Bilosomes were prepared using the sodium salt of three different bile acids (cholic, deoxycholic, taurodeoxycholic) and two different nonionic surfactants (Span 40 and 65). The effects of experimental variables were thoroughly studied to obtain an optimum formulation loading EHEM. The selected formulation (EH-Bilo-2) prepared with sodium cholate and Span 65 displayed nano-sized (181.1 ± 16.80 nm) spherical vesicles with reasonable entrapment efficiency (71.60 ± 0.25%) and controlled release properties; and thus was investigated as anti-hepatocarcinogenic candidate for in vivo studies. Treatment of hepatocellular carcinoma (HCC) bearing rats with EH-Bilo-2 experienced significant decrease in serum α-fetoprotein, endoglin, lipocalin-2, and heat shock protein 70 levels vs. the untreated counterparts. Furthermore, the photomicrographs of their liver tissue sections showed focal area of degenerated pleomorphic hepatocytes with fine fibrosis originating from the portal area. Thus, the optimized bilosomal formulation is a promising delegate for tackling hepatocellular carcinoma owing to its powerful anti-cancer and anti-angiogenic activity.

An efficient model for auxiliary diagnosis of hepatocellular carcinoma based on gene expression programming.

PubMed

Zhang, Li; Chen, Jiasheng; Gao, Chunming; Liu, Chuanmiao; Xu, Kuihua

2018-03-16

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. The early diagnosis of HCC is greatly helpful to achieve long-term disease-free survival. However, HCC is usually difficult to be diagnosed at an early stage. The aim of this study was to create the prediction model to diagnose HCC based on gene expression programming (GEP). GEP is an evolutionary algorithm and a domain-independent problem-solving technique. Clinical data show that six serum biomarkers, including gamma-glutamyl transferase, C-reaction protein, carcinoembryonic antigen, alpha-fetoprotein, carbohydrate antigen 153, and carbohydrate antigen 199, are related to HCC characteristics. In this study, the prediction of HCC was made based on these six biomarkers (195 HCC patients and 215 non-HCC controls) by setting up optimal joint models with GEP. The GEP model discriminated 353 out of 410 subjects, representing a determination coefficient of 86.28% (283/328) and 85.37% (70/82) for training and test sets, respectively. Compared to the results from the support vector machine, the artificial neural network, and the multilayer perceptron, GEP showed a better outcome. The results suggested that GEP modeling was a promising and excellent tool in diagnosis of hepatocellular carcinoma, and it could be widely used in HCC auxiliary diagnosis. Graphical abstract The process to establish an efficient model for auxiliary diagnosis of hepatocellular carcinoma.

Transforming growth factor-β decreases side population cells in hepatocellular carcinoma in vitro.

PubMed

Kim, Jong Bin; Lee, Seulki; Kim, Hye Ri; Park, Seo-Young; Lee, Minjong; Yoon, Jung-Hwan; Kim, Yoon Jun

2018-06-01

Hepatocellular carcinoma (HCC) can result from hepatitis B or C infection, fibrosis or cirrhosis. Transforming growth factor-β (TGF-β) is one of the main growth factors associated with fibrosis or cirrhosis progression in the liver, but its role is controversial in hepatocarcinogenesis. In the present study, the effect of TGF-β on the HCC Huh-7 and Huh-Bat cell lines was evaluated. To study the effect of TGF-β, Huh-7 and Huh-Bat cells were treated with TGF-β and a TGF-β receptor inhibitor (SB431542). Cell survival, cell cycle, numbers of side population (SP) cells and expression of the cancer stem cell marker cluster of differentiation (CD)133, epithelial-mesenchymal transition markers (E-cadherin, α-smooth muscle actin and vimentin) and TGF-β-regulated proteins [phospho-c-Jun N-terminal kinase (p-JNK), p-c-Jun and p-smad2] were investigated. TGF-β treatment resulted in decreased cell survival with a targeted effect on SP cells. Expression of CD133 and vimentin was upregulated by treatment with the TGF-β receptor antagonist SB431542, but not with TGF-β. By contrast, TGF-β induced accumulation of cells at G0/G1, and upregulated expression of p-JNK, p-c-Jun and p-smad2. However, these effects were blocked when cells were treated with TGF-β plus SB431542, indicating the specificity of the TGF-β effect. The present results indicated that TGF-β has anticancer effects mediated by survival inhibition of cancer stem cells, which may be developed as a novel therapy for HCC.

Hepatocellular carcinoma in two captive golden-headed lion tamarins (Leontopithecus chrysomelas).

PubMed

de Carvalho, Tatiane Furtado; de Paula Martins Pereira, Marianna; Pessanha, Angela Tinoco; Tinoco, Herlandes Penha; Paixão, Tatiane Alves; Santos, Renato Lima

2018-04-01

Two cases of hepatocellular carcinoma (HCC) in 2 female captive golden-headed lion tamarins (Leontopithecus chrysomelas) are described. HCC was diagnosed in both, with pulmonary metastasis in one of them. Neoplastic cells were positive for hepatocyte-specific antigen (HSA) by immunohistochemistry, confirming the diagnosis. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Identification of DNA-PKcs as a primary resistance factor of TIC10 in hepatocellular carcinoma cells.

PubMed

Cheng, Long; Liu, Yuan-Yuan; Lu, Pei-Hua; Peng, Yi; Yuan, Qiang; Gu, Xin-Shi; Jin, Yong; Chen, Min-Bin; Bai, Xu-Ming

2017-04-25

The current study tested the anti-hepatocellular carcinoma (HCC) cell activity of TIC10, a first-in-class small-molecule tumor necrosis (TNF)-related apoptosis-inducing ligand (TRAIL) inducer. TIC10 exerted potent anti-proliferative and pro-apoptotic actions in primary and established human HCC cells. TIC10 blocked Akt-Erk activation, leading to Foxo3a nuclear translocation, as well as TRAIL and death receptor-5 (DR5) transcription in HCC cells. We propose that DNA-PKcs is a major resistance factor of TIC10 possibly via inhibiting Foxo3a nuclear translocation. DNA-PKcs inhibition, knockdown or mutation facilitated TIC10-induced Foxo3a nuclear translocation, TRAIL/DR5 expression and cell apoptosis. Reversely, exogenous DNA-PKcs over-expression inhibited above actions by TIC10. In vivo, oral administration of TIC10 significantly inhibited HepG2 tumor growth in nude mice, which was further potentiated with Nu7026 co-administration. Thus, TIC10 shows promising anti-HCC activity, alone or together with DNA-PKcs inhibitors.

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

PubMed Central

Barakat, Omar; Skolkin, Mark D; Toombs, Barry D; Fischer, John H; Ozaki, Claire F; Wood, R Patrick

2008-01-01

Background Morbid obesity strongly predicts morbidity and mortality in surgical patients. However, obesity's impact on outcome after major liver resection is unknown. Case presentation We describe the management of a large hepatocellular carcinoma in a morbidly obese patient (body mass index >50 kg/m2). Additionally, we propose a strategy for reducing postoperative complications and improving outcome after major liver resection. Conclusion To our knowledge, this is the first report of major liver resection in a morbidly obese patient with hepatocellular carcinoma. The approach we used could make this operation nearly as safe in obese patients as it is in their normal-weight counterparts. PMID:18783621

HBV-specific CD4+ cytotoxic T cells in hepatocellular carcinoma are less cytolytic toward tumor cells and suppress CD8+ T cell-mediated antitumor immunity.

PubMed

Meng, Fanzhi; Zhen, Shoumei; Song, Bin

2017-08-01

In East Asia and sub-Saharan Africa, chronic infection is the main cause of the development of hepatocellular carcinoma, an aggressive cancer with low survival rate. Cytotoxic T cell-based immunotherapy is a promising treatment strategy. Here, we investigated the possibility of using HBV-specific CD4 + cytotoxic T cells to eliminate tumor cells. The naturally occurring HBV-specific cytotoxic CD4 + and CD8 + T cells were identified by HBV peptide pool stimulation. We found that in HBV-induced hepatocellular carcinoma patients, the HBV-specific cytotoxic CD4 + T cells and cytotoxic CD8 + T cells were present at similar numbers. But compared to the CD8 + cytotoxic T cells, the CD4 + cytotoxic T cells secreted less cytolytic factors granzyme A (GzmA) and granzyme B (GzmB), and were less effective at eliminating tumor cells. In addition, despite being able to secrete cytolytic factors, CD4 + T cells suppressed the cytotoxicity mediated by CD8 + T cells, even when CD4 + CD25 + regulator T cells were absent. Interestingly, we found that interleukin 10 (IL-10)-secreting Tr1 cells were enriched in the cytotoxic CD4 + T cells. Neutralization of IL-10 abrogated the suppression of CD8 + T cells by CD4 + CD25 - T cells. Neither the frequency nor the absolute number of HBV-specific CD4 + cytotoxic T cells were correlated with the clinical outcome of advanced stage hepatocellular carcinoma patients. Together, this study demonstrated that in HBV-related hepatocellular carcinoma, CD4 + T cell-mediated cytotoxicity was present naturally in the host and had the potential to exert antitumor immunity, but its capacity was limited and was associated with immunoregulatory properties. © 2017 APMIS. Published by John Wiley & Sons Ltd.

NF-κB in the liver—linking injury, fibrosis and hepatocellular carcinoma

PubMed Central

Luedde, Tom; Schwabe, Robert F.

2012-01-01

Hepatic cirrhosis and hepatocellular carcinoma (HCC) are the most common causes of death in patients with chronic liver disease. Chronic liver injury of virtually any etiology triggers inflammatory and wound healing responses that in the long run promote the development of hepatic fibrosis and HCC. Here, we review the role of the transcription factor nuclear factor-κB (NF-κB), a master regulator of inflammation and cell death, in the development of hepatocellular injury, liver fibrosis and HCC, with a particular focus on the role of NF-κB in different cellular compartments of the liver. We propose that NF-κB acts as a central link between hepatic injury, fibrosis and HCC, and that it may represent a target for the prevention or treatment of liver fibrosis and HCC. However, NF-κB acts as a two-edged sword and inhibition of NF-κB may not only exert beneficial effects but also negatively impact hepatocyte viability, especially when NF-κB inhibition is pronounced. Finding appropriate targets or identifying drugs that either exert only a moderate effect on NFκB activity or that can be specifically delivered to nonparenchymal cells will be essential to avoid the increase in liver injury associated with complete NF-κB blockade in hepatocytes. PMID:21293511

Gamma-irradiated β-glucan modulates signaling molecular targets of hepatocellular carcinoma in rats.

PubMed

Elsonbaty, Sawsan M; Zahran, Walid E; Moawed, Fatma Sm

2017-08-01

β-glucans are one of the most abundant forms of polysaccharides known as biological response modifiers which influence host's biological response and stimulate immune system. Accordingly, this study was initiated to evaluate irradiated β-glucan as a modulator for cellular signaling growth factors involved in the pathogenesis of hepatocellular carcinoma in rats. Hepatocellular carcinoma was induced with 20 mg diethylnitrosamine/kg BW. Rats received daily by gastric gavage 65 mg irradiated β-glucan/kg BW. It was found that treatment of rats with diethylnitrosamine induced hepatic injury and caused significant increase in liver injury markers with a concomitant significant increase in both hepatic oxidative and inflammatory indices: alpha-fetoprotein, interferon gamma, and interleukin 6 in comparison with normal and irradiated β-glucan-treated groups. Western immunoblotting showed a significant increase in the signaling growth factors: extracellular signal-regulated kinase 1 and phosphoinositide 3-kinase proteins in a diethylnitrosamine-treated group while both preventive and therapeutic irradiated β-glucan treatments recorded significant improvement versus diethylnitrosamine group via the modulation of growth factors that encounters hepatic toxicity. The transcript levels of vascular endothelial growth factor A and inducible nitric oxide synthase genes were significantly higher in the diethylnitrosamine-treated group in comparison with controls. Preventive and therapeutic treatments with irradiated β-glucan demonstrated that the transcript level of these genes was significantly decreased which demonstrates the protective effect of β-glucan. Histological investigations revealed that diethylnitrosamine treatment affects the hepatic architecture throughout the significant severe appearance of inflammatory cell infiltration in the portal area and congestion in the portal vein in association with severe degeneration and dysplasia in hepatocytes all over hepatic

Understanding the tumor suppressor PTEN in chronic alcoholism and hepatocellular carcinoma.

PubMed

Shearn, Colin T; Petersen, Dennis R

2015-01-01

The tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a phosphatidylinositol (PtdIns) phosphatase that regulates Akt activation via PtdIns 3 kinase. Changes in PTEN expression and/or activity have been identified in a variety of chronic hepatocellular disorders including obesity, NAFLD, NASH, and alcoholism. In cancer biology, PTEN is frequently mutated or deleted in a wide variety of tumors. Mutations, decreased promoter activity, and decreased expression in PTEN are frequently identified in patients with hepatocellular carcinoma. While the majority of research on PTEN concerns obesity and NASH, PTEN clearly has a role in hepatic insulin sensitivity and in the development of steatosis during chronic alcoholism. Yet, in chronic alcoholics and HCC, very little is known concerning PTEN mutation/deletion or low PTEN expression. This review is focused on an overview of the current knowledge on molecular mechanisms of dysregulation of PTEN expression/activity in the liver and their relationship to development of ethanol-induced hepatocellular damage and cancer.

Imaging findings of mimickers of hepatocellular carcinoma

PubMed Central

Lee, Eunchae; Jang, Hyun-Jung

2015-01-01

Radiological imaging plays a crucial role in the diagnosis of hepatocellular carcinoma (HCC) as the noninvasive diagnosis of HCC in high-risk patients by typical imaging findings alone is widely adopted in major practice guidelines for HCC. While imaging techniques have markedly improved in detecting small liver lesions, they often detect incidental benign liver lesions and non-hepatocellular malignancy that can be misdiagnosed as HCC. The most common mimicker of HCC in cirrhotic liver is nontumorous arterioportal shunts that are seen as focal hypervascular liver lesions on dynamic contrast-enhanced cross-sectional imaging. Rapidly enhancing hemangiomas can be easily misdiagnosed as HCC especially on MR imaging with liver-specific contrast agent. Focal inflammatory liver lesions mimic HCC by demonstrating arterial-phase hypervascularity and subsequent washout on dynamic contrast-enhanced imaging. It is important to recognize the suggestive imaging findings for intrahepatic cholangiocarcinoma (CC) as the management of CC is largely different from that of HCC. There are other benign mimickers of HCC such as angiomyolipomas and focal nodular hyperplasia-like nodules. Recognition of their typical imaging findings can reduce false-positive HCC diagnosis. PMID:26770920

Over Expression of Long Non-Coding RNA PANDA Promotes Hepatocellular Carcinoma by Inhibiting Senescence Associated Inflammatory Factor IL8.

PubMed

Peng, Chuanhui; Hu, Wendi; Weng, Xiaoyu; Tong, Rongliang; Cheng, Shaobing; Ding, Chaofeng; Xiao, Heng; Lv, Zhen; Xie, Haiyang; Zhou, Lin; Wu, Jian; Zheng, Shusen

2017-06-23

It has been reported that long non-coding RNA PANDA was disregulated in varieties types of tumor, but its expression level and biological role in hepatocellular carcinoma (HCC) remains contradictory. We detected PANDA expression in two independent cohorts (48 HCC patients following liver transplantation and 84 HCC patients following liver resection), and found that PANDA was down-regulated in HCC. Thereafter we explored its function in cancer biology by inversing its low expression. Surprisingly, overexpression of PANDA promoted HCC proliferation and carcinogenesis in vitro and in vivo. Mechanistically, PANDA repressed transcriptional activity of senescence associated inflammatory factor IL8, which leaded to inhibition of cellular senescence. Therefore, our research help to better understand the complex role of PANDA in HCC, and suggest more thoughtful strategies should be applied before it can be treated as a potential therapeutic target.

Review of hepatocellular carcinoma: Epidemiology, etiology, and carcinogenesis

PubMed Central

Ghouri, Yezaz Ahmed; Mian, Idrees; Rowe, Julie H.

2017-01-01

Since the 1970s, the epidemic of hepatocellular carcinoma (HCC) has spread beyond the Eastern Asian predominance and has been increasing in Northern hemisphere, especially in the United States (US) and Western Europe. It occurs more commonly in males in the fourth and fifth decades of life. Among all cancers, HCC is one of the fastest growing causes of death in the US and poses a significant economic burden on healthcare. Chronic liver disease due to hepatitis B virus or hepatitis C virus and alcohol accounts for the majority of HCC cases. Incidence of nonalcoholic fatty liver disease has been on the risem and it has also been associated with the development of HCC. Its pathogenesis varies based on the underlying etiological factor although majority of cases develop in the setting of background cirrhosis. Carcinogenesis of HCC includes angiogenesis, chronic inflammation, and tumor macroenvironment and microenvironment. There is a significant role of both intrinsic genetic risk factors and extrinsic influences such as alcohol or viral infections that lead to the development of HCC. Understanding its etiopathogenesis helps select appropriate diagnostic tests and treatments. PMID:28694740

Radiofrequency ablation for hepatocellular carcinoma measuring 2 cm or smaller: results and risk factors for local recurrence.

