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Sample records for hepatocellular carcinoma differentiated

  1. Hepatocellular carcinoma.

    PubMed

    Buendia, Marie-Annick; Neuveut, Christine

    2015-02-01

    The hepatitis B virus (HBV) is a widespread human pathogen that causes liver inflammation, cirrhosis, and hepatocellular carcinoma (HCC). Recent sequencing technologies have refined our knowledge of the genomic landscape and pathogenesis of HCC, but the mechanisms by which HBV exerts its oncogenic role remain controversial. In a prevailing view, inflammation, liver damage, and regeneration may foster the accumulation of genetic and epigenetic defects leading to cancer onset. However, a more direct and specific contribution of the virus is supported by clinical and biological observations. Among genetically heterogeneous HCCs, HBV-related tumors display high genomic instability, which may be attributed to the ability of HBV to integrate its DNA into the host cell genome, provoking chromosomal alterations and insertional mutagenesis of cancer genes. The viral transactivator HBx may also participate in transformation by deregulating diverse cellular machineries. A better understanding of the complex mechanisms linking HBV to HCC will improve prevention and treatment strategies. PMID:25646384

  2. Liver cancer - hepatocellular carcinoma

    MedlinePlus

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

  3. [Hepatocellular carcinoma].

    PubMed

    Colombo, Massimo; Sangiovanni, Angelo

    2016-07-01

    Hepatocellular carcinoma (HCC) is the third leading cause of cancer death and the first in patients with compensated cirrhosis. Chronic infection with hepatitis B and C, alcohol, smoking, exposure to aflatoxin and metabolic syndrome, associated with diabetes and obesity are the main etiological factors. Regardless of etiology, patients with cirrhosis stand as the category at higher risk of developing HCC, and indeed are the target of surveillance programs aimed to the early diagnosis of HCC, the only chance to reduce HCC-related mortality. This notwithstanding, International Scientific Societies have issued recommendations for the management of HCC, a significant number of patients are treated outside guidelines, due to several reasons. Among queries still unsolved, the impact of biological characterization of HCC, along with the biological profiling of patients at risk of developing HCC represent main challenges for the future. Treatment personalization and multimodal treatment being further challenges. This chapter summarizes the recommendations for surveillance, diagnosis and treatment of HCC and focus on future directions. PMID:27571469

  4. LIGHT MICROSCOPICAL AND ELECTRON MICROSCOPICAL COMPARISONS OF NORMAL HEPATOCYTES OF WELL-DIFFERENTIATED HEPATOCELLULAR CARCINOMAS IN A TELEOST FISH

    EPA Science Inventory

    Well-differentiated hepatocellular carcinomas (HCC's) induced in the sheepshead minnow (Cyprinodon variagatus) with N-nitrosodiethylamine, permitted light microscopical and ultrastructural comparisons of normal hepatocytes and adjacent HCC cells. ormal hepatocytes contained typic...

  5. Combined use of heat-shock protein 70 and glutamine synthetase is useful in the distinction of typical hepatocellular adenoma from atypical hepatocellular neoplasms and well-differentiated hepatocellular carcinoma.

    PubMed

    Nguyen, Thuy B; Roncalli, Massimo; Di Tommaso, Luca; Kakar, Sanjay

    2016-03-01

    Well-differentiated hepatocellular carcinoma can mimic high-grade dysplastic nodule in cirrhotic liver and hepatocellular adenoma in non-cirrhotic liver. This study evaluates the efficacy of combined use of heat-shock protein 70 (HSP70), glutamine synthetase (GS) and glypican-3 in this setting. Immunohistochemistry for these three markers was done in 17 typical hepatocellular adenoma, 15 high-grade dysplastic nodules, 20 atypical hepatocellular neoplasms (14 clinically atypical and 6 pathologically atypical), 14 very well-differentiated hepatocellular carcinoma, and 43 well-differentiated hepatocellular carcinoma. All three markers were negative in typical adenomas. HSP70 was positive in 10, 71, and 67% of atypical neoplasms, very well-differentiated and well-differentiated HCC, respectively, while GS was positive in 60, 50, and 60% of atypical neoplasms, very well-differentiated and well-differentiated hepatocellular carcinoma, respectively. Glypican-3 was negative in all atypical neoplasms and very well-differentiated hepatocellular carcinoma, and was positive in 27% of well-differentiated hepatocellular carcinoma. Positive staining with at least one marker (HSP70 and/or GS) was seen in 85% of very well-differentiated hepatocellular carcinoma, which was similar to well-differentiated hepatocellular carcinoma (78%, P=0.4), and pathologically atypical cases (100%, P=0.5), but significantly higher compared with clinically atypical cases (43%. P=0.03) and none of typical adenomas (P<0.001). Positive staining with both GS and HSP70 was seen significantly more often in hepatocellular carcinoma compared with atypical neoplasms (45 vs 10%, P=0.004). Both these markers were also more often expressed in very well-differentiated hepatocellular carcinoma compared with atypical cases (38 vs 10%, P=0.06). In conclusion, the combined use of GS and HSP70 can be useful in the diagnosis of very well-differentiated hepatocellular carcinoma. These stains can also help in the

  6. Hepatocellular carcinoma.

    PubMed

    Edwards, J T; Macdonald, G A

    2000-05-01

    The incidence of hepatocellular carcinoma (HCC) appears to be declining in Taiwan and potentially in other high-prevalence areas as a consequence of vaccination for hepatitis B virus (HBV). However, there is evidence that the incidence of HCC is increasing in North America and Europe. This appears to be related to the increasing prevalence and duration of hepatitis C virus (HCV) infection in these countries. There is also growing evidence to support an increase in the risk of HCC in patients with HCV who are coinfected with occult HBV (patients who have lost HBV surface antigen but still have detectable HBV DNA either in blood or liver). Occult HBV infection in patients with HCV may be more common than previously thought, and HCC that occurs in this setting appears to have a worse prognosis. There is continuing interest in the effect of interferon therapy on the incidence of HCC in patients with HCV. Several studies from Japan have shown a benefit in patients without cirrhosis, although there are a number of potentially confounding variables that may partly explain these results. Prospective randomized studies are needed to investigate this important question. The molecular biology of HCC and the events of malignant transformation in the liver continue to be areas of intense study. Recently, there has been considerable interest in telomeres, the repeat units on the ends of chromosomes, and the enzyme that maintains these, telomerase. Telomeres shorten with each cell division and can be used to determine the number of divisions a cell has undergone. Eventually they reach a critical length, with further loss resulting in cellular senescence. Telomerase restores telomere length and may help malignant cells escape senescence. Nearly all HCCs have telomerase activity and assessments of telomeres and telomerase may be clinically useful. PMID:17023886

  7. Immunohistochemical expression of SALL4 in hepatocellular carcinoma, a potential pitfall in the differential diagnosis of yolk sac tumors.

    PubMed

    Gonzalez-Roibon, Nilda; Katz, Betina; Chaux, Alcides; Sharma, Rajni; Munari, Enrico; Faraj, Sheila F; Illei, Peter B; Torbenson, Michael; Netto, George J

    2013-07-01

    SALL4 is a transcription factor that serves as a marker of yolk sac tumor. Yolk sac tumor and hepatocellular carcinoma share histologic, serologic, and immunohistochemical features. Previous studies have shown lack of SALL4 expression in hepatocellular carcinoma, suggesting utility in this differential diagnosis. Sixty-nine samples of hepatocellular carcinoma were retrieved from surgical pathology archives and used to construct 9 tissue microarrays. A germ cell tumor tissue microarray containing 10 yolk sac tumors was used for comparison. Extent, intensity, and pattern of nuclear SALL4 expression were assessed in each spot. Mean percentage of expression was calculated for each tumor and used during analysis. Optimal discriminatory extent of expression cutoff was determined by receiver operating characteristic curve analysis. Other potential discriminatory markers including Hep Par1 were also evaluated. Forty-six percent (32/69) of hepatocellular carcinoma and all yolk sac tumors revealed at least focal expression of SALL4. A unique punctuate/clumped pattern of nuclear staining was present in 94% (30/32) of hepatocellular carcinoma, whereas all yolk sac tumors displayed a diffuse finely granular nuclear staining pattern. A 25% extent of SALL4 expression cutoff was found to be optimal for the distinction of yolk sac tumor from hepatocellular carcinoma yielding a sensitivity of 100%, specificity of 92.8%, and a positive predictive value of 66.6% for yolk sac tumor diagnosis. The addition of Hep Par1 increased the specificity (99%) and positive predictive value (90%). This is the first report of SALL4 expression in hepatocellular carcinoma. Our finding should be taken into consideration in the differential diagnosis of hepatocellular carcinoma and yolk sac tumor. The unique punctuate/clumped pattern seen in hepatocellular carcinoma cases could be of further discriminatory value. PMID:23347651

  8. Well-differentiated hepatocellular carcinoma in a ring-tailed lemur (Lemur catta).

    PubMed

    Nemeth, N M; Blas-Machado, U; Cazzini, P; Oguni, J; Camus, M S; Dockery, K K; Butler, A M

    2013-02-01

    A 16-year-old male ring-tailed lemur (Lemur catta) was presented with severe cachexia and an abdominal mass. The encapsulated, multilobular mass replaced the right medial lobe of the liver and compressed the adjacent gall bladder. Multiple haemorrhages and necrotic foci were found within the mass. Microscopically, neoplastic cells formed cords of moderately pleomorphic, polygonal cells with mild to moderate anaplasia. Immunohistochemical markers used for diagnosis of hepatocellular carcinomas in man were used to characterize the neoplastic cells, which expressed hepatocyte-specific antigen, but not glypican-3 or polyclonal carcinoembryonic antigen. Gross, microscopical and immunohistochemical features of the tumour were most consistent with a well-differentiated hepatocellular carcinoma. Although this tumour is common among prosimians, to the authors' knowledge this is the first documented case in a ring-tailed lemur. Hepatocellular carcinomas have been associated with hepatitis virus infections and excessive hepatic iron in man; however, no association was established between this tumour and viral infection or hepatic iron storage disease in the present case. PMID:22819017

  9. Liver cancer - hepatocellular carcinoma

    MedlinePlus

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

  10. Differentially expressed gene profiles of intrahepatic cholangiocarcinoma, hepatocellular carcinoma, and combined hepatocellular-cholangiocarcinoma by integrated microarray analysis.

    PubMed

    Xue, Tong-Chun; Zhang, Bo-Heng; Ye, Sheng-Long; Ren, Zheng-Gang

    2015-08-01

    Intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC) are common primary liver cancers worldwide. However, the survival and prognosis of ICC are much poorer than those of HCC, indicating the different molecular characteristics and mechanisms between ICC and HCC. To identify differentially expressed (DE) genes between ICC and HCC or combined hepatocellular-cholangiocarcinoma (CHC), we performed integrated analysis of publicly available microarray Gene Expression Omnibus (GEO) datasets by MetaOmics. Three GEO datasets comprising 32 ICC biochips, 77 HCC biochips, and 34 CHC biochips were available for the data integration. We identified 7313 DE genes between ICC and HCC, including 3650 upregulated genes and 3663 downregulated genes. The S100 family members on chromosome 1q21 were extensively upregulated in ICC, and S100A11 had the greatest degree of upregulation in ICC. Based on the DE genes, combined gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis showed the enhanced pathways of local adhesion, ECM-receptor interaction, and regulation of action cytoskeleton, suggesting the enhanced communication between ICC and the microenvironment. Additionally, development-related genes and development-related pathways, including the Notch, Wnt, and TGF-β signaling pathways, were shown to be active prominently in ICC. Taken together, we identified the characteristically upregulated or downregulated DE genes and pathways in ICC compared with HCC or CHC. These DE genes and pathways supply new transcriptomics evidence for ICC and could help identify new therapeutic targets. PMID:25712376

  11. Quantitative proteomic analysis for high-throughput screening of differential glycoproteins in hepatocellular carcinoma serum

    PubMed Central

    Gao, Hua-Jun; Chen, Ya-Jing; Zuo, Duo; Xiao, Ming-Ming; Li, Ying; Guo, Hua; Zhang, Ning; Chen, Rui-Bing

    2015-01-01

    Objective Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths. Novel serum biomarkers are required to increase the sensitivity and specificity of serum screening for early HCC diagnosis. This study employed a quantitative proteomic strategy to analyze the differential expression of serum glycoproteins between HCC and normal control serum samples. Methods Lectin affinity chromatography (LAC) was used to enrich glycoproteins from the serum samples. Quantitative mass spectrometric analysis combined with stable isotope dimethyl labeling and 2D liquid chromatography (LC) separations were performed to examine the differential levels of the detected proteins between HCC and control serum samples. Western blot was used to analyze the differential expression levels of the three serum proteins. Results A total of 2,280 protein groups were identified in the serum samples from HCC patients by using the 2D LC-MS/MS method. Up to 36 proteins were up-regulated in the HCC serum, whereas 19 proteins were down-regulated. Three differential glycoproteins, namely, fibrinogen gamma chain (FGG), FOS-like antigen 2 (FOSL2), and α-1,6-mannosylglycoprotein 6-β-N-acetylglucosaminyltransferase B (MGAT5B) were validated by Western blot. All these three proteins were up-regulated in the HCC serum samples. Conclusion A quantitative glycoproteomic method was established and proven useful to determine potential novel biomarkers for HCC. PMID:26487969

  12. Enhanced glypican-3 expression differentiates the majority of hepatocellular carcinomas from benign hepatic disorders

    PubMed Central

    Zhu, Z; Friess, H; Wang, L; Abou-Shady, M; Zimmermann, A; Lander, A; Korc, M; Kleeff, J; Buchler, M

    2001-01-01

    BACKGROUND/AIMS—Hepatocellular carcinoma (HCC) is a common malignant tumour worldwide, and its differential diagnosis from benign lesions of the liver is often difficult yet of great clinical importance. In the present study, we analysed whether glypican-3 is useful in differentiating between benign and malignant liver diseases and whether it influences the growth behaviour of HCC.
METHODS—Northern blot analysis and in situ hybridisation.
RESULTS—Northern blot analysis indicated that expression of glypican-3 mRNA was either low or absent in normal liver, in focal nodular hyperplasia (FNH), and in liver cirrhosis. In contrast, expression of glypican-3 mRNA was markedly increased in 20 of 30 and moderately increased in five of 30 HCC samples. The average increase in glypican-3 mRNA expression in HCC was significant compared with expression in normal liver (21.7-fold increase, p<0.01). In comparison with FNH or liver cirrhosis, glypican-3 mRNA expression in HCC was increased 7.2- (p<0.05) and 10.8-fold (p<0.01), respectively. In addition, pushing HCCs exhibited significantly higher glypican-3 mRNA expression than invading tumours (p<0.05). In situ hybridisation analysis demonstrated weak expression of glypican-3 mRNA in normal hepatocytes and bile ductular cells, and weak to occasionally moderate signals in hepatocytes forming nodules of liver cirrhosis and in regenerated hepatic nodules of FNH. In contrast, glypican-3 in situ hybridisation signals were intense in hepatic cancer cells with even higher levels in pushing HCCs than in invading HCCs.
CONCLUSIONS—These findings suggest that glypican-3, in many cases, has the potential to differentiate between benign and malignant liver diseases.


Keywords: focal nodular hyperplasia; liver cirrhosis; hepatocellular cancer; glypican-3 PMID:11247902

  13. Association Between Expression of Cancer Stem Cell Markers and Poor Differentiation of Hepatocellular Carcinoma

    PubMed Central

    Liu, Rui; Shen, Yuan; Nan, Kejun; Mi, Baibing; Wu, Tao; Guo, Jinyue; Li, Miaojing; Lv, Yi; Guo, Hui

    2015-01-01

    Abstract The role of cancer stem cell (CSC) markers in differentiation of hepatocellular carcinoma (HCC) remains uncertain. We conducted a meta-analysis to first investigate the association between expression of CSC markers (CD133, CD90, CD44, and EpCAM) and poor differentiation of HCC, and second, to determine if these CSC markers can be classified as biomarkers for patient classification and HCC differentiated therapy. The relevant literature was searched using PubMed, EMBASE, Elsevier, and Chinese Biological Medicine databases for association between CSC markers and HCC from January 1, 2000 to June 30, 2014. Data were synthesized using random-effect or fixed-effect models. The effect sizes were estimated by measuring odds ratios (OR) with 95% confidence interval (CI). The meta-analysis included 27 studies consisting of 2897 patients with HCC. The positive expression of CSC markers was associated with poor differentiation (OR = 2.37, 95% CI = 2.03–2.77, P < 0.00001). Similarly, the positive expression of CSC markers was only associated with HCC tissues compared with noncancerous liver tissues (OR = 9.26, 95% CI = 3.10–27.65, P < 0.0001). CD90 has a specificity of 91.9% for HCC and a sensitivity of 48.22% in predicting poor differentiation. The positive expression of CSC markers is associated with poor differentiation and aggressive phenotype of patients with HCC. The CD90 marker might be a promising target for patient with HCC classification and differentiation therapy. PMID:26252310

  14. Differential Expression of Sonic Hedgehog Protein in Human Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma.

    PubMed

    Al-Bahrani, Redha; Nagamori, Seishi; Leng, Roger; Petryk, Anna; Sergi, Consolato

    2015-09-01

    Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (CCA) are the two most common primary liver malignancies in adult patients. The molecular mechanisms underlying the pathogenesis of HCC and CCA are still poorly understood. Sonic hedgehog (SHH) signaling plays an essential role during mammalian development, i.e., promoting organ growth, tissue differentiation, and cell polarity. The upregulation of SHH has been observed during carcinogenesis, including colorectal carcinoma. Our aim was to investigate the expression pattern of SHH in HCC and CCA. We investigated 40 malignant tumors of the liver, including 21 HCC and 19 of intrahepatic CCA cases by immunohistochemistry (IHC) using a polyclonal antibody against SHH and Avidin-Biotin Complex method. We also investigated the co-localization of SHH and Bone morphogenetic protein 4 (BMP4) in CCA using indirect double IHC. Moreover, we examined whether SHH is expressed in two HCC cell lines HepG2 and HuH-7 and three CCA cell lines OZ, HuCCT1 and HuH28. We found that SHH was expressed in 15 out of 21 cases (71.4 %) of HCC and 100 % of CCA cases by immunohistochemistry. SHH expression showed a positive trend in liver tumors (HCC, CCA) with high grade (G2-G3). SHH localized to the epithelial cells, while BMP4 was expressed in the stromal cells in CCA by double IHC. However, both HCC and CCA cell lines showed SHH expression by Western blot analysis. In conclusion, SHH seems to be an interesting marker of de-differentiation in liver tumors and the simultaneous epithelial-mesenchymal expression may be an intriguing prompt to investigate cross-talks between SHH and BMP4. PMID:25740074

  15. Enhanced reactive oxygen species overexpression by CuO nanoparticles in poorly differentiated hepatocellular carcinoma cells

    NASA Astrophysics Data System (ADS)

    Kung, Mei-Lang; Hsieh, Shu-Ling; Wu, Chih-Chung; Chu, Tian-Huei; Lin, Yu-Chun; Yeh, Bi-Wen; Hsieh, Shuchen

    2015-01-01

    Copper oxide nanoparticles (CuO NPs) are known to exhibit toxic effects on a variety of cell types and organs. To determine the oxidative impact of CuO NPs on hepatocellular carcinoma (HCC) cells, well-differentiated (HepG2) and poorly differentiated (SK-Hep-1) cells were exposed to CuO NPs. Cell viability assay showed that the median inhibition concentration (IC50) for SK-Hep-1 and HepG2 cells was 25 μg ml-1 and 85 μg ml-1, respectively. Cellular fluorescence intensity using DCFH-DA staining analysis revealed significant intracellular reactive oxygen species (ROS) generation of up to 242% in SK-Hep-1 cells, compared with 86% in HepG2 cells. HPLC analysis demonstrated that a CuO NP treatment caused cellular GSH depletion of 58% and a GSH/GSSG ratio decrease to ~0.1 in SK-Hep-1 cells. The oxidative stress caused by enhanced superoxide anion production was observed in both HepG2 (146%) and SK-Hep-1 (192%) cells. The Griess assay verified that CuO NPs induced NO production (170%) in SK-Hep-1 cells. Comet assay and western blot further demonstrated that CuO NPs induced severe DNA strand breakage (70%) in SK-Hep-1 cells and caused DNA damage via increased γ-H2AX levels. These results suggest that well-differentiated HepG2 cells possess a robust antioxidant defense system against CuO NP-induced ROS stress and exhibit more tolerance to oxidative stress. Conversely, poorly differentiated SK-Hep-1 cells exhibited a deregulated antioxidant defense system that allowed accumulation of CuO NP-induced ROS and resulted in severe cytotoxicity.Copper oxide nanoparticles (CuO NPs) are known to exhibit toxic effects on a variety of cell types and organs. To determine the oxidative impact of CuO NPs on hepatocellular carcinoma (HCC) cells, well-differentiated (HepG2) and poorly differentiated (SK-Hep-1) cells were exposed to CuO NPs. Cell viability assay showed that the median inhibition concentration (IC50) for SK-Hep-1 and HepG2 cells was 25 μg ml-1 and 85 μg ml-1, respectively

  16. Co-expression analysis of differentially expressed genes in hepatitis C virus-induced hepatocellular carcinoma.

    PubMed

    Song, Qingfeng; Zhao, Chang; Ou, Shengqiu; Meng, Zhibin; Kang, Ping; Fan, Liwei; Qi, Feng; Ma, Yilong

    2015-01-01

    The aim of the current study was to investigate the molecular mechanisms underlying hepatitis C virus (HCV)-induced hepatocellular carcinoma (HCC) using the expression profiles of HCV-infected Huh7 cells at different time points. The differentially expressed genes (DEGs) were identified with the Samr package in R software once the data were normalized. Functional and pathway enrichment analysis of the identified DEGs was also performed. Subsequently, MCODE in Cytoscape software was applied to conduct module analysis of the constructed co-expression networks. A total of 1,100 DEGs were identified between the HCV-infected and control samples at 12, 18, 24 and 48 h post-infection. DEGs at 24 and 48 h were involved in the same signaling pathways and biological processes, including sterol biosynthetic processes and tRNA amino-acylation. There were 22 time series genes which were clustered into 3 expression patterns, and the demarcation point of the 2 expression patterns that 401 overlapping DEGs at 24 and 48 h clustered into was 24 h post-infection. tRNA synthesis-related biological processes emerged at 24 and 48 h. Replication and assembly of HCV in HCV-infected Huh7 cells occurred mainly at 24 h post-infection. In view of this, the screened time series genes have the potential to become candidate target molecules for monitoring, diagnosing and treating HCV-induced HCC. PMID:25339452