PubMed

Kono, Masashi; Inoue, Tatsuo; Kudo, Masatoshi; Chishina, Hirokazu; Arizumi, Tadaaki; Takita, Masahiro; Kitai, Satoshi; Yada, Norihisa; Hagiwara, Satoru; Minami, Yasunori; Ueshima, Kazuomi; Nishida, Naoshi; Murakami, Takamichi

2014-01-01

The purpose of this study was to evaluate the risk factors for local recurrence with radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) measuring ≤2 cm. This study involved 234 patients with 274 HCCs measuring ≤2 cm who had undergone RFA as the initial treatment. The mean tumor diameter was 1.478 cm. The median follow-up period was 829 days. We evaluated the post-RFA cumulative local recurrence rate and analyzed the risk factors contributing to clinical outcomes. Cumulative local recurrence rates were 9, 19 and 19% at 1, 2 and 3 years, respectively. Among the 145 cases with a complete safety margin (SM) after RFA, only 4 developed local tumor recurrence and the cumulative rates of local tumor recurrence at 1, 2 and 3 years were 2, 3 and 3%, respectively. Among the 129 cases with incomplete SM, local tumor recurrence developed in 34 and the cumulative rates of local tumor progression at 1, 2 and 3 years were 14, 36 and 36%, respectively. In multivariate analysis, significant risk factors were tumor location (liver surface), irregular gross type and SM <5 mm. Even with HCC measuring ≤2 cm, location and gross type of tumor should be carefully evaluated before RFA is performed.

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.

Single-domain monoclonal antibodies for the treatment of hepatocellular carcinoma | NCI Technology Transfer Center | TTC

Cancer.gov

The National Cancer Institute seeks parties to license human monoclonal antibodies and immunoconjugates and co-develop, evaluate, and/or commercialize large-scale antibody production and hepatocellular carcinoma (HCC) xenograft mouse models.

Hepatocellular Carcinoma in Pakistan: National Trends and Global Perspective

PubMed Central

Hafeez Bhatti, Abu Bakar; Dar, Faisal Saud; Waheed, Anum; Shafique, Kashif; Sultan, Faisal; Shah, Najmul Hassan

2016-01-01

Hepatocellular carcinoma (HCC) ranks second amongst all causes of cancer deaths globally. It is on a rise in Pakistan and might represent the most common cancer in adult males. Pakistan contributes significantly to global burden of hepatitis C, which is a known risk factor for HCC, and has one of the highest prevalence rates (>3%) in the world. In the absence of a national cancer registry and screening programs, prevalence of hepatitis and HCC only represents estimates of the real magnitude of this problem. In this review, we present various aspects of HCC in Pakistan, comparing and contrasting it with the global trends in cancer care. There is a general lack of awareness regarding risk factors of HCC in Pakistani population and prevalence of hepatitis C has increased. In addition, less common risk factors are also on a rise. Majority of patients present with advanced HCC and are not eligible for definitive treatment. We have attempted to highlight issues that have a significant bearing on HCC outcome in Pakistan. A set of strategies have been put forth that can potentially help reduce incidence and improve HCC outcome on national level. PMID:26955390

DNA Alkylating Agent Protects Against Spontaneous Hepatocellular Carcinoma Regardless of O6-Methylguanine-DNA Methyltransferase Status.

PubMed

Herzig, Maryanne C S; Zavadil, Jessica A; Street, Karah; Hildreth, Kim; Drinkwater, Norman R; Reddick, Traci; Herbert, Damon C; Hanes, Martha A; McMahan, C Alex; Reddick, Robert L; Walter, Christi A

2016-03-01

Hepatocellular carcinoma is increasingly important in the United States as the incidence rate rose over the last 30 years. C3HeB/FeJ mice serve as a unique model to study hepatocellular carcinoma tumorigenesis because they mimic human hepatocellular carcinoma with delayed onset, male gender bias, approximately 50% incidence, and susceptibility to tumorigenesis is mediated through multiple genetic loci. Because a human O(6)-methylguanine-DNA methyltransferase (hMGMT) transgene reduces spontaneous tumorigenesis in this model, we hypothesized that hMGMT would also protect from methylation-induced hepatocarcinogenesis. To test this hypothesis, wild-type and hMGMT transgenic C3HeB/FeJ male mice were treated with two monofunctional alkylating agents: diethylnitrosamine (DEN; 0.025 μmol/g body weight) on day 12 of life with evaluation for glucose-6-phosphatase-deficient (G6PD) foci at 16, 24, and 32 weeks or N-methyl-N-nitrosurea (MNU; 25 mg MNU/kg body weight) once monthly for 7 months starting at 3 months of age with evaluation for liver tumors at 12 to 15 months of age. No difference in abundance or size of G6PD foci was measured with DEN treatment. In contrast, it was unexpectedly found that MNU reduces liver tumor prevalence in wild-type and hMGMT transgenic mice despite increased tumor prevalence in other tissues. hMGMT and MNU protections were additive, suggesting that MNU protects through a different mechanism, perhaps through the cytotoxic N7-alkylguanine and N3-alkyladenine lesions which have low mutagenic potential compared with O(6)-alkylguanine lesions. Together, these results suggest that targeting the repair of cytotoxic lesions may be a good preventative for patients at high risk of developing hepatocellular carcinoma. ©2015 American Association for Cancer Research.

NEIL1 protects against aflatoxin-induced hepatocellular carcinoma in mice.

PubMed

Vartanian, Vladimir; Minko, Irina G; Chawanthayatham, Supawadee; Egner, Patricia A; Lin, Ying-Chih; Earley, Lauriel F; Makar, Rosemary; Eng, Jennifer R; Camp, Matthew T; Li, Liang; Stone, Michael P; Lasarev, Michael R; Groopman, John D; Croy, Robert G; Essigmann, John M; McCullough, Amanda K; Lloyd, R Stephen

2017-04-18

Global distribution of hepatocellular carcinomas (HCCs) is dominated by its incidence in developing countries, accounting for >700,000 estimated deaths per year, with dietary exposures to aflatoxin (AFB 1 ) and subsequent DNA adduct formation being a significant driver. Genetic variants that increase individual susceptibility to AFB 1 -induced HCCs are poorly understood. Herein, it is shown that the DNA base excision repair (BER) enzyme, DNA glycosylase NEIL1, efficiently recognizes and excises the highly mutagenic imidazole ring-opened AFB 1 -deoxyguanosine adduct (AFB 1 -Fapy-dG). Consistent with this in vitro result, newborn mice injected with AFB 1 show significant increases in the levels of AFB 1 -Fapy-dG in Neil1 -/- vs. wild-type liver DNA. Further, Neil1 -/- mice are highly susceptible to AFB 1 -induced HCCs relative to WT controls, with both the frequency and average size of hepatocellular carcinomas being elevated in Neil1 -/- The magnitude of this effect in Neil1 -/- mice is greater than that previously measured in Xeroderma pigmentosum complementation group A (XPA) mice that are deficient in nucleotide excision repair (NER). Given that several human polymorphic variants of NEIL1 are catalytically inactive for their DNA glycosylase activity, these deficiencies may increase susceptibility to AFB 1 -associated HCCs.

The evolving landscape of therapeutic drug development for hepatocellular carcinoma.

PubMed

Chong, Dawn Qingqing; Tan, Iain Beehuat; Choo, Su-Pin; Toh, Han Chong

2013-11-01

Currently, only one drug, sorafenib, is FDA approved for the treatment of advanced hepatocellular carcinoma (HCC), achieving modest objective response rates while still conferring an overall survival benefit. Unlike other solid tumors, no oncogenic addiction loops have been validated as clinically actionable targets in HCC. Outcomes of HCC could potentially be improved if critical molecular subclasses with distinct therapeutic vulnerabilities can be identified, biomarkers that predict recurrence or progression early can be determined and key epigenetic, genetic or microenvironment drivers that determine best response to a specific targeting treatment can be uncovered. Our group and others have examined the molecular heterogeneity of hepatocellular carcinoma. We have developed a panel of patient derived xenograft models to enable focused pre-clinical drug development of rationally designed therapies in specific molecular subgroups. We observed unique patterns, including synergies, of drug activity across our molecularly diverse HCC xenografts, pointing to specific therapeutic vulnerabilities for individual tumors. These efforts inform clinical trial designs and catalyze therapeutic development. It also argues for efficient strategic allocation of patients into appropriate enriched clinical trials. Here, we will discuss some of the recent important therapeutic studies in advanced HCC and also some of the potential strategies to optimize clinical therapeutic development moving forward. Copyright © 2013 Elsevier Inc. All rights reserved.

Hepatitis B virus X promotes hepatocellular carcinoma development via nuclear protein 1 pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bak, Yesol; Shin, Hye-jun; Bak, In seon

Hepatocellular carcinoma (HCC) is one of the most common malignancies and chronic hepatitis B virus (HBV) infection is a major risk factor for HCC. Hepatitis B virus X (HBx) protein relates to trigger oncogenesis. HBx has oncogenic properties with a hyperproliferative response to HCC. Nuclear protein 1 (NUPR1) is a stress-response protein, frequently upregulated in several cancers. Recent data revealed that NUPR1 is involved in tumor progression, but its function in HCC is not revealed yet. Here we report HBx can induce NUPR1 in patients, mice, and HCC cell lines. In an HBx transgenic mouse model, we found that HBxmore » overexpression upregulates NUPR1 expression consistently with tumor progression. Further, in cultured HBV positive cells, HBx knockdown induces downregulation of NUPR1. Smad4 is a representative transcription factor, regulated by HBx, and we showed that HBx upregulates NUPR1 by Smad4 dependent way. We found that NUPR1 can inhibit cell death and induce vasculogenic mimicry in HCC cell lines. Moreover, NUPR1 silencing in HepG2-HBx showed reduced cell motility. These results suggest that HBx can modulate NUPR1 expression through the Smad4 pathway and NUPR1 has a role in hepatocellular carcinoma progression. - Highlights: • NUPR1 is overexpressed in HBx transgenic mouse and HCC patients. • NUPR1 inactivation hampers the HBx induced growth, VM formation, and migration of HepG2 cells in vitro. • NUPR1 has a role for survival of HCC and mechanistically NUPR1 is activated by HBx-Smad4 axis.« less

SU-E-I-91: Quantitative Assessment of Early Hepatocellular Carcinoma and Cavernous Hemangioma of Live Using In-Line Phase-Contrast X-Ray Imaging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Duan, J

Purpose: To investigate the potential utility of in-line phase-contrast imaging (ILPCI) technique with synchrotron radiation in detecting early hepatocellular carcinoma and cavernous hemangioma of live using in vitro model system. Methods: Without contrast agents, three typical early hepatocellular carcinoma specimens and three typical cavernous hemangioma of live specimens were imaged using ILPCI. To quantitatively discriminate early hepatocellular carcinoma tissues and cavernous hemangioma tissues, the projection images texture feature based on gray level co-occurrence matrix (GLCM) were extracted. The texture parameters of energy, inertia, entropy, correlation, sum average, sum entropy, difference average, difference entropy and inverse difference moment, were obtained respectively.more » Results: In the ILPCI planar images of early hepatocellular carcinoma specimens, vessel trees were clearly visualized on the micrometer scale. Obvious distortion deformation was presented, and the vessel mostly appeared as a ‘dry stick’. Liver textures appeared not regularly. In the ILPCI planar images of cavernous hemangioma of live specimens, typical vessels had not been found compared with the early hepatocellular carcinoma planar images. The planar images of cavernous hemangioma of live specimens clearly displayed the dilated hepatic sinusoids with the diameter of less than 100 microns, but all of them were overlapped with each other. The texture parameters of energy, inertia, entropy, correlation, sum average, sum entropy, and difference average, showed a statistically significant between the two types specimens image (P<0.01), except the texture parameters of difference entropy and inverse difference moment(P>0.01). Conclusion: The results indicate that there are obvious changes in morphological levels including vessel structures and liver textures. The study proves that this imaging technique has a potential value in evaluating early hepatocellular carcinoma and

Development of a novel mouse model of hepatocellular carcinoma with nonalcoholic steatohepatitis using a high-fat, choline-deficient diet and intraperitoneal injection of diethylnitrosamine.

PubMed

Kishida, Norihiro; Matsuda, Sachiko; Itano, Osamu; Shinoda, Masahiro; Kitago, Minoru; Yagi, Hiroshi; Abe, Yuta; Hibi, Taizo; Masugi, Yohei; Aiura, Koichi; Sakamoto, Michiie; Kitagawa, Yuko

2016-06-13

The incidence of hepatocellular carcinoma with nonalcoholic steatohepatitis is increasing, and its clinicopathological features are well established. Several animal models of nonalcoholic steatohepatitis have been developed to facilitate its study; however, few fully recapitulate all its clinical features, which include insulin resistance, inflammation, fibrosis, and carcinogenesis. Moreover, these models require a relatively long time to produce hepatocellular carcinoma reliably. The aim of this study was to develop a mouse model of hepatocellular carcinoma with nonalcoholic steatohepatitis that develops quickly and reflects all clinically relevant features. Three-week-old C57BL/6J male mice were fed either a standard diet (MF) or a choline-deficient, high-fat diet (HFCD). The mice in the MF + diethylnitrosamine (DEN) and HFCD + DEN groups received a one-time intraperitoneal injection of DEN at the start of the respective feeding protocols. The mice in the HFCD and HFCD + DEN groups developed obesity early in the experiment and insulin resistance after 12 weeks. Triglyceride levels peaked at 8 weeks for all four groups and decreased thereafter. Alanine aminotransferase levels increased every 4 weeks, with the HFCD and HFCD + DEN groups showing remarkably high levels; the HFCD + DEN group presented the highest incidence of nonalcoholic steatohepatitis. The levels of fibrosis and steatosis varied, but they tended to increase every 4 weeks in the HFCD and HFCD + DEN groups. Computed tomography scans indicated that all the HFCD + DEN mice developed hepatic tumors from 20 weeks, some of which were glutamine synthetase-positive. The nonalcoholic steatohepatitis-hepatocellular carcinoma model we describe here is simple to establish, results in rapid tumor formation, and recapitulates most of the key features of nonalcoholic steatohepatitis. It could therefore facilitate further studies of the development, oncogenic potential, diagnosis

Biodegradable human serum albumin nanoparticles as contrast agents for the detection of hepatocellular carcinoma by magnetic resonance imaging.

PubMed

Watcharin, Waralee; Schmithals, Christian; Pleli, Thomas; Köberle, Verena; Korkusuz, Hüdayi; Huebner, Frank; Zeuzem, Stefan; Korf, Hans W; Vogl, Thomas J; Rittmeyer, Claudia; Terfort, Andreas; Piiper, Albrecht; Gelperina, Svetlana; Kreuter, Jörg

2014-05-01

Tumor visualization by magnetic resonance imaging (MRI) and nanoparticle-based contrast agents may improve the imaging of solid tumors such as hepatocellular carcinoma (HCC). In particular, human serum albumin (HSA) nanoparticles appear to be a suitable carrier due to their safety and feasibility of functionalization. In the present study HSA nanoparticles were conjugated with gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) using carbodiimide chemistry. The nanoparticles had a uniform spherical shape and a diameter of 235±19nm. For better optical visualization in vitro and in vivo, the HSA-Gd nanoparticles were additionally labeled with rhodamine 123. As shown by confocal microscopy and flow cytometry analysis, the fluorescent nanoparticles were readily taken up by Huh-7 hepatocellular carcinoma cells. After 24h incubation in blood serum, less than 5% of the Gd(III) was released from the particles, which suggests that this nanoparticulate system may be stable in vivo and, therefore, may serve as potentially safe T1 MRI contrast agent for MRI of hepatocellular carcinoma. Copyright © 2013 Elsevier B.V. All rights reserved.

Phase II study of combination doxorubicin, interferon-alpha, and high-dose tamoxifen treatment for advanced hepatocellular carcinoma.

PubMed

Lu, Yen-Shen; Hsu, Chiun; Li, Chi-Cheng; Kuo, Sung-Hsin; Yeh, Kun-Huei; Yang, Chih-Hsin; Hsu, Chih-Hung; Wu, Chen-Yao; Cheng, Ann-Lii

2004-01-01

Our previous studies showed that high-dose tamoxifen may improve the therapeutic efficacy of doxorubicin (HTD regimen) in hepatocellular carcinoma. Interferon-alpha, either as a single-agent treatment or as a biochemical modulator, has also been reported to be effective in the treatment of hepatocellular carcinoma. In this study, we sought to clarify if the addition of Interferon-alpha2b to HTD regimen could further improve the control of advanced hepatocellular carcinoma. Eligible patients had unresectable and non-embolizable hepatocellular carcinoma, objectively measurable tumors, adequate hemogram and major organ function, age > or = 75 year, and a Karnofsky performance status > or = 60%. The treatment included oral tamoxifen 40 mg/m2, q.i.d., Day 1-7; interferon-alpha2b subcutaneous injection, 5 MU/m2, q.d. (Day 3-5) and 3 MU/m2, q.o.d. (Day 6-21); and intravenous doxorubicin 60 mg/m2, Day 4, repeated every 4 weeks. From May 1997 through July 2002, a total of 30 patients were enrolled, 25 of whom were eligible for assessment of response and toxicity. These included 20 men and 5 women, with a median age of 45 years. They received an average of 3.5 (range: 1-8) courses of chemotherapy. Grade 3-4 leukopenia and Grade 3-4 thrombocytopenia developed in 46.7% and 51.0% of treatment courses, respectively. Gastrointestinal toxicity was generally mild. One patient achieved a complete remission and remained disease-free at this report, with a progression-free survival of 49 months at last follow-up in September 2002. Five patients achieved a partial remission, with a median progression-free survival of 7 months. The total response rate was 24% (95% confidence interval 9.4-45.1%). Median survival for all 25 patients was 6.0 months and the 1-year survival rate was 16%. Combination of interferon-alpha2b, high-dose tamoxifen, and doxorubicin is an effective treatment for advanced hepatocellular carcinoma. However, the data does not support that addition of interferon-alpha2b

Targeting survivin with prodigiosin isolated from cell wall of Serratia marcescens induces apoptosis in hepatocellular carcinoma cells.

PubMed

Yenkejeh, R A; Sam, M R; Esmaeillou, M

2017-04-01

Abnormal activation of the Wnt/β-catenin signaling pathway increases survivin expression that is involved in hepatocarcinogenesis. Therefore, downregulation of survivin may provide an attractive strategy for treatment of hepatocellular carcinoma. In this regard, little is known about the anticancer effects of prodigiosin isolated from cell wall of Serratia marcescens on the survivin expression and induction of apoptosis in hepatocellular carcinoma cells. Human hepatocellular carcinoma (HepG2) cells were treated with 100-, 200-, 400-, and 600-nM prodigiosin after which morphology of cells, cell number, growth inhibition, survivin expression, caspase-3 activation, and apoptotic rate were evaluated by inverted microscope, hemocytometer, MTT assay, RT-PCR, fluorometric immunosorbent enzyme assay, and flow cytometric analysis, respectively. Prodigiosin changed morphology of cells to apoptotic forms and disrupted cell connections. This compound significantly increased growth inhibition rate and decreased metabolic activity of HepG2 cells in a dose- and time-dependent manner. After 24-, 48-, and 72-h treatments with prodigiosin at concentrations ranging from 100 nM to 600 nM, growth inhibition rates were measured to be 1.5-10%, 24-47.5%, and 55.5-72.5%, respectively, compared to untreated cells. At the same conditions, metabolic activities were measured to be 91-83%, 74-53%, and 47-31% for indicated concentrations of prodigiosin, respectively, compared to untreated cells. We also found that treatment of HepG2 cells for 48 h decreased significantly cell number and survivin expression and increased caspase-3 activation in a dose-dependent manner. Specifically, treatment with 600-nM prodigiosin resulted in 77% decrease in cell number, 88.5% decrease in survivin messenger RNA level, and 330% increase in caspase-3 activation level compared to untreated cells. An increase in the number of apoptotic cells (late apoptosis) ranging from 36.9% to 97.4% was observed with increasing

[Changes of metastatic potential of residual hepatocellular carcinoma in nude mice after in vivo chemotherapy and the corresponding mechanisms].

PubMed

Xiong, Wei; Tang, Zhao-you; Ren, Zheng-gang; Zhu, Xiao-dong; Liu, Liang; Zhang, Wei; Wang, Wen-quan

2012-11-01

To explore the changes of metastatic potential of residual hepatocellular carcinoma (HCC) after in vivo chemotherapy and its mechanism. Nude mouse models of orthotopic HCC in the nude mouse livers was established using human hepatocellular carcinoma cell line MHCC97L cells. Oxaliplatin (10 mg/kg, once per week) was administered intraperitoneally (i.p.) to mice in the trial group. Mice in the control group received 0.2 ml of 0.9% sodium chloride on the same days. On day 7 after the third injection, all mice were sacrificed and tumor fragments of equal volume (2 mm×2 mm×2 mm) from each mouse of the oxaliplatin-treated and untreated groups were reinoculated into the livers of each new recipient mouse correspondingly. The growth, metastasis and molecular phenotype of the reinoculated tumors in both groups were determined. In the new recipient mice, compared with untreated tumors, oxaliplatin pre-treated tumors grew significantly slower [(2624.59 ± 491.60) mm(3) vs. (3849.72 ± 827.09) mm(3), P < 0.001], but gave more spontaneous metastasis to the lung (10/12 vs. 3/12, P = 0.012). A decreased expression of E-cadherin and increased expression of N-cadherin, vimentin and transcription factor Snail were detected in the oxaliplatin pre-treated tumors by immunohistochemistry, which provided the evidence of epithelial mesenchymal transition (EMT) in these tumors. Residual hepatocellular carcinomas after in vivo chemotherapy grow slower but gain enhanced metastatic potential to the lung, associated with epithelial mesenchymal transition.

Hepatocellular Carcinoma: Molecular Biology and Therapy

PubMed Central

Abou-Alfa, Ghassan

2007-01-01

Advanced and metastatic hepatocellular carcinomas (HCC) are challenging to treat, and no cytotoxic agents have impacted survival. The underlying liver cirrhosis that commonly accompanies HCC provides an additional challenge; indeed, functional scoring of cirrhosis and HCC is a critical component of patient evaluation. Currently, the molecular biology and pathogenesis of HCC are being increasingly investigated, which may lead to better understanding of the evolution of the disease, especially differing etiologies and identification of survival genes that may affect outcome. Early studies of targeted therapies in HCC have shown disease stabilization, and an increased understanding of the mechanism(s) of these novel agents combined with correlative studies may lead to the identification of an active agent or combination of agents that impacts the natural history of HCC. PMID:17178294

Bone metastases as initial presentation of hepatocellular carcinoma.

PubMed

Monteserin, Luzdivina; Mesa, Alicia; Fernandez-Garcia, Maria Soledad; Gadanon-Garcia, Arantza; Rodriguez, Manuel; Varela, María

2017-10-18

Extra-hepatic spread is present in 5% to 15% of patients with hepatocellular carcinoma (HCC) at the time of diagnosis. The most frequent sites are lung and regional lymph nodes. Here, we report 3 cases of unsuspected HCC with symptoms due to bone lesions as initial presentation. Morphological characteristics and immunohistochemistry from the examined bone were the key data for diagnosis. None of the patients had an already known chronic liver disease. Differential diagnoses with HCC upon ectopic liver disease or hepatoid adenocarcinoma were shown. Therapy with the orally active multikinase inhibitor sorafenib plus symptomatic treatment was indicated.

Evaluation of the antitumor activity of platinum nanoparticles in the treatment of hepatocellular carcinoma induced in rats.

PubMed

Medhat, Amina; Mansour, Somaya; El-Sonbaty, Sawsan; Kandil, Eman; Mahmoud, Mustafa

2017-07-01

This study aimed to evaluate the antitumor activity of platinum nanoparticles compared with cis-platin both in vitro and in vivo in the treatment of hepatocellular carcinoma induced in rats. The treatment efficacy of platinum nanoparticles was evaluated by measuring antioxidant activities against oxidative stress caused by diethylnitrosamine in liver tissue. The measurements included reduced glutathione content and superoxide dismutase activity, as well as malondialdehyde level. Liver function tests were also determined, in addition to the evaluation of serum alpha-fetoprotein, caspase-3, and cytochrome c in liver tissue. Total RNA extraction from liver tissue samples was also done for the relative quantification of B-cell lymphoma 2, matrix metallopeptidase 9, and tumor protein p53 genes. Histopathological examination was also performed for liver tissue. Results showed that platinum nanoparticles are more potent than cis-platin in treatment of hepatocellular carcinoma induced by diethylnitrosamine in rats as it ameliorated the investigated parameters toward normal control animals. These findings were well appreciated with histopathological studies of diethylnitrosamine group treated with platinum nanoparticles, suggesting that platinum nanoparticles can serve as a good therapeutic agent for the treatment of hepatocellular carcinoma which should attract further studies.

New advances in hepatocellular carcinoma

PubMed Central

Pascual, Sonia; Herrera, Iván; Irurzun, Javier

2016-01-01

Hepatocellular carcinoma (HCC) is the leading cause of deaths in cirrhotic patients and the third cause of cancer related deaths. Most HCC are associated with well known underlying risk factors, in fact, HCC arise in cirrhotic patients in up to 90% of cases, mainly due to chronic viral hepatitis and alcohol abuse. The worldwide prevention strategies are conducted to avoid the infection of new subjects and to minimize the risk of liver disease progression in infected patients. HCC is a condition which lends itself to surveillance as at-risk individuals can readily be identified. The American and European guidelines recommended implementation of surveillance programs with ultrasound every six months in patient at-risk for developing HCC. The diagnosis of HCC can be based on non-invasive criteria (only in cirrhotic patient) or pathology. Accurately staging patients is essential to oncology practice. The ideal tumour staging system in HCC needs to account for both tumour characteristics and liver function. Treatment allocation is based on several factors: Liver function, size and number of tumours, macrovascular invasion or extrahepatic spread. The recommendations in terms of selection for different treatment strategies must be based on evidence-based data. Resection, liver transplant and interventional radiology treatment are mainstays of HCC therapy and achieve the best outcomes in well-selected candidates. Chemoembolization is the most widely used treatment for unresectable HCC or progression after curative treatment. Finally, in patients with advanced HCC with preserved liver function, sorafenib is the only approved systemic drug that has demonstrated a survival benefit and is the standard of care in this group of patients. PMID:27028578

Nonlinear tumor evolution from dysplastic nodules to hepatocellular carcinoma.

PubMed

Joung, Je-Gun; Ha, Sang Yun; Bae, Joon Seol; Nam, Jae-Yong; Gwak, Geum-Youn; Lee, Hae-Ock; Son, Dae-Soon; Park, Cheol-Keun; Park, Woong-Yang

2017-01-10

Dysplastic nodules are premalignant neoplastic nodules found in explanted livers with cirrhosis. Genetic signatures of premalignant dysplastic nodules (DNs) with concurrent hepatocellular carcinoma (HCC) may provide an insight in the molecular evolution of hepatocellular carcinogenesis. We analyzed four patients with multifocal nodular lesions and cirrhotic background by whole-exome sequencing (WES). The genomic profiles of somatic single nucleotide variations (SNV) and copy number variations (CNV) in DNs were compared to those of HCCs. The number and variant allele frequency of somatic SNVs of DNs and HCCs in each patient was identical along the progression of pathological grade. The somatic SNVs in DNs showed little conservation in HCC. Additionally, CNVs showed no conservation. Phylogenetic analysis based on SNVs and copy number profiles indicated a nonlinear segregation pattern, implying independent development of DNs and HCC in each patient. Thus, somatic mutations in DNs may be developed separately from other malignant nodules in the same liver, suggesting a nonlinear model for hepatocarcinogenesis from DNs to HCC.

Damnacanthal, a noni anthraquinone, inhibits c-Met and is a potent antitumor compound against Hep G2 human hepatocellular carcinoma cells.

PubMed

García-Vilas, Javier A; Quesada, Ana R; Medina, Miguel A

2015-01-26

Damnacanthal, an anthraquinone present in noni plants, targets several tyrosine kinases and has antitumoral effects. This study aims at getting additional insight on the potential of damnacanthal as a natural antitumor compound. The direct effect of damnacanthal on c-Met was tested by in vitro activity assays. Additionally, Western blots of c-Met phosphorylation in human hepatocellular carcinoma Hep G2 cells were performed. The antitumor effects of damnacanthal were tested by using cell growth, soft agar clonogenic, migration and invasion assays. Their mechanisms were studied by Western blot, and cell cycle, apoptosis and zymographic assays. Results show that damnacanthal targets c-Met both in vitro and in cell culture. On the other hand, damnacanthal also decreases the phosphorylation levels of Akt and targets matrix metalloproteinase-2 secretion in Hep G2 cells. These molecular effects are accompanied by inhibition of the growth and clonogenic potential of Hep G2 hepatocellular carcinoma cells, as well as induction of Hep G2 apoptosis. Since c-Met has been identified as a new potential therapeutical target for personalized treatment of hepatocellular carcinoma, damnacanthal and noni extract supplements containing it could be potentially interesting for the treatment and/or chemoprevention of hepatocellular carcinoma through its inhibitory effects on the HGF/c-Met axis.

Systematic review of guidelines for management of intermediate hepatocellular carcinoma using the Appraisal of Guidelines Research and Evaluation II instrument.

PubMed

Holvoet, Tom; Raevens, Sarah; Vandewynckel, Yves-Paul; Van Biesen, Wim; Geboes, Karen; Van Vlierberghe, Hans

2015-10-01

Hepatocellular carcinoma is the second leading cause of cancer-related mortality worldwide. Multiple guidelines have been developed to assist clinicians in its management. We aimed to explore methodological quality of these guidelines focusing on treatment of intermediate hepatocellular carcinoma by transarterial chemoembolization. A systematic search was performed for Clinical Practice Guidelines and Consensus statements for hepatocellular carcinoma management. Guideline quality was appraised using the Appraisal of Guidelines Research and Evaluation II instrument, which rates guideline development processes across 6 domains: 'Scope and purpose', 'Stakeholder involvement', 'Rigour of development', 'Clarity of presentation', 'Applicability' and 'Editorial independence'. Thematic analysis of guidelines was performed to map differences in recommendations. Quality of 21 included guidelines varied widely, but was overall poor with only one guideline passing the 50% mark on all domains. Key recommendations as (contra)indications and technical aspects were inconsistent between guidelines. Aspects on side effects and health economics were mainly neglected. Methodological quality of guidelines on transarterial chemoembolization in hepatocellular carcinoma management is poor. This results in important discrepancies between guideline recommendations, creating confusion in clinical practice. Incorporation of the Appraisal of Guidelines Research and Evaluation II instrument in guideline development may improve quality of future guidelines by increasing focus on methodological aspects. Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

[Radiofrequency ablation of hepatocellular carcinoma].

PubMed

Widmann, Gerlig; Schullian, Peter; Bale, Reto

2013-03-01

Percutaneous radiofrequency ablation (RFA) is well established in the treatment of hepatocellular carcinoma (HCC). Due to its curative potential, it is the method of choice for non resectable BCLC (Barcelona Liver Clinic) 0 and A. RFA challenges surgical resection for small HCC and is the method of choice in bridging for transplantation and recurrence after resection or transplantation. The technical feasibility of RFA depends on the size and location of the HCC and the availability of ablation techniques (one needle techniques, multi-needle techniques). More recently, stereotactic multi-needle techniques with 3D trajectory planning and guided needle placement substantially improve the spectrum of treatable lesions including large volume tumors. Treatment success depends on the realization of ablations with large intentional margins of tumor free tissue (A0 ablation in analogy to R0 resection), which has to be documented by fusion of post- with pre-ablation images, and confirmed during follow-up imaging.

Novel drugs in clinical development for hepatocellular carcinoma.

PubMed

Waidmann, Oliver; Trojan, Jörg

2015-01-01

Sorafenib is the only systemic drug approved for the treatment of advanced hepatocellular carcinoma (HCC). Within recent years, several investigational agents mainly targeting angiogenesis failed in late-phase clinical development either due to toxicity or lack of benefit. This review covers recent clinical data on systemic agents and ongoing trials in patients with advanced HCC. In unselected patients with advanced HCC, disappointing results have been reported from several large trials. However, in two subgroups encouraging results have been achieved. Treatment with the MET inhibitor tivantinib resulted in a substantial survival benefit in the subgroup of MET overexpressing tumors in a randomized Phase II trial. Furthermore, the vascular endothelial growth factor receptor 2 antibody ramucirumab resulted in improved overall survival in patients with baseline α-fetoprotein (AFP) ≥ 400 ng/ml in a Phase III trial. These two agents, and several others, will be further developed in HCC. Moreover, immunotherapeutics such as checkpoint inhibitors, programmed death receptor-1 blocking antibodies and oncolytic viruses are under investigation in advanced HCC.

The evaluation of p,p'-DDT exposure on cell adhesion of hepatocellular carcinoma.

PubMed

Jin, Xiaoting; Chen, Meilan; Song, Li; Li, Hanqing; Li, Zhuoyu

2014-08-01

Many studies have found a positive association between the progression of hepatocellular carcinoma and DDT exposure. These studies mainly focus on the effect of DDT exposure on cell proliferation and epithelial to mesenchymal transition (EMT) promotion. However, the influence of DDT on cell adhesion of hepatocellular carcinoma remains to be unclear. The aim of our study was to determine the effect of p,p'-DDT on cell adhesion of hepatocellular carcinoma in vitro and in vivo. The data showed that p,p'-DDT, exposing HepG2 cells for 6 days, decreased cell-cell adhesion and elevated cell-matrix adhesion. Strikingly, p,p'-DDT increased reactive oxygen species (ROS) content, and this was accompanied by the activation of JAK/STAT3 pathway. Moreover, ROS inhibitor supplement reversed these effects significantly. However, the addition of ER inhibitor, ICI, had no effect on the p,p'-DDT-induced effects. p,p'-DDT altered the mRNA levels of related adhesion molecules, including inhibition of E-cadherin and promotion of N-cadherin along with CD29. Interestingly, the p,p'-DDT-altered adhesion molecules could be reversed with JAK inhibitor or STAT3 inhibitor. Likewise, p,p'-DDT stimulated the JAK/STAT3 pathway in nude mice, as well as altered the mRNA levels of E-cadherin, N-cadherin, and CD29. Taken together, these results indicate that p,p'-DDT profoundly promotes the adhesion process by decreasing cell-cell adhesion and inducing cell-matrix adhesion via the ROS-mediated JAK/STAT3 pathway. All these events account for the carcinogenic potential of p,p'-DDT in liver. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Outcome of ABO-incompatible adult living-donor liver transplantation for patients with hepatocellular carcinoma.