  17. Assessment of XAF1 as A Biomarker to Differentiate Hepatocellular Carcinoma from Nonneoplastic Liver Tissues

    PubMed Central

    Lin, Ying

    2012-01-01

    Objective XIAP-associated factor 1 (XAF1) expression has been shown to be related with apoptosis in hepatocellular carcinoma (HCC). However, the correlation of XAF1 expression with HCC tumor grade has not been intensively assessed. XIAP-associated factor-1 (XAF1) is an important apoptosis inducer in human HCC. The aim of this study is to determine the correlation between XAF1 expression and HCC histopathological grades. Methods The mRNA levels of XAF1 in 24 paired HCC-nonneoplastic specimens were quantified by real-time reverse transcription PCR (RT-PCR). Protein levels of XAF1 in 110 paired HCC-noncancer tissues were investigated by immunostaining specimens on a tissue microarray (TMA). Correlations between XAF1 mRNA levels or protein expression and clinicopathological features were assessed by statistical analysis. Results Both XAF1 mRNA and protein were significantly under-expressed in HCC tissues compared to their non-neoplastic counterparts. No significant relationship was found between XAF1 mRNA or protein expression and histological tumor grade. Conclusion All these data suggest that XAF1 is a potential biomarker for differentiating HCC with noncancerous tissues. PMID:23358741

  18. Co-expression analysis of differentially expressed genes in hepatitis C virus-induced hepatocellular carcinoma

    PubMed Central

    SONG, QINGFENG; ZHAO, CHANG; OU, SHENGQIU; MENG, ZHIBIN; KANG, PING; FAN, LIWEI; QI, FENG; MA, YILONG

    2015-01-01

    The aim of the current study was to investigate the molecular mechanisms underlying hepatitis C virus (HCV)-induced hepatocellular carcinoma (HCC) using the expression profiles of HCV-infected Huh7 cells at different time points. The differentially expressed genes (DEGs) were identified with the Samr package in R software once the data were normalized. Functional and pathway enrichment analysis of the identified DEGs was also performed. Subsequently, MCODE in Cytoscape software was applied to conduct module analysis of the constructed co-expression networks. A total of 1,100 DEGs were identified between the HCV-infected and control samples at 12, 18, 24 and 48 h post-infection. DEGs at 24 and 48 h were involved in the same signaling pathways and biological processes, including sterol biosynthetic processes and tRNA amino-acylation. There were 22 time series genes which were clustered into 3 expression patterns, and the demarcation point of the 2 expression patterns that 401 overlapping DEGs at 24 and 48 h clustered into was 24 h post-infection. tRNA synthesis-related biological processes emerged at 24 and 48 h. Replication and assembly of HCV in HCV-infected Huh7 cells occurred mainly at 24 h post-infection. In view of this, the screened time series genes have the potential to become candidate target molecules for monitoring, diagnosing and treating HCV-induced HCC. PMID:25339452

  19. Genome-wide identification of differential methylation between primary and recurrent hepatocellular carcinomas.

    PubMed

    Cui, Chenghua; Lu, Zheming; Yang, Liu; Gao, Yanhong; Liu, Wei; Gu, Liankun; Yang, Chen; Wilson, James; Zhang, Zhiqian; Xing, Baocai; Deng, Dajun; Sun, Zhong Sheng

    2016-07-01

    A biomarker capable of clinically predicting hepatocellular carcinoma (HCC) recurrence has not previously been established. Here genome-wide differential methylation between primary and recurrent HCC cell lines (Hep-11 and Hep-12) from the same patient was characterized. The HCC samples from two independent cohorts, complete with follow-up data, were used to validate the feasibility of the selected methylation biomarkers in predicting HCC prognosis. A methylation array assay identified 30 candidate genes or intergenic-fragments with an absolute methylation fold-change >2.0 between these cell lines; 22 candidates were hypomethylated in Hep-12 cells relative to Hep-11 cells. Bisulfite sequencing confirmed these results. Most importantly, classification of tumors by LINE-2 methylation level was significantly associated with HCC recurrence in both cohorts (P < 0.02). Similarly, MAD1L1 and LINC00682 methylation levels also correlated with HCC recurrence. Survival analysis showed that a combined baseline LINE-2, MAD1L1, and LINC00682 methylation signature was significantly associated with short recurrence-free survival in patients from both cohorts. A synergic effect was observed between these markers on both recurrence-free survival (P < 0.010) and overall survival (P < 0.040). In conclusion, low levels of LINE-2, MAD1L1, and LINC00682 methylation were associated with recurrence and decreased overall survival in HCC patients. © 2015 Wiley Periodicals, Inc. PMID:26138747

  20. Biomarkers for Hepatocellular Carcinoma

    PubMed Central

    Behne, Tara; Copur, M. Sitki

    2012-01-01

    The hepatocellular carcinoma (HCC) is one of the most common malignant tumors and carries a poor survival rate. The management of patients at risk for developing HCC remains challenging. Increased understanding of cancer biology and technological advances have enabled identification of a multitude of pathological, genetic, and molecular events that drive hepatocarcinogenesis leading to discovery of numerous potential biomarkers in this disease. They are currently being aggressively evaluated to establish their value in early diagnosis, optimization of therapy, reducing the emergence of new tumors, and preventing the recurrence after surgical resection or liver transplantation. These markers not only help in prediction of prognosis or recurrence but may also assist in deciding appropriate modality of therapy and may represent novel potential targets for therapeutic interventions. In this paper, a summary of most relevant available data from published papers reporting various tissue and serum biomarkers involved in hepatocellular carcinoma was presented. PMID:22655201

  1. Biomarkers for hepatocellular carcinoma.

    PubMed

    Behne, Tara; Copur, M Sitki

    2012-01-01

    The hepatocellular carcinoma (HCC) is one of the most common malignant tumors and carries a poor survival rate. The management of patients at risk for developing HCC remains challenging. Increased understanding of cancer biology and technological advances have enabled identification of a multitude of pathological, genetic, and molecular events that drive hepatocarcinogenesis leading to discovery of numerous potential biomarkers in this disease. They are currently being aggressively evaluated to establish their value in early diagnosis, optimization of therapy, reducing the emergence of new tumors, and preventing the recurrence after surgical resection or liver transplantation. These markers not only help in prediction of prognosis or recurrence but may also assist in deciding appropriate modality of therapy and may represent novel potential targets for therapeutic interventions. In this paper, a summary of most relevant available data from published papers reporting various tissue and serum biomarkers involved in hepatocellular carcinoma was presented. PMID:22655201

  2. Prevention of hepatocellular carcinoma.

    PubMed

    Kew, Michael C

    2010-01-01

    Because of its frequency and grave prognosis, preventing hepatocellular carcinoma is an urgent priority. Prevention should be possible because environmental carcinogens-chronic hepatitis B and C virus infections, dietary exposure to aflatoxins, and iron overload-cause the great majority of these tumors. Chronic hepatitis B virus infection accounts for 55% of global hepatocellular carcinomas and 80% of those in the high-incidence Asia Pacific and sub-Saharan African regions. In these regions the infection that becomes chronic is predominantly acquired very early in life. A safe and effective vaccine against this virus is available and its universal inclusion in the immunization of infants has already resulted in a marked reduction of chronic infection and a 70% decrease in the occurrence of hepatocellular carcinoma in those immunized. Chronic hepatitis C virus infection is the major cause of hepatocellular carcinoma in industrialized countries. The infection is mainly acquired in adulthood and, until a vaccine becomes available, prevention will consist mainly of identifying, counselling, and treating chronically infected individuals, preventing spread of the virus by the use of safe injection practices (particularly in intravenous drug abusers), and screening all donated blood for the presence of the virus. 4.5 billion of the world.s population are exposed to dietary aflatoxins. Prevention involves treating susceptible crops to prevent fungal contamination, and handling the foodstuffs in such a way as to prevent contamination during storage. Iron overload in hereditary hemochromatosis can be prevented by repeated venesection and in African dietary iron overload by fermenting the home-brewed beer in iron-free containers. PMID:20526004

  3. Distinguishing intrahepatic cholangiocarcinoma from poorly differentiated hepatocellular carcinoma using precontrast and gadoxetic acid-enhanced MRI

    PubMed Central

    Asayama, Yoshiki; Nishie, Akihiro; Ishigami, Kousei; Ushijima, Yasuhiro; Takayama, Yukihisa; Fujita, Nobuhiro; Kubo, Yuichiro; Aishima, Shinichi; Shirabe, Ken; Yoshiura, Takashi; Honda, Hiroshi

    2015-01-01

    PURPOSE We aimed to gain further insight in magnetic resonance imaging characteristics of mass-forming intrahepatic cholangiocarcinoma (mICC), its enhancement pattern with gadoxetic acid contrast agent, and distinction from poorly differentiated hepatocellular carcinoma (pHCC). METHODS Fourteen mICC and 22 pHCC nodules were included in this study. Two observers recorded the tumor shape, intratumoral hemorrhage, fat on chemical shift imaging, signal intensity at the center of the tumor on T2-weighted image, fibrous capsule, enhancement pattern on arterial phase of dynamic study, late enhancement three minutes after contrast injection (dynamic late phase), contrast uptake on hepatobiliary phase, apparent diffusion coefficient, vascular invasion, and intrahepatic metastasis. RESULTS Late enhancement was more common in mICC (n=10, 71%) than in pHCC (n=3, 14%) (P < 0.001). A fat component was observed in 11 pHCC cases (50%) versus none of mICC cases (P = 0.002). Fibrous capsule was observed in 13 pHCC cases (59%) versus none of mICC cases (P < 0.001). On T2-weighted images a hypointense area was seen at the center of the tumor in 43% of mICC (6/14) and 9% of pHCC (2/22) cases (P = 0.018). Other parameters were not significantly different between the two types of nodules. CONCLUSION The absence of fat and fibrous capsule, and presence of enhancement at three minutes appear to be most characteristic for mICC and may help its differentiation from pHCC. PMID:25698097

  4. Fractal analysis differentiation of nuclear and vascular patterns in hepatocellular carcinomas and hepatic metastasis.

    PubMed

    Streba, C T; Pirici, D; Vere, C C; Mogoantă, L; Comănescu, Violeta; Rogoveanu, I

    2011-01-01

    Hepatocellular carcinoma (HCC) currently represents the fifth most common cancer worldwide, while being the third leading cause of cancer death. Fractal analysis is a novel tool used in quantitative and qualitative image assessment. Vascular patterns and cellular nuclei particularities in tumoral pathology make ideal candidates for this technique. Our aim was to apply fractal analysis in quantifying nuclear chromatin patterns and vascular axels in order to identify differences between images of primary HCC, liver metastasis (LM) and surrounding normal liver tissue. Formalin-fixed, paraffin-embedded tissue sections from 40 cases of HCC and 40 LM of various origins were used. We performed Hematoxylin staining for nuclear chromatin as well as immunohistochemical staining for vascular patterns. High-resolution images were captured; nuclear and vascular morphologies were assessed on binarized skeleton masks using the fractal box counting method. Analysis was performed using the free, public domain Java-based image processing tool, ImageJ, which provided the fractal dimensions (FDs) for each studied element. Statistical analysis was performed using the ANOVA test with Bonferroni post-tests and t-tests for paired samples. Fractal analysis of vascular patterns clearly differentiated between tumoral tissue and normal surrounding tissue (p<0.01). Further analysis of nuclear FDs improved the specificity of these results, providing clear differentiation between pathological and normal tissue (p<0.01). When comparing primary HCC images with metastatic formations, we encountered statistically significant differences in nuclear chromatin assessment. However, blood vessels had a higher FD in primary tumors when compared with liver metastasis (p<0.05) and also allowed for a differentiation between primary liver tumors with and without neurodifferentiation. Fractal analysis represents a potent tool for discriminating between tumoral and non-tumoral tissue images. It provides

  5. Hypervascular Benign and Malignant Liver Tumors That Require Differentiation from Hepatocellular Carcinoma: Key Points of Imaging Diagnosis

    PubMed Central

    Murakami, Takamichi; Tsurusaki, Masakatsu

    2014-01-01

    Most liver tumors are benign and hypervascular, and it is important to avoid unnecessary interventions for benign lesions. This review describes the typical and atypical imaging features of common hypervascular benign liver tumors and outlines a general approach to distinguishing between benign and malignant hepatic lesions. There are many types of benign liver tumors that need to be differentiated from hepatocellular carcinoma (HCC). Therefore, it is very important to know the imaging characteristics of benign tumors. Gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging is helpful in diagnosing hypervascular pseudotumors, focal nodular hyperplasia, and nodular lesions associated with alcohol-induced hepatitis. There are also some hypervascular malignant tumors, such as cholangiocarcinoma, cholangiolocellular carcinoma, mixed type tumors, and metastatic liver tumors, which also required differentiation from HCC. PMID:24944999

  6. Elevated alpha-fetoprotein: differential diagnosis - hepatocellular carcinoma and other disorders.

    PubMed

    Wong, Robert J; Ahmed, Aijaz; Gish, Robert G

    2015-05-01

    The incidence of cirrhosis-related hepatocellular carcinoma (HCC) is rising. Curative surgical options are available; outcomes are acceptable with early diagnosis. Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3) and des-gamma-carboxy prothrombin (DCP) are HCC risk markers. A high or increasing serum biomarker level can be predictive of the eventual development of HCC, large tumor size, advanced stage, extrahepatic metastases, portal vein thrombosis, and postoperative HCC recurrence. Based on FDA guidelines for HCC risk assessment, clinicians can consider using either the combination of AFP-L3 with DCP, or the combination of AFP-L3 with AFP and DCP. PMID:25921665

  7. Contrast-enhanced ultrasound in differentiating malignant from benign portal vein thrombosis in hepatocellular carcinoma

    PubMed Central

    Tarantino, Luciano; Ambrosino, Pasquale; Di Minno, Matteo Nicola Dario

    2015-01-01

    Portal vein thrombosis (PVT) may occur in liver cirrhosis patients. Malignant PVT is a common complication in cirrhotic patients with concomitant hepatocellular carcinoma (HCC) and, in some cases, it may be even the initial sign of an undetected HCC. Detection of malignant PVT in a patient with liver cirrhosis heavily affects the therapeutic strategy. Gray-scale ultrasound (US) is widely unreliable for differentiating benign and malignant thrombi. Although effective for this differential diagnosis, fine-needle biopsy remains an invasive technique. Sensitivity of color-doppler US in detection of malignant thrombi is highly dependent on the size of the thrombus. Contrast-enhanced computed tomography (CT) and contrast-enhanced magnetic resonance (MRI) can be useful to assess the nature of portal thrombus, while limited data are currently available about the role of positron emission tomography (PET) and PET-CT. In contrast with CT, MRI, PET, and PET-CT, contrast-enhanced ultrasound (CEUS) is a fast, effective, well tolerated and cheap technique, that can be performed even in the same session in which the thrombus has been detected. CEUS can be performed bedside and can be available also in transplanted patients. Moreover, CT and MRI only yield a snapshot analysis during contrast diffusion, while CEUS allows for a continuous real-time imaging of the microcirculation that lasts several minutes, so that the whole arterial phase and the late parenchymal phase of the contrast diffusion can be analyzed continuously by real-time US scanning. Continuous real-time monitoring of contrast diffusion entails an easy detection of thrombus maximum enhancement. Moreover, continuous quantitative analyses of enhancement (wash in - wash out studies) by CEUS during contrast diffusion is nowadays available in most CEUS machines, thus giving a more sophisticated and accurate evaluation of the contrast distribution and an increased confidence in diagnosis in difficult cases. In conclusion

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

    PubMed

    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

  9. Histopathology of hepatocellular carcinoma

    PubMed Central

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

    2014-01-01

    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. PMID:25473149

  10. Association of Serum Level of Growth Differentiation Factor 15 with Liver Cirrhosis and Hepatocellular Carcinoma

    PubMed Central

    Gao, Lei; Niu, Yuqiang; Chi, Xiaojing; Cheng, Min; Si, Youhui; Wang, Maorong; Zhong, Jin; Niu, Junqi; Yang, Wei

    2015-01-01

    Hepatocellular carcinoma (HCC) and liver cirrhosis are associated with high mortality worldwide. Currently, alpha-fetoprotein (AFP) is used as a standard serum marker for the detection of HCC, but its sensitivity and specificity are unsatisfactory, and optimal diagnostic markers for cirrhosis are lacking. We previously reported that growth differentiation factor 15 (GDF15) was significantly induced in HCV-infected hepatocytes. This study aimed to investigate GDF15 expression and its correlation with hepatitis virus-related liver diseases. A total of 412 patients with various liver diseases were studied. Healthy and Mycobacterium tuberculosis-infected subjects were included as controls. Serum and tissue GDF15 levels were measured. Serum GDF15 levels were significantly increased in patients with HCC (6.66±0.67 ng/mL, p<0.0001) and cirrhosis (6.51±1.47 ng/mL, p<0.0001) compared with healthy controls (0.31±0.01 ng/mL), though the GDF15 levels in HBV and HCV carriers were moderately elevated (1.34±0.19 ng/mL and 2.13±0.53 ng/mL, respectively). Compared with HBV or HCV carriers, GDF15 had a sensitivity of 63.1% and a specificity of 86.6% at the optimal cut-off point of 2.463 ng/mL in patients with liver cirrhosis or HCC. In HCC patients, the area under the receiver operating curve was 0.84 for GDF15 and 0.76 for AFP, but 0.91 for the combined GDF15 and AFP. Serum GDF15 levels did not significantly differ between the high-AFP and low-AFP groups. GDF15 protein expression in HCC was significantly higher than that in the corresponding adjacent paracarcinomatous tissue and normal liver. Using a combination of GDF15 and AFP will improve the sensitivity and specificity of HCC diagnosis. Further research and the clinical implementation of serum GDF15 measurement as a biomarker for HCC and cirrhosis are recommended. PMID:25996938

  11. Expression of liver fatty acid binding protein in hepatocellular carcinoma.

    PubMed

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

    2016-04-01

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

  12. Microvascular invasion in hepatocellular carcinoma

    PubMed Central

    Ünal, Emre; İdilman, İlkay Sedakat; Akata, Deniz; Özmen, Mustafa Nasuh; Karçaaltıncaba, Muşturay

    2016-01-01

    Microvascular invasion is a crucial histopathologic prognostic factor for hepatocellular carcinoma. We reviewed the literature and aimed to draw attention to clinicopathologic and imaging findings that may predict the presence of microvascular invasion in hepatocellular carcinoma. Imaging findings suggesting microvascular invasion are disruption of capsule, irregular tumor margin, peritumoral enhancement, multifocal tumor, increased tumor size, and increased glucose metabolism on positron emission tomography-computed tomography. In the presence of typical findings, microvascular invasion may be predicted. PMID:26782155

  13. Radiological Features of Hepatocellular Carcinoma

    PubMed Central

    Shah, Samir; Shukla, Akash; Paunipagar, Bhawan

    2014-01-01

    Present article is a review of radiological features of hepatocellular carcinoma on various imaging modalities. With the advancement in imaging techniques, biopsy is rarely needed for diagnosis of hepatocellular carcinoma (HCC), unlike other malignancies. Imaging is useful not only for diagnosis but also for surveillance, therapy and assessing response to treatment. The classical and the atypical radiological features of HCC have been described. PMID:25755613

  14. 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).

  15. Diagnosis of hepatocellular carcinoma

    PubMed Central

    Di Bisceglie, Adrian M.