PubMed

Yoon, Young-In; Song, Gi-Won; Lee, Sung-Gyu; Hwang, Shin; Kim, Ki-Hun; Kim, Seok-Hwan; Kang, Woo-Hyoung; Cho, Hwui-Dong; Jwa, Eun-Kyoung; Kwon, Jae-Hyun; Tak, Eun-Young; Kirchner, Varvara A

2018-06-01

Living-donor liver transplantation (LDLT) can simultaneously cure hepatocellular carcinoma (HCC) and underlying liver cirrhosis, improving long-term results in patients with HCC. ABO-incompatible LDLT could expand the living-donor pool, reduce waiting times for deceased-donor liver transplantation, and improve long-term survival for some patients with HCC. We retrospectively reviewed the medical records of patients undergoing LDLT for HCC from November 2008 to December 2015 at a single institution in Korea. In total, 165 patients underwent ABO-incompatible and 753 patients underwent ABO-compatible LDLT for HCC. ABO-incompatible recipients underwent desensitization to overcome the ABO blood group barrier, including pretransplant plasma exchange and rituximab administration (300-375 mg/m 2 /body surface area). We performed 1:1 propensity score matching and included 165 patients in each group. 82.4% of ABO-incompatible and 83.0% of -compatible LDLT groups had HCC within conventional Milan criteria, respectively, and 92.1% and 92.7% of patients in each group had a Child-Pugh score of A or B. ABO-incompatible and -compatible LDLT groups were followed up for 48.0 and 48.7 months, respectively, with both groups showing comparable recurrence-free survival rates (hazard ratio [HR] 1.14; 95% CI 0.68-1.90; p = 0.630) and overall patient-survival outcomes (HR 1.10; 95% CI 0.60-2.00; p = 0.763). These findings suggested that ABO-incompatible liver transplantation is a feasible option for patients with HCC, especially for those with compensated cirrhosis with HCC within conventional Milan criteria. Despite hypothetical immunological concerns that the desensitization protocol for breaking through the ABO blood group barrier might have a negative impact on the recurrence of hepatocellular carcinoma, our experience demonstrated no significant differences in the long-term overall survival and recurrence-free survival rates between patients receiving ABO-compatible or ABO

Expression of connective tissue growth factor in the livers of non-viral hepatocellular carcinoma patients with metabolic risk factors.

PubMed

Akahoshi, Keiichi; Tanaka, Shinji; Mogushi, Kaoru; Shimada, Shu; Matsumura, Satoshi; Akiyama, Yoshimitsu; Aihara, Arihiro; Mitsunori, Yusuke; Ban, Daisuke; Ochiai, Takanori; Kudo, Atsushi; Arii, Shigeki; Tanabe, Minoru

2016-09-01

The incidence of hepatocellular carcinoma (HCC) associated with metabolic risk factors, such as diabetes and obesity, has been increasing. However, the underlying mechanism that links these diseases remains unclear. We performed genome-wide expression analysis of human liver tissues of non-viral HCC patients with or without metabolic risk factors. The upregulated genes that associated with diabetes and obesity were investigated by in vitro and in vivo experiments, and immunohistochemistry of human liver tissues was performed. Among the upregulated genes, connective tissue growth factor (CTGF) expression was induced to a greater extent by combined glucose and insulin administration to human hepatoma cells. Genome-wide expression analysis revealed upregulation of a chemokine network in CTGF-overexpressing hepatoma cells, which displayed an increased ability to induce in vitro activation of macrophages, and in vivo infiltration of liver macrophages. Immunohistochemistry of human liver tissues validated the correlations between CTGF expression and diabetes or obesity as well as activation of liver macrophages in patients with non-viral HCC. Recurrence-free survival was significantly poorer in the CTGF-positive patients compared with the CTGF-negative patients (p = 0.002). Multivariate analysis determined that CTGF expression (HR 2.361; 95 % CI 1.195-4.665; p = 0.013) and vascular invasion (HR 2.367; 95 % CI 1.270-4.410; p = 0.007) were independent prognostic factors for recurrence of non-viral HCC. Our data suggest that CTGF could be involved in oncogenic pathways promoting non-viral HCC associated with metabolic risk factors via induction of liver inflammation and is expected to be a novel HCC risk biomarker and potential therapeutic target.

High expression of forkhead box protein C2 is associated with aggressive phenotypes and poor prognosis in clinical hepatocellular carcinoma.

PubMed

Shimoda, Yuki; Ubukata, Yasunari; Handa, Tadashi; Yokobori, Takehiko; Watanabe, Takayoshi; Gantumur, Dolgormaa; Hagiwara, Kei; Yamanaka, Takahiro; Tsukagoshi, Mariko; Igarashi, Takamichi; Watanabe, Akira; Kubo, Norio; Araki, Kenichiro; Harimoto, Norifumi; Katayama, Ayaka; Hikino, Toshiaki; Sano, Takaaki; Ogata, Kyoichi; Kuwano, Hiroyuki; Shirabe, Ken; Oyama, Tetsunari

2018-05-25

Hepatocellular carcinoma (HCC) is one of the major causes of tumor death; thus, the identification of markers related to its diagnosis and prognosis is critical. Previous studies have revealed that epithelial-to-mesenchymal transition (EMT) is involved in tumor invasion and metastasis, and the forkhead box protein C2 (FOXC2) has been shown to promote tumor cell proliferation, invasion, and EMT. In the present study, we examined the clinicopathological significance of FOXC2 and EMT-related markers in clinical HCC specimens and identified factors related to the diagnosis and prognosis of HCC. The expression of FOXC2 and EMT-related markers was evaluated by immunohistochemistry in 84 cases of hepatocellular carcinoma. A high expression of FOXC2 was observed in 26 of 84 cases, and expression was significantly correlated with background liver cirrhosis, poor tumor differentiation, high serum AFP, and elevated cell proliferation markers. In addition, this high expression was related to the induction of the Cadherin switch and vimentin expression and was an independent predictor for poor prognosis. The high expression of FOXC2 in HCC is correlated with tumor malignancy and poor prognosis, suggesting that FOXC2 may be an important prognostic factor for HCC.

NFκB1 is a suppressor of neutrophil-driven hepatocellular carcinoma

NASA Astrophysics Data System (ADS)

Wilson, C. L.; Jurk, D.; Fullard, N.; Banks, P.; Page, A.; Luli, S.; Elsharkawy, A. M.; Gieling, R. G.; Chakraborty, J. Bagchi; Fox, C.; Richardson, C.; Callaghan, K.; Blair, G. E.; Fox, N.; Lagnado, A.; Passos, J. F.; Moore, A. J.; Smith, G. R.; Tiniakos, D. G.; Mann, J.; Oakley, F.; Mann, D. A.

2015-04-01

Hepatocellular carcinoma (HCC) develops on the background of chronic hepatitis. Leukocytes found within the HCC microenvironment are implicated as regulators of tumour growth. We show that diethylnitrosamine (DEN)-induced murine HCC is attenuated by antibody-mediated depletion of hepatic neutrophils, the latter stimulating hepatocellular ROS and telomere DNA damage. We additionally report a previously unappreciated tumour suppressor function for hepatocellular nfkb1 operating via p50:p50 dimers and the co-repressor HDAC1. These anti-inflammatory proteins combine to transcriptionally repress hepatic expression of a S100A8/9, CXCL1 and CXCL2 neutrophil chemokine network. Loss of nfkb1 promotes ageing-associated chronic liver disease (CLD), characterized by steatosis, neutrophillia, fibrosis, hepatocyte telomere damage and HCC. Nfkb1S340A/S340Amice carrying a mutation designed to selectively disrupt p50:p50:HDAC1 complexes are more susceptible to HCC; by contrast, mice lacking S100A9 express reduced neutrophil chemokines and are protected from HCC. Inhibiting neutrophil accumulation in CLD or targeting their tumour-promoting activities may offer therapeutic opportunities in HCC.

Pain Palliation by Percutaneous Acetabular Osteoplasty for Metastatic Hepatocellular Carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hokotate, Hirofumi; Baba, Yasutaka; Churei, Hisahiko

2001-09-15

A 68-year-old man with hepatocellular carcinoma and known skeletal metastasis developed right hip pain and gait disturbance due to an osteolytic metastasis in the right acetabulum. This was treated initially with chemoembolization and radiation therapy. When these procedures proved unsuccessful percutaneous injection of acrylic bone cement into the acetabulum was undertaken. Immediately after this procedure, he obtained sufficient pain relief and improved walking ability, which continued for 3 months until he died of hepatic insufficiency.

Hypoxia induces copper stable isotope fractionation in hepatocellular carcinoma, in a HIF-independent manner.

PubMed

Bondanese, Victor P; Lamboux, Aline; Simon, Melanie; Lafont, Jérôme E; Albalat, Emmanuelle; Pichat, Sylvain; Vanacker, Jean-Marc; Telouk, Philippe; Balter, Vincent; Oger, Philippe; Albarède, Francis

2016-11-09

Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer, with increasing incidence worldwide. The unrestrained proliferation of tumour cells leads to tumour hypoxia which in turn promotes cancer aggressiveness. While changes in the concentration of copper (Cu) have long been observed upon cancerization, we have recently reported that the isotopic composition of copper is also altered in several types of cancer. In particular, we showed that in hepatocellular carcinoma, tumour tissue contains heavier copper compared to the surrounding parenchyma. However, the reasons behind such isotopic signature remained elusive. Here we show that hypoxia causes heavy copper enrichment in several human cell lines. We also demonstrate that this effect of hypoxia is pH, HIF-1 and -2 independent. Our data identify a previously unrecognized cellular process associated with hypoxia, and suggests that in vivo tumour hypoxia determines copper isotope fractionation in HCC and other solid cancers.

Synergistic anticancer effects of curcumin and resveratrol in Hepa1-6 hepatocellular carcinoma cells.

PubMed

Du, Qin; Hu, Bing; An, Hong-Mei; Shen, Ke-Ping; Xu, Ling; Deng, Shan; Wei, Meng-Meng

2013-05-01

Hepatocellular carcinoma remains one of the most prevalent malignancies worldwide. Curcuma aromatica and Polygonum cuspidatum are one of the commonly used paired-herbs for liver cancer treatment. Curcumin and resveratrol are the major anticancer constituents of Curcuma aromatica and Polygonum cuspidatum, respectively. Curcumin and resveratrol have been found to exhibit a synergistic anticancer effect in colon cancer. However, the combined effect of curcumin and resveratrol against hepatocellular carcinoma remains unknown. In the present study, we evaluated the combined effects of curcumin and resveratrol in hepatocellular carcinoma Hepa1-6 cells. The results showed that curcumin and resveratrol significantly inhibited the proliferation of Hepa1-6 cells in a dose- and time-dependent manner. The combination treatment of curcumin and resveratrol elicited a synergistic antiproliferative effect in Hepa1-6 cells. The apoptosis of Hepa1-6 cells induced by the combination treatment with curcumin and resveratrol was accompanied by caspase-3, -8 and -9 activation, which was completely abrogated by a pan caspase inhibitor, Z-VAD-FMK. Combination of curcumin and resveratrol upregulated intracellular reactive oxygen species (ROS) levels in Hepa1-6 cells. The ROS scavenger, NAC, partially attenuated the apoptosis and caspase activation induced by the combination treatment of curcumin and resveratrol. In addition, the combination of curcumin and resveratrol downregulated XIAP and survivin expression. These data suggest that the combination treatment of curcumin and resveratrol is a promising novel anticancer strategy for liver cancer. The present study also provides new insights into the effective mechanism of paired-herbs in traditional Chinese medicine.

Hepatic arterial infusion of oxaliplatin plus fluorouracil/leucovorin vs. sorafenib for advanced hepatocellular carcinoma.

PubMed

Lyu, Ning; Kong, Yanan; Mu, Luwen; Lin, Youen; Li, Jibin; Liu, Yaru; Zhang, Zhenfeng; Zheng, Lie; Deng, Haijing; Li, Shaolong; Xie, Qiankun; Guo, Rongping; Shi, Ming; Xu, Li; Cai, Xiuyu; Wu, Peihong; Zhao, Ming

2018-07-01

To compare the overall survival (OS) and disease progression free survival (PFS) in patients with advanced hepatocellular carcinoma (Ad-HCC) who are undergoing hepatic arterial infusion (HAI) of oxaliplatin, fluorouracil/leucovorin (FOLFOX) treatment vs. sorafenib. This retrospective study was approved by the ethical review committee, and informed consent was obtained from all patients before treatment. HAI of FOLFOX (HAIF) was recommended as an alternative treatment option for patients who refused sorafenib. Of the 412 patients with Ad-HCC (376 men and 36 women) between Jan 2012 to Dec 2015, 232 patients were treated with sorafenib; 180 patients were given HAIF therapy. The median age was 51 years (range, 16-82 years). Propensity-score matched estimates were used to reduce bias when evaluating survival. Survival curves were calculated by performing the Kaplan-Meier method and compared by using the log-rank test and Cox regression models. The median PFS and OS in the HAIF group were significantly longer than those in the sorafenib group (PFS 7.1 vs. 3.3 months [RECIST]/7.4 vs. 3.6 months [mRECIST], respectively; OS 14.5 vs. 7.0 months; p <0.001 for each). In the propensity-score matched cohorts (147 pairs), both PFS and OS in the HAIF group were longer than those in the sorafenib group (p <0.001). At multivariate analysis, HAIF treatment was an independent factor for PFS (hazard ratio [HR] 0.389 [RECIST]/0.402 [mRECIST]; p <0.001 for each) and OS (HR 0.129; p <0.001). HAIF therapy may improve survival compared to sorafenib in patients with Ad-HCC. A prospective randomized trial is ongoing to confirm this finding. We compared the hepatic arterial infusion of FOLFOX (a combination chemotherapy) with sorafenib (a tyrosine kinase inhibitor) in patients with advanced hepatocellular carcinoma, retrospectively. It was found that hepatic arterial infusion of FOLFOX therapy may improve both progression free and overall survival in patients with advanced

Safety validation of decision trees for hepatocellular carcinoma.

PubMed

Wang, Xian-Qiang; Liu, Zhe; Lv, Wen-Ping; Luo, Ying; Yang, Guang-Yun; Li, Chong-Hui; Meng, Xiang-Fei; Liu, Yang; Xu, Ke-Sen; Dong, Jia-Hong

2015-08-21

To evaluate a different decision tree for safe liver resection and verify its efficiency. A total of 2457 patients underwent hepatic resection between January 2004 and December 2010 at the Chinese PLA General Hospital, and 634 hepatocellular carcinoma (HCC) patients were eligible for the final analyses. Post-hepatectomy liver failure (PHLF) was identified by the association of prothrombin time < 50% and serum bilirubin > 50 μmol/L (the "50-50" criteria), which were assessed at day 5 postoperatively or later. The Swiss-Clavien decision tree, Tokyo University-Makuuchi decision tree, and Chinese consensus decision tree were adopted to divide patients into two groups based on those decision trees in sequence, and the PHLF rates were recorded. The overall mortality and PHLF rate were 0.16% and 3.0%. A total of 19 patients experienced PHLF. The numbers of patients to whom the Swiss-Clavien, Tokyo University-Makuuchi, and Chinese consensus decision trees were applied were 581, 573, and 622, and the PHLF rates were 2.75%, 2.62%, and 2.73%, respectively. Significantly more cases satisfied the Chinese consensus decision tree than the Swiss-Clavien decision tree and Tokyo University-Makuuchi decision tree (P < 0.01，P < 0.01); nevertheless, the latter two shared no difference (P = 0.147). The PHLF rate exhibited no significant difference with respect to the three decision trees. The Chinese consensus decision tree expands the indications for hepatic resection for HCC patients and does not increase the PHLF rate compared to the Swiss-Clavien and Tokyo University-Makuuchi decision trees. It would be a safe and effective algorithm for hepatectomy in patients with hepatocellular carcinoma.

The FIB-4 score predicts postoperative short-term outcomes of hepatocellular carcinoma fulfilling the milan criteria.

PubMed

Dong, J; Xu, X-h; Ke, M-y; Xiang, J-x; Liu, W-y; Liu, X-m; Wang, B; Zhang, X-f; Lv, Y

2016-05-01

The fibrosis score 4 (FIB-4) score is a useful tool to determine the degree of hepatic fibrosis. Liver fibrosis and cirrhosis are well-known predictors of postoperative complications after hepatectomy. This study examined the impact of FIB-4 on postoperative short-term outcomes of patients with hepatocellular carcinoma (HCC). Three hundred and fifty patients undergoing hepatectomy for HCC between 2008 and 2013 were enrolled. The receiver operating characteristic (ROC) curve analysis was performed to determine the cutoff value of the FIB-4. Univariate and multivariate analysis was performed to identify the risk factors. The correlation of the preoperative FIB-4 value with clinicopathological parameters was examined. Postoperative complications were observed in 202 (57.7%) patients. The optimal cutoff value of the FIB-4 was set at 2.88 and 3.85 for postoperative complications and intraoperative blood loss respectively. It was also an independent prognostic factor for postoperative complications (hazard ratio [HR], 1.202; 95% CI, 1.076-1.344; P = 0.001) and intraoperative blood loss (HR, 1.196; 95% CI, 1.091-1.343; P < 0.001) by multivariate analysis. The FIB-4 was significantly correlated with age, liver function, coagulation function, blood loss, intraoperative blood transfusion (all P < 0.05). Preoperative FIB-4 is a useful index to predict postoperative outcomes in patients with HCC. The FIB-4 should be assessed routinely for hepatocellular carcinoma patients. Copyright © 2016 Elsevier Ltd. All rights reserved.

Hepatocellular carcinoma presenting as uterine metastasis.