    2005-01-01

    Hepatocellular carcinoma (HCC) is responsible for a large proportion of cancer deaths worldwide. HCC is frequently diagnosed after the development of clinical deterioration at which time survival is measured in months. Long-term survival requires detection of small tumors, often present in asymptomatic individuals, which may be more amenable to invasive therapeutic options. Surveillance of high-risk individuals for HCC is commonly performed using the serum marker alfa-fetoprotein (AFP) often in combination with ultrasonography. Various other serologic markers are currently being tested to help improve surveillance accuracy. Diagnosis of HCC often requires more sophisticated imaging modalities such as CT scan and MRI, which have multiphasic contrast enhancement capabilities. Serum AFP used alone can be helpful if levels are markedly elevated, which occurs in fewer than half of cases at time of diagnosis. Confirmation by liver biopsy can be performed under circumstances when the diagnosis of HCC remains unclear. PMID:18333158

  16. Differential impact of telomere dysfunction on initiation and progression of hepatocellular carcinoma.

    PubMed

    Farazi, Paraskevi A; Glickman, Jonathan; Jiang, Shan; Yu, Alice; Rudolph, Karl Lenhard; DePinho, Ronald A

    2003-08-15

    Telomere maintenance and telomerase reactivation are near universal features of human hepatocellular carcinoma (HCC), yet the shorter telomeres and highly abnormal cytogenetic profiles of HCC suggest that telomere erosion and dysfunction may be operative during the formative stages of tumorigenesis. Previous studies have established that the cancer-enhancing or suppressing impact of telomere dysfunction is highly dependent on several parameters including cell type, tumor stage, and p53 status. Here, to understand better the pathogenetic role of telomere dysfunction in the initiation and progression in human HCC, we have used three mechanistically distinct liver cancer-prone model systems (urokinase plasminogen activator transgenic mice, carbon tetrachloride exposure, and diethylnistrosamine treatment) in the context of successive generations of telomerase-deficient mice null for the telomerase RNA component, mTERC. Across all of the HCC model systems, telomere dysfunction suppressed both the incidence and growth of HCC lesions, a trend that mirrored the level of intratumoral proliferative arrest and apoptosis. On the histological level, telomere dysfunction was associated with a significant increase in the number of early stage neoplastic lesions and a reciprocal decline in the occurrence of high-grade malignancies. These genetic data in the mouse indicate that telomere dysfunction exerts an opposing role in the initiation versus progression of HCC and provide a framework for understanding the intimate link among chronic liver disease, chromosomal instability, and increased HCC in humans. PMID:12941829

  17. Immunology of hepatocellular carcinoma

    PubMed Central

    Sachdeva, Meenakshi; Chawla, Yogesh K; Arora, Sunil K

    2015-01-01

    Hepatocellular carcinoma (HCC) is primarily a malignancy of the liver, advancing from a damaged, cirrhotic liver to HCC. Globally, HCC is the sixth most prevalent cancer and the third-most prevalent reason for neoplastic disease-related deaths. A diverse array of infiltrating immunocytes regulates the development and progression of HCC, as is the case in many other cancers. An understanding of the various immune components during HCC becomes necessary so that novel therapeutic strategies can be designed to combat the disease. A dysregulated immune system (including changes in the number and/or function of immune cells, cytokine levels, and the expression of inhibitory receptors or their ligands) plays a key role in the development of HCC. Alterations in either the innate or adaptive arm of the immune system and cross-talk between them make the immune system tolerant to tumors, leading to disease progression. In this review, we have discussed the status and roles of various immune effector cells (e.g., dendritic cells, natural killer cells, macrophages, and T cells), their cytokine profile, and the chemokine-receptor axis in promoting or impeding HCC. PMID:26301050

  18. Screening for hepatocellular carcinoma.

    PubMed

    Nguyen, Mindie H; Keeffe, Emmet B

    2002-01-01

    Hepatocellular carcinoma (HCC) is common throughout the world and most often develops as a late complication of chronic viral hepatitis or cirrhosis of any cause. As a result of the high prevalence rate of chronic hepatitis C, the incidence of HCC is rising in the United States, as well as in European and Asian countries. The overall survival rate of HCC is poor, and surgical resection and liver transplantation are the only curative treatment options. Screening for HCC offers the best hope for early detection, eligibility for treatment, and improved survival. Most physicians routinely screen at-risk patients with chronic viral hepatitis and cirrhosis for HCC, despite the lack of official guidelines. The current consensus recommendations are to screen healthy hepatitis B virus carriers with annual or semiannual serum alpha-fetoprotein; carriers with chronic hepatitis or cirrhosis and patients with cirrhosis of any etiology are surveyed with twice yearly serum alpha-fetoprotein and liver ultrasound. This article will review the current recommendations for HCC screening, the rationale that led to these recommendations, and the challenges of cost-effectiveness research in this area. PMID:12394211

  19. Staging of hepatocellular carcinoma.

    PubMed

    Duseja, Ajay

    2014-08-01

    Hepatocellular carcinoma (HCC) is different from other malignancies because the prognosis in HCC is not only dependent upon the tumor stage but also on the liver function impairment due to accompanying cirrhosis liver. Various other staging systems used in HCC include the European systems [French staging system, Barcelona Clinic Liver Cancer (BCLC) staging system and the cancer of the liver Italian program (CLIP)] and Asian systems [Okuda staging system, Japan integrated Staging (JIS), Tokyo score and Chinese University Prognostic Index (CUPI)]. Out of all the staging systems used in HCC, Barcelona Clinic Liver Cancer (BCLC) staging system is probably the best because it takes in to account the tumor status (defined by tumor size and number, presence of vascular invasion and extrahepatic spread), liver function (defined either by the Child-Pugh's class) and general health status of the patient (defined by the ECOG classification and the presence of symptoms). Since most of the extrahepatic spread in HCC occurs to lymph nodes, lungs and bones, the assessment can be done with either PET/CT or a combination of CT (Chest and abdomen) and a bone scan. This article describes the various staging systems used in HCC, guides choosing a staging system particularly in the Indian context and the assessment of extra-hepatic spread in HCC. PMID:25755615

  20. Chemoembolization for hepatocellular carcinoma.

    PubMed

    Lencioni, Riccardo

    2012-08-01

    Transcatheter arterial chemoembolization (TACE) is the standard of care for patients with preserved liver function and asymptomatic, noninvasive multinodular hepatocellular carcinoma (HCC) confined to the liver. However, the survival benefit of conventional TACE-including the administration of an anticancer agent-in-oil emulsion followed by embolic agents-reported in randomized controlled trials and meta-analyses was described as modest. Various strategies to improve outcomes for this patient group have become the subject of much ongoing clinical research. The introduction of embolic, drug-eluting beads (DEB) for transarterial administration has been shown to significantly reduce liver toxicity and systemic drug exposure compared to conventional regimens. The addition of molecular targeted drugs to the therapeutic armamentarium for HCC has prompted the design of clinical trials aimed at investigating the synergies between TACE and systemic treatments. Combining TACE with agents with anti-angiogenic properties represents a promising strategy, because TACE is thought to cause local hypoxia, resulting in a temporary increase in levels of vascular endothelial growth factor. Recently, a large phase II randomized, double-blind, placebo-controlled trial (the SPACE study) has shown that the concurrent administration of DEB-TACE and sorafenib has a manageable safety profile and has suggested that time to progression and time to vascular invasion or extrahepatic spread may be improved with respect to DEB-TACE alone. These data support the further evaluation of molecular targeted, systemically active agents in combination with DEB-TACE in a phase III setting. PMID:22846867

  1. Chemoembolization of hepatocellular carcinoma.

    PubMed

    Lencioni, Riccardo; Petruzzi, Pasquale; Crocetti, Laura

    2013-03-01

    Transarterial chemoembolization (TACE) is the current standard of care for patients with intermediate-stage hepatocellular carcinoma (HCC) and relatively preserved liver function. In a meta-analysis of randomized controlled trials comparing conventional TACE regimens-including the administration of an anticancer-in-oil emulsion followed by embolic agents-versus best supportive care, TACE was shown to improve median survival from 16 to 20 months. Various strategies to improve outcomes for this patient group have become the subject of much ongoing clinical research. The introduction of an embolic drug-eluting bead (DEB) has been shown to substantially improve the pharmacokinetic profile of TACE, providing levels of consistency and repeatability not available with conventional regimens while concomitantly significantly diminishing systemic drug exposure. In randomized trials, DEB-TACE significantly reduced liver toxicity and drug-related adverse events compared with conventional TACE. In this article, technique, indications and contraindications, and clinical outcomes of conventional and DEB-TACE in the management of HCC are reviewed. In addition, scientific background and early clinical experience with the use of combination regimens including TACE and systemically active molecular-targeted agents with antiangiogenic properties are discussed. The combination of DEB-TACE and antiangiogenic therapy represents a potentially powerful approach that is currently undergoing clinical investigation in a phase 3 setting. PMID:24436512

  2. Chemoembolization of Hepatocellular Carcinoma

    PubMed Central

    Lencioni, Riccardo; Petruzzi, Pasquale; Crocetti, Laura

    2013-01-01

    Transarterial chemoembolization (TACE) is the current standard of care for patients with intermediate-stage hepatocellular carcinoma (HCC) and relatively preserved liver function. In a meta-analysis of randomized controlled trials comparing conventional TACE regimens—including the administration of an anticancer-in-oil emulsion followed by embolic agents—versus best supportive care, TACE was shown to improve median survival from 16 to 20 months. Various strategies to improve outcomes for this patient group have become the subject of much ongoing clinical research. The introduction of an embolic drug-eluting bead (DEB) has been shown to substantially improve the pharmacokinetic profile of TACE, providing levels of consistency and repeatability not available with conventional regimens while concomitantly significantly diminishing systemic drug exposure. In randomized trials, DEB-TACE significantly reduced liver toxicity and drug-related adverse events compared with conventional TACE. In this article, technique, indications and contraindications, and clinical outcomes of conventional and DEB-TACE in the management of HCC are reviewed. In addition, scientific background and early clinical experience with the use of combination regimens including TACE and systemically active molecular-targeted agents with antiangiogenic properties are discussed. The combination of DEB-TACE and antiangiogenic therapy represents a potentially powerful approach that is currently undergoing clinical investigation in a phase 3 setting. PMID:24436512

  3. Genetic heterogeneity of hepatocellular carcinoma

    SciTech Connect

    Unsal, H.; Isselbacher, K.J. ); Yakicier, C.; Marcais, C.; Ozturk, M. ); Kew, M. ); Volkmann, M. ); Zentgraf, H. )

    1994-01-18

    The authors studied 80 hepatocellular carcinomas from three continents for p53 gene (TP53) mutations and hepatitis B virus (HBV) sequences. p53 mutations were frequent in tumors from Mozambique but not in tumors from South Africa, China, and Germany. Independent of geographic origin, most tumors were positive for HBV sequences. X gene coding sequences of HBV were detected in 78% of tumors, whereas viral sequences in the surface antigen- and core antigen-encoding regions were present in less than 35% of tumors. These observations indicate that hepatocellular carcinomas are genetically heterogeneous. Mozambican-types of hepatocellular carcinomas are characterized by a high incidence of p53 mutations related to aflatoxins. In other tumors, the rarity of p53 mutations combined with the frequent presence of viral X gene coding sequences suggests a possible interference of HBV with the wild-type p53 function.

  4. Prognostic factors for hepatocellular carcinoma recurrence

    PubMed Central

    Colecchia, Antonio; Schiumerini, Ramona; Cucchetti, Alessandro; Cescon, Matteo; Taddia, Martina; Marasco, Giovanni; Festi, Davide

    2014-01-01

    The recurrence of hepatocellular carcinoma, the sixth most common neoplasm and the third leading cause of cancer-related mortality worldwide, represents an important clinical problem, since it may occur after both surgical and medical treatment. The recurrence rate involves 2 phases: an early phase and a late phase. The early phase usually occurs within 2 years after resection; it is mainly related to local invasion and intrahepatic metastases and, therefore, to the intrinsic biology of the tumor. On the other hand, the late phase occurs more than 2 years after surgery and is mainly related to de novo tumor formation as a consequence of the carcinogenic cirrhotic environment. Since recent studies have reported that early and late recurrences may have different risk factors, it is clinically important to recognize these factors in the individual patient as soon as possible. The aim of this review was, therefore, to identify predicting factors for the recurrence of hepatocellular carcinoma, by means of invasive and non-invasive methods, according to the different therapeutic strategies available. In particular the role of emerging techniques (e.g., transient elastography) and biological features of hepatocellular carcinoma in predicting recurrence have been discussed. In particular, invasive methods were differentiated from non-invasive ones for research purposes, taking into consideration the emerging role of the genetic signature of hepatocellular carcinoma in order to better allocate treatment strategies and surveillance follow-up in patients with this type of tumor. PMID:24876717

  5. Technetium-99m DISIDA hepatobiliary agent in diagnosis of hepatocellular carcinoma: relationship between detectability and tumor differentiation

    SciTech Connect

    Calvet, X.; Pons, F.; Bruix, J.; Bru, C.; Lomena, F.; Herranz, R.; Brugera, M.; Faus, R.; Rodes, J.

    1988-12-01

    The present investigation was aimed to assess the usefulness of biliary agents scintigraphy in the diagnosis of hepatocellular carcinoma (HCC) and to ascertain the relationship between the uptake of these agents and the degree of HCC differentiation. Forty-four patients with this hepatic cancer were included in the study. Liver scans were performed 20 min and 3 hr after the administration of 99mTc diisopropyliminodiacetic acid (DISIDA). DISIDA scintigraphy could not be assessed in six cases. In 16 (42%) out of the remaining 38 patients, the tumor exhibited equal or greater radioactivity uptake than the surrounding liver. In six out of these 16 patients, tumor uptake was apparent in the early and delayed hepatic scans, while in the other ten subjects radioactivity uptake by the HCC could only be detected in the 3-hr delayed scans. In the remaining 22 patients, HCC appeared as a cold area. Tumor location by this technique did not differ from that observed by 99mTc-sulfur colloid scan or ultrasound. DISIDA uptake was significantly related to tumor differentiation: 70% of those well differentiated tumors exhibited DISIDA uptake, whereas it was found in only 30% of those moderately differentiated and in none of those poorly differentiated (p less than 0.05). These results show that DISIDA scintigraphy can be useful in the diagnosis of HCC. Since its sensitivity is related to the degree of tumor differentiation, it may be indicated when aspiration cytology is unable to distinguish between well differentiated HCC and reactive changes due to hepatic cirrhosis.

  6. Infiltrative Hepatocellular Carcinoma

    PubMed Central

    Yan, Xiaopeng; Fu, Xu; Deng, Min; Chen, Jun; He, Jian; Shi, Jiong; Qiu, Yudong

    2016-01-01

    Abstract Data on infiltrative hepatocellular carcinoma (iHCC) receiving hepatectomy are unclear. Our study assessed the outcomes, effects of anatomical resection, and prognostic factors in a cohort of Chinese patients with iHCC undergoing hepatectomy. Data from 47 patients with iHCC undergoing hepatectomy were analyzed in a retrospective study. Independent prognostic factors of overall survival (OS) and recurrence-free survival (RFS) were identified using univariate and multivariate analyses. Correlations between microvascular invasion (MVI) and clinicopathological features were assessed using the χ2 test, Student t test, or the Mann–Whitney U test. Survival outcomes were estimated using the Kaplan-Meier method. The median OS was 27.37 months and the 1-year RFS rate were 61.7%. Alpha-fetoprotein (AFP) level was not a specific parameter in iHCC patients undergoing hepatectomy. Anatomic resection was significantly associated with increased RFS (P = 0.007). Patients showing MVI were observed with decreased RFS (P < 0.001). A high lactate dehydrogenase (LDH) level was significantly associated with decreased OS and RFS (P = 0.003 and P = 0.020, respectively). MVI was shown correlated with the levels of aspartate aminotransferase (AST), gamma glutamyl transpeptidase (GGT), and LDH. Subgroup analysis indicated that in mild MVI group, survival outcome was significantly more favorable in patients with high LDH level (P = 0.019). iHCC patients are related with higher MVI rate and patients may still derive survival benefit from anatomic resection at early and intermediate stages. MVI classification could be used to identify iHCC patients with a poorer survival, especially those with a high preoperative LDH level. PMID:27175659

  7. Interventional therapies for hepatocellular carcinoma

    PubMed Central

    Francis, Isaac R.; Novelli, Paula M.; Vellody, Ranjith; Pandya, Amit; Krishnamurthy, V.N.

    2012-01-01

    Abstract Hepatocellular carcinoma is the third most common cause of cancer-related death. In the past few years, staging systems have been developed that enable patients to be stratified into treatment algorithms in a multidisciplinary setting. Several of these treatments involve minimally invasive image-guided therapy that can be performed by radiologists. PMID:22487698

  8. Differentiation of hepatocellular carcinoma from its various mimickers in liver magnetic resonance imaging: What are the tips when using hepatocyte-specific agents?

    PubMed Central

    Park, Yang Shin; Lee, Chang Hee; Kim, Jeong Woo; Shin, Sora; Park, Cheol Min

    2016-01-01

    Hepatocellular carcinoma is the most common primary hepatic malignant tumor. With widespread use of liver imaging, various cirrhosis-related nodules are frequently detected in patients with chronic liver disease, while diverse hypervascular hepatic lesions are incidentally detected but undiagnosed on dynamic computed tomography and magnetic resonance imaging (MRI). However, use of hepatocyte-specific MR contrast agents with combined perfusion and hepatocyte-selective properties have improved diagnostic performance in detection and characterization of focal liver lesions. Meanwhile, the enhancement patterns observed during dynamic phases using hepatocyte-specific agents may be different from those observed during MRI using conventional extracellular fluid agents, leading to confusion in diagnosis. Therefore, we discuss useful tips for the differentiation of hepatocellular carcinoma from similar lesions in patients with and without chronic liver disease using liver MRI with hepatocyte-specific agents. PMID:26755877

  9. Transcriptomic characterization of fibrolamellar hepatocellular carcinoma.

    PubMed

    Simon, Elana P; Freije, Catherine A; Farber, Benjamin A; Lalazar, Gadi; Darcy, David G; Honeyman, Joshua N; Chiaroni-Clarke, Rachel; Dill, Brian D; Molina, Henrik; Bhanot, Umesh K; La Quaglia, Michael P; Rosenberg, Brad R; Simon, Sanford M

    2015-11-01

    Fibrolamellar hepatocellular carcinoma (FLHCC) tumors all carry a deletion of ∼ 400 kb in chromosome 19, resulting in a fusion of the genes for the heat shock protein, DNAJ (Hsp40) homolog, subfamily B, member 1, DNAJB1, and the catalytic subunit of protein kinase A, PRKACA. The resulting chimeric transcript produces a fusion protein that retains kinase activity. No other recurrent genomic alterations have been identified. Here we characterize the molecular pathogenesis of FLHCC with transcriptome sequencing (RNA sequencing). Differential expression (tumor vs. adjacent normal tissue) was detected for more than 3,500 genes (log2 fold change ≥ 1, false discovery rate ≤ 0.01), many of which were distinct from those found in hepatocellular carcinoma. Expression of several known oncogenes, such as ErbB2 and Aurora Kinase A, was increased in tumor samples. These and other dysregulated genes may serve as potential targets for therapeutic intervention. PMID:26489647

  10. Transcriptomic characterization of fibrolamellar hepatocellular carcinoma

    PubMed Central

    Simon, Elana P.; Freije, Catherine A.; Farber, Benjamin A.; Lalazar, Gadi; Darcy, David G.; Honeyman, Joshua N.; Chiaroni-Clarke, Rachel; Dill, Brian D.; Molina, Henrik; Bhanot, Umesh K.; La Quaglia, Michael P.; Rosenberg, Brad R.; Simon, Sanford M.

    2015-01-01

    Fibrolamellar hepatocellular carcinoma (FLHCC) tumors all carry a deletion of ∼400 kb in chromosome 19, resulting in a fusion of the genes for the heat shock protein, DNAJ (Hsp40) homolog, subfamily B, member 1, DNAJB1, and the catalytic subunit of protein kinase A, PRKACA. The resulting chimeric transcript produces a fusion protein that retains kinase activity. No other recurrent genomic alterations have been identified. Here we characterize the molecular pathogenesis of FLHCC with transcriptome sequencing (RNA sequencing). Differential expression (tumor vs. adjacent normal tissue) was detected for more than 3,500 genes (log2 fold change ≥1, false discovery rate ≤0.01), many of which were distinct from those found in hepatocellular carcinoma. Expression of several known oncogenes, such as ErbB2 and Aurora Kinase A, was increased in tumor samples. These and other dysregulated genes may serve as potential targets for therapeutic intervention. PMID:26489647

  11. Tissue Diagnosis of Hepatocellular Carcinoma

    PubMed Central

    Jain, Deepali

    2014-01-01

    The current American Association for the Study of Liver Diseases (AASLD) guideline provides strategies for achieving the diagnosis of hepatocellular carcinoma (HCC) based on the size of liver nodules seen on surveillance imaging. For lesions less than 1 cm in size, follow-up surveillance imaging is recommended. Lesions larger than 2 cm require typical radiological hallmark on dynamic imaging. Lesions of 1–2 cm in size require typical imaging features including intense uptake of contrast during arterial phases followed by decreased enhancement during portal venous phases on at least 2 imaging modalities. In cases of atypical radiological features of the suspected lesion, tissue diagnosis either by fine needle aspiration or biopsy should be obtained. Although fine needle aspiration could give a smaller risk of seeding than biopsy, biopsy has been preferred over cytology. Percutaneous biopsy of HCC carries a potential risk of tumor seeding along the needle tract. However the risk is low and there is no clear evidence of post transplant recurrence due to needle tract seeding. Histopathologic assessment can differentiate between premalignant lesions such as dysplastic nodules and early HCC. Atypical variants of HCC can be recognized morphologically which may have associated prognostic value. PMID:25755614

  12. Proteome Analyses of Hepatocellular Carcinoma

    PubMed Central

    Megger, Dominik A.; Naboulsi, Wael; Meyer, Helmut E.; Sitek, Barbara

    2014-01-01

    Proteomics has evolved into a powerful and widely used bioanalytical technique in the study of cancer, especially hepatocellular carcinoma (HCC). In this review, we provide an up to date overview of feasible proteome-analytical techniques for clinical questions. In addition, we present a broad summary of proteomic studies of HCC utilizing various technical approaches for the analysis of samples derived from diverse sources like HCC cell lines, animal models, human tissue and body fluids. PMID:26357614

  13. ALDH1A1-overexpressing cells are differentiated cells but not cancer stem or progenitor cells in human hepatocellular carcinoma

    PubMed Central

    Tanaka, Kaori; Tomita, Hiroyuki; Hisamatsu, Kenji; Nakashima, Takayuki; Hatano, Yuichiro; Sasaki, Yoshiyuki; Osada, Shinji; Tanaka, Takuji; Miyazaki, Tatsuhiko; Yoshida, Kazuhiro; Hara, Akira

    2015-01-01

    Aldehyde dehydrogenase 1A1 (ALDH1A1) is considered to be a cancer stem cell marker in several human malignancies. However, the role of ALDH1A1 in hepatocellular carcinoma (HCC) has not been well elucidated. In this study, we investigated the relationship between ALDH1A1 and clinicopathological findings and examined whether ALDH1A1 deserves to be a cancer stem cell marker in HCC. Sixty HCC samples obtained from surgical resection were collected for immunohistochemical (IHC) staining. Of these 60 samples, 47 samples of HCC tumorous and non-tumorous tissues were evaluated with qRT-PCR. There was no significant difference in the ALDH1A1-mRNA level between tumorous and non-tumorous tissues. Tumorous ALDH1A1-mRNA level had no relationship with the clinicopathological features. Immunoreactivity of ALDH1A1 was classified into two groups based on the percentage of ALDH1A1-overexpressing cells. The ALDH1A1-high group was significantly associated with low serum levels of α-fetoprotein, small tumor diameter, very little lymphovascular invasion, more differentiated pathology and good stage. The ALDH1A1-high group showed more favorable prognosis for recurrence-free survival. In double-staining IHC, ALDH1A1 was not co-expressed with BMI1, EpCAM, CD13, CD24, CD90 and CD133, which reported as cancer stem cell markers in HCC. In conclusion, ALDH1A1-overexpressing cells could appear to be differentiated cells rather than cancer stem cells in HCC. PMID:26160842

  14. Differentially Expressed miRNAs in Hepatocellular Carcinoma Target Genes in the Genetic Information Processing and Metabolism Pathways

    PubMed Central

    Thurnherr, Thomas; Mah, Way-Champ; Lei, Zhengdeng; Jin, Yu; Rozen, Steven G.; Lee, Caroline G.