PubMed

Kang, Woo Dae; Kim, Cheol Hong; Cho, Moon Kyung; Kim, Jong Woon; Lee, Ji Shin; Kim, Yoon Ha; Choi, Ho Sun; Kim, Seok Mo

2008-09-01

Metastatic extragenital cancer that spreads to the uterus is rare. When it occurs, the extragenital primary disease is often in the breast or gastrointestinal tract. We report here on a case of hepatocellular carcinoma (HCC) that metastasis to the uterus. The patient was admitted for evaluation of a pelvic mass. The serum alpha-fetoprotein level was highly elevated. Magnetic resonance imaging of the abdomen and pelvis showed hepatic and uterine masses. The patient underwent surgical treatment. The histopathologic findings and immunohistochemical staining results of the uterine mass were characteristics of metastatic HCC. The endometrium and both ovaries were free of tumor. Up to now, there have been only two cases of uterine metastasis from HCC reported in the English literature. This case is the first documented instance of a metastatic uterine tumor from HCC that spared both ovaries.

[The Development of Hepatocellular Carcinoma in Non-alcoholic Fatty Liver Disease].

PubMed

Kwon, Oh Sang; Kim, Joon Hwan; Kim, Ju Hyun

2017-06-25

Non-alcoholic fatty liver disease (NAFLD) may be one of the important causes of cryptogenic hepatocellular carcinoma (HCC). NAFLD-related HCCs (NAFLD-HCCs) have the following clinical features: high body mass index, deranged lipid profiles, diabetes mellitus, hypertension, and metabolic syndrome. Among them, obesity, diabetes mellitus, and high Fe contents in the liver are risk factors of developing HCC in patients with NAFLD. Inflammatory cytokines, adipokines, insulin like growth factor-I, and lipotoxicity are intermingled and may cross react with each other to develop HCC. Because there is no guideline for early detection of HCC in patients with NAFLD, NAFLD-HCCs tend to be greater in size and in advanced stages when detected compared with hepatitis virus-related HCCs. Therefore, there is an urgent need of a surveillance program for the early detection of HCC. Treatment of NAFLD-HCCs is not different from other causes-related HCCs. However, patients with NAFLD-HCCs have cardiovascular disease and other metabolic problems, which may complicate treatment.

Prospective study to determine early hypertrophy of the contra-lateral liver lobe after unilobar, Yttrium-90, selective internal radiation therapy in patients with hepatocellular carcinoma.

PubMed

Teo, Jin Yao; Allen, John Carson; Ng, David Chee Eng; Abdul Latiff, Julianah Bee; Choo, Su Pin; Tai, David Wai-Meng; Low, Albert Su Chong; Cheah, Foong Koon; Chang, Jason Pik Eu; Kam, Juinn Huar; Lee, Victor T W; Chung, Alexander Yaw Fui; Chan, Chung Yip; Chow, Pierce Kah Hoe; Goh, Brian K P

2018-05-01

Liver resection is a major curative option in patients presenting with hepatocellular carcinoma. An inadequate functional liver remnant is a major limiting factor precluding liver resection. In recent years, hypertrophy of the functional liver remnant after selective internal radiation therapy hypertrophy has been observed, but the degree of hypertrophy in the early postselective internal radiation therapy period has not been well studied. We conducted a prospective study on patients undergoing unilobar, Yttrium-90 selective internal radiation therapy for hepatocellular carcinoma to evaluate early hypertrophy at 4-6 weeks and 8-12 weeks after selective internal radiation therapy. In the study, 24 eligible patients were recruited and had serial volumetric measurements performed. The median age was 66 years (38-75 years). All patients were either Child-Pugh Class A or B, and 6/24 patients had documented, clinically relevant portal hypertension; 15 of the 24 patients were hepatitis B positive. At 4-6 weeks, modest hypertrophy was seen (median 3%; range -12 to 42%) and this increased at 8-12 weeks (median 9%; range -12 to 179%). No preprocedural factors predictive of hypertrophy were identified. Hypertrophy of the functional liver remnant after selective internal radiation therapy with Yttrium-90 occurred in a subset of patients but was modest and unpredictable in the early stages. Selective internal radiation therapy cannot be recommended as a standard treatment modality to induce early hypertrophy for patients with hepatocellular carcinoma. (Surgery 2017;160:XXX-XXX.). Copyright © 2017 Elsevier Inc. All rights reserved.

Suppression of Hepatocellular Carcinoma by Inhibition of Overexpressed Ornithine Aminotransferase.

PubMed

Zigmond, Ehud; Ben Ya'acov, Ami; Lee, Hyunbeom; Lichtenstein, Yoav; Shalev, Zvi; Smith, Yoav; Zolotarov, Lidya; Ziv, Ehud; Kalman, Rony; Le, Hoang V; Lu, Hejun; Silverman, Richard B; Ilan, Yaron

2015-08-13

Hepatocellular carcinoma is the second leading cause of cancer death worldwide. DNA microarray analysis identified the ornithine aminotransferase (OAT) gene as a prominent gene overexpressed in hepatocellular carcinoma (HCC) from Psammomys obesus. In vitro studies demonstrated inactivation of OAT by gabaculine (1), a neurotoxic natural product, which suppressed in vitro proliferation of two HCC cell lines. Alpha-fetoprotein (AFP) secretion, a biomarker for HCC, was suppressed by gabaculine in both cell lines, but not significantly. Because of the active site similarity between GABA aminotransferase (GABA-AT) and OAT, a library of 24 GABA-AT inhibitors was screened to identify a more selective inhibitor of OAT. (1S,3S)-3-Amino-4-(hexafluoropropan-2-ylidene)cyclopentane-1-carboxylic acid (2) was found to be an inactivator of OAT that only weakly inhibits GABA-AT, l-aspartate aminotransferase, and l-alanine aminotransferase. In vitro administration of 2 significantly suppressed AFP secretion in both Hep3B and HepG2 HCC cells; in vivo, 2 significantly suppressed AFP serum levels and tumor growth in HCC-harboring mice, even at 0.1 mg/kg. Overexpression of the OAT gene in HCC and the ability to block the growth of HCC by OAT inhibitors support the role of OAT as a potential therapeutic target to inhibit HCC growth. This is the first demonstration of suppression of HCC by an OAT inactivator.

Post-recurrence survival in hepatocellular carcinoma after percutaneous radiofrequency ablation.

PubMed

Facciorusso, Antonio; Del Prete, Valentina; Antonino, Matteo; Crucinio, Nicola; Neve, Viviana; Di Leo, Alfredo; Carr, Brian I; Barone, Michele

2014-11-01

Overall survival in hepatocellular carcinoma patients treated with percutaneous radiofrequency ablation is influenced by both recurrence and successive treatments. We investigated post-recurrence survival after radiofrequency ablation. Data on 103 early/intermediate patients initially treated with radiofrequency ablation and followed for a median of 78 months (range 68-82) were retrospectively analysed. If intrahepatic disease recurrence occurred within or contiguous to the previously treated area it was defined as local, otherwise as distant; recurrence classified as Barcelona Clinic Liver Cancer stage C was defined by neoplastic portal vein thrombosis or metastases. A total of 103 patients were included (82.5% male; median age 70 years, range 39-86). During follow-up, 64 recurrences were observed. Median overall survival was 62 months (95% confidence interval: 54-78) and survival rates were 97%, 65% and 52% at 1, 4 and 5 years, respectively. Median post-recurrence survival was 22 months (95% confidence interval: 16-35). Child-Pugh score, performance status, sum of tumour diameters at recurrence and recurrence patterns were independent predictors of post-recurrence survival. In patients with hepatocellular carcinoma after radiofrequency ablation, clinical and tumour parameters assessed at relapse, in particular the type of recurrence pattern, influence post-recurrence survival. Copyright © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Prebiotics: A Novel Approach to Treat Hepatocellular Carcinoma.

PubMed

Fatima, Naz; Akhtar, Tasleem; Sheikh, Nadeem

2017-01-01

Hepatocellular carcinoma is one of the fatal malignancies and is considered as the third leading cause of death. Mutations, genetic modifications, dietary aflatoxins, or impairments in the regulation of oncogenic pathways may bring about liver cancer. An effective barrier against hepatotoxins is offered by gut-liver axis as a change in gut permeability and expanded translocation of lipopolysaccharides triggers the activation of Toll-like receptors which stimulate the process of hepatocarcinogenesis. Prebiotics, nondigestible oligosaccharides, have a pivotal role to play when it comes to inducing an antitumor effect. A healthy gut flora balance is imperative to downregulation of inflammatory cytokines and reducing lipopolysaccharides induced endotoxemia, thus inducing the antitumor effect.

Chronic Japanese schistosomiasis and hepatocellular carcinoma: ten years of follow-up in Yamanashi Prefecture, Japan.

PubMed Central

Iida, F.; Iida, R.; Kamijo, H.; Takaso, K.; Miyazaki, Y.; Funabashi, W.; Tsuchiya, K.; Matsumoto, Y.

1999-01-01

In a preliminary study carried out in the study area we found that 19.1% (173/907) of patients with chronic liver disease and 51% (35/68) of hepatocellular carcinoma cases were infected with Japanese schistosomiasis. Analysis of data from 571 autopsies revealed a similarly high incidence of schistosomiasis among cases of hepatoma and other liver diseases. A prospective case-control study conducted over 10 years showed that hepatoma developed in 5.4% (26/484) of chronic schistosomiasis cases and in 7.5% (23/307) of patients with chronic liver disease (hepatitis, cirrhosis, etc). The difference was not statistically significant (P = 0.228). A high incidence of hepatitis C virus (HCV) antibody (HCVAb) was found in the schistosomiasis group (36.5%; 95% CI = 44.9-28.1%) and in the chronic liver disease group (56.0%), 39% of whom had chronic hepatitis (P = 0.028). Various factors that might have contributed to the development of hepatoma and schistosomiasis were investigated, but no evidence of a significant correlation between schistosomiasis and hepatoma was found. The high incidence of HCVAb was considered to have been responsible for the development of hepatocellular carcinoma in chronic schistosomiasis patients. The role of HBV infection in the development of hepatoma in schistosomiasis patients was not confirmed after an assay for HCVAb was included in the study. PMID:10444881

High immunosuppressive burden in advanced hepatocellular carcinoma patients: Can effector functions be restored?

PubMed

Lugade, Amit A; Kalathil, Suresh; Miller, Austin; Iyer, Renuka; Thanavala, Yasmin

2013-07-01

The accumulation of immunosuppressive cells and exhausted effector T cells highlight an important immune dysfunction in advanced stage hepatocellular carcinoma (HCC) patients. These cells significantly hamper the efficacy immunotherapies and facilitate HCC progression. We have recently demonstrated that the multipronged depletion of immunosuppressive cells potentially restores effector T-cell function in HCC.

Laparoscopic versus robotic surgery for hepatocellular carcinoma: the first 46 consecutive cases.

PubMed

Magistri, Paolo; Tarantino, Giuseppe; Guidetti, Cristiano; Assirati, Giacomo; Olivieri, Tiziana; Ballarin, Roberto; Coratti, Andrea; Di Benedetto, Fabrizio

2017-09-01

Hepatocellular carcinoma has a growing incidence worldwide, and represents a leading cause of death in patients with cirrhosis. Nowadays, minimally invasive approaches are spreading in every field of surgery and in liver surgery as well. We retrospectively reviewed demographics, clinical, and pathologic characteristics and short-term outcomes of patients who had undergone minimally invasive resections for hepatocellular carcinoma at our institution between June 2012 and May 2016. No significant differences in demographics and comorbidities were found between patients in the laparoscopic (n = 24) and robotic (n = 22) groups, except for the rates of cirrhotic patients (91.7% and 68.2%, respectively, P = 0.046). Perioperative data analysis showed that the operative time (mean, 211 and 318 min, respectively, P < 0.001) was the only parameter in favor of laparoscopy. Conversely, robotic-assisted resections were related to less Clavien I-II postoperative complications (22 cases versus 13 cases; P = 0.03). As regards resection margins, the two groups were similar with no statistically significant differences in rates of disease-free resection margins. A modern hepatobiliary center should offer both open and minimally invasive approaches to liver disease to provide the best care for each patient, according to the individual comorbidities, risk factors, and personal quality of life expectations. Our results show that the robotic approach is a reliable tool for accurate oncologic surgery, comparable to the laparoscopic approach. Robotic surgery also allows the surgeon to safely approach liver segments that are difficult to resect in laparoscopy, namely segments I-VII-VIII. Copyright © 2017 Elsevier Inc. All rights reserved.

[Hepatocellular carcinoma originated in the caudate lobe. Surgical strategy for resection. A propos of a case].

PubMed

Martínez-Mier, Gustavo; Esquivel-Torres, Sergio; Calzada-Grijalva, José Francisco; Grube-Pagola, Peter

2015-01-01

Hepatocellular carcinoma originating from the caudate lobe has a worse prognosis than other hepatocellular carcinoma in another segment of the liver. An isolated caudate lobe resection of the liver represents a significant technical challenge. Caudate lobe resection can be performed along with a lobectomy or as an isolated liver resection. There are very few reports about isolated caudate lobe liver resection. We report a case of successful isolated resection of hepatocellular carcinoma in the caudate lobe with excellent long-term survival. A 74 years old female with 8cm mass lesion in the caudate lobe without clinical or biochemical evidence of liver cirrhosis, serum alpha-fetoprotein 3.7 U/l, and negative hepatitis serology was evaluated for surgery. Complete resection of the lesion in 270minutes with Pringle maneuver for 13minutes was satisfactorily performed. Patient was discharged ten days after surgery without complications. Patient is currently asymptomatic, without deterioration of liver function and 48 month tumor free survival after the procedure. Isolated caudate lobe resection is an uncommon but technically possible procedure. In order to achieve a successful resection, one must have a detailed knowledge of complete liver anatomy. Tumor free margins must be obtained to provide long survival for these patients who have a malignancy in this anatomic location. Copyright © 2015. Published by Masson Doyma México S.A.

Osthole inhibits the tumorigenesis of hepatocellular carcinoma cells.

PubMed

Lin, Zhi-Kun; Liu, Jia; Jiang, Guo-Qiang; Tan, Guang; Gong, Peng; Luo, Hai-Feng; Li, Hui-Min; Du, Jian; Ning, Zhen; Xin, Yi; Wang, Zhong-Yu

2017-03-01

Hepatocellular carcinoma (HCC) accounts for approximately 90% of all cases of primary liver cancer, and the majority of patients with HCC are deprived of effective curative methods. Osthole is a Chinese herbal medicine which has been reported to possess various pharmacological functions, including hepatocellular protection. In the present study, we investigated the anticancer activity of osthole using HCC cell lines. We found that osthole inhibited HCC cell proliferation, induced cell cycle arrest, triggered DNA damage and suppressed migration in HCC cell lines. Furthermore, we demonstrated that osthole not only contributed to cell cycle G2/M phase arrest via downregulation of Cdc2 and cyclin B1 levels, but also induced DNA damage via an increase in ERCC1 expression. In addition, osthole inhibited the migration of HCC cell lines by significantly downregulating MMP-2 and MMP-9 levels. Finally, we demonstrated that osthole inhibited epithelial-mesenchymal transition (EMT) via increasing the expression of epithelial biomarkers E-cadherin and β-catenin, and significantly decreasing mesenchymal N-cadherin and vimentin protein expression. These results suggest that osthole may have potential chemotherapeutic activity against HCC.

Heterogeneous expression and regulation of CD40 in human hepatocellular carcinoma.

PubMed

Holub, Margareta; Zakeri, Schaker M; Lichtenberger, Cornelia; Pammer, Johannes; Paolini, Pierre; Leifeld, Ludger; Rockenschaub, Susanne; Wolschek, Markus F; Steger, Günther; Willheim, Martin; Gangl, Alfred; Reinisch, Walter

2003-02-01

CD40, a member of the tumour necrosis factor receptor family, plays a major role in adaptive immune responses and contributes to cancer surveillance. Conflicting results have been reported recently on the expression and function of CD40 in carcinomas. The aim of the present study was to investigate the role of CD40 in human hepatoma. CD40 expression was examined in hepatomas and derived cell lines by immunohistochemistry, flow cytometry and reverse transcriptase polymerase chain reaction. We investigated in hepatoma cell lines the regulation of CD40 by pro-inflammatory cytokines and the effects of its ligation with soluble CD40L on the expression of co-stimulatory and pro-apoptotic cell-surface molecules and survival. CD40 was detected with a similar frequency of about 40% in hepatoma specimens and derived cell lines but not in normal hepatocytes. Tumour necrosis factor alpha and its combination with interferon gamma upregulated CD40 only in intrinsically positive cell lines. CD40 ligation had no effect on cell viability or surface expression of CD54, CD80, CD86 or CD95. CD40 is expressed variably in human hepatoma and enhanced by distinct pro-inflammatory cytokines. The lack of detectable effects of CD40 ligation does not support a major role of this molecule in hepatocellular carcinoma biology.

Effects of marital status on survival of hepatocellular carcinoma by race/ethnicity and gender.