    2016-01-01

    To date, studies of the roles of microRNAs (miRNAs) in hepatocellular carcinoma (HCC) have either focused on specific individual miRNAs and a small number of suspected targets or simply reported a list of differentially expressed miRNAs based on expression profiling. Here, we seek a more in-depth understanding of the roles of miRNAs and their targets in HCC by integrating the miRNA and messenger RNA (mRNA) expression profiles of tumorous and adjacent non-tumorous liver tissues of 100 HCC patients. We assessed the levels of 829 mature miRNAs, of which 32 were significantly differentially expressed. Statistical analysis indicates that six of these miRNAs regulate a significant proportion of their in silico predicted target mRNAs. Three of these miRNAs (miR-26a, miR-122, and miR-130a) were down-regulated in HCC, and their up-regulated gene targets are primarily associated with aberrant cell proliferation that involves DNA replication, transcription and nucleotide metabolism. The other three miRNAs (miR-21, miR-93, and miR-221) were up-regulated in HCC, and their down-regulated gene targets are primarily involved in metabolism and immune system processes. We further found evidence for a coordinated miRNA-induced regulation of important cellular processes, a finding to be considered when designing therapeutic applications based on miRNAs. PMID:26817861

  15. Detailed Analysis of Temporal Features on Contrast Enhanced Ultrasound May Help Differentiate Intrahepatic Cholangiocarcinoma from Hepatocellular Carcinoma in Cirrhosis

    PubMed Central

    Li, Rui; Yuan, Meng-Xia; Ma, Kuan-sheng; Li, Xiao-Wu; Tang, Chun-Lin; Zhang, Xiao-Hang; Guo, De-Yu; Yan, Xiao-Chu

    2014-01-01

    Aim To verify if detailed analysis of temporal enhancement patterns on contrast enhanced ultrasound (CEUS) may help differentiate intrahepatic cholangiocarcinoma (ICC) from hepatocellular carcinoma (HCC) in cirrhosis. Methods Thirty three ICC and fifty HCC in cirrhosis were enrolled in this study. The contrast kinetics of ICC and HCC was analyzed and compared. Results Statistical analysis did not reveal significant difference between ICC and HCC in the time of contrast first appearance and arterial peak maximum time. ICC displayed much earlier washout than that of HCC (47.93±26.45 seconds vs 90.86±31.26 seconds) in the portal phase, and most ICC (87.9%) showed washout before 60 seconds than HCC (16.0%). Much more ICC (78.8%) revealed marked washout than HCC (12.0%) while most HCC (88.0%) showed mild washout or no washout in late part of the portal phase (90–120 seconds). Twenty six out of thirty three ICC (78.8%) demonstrated both early washout(<60seconds) and marked washout in late part of the portal phase, whereas, only six of fifty HCC (12.0%)showed these temporal enhancement features (p = 0.000).When both early washout and marked washout in the portal phase are taken as diagnostic criterion for ICC, the diagnostic sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 78.8%,88.0%,81.3%,86.3%,and 84.3% respectively by CEUS. Conclusions Analysis of detailed temporal enhancement features on CEUS is helpful differentiate ICC from HCC in cirrhosis.If a nodule in cirrhotic liver displays hyper-enhancement in the arterial phase followed by early and marked washout in the portal phase, the nodule is highly suspicious of ICC rather than HCC. PMID:24874413

  16. Advances in managing hepatocellular carcinoma.

    PubMed

    Reataza, Marielle; Imagawa, David K

    2014-06-01

    Multiple modalities for treatment of hepatocellular carcinoma are available, depending on tumor size and number. Surgical resection remains the gold standard, so long as the residual liver function reserve is sufficient. In patients with advanced cirrhosis, liver transplantation is the preferred option, as these patients may not have adequate hepatic reserve after resection. Salvage liver transplantation has also become an option for a select few patients who recur after surgical resection. Ablative techniques have been used for palliation as well as to either completely destroy the tumor, act as an adjunct to resection, or downstage the tumor to meet Milan criteria such that a patient may be a candidate for liver transplantation. Radiofrequency ablation, microwave ablation, chemoembolization, radioembolization, and irreversible electroporation have all been used in this capacity. Currently, sorafenib is the only US Food and Drug Administration-approved chemotherapeutic for hepatocellular carcinoma. The efficacy of sorafenib, in combination with other agents, transarterial chemoembolization, and surgical resection is currently being investigated. Sunitinib and brivanib, tyrosine kinase inhibitors, have failed as potential first- or second-line options for chemotherapy. Bevacizumab in combination with erlotinib is also currently being studied. Final analysis for ramucirumab and axitinib are pending. Tivantinib, a selective mesenchymal-epithelial transition factor (MET) inhibitor, is also undergoing clinical trials for efficacy in MET-high tumors. This review serves to emphasize the current and new technologies emerging in the treatment of hepatocellular carcinoma. PMID:24810646

  17. Fibrolamellar Hepatocellular Carcinoma: Mechanistic Distinction From Adult Hepatocellular Carcinoma.

    PubMed

    Riggle, Kevin M; Turnham, Rigney; Scott, John D; Yeung, Raymond S; Riehle, Kimberly J

    2016-07-01

    Fibrolamellar hepatocellular carcinoma (FL-HCC) has historically been classified as a rare subtype of HCC. However, unlike "classic" HCC, it occurs in children and young adults without underlying liver disease. The recent discovery of a deletion mutation in all FL-HCCs represented a major advancement in understanding the pathogenesis of this disease. This deletion results in the fusion of the genes encoding a heat shock protein (DNAJB1) and the catalytic subunit of protein kinase A (PKA, PRKACA), and overexpression of PRKACA and enhanced cAMP-dependent PKA activity. This review summarizes recent advancements in FL-HCC pathogenesis and characteristics of the HSP40-PKA C protein. PMID:26990031

  18. Transhemangioma Ablation of Hepatocellular Carcinoma

    SciTech Connect

    Pua, Uei

    2012-12-15

    Radiofrequency ablation (RFA) is a well-established treatment modality in the treatment of early hepatocellular carcinoma (HCC) [1]. Safe trajectory of the RFA probe is crucial in decreasing collateral tissue damage and unwarranted probe transgression. As a percutaneous technique, however, the trajectory of the needle is sometimes constrained by the available imaging plane. The presence of a hemangioma beside an HCC is uncommon but poses the question of safety related to probe transgression. We hereby describe a case of transhemangioma ablation of a dome HCC.

  19. Oncogenic viruses and hepatocellular carcinoma.

    PubMed

    Ben Ari, Ziv; Weitzman, Ella; Safran, Michal

    2015-05-01

    About 80% of hepatocellular carcinoma (HCC) is caused by hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections especially in the setting of established cirrhosis or advanced fibrosis, making HCC prevention a major goal of antiviral therapy. HCC tumors are highly complex and heterogeneous resulting from the aberrant function of multiple molecular pathways. The roles of HCV or HBV in promoting HCC development are still either directly or indirectly are still speculative, but the evidence for both effects is compelling. In patients with chronic hepatitis viral infection, cirrhosis is not a prerequisite for tumorigenesis. PMID:25921667

  20. 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

  1. Nonalcoholic steatohepatitis and hepatocellular carcinoma: Brazilian survey

    PubMed Central

    Cotrim, Helma P.; Oliveira, Claudia P.; Coelho, Henrique Sérgio M.; Alvares-da-Silva, Mario R.; Nabuco, Leticia; Parise, Edison Roberto; Ivantes, Claúdia; Martinelli, Ana LC; Galizzi-Filho, João; Carrilho, Flair J.

    2016-01-01

    OBJECTIVE: The majority of cases of hepatocellular carcinoma have been reported in individuals with cirrhosis due to chronic viral hepatitis and alcoholism, but recently, the prevalence has become increasingly related to nonalcoholic steatohepatitis around the world. The study aimed to evaluate the clinical and histophatological characteristics of hepatocellular carcinoma in Brazilians' patients with nonalcoholic steatohepatitis at the present time. METHODS: Members of the Brazilian Society of Hepatology were invited to complete a survey regarding patients with hepatocellular carcinoma related to nonalcoholic steatohepatitis. Patients with a history of alcohol intake (>20 g/day) and other liver diseases were excluded. Hepatocellular carcinoma diagnosis was performed by liver biopsy or imaging methods according to the American Association for the Study of Liver Diseases' 2011 guidelines. RESULTS: The survey included 110 patients with a diagnosis of hepatocellular carcinoma and nonalcoholic fatty liver disease from nine hepatology units in six Brazilian states (Bahia, Minas Gerais, Rio de Janeiro, São Paulo, Paraná and Rio Grande do Sul). The mean age was 67±11 years old, and 65.5% were male. Obesity was observed in 52.7% of the cases; diabetes, in 73.6%; dyslipidemia, in 41.0%; arterial hypertension, in 60%; and metabolic syndrome, in 57.2%. Steatohepatitis without fibrosis was observed in 3.8% of cases; steatohepatitis with fibrosis (grades 1-3), in 27%; and cirrhosis, in 61.5%. Histological diagnosis of hepatocellular carcinoma was performed in 47.2% of the patients, with hepatocellular carcinoma without cirrhosis accounting for 7.7%. In total, 58 patients with cirrhosis had their diagnosis by ultrasound confirmed by computed tomography or magnetic resonance imaging. Of these, 55% had 1 nodule; 17%, 2 nodules; and 28%, ≥3 nodules. CONCLUSIONS: Nonalcoholic steatohepatitis is a relevant risk factor associated with hepatocellular carcinoma in patients with and

  2. Intracellular signaling and hepatocellular carcinoma.

    PubMed

    Iakova, Polina; Timchenko, Lubov; Timchenko, Nikolai A

    2011-02-01

    Liver cancer is the fifth most common cancer and the third most common cause of cancer related death in the world. The recent development of new techniques for the investigations of global change in the gene expression, signaling pathways and wide genome binding has provided novel information for the mechanisms underlying liver cancer progression. Although these studies identified gene expression signatures in hepatocellular carcinoma, the early steps of the development of hepatocellular carcinomas (HCC) are not well understood. The development of HCC is a multistep process which includes the progressive alterations of gene expression leading to the increased proliferation and to liver cancer. This review summarizes recent progress in the identification of the key steps of the development of HCC with the focus on early events of carcinogenesis and on the role of translational and epigenetic alterations in the development of HCC. Quiescent stage of the liver is supported by several tumor suppressor proteins including p53, Rb and C/EBPα. Studies with chemical models of liver carcinogenesis and with human HCC have shown that the elevation of gankyrin is responsible for the elimination of these three proteins at early steps of carcinogenesis. Later stages of progression of the liver cancer are associated with alterations in many signaling pathways including translation which leads to epigenetic silencing/activation of many genes. Particularly, recent reports suggest a critical role of histone deacetylase 1, HDAC1, in the development of HCC through the interactions with transcription factors such as C/EBP family proteins. PMID:20850540

  3. Hepatocellular carcinoma: From diagnosis to treatment.

    PubMed

    Grandhi, Miral Sadaria; Kim, Amy K; Ronnekleiv-Kelly, Sean M; Kamel, Ihab R; Ghasebeh, Mounes A; Pawlik, Timothy M

    2016-06-01

    Primary liver cancer is the sixth most common cancer overall and the second most common cause of cancer mortality worldwide. Hepatocellular carcinoma accounts for up to 90% of all primary hepatic malignancies and represents a major international health problem. While surgical resection and transplantation are the cornerstone of therapy in early-stage hepatocellular carcinoma, locoregional therapy and sorafenib are beneficial in those with more advanced disease or those who are not surgical candidates. At times, the integration of both surgical and locoregional therapy may be necessary. Hence, hepatocellular carcinoma requires a multidisciplinary approach to determine the most appropriate treatment as well as the timing of various treatments for optimal outcomes. PMID:27312032

  4. Differential hepatic avoidance radiation therapy: Proof of concept in hepatocellular carcinoma patients

    PubMed Central

    Bowen, Stephen R.; Saini, Jatinder; Chapman, Tobias R.; Miyaoka, Robert S.; Kinahan, Paul E.; Sandison, George A.; Wong, Tony; Vesselle, Hubert J.; Nyflot, Matthew J.; Apisarnthanarax, Smith

    2015-01-01

    Purpose To evaluate the feasibility of a novel planning concept that differentially redistributes RT dose away from functional liver regions as defined by 99mTc-sulphur colloid (SC) uptake on patient SPECT/ CT images. Materials and methods Ten HCC patients with different Child–Turcotte–Pugh scores (A5-B9) underwent SC SPECT/CT scans in treatment position prior to RT that were registered to planning CT scans. Proton pencil beam scanning (PBS) therapy plans were optimized to deliver 37.5–60.0 Gy (RBE) over 5–15 fractions using single field uniform dose technique robust to range and setup uncertainty. Photon volumetrically modulated arc therapy (VMAT) plans were optimized to the same prescribed dose and minimum target coverage. For both treatment modalities, differential hepatic avoidance RT (DHART) plans were generated to decrease dose to functional liver volumes (FLV) defined by a range of thresholds relative to maximum SC uptake (43–90%) in the tumor-subtracted liver. Radiation dose was redistributed away from regions of increased SC uptake in each FLV by linearly scaling mean dose objectives during PBS or VMAT optimization. DHART planning feasibility was assessed by a significantly negative Spearman’s rank correlation (RS) between dose difference and SC uptake. Patient, tumor, and treatment planning characteristics were tested for association to DHART planning feasibility using non-parametric Kruskal–Wallis ANOVA. Results Compared to conventional plans, DHART plans achieved a 3% FLV dose reduction for every 10% SC uptake increase. DHART planning was feasible in the majority of patients with 60% of patients having RS < −0.5 (p < 0.01, range −1.0 to 0.2) and was particularly effective in 30% of patients (RS < −0.9). Mean dose to FLV was reduced by up to 20% in these patients. Only fractionation regimen was associated with DHART planning feasibility: 15 fraction courses were more feasible than 5–6 fraction courses (RS < −0.93 vs. RS > −0

  5. Liver transplantation for hepatocellular carcinoma

    PubMed Central

    Tanwar, Sudeep; Khan, Shahid A; Grover, Vijay Paul Bob; Gwilt, Catherine; Smith, Belinda; Brown, Ashley

    2009-01-01

    Hepatocellular carcinoma (HCC) is the commonest primary malignancy of the liver. It usually occurs in the setting of chronic liver disease and has a poor prognosis if untreated. Orthotopic liver transplantation (OLT) is a suitable therapeutic option for early, unresectable HCC particularly in the setting of chronic liver disease. Following on from disappointing initial results, the seminal study by Mazzaferro et al in 1996 established OLT as a viable treatment for HCC. In this study, the “Milan criteria” were applied achieving a 4-year survival rate similar to OLT for benign disease. Since then various groups have attempted to expand these criteria whilst maintaining long term survival rates. The technique of living donor liver transplantation has evolved over the past decade, particularly in Asia, and published outcome data is comparable to that of OLT. This article will review the evidence, indications, and the future direction of liver transplantation for liver cancer. PMID:19938188

  6. Alcoholic cirrhosis and hepatocellular carcinoma.

    PubMed

    Stickel, Felix

    2015-01-01

    Hepatocellular carcinoma shows a rising incidence worldwide, and the largest burden of disease in Western countries derives from patients with alcoholic liver disease (ALD) and cirrhosis, the latter being the premier premalignant factor for HCC. The present chapter addresses key issues including the epidemiology of alcohol-associated HCC, and its link to other coexisting non-alcoholic liver diseases, and additional host and environmental risk factors including the underlying genetics. Also discussed are molecular mechanisms of alcohol-associated liver cancer evolution involving the mediators of alcohol toxicity and carcinogenicity, acetaldehyde and reactive oxygen species, as well as the recently described mutagenic adducts which these mediators form with DNA. Specifically, interference of alcohol with retinoids and cofactors of transmethylation processes are outlined. Information presented in this chapter illustrates that the development of HCC in the context of ALD is multifaceted and suggests several molecular targets for prevention and markers for the screening of risk groups. PMID:25427904

  7. Hepatocellular carcinoma: A comprehensive review

    PubMed Central

    Waller, Lisa P; Deshpande, Vrushak; Pyrsopoulos, Nikolaos

    2015-01-01

    Hepatocellular carcinoma (HCC) is rapidly becoming one of the most prevalent cancers worldwide. With a rising rate, it is a prominent source of mortality. Patients with advanced fibrosis, predominantly cirrhosis and hepatitis B are predisposed to developing HCC. Individuals with chronic hepatitis B and C infections are most commonly afflicted. Different therapeutic options, including liver resection, transplantation, systemic and local therapy, must be tailored to each patient. Liver transplantation offers leading results to achieve a cure. The Milan criteria is acknowledged as the model to classify the individuals that meet requirements to undergo transplantation. Mean survival remains suboptimal because of long waiting times and limited donor organ resources. Recent debates involve expansion of these criteria to create options for patients with HCC to increase overall survival. PMID:26609342

  8. Experimental models of hepatocellular carcinoma.

    PubMed

    Newell, Philippa; Villanueva, Augusto; Friedman, Scott L; Koike, Kazuhiko; Llovet, Josep M

    2008-05-01

    Hepatocellular carcinoma (HCC) is a common and deadly cancer whose pathogenesis is incompletely understood. Comparative genomic studies from human HCC samples have classified HCCs into different molecular subgroups; yet, the unifying feature of this tumor is its propensity to arise upon a background of inflammation and fibrosis. This review seeks to analyze the available experimental models in HCC research and to correlate data from human populations with them in order to consolidate our efforts to date, as it is increasingly clear that different models will be required to mimic different subclasses of the neoplasm. These models will be instrumental in the evaluation of compounds targeting specific molecular pathways in future preclinical studies. PMID:18314222

  9. Fibrolamellar hepatocellular carcinoma: a case report.

    PubMed

    Khoo, J J; Clouston, A

    2001-12-01

    A 6-year-old Malay boy presented with fever and abdominal pain for 2 months. Computerised tomography showed a nodular mass in the left lobe of the liver. There was also portal vein thrombosis on the left side. Serum alpha-fetoprotein was not elevated and Hepatitis B antigen was negative. Biopsy of the liver mass led to a histological diagnosis of fibrolamellar hepatocellular carcinoma. In view of extensive tumour involvement, he could not be operated on but was treated with chemotherapy. However, the tumour did not respond. While this is expected for fibrolamellar hepatocellular carcinoma, the possibility of the tumour having a component of ordinary hepatocellular carcinoma could not be excluded as the tumour was not resected. Fibrolamellar hepatocellular carcinoma is a rare histological subtype of hepatocellular carcinoma, associated with a better prognosis. It affects the younger age group and has no association with cirrhosis, hepatitis B virus infection or exposure to oral contraceptives, all of which are implicated in ordinary hepatocellular carcinoma. Serum alpha-fetoprotein level is usually within normal limits and other laboratory values are not contributory to the diagnosis. The diagnosis is usually suggested by radiographic studies viz. CT scan of the abdomen, which would show an irregular non-homogenous mass in the liver, and confirmed by histological examination. The most characteristic microscopical feature is fibrosis arranged in a lamellar fashion around polygonal and deeply eosinophilic neoplastic hepatocytes. PMID:12166592

  10. Hepatocellular carcinoma: epidemiology and risk factors

    PubMed Central

    Kew, Michael C

    2014-01-01

    Hepatocellular carcinoma is one of the major malignant tumors in the world today. The number of new cases of the tumor increases year by year, and hepatocellular carcinoma almost always runs a fulminant course and carries an especially grave prognosis. It has a low resectability rate and a high recurrence rate after surgical intervention, and responds poorly to anticancer drugs and radiotherapy. Hepatocellular carcinoma does not have a uniform geographical distribution: rather, very high incidences occur in Eastern and Southeastern Asia and in sub-Saharan Black Africans. In these regions and populations, the tumor shows a distinct shift in age distribution toward the younger ages, seen to greatest extent in sub-Saharan Black Africans. In all populations, males are more commonly affected. The most common risk factors for hepatocellular carcinoma in resource-poor populations with a high incidence of the tumor are chronic hepatitis B virus infection and dietary exposure to the fungal hepatocarcinogen aflatoxin B1. These two causative agents act either singly or synergistically. Both the viral infection and exposure to the fungus occur from early childhood, and the tumor typically presents at an early age. Chronic hepatitis C virus infection is an important cause of hepatocellular carcinoma in resource-rich countries with a low incidence of the tumor. The infection is acquired in adulthood and hepatocellular carcinoma occurs later than it does with hepatitis B virus-induced tumors. In recent years, obesity and the metabolic syndrome have increased markedly in incidence and importance as a cause of hepatocellular carcinoma in some resource-rich regions. Chronic alcohol abuse remains an important risk factor for malignant transformation of hepatocytes, frequently in association with alcohol-induced cirrhosis. Excessive iron accumulation in hereditary hemochromatosis and dietary iron overload in the Black African population and membranous obstruction of the inferior cava

  11. Differentiating the impact of anatomic and non-anatomic liver resection on early recurrence in patients with Hepatocellular Carcinoma

    PubMed Central

    2010-01-01

    Background For Hepatocellular Carcinoma (HCC) treated with hepatectomy, the extent of the resection margin remains controversial and data available on its effect on early tumor recurrence are very few and contradictory. The purpose of this study was to compare the impact of the type of resection (anatomic versus non-anatomic) on early intra-hepatic HCC recurrence in patients with solitary HCC and preserved liver function. Methods Among 53 patients with similar clinico-pathologic data who underwent curative liver resection for HCC between 2000 and 2006, 28 patients underwent anatomic resection of at least one liver segment and 25 patients underwent limited resection with a margin of at least 1 cm. Results After a close follow-up period of 24 months, no difference was detected in recurrence rates between the anatomic (35.7%) and the non-anatomic (40%) groups in either univariate (p = 0.74) and multivariate (p = 0.65) analysis. Factors contributing to early recurrence were tumor size (p = 0.012) and tumor stage including vascular invasion (p = 0.009). Conclusion The choice of the type of resection for HCC should be based on the maintenance of adequate hepatic reserve. The type of resection (anatomic vs non-anatomic) was found not to be a risk factor for early tumor recurrence. PMID:20497548

  12. NMR and LC/MS-based global metabolomics to identify serum biomarkers differentiating hepatocellular carcinoma from liver cirrhosis.

    PubMed

    Liu, Yue; Hong, Zhanying; Tan, Guangguo; Dong, Xin; Yang, Genjin; Zhao, Liang; Chen, Xiaofei; Zhu, Zhenyu; Lou, Ziyang; Qian, Baohua; Zhang, Guoqing; Chai, Yifeng

    2014-08-01

    Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world. However, current biomarkers that discriminate HCC from liver cirrhosis (LC) are important but are limited. More reliable biomarkers for HCC diagnosis are therefore needed. Serum from HCC patients, LC patients and healthy volunteers were analyzed using NMR and LC/MS-based approach in conjunction with random forest (RF) analysis to discriminate their serum metabolic profiles. Thirty-two potential biomarkers have been identified, and the feasibility of using these biomarkers for the diagnosis of HCC was evaluated, where 100% sensitivity was achieved in detecting HCC patients even with AFP values lower than 20 ng/mL. The metabolic alterations induced by HCC showed perturbations in synthesis of ketone bodies, citrate cycle, phospholipid metabolism, sphingolipid metabolism, fatty acid oxidation, amino acid catabolism and bile acid metabolism in HCC patients. Our results suggested that these potential biomarkers identified appeared to have diagnostic and/or prognostic values for HCC, which deserve to be further investigated. In addition, it also suggested that RF is a classification algorithm well suited for selection of biologically relevant features in metabolomics. PMID:24382646

  13. Cancer Specific Long Noncoding RNAs Show Differential Expression Patterns and Competing Endogenous RNA Potential in Hepatocellular Carcinoma

    PubMed Central

    Jian, Zhixiang; Chen, George G.; Lai, Paul B. S.

    2015-01-01

    Long noncoding RNAs (lncRNAs) regulate gene expression by acting with microRNAs (miRNAs). However, the roles of cancer specific lncRNA and its related competitive endogenous RNAs (ceRNA) network in hepatocellular cell carcinoma (HCC) are not fully understood. The lncRNA profiles in 372 HCC patients, including 372 tumor and 48 adjacent non-tumor liver tissues, from The Cancer Genome Atlas (TCGA) and NCBI GEO omnibus (GSE65485) were analyzed. Cancer specific lncRNAs (or HCC related lncRNAs) were identified and correlated with clinical features. Based on bioinformatics generated from miRcode, starBase, and miRTarBase, we constructed an lncRNA-miRNA-mRNA network (ceRNA network) in HCC. We found 177 cancer specific lncRNAs in HCC (fold change ≥ 1.5, P < 0.01), 41 of them were also discriminatively expressed with gender, race, tumor grade, AJCC tumor stage, and AJCC TNM staging system. Six lncRNAs (CECR7, LINC00346, MAPKAPK5-AS1, LOC338651, FLJ90757, and LOC283663) were found to be significantly associated with overall survival (OS, log-rank P < 0.05). Collectively, our results showed the lncRNA expression patterns and a complex ceRNA network in HCC, and identified a complex cancer specific ceRNA network, which includes 14 lncRNAs and 17 miRNAs in HCC. PMID:26492393

  14. Radiofrequency ablation for hepatocellular carcinoma.

    PubMed

    Nishikawa, Hiroki; Kimura, Toru; Kita, Ryuichi; Osaki, Yukio

    2013-09-01

    Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related mortality worldwide. Unfortunately, only 20% of HCC patients are amenable to curative therapy (liver transplantation or surgical resection). Locoregional therapies such as radiofrequency ablation (RFA), percutaneous ethanol injection, microwave coagulation therapy, and transcatheter arterial chemoembolisation play a key role in the management of HCC. The choice of the treatment modality depends on the size of the tumour, tumour location, anatomic considerations and the number of tumours present and liver function. RFA therapy for HCC can be performed safely using a percutaneous, laparoscopic, or an open approach, even in patients with poor functional reserve. Since the introduction of RFA, several randomised controlled trials and non-randomised studies comparing RFA and other therapies for HCC have been conducted. In addition, in the last decade there have been technical advances in RFA therapy for HCC, resulting in significant improvement in the prognosis of HCC patients treated with this modality. In this review, we primarily focus on percutaneous RFA therapy for HCC and refer to current knowledge and future perspectives for this therapy. We also discuss new emerging ablation techniques. PMID:23937321

  15. Hepatitis D and hepatocellular carcinoma

    PubMed Central

    Abbas, Zaigham; Abbas, Minaam; Abbas, Sarim; Shazi, Lubna

    2015-01-01

    Hepatitis D virus (HDV) is a defective circular shape single stranded HDV RNA virus with two types of viral proteins, small and large hepatitis D antigens, surrounded by hepatitis B surface antigen. Superinfection with HDV in chronic hepatitis B is associated with a more threatening form of liver disease leading to rapid progression to cirrhosis. In spite of some controversy in the epidemiological studies, HDV infection does increase the risk of hepatocellular carcinoma (HCC) compared to hepatitis B virus (HBV) monoinfection. Hepatic decompensation, rather than development of HCC, is the first usual clinical endpoint during the course of HDV infection. Oxidative stress as a result of severe necroinflammation may progress to HCC. The large hepatitis D antigen is a regulator of various cellular functions and an activator of signal transducer and activator of transcription (STAT)3 and the nuclear factor kappa B pathway. Another proposed epigenetic mechanism by which HCC may form is the aberrant silencing of tumor suppressor genes by DNA Methyltransferases. HDV antigens have also been associated with increased histone H3 acetylation of the clusterin promoter. This enhances the expression of clusterin in infected cells, increasing cell survival potential. Any contribution of HBV DNA integration with chromosomes of infected hepatocytes is not clear at this stage. The targeted inhibition of STAT3 and cyclophilin, and augmentation of peroxisome proliferator-activated receptor γ have a potential therapeutic role in HCC. PMID:25914778

  16. Liver transplantation for hepatocellular carcinoma.

    PubMed

    Sarpel, Umut; Schwartz, Myron

    2007-09-01

    Hepatocellular carcinoma can only be cured by physical removal or destruction of the tumor before it has spread. This can be accomplished by the ablation of the tumor, surgical resection of the tumor-bearing liver, or by liver transplantation. Ablation and resection can only be performed in patients who will be left with sufficient liver volume to sustain normal hepatic function. Unfortunately, the same disease that caused the HCC also limits the amount of parenchymal loss that can be tolerated by the patient. Liver transplantation is an appealing treatment option because it has the potential to cure patient of both the cancer and the predisposinig liver disease. Excellent survival rates are possible in patients with early HCC who receive a transplant, but dismal results are seen when patients with advanced tumors are transplanted.Wide criteria for transplant allow for more patients to be cured of HCC, but this comes at the expense of a greater overall recurrence rate. The acceptable recurrence rate is not a concrete number, but this is a function of donor organ availability. A 50% cure rate is viewed as an excellent outcome for many accepted cancer operations; however, in the case of transplant for HCC, this would represent a poor use of the scarce donor resource when the same liver offers a 70% 5-year survival rate to a non-HCC patient. These issues and methods retarding tumor progression while on the transplant waiting list are reviewed herein. PMID:17877492

  17. Gut Microbiota and Hepatocellular Carcinoma

    PubMed Central

    Tao, Xuemei; Wang, Ning; Qin, Wenxin

    2015-01-01

    Background Hepatocellular carcinoma (HCC) is a common complication of liver diseases such as those related to viral hepatitis and liver cirrhosis. The gut-liver axis is gaining increasing attention as a key pathophysiological mechanism responsible for the progression of HCC. Here, we will review the data from the published literature to address the association between HCC and gut microbiota. Summary The presence of high levels of endotoxemia in the blood results in portal hypertension and ensuing hepatocyte damage, thus leading to the development of HCC. Probiotics can be used to treat or prevent the progression of HCC, because they may decrease the counts of gut microbiota and thus improve the endotoxemia. Key Message Increased bacterial translocation can result in endotoxemia, which may play a critical role in the progression of HCC. Modulation of the gut microbiota by probiotics may represent a new avenue for therapeutic intervention in HCC. Practical Implications Breakdown in intestinal barrier function and bacterial overgrowth are main events in the development of HCC. When the intestinal barrier function is disrupted, large amounts of bacterial products can enter the liver and induce inflammation through their receptors, leading to liver diseases. Altering the gut microflora has been proposed as an adjunctive therapy to reduce bacterial translocation and prevent progression of HCC. The purpose of this review is to discuss the relationship between gut microbiota and HCC in both pathogenesis and treatment by probiotics. PMID:26673641

  18. Anatomic pathology of hepatocellular carcinoma: histopathology using classic and new diagnostic tools.

    PubMed

    Pittman, Meredith E; Brunt, Elizabeth M

    2015-05-01

    Hepatocellular carcinoma can be diagnosed on a needle biopsy of the liver; however, uncertainty may arise because of the inherent complexity of liver histology. This article aims to provide practicing pathologists with tools for the approach to mass-directed liver biopsies clinically concerning for hepatocellular carcinoma. The examination of routine hematoxylin-eosin stains and the use of ancillary histochemical and immunohistochemical stains are discussed. Sections reviewing liver carcinoma with biphenotypic differentiation and the challenge of dysplastic nodules are included. PMID:25921661

  19. Diffuse fatty metamorphosis of a large, well-differentiated hepatocellular carcinoma originating in the normal liver: a case report and literature review.

    PubMed

    Komiyama, Satoshi; Okazaki, Hiroshi; Nakao, Satoshi; Nishigori, Shuhei; Terada, Masahiro; Hamanaka, Jun; Miura, Yuki; Oka, Hiroyuki; Suzaki, Fumio; Tanaka, Katsuaki

    2015-10-01

    Fatty changes are frequently observed in small, well-differentiated hepatocellular carcinomas (HCCs), but are rarely observed in large (over 30 mm in diameter) lesions. Here, we report a 76-year-old man who developed a large (58 mm in diameter), well-differentiated HCC with diffuse extensive fatty changes in the right lobe of the liver. He had no history of alcohol abuse, obesity, or hepatitis B or C infection, and no autoantibodies, but he did have type 2 diabetes. The serum alpha-fetoprotein level was within the normal range, and ultrasonography showed a round hyperechoic lesion. Dynamic contrast-enhanced computed tomography revealed a tumor with inhomogeneous low attenuation in the arterial, portal, and venous phases, mimicking an angiomyolipoma. The patient underwent central bisegmentectomy of the liver, and the histological diagnosis was well-differentiated HCC with diffuse extensive fatty changes. The surrounding non-cancerous area was normal. A review of the published literature found six published cases of large, well-differentiated HCC with extensive fatty changes. Unlike the patients in most previous reports, our patient did not have any underlying liver disease and had no history of alcohol abuse. PMID:26416601

  20. 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

  1. Yttrium-90 microsphere radioembolization for hepatocellular carcinoma.

    PubMed

    Edeline, Julien; Gilabert, Marine; Garin, Etienne; Boucher, Eveline; Raoul, Jean-Luc

    2015-03-01

    Yttrium-90 (Y90) radioembolization is an emerging strategy to treat liver malignancies, and clinical data supporting its use have accumulated in recent years. Y90-radioembolization has shown clinical effectiveness in intermediate and advanced hepatocellular carcinoma, with a favorable safety profile. Retrospective data show similar levels of effectiveness to transarterial chemoembolization in intermediate hepatocellular carcinoma, with some evidence of better tolerance. While phase 3 studies comparing Y90-radioembolization to chemoembolization in intermediate hepatocellular carcinoma would be difficult to conduct, studies comparing or combining Y90-radioembolization with sorafenib are under way. Questions also remain about the most suitable modalities for defining the dose to administer. Phase 3 studies are under way to clarify the place of Y90-radioembolization in the algorithm of HCC treatment. PMID:26020026

  2. Hepatocellular Carcinoma: Risk Factors, Diagnosis and Treatment

    PubMed Central

    Janevska, Dafina; Chaloska-Ivanova, Viktorija; Janevski, Vlado

    2015-01-01

    Hepatocellular carcinoma (HCC) is the most often primary cancer of the liver and is one if the leading cause of cancer-related death worldwide. The incidence of HCC has geographic distribution with the highest levels in countries with developing economies. Patients with hepatocellular carcinoma have poor prognosis despite the achievements in surgery techniques and other therapeutic procedures and it is a reason why continuous attention should be paid to this issue. This article provides an overview of this disease based on an extensive review of relevant literature. The article summarizes the current risk factors, diagnosis, staging and the management of HCC. PMID:27275318

  3. Synchronous Fibrolamellar Hepatocellular Carcinoma and Auricular Myxoma

    PubMed Central

    González-Cantú, Yessica M.; Rodriguez-Padilla, Cristina; Tena-Suck, Martha Lilia; García de la Fuente, Alberto; Mejía-Bañuelos, Rosa María; Díaz Mendoza, Raymundo; Quintanilla-Garza, Samuel; Batisda-Acuña, Yolaester

    2015-01-01

    Synchronic occurrence of benign and malignant tumors is extremely rare. Fibrolamellar hepatocellular carcinoma represents 1% to 2% of all hepatocarcinomas, while myxomas represent about half of all the cases of primary tumors of the heart. We present the case of a 53-year-old woman with a left atrial myxoma that was surgically removed. Several weeks later, the patient returned to the hospital with abdominal pain. CT scan showed a mass in the left lobe of the liver that was resected and diagnosed as fibrolamellar hepatocellular carcinoma. As of this writing, the patient is healthy. PMID:26509093

  4. Synchronous Fibrolamellar Hepatocellular Carcinoma and Auricular Myxoma.

    PubMed

    González-Cantú, Yessica M; Rodriguez-Padilla, Cristina; Tena-Suck, Martha Lilia; García de la Fuente, Alberto; Mejía-Bañuelos, Rosa María; Díaz Mendoza, Raymundo; Quintanilla-Garza, Samuel; Batisda-Acuña, Yolaester

    2015-01-01

    Synchronic occurrence of benign and malignant tumors is extremely rare. Fibrolamellar hepatocellular carcinoma represents 1% to 2% of all hepatocarcinomas, while myxomas represent about half of all the cases of primary tumors of the heart. We present the case of a 53-year-old woman with a left atrial myxoma that was surgically removed. Several weeks later, the patient returned to the hospital with abdominal pain. CT scan showed a mass in the left lobe of the liver that was resected and diagnosed as fibrolamellar hepatocellular carcinoma. As of this writing, the patient is healthy. PMID:26509093

  5. Expression of HNFs and C/EBP alpha is correlated with immunocytochemical differentiation of cell lines derived from human hepatocellular carcinomas, hepatoblastomas and immortalized hepatocytes.

    PubMed

    Ishiyama, Tadashi; Kano, Junko; Minami, Yuko; Iijima, Tatsuo; Morishita, Yukio; Noguchi, Masayuki

    2003-09-01

    Objective assessment of the differentiation grade of hepatocellular carcinomas (HCCs) is important for evaluation of the pathological diagnosis, prognosis and therapeutic treatment. Differentiation of hepatocytes is reflected by their expression of hepatic functional proteins in the mouse embryo, and liver-enriched transcription factors (LETFs) have been shown to regulate hepatic functional genes strictly. Previous reports demonstrated that the level of LETF expression is altered in HCC or preneoplastic nodules compared with noncancerous tissues. Therefore, LETF expression levels might be useful as a measure of HCC maturation. In this study, to clarify the correlation between the expression of LETFs and the differentiation grade of HCCs, we performed a quantitative analysis of the mRNA expressions of HNFs and C/EBP alpha using real-time reverse-transcription PCR and immunocytochemical analysis for hepatic functional proteins in twelve cell lines. Furthermore, we examined orthotopic transplantations of the HCC cell lines in C.B-17/Icrj-scid/scid mice and characterized the histologic and cytologic differentiation of the tumors that developed. Our results showed that comprehensive expressions of HNF-3beta, HNF-4 alpha, HNF-1 alpha, and C/EBP alpha were specific to HCCs with well-differentiated function and morphology. Furthermore, among these four transcription factors, HNF-4 alpha and HNF-1 alpha expressions showed synchronism and had a close relation with HCC differentiation. These in vitro results were confirmed in tumors developed in SCID mice in vivo. These findings suggested that HNF-4 alpha and HNF-1 alpha are useful markers to assess the degree of HCC differentiation, which we suggest could be evaluated objectively by the quantitative analysis of HNFs and C/EBP alpha in HCCs. PMID:12967472

  6. Current Management of Hepatocellular Carcinoma

    PubMed Central

    Crissien, Ana Maria

    2014-01-01

    Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. Despite efforts for prevention and screening as well as development of new technologies for diagnosis and treatment, the incidence of HCC has doubled, and mortality rates have increased in recent decades. A variety of important risk factors are associated with the development of HCC, with any type of cirrhosis, regardless of etiology, being the major contributor. Hepatitis C virus infection with bridging fibrosis or cirrhosis and hepatitis B virus infection are independent risk factors. The diagnosis of HCC is made without liver biopsy in over 90% of cases. Screening with ultrasound and alpha-fetoprotein (AFP) at 6-month intervals is advised; however, it is not adequate for patients on the orthotopic liver transplantation (OLT) list. Triple-phase computed tomography and/or magnetic resonance imaging are used in combination with the detection of AFP, AFP-L3%, and/or des-gamma-carboxy prothrombin due to their superior sensitivities and specificities. Several treatment modalities are available, but only surgical resection and OLT are curative. OLT is available only for patients who meet or are downstaged into Milan or University of California, San Francisco criteria. Other treatment options include radiofrequency ablation, microwave ablation, percutaneous ethanol injection, transarterial chemoembolization, radioembolization, cryoablation, radiation therapy, stereotactic radiotherapy, systemic chemotherapy, and molecularly targeted therapies. The management of HCC is based on tumor size and location, extrahepatic spread, and underlying liver function. Given the complexity of the disease, patients are often best served in centers with experience in HCC management, where a multi-disciplinary approach can take place. PMID:24829542

  7. Microwave ablation of hepatocellular carcinoma

    PubMed Central

    Poggi, Guido; Tosoratti, Nevio; Montagna, Benedetta; Picchi, Chiara

    2015-01-01

    Although surgical resection is still the optimal treatment option for early-stage hepatocellular carcinoma (HCC) in patients with well compensated cirrhosis, thermal ablation techniques provide a valid non-surgical treatment alternative, thanks to their minimal invasiveness, excellent tolerability and safety profile, proven efficacy in local disease control, virtually unlimited repeatability and cost-effectiveness. Different energy sources are currently employed in clinics as physical agents for percutaneous or intra-surgical thermal ablation of HCC nodules. Among them, radiofrequency (RF) currents are the most used, while microwave ablations (MWA) are becoming increasingly popular. Starting from the 90s’, RF ablation (RFA) rapidly became the standard of care in ablation, especially in the treatment of small HCC nodules; however, RFA exhibits substantial performance limitations in the treatment of large lesions and/or tumors located near major heat sinks. MWA, first introduced in the Far Eastern clinical practice in the 80s’, showing promising results but also severe limitations in the controllability of the emitted field and in the high amount of power employed for the ablation of large tumors, resulting in a poor coagulative performance and a relatively high complication rate, nowadays shows better results both in terms of treatment controllability and of overall coagulative performance, thanks to the improvement of technology. In this review we provide an extensive and detailed overview of the key physical and technical aspects of MWA and of the currently available systems, and we want to discuss the most relevant published data on MWA treatments of HCC nodules in regard to clinical results and to the type and rate of complications, both in absolute terms and in comparison with RFA. PMID:26557950

  8. Newer markers for hepatocellular carcinoma.

    PubMed

    Marrero, Jorge A; Lok, Anna S F

    2004-11-01

    The incidence of hepatocellular carcinoma (HCC) is increasing worldwide; the overall survival of patients with HCC is grim because most patients are diagnosed late, when curative treatment is not possible. Cirrhosis is the strongest risk factor for the development of HCC. HCC surveillance with alpha-fetoprotein (AFP) and ultrasonography has been recommended for persons with cirrhosis. However, AFP level is insensitive for the early detection of HCC, and ultrasonography is expensive and operator dependent. Clearly, there is a need for novel strategies for the early detection of HCC. The ideal biomarker assay for HCC would be sensitive, specific, noninvasive, reproducible, inexpensive, and acceptable to patients. The Early Detection Research Network of the National Cancer Institute has proposed 5 phases for biomarker validation: preclinical exploratory studies, clinical assay development for disease, retrospective longitudinal study to detect preclinical disease, prospective screening study, and cancer control studies. Several biomarkers, such as des-gamma carboxyprothrombin, lens culinaris agglutinin-reactive AFP, human hepatocyte growth factor, and insulin-like growth factor-1, are promising, but none of these markers has been validated for clinical use. Limitations of the current literature include inadequate sample size, heterogeneity in biomarker assay methods and result reporting, limited analysis of demographics and cause of liver disease as covariates in the expression of these markers, and a scarcity of longitudinal studies evaluating the ability of biomarkers to detect preclinical disease. There is an urgent need for novel biomarkers for the detection of early HCC; the National Cancer Institute proposal provides a framework for future validation studies. PMID:15508074

  9. 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

  10. Hepatocellular carcinoma: Where are we?

    PubMed Central

    Mazzanti, Roberto; Arena, Umberto; Tassi, Renato

    2016-01-01

    Hepatocellular carcinoma (HCC) is the second cause of death due to malignancy in the world, following lung cancer. The geographic distribution of this disease accompanies its principal risk factors: Chronic hepatitis B virus and hepatitis C virus infection, alcoholism, aflatoxin B1 intoxication, liver cirrhosis, and some genetic attributes. Recently, type II diabetes has been shown to be a risk factor for HCC together with obesity and metabolic syndrome. Although the risk factors are quite well known and it is possible to diagnose HCC when the tumor is less than 1 cm diameter, it remains elusive at the beginning and treatment is often unsuccessful. Liver transplantation is thus far considered the best treatment for HCC as it cures HCC and the underlying liver disease. Using the Milan criteria, overall survival after liver transplantation for HCC is about 70% after 5 years. Many attempts have been made to go beyond the Milan Criteria and according to recent works reasonably good results have been achieved by using a histochemical marker such as cytokeratine 19 and the so-called “up to seven criteria” to divide patients into categories according to their risk of relapse. In addition to liver transplantation other therapies have been proposed such as resection, tumor ablation by different means, embolization and chemotherapy. An important step in the treatment of advanced HCC has been the introduction of sorafenib, the first oral, systemic drug that has provided significant improvement in survival. Treatment of HCC patients must be multidisciplinary and by using the different approaches discussed in this review it is possible to offer prolonged survival and quite good and sometimes even excellent quality of life to many patients. PMID:26929917