PubMed

Wu, Wenrui; Fang, Daiqiong; Shi, Ding; Bian, Xiaoyuan; Li, Lanjuan

2018-01-01

It is well demonstrated that being married is associated with a better prognosis in multiple types of cancer. However, whether the protective effect of marital status varied across race/ethnicity and gender in patients with hepatocellular carcinoma remains unclear. Therefore, we aimed to evaluate the roles of race/ethnicity and gender in this relationship. We identified eligible patients from Surveillance, Epidemiology and End Results (SEER) database during 2004-2012. Overall and cancer-specific survival differences across marital status were compared by Kaplan-Meier curves. We also estimated crude hazard ratios (CHRs) and adjusted hazard ratios (AHRs) with 95% confidence intervals (CIs) for marital status associated with survival by race/ethnicity and gender in Cox proportional hazard models. A total of 12,168 eligible patients diagnosed with hepatocellular carcinoma were included. We observed that married status was an independent protective prognostic factor for overall and cancer-specific survival. In stratified analyses by race/ethnicity, the AHR of overall mortality (unmarried vs married) was highest for Hispanic (AHR =1.25, 95% CI, 1.13-1.39; P <0.001) and lowest for Asian or Pacific Islander (AHR =1.13; 95% CI, 1.00-1.28; P =0.042). Stratified by gender, the AHR was higher in males (AHR =1.27; 95% CI, 1.20-1.33; P <0.001). Conclusion: We demonstrated that married patients obtained better survival advantages. Race/ethnicity and gender could influence the magnitude of associations between marital status and risk of mortality.

MICA/B expression is inhibited by unfolded protein response and associated with poor prognosis in human hepatocellular carcinoma.

PubMed

Fang, Liang; Gong, Jiuyu; Wang, Ying; Liu, Rongrong; Li, Zengshan; Wang, Zhe; Zhang, Yun; Zhang, Chunmei; Song, Chaojun; Yang, Angang; Ting, Jenny P-Y; Jin, Boquan; Chen, Lihua

2014-09-18

MICA/B are major ligands for NK cell activating receptor NKG2D and previous studies showed that the serum level of soluble MICA (sMICA) is an independent prognostic factor for advanced human hepatocellular carcinoma. However, the correlation between cellular MICA/B expression pattern and human hepatocellular carcinoma progression has not been well explored. The unfolded protein response is one of the main causes of resistance to chemotherapy and radiotherapy in tumor cells. However, whether the UPR in HCC could regulate the expression levels of MICA/B and affect the sensitivity of HCC cells to NK cell cytolysis has not been established yet. MICA/B expression pattern was evaluated by immunohistochemistry and Kaplan-Meier survival analysis was done to explore the relationship between MICA/B expression level and patient survival. The protein and mRNA expression levels of MICA/B in SMMC7721 and HepG2 cells treated by tunicamycin were evaluated by flow cytometry, Western Blot and RT-PCR. The cytotoxicity analysis was performed with the CytoTox 96 Non-Radioactive LDH Cytotoxicity Assay. MICA/B was highly expressed in human hepatocellular carcinoma and the expression level was significantly and negatively associated with tumor-node metastasis (TNM) stages. Patients with low level of MICA/B expression showed a trend of shorter survival time. The unfolded protein response (UPR) downregulated the expression of MICA/B. This decreased protein expression occurred via post-transcriptional regulation and was associated with proteasomal degradation. Moreover, decreased expression level of MICA/B led to the attenuated sensitivity of human HCC to NK cell cytotoxicity. These new findings of the connection of MICA/B, UPR and NK cells may represent a new concrete theory of NK cell regulation in HCC, and suggest that targeting this novel NK cell-associated immune evasion pathway may be meaningful in treating patients with HCC.

Dual oxidase 1: A predictive tool for the prognosis of hepatocellular carcinoma patients.

PubMed

Chen, Shengsen; Ling, Qingxia; Yu, Kangkang; Huang, Chong; Li, Ning; Zheng, Jianming; Bao, Suxia; Cheng, Qi; Zhu, Mengqi; Chen, Mingquan

2016-06-01

Dual oxidase 1 (DUOX1), which is the main source of reactive oxygen species (ROS) production in the airway, can be silenced in human lung cancer and hepatocellular carcinomas. However, the prognostic value of DUOX1 expression in hepatocellular carcinoma patients is still unclear. We investigated the prognostic value of DUOX1 expression in liver cancer patients. DUOX1 mRNA expression was determined in tumor tissues and non-tumor tissues by real‑time PCR. For evaluation of the prognostic value of DUOX1 expression, Kaplan-Meier method and Cox's proportional hazards model (univariate analysis and multivariate analysis) were employed. A simple risk score was devised by using significant variables obtained from the Cox's regression analysis to further predict the HCC patient prognosis. We observed a reduced DUOX1 mRNA level in the cancer tissues in comparison to the non‑cancer tissues. More importantly, Kaplan-Meier analysis showed that patients with high DUOX1 expression had longer disease-free survival and overall survival compared with those with low expression of DUOX1. Cox's regression analysis indicated that DUOX1 expression, age, and intrahepatic metastasis may be significant prognostic factors for disease-free survival and overall survival. Finally, we found that patients with total scores of >2 and >1 were more likely to relapse and succumb to the disease than patients whose total scores were ≤2 and ≤1. In conclusion, DUOX1 expression in liver tumors is a potential prognostic tool for patients. The risk scoring system is useful for predicting the survival of liver cancer patients after tumor resection.

Tumour seeding after percutaneous cryoablation for hepatocellular carcinoma

PubMed Central

Wang, Chun-Ping; Wang, Hong; Qu, Jian-Hui; Lu, Yin-Ying; Bai, Wen-Lin; Dong, Zheng; Gao, Xu-Dong; Rong, Guang-Hua; Zeng, Zhen; Yang, Yong-Ping

2012-01-01

AIM: To assess the rate and risk factors for tumour seeding in a large cohort of patients. METHODS: Over an 8-year period, 1436 hepatocellular carcinoma (HCC) patients with 2423 tumour nodules underwent 3015 image-guided percutaneous cryoablation sessions [1215 guided by ultrasonography and 221 by spiral computed tomography (CT)]. Follow-up CT or magnetic resonance imaging was performed every 3 mo. The detailed clinical data were recorded to analyse the risk factors for seeding. RESULTS: The median follow-up time was 18 (range 1-90) mo. Seeding was detected in 11 patients (0.76%) at 1-24 (median 6.0) mo after cryoablation. Seeding occurred along the needle tract in 10 patients and at a distant location in 1 patient. Seeded tumours usually showed similar imaging and histopathological features to the primary HCCs. Univariate analyses identified subcapsular tumour location and direct subcapsular needle insertion as risk factors for seeding. Multivariate analysis showed that only direct subcapsular needle insertion was an independent risk factor for seeding (P = 0.017; odds ratio 2.57; 95%CI: 1.47-3.65). Seeding after cryoablation occurred earlier in patients with poorly differentiated HCC than those with well or moderately differentiated HCC [1.33 ± 0.577 mo vs 11.12 ± 6.896 mo; P = 0.042; 95%CI: (-19.115)-(-0.468)]. CONCLUSION: The risk of seeding after cryoablation for HCC is small. Direct puncture of subcapsular tumours should be avoided to minimise seeding. PMID:23236233

Effect of the herbal formulation Jianpijiedu on the TCRVβCDR3 repertoire in rats with hepatocellular carcinoma and subjected to food restriction combined with laxative.

PubMed

Sun, Baoguo; Meng, Jun; Xiang, Ting; Zhang, Lei; Deng, Liuxiang; Chen, Yan; Luo, Haoxuan; Yang, Zhangbin; Chen, Zexiong; Zhang, Shijun

2016-03-01

The aim of this study was to investigate the effects of the Chinese herbal formulation Jianpijiedu (JPJD) in a rat model of orthotopic hepatocellular carcinoma (OHC). The tumor-bearing rats underwent food restriction combined with laxative (FRL) treatment in order to model the nutritional and digestive symptoms of patients with hepatocellular carcinoma. In addition, the study aimed to elucidate the effect of JPJD on the T cell receptor Vβ-chain complementarity-determining region 3 (TCRVβCDR3) repertoire and the underlying mechanism. The FRL rat model was established by alternate-day food restriction and the oral administration of Glauber's salt (sodium sulfate), based on which the OHC model was then established. Subsequently, the FRL-OHC induced animals received JPJD or thymopentin-5 (TP5) for 17 days. Differences in the TCRVβCDR3 repertoire in the rat thymus, liver and hepatocellular carcinoma tissues were analyzed by polymerase chain reaction. Compared with the FRL-OHC model animals without any treatment, those treated with JPJD exhibited significantly inhibited hepatocellular carcinoma growth (P<0.05), reduced weight loss (P<0.01) and stable visceral indices (P<0.05). Furthermore, the JPJD treatment appeared to improve Simpsons diversity index (Ds) values and the quasi-Gaussian distribution rate of the TCRVβCDR3 repertoire in the thymus, liver and hepatocellular carcinoma tissues. However, no anti-hepatoma effects were evident in the rats treated with TP5. In addition, TP5 increased the Ds values and the quasi-Gaussian distribution rate of the TCRVβCDR3 repertoire in hepatocellular carcinoma tissues compared with those in the JPJD-treated group. The anti-hepatoma effects of JPJD in FRL-OHC-induced animals may be due to the promotion of the Ds values of the TCRVβCDR3 repertoire.

Effect of the herbal formulation Jianpijiedu on the TCRVβCDR3 repertoire in rats with hepatocellular carcinoma and subjected to food restriction combined with laxative

PubMed Central

SUN, BAOGUO; MENG, JUN; XIANG, TING; ZHANG, LEI; DENG, LIUXIANG; CHEN, YAN; LUO, HAOXUAN; YANG, ZHANGBIN; CHEN, ZEXIONG; ZHANG, SHIJUN

2016-01-01

The aim of this study was to investigate the effects of the Chinese herbal formulation Jianpijiedu (JPJD) in a rat model of orthotopic hepatocellular carcinoma (OHC). The tumor-bearing rats underwent food restriction combined with laxative (FRL) treatment in order to model the nutritional and digestive symptoms of patients with hepatocellular carcinoma. In addition, the study aimed to elucidate the effect of JPJD on the T cell receptor Vβ-chain complementarity-determining region 3 (TCRVβCDR3) repertoire and the underlying mechanism. The FRL rat model was established by alternate-day food restriction and the oral administration of Glauber's salt (sodium sulfate), based on which the OHC model was then established. Subsequently, the FRL-OHC induced animals received JPJD or thymopentin-5 (TP5) for 17 days. Differences in the TCRVβCDR3 repertoire in the rat thymus, liver and hepatocellular carcinoma tissues were analyzed by polymerase chain reaction. Compared with the FRL-OHC model animals without any treatment, those treated with JPJD exhibited significantly inhibited hepatocellular carcinoma growth (P<0.05), reduced weight loss (P<0.01) and stable visceral indices (P<0.05). Furthermore, the JPJD treatment appeared to improve Simpsons diversity index (Ds) values and the quasi-Gaussian distribution rate of the TCRVβCDR3 repertoire in the thymus, liver and hepatocellular carcinoma tissues. However, no anti-hepatoma effects were evident in the rats treated with TP5. In addition, TP5 increased the Ds values and the quasi-Gaussian distribution rate of the TCRVβCDR3 repertoire in hepatocellular carcinoma tissues compared with those in the JPJD-treated group. The anti-hepatoma effects of JPJD in FRL-OHC-induced animals may be due to the promotion of the Ds values of the TCRVβCDR3 repertoire. PMID:26997998

Antibiotic prophylaxis in transarterial therapy of hepatocellular carcinoma: A meta-analysis

PubMed Central

Wang, Jun; He, Xiao Dong; Zhang, You Cheng

2012-01-01

BACKGROUND: The use of prophylactic antibiotics against postprocedure infection in patients undergoing transarterial therapy for hepatocellular carcinoma is controversial. AIM: To compare the effects of prophylactic antibiotic treatment and no prophylactic antibiotic treatment on infectious complications following transarterial procedures. METHODS: Clinical trials fulfilling predefined selection criteria were identified by searching several bibliographic databases; a meta-analysis was performed where appropriate. RESULTS: Four trials of inadequate quality consisting of 210 patients were included in the analysis. Only one case of possible postprocedure infection in each group was reported. The rate of patients developing fever (RR 0.91 [95% CI 0.61 to 1.35]), changes in peripheral white blood cell count or serum C-reactive protein levels, and the mean length of hospital stay (mean difference 0.20 [95% CI 0.75 to 1.14]) showed no significant intergroup differences between antibiotic and no antibiotic treatment. Furthermore, the results of the present study indicated that the incidence of bacteremia, septicemia, sepsis or hepatic abscess after transarterial therapy was rare. CONCLUSION: Antibiotic prophylaxis in patients undergoing transarterial therapy for hepatocellular carcinoma may not be routinely necessary. However, a more judicious use of antibiotics is recommended for patients who are at an increased risk of infection. Nevertheless, prospective trials on a larger scale are clearly needed. PMID:22312607

Antibiotic prophylaxis in transarterial therapy of hepatocellular carcinoma: a meta-analysis.

PubMed

Wang, Jun; He, Xiao Dong; Zhang, You Cheng

2012-02-01

The use of prophylactic antibiotics against postprocedure infection in patients undergoing transarterial therapy for hepatocellular carcinoma is controversial. To compare the effects of prophylactic antibiotic treatment and no prophylactic antibiotic treatment on infectious complications following transarterial procedures. Clinical trials fulfilling predefined selection criteria were identified by searching several bibliographic databases; a meta-analysis was performed where appropriate. Four trials of inadequate quality consisting of 210 patients were included in the analysis. Only one case of possible postprocedure infection in each group was reported. The rate of patients developing fever (RR 0.91 [95% CI 0.61 to 1.35]), changes in peripheral white blood cell count or serum C-reactive protein levels, and the mean length of hospital stay (mean difference 0.20 [95% CI 0.75 to 1.14]) showed no significant intergroup differences between antibiotic and no antibiotic treatment. Furthermore, the results of the present study indicated that the incidence of bacteremia, septicemia, sepsis or hepatic abscess after transarterial therapy was rare. Antibiotic prophylaxis in patients undergoing transarterial therapy for hepatocellular carcinoma may not be routinely necessary. However, a more judicious use of antibiotics is recommended for patients who are at an increased risk of infection. Nevertheless, prospective trials on a larger scale are clearly needed.

Atypical β-Catenin Activated Child Hepatocellular Tumor

PubMed Central

Unlu, Havva Akmaz; Karakus, Esra; Yazal Erdem, Arzu; Yakut, Zeynep Ilerisoy

2015-01-01

Hepatocellular adenomas are a benign, focal, hepatic neoplasm that have been divided into four subtypes according to the genetic and pathological features. The β-catenin activated subtype accounts for 10-15% of all hepatocellular adenomas and specific magnetic resonance imaging features have been defined for different hepatocellular adenomas subtypes. The current study aimed to report the magnetic resonance imaging features of a well differentiated hepatocellular carcinoma that developed on the basis of β-catenin activated hepatocellular adenomas in a child. In this case, atypical diffuse steatosis was determined in the lesion. In the literature, diffuse steatosis, which is defined as a feature of the hepatocyte nuclear factor-1α-inactivated hepatocellular adenomas subtype, has not been previously reported in any β-catenin activated hepatocellular adenomas case. Interlacing magnetic resonance imaging findings between subtypes show that there are still many mysteries about this topic and larger studies are warranted. PMID:26157702

Long non-coding RNA colon cancer-associated transcript 1 functions as a competing endogenous RNA to regulate cyclin-dependent kinase 1 expression by sponging miR-490-3p in hepatocellular carcinoma progression.

PubMed

Dou, Chunqing; Sun, Liyuan; Jin, Xin; Han, Mingming; Zhang, Bao; Li, Tao

2017-04-01

Hepatocellular carcinoma is an aggressive neoplasm and is one of the most common human cancers. Recently, long non-coding RNAs have been demonstrated to participate in pathogenesis of many diseases including the progression in several cancers. In this study, we found that the long non-coding RNA colon cancer-associated transcript 1 was upregulated in hepatocellular carcinoma tissues (p < 0.05), and high colon cancer-associated transcript 1 expression level was positively associated with tumor volume (p < 0.05) and American Joint Committee on Cancer stage (p < 0.05) in hepatocellular carcinoma patients. Luciferase reporter assays and RNA-pulldown assays showed that colon cancer-associated transcript 1 is a target of miR-490-3p. Real-time quantitative polymerase chain reaction and Western blot analysis indicated that colon cancer-associated transcript 1 regulated cyclin-dependent kinase 1 expression as a competing endogenous RNA by sponging miR-490-3p in hepatocellular carcinoma cells. Furthermore, colon cancer-associated transcript 1 silencing decreased hepatocellular carcinoma cells proliferation and invasion and overexpression promoted cell proliferation and invasion in vitro. These data demonstrated that the colon cancer-associated transcript 1/miR-490-3p/cyclin-dependent kinase 1 regulatory pathway promotes the progression of hepatocellular carcinoma. Inhibition of colon cancer-associated transcript 1 expression may be a novel therapeutic strategy for hepatocellular carcinoma.

[Targeted therapies in hepatocellular carcinomas: recent results and future development].

PubMed

Marijon, H; Faivre, S; Raymond, E

2009-05-01

Hepatocellular carcinoma (HCC) is one of the 5th most common cancers around the world with a limited number of systemic therapeutic options. Cytotoxic agents, hormonotherapy and immunotherapy have failed to demonstrate benefit compared to best supportive care in patients with advanced HCC. The recent development of targeted therapies provided hope for the treatment of advanced HCC. We reviewed phases II-III trials presented in 2007 and 2008. Results are promising with a clinical benefit reported with molecular therapies targeting EGF/EGFR and VEGF/VEGFR pathways.

Frequency of deaths in hepatitis C virus infected hepatocellular carcinoma patients and its relationship with raised serum alpha-fetoprotein levels.