  11. New advances in hepatocellular carcinoma.

    PubMed

    Pascual, Sonia; Herrera, Iván; Irurzun, Javier

    2016-03-28

    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

  12. Microwave ablation of hepatocellular carcinoma.

    PubMed

    Poggi, Guido; Tosoratti, Nevio; Montagna, Benedetta; Picchi, Chiara

    2015-11-01

    Although surgical resection is still the optimal treatment option for early-stage hepatocellular carcinoma (HCC) in patients with well compensated cirrhosis, thermal ablation techniques provide a valid non-surgical treatment alternative, thanks to their minimal invasiveness, excellent tolerability and safety profile, proven efficacy in local disease control, virtually unlimited repeatability and cost-effectiveness. Different energy sources are currently employed in clinics as physical agents for percutaneous or intra-surgical thermal ablation of HCC nodules. Among them, radiofrequency (RF) currents are the most used, while microwave ablations (MWA) are becoming increasingly popular. Starting from the 90s', RF ablation (RFA) rapidly became the standard of care in ablation, especially in the treatment of small HCC nodules; however, RFA exhibits substantial performance limitations in the treatment of large lesions and/or tumors located near major heat sinks. MWA, first introduced in the Far Eastern clinical practice in the 80s', showing promising results but also severe limitations in the controllability of the emitted field and in the high amount of power employed for the ablation of large tumors, resulting in a poor coagulative performance and a relatively high complication rate, nowadays shows better results both in terms of treatment controllability and of overall coagulative performance, thanks to the improvement of technology. In this review we provide an extensive and detailed overview of the key physical and technical aspects of MWA and of the currently available systems, and we want to discuss the most relevant published data on MWA treatments of HCC nodules in regard to clinical results and to the type and rate of complications, both in absolute terms and in comparison with RFA. PMID:26557950

  13. 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

  14. Non-hepatocellular carcinoma spinal metastases.

    PubMed

    Goodwin, C Rory; Abu-Bonsrah, Nancy; Boone, Christine; Ruiz-Valls, Alejandro; Sankey, Eric W; Sarabia-Estrada, Rachel; Elder, Benjamin D; Kosztowski, Thomas; Sciubba, Daniel M

    2016-05-01

    Metastases to the spine from non-hepatocellular carcinomas, such as cholangiocarcinoma and angiosarcoma, occur rarely. With improvements in oncologic care, the number of patients diagnosed with metastatic cancer is expected to increase. We performed a systematic review of the literature to assess the clinical presentation, treatment, outcome and survival of patients diagnosed with non-hepatocellular carcinoma spinal metastasis using PubMed, Embase, CINAHL, Cochrane Library and Web of Science. We identified 19 cases of spinal metastases from non-hepatocellular carcinomas that fit our pre-specified criteria. The mean age at presentation was 62.3years and cholangiocarcinoma was the most common subtype. Patients frequently presented with pain, weakness or paraparesis and at the time of diagnosis, most of them had multi-level involvement of the spine. A majority of patients with spinal metastasis were treated either with radiation or chemotherapy or received no treatment. A minority of the reports included information on survival, which revealed a median survival of 1.5months following diagnosis of the spinal metastasis. Although there is a paucity of published literature on non-hepatocellular carcinoma spinal metastasis, this systematic review provides descriptive clinical characteristics of these patients. PMID:26778049

  15. Tricking an ancient immune function to eradicate hepatocellular carcinoma

    PubMed Central

    Miyazaki, Toru; Arai, Satoko

    2015-01-01

    The circulating apoptosis inhibitor of macrophage (AIM) protein performs differential preventive roles against liver steatosis and hepatocellular carcinoma (HCC) development. Since non-alcoholic fatty liver disease, which is known as a manifestation of metabolic syndrome, has been increasingly highlighted for its association with HCC, therapeutic application of AIM would open the door toward a new mode of treatment for modern hepatic diseases. PMID:27308467

  16. GRP78 and GAL3, differentially regulated by lymph node homogenates, as potential biomarkers for lymph node metastasis in mouse hepatocellular carcinoma cells

    PubMed Central

    ZHU, WENJUN; OWUSU, LAWRENCE; ZANG, SHIZHU; ZHANG, YUNJUAN; XIN, YI; YAN, CHAO

    2012-01-01

    In order to systematically evaluate the influence of lymph nodes (LNs) in lymph node metastases (LNM) of hepatocellular carcinoma (HCC), we set up a new in vitro model in which Hca-F and Hca-P cells were cultured in medium containing lymph node homogenates (LNHs). Differential protein expression was measured by two-dimensional gel electrophoresis (2-DE) combined with matrix-assisted laser desorption/ionization time-of-flight/time-of-flight mass spectrometry (MALDI TOF/TOF MS). Results from protein identification revealed two metastatic correlative proteins, 78-kDa glucose-regulated protein (GRP78) and galectin-3 (GAL3). Western blotting confirmed that GRP78, a protein positively correlated with metastasis, increased 2.4-fold in Hca-F cells but decreased to almost a half in Hca-P cells (P<0.05). However, GAL3, a protein negatively correlated with metastasis, was decreased by a half in Hca-F cells but slightly increased non-significantly in Hca-P cells. Thus, our results reveal that some components of LNHs may facilitate a permissive environment for cancer cells with high metastasis potential to eventually metastasize. GRP78 and GAL3 may serve as potential biomarkers for the diagnosis of LNM in HCC. PMID:23205138

  17. DNA methylation: potential biomarker in Hepatocellular Carcinoma

    PubMed Central

    2014-01-01

    Hepatocellular Carcinoma (HCC) is one of the most common cancers in the world and it is often associated with poor prognosis. Liver transplantation and resection are two currently available curative therapies. However, most patients cannot be treated with such therapies due to late diagnosis. This underscores the urgent need to identify potential markers that ensure early diagnosis of HCC. As more evidences are suggesting that epigenetic changes contribute hepatocarcinogenesis, DNA methylation was poised as one promising biomarker. Indeed, genome wide profiling reveals that aberrant methylation is frequent event in HCC. Many studies showed that differentially methylated genes and CpG island methylator phenotype (CIMP) status in HCC were associated with clinicopathological data. Some commonly studied hypermethylated genes include p16, SOCS1, GSTP1 and CDH1. In addition, studies have also revealed that methylation markers could be detected in patient blood samples and associated with poor prognosis of the disease. Undeniably, increasing number of methylation markers are being discovered through high throughput genome wide data in recent years. Proper and systematic validation of these candidate markers in prospective cohort is required so that their actual prognostication and surveillance value could be accurately determined. It is hope that in near future, methylation marker could be translate into clinical use, where patients at risk could be diagnosed early and that the progression of disease could be more correctly assessed. PMID:24635883

  18. Acute myeloid leukemia masquerading as hepatocellular carcinoma

    PubMed Central

    Abu-Zeinah, Ghaith F.; Weisman, Paul; Ganesh, Karuna; Katz, Seth S.; Dogan, Ahmet; Abou-Alfa, Ghassan K.; Stein, Eytan M.; Jarnagin, William; Mauro, Michael J.

    2016-01-01

    Hepatocellular carcinoma (HCC) is often diagnosed on the basis of high quality imaging without a biopsy in the cirrhotic liver. This is a case of a 64-year-old Caucasian man with no history of liver disease or cirrhosis that presented with fatigue, weight loss, and abdominal distension and was found to have a large, isolated liver mass with arterial enhancement and portal venous washout on triple-phase computed tomography (CT) suspicious for HCC. The patient was initially referred for a surgical evaluation. Meanwhile, he developed fevers, pancytopenia, and worsening back pain, and a subsequent spinal MRI revealed a heterogeneous bone marrow signal suspicious for metastatic disease. A bone marrow biopsy that followed was diffusely necrotic. A core biopsy of the patient’s liver mass was then performed and was diagnostic of acute monocytic-monoblastic leukemia. Findings from peripheral flow cytometry and a repeat bone marrow biopsy were also consistent with this diagnosis, and induction chemotherapy with cytarabine and idarubicin was initiated. This case describes a rare presentation of myeloid sarcoma (MS) as an isolated, hypervascular liver mass that mimics HCC in its radiographic appearance. Due to the broad differential for a liver mass, a confirmatory biopsy should routinely be considered prior to surgical intervention. PMID:27284485

  19. Acute myeloid leukemia masquerading as hepatocellular carcinoma.

    PubMed

    Abu-Zeinah, Ghaith F; Weisman, Paul; Ganesh, Karuna; Katz, Seth S; Dogan, Ahmet; Abou-Alfa, Ghassan K; Stein, Eytan M; Jarnagin, William; Mauro, Michael J; Harding, James J

    2016-06-01

    Hepatocellular carcinoma (HCC) is often diagnosed on the basis of high quality imaging without a biopsy in the cirrhotic liver. This is a case of a 64-year-old Caucasian man with no history of liver disease or cirrhosis that presented with fatigue, weight loss, and abdominal distension and was found to have a large, isolated liver mass with arterial enhancement and portal venous washout on triple-phase computed tomography (CT) suspicious for HCC. The patient was initially referred for a surgical evaluation. Meanwhile, he developed fevers, pancytopenia, and worsening back pain, and a subsequent spinal MRI revealed a heterogeneous bone marrow signal suspicious for metastatic disease. A bone marrow biopsy that followed was diffusely necrotic. A core biopsy of the patient's liver mass was then performed and was diagnostic of acute monocytic-monoblastic leukemia. Findings from peripheral flow cytometry and a repeat bone marrow biopsy were also consistent with this diagnosis, and induction chemotherapy with cytarabine and idarubicin was initiated. This case describes a rare presentation of myeloid sarcoma (MS) as an isolated, hypervascular liver mass that mimics HCC in its radiographic appearance. Due to the broad differential for a liver mass, a confirmatory biopsy should routinely be considered prior to surgical intervention. PMID:27284485

  20. Cellular reprogramming and hepatocellular carcinoma development.

    PubMed

    Zheng, Yun-Wen; Nie, Yun-Zhong; Taniguchi, Hideki

    2013-12-21

    Hepatocellular carcinoma (HCC) is one of the most common cancers, and is also the leading cause of death worldwide. Studies have shown that cellular reprogramming contributes to chemotherapy and/or radiotherapy resistance and the recurrence of cancers. In this article, we summarize and discuss the latest findings in the area of cellular reprogramming in HCC. The aberrant expression of transcription factors OCT4, KLF4, SOX2, c-MYC, NANOG, and LIN28 have been also observed, and the expression of these transcription factors is associated with unfavorable clinical outcomes in HCC. Studies indicate that cellular reprogramming may play a critical role in the occurrence and recurrence of HCC. Recent reports have shown that DNA methylation, miRNAs, tumor microenvironment, and signaling pathways can induce the expression of stemness transcription factors, which leads to cellular reprogramming in HCC. Furthermore, studies indicate that therapies based on cellular reprogramming could revolutionize HCC treatment. Finally, a novel therapeutic concept is discussed: reprogramming control therapy. A potential reprogramming control therapy method could be developed based on the reprogramming demonstrated in HCC studies and applied at two opposing levels: differentiation and reprogramming. Our increasing understanding and control of cellular programming should facilitate the exploitation of this novel therapeutic concept and its application in clinical HCC treatment, which may represent a promising strategy in the future that is not restricted to liver cancer. PMID:24379607

  1. Survivin in survival of hepatocellular carcinoma.

    PubMed

    Su, Changqing

    2016-09-01

    Survivin is an anti-apoptotic protein belonging to the inhibitor of apoptosis protein (IAP) family. It is involved in the regulation of important physiological and pathological processes in cells and functions to inhibit cell apoptosis and promote cell proliferation. Normally and terminally differentiated tissues are nearly negative for survivin. In contrast, survivin is highly expressed in most human tumor tissues, including hepatocellular carcinoma (HCC). The abnormal overexpression of survivin is closely related to the malignant biological behaviors of tumors. During the development and progression of HCC, the high level of survivin expression promotes cancer cell proliferation, inhibits cancer cell apoptosis, induces tumor stromal angiogenesis, reduces the sensitivity of cancer cells to radiotherapy and chemotherapy, and ultimately affects the prognosis of patients with HCC. Survivin expression is regulated by a large number of factors. The latest discovery indicated that the transcription factor octamer-binding transcription factor 4 (OCT4) enhances the expression of survivin though cyclin D1 (CCND1), which, in part, accounts for tumor cell proliferation, recurrence and metastasis. Survivin plays key roles in HCC, which renders it an ideal target for the treatment of HCC. The present article reviews the research progress on the relationship between survivin and HCC and on the HCC treatment strategies targeting survivin. PMID:26118774

  2. 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. PMID:26632539

  3. Hepatocellular carcinoma in the Malaysian Orang Asli.

    PubMed

    Sumithran, E; Prathap, K

    1976-05-01

    Necropsies were performed on 285 consecutively unclaimed Orang Asli bodies from Gombak Orang Asli Hospital during an eight-year period from May 1967 to April 1975. Of the 25 malignant neoplasms, hepatocellular carcinoma was by far the commonest (36%). The nine patients with this neoplasm had coexistant macronodular cirrhosis. There were 20 cases of cirrhosis; 45% of these had coexistant hepatocellular carcinoma. The 53,000 Orang Aslis living in West Malaysia comprise three tribes, the Negrito, Senoi, and Melayu Asli (Proto Malays). The Sinoi appear to have a high predilection for liver cancer, all our nine cases occurring in this group. These aboriginal people live in the jungles where they practice shifting cultivation and maintain their own dietary and social customs. Detailed studies of their dietary habits may provide a clue to the etiology of liver cancer in these people. PMID:177187

  4. Predictors of Microvascular Invasion in Hepatocellular Carcinoma.

    PubMed

    Yamashita, Yo-Ichi; Shirabe, Ken; Aishima, Shinichi; Maehara, Yoshihiko

    2015-09-01

    This chapter covers a range of important topics in the evaluation of the microvascular invasion (MVI) in hepatocellular carcinoma (HCC) before treatment. The malignant potential of HCC is reflected by the types of MVI such as portal venous (vp), hepatic vein (vv) or bile duct (b) infiltration. The identification of the type of MVI in HCC has a key role in decisions regarding the effective treatment of HCC. Here, we describe the possible and important predictors of MVI in HCC. PMID:26398341

  5. Chemoembolization and Radioembolization for Hepatocellular Carcinoma

    PubMed Central

    Salem, Riad; Lewandowski, Robert J.

    2013-01-01

    Hepatocellular carcinoma (HCC) continues to represent a major worldwide problem. While treatments such as resection, transplantation and ablation may provide a chance for cure, these options are often precluded because of advanced disease presentation. Palliative treatments include transarterial embolization and systemic therapies. This review will summarize the state of the science for embolic therapies in HCC (conventional and drug-eluting chemoembolization, radioembolization), as well as discuss related topics including HCC staging, assessment of response and ongoing clinical trials. PMID:23357493

  6. Higher LPA2 and LPA6 mRNA Levels in Hepatocellular Carcinoma Are Associated with Poorer Differentiation, Microvascular Invasion and Earlier Recurrence with Higher Serum Autotaxin Levels.

    PubMed

    Enooku, Kenichiro; Uranbileg, Baasanjav; Ikeda, Hitoshi; Kurano, Makoto; Sato, Masaya; Kudo, Hiroki; Maki, Harufumi; Koike, Kazuhiko; Hasegawa, Kiyoshi; Kokudo, Norihiro; Yatomi, Yutaka

    2016-01-01

    Hepatocellular carcinoma (HCC) commonly develops in patients with liver fibrosis; in these patients, the blood levels of lysophosphatidic acid (LPA) and its generating enzyme autotaxin (ATX) increase with the liver fibrosis stage. We aimed to examine the potential relevance of ATX and LPA in HCC. Fifty-eight HCC patients who underwent surgical treatment were consecutively enrolled in the study. Among the LPA receptors in HCC, higher LPA2 mRNA levels correlated with poorer differentiation, and higher LPA6 mRNA levels correlated with microvascular invasion, which suggested a higher malignant potential of HCC with increased LPA2 and LPA6 expression. In patients with primary HCC, neither LPA2 nor LPA6 mRNA levels were associated with recurrence. However, when serum ATX levels were combined for analysis as a surrogate for plasma LPA levels, the cumulative intra-hepatic recurrence rate was higher in patients in whom both serum ATX levels and LPA2 or LPA6 mRNA levels were higher than the median. However, the mRNA level of phosphatidic acid-selective phospholipase A1ɑ, another LPA-generating enzyme, in HCC patients was not associated with pathological findings or recurrence, even in combination with the expression of LPA receptors. Higher LPA2 mRNA levels were associated with poorer differentiation, and higher LPA6 levels were associated with microvascular invasion in HCC; both became a risk factor for recurrence after surgical treatment when combined with increased serum ATX levels. ATX and LPA receptors merit consideration as therapeutic targets of HCC. PMID:27583415

  7. [Hepatocellular carcinoma: occurrence, risk factors, biomarkers].

    PubMed

    Fehér, János; Lengyel, Gabriella

    2010-06-01

    Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide. Primary hepatocellular carcinoma can be found most frequently (80-90 %) in patients with liver cirrhosis. The most frequent causes of liver cirrhosis are chronic hepatitis B and C virus infections and chronic alcohol consumption. The occurrence of hepatocellular carcinoma is about 3-15 % in patients with alcoholic liver disease. Other predisposing causes can be: non-alcoholic steatohepatitis (NASH), obesity, diabetes mellitus, autoimmune hepatitis, intrahepatic biliary inflammations (primary biliary cirrhosis, primary sclerosing cholangitis), copper and iron metabolic diseases (Wilson-disease, haemochromatosis), congenital alpha-1-antitripsin deficiency. The causative role of hepatitis B és C viruses have been well established in the pathogenesis of liver cancer. Other pathogenic factors are smoking, and different chemical agents. Treatment options for these patients have previously been limited to best supportive care and palliative therapy. Beside surgical treatment (resection, liver transplantation) the invasive radiologic therapy also has been widely used. The effectiveness of targeted therapy with monoclonal antibodies or small-molecule kinase inhibitors has now been demonstrated for the treatment of different tumors. In year 2007, sorafenib, a multitargeted kinase inhibitor was introduced to clinical practice and found to prolong survival significantly for patients with advanced HCC. PMID:20494888

  8. Utility of FNAC in Conjunction with Cell Block for Diagnosing Space-Occupying Lesion (SOL) of Liver with Emphasis on Differentiating Hepatocellular Carcinoma from Metastatic SOL: Analysis of 61 Cases

    PubMed Central

    Sheefa, Haq; Lata, Jadhav; Basharat, Mubeen; Rumana, Makhdoomi; Veena, Malhotra

    2016-01-01

    Objectives To study the cytological patterns of fine-needle aspiration cytology (FNAC) obtained from space-occupying lesions (SOLs) of the liver with an aim to differentiate primary hepatocellular carcinoma from metastatic deposits and to evaluate the added advantage and efficacy of studying cell blocks in conjunction with smears for enhancing diagnostic accuracy.   Methods This prospective study took place over two years (September 2007 to 2009) and included 61 patients with cases of liver SOLs that were clinically or radiologically suspicious for malignancy and who were referred for computed tomography or ultrasonography-guided FNAC. Smears were prepared from the aspirated material, and any remainder was used to make the cell block (n = 55). A final diagnosis was made after evaluating the smears and cell block sections.   Results On cytomorphology, a diagnosis of moderately differentiated hepatocellular carcinoma (HCC) and metastatic carcinoma was made in 10 (18.2%) and 25 (45.5%) cases, respectively, and were confirmed using cell block sections. In cases where it was difficult to differentiate between well-differentiated HCC and regenerative nodules, and between poorly differentiated HCC and poorly differentiated metastatic carcinoma, a final diagnosis was made with the help of cell blocks sections. Cell blocks assisted in reaching a final diagnosis in 16 (29.1%) cases. Cases that were diagnosed using cytomorphology were confirmed by the cell block method. In these 39 (70.9%) cases we were able to render a diagnosis with much more confidence.   Conclusion In our experience, difficulties in diagnosing SOL liver are attributed to differentiation of the tumor. Cell block preparation gives an additional advantage as architectural details can be studied that help to reach an accurate diagnosis in problematic and challenging cases. Thus, we strongly recommend the use of the cell block technique in conjunction with cytosmears for the purpose of diagnosis. PMID

  9. The role of the diffusion sequence in magnetic resonance imaging for the differential diagnosis between hepatocellular carcinoma and benign liver lesions

    PubMed Central

    CARAIANI, COSMIN-NICOLAE; MARIAN, DAN; MILITARU, CLAUDIA; CALIN, ADRIANA; BADEA, RADU

    2016-01-01

    Background and aim To assess the role of diffusion weighted imaging sequence (DWI), routinely used in hepatic magnetic resonance imaging (MRI) for the differentiation of hepatocellular carcinoma (HCC) from benign liver lesions. Methods A number of 56 liver MRI examinations were retrospectively analyzed independently by two experienced radiologists, blinded to each other results. A total number of 70 Focal Liver Lesions (FLLs) assessed by liver MRI in 56 patients were included in the present study. All lesions were retrospectively analyzed by two experienced radiologists, independently from each other and who were not aware of the previous results given by using different imaging techniques. All included FLLs had a final histological diagnosis, or the final diagnosis was based on consensus reading by two experienced radiologists. The signal of the included FLLs was qualitatively appreciated on the b-800 sequences and on the apparent diffusion coefficient (ADC) map. The ADC value of each FLL was measured and the ADC ratio between the ADC value of the assessed FLL and that of the surrounding liver parenchyma was calculated. Results The mean ADC value for benign FLLs as assessed by the two independent readers was 1.75 × 10−3 and 1.72 × 10−3. The mean ADC value for HCC nodules was 0.92 × 10−3 for the first reader and 0.91 × 10−3 for the second reader respectively. The mean ADC ratio for benign FLLs was 1.81 and 1.84 for the two readers, respectively. The ADC ratio for HCC nodules was 0.91 and 0.91, respectively. The ADC value is an indicator which is less prone to interobserver variability (correlation of 0.919→1). The ADC ratio has, as the analysis of the ROC curve shows, the best predictive value for differentiation between benign FLLs and HCC nodules. Analysis of the signal intensity on the DWI b-800 image alone is of no significance in differentiating benign FLLs from HCC nodules (p>0.005). Conclusions The ADC value and the ADC ratio assessed on liver

  10. Hypertrophic osteopathy associated with hepatocellular carcinoma in a dog

    PubMed Central

    Randall, Victoria D.; Souza, Carlos; Vanderhart, Daniel; Boston, Sarah

    2015-01-01

    A 9-year-old spayed female dog diagnosed with hepatocellular carcinoma and hypertrophic osteopathy was negative for additional lesions on computed tomography of the thorax and abdomen. Resection of the affected liver lobe resulted in resolution of clinical signs. This is the first case of hypertrophic osteopathy secondary to hepatocellular carcinoma. PMID:26130837

  11. Genetic Landscape and Biomarkers of Hepatocellular Carcinoma.

    PubMed

    Zucman-Rossi, Jessica; Villanueva, Augusto; Nault, Jean-Charles; Llovet, Josep M

    2015-10-01

    Hepatocellular carcinoma (HCC) has emerged as a major cause of cancer-related death. Its mortality has increased in Western populations, with a minority of patients diagnosed at early stages, when curative treatments are feasible. Only the multikinase inhibitor sorafenib is available for the management of advanced cases. During the last 10 years, there has been a clear delineation of the landscape of genetic alterations in HCC, including high-level DNA amplifications in chromosome 6p21 (VEGFA) and 11q13 (FGF19/CNND1), as well as homozygous deletions in chromosome 9 (CDKN2A). The most frequent mutations affect TERT promoter (60%), associated with an increased telomerase expression. TERT promoter can also be affected by copy number variations and hepatitis B DNA insertions, and it can be found mutated in preneoplastic lesions. TP53 and CTNNB1 are the next most prevalent mutations, affecting 25%-30% of HCC patients, that, in addition to low-frequency mutated genes (eg, AXIN1, ARID2, ARID1A, TSC1/TSC2, RPS6KA3, KEAP1, MLL2), help define some of the core deregulated pathways in HCC. Conceptually, some of these changes behave as prototypic oncogenic addiction loops, being ideal biomarkers for specific therapeutic approaches. Data from genomic profiling enabled a proposal of HCC in 2 major molecular clusters (proliferation and nonproliferation), with differential enrichment in prognostic signatures, pathway activation and tumor phenotype. Translation of these discoveries into specific therapeutic decisions is an unmet medical need in this field. PMID:26099527

  12. Targeting the tumor stroma in hepatocellular carcinoma

    PubMed Central

    Heindryckx, Femke; Gerwins, Pär

    2015-01-01

    Hepatocellular carcinoma (HCC) is one of the most common and deadly cancers worldwide. In ninety percent of the cases it develops as a result of chronic liver damage and it is thus a typical inflammation-related cancer characterized by the close relation between the tumor microenvironment and tumor cells. The stromal environment consists out of several cell types, including hepatic stellate cells, macrophages and endothelial cells. They are not just active bystanders in the pathogenesis of HCC, but play an important and active role in tumor initiation, progression and metastasis. Furthermore, the tumor itself influences these cells to create a background that is beneficial for sustaining tumor growth. One of the key players is the hepatic stellate cell, which is activated during liver damage and differentiates towards a myofibroblast-like cell. Activated stellate cells are responsible for the deposition of extracellular matrix, increase the production of angiogenic factors and stimulate the recruitment of macrophages. The increase of angiogenic factors (which are secreted by macrophages, tumor cells and activated stellate cells) will induce the formation of new blood vessels, thereby supplying the tumor with more oxygen and nutrients, thus supporting tumor growth and offering a passageway in the circulatory system. In addition, the secretion of chemokines by the tumor cells leads to the recruitment of tumor associated macrophages. These tumor associated macrophages are key actors of cancer-related inflammation, being the main type of inflammatory cells infiltrating the tumor environment and exerting a tumor promoting effect by secreting growth factors, stimulating angiogenesis and influencing the activation of stellate cells. This complex interplay between the several cell types involved in liver cancer emphasizes the need for targeting the tumor stroma in HCC patients. PMID:25729472

  13. Lung metastasis of fatty hepatocellular carcinoma after liver transplant: a case report.

    PubMed

    Tepeoğlu, Merih; Özdemir, B Handan; Ok Atılgan, Alev; Akdur, Aydıncan; Haberal, Mehmet

    2014-03-01

    Hepatocellular carcinoma with prominent fatty change is rare, and to date only a few cases have been reported. In this article, we present a 57-yearold woman who underwent a liver transplant for hepatocellular carcinoma. Ten months after liver transplant, she presented with a persistent cough. Computed tomography of the chest was performed, revealing a solid lung mass that measured 1 × 0.9 cm in the right inferior lobe. Right inferior lobectomy was performed, and the final diagnosis was noted as hepatocellular carcinoma with prominent fatty change. Fatty change was extensive in the tumor; therefore, lipoid pneumonia was the first condition that was considered in the differential diagnosis during examination of the lobectomy material. For the differential diagnosis, the immunohistochemistry panel was studied to show the hepatocellular nature of the tumor. Although metastasis of hepatocellular carcinoma to the lungs is expected, hepatocellular carcinoma with prominent fatty change can cause diagnostic difficulties, such as lipoid pneumonia, especially in small lung biopsies. PMID:24635803

  14. Role of immunosuppression and tumor differentiation in predicting recurrence after liver transplantation for hepatocellular carcinoma: A multicenter study of 412 patients

    PubMed Central

    Decaens, Thomas; Roudot-Thoraval, Françoise; Bresson-Hadni, Solange; Meyer, Carole; Gugenheim, Jean; Durand, Francois; Bernard, Pierre-Henri; Boillot, Olivier; Compagnon, Philippe; Calmus, Yvon; Hardwigsen, Jean; Ducerf, Christian; Pageaux, Georges Philippe; Dharancy, Sébastien; Chazouillères, Olivier; Cherqui, Daniel; Duvoux, Christophe

    2006-01-01

    AIM: To assess pre-orthotopic liver transplantation (OLT) factors that could be evaluated pre-operatively or controlled post-operatively associated with hepatocellular carcinoma (HCC) recurrence and disease-free survival after liver transplantation (LT). METHODS: Four hundred and twelve patients transplanted for HCC between 1988 and 1998 in 14 French centers, who survived the postoperative period were studied. Kaplan Meier estimates were calculated for 24 variables potentially associated with recurrence of HCC. Uni- and multivariate analyses were conducted to identify independent predictors of recurrence. RESULTS: Overall 5-year disease-free survival was 57.1%. By univariate analysis, variables associated with disease-free survival were: presence of cirrhosis (P = 0.001), etiology of liver disease (P = 0.03), α fetoprotein level (< 200, 200 to 2000, or > 2000; P < 0.0001), γ-GT activity (N, N to 2N or > 2N; P = 0.02), the number of nodules (1, 2-3 or ≥ 4; P = 0.02), maximal diameter of the largest nodule (< 3 cm, 3 to 5 cm or > 5 cm; P < 0.0001), the sum of the diameter of the nodules (< 3 cm, 3 to 5 cm, 5 to 10 cm or >10 cm; P < 0.0001), bi-lobar location (P = 0.01), preoperative portal thrombosis (P < 0.0001), peri-operative treatment of the tumor (P = 0.002) and chemoembolization (P = 0.03), tumor differentiation (P = 0.01), initial type of calcineurin inhibitor (P = 0.003), the use of antilymphocyte antibodies (P = 0.02), rejection episodes (P = 0.003) and period of LT (P < 0.0001). By multivariate analysis, 6 variables were independently associated with HCC recurrence: maximal diameter of the largest nodule (P < 0.0001), time of LT (P < 0.0001), tumor differentiation (P < 0.0001), use of anti-lymphocyte antibody (ATG) or anti-CD3 antibody (OKT3) (P = 0.005), preoperative portal thrombosis (P = 0.06) and the number of nodules (P = 0.06). CONCLUSION: This study identifies immunosuppression, through the use of ATG or OKT3, as a predictive factor of tumor

  15. Elevated serum levels of Chromogranin A in hepatocellular carcinoma

    PubMed Central

    2012-01-01

    Background During the past three decades, the incidence of hepatocellular carcinoma in the United States has tripled. The neuroendocrine character has been observed in some tumor cells within some hepatocellular carcinoma nodules and elevated serum chromogranin A also been reported in patients with hepatocellular carcinoma. The aim of this work was to investigate the role of serum concentration of chromogranin A in patients with hepatocellular carcinoma at different stages. Methods The study population consisted of 96 patients (63 males and 33 females age range 52-84) at their first hospital admission for hepatocellular carcinoma. The control group consisted of 35 volunteers (20 males and 15 females age range 50-80). The hepatocellular carcinoma patients were stratified according the Barcelona-Clinic Liver Cancer classification. Venous blood samples were collected before treatment from each patients before surgery, centrifuged to obtain serum samples and stored at -80° C until assayed. Results The chromogranin A serum levels were elevated (> 100 ng/ml) in 72/96 patients with hepatocellular carcinoma. The serum levels of chromogranin A were significantly correlated (p<0.05) with alpha-fetoprotein. In comparison with controls, the hepatocellular carcinoma patients showed a significant increase (p<0.001) vs controls. The chromogranin A levels in the Barcelona staging of hepatocellular carcinoma was higher in stage D compared to stage C (p<0.01), to stage B (p<0.001), and to stage A (p<0.001). Conclusions Molecular markers, such as chromogranin A, could be very useful tools for hepatocellular carcinoma diagnosis. However the molecular classification should be incorporated into a staging scheme, which effectively separated patients into groups with homogeneous prognosis and response to treatment, and thus serves to aid in the selection of appropriate therapy. PMID:23173843

  16. Transarterial radioembolization for hepatocellular carcinoma: a review

    PubMed Central

    Sacco, Rodolfo; Conte, Caterina; Tumino, Emanuele; Parisi, Giuseppe; Marceglia, Sara; Metrangolo, Salvatore; Eggenhoffner, Roberto; Bresci, Giampaolo; Cabibbo, Giuseppe; Giacomelli, Luca

    2016-01-01

    Hepatocellular carcinoma (HCC) is the most common type of liver cancer and is the second cause of death due to malignancy in the world. The treatment of HCC is complex and includes potentially curative and palliative approaches. However, both curative and palliative treatments for HCC are often associated with a not-completely favorable safety/efficacy ratio. Therefore, other treatment options appear necessary in clinical practice. Transarterial radioembolization has shown a promising efficacy in terms of disease control and is associated with a good safety profile. This review discusses the use of transarterial radioembolization in HCC, with a focus on the clinical aspects of this therapeutic strategy. PMID:27574589

  17. Innovative surgical approaches for hepatocellular carcinoma

    PubMed Central

    Memeo, Riccardo; de’Angelis, Nicola; de Blasi, Vito; Cherkaoui, Zineb; Brunetti, Oronzo; Longo, Vito; Piardi, Tullio; Sommacale, Daniele; Marescaux, Jacques; Mutter, Didier; Pessaux, Patrick

    2016-01-01

    Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide, with an increasing diffusion in Europe and the United States. The management of such a cancer is continuously progressing and the objective of this paper is to evaluate innovation in the surgical treatment of HCC. In this review, we will analyze the modern concept of preoperative management, the role of laparoscopic and robotic surgery, the intrao-perative use of three dimensional models and augme-nted reality, as well as the potential application of fluore-scence. PMID:27168871

  18. Non-viral causes of hepatocellular carcinoma

    PubMed Central

    Blonski, Wojciech; Kotlyar, David S; Forde, Kimberly A

    2010-01-01

    Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and represents an international public health concern as one of the most deadly cancers worldwide. The main etiology of HCC is chronic infection with hepatitis B and hepatitis C viruses. However, there are other important factors that contribute to the international burden of HCC. Among these are obesity, diabetes, non-alcoholic steatohepatitis and dietary exposures. Emerging evidence suggests that the etiology of many cases of HCC is in fact multifactorial, encompassing infectious etiologies, comorbid conditions and environmental exposures. Clarification of relevant non-viral causes of HCC will aid in preventative efforts to curb the rising incidence of this disease. PMID:20677332

  19. Innovative surgical approaches for hepatocellular carcinoma.

    PubMed

    Memeo, Riccardo; de'Angelis, Nicola; de Blasi, Vito; Cherkaoui, Zineb; Brunetti, Oronzo; Longo, Vito; Piardi, Tullio; Sommacale, Daniele; Marescaux, Jacques; Mutter, Didier; Pessaux, Patrick

    2016-05-01

    Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide, with an increasing diffusion in Europe and the United States. The management of such a cancer is continuously progressing and the objective of this paper is to evaluate innovation in the surgical treatment of HCC. In this review, we will analyze the modern concept of preoperative management, the role of laparoscopic and robotic surgery, the intrao-perative use of three dimensional models and augme-nted reality, as well as the potential application of fluore-scence. PMID:27168871

  20. Cellular prognostic markers in hepatocellular carcinoma.

    PubMed

    Buonaguro, Luigi; Tagliamonte, Maria; Petrizzo, Annacarmen; Damiano, Elvira; Tornesello, Maria Lina; Buonaguro, Franco M

    2015-01-01

    Hepatocellular carcinoma (HCC) is one of the five big killers worldwide and is frequently associated with chronic hepatitis B and C virus (HBV and HCV) infections. Tumor microenvironment consists of a complex network of cells and factors that plays a key role in the tumor progression and prognosis. This is true also for HCC. Several studies have shown strikingly strong correlation between HCC clinical prognosis and intratumoral infiltration of cells affecting tumor growth, invasion, angiogenesis and metastasis. None of such cells is yet validated for routine diagnostic and prognostic assessment. The present review aims at providing a state-of-the-art of such studies. PMID:26043213

  1. The Role of Autophagy in Hepatocellular Carcinoma

    PubMed Central

    Lee, Yoo Jin; Jang, Byoung Kuk

    2015-01-01

    Autophagy is a catabolic process involved in cellular homeostasis under basal and stressed conditions. Autophagy is crucial for normal liver physiology and the pathogenesis of liver diseases. During the last decade, the function of autophagy in hepatocellular carcinoma (HCC) has been evaluated extensively. Currently, autophagy is thought to play a dual role in HCC, i.e., autophagy is involved in tumorigenesis and tumor suppression. Recent investigations of autophagy have suggested that autophagy biomarkers can facilitate HCC prognosis and the establishment of therapeutic approaches. In this review, we briefly summarize the current understanding of autophagy and discuss recent evidence for its role in HCC. PMID:26561802

  2. The Role of Autophagy in Hepatocellular Carcinoma.

    PubMed

    Lee, Yoo Jin; Jang, Byoung Kuk

    2015-01-01

    Autophagy is a catabolic process involved in cellular homeostasis under basal and stressed conditions. Autophagy is crucial for normal liver physiology and the pathogenesis of liver diseases. During the last decade, the function of autophagy in hepatocellular carcinoma (HCC) has been evaluated extensively. Currently, autophagy is thought to play a dual role in HCC, i.e., autophagy is involved in tumorigenesis and tumor suppression. Recent investigations of autophagy have suggested that autophagy biomarkers can facilitate HCC prognosis and the establishment of therapeutic approaches. In this review, we briefly summarize the current understanding of autophagy and discuss recent evidence for its role in HCC. PMID:26561802

  3. [Hepatocellular carcinoma and vitamin K2].

    PubMed

    Mizuta, Toshihiko; Ozaki, Iwata

    2015-11-01

    Despite recent progress in diagnosis and therapy, hepatocellular carcinoma(HCC)remains among the cancers with the poorest prognoses. Vitamin Ks(VKs)have been shown to suppress the growth of HCC cells. Long-term administration of VK2 has established its clinical safety, but it does not appear to exhibit marked anti-tumor effects when administered alone. For more effective use of VK2 against HCC, co-administration of VK2 with other proven anticancer agents or development of a new VK preparation with a modified side-chain should be investigated in the future. PMID:26503869

  4. Fibrolamellar hepatocellular carcinoma: current clinical perspectives

    PubMed Central

    Lafaro, Kelly J; Pawlik, Timothy M

    2015-01-01

    Fibrolamellar carcinoma (FLC) is a variant of hepatocellular carcinoma (HCC), which comprises ∼1%–9% of all HCCs. Although FLC is a variant of HCC, it is distinct from HCC in that it most often affects younger patients (10–35 years of age) with no underlying liver disease. FLC often presents with vague abdominal pain, nausea, abdominal fullness, malaise, and weight loss. Surgery is the current mainstay of treatment for FLC and remains the only potentially curative option. While FLCs are considered less responsive to chemotherapy than their classic HCC counterparts, there have been suggestions that multimodality treatments may be effective, especially in advanced cases. Further research is necessary to determine effective systemic therapies as an adjunct to surgery for FLC. PMID:27508204

  5. Primary hepatocellular carcinoma and metabolic syndrome: An update

    PubMed Central

    Rahman, Rubayat; Hammoud, Ghassan M; Almashhrawi, Ashraf A; Ahmed, Khulood T; Ibdah, Jamal A

    2013-01-01

    Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. The incidence of hepatocellular carcinoma has increased dramatically by 80% over the past two decades in the United States. Numerous basic science and clinical studies have documented a strong association between hepatocellular carcinoma and the metabolic syndrome. These studies have documented that, in most patients, non-alcoholic fatty liver disease is the hepatic manifestation of the metabolic syndrome, which may progress to hepatocellular carcinoma through the cirrhotic process. However, minority of patients with non-alcoholic fatty liver disease may progress to hepatocellular carcinoma without cirrhosis. This review summarizes the current literature of the link between hepatocellular carcinoma and metabolic syndrome with special emphasis on various components of the metabolic syndrome including risk of association with obesity, diabetes mellitus, hyperlipidemia, and hypertension. Current understanding of pathophysiology, clinical features, treatments, outcomes, and surveillance of hepatocellular carcinoma in the background of metabolic syndrome and non-alcoholic fatty liver disease is reviewed. With the current epidemic of metabolic syndrome, the number of patients with non-alcoholic fatty liver disease is increasing. Subsequently, it is expected that the incidence and prevalence of HCC will also increase. It is very important for the scientific community to shed more light on the pathogenesis of HCC with metabolic syndrome, both with and without cirrhosis. At the same time it is also important to quantify the risk of hepatocellular carcinoma associated with the metabolic syndrome in a prospective setting and develop surveillance recommendations for detection of hepatocellular carcinoma in patients with metabolic syndrome. PMID:24069511

  6. Antineoplastic activity of monocrotaline against hepatocellular carcinoma.

    PubMed

    Kusuma, Sandeep Solmon; Tanneeru, Karunakar; Didla, Swroopa; Devendra, Bellary Nagaraju; Kiranmayi, Patnala

    2014-01-01

    Plants are fantastic sources for present day life saving drugs. Monocrotaline a natural ligand exhibits dose-dependent cytotoxicity with potent antineoplastic activity. This study was intended to disclose the therapeutic potential of monocrotaline against hepatocellular carcinoma. The in silico predictions have highlighted the antineoplastic potential, druglikeness and biodegradability of monocrotaline. The in silico docking study has provided an insight and evidence for the antineoplastic activity of monocrotaline against p53, HGF and TREM1 proteins which play a threatening role in causing hepatocellular carcinoma. The mode of action of monocrotaline was determined experimentally by in vitro techniques such as XTT assay, NRU assay and whole cell brine shrimp assay have further supported our in silico studies. The in vitro cytotoxicity of monocrotaline was proved at IC50 24.966 µg/mL and genotoxicity at 2 X IC50 against HepG2 cells. Further, the credible druglike properties with non-mutagenicity, non-toxic on mammalian fibroblast and the potential antineoplastic activity through in vitro experimental validations established monocrotaline as a novel scaffold for liver cancer with superior efficacy and lesser side effects. PMID:25028149

  7. Differential association of STAT3 and HK-II expression in hepatitis B virus- and hepatitis C virus-related hepatocellular carcinoma.

    PubMed

    Li, Man; Wang, Weihua; Jin, Rui; Zhang, Tieying; Li, Na; Han, Qunying; Wei, Ping; Liu, Zhengwen

    2016-09-01

    STAT3 and hexokinase II (HK-II) are involved in viral infection and carcinogenesis of various cancers including hepatocellular carcinoma (HCC). The roles of STAT3 and HK-II in hepatitis B virus (HBV)- and hepatitis C virus (HCV)-related HCC remain largely unclear. This study examined STAT3 and HK-II expression in HBV- and HCV-related HCC, HBV-related liver fibrosis, and normal control liver by using tissue microarray and immunohistochemical method. Results showed that STAT3 expression in HBV-related HCC, HCV-related HCC, and HBV-related liver fibrosis was significantly higher than in control liver (P < 0.001, P = 0.016, and P = 0.005, respectively) and had no significant differences between these three diseased liver tissues. The HK-II expression in HBV-related HCC was significantly higher than that in HCV-related HCC, HBV-related liver fibrosis, and control liver (P = 0.007, P = 0.029, and P = 0.008, respectively) but had no significant elevation in and no significant differences between HCV-related HCC, HBV-related liver fibrosis, and control liver. The HK-II expression was significantly correlated to STAT3 expression in HBV-related HCC (P = 0.022), but no correlation was observed in HCV-related HCC, HBV-related liver fibrosis, and control liver. In conclusion, STAT3 expression is upregulated in both HBV- and HCV-related HCC, while HK-II is predominantly upregulated and correlated to STAT3 in HBV-related HCC. These differential expression and association may suggest the distinct roles of STAT3 and HK-II in hepatocarcinogenesis of HBV and HCV infection. Studies are needed to confirm the relationship of STAT3 and HK-II and to examine the underlying mechanisms. J. Med. Virol. 88:1552-1559, 2016. © 2016 Wiley Periodicals, Inc. PMID:26889748

  8. Genome-Wide and Differential Proteomic Analysis of Hepatitis B Virus and Aflatoxin B1 Related Hepatocellular Carcinoma in Guangxi, China

    PubMed Central

    Chen, Zhao-Hong; Bai, Tao; Xiang, Bang-De; Qin, Xiao; Xiao, Kai-Yin; Peng, Min-Hao; Liu, Zhi-Ming; Liu, Tang-Wei; Qin, Xue; Li, Shan; Han, Ze-Guang; Mo, Zeng-Nan; Santella, Regina M.; Winkler, Cheryl A.; O’Brien, Stephen J.; Peng, Tao

    2013-01-01

    Both hepatitis B virus (HBV) and aflatoxin B1 (AFB1) exposure can cause liver damage as well as increase the probability of hepatocellular carcinoma (HCC). To investigate the underlying genetic changes that may influence development of HCC associated with HBV infection and AFB1 exposure, HCC patients were subdivided into 4 groups depending upon HBV and AFB1 exposure status: (HBV(+)/AFB1(+), HBV(+)/AFB1(-), HBV(-)/AFB1(+), HBV(-)/AFB1(-)). Genetic abnormalities and protein expression profiles were analyzed by array-based comparative genomic hybridization and isobaric tagging for quantitation. A total of 573 chromosomal aberrations (CNAs) including 184 increased and 389 decreased were detected in our study population. Twenty-five recurrently altered regions (RARs; chromosomal alterations observed in ≥10 patients) in chromosomes were identified. Loss of 4q13.3-q35.2, 13q12.1-q21.2 and gain of 7q11.2-q35 were observed with a higher frequency in the HBV(+)/AFB1(+), HBV(+)/AFB1(-) and HBV(-)/AFB1(+) groups compared to the HBV(-)/AFB(-) group. Loss of 8p12-p23.2 was associated with high TNM stage tumors (P = 0.038) and was an unfavorable prognostic factor for tumor-free survival (P =0.045). A total of 133 differentially expressed proteins were identified in iTRAQ proteomics analysis, 69 (51.8%) of which mapped within identified RARs. The most common biological processes affected by HBV and AFB1 status in HCC tumorigenesis were detoxification and drug metabolism pathways, antigen processing and anti-apoptosis pathways. Expression of AKR1B10 was increased significantly in the HBV(+)/AFB1(+) and HBV(-)/AFB1(+) groups. A significant correlation between the expression of AKR1B10 mRNA and protein levels as well as AKR1B10 copy number was observered, which suggest that AKR1B10 may play a role in AFB1-related hepatocarcinogenesis. In summary, a number of genetic and gene expression alterations were found to be associated with HBV and AFB1- related HCC. The possible synergistic

  9. Introducing differential expression of human heat shock protein 27 in hepatocellular carcinoma: moving toward identification of cancer biomarker.