PubMed

Shaikh, Fida Hussain; Zeb, Shaista; Chandio, Sultan Ahmed; Munaf, Alvina; Ghori, Muhamad Aamir; Memon, Mohammad Sadik; Burney, Asif Ali

2016-01-01

To determine the frequency of deaths in hepatitis C virus infected hepatocellular carcinoma patients, and its relationship with raised serum alpha-fetoprotein levels. The cross-sectional study was conducted at Isra University Hospital, Hyderabad, Pakistan, between March 2013 and April 2014, and comprised all patients diagnosed with hepatitis C virus and hepatocellular carcinoma over 30 years ofage. Blood sample was drawn for the measurement of serum Alfa fetoprotein levels. Data was analysed using SPSS 16. The mean age of the 165 patients was55.49±11.67 years. The mean tumour size was 5.63 ± 2.14cm. Of the total, 31(18.8%) patients had tumour size <3cm, 65(39.4%) 3-5cm and 69(41.8%) >5cm. The mean serum Alfa fetoprotein level was 7641.0±3665.32 IU/ml. Overall mortality rate was 70(41.9%). Tumour size >5cm was significantly associated with mortality (p=0.016). Serum Alfa fetoprotein levels were a useful tool for the detection of hepatocellular carcinoma in hepatitis C virus patients.

Prognostic factors and recurrence of hepatitis B-related hepatocellular carcinoma after argon-helium cryoablation: a prospective study.

PubMed

Wang, Chunping; Lu, Yinying; Chen, Yan; Feng, Yongyi; An, Linjing; Wang, Xinzhen; Su, Shuhui; Bai, Wenlin; Zhou, Lin; Yang, Yongping; Xu, Dongping

2009-01-01

To determine the long-term prognosis of hepatocellular carcinoma (HCC) after argon-helium cryoablation and identify the risk factors that predict metastasis and recurrence. A total of 156 patients with hepatitis B-related HCC less than 5 cm in diameter who underwent curative cryoablation were followed up prospectively for tumor metastasis and recurrence. Immunohistochemistry was used to analyze the expression of vascular endothelial growth factor (VEGF). HBV basal core promoter (BCP) and precore mutations were detected by DNA sequence analysis. Post-treatment prognostic factors influencing survival, tumor metastasis and recurrence were assessed by univariate and multivariate analyses. The variables included the expression of VEGF in HCC tissues, clinical and pathologic characteristics of patients, and HBV features (HBV DNA level, HBV genotype, BCP mutation). The median follow-up period of the 156 patients was 37 months (range 8-48 months). The 1-, 2-, and 3-year overall survival rates were 92, 82 and 64%, respectively. The 1-, 2-, and 3-year recurrence-free survival rates were 72, 56 and 43%, respectively. Eighty-five patients (54.5%) had tumor recurrence or metastasis. The multivariate analysis showed that Child-Pugh class and the expression of VEGF in HCC tissues could be used as independent prognostic factors for overall survival. Meanwhile, the expression of VEGF in HCC tissues and HBV BCP mutations were found to be independent prognostic factors for recurrence-free survival. Strong expression of VEGF in HCC tissues and HBV BCP mutations are important risk predictors for recurrence or metastasis of HCC smaller than 5 cm in diameter.

Micronutrient Synergy in the Fight against Hepatocellular Carcinoma.

PubMed

Roomi, M Waheed; Roomi, Nusrath W; Kalinovsky, Tatiana; Niedzwiecki, Aleksandra; Rath, Matthias

2012-03-23

The incidence of hepatocellular carcinoma (HCC), once thought to be a rare tumor in North America, has rapidly increased in recent years in the United States. Current treatment modalities to halt the progression of this disease are only marginally effective. The mainstay treatment is liver transplantation, which is often confronted with donor shortage. Invasion, metastasis and recurrence contribute to the high mortality rate of this disease. Matrix metalloproteinases (MMPs) that degrade the extracellular matrix (ECM) have been associated with the progression, invasion and metastasis of the disease. We have developed strategies to strengthen the ECM collagen and inhibit MMPs through micronutrients such as lysine, proline and ascorbic acid. Addition of epigallocatechin gallate or green tea extract to these micronutrients synergistically enhanced anti-carcinogenic activity in HepG2 cells. Addition of certain other micronutrients, such as N-acetylcysteine, selenium, copper and zinc (NM) synergistically enhanced the anticancer activity of the mixture in a model of hepatocellular carcinoma using HepG2 cells. In vitro studies using HepG2 demonstrated that NM was very effective in inhibiting cell proliferation (by MTT assay), MMPs secretion (by gelatinase zymography), cell invasion (through Matrigel) and induction of apoptosis (by live green caspase). In addition, NM was shown to down-regulate urokinase plasminogen activator (by fibrin zymography) and up-regulate tissue inhibitors of metalloproteinases (by reverse zymography) in another HCC cell line, SK-Hep-1. MMP-2 and MMP-9 activities were further modulated by phorbol 12-myristate 13-acetate (PMA) induction and inhibited by NM. In previous studies, NM inhibited Sk-Hep-1 xenografts in nude mice and also inhibited hepatic metastasis of B16FO melanoma cells. Our results suggest that NM is an excellent candidate for therapeutic use in the treatment HCC by inhibiting critical parameters in cancer development and progression

Effects of Lidocaine-Mediated CPEB3 Upregulation in Human Hepatocellular Carcinoma Cell Proliferation In Vitro

PubMed Central

Liu, Hongjun; Wang, Yiru; Chen, Bing

2018-01-01

Lidocaine displays antitumor activity by inducing apoptosis and suppressing tumor growth in human hepatocellular carcinoma (HepG2) cells in vitro. However, the molecular mechanism underlying lidocaine-mediated antitumor activity is unclear. In this study, HepG2 cells were treated with lidocaine, and cell proliferation and colony-forming ability were assessed. The expression level of cytoplasmic polyadenylation element binding protein 3 (CPEB3) was detected by real-time quantitative PCR and western blot. Lidocaine treatment resulted in decreased HepG2 cell viability and colony formation in a dose-dependent manner. In hepatocellular carcinoma patient samples, CPEB3 was downregulated and was associated with poor prognosis and high-grade malignancy. Additionally, CPEB3 was a critical mediator of lidocaine-induced repression of HepG2 cell proliferation. These results demonstrated that lidocaine decreased cell viability and colony-forming ability of HepG2 cells by upregulating CPEB3 expression.

Hepatocellular carcinoma redirects to ketolysis for progression under nutrition deprivation stress

PubMed Central

Huang, De; Li, Tingting; Wang, Lin; Zhang, Long; Yan, Ronghui; Li, Kui; Xing, Songge; Wu, Gongwei; Hu, Lan; Jia, Weidong; Lin, Sheng-Cai; Dang, Chi V; Song, Libing; Gao, Ping; Zhang, Huafeng

2016-01-01

Cancer cells are known for their capacity to rewire metabolic pathways to support survival and proliferation under various stress conditions. Ketone bodies, though produced in the liver, are not consumed in normal adult liver cells. We find here that ketone catabolism or ketolysis is re-activated in hepatocellular carcinoma (HCC) cells under nutrition deprivation conditions. Mechanistically, 3-oxoacid CoA-transferase 1 (OXCT1), a rate-limiting ketolytic enzyme whose expression is suppressed in normal adult liver tissues, is re-induced by serum starvation-triggered mTORC2-AKT-SP1 signaling in HCC cells. Moreover, we observe that enhanced ketolysis in HCC is critical for repression of AMPK activation and protects HCC cells from excessive autophagy, thereby enhancing tumor growth. Importantly, analysis of clinical HCC samples reveals that increased OXCT1 expression predicts higher patient mortality. Taken together, we uncover here a novel metabolic adaptation by which nutrition-deprived HCC cells employ ketone bodies for energy supply and cancer progression. PMID:27644987

Ultrasound-guided percutaneous treatment of hepatocellular carcinoma by radiofrequency hyperthermia with a 'cooled-tip needle'. A preliminary clinical experience.

PubMed

Francica, G; Marone, G

1999-05-01

Radiofrequency hyperthermia using the newly-developed 'cooled-tip' needle has recently been proposed as a therapeutic modality for hepatocellular carcinoma (HCC). Herein we report our preliminary results on feasibility and effectiveness of the thermal ablation of mono- or pauci-focal hepatocellular carcinoma with the cooled-tip needle. We treated 15 cirrhotic patients (mean age 68.8 years; 12 males; 14 HCV-positive; 13 in Child's Class A and 2 in Class B) with 20 hepatocellular carcinoma nodules (mean diameter 28.1 mm; range 10-43 mm; nine lesions with diameter greater than 3 cm). None of the patients had portal thrombosis and/or extrahepatic spread. We used a radiofrequency generator (100 W of power) connected to a 18 g perfusion electrode needle with an exposed tip of 2-3 cm. The circuit was closed through a dispersive electrode positioned under the patient's thighs. A peristaltic pump infused a chilled (2-5 degrees C) saline solution to guarantee the continuous cooling of the needle tip. The needle was placed into target lesions under US guidance. The interventional procedure was carried out in general anesthesia without intubation. Dynamic helical CT was carried out 15-20 days after thermal ablation to assess therapeutic efficacy. In all, 38 areas of coagulation necrosis (at 1000-1200 mA for 10-15 min) were generated in 24 sessions in the 20 hepatocellular carcinoma nodules (mean 1.9 lesions per nodule and 1.2 sessions per nodule). Complete necrosis as assessed at dynamic CT (lack of enhancement during the arteriographic phase) was achieved in 75% of cases in a single session; after a second RF session success rate was 90% (18 out of 20 nodules). A self-limited pleurisy along with a 5-fold increase in transaminases occurred in one patient; a 3-fold elevation of transaminases was encountered in three other patients. During the follow-up (median 15 months) five patients had recurrent hepatocellular carcinoma with a 1-year disease free interval of 64%. Of the

Trend of hepatocellular carcinoma incidence after Bayesian correction for misclassified data in Iranian provinces.

PubMed

Hajizadeh, Nastaran; Baghestani, Ahmad Reza; Pourhoseingholi, Mohamad Amin; Ashtari, Sara; Fazeli, Zeinab; Vahedi, Mohsen; Zali, Mohammad Reza

2017-05-28

To study the trend of hepatocellular carcinoma incidence after correcting the misclassification in registering cancer incidence across Iranian provinces in cancer registry data. Incidence data of hepatocellular carcinoma were extracted from Iranian annual of national cancer registration reports 2004 to 2008. A Bayesian method was implemented to estimate the rate of misclassification in registering cancer incidence in neighboring province. A beta prior is considered for misclassification parameter. Each time two neighboring provinces were selected to be entered in the Bayesian model based on their expected coverage of cancer cases which is reported by medical university of the province. It is assumed that some cancer cases from a province that has an expected coverage of cancer cases lower than 100% are registered in their neighboring facilitate province with more than 100% expected coverage. There is an increase in the rate of hepatocellular carcinoma in Iran. Among total of 30 provinces of Iran, 21 provinces were selected to be entered to the Bayesian model for correcting the existed misclassification. Provinces with more medical facilities of Iran are Tehran (capital of the country), Razavi Khorasan in north-east of Iran, East Azerbaijan in north-west of the country, Isfahan in central part and near to Tehran, Khozestan and Fars in south and Mazandaran in north of the Iran, had an expected coverage more than their expectation. Those provinces had significantly higher rates of hepatocellular carcinoma than their neighboring provinces. In years 2004 to 2008, it was estimated to be on average 34% misclassification between North Khorasan province and Razavi Khorasan, 43% between South Khorasan province and Razavi Khorasan, 47% between Sistan and balochestan province and Razavi Khorasan, 23% between West Azerbaijan province and East Azerbaijan province, 25% between Ardebil province and East Azerbaijan province, 41% between Hormozgan province and Fars province, 22

Apigenin sensitizes hepatocellular carcinoma cells to doxorubic through regulating miR-520b/ATG7 axis.

PubMed

Gao, Ai-Mei; Zhang, Xiao-Yu; Hu, Juan-Ni; Ke, Zun-Ping

2018-01-25

Chemo-resistance is a serious obstacle for successful treatment of cancer. Apigenin, a dietary flavonoid, has been reported as an anticancer drug in various malignant cancers. This study aimed to investigate the potential chemo-sensitization effect of apigenin in doxorubicin-resistant hepatocellular carcinoma cell line BEL-7402/ADM. We observed that apigenin significantly enhanced doxorubicin sensitivity, induced miR-520b expression and inhibited ATG7-dependent autophagy in BEL-7402/ADM cells. In addition, we also showed that miR-520b mimics increased doxorubicin sensitivity and inhibited ATG7-dependent autophagy. Meanwhile, we indicated that ATG7 was a potential target of miR-520b. Furthermore, APG inhibited the growth of hepatocellar carcinoma xenografts in nude mice by up-regulating miR-520b and inhibiting ATG7. Our finding provides evidence that apigenin sensitizes BEL-7402/ADM cells to doxorubicin through miR-520b/ATG7 pathway, which furtherly supports apigenin as a potential chemo-sensitizer for hepatocellular carcinoma. Copyright © 2017 Elsevier B.V. All rights reserved.

Prebiotics: A Novel Approach to Treat Hepatocellular Carcinoma

PubMed Central

2017-01-01

Hepatocellular carcinoma is one of the fatal malignancies and is considered as the third leading cause of death. Mutations, genetic modifications, dietary aflatoxins, or impairments in the regulation of oncogenic pathways may bring about liver cancer. An effective barrier against hepatotoxins is offered by gut-liver axis as a change in gut permeability and expanded translocation of lipopolysaccharides triggers the activation of Toll-like receptors which stimulate the process of hepatocarcinogenesis. Prebiotics, nondigestible oligosaccharides, have a pivotal role to play when it comes to inducing an antitumor effect. A healthy gut flora balance is imperative to downregulation of inflammatory cytokines and reducing lipopolysaccharides induced endotoxemia, thus inducing the antitumor effect. PMID:28573132

α-Hispanolol sensitizes hepatocellular carcinoma cells to TRAIL-induced apoptosis via death receptor up-regulation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mota, Alba, E-mail: amota@iib.uam.es; Jiménez-Garcia, Lidia, E-mail: ljimenez@isciii.es; Herránz, Sandra, E-mail: sherranz@isciii.es

Hispanolone derivatives have been previously described as anti-inflammatory and antitumoral agents. However, their effects on overcoming Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance remain to be elucidated. In this study, we analyzed the cytotoxic effects of the synthetic hispanolone derivative α-hispanolol (α-H) in several tumor cell lines, and we evaluated the induction of apoptosis, as well as the TRAIL-sensitizing potential of α-H in the hepatocellular carcinoma cell line HepG2. Our data show that α-H decreased cell viability in a dose-dependent manner in HeLa, MDA-MB231, U87 and HepG2 cell lines, with a more prominent effect in HepG2 cells. Interestingly, α-H hadmore » no effect on non-tumoral cells. α-H induced activation of caspase-8 and caspase-9 and also increased levels of the proapoptotic protein Bax, decreasing antiapoptotic proteins (Bcl-2, X-IAP and IAP-1) in HepG2 cells. Specific inhibition of caspase-8 abrogated the cascade of caspase activation, suggesting that the extrinsic pathway has a critical role in the apoptotic events induced by α-H. Furthermore, combined treatment of α-H with TRAIL enhanced apoptosis in HepG2 cells, activating caspase-8 and caspase-9. This correlated with up-regulation of both the TRAIL death receptor DR4 and DR5. DR4 or DR5 neutralizing antibodies abolished the effect of α-H on TRAIL-induced apoptosis, suggesting that sensitization was mediated through the death receptor pathway. Our results demonstrate that α-H induced apoptosis in the human hepatocellular carcinoma cell line HepG2 through activation of caspases and induction of the death receptor pathway. In addition, we describe a novel function of α-H as a sensitizer on TRAIL-induced apoptotic cell death in HepG2 cells. - Highlights: • α-Hispanolol induced apoptosis in the human hepatocellular carcinoma cell line HepG2. • α-Hispanolol induced activation of caspases and the death receptor pathway. • �

Tumor Microenvironment, a Paradigm in Hepatocellular Carcinoma Progression and Therapy

PubMed Central

Tahmasebi Birgani, Maryam; Carloni, Vinicio

2017-01-01

Hepatocellular carcinoma (HCC) is among the most lethal and prevalent cancers in the human population. Different etiological factors such as hepatitis B and C virus, alcohol and diabetes cause liver injury followed by inflammation, necrosis and hepatocytes proliferation. Continuous cycles of this destructive–regenerative process culminates in liver cirrhosis which is characterized by regenerating nodules that progress to dysplastic nodules and ultimately HCC. Despite its significance, there is only an elemental understanding of the pathogenetic mechanisms, and there are only limited therapeutic options. Therefore, the study of the involved molecular mechanisms can open a new insight to define more effective treatment strategies. A variety of alterations have been reported in HCC patients, particularly the cancer-associated microenvironment components including immune cells, fibroblast cells, endothelial cells and extracellular matrix can support the neoplastic cells to proliferate, growth and invade. This review summarizes the current state of knowledge and highlights the principal challenges that are relevant to controlling this milieu. PMID:28216578

Guide for diagnosis and treatment of hepatocellular carcinoma

PubMed Central

Attwa, Magdy Hamed; El-Etreby, Shahira Aly

2015-01-01

Hepatocellular carcinoma (HCC) is ranked as the 5th common type of cancer worldwide and is considered as the 3rd common reason for cancer-related deaths. HCC often occurs on top of a cirrhotic liver. The prognosis is determined by several factors; tumour extension, alpha-fetoprotein (AFP) concentration, histologic subtype of the tumour, degree of liver dysfunction, and the patient’s performance status. HCC prognosis is strongly correlated with diagnostic delay. To date, no ideal screening modality has been developed. Analysis of recent studies showed that AFP assessment lacks adequate sensitivity and specificity for effective surveillance and diagnosis. Many tumour markers have been tested in clinical trials without progressing to routine use in clinical practice. Thus, surveillance is still based on ultrasound (US) examination every 6 mo. Imaging studies for diagnosis of HCC can fall into one of two main categories: routine non-invasive studies such as US, computed tomography (CT), and magnetic resonance imaging, and more specialized invasive techniques including CT during hepatic arteriography and CT arterial portography in addition to the conventional hepatic angiography. This article provides an overview and spotlight on the different diagnostic modalities and treatment options of HCC. PMID:26140083

Sorafenib induced thyroiditis in two patients with hepatocellular carcinoma.