    PubMed

    Khan, Rizma; Siddiqui, Nadir Naveed; Ul Haq, Ahtesham; Rahman, M Ataur

    2016-01-01

    Previously, it has to be acknowledged that overexpressed heat shock protein B27 (HSPB27) have been implicated in the etiology of wide range of human cancers. However, the molecular mechanism leading to the disease initiation to progression in liver cancer is still unknown. Present work was undertaken to investigate the differentially expressed HSPB27 in association with those damages that lead to liver cancer development. For the identification of liver cancer biomarker, samples were subjected to comparative proteomic analysis using two-dimensional gel electrophoresis (2-DE) and were further validated by Western blot and immunohistochemical analysis. After validation, in silico studies were applied to demonstrate the significantly induced phosphorylated and S-nitrosylated signals. The later included the interacting partner of HSPB27, i.e., mitogen-activated protein kinase-3 and 5 (MAPK3 and 5), ubiquitin C (UBC), v-akt murine thymoma viral oncogene homolog 1 (AKT1), mitogen-activated protein kinase 14 (MAPK14), and tumor protein p53 (TP53), which bestowed with critical capabilities, namely, apoptosis, cell cycling, stress activation, tumor suppression, cell survival, angiogenesis, proliferation, and stress resistance. Taking together, these results shed new light on the potential biomarker HSPB27 that overexpression of HSPB27 did lead to upregulation of their interacting partner that together demonstrate their possible role as a novel tumor progressive agent for the treatment of metastasis in liver cancer. HSPB27 is a promising diagnostic marker for liver cancer although further large-scale studies are required. Also, molecular profiling may help pave the road to the discovery of new therapies. PMID:26242269

  10. 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

  11. Nonsurgical therapies for hepatocellular and cholangiocellular carcinoma.

    PubMed

    Schmassmann, A

    1999-01-01

    Surgical resection is the first choice of treatment for patients with hepatocellular (HCC) and cholangiocellular carcinomas. Prolongation of survival is, however, the only realistic goal for most patients, which can be often achieved by nonsurgical therapies. Inoperable patients with large or multiple HCCs are usually treated with transarterial chemoembolization (TACE) with lipiodol in combination with a chemotherapeutic drug and gelfoam. Three-year survival depends on the stage of the disease and is about 20%. Patients with earlier tumor stages (one or two tumor nodules less than 3 cm in size) are suitable for treatment with percutaneous ethanol injection (PEI) alone or in combination with TACE. Several studies have shown that in these early stages, the 3-year survival rate is approximately 55%-70% in the actively treated patients which is significantly higher than in untreated patients. In advanced stages of the disease, TACE and PEI have no effect on survival and should not be performed. Some of these patients have been successfully treated with octreotide. Patients with inoperable cholangiocellular carcinoma are treated by endoscopic or percutaneous stent placement. If stenting does not achieve adequate biliary drainage, multidisciplinary therapy including internal/external radiotherapy or photodynamic therapy should be considered in patients with potential long-term survival. In conclusion, nonresectional therapies play an essential role in the therapy of inoperable hepato- and cholangiocellular carcinomas as they lead to satisfactory survival. Multidisciplinary therapy appears to be the current trend of management. PMID:10414182

  12. Differentiation therapy of hepatocellular carcinoma by inhibiting the activity of AKT/GSK-3β/β-catenin axis and TGF-β induced EMT with sophocarpine.

    PubMed

    Zhang, Ping-Ping; Wang, Pei-Qin; Qiao, Chun-Ping; Zhang, Qing; Zhang, Jun-Ping; Chen, Fei; Zhang, Xin; Xie, Wei-Fen; Yuan, Zong-Li; Li, Zhao-Shen; Chen, Yue-Xiang

    2016-06-28

    Hepatocellular carcinoma progression is thought to be driven by cancer stem cells (CSCs). No clinical trial has, as yet, shown convincing long-term disease free survival results for the majority of patients in HCC. So it is important to discover new anti-cancer agents. In our study, we chose sophocarpine, which is derived from the foxtail-like sophora herb, for its efficacy to inhibit HCC including CSCs and potential mechanism study. Our results show that sophocarpine could not only reduce HCC cell viability, eliminate HCC and reverse hepatoma cells malignant phenotype, but also reduce the ratio of CSCs and inhibit the sphere formation of CSCs in vitro. In vivo, sophocarpine significantly displayed antitumor effects in subcutaneous xenograft HCC models and orthotopic transplantation tumor models. Further studies showed that sophocarpine could exert anti-tumor effects partly via downregulating the activity of the cancer stem cell related pathways and inhibiting EMT induced by TGF-β. PMID:26945965

  13. 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

  14. Hepatocellular carcinoma detected by iodized oil

    SciTech Connect

    Yumoto, Y.; Jinno, K.; Tokuyama, K.; Araki, Y.; Ishimitsu, T.; Maeda, H.; Konno, T.; Iwamoto, S.; Ohnishi, K.; Okuda, K.

    1985-01-01

    This study assesses the diagnostic value of Lipiodol (iodized oil) and computed tomography (CT) in detecting hepatocellular carcinoma (HCC). Twenty-four patients who were suspected of having HCC received injections of a small amount of Lipiodol, along with an antitumor agent, in the hepatic artery following routine celiac angiography. CT scans obtained 7-10 days after Lipiodol administration demonstrated HCC in distinct contrast to the surrounding noncancerous parenchyma. In particular, the CT-Lipiodol procedure disclosed many small HCC lesions that were not shown by celiac angiography, scintigraphy, CT with an without contrast medium enhancement, and ultrasonography. Although this procedure may miss very small or highly fibrotic lesions, it is recommended for patients suspected of having HCC and for patients for whom hepatic resection is being considered.

  15. Biomarkers for Hepatocellular Carcinoma (HCC): An Update.

    PubMed

    Li, Dave; Satomura, Shinji

    2015-01-01

    The past decades have witnessed increased use of biomarkers in disease management. A biomarker is any characteristic that can be objectively measured and evaluated as an indicator of normal biological process, pathogenic process, or pharmacological response to a therapeutic intervention. The clinical measurements of biomarkers can be carried out in vivo using imaging modalities like ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI), as well as in vitro utilizing serum or plasma or other body fluids as specimens. In contrast to the imaging modalities, a prominent value of serum biomarkers is that they could be biologically relevant and disease-specific to pathophysiologic or pathologic process of disease development. This article provides an update of serum biomarkers for hepatocellular carcinoma (HCC) in risk assessment for early detection through surveillance. PMID:26530367

  16. Metastatic Hepatocellular Carcinoma Responsive to Pembrolizumab

    PubMed Central

    Truong, Phu; Kallail, K. James

    2016-01-01

    Hepatocellular carcinoma (HCC) is an aggressive liver tumor that occurs with chronic liver disease. Surgical resection is the mainstay of therapy for localized disease whereas therapeutic options for advanced disease are limited. The innovative blockade of immune checkpoints with targeted immunotherapies, such as monoclonal antibodies against programmed death receptor 1 (PD-1), have shown promise in the treatment of solid malignancies. The PD-1 inhibiting antibodies, nivolumab and pembrolizumab prolonged overall survival in randomized trials in metastatic melanoma and advanced non-small cell lung cancer. This is a report of a 75-year-old male patient with metastatic HCC who was initially treated with the standard of therapy sorafenib. After failure of sorafenib therapy, pembrolizumab was started. There was a dramatic response to pembrolizumab with decrease in tumor size and drop in alfa fetoprotein. To the best of our knowledge, this is the first case report of metastatic HCC responsive to pembrolizumab after failure of sorafenib. PMID:27433410

  17. Immunological landscape and immunotherapy of hepatocellular carcinoma.

    PubMed

    Prieto, Jesús; Melero, Ignacio; Sangro, Bruno

    2015-12-01

    Advanced hepatocellular carcinoma (HCC) is a serious therapeutic challenge and targeted therapies only provide a modest benefit in terms of overall survival. Novel approaches are urgently needed for the treatment of this prevalent malignancy. Evidence demonstrating the antigenicity of tumour cells, the discovery that immune checkpoint molecules have an essential role in immune evasion of tumour cells, and the impressive clinical results achieved by blocking these inhibitory receptors, are revolutionizing cancer immunotherapy. Here, we review the data on HCC immunogenicity, the mechanisms for HCC immune subversion and the different immunotherapies that have been tested to treat HCC. Taking into account the multiplicity of hyperadditive immunosuppressive forces acting within the HCC microenvironment, a combinatorial approach is advised. Strategies include combinations of systemic immunomodulation and gene therapy, cell therapy or virotherapy. PMID:26484443

  18. The mutational landscape of hepatocellular carcinoma

    PubMed Central

    2015-01-01

    The development of hepatocellular carcinoma (HCC) is a complex process, and HCC arises from the accumulation of multiple genetic alterations leading to changes in the genomic landscape. Current advances in genomic technologies have revolutionized the search for genetic alterations in cancer genomes. Recent studies in which all coding exons in HCC were sequenced have shed new light on the genomic landscape of this malignant disease. Catalogues of these somatic mutations and systematic analysis of catalogued mutations will lead us to uncover candidate HCC driver genes, although further functional validation is needed to determine whether these genes play a causal role in the development of HCC. This review provides an overview of previously known oncogenes and new oncogene candidates in HCC that were uncovered from recent exome or whole-genome sequencing studies. This knowledge provides direction for future personalized treatment approaches for patients with HCC. PMID:26523267

  19. Gene Signatures in Hepatocellular Carcinoma (HCC)

    PubMed Central

    Studach, Leo; Merle, Philippe

    2010-01-01

    Primary hepatocellular carcinoma (HCC) is a significant human cancer globally, with poor prognosis. New and efficacious therapy strategies are needed as well as new biomarkers for early detection of at-risk patients. In this review, we discuss select microarray studies of human HCCs, and propose a gene signature that has promise for clinical/translational application. This gene signature combines the proliferation cluster of genes and the hepatic cancer initiating/stem cell gene cluster for identification of HCCs with poor prognosis. Evidence from cell-based assays identifies the existence of a mechanistic link between these two gene clusters, involving the proliferation cluster gene Polo-like kinase 1 (PLK1). We propose that PLK1 is a promising therapy target for HCC. PMID:20851183

  20. Charged Particle Therapy for Hepatocellular Carcinoma

    PubMed Central

    Skinner, Heath D.; Hong, Theodore S.; Krishnan, Sunil

    2011-01-01

    Historically, the use of external beam radiotherapy for hepatocellular carcinoma (HCC) has been limited by toxicity to the uninvolved liver and surrounding structures. Advances in photon radiotherapy have improved dose conformality to the tumor and facilitated dose escalation, a key contributor to improved HCC radiation treatment outcomes. However, despite these advances in photon radiotherapy, significant volumes of liver still receive low doses of radiation that can preclude dose escalation, particularly in patients with limited functional liver reserves. By capitalizing on the lack of exit dose along the beam path beyond the tumor and higher biological effectiveness, charged particle therapy offers the promise of maximizing tumor control via dose escalation without excessive liver toxicity. In this review we discuss the distinctive biophysical attributes of both proton and carbon ion radiotherapy, particularly as they pertain to treatment of HCC. We also review the available literature regarding clinical outcomes and toxicity of using charged particles for the treatment of HCC. PMID:21939857

  1. Image-guided ablation for hepatocellular carcinoma.

    PubMed

    Lencioni, Riccardo; Crocetti, Laura

    2013-01-01

    Image-guided ablation is accepted as the best therapeutic choice for patients with early-stage hepatocellular carcinoma (HCC) when surgical options-including resection and transplantation-are precluded. The term image-guided tumor ablation is defined as the direct application of chemical substances or sources of energy to a focal tumor in an attempt to achieve eradication or substantial tumor destruction. Over the past 25 years, several methods for local tumor destruction have been developed and clinically tested. Radiofrequency ablation (RFA) has shown superior anticancer effect and greater survival benefit with respect to the seminal percutaneous technique, ethanol injection, in meta-analyses of randomized controlled trials, and is currently established as the standard ablative modality. Nevertheless, novel thermal and nonthermal techniques for tumor ablation-including microwave ablation and irreversible electroporation-seem to have potential to improve the efficacy of RFA and are currently undergoing clinical investigation. PMID:22941021

  2. Undiagnosed Hepatocellular Carcinoma Presenting as Nasal Metastases

    PubMed Central

    Mohammed, Hassen; Sheikh, Rashid; Rahman, Waheed; Sheta, Sally; Dogan, Zeynel

    2015-01-01

    Hepatocellular carcinoma (HCC) is a primary malignancy of the liver with up to half of cases suffering from extrahepatic metastasis in the later stages of the disease. Commonly reported and encountered metastatic sites include the lymph nodes, lung, bone, and adrenal glands. This is an effort to throw a spotlight on a rare case of metastatic HCC which presented to us as two distinct lesions in the nose. It focuses on the presentation and the steps that were taken to reach this rare and unusual diagnosis. It sparks interest from a clinical and histopathology perspective. Our cynosure is the findings of the case coupled with a probe on the possible routes of spread of HCC to sinonasal region. PMID:26618018

  3. Cold agglutinin disease in fibrolamellar hepatocellular carcinoma: a rare association with a rare cancer variant.

    PubMed

    Al-Matham, Khalid; Alabed, Iehab; Zaidi, Syed Z A; Qushmaq, Khalid A

    2011-01-01

    Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia. Although it can occur secondary to lymphoproliferative disorders and autoimmune or infectious diseases, CAD is rarely reported as secondary to solid tumors. We report a case of a woman aged 18 years diagnosed with a well-differentiated hepatocellular carcinoma of the fibrolamellar subtype, who was shown to have CAD also. Her general condition, including CAD, improved after targeted therapy with sorafenib for the hepatocellular carcinoma and only conservative measures for the CAD that consisted of avoidance of cold. In summary, although it is an extremely rare association and less common than lymphoproliferative disorders, CAD can be associated with solid tumors. PMID:21293066

  4. Chronic renal disease in a captive two-toed sloth (Choloepus didactylus) with concurrent hepatocellular carcinoma.

    PubMed

    Salas, Elisa; Wolf, Tiffany; Harris, Seth

    2014-06-01

    A 13-yr-old female two-toed sloth (Choloepus didactylus) with a prolonged history of worsening azotemia was necropsied shortly after euthanasia. On necropsy, the sloth had poor body condition, bilaterally shrunken kidneys, and a large neoplastic mass replacing the right liver lobe. Histologic examination demonstrated chronic renal disease with metastatic mineralization as the cause of morbidity. The liver mass was not associated with any known clinical signs and was diagnosed as a solitary and well-differentiated hepatocellular carcinoma. To the authors' knowledge, this is the first report of hepatocellular carcinoma diagnosed in a sloth and the first detailed description of chronic renal disease in this species. PMID:25000707

  5. The histone acetyltransferase hMOF suppresses hepatocellular carcinoma growth.

    PubMed

    Zhang, Jin; Liu, Hui; Pan, Hao; Yang, Yuan; Huang, Gang; Yang, Yun; Zhou, Wei-Ping; Pan, Ze-Ya

    2014-09-26

    Males absent on the first (MOF) is a histone acetyltransferase belongs to the MYST (MOZ, Ybf2/Sas3, Sas2 and TIP60) family. In mammals, MOF plays critical roles in transcription activation by acetylating histone H4K16, a prevalent mark associated with chromatin decondensation. MOF can also acetylate transcription factor p53 on K120, which is important for activation of pro-apoptotic genes; and TIP5, the largest subunit of NoRC, on K633. However, the role of hMOF in hepatocellular carcinoma remains unknown. Here we find that the expression of hMOF is significantly down-regulated in human hepatocellular carcinoma and cell lines. Furthermore, our survival analysis indicates that low hMOF expression predicts poor overall and disease-free survival. We demonstrate that hMOF knockdown promotes hepatocellular carcinoma growth in vitro and in vivo, while hMOF overexpression reduces hepatocellular carcinoma growth in vitro and in vivo. Mechanically, we show that hMOF regulates the expression of SIRT6 and its downstream genes. In summary, our findings demonstrate that hMOF participates in human hepatocellular carcinoma by targeting SIRT6, and hMOF activators may serve as potential drug candidates for hepatocellular carcinoma therapy. PMID:25181338

  6. [Telomere length and telomerase activity in hepatocellular carcinoma].

    PubMed

    Nakashio, R; Kitamoto, M; Nakanishi, T; Takaishi, H; Takahashi, S; Kajiyama, G

    1998-05-01

    Telomerase activity and terminal restriction fragment (TRF) length were examined in hepatocellular carcinoma (HCC). Telomerase activity was assayed by telomeric repeat amplification protocol (TRAP) connected with an internal telomerase assay standard (ITAS). The incidence of strong telomerase activity (highly variable level compared with the activity of non-cancerous liver tissue) was 79% in well, 84% in moderately, and 100% in poorly differentiated HCC, while 0% in non-cancerous liver tissues. The incidence of TRF length alteration (reduction or elongation) was 53% in HCC. The incidence of TRF alteration was significantly higher in HCC exceeding 3 cm in diameter, moderately or poorly differentiated in histology. Telomerase activity was not associated with TRF length alteration in HCC. In conclusion, strong telomerase activity and TRF length alteration increased with HCC tumor progressions. PMID:9613130

  7. Metastatic Periampullary Tumor from Hepatocellular Carcinoma Presenting as Gastrointestinal Bleeding

    PubMed Central

    Nissen, Nicholas N.; Guindi, Maha; Jamil, Laith H.

    2015-01-01

    Periampullary tumors constitute a number of diverse neoplastic lesions located within 2 cm of the major duodenal papilla; among these, metastatic lesions account for only a small proportion of the periampullary tumors. To our knowledge, a metastatic periampullary tumor from hepatocellular carcinoma has never been reported. A 62-year-old male reported to our institute for fatigue and low hemoglobin. His medical history was remarkable for multifocal hepatocellular carcinoma (HCC) treated with selective transcatheter arterial chemoembolization (TACE). An esophagogastroduodenoscopy (EGD) was performed which revealed a periampullary mass. Histopathology was consistent with metastatic moderately differentiated HCC. Two endoloops were deployed around the base of the mass one month apart. The mass eventually sloughed off and patient's hemoglobin level stabilized. We postulated that periampullary metastasis in this patient was the result of tumor fragments migration through the biliary tracts and that TACE which increases tumor fragments burden might have played a contributory role. Metastasis of HCC to the gastrointestinal (GI) tract should be considered as a cause of GI bleeding. PMID:26064707

  8. Nonalcoholic fatty liver disease and hepatocellular carcinoma.

    PubMed

    Zoller, Heinz; Tilg, Herbert

    2016-08-01

    The fastest growing cause of cancer-related death is hepatocellular carcinoma (HCC), which is at least partly attributable to the rising prevalence of non-alcoholic fatty liver disease. Non-alcoholic fatty liver disease (NAFLD) encompasses a broad spectrum of conditions, ranging from non-progressive bland steatosis to malignant transformation into hepatocellular cancer. The estimated annual HCC incidence in the progressive form of NAFLD - non-alcoholic steatohepatitis (NASH) - is about 0.3%. The risk of HCC development is higher in men and increases with age, more advanced fibrosis, progressive obesity, insulin resistance and diabetes mellitus. Studies on the molecular mechanism of HCC development in NAFLD have shown that hepatocarcinogenesis is associated with complex changes at the immunometabolic interface. In line with these clinical risk factors, administration of a choline-deficient high-fat diet to mice over a prolonged period results in spontaneous HCC development in a high percentage of animals. The role of altered insulin signaling in tumorigenesis is further supported by the observation that components of the insulin-signaling cascade are frequently mutated in hepatocellular cancer cells. These changes further enhance insulin-mediated growth and cell division of hepatocytes. Furthermore, studies investigating nuclear factor kappa B (NF-κB) signaling and HCC development allowed dissection of the complex links between inflammation and carcinogenesis. To conclude, NAFLD reflects an important risk factor for HCC, develops also in non-cirrhotic livers and is a prototypic cancer involving inflammatory and metabolic pathways. STRENGTHS/WEAKNESSES AND SUMMARY OF THE TRANSLATIONAL POTENTIAL OF THE MESSAGES IN THE PAPER: The systematic review summarizes findings from unbiased clinical and translational studies on hepatocellular cancer in non-alcoholic fatty liver disease. This provides a concise overview on the epidemiology, risk factors and molecular

  9. BSEP and MDR3: Useful Immunohistochemical Markers to Discriminate Hepatocellular Carcinomas From Intrahepatic Cholangiocarcinomas and Hepatoid Carcinomas.

    PubMed

    Fujikura, Kohei; Yamasaki, Takashi; Otani, Kyoko; Kanzawa, Maki; Fukumoto, Takumi; Ku, Yonson; Hirose, Takanori; Itoh, Tomoo; Zen, Yoh

    2016-05-01

    We herein examined the immunohistochemical expression of 2 hepatocyte-specific transporters (bile salt export pump [BSEP] and multidrug-resistance protein 3 [MDR3]) in hepatocellular carcinomas (HCCs, n=54), intrahepatic cholangiocarcinomas (n=34), combined hepatocellular and cholangiocarcinomas (n=23), and hepatoid carcinomas originated from extrahepatic organs (n=27) to compare their diagnostic values with those of arginase-1 (ARG1) and