PubMed

van Doorn, Leni; Eskens, Ferry A L M; Visser, Theo J; van der Lugt, Aad; Mathijssen, Ron H J; Peeters, Robin P

2011-02-01

Sorafenib is a multi-targeted tyrosine kinase inhibitor licensed for the treatment of hepatocellular carcinoma and renal cell carcinoma. Thyroid function test abnormalities have been reported for different tyrosine kinase inhibitors, but only limited data on thyroid function test abnormalities related to sorafenib are available, demonstrating the occurrence of hypothyroidism in patients treated with sorafenib. We describe two patients who developed temporary hyperthyroidism during the course of sorafenib treatment, which was followed by overt and subclinical hypothyroidism, respectively. Thyroid ultrasonography showed an atrophic thyroid gland in patient 1 , and signs of thyroiditis in patient 2 . Detailed reassessment of thyroid volumes on routinely performed computerized tomography scans showed a gradual decrease in thyroid volume during sorafenib treatment in one patient, suggesting progressive thyroid destruction. This case report describes in detail and for the first time two cases of sorafenib-induced thyroiditis. We assume that this sorafenib-induced destructive thyroiditis is an important cause of sorafenib-induced hypothyroidism.

Agaricus blazei Murill enhances doxorubicin-induced apoptosis in human hepatocellular carcinoma cells by NFκB-mediated increase of intracellular doxorubicin accumulation.

PubMed

Lee, Jong Seok; Hong, Eock Kee

2011-02-01

It has been demonstrated that the Agaricus blazei Murill (ABM) mushroom, which primarily consists of polysaccharides, possesses anti-tumor activities. However, the mechanisms by which ABM inhibits human hepatocellular carcinoma growth remain unknown. Our study demonstrates that ABM acts as an enhancer to sensitize doxorubicin (Dox)-mediated apoptotic signaling, and this sensitization can be achieved by enhancing intracellular Dox accumulation via the inhibition of NFκB activity. These findings suggest that ABM, when combined with low doses of Dox, has the potential to provide more efficient therapeutic effects against drug-resistant human hepatocellular carcinoma.

Combination of Permanent Interstitial 125I-Seed Brachytherapy and Surgery for the Treatment of Large Hepatocellular Carcinoma

PubMed Central

Li, Xiaogang; Li, Bo; Yang, Rong; Luo, Kaiyuan

2017-01-01

The treatment methods available for large primary hepatocellular carcinomas (diameter >5 cm) are inadequate. Here, we report the successful management of 80 cases of large hepatocellular carcinoma, using a combination of custom-designed permanent interstitial iodine-125 seed brachytherapy and palliative surgery. Patients were enrolled in the study between 2011 and 2014. All patients underwent surgical treatment along with permanent interstitial iodine-125 seed brachytherapy; for the latter, patients received minimum doses covering 90% of the target (D90 s) of iodine-125 seeds ranging from 100 to 160 Gy (median: 110 Gy). All patients received 6 cycles of chemotherapy and were followed up at 6, 12, 24, and 36 months postoperatively. The clinical symptom remission rate was 95.3% (61 of 64). Alanine aminotransferase and aspartate aminotransferase levels decreased to normal in 80% (50 of 60) and 75% of the patients (45 of 60), respectively. The posttreatment alpha-fetoprotein levels decreased by 50% in 80% of the patients (40 of 50). The effective therapy rates were 80% (76 of 95) for 95 tumor nodules (diameters 5-10 cm) and 78.6% (33 of 42) for 42 tumor nodules (diameters >10 cm). The 3-year disease-free survival rate was 66.6%. Palliative surgery plus permanent interstitial iodine-125 seed brachytherapy appears to be a reasonable therapeutic alternative for large hepatocellular carcinoma. PMID:28585493

Long non-coding RNA PVT1 serves as a competing endogenous RNA for miR-186-5p to promote the tumorigenesis and metastasis of hepatocellular carcinoma.

PubMed

Lan, Tian; Yan, Xia; Li, Zhuo; Xu, Xin; Mao, Qi; Ma, Weijie; Hong, Zhenfei; Chen, Xi; Yuan, Yufeng

2017-06-01

Hepatocellular carcinoma is third leading cause of cancer-related death globally. Long non-coding RNA plasmacytoma variant translocation 1 has been reported to be dysregulated and plays a crucial role in various cancers. In this study, we investigated the interactions between plasmacytoma variant translocation 1 and miR-186-5p in the progression of hepatocellular carcinoma and explored the functional significance of plasmacytoma variant translocation 1. It was determined that plasmacytoma variant translocation 1 was significantly higher, while miR-186-5p was statistically lower in the hepatocellular carcinoma tissues than that in the adjacent normal tissues. Using gain-of-function and loss-of-function methods, our results revealed that plasmacytoma variant translocation 1 affected hepatocellular carcinoma cells proliferation, invasion, and migration. It was found that there was direct interaction between miR-186-5p and the binding site of plasmacytoma variant translocation 1 by performing dual-luciferase assay and RNA immunoprecipitation assay. Furthermore, it was identified that plasmacytoma variant translocation 1 regulated the expression of the miR-186-5p target gene, yes-associated protein 1. Taken together, plasmacytoma variant translocation 1 served as an endogenous sponge for miR-186-5p to reduce its inhibiting effect on yes-associated protein 1 and thus promoted the tumorigenesis of hepatocellular carcinoma.

Targeted nanobubbles in low-frequency ultrasound-mediated gene transfection and growth inhibition of hepatocellular carcinoma cells.

PubMed

Wu, Bolin; Qiao, Qiang; Han, Xue; Jing, Hui; Zhang, Hao; Liang, Hongjian; Cheng, Wen

2016-09-01

The use of SonoVue combined with ultrasound exposure increases the transfection efficiency of short interfering RNA (siRNA). The objective of this study was to prepare targeted nanobubbles (TNB) conjugated with NET-1 siRNA and an antibody GPC3 to direct nanobubbles to hepatocellular carcinoma cells. SMMC-7721 human hepatocellular carcinoma cells were treated with six different groups. The transfection efficiency and cellular apoptosis were measured by flow cytometry. The protein and messenger RNA (mRNA) expression were measured by Western blot and quantitative real-time PCR, respectively. The migration and invasion potential of the cells were determined by Transwell analysis. The results show that US-guided siRNA-TNB transfection effectively enhanced gene silencing. In summary, siRNA-TNB may be an effective delivery vector to mediate highly effective RNA interference in tumor treatment.

Tissue-Specific Expression of Herpes Simplex Virus Thymidine Kinase Gene Delivered by Adeno-Associated Virus Inhibits the Growth of Human Hepatocellular Carcinoma in Athymic Mice

NASA Astrophysics Data System (ADS)

Su, Hua; Lu, Ronghua; Chang, Judy C.; Kan, Yuet Wai

1997-12-01

About 70% of hepatocellular carcinomas are known to express α -fetoprotein, which is normally expressed in fetal but not in adult livers. To induce herpes simplex virus-thymidine kinase expression in these cancer cells, we constructed an adeno-associated viral vector containing the HSV-TK gene under the control of the α -fetoprotein enhancer and albumin promoter. We previously demonstrated in vitro that although this vector can transduce a variety of human cells, only transduced AFP and albumin-expressing hepatocellular carcinoma cell lines were sensitive to killing by ganciclovir (GCV). In the present study, we explored the effect of this vector on hepatocellular carcinoma cells in vivo. Subcutaneous tumors generated in nude mice by implanting hepatocellular carcinoma cells previously transduced with this vector shrank dramatically after treatment with GCV. Bystander effect was also observed on the tumors generated by mixing transduced and untransduced cells. To test whether the tumor cells can be transduced by the virus in vivo, we injected the recombinant adeno-associated virus into tumors generated by untransduced hepatocarcinoma cell line. Tumor growth were retarded after treatment with GCV. These experiments demonstrate the feasibility of in vivo transduction of tumor cell with rAAV.

FOXO/TXNIP pathway is involved in the suppression of hepatocellular carcinoma growth by glutamate antagonist MK-801

PubMed Central

2013-01-01

Background Accumulating evidence has suggested the importance of glutamate signaling in cancer growth, yet the signaling pathway has not been fully elucidated. N-methyl-D-aspartic acid (NMDA) receptor activates intracellular signaling pathways such as the extracellular-signal-regulated kinase (ERK) and forkhead box, class O (FOXO). Suppression of lung carcinoma growth by NMDA receptor antagonists via the ERK pathway has been reported. However, series of evidences suggested the importance of FOXO pathways for the regulation of normal and cancer cell growth. In the liver, FOXO1 play important roles for the cell proliferation such as hepatic stellate cells as well as liver metabolism. Our aim was to investigate the involvement of the FOXO pathway and the target genes in the growth inhibitory effects of NMDA receptor antagonist MK-801 in human hepatocellular carcinoma. Methods Expression of NMDAR1 in cancer cell lines from different tissues was examined by Western blot. NMDA receptor subunits in HepG2, HuH-7, and HLF were examined by reverse transcriptase polymerase chain reaction (RT-PCR), and growth inhibition by MK-801 and NBQX was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The effects of MK-801 on the cell cycle were examined by flow cytometry and Western blot analysis. Expression of thioredoxin-interacting protein (TXNIP) and p27 was determined by real-time PCR and Western blotting. Activation of the FOXO pathway and TXNIP induction were examined by Western blotting, fluorescence microscopy, Chromatin immunoprecipitation (ChIP) assay, and reporter gene assay. The effects of TXNIP on growth inhibition were examined using the gene silencing technique. Results NMDA receptor subunits were expressed in all cell lines examined, and MK-801, but not NBQX, inhibited cell growth of hepatocellular carcinomas. Cell cycle analysis showed that MK-801 induced G1 cell cycle arrest by down-regulating cyclin D1 and up-regulating p

FABP4 suppresses proliferation and invasion of hepatocellular carcinoma cells and predicts a poor prognosis for hepatocellular carcinoma.

PubMed

Zhong, Cheng-Qian; Zhang, Xiu-Ping; Ma, Ning; Zhang, Er-Bin; Li, Jing-Jing; Jiang, Ya-Bo; Gao, Yu-Zhen; Yuan, Yan-Mei; Lan, Shi-Qian; Xie, Dong; Cheng, Shu-Qun

2018-05-07

Adipocyte fatty acid-binding protein (FABP4) is abundant in macrophage and adipocyte. It is known to be involved in lipid metabolism. The role of FABP4 has been reported in various cancers, such as non-small cell lung cancer, breast cancer, ovarian cancer, and prostatic cancer. However, its role remains unclear in hepatocellular carcinoma (HCC). In our study, we investigated the expression of FABP4 at both mRNA and protein levels, and by examining 175 cases of patients with cancer of the liver tissue microarray, the significance between the expression of FABP4 and clinical characteristics had been discussed. We found that FABP4 was lowly expressed in HCC tissues compared to the corresponding tissue adjacent, and the expression of FABP4 was significantly associated with the tumor size, PVTT, recurrence-free survival and overall survival. Moreover, multivariate Cox regression analysis indicated that the expression of FABP4, Alb, AFP, HBsAg, and PVTT were independent risk factors for overall survival, and the expression of FABP4, AFP, GGT, tumor size, and encapsulation were independent risk factors for HCC recurrence. In addition, we revealed that FABP4 suppressed HCC cell proliferation and invasion in vitro. Moreover, overexpression of FABP4 led to inhibit tumor growth and decreased tumor volume in vivo. These phenotypes were associated with altered expression of Snail and p-STAT3. Our studies thus suggest that FABP4 could be a potential target for HCC chemotherapy. © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Pilot Evaluation of Angiogenesis Signaling Factor Response after Transcatheter Arterial Embolization for Hepatocellular Carcinoma.

PubMed

Ronald, James; Nixon, Andrew B; Marin, Daniele; Gupta, Rajan T; Janas, Gemini; Chen, Willa; Suhocki, Paul V; Pabon-Ramos, Waleska; Sopko, David R; Starr, Mark D; Brady, John C; Hurwitz, Herbert I; Kim, Charles Y

2017-10-01

Purpose To identify changes in a broad panel of circulating angiogenesis factors after bland transcatheter arterial embolization (TAE), a purely ischemic treatment for hepatocellular carcinoma (HCC). Materials and Methods This prospective HIPAA-compliant study was approved by the institutional review board. Informed written consent was obtained from all participants prior to entry into the study. Twenty-five patients (21 men; mean age, 61 years; range, 30-81 years) with Liver Imaging Reporting and Data System category 5 or biopsy-proven HCC and who were undergoing TAE were enrolled from October 15, 2014, through December 2, 2015. Nineteen plasma angiogenesis factors (angiopoietin 2; hepatocyte growth factor; platelet-derived growth factor AA and BB; placental growth factor; vascular endothelial growth factor A and D; vascular endothelial growth factor receptor 1, 2, and 3; osteopontin; transforming growth factor β1 and β2; thrombospondin 2; intercellular adhesion molecule 1; interleukin 6 [IL-6]; stromal cell-derived factor 1; tissue inhibitor of metalloproteinases 1; and vascular cell adhesion molecule 1 [VCAM-1]) were measured by using enzyme-linked immunosorbent assays at 1 day, 2 weeks, and 5 weeks after TAE and were compared with baseline levels by using paired Wilcoxon tests. Tumor response was assessed according to modified Response Evaluation Criteria in Solid Tumors (mRECIST). Angiogenesis factor levels were compared between responders and nonresponders by mRECIST criteria by using unpaired Wilcoxon tests. Results All procedures were technically successful with no complications. Fourteen angiogenesis factors showed statistically significant changes following TAE, but most changes were transient. IL-6 was upregulated only 1 day after the procedure, but showed the largest increases of any factor. Osteopontin and VCAM-1 demonstrated sustained upregulation at all time points following TAE. At 3-month follow-up imaging, 11 patients had responses to TAE

Hepatocellular carcinoma: early-stage management challenges

PubMed Central

Erstad, Derek J; Tanabe, Kenneth K

2017-01-01

Hepatocellular carcinoma (HCC) is a major cause of cancer death and is increasing in incidence. This review focuses on HCC surveillance and treatment of early-stage disease, which are essential to improving outcomes. Multiple societies have published HCC surveillance guidelines, but screening efforts have been limited by noncompliance and overall lack of testing for patients with undiagnosed chronic liver disease. Treatment of early-stage HCC has become increasingly complex due to expanding therapeutic options and better outcomes with established treatments. Surgical indications for HCC have broadened with improved preoperative liver testing, neoadjuvant therapy, portal vein embolization, and perioperative care. Advances in post-procedural monitoring have improved efficacies of transarterial chemoembolization and radiofrequency ablation, and novel therapies involving delivery of radiochemicals are being studied in small trials. Finally, advances in liver transplantation have allowed for expanded indications beyond Milan criteria with non-inferior outcomes. More clinical trials evaluating new therapies and multimodal regimens are necessary to help clinicians design better treatment algorithms and improve outcomes. PMID:28721349

Traditional herbal medicine prevents postoperative recurrence of small hepatocellular carcinoma: A randomized controlled study.

PubMed

Zhai, Xiao-Feng; Liu, Xiao-Lin; Shen, Feng; Fan, Jia; Ling, Chang-Quan

2018-05-15

To explore the clinical efficacy of traditional herbal medicine (THM) in the prevention of disease recurrence of small hepatocellular carcinoma after surgery, a prospective randomized controlled study was conducted between October 2006 and May 2010. The results indicated that THM prevented the recurrence of SHCC with an efficacy that was superior to that of transarterial chemoembolization (TACE) during a median follow-up of 26.61 months. The patients were followed up every 6 months, and the clinical data before October 20, 2015 were analyzed. The primary outcome measure was recurrence-free survival (RFS), and the secondary outcome measure was overall survival (OS). The 364 patients included 180 in the THM group and 184 in the TACE group. At the time of the data cutoff of October 20, 2015, a total of 205 patients demonstrated disease recurrence, including 85 patients in the THM group and 120 patients in the TACE group. The median RFS of the THM and TACE groups demonstrated a statistically significant difference (P<.001). Until October 20, 2105, there were 91 deaths, including 34 in the THM group and 57 in the TACE group. The median OS demonstrated a significant difference between the 2 groups (P = .008). Multivariate analysis indicated that THM was an independent factor influencing RFS and OS. The efficacy of THM was found to be superior to that of TACE in preventing disease recurrence in patients with small hepatocellular carcinoma and prolonging OS. Cancer 2018;124:2161-8. © 2018 American Cancer Society. © 2018 American Cancer Society.

Agenesis of the left hepatic lobe undergoing laparoscopic hepatectomy for hepatocellular carcinoma: a case report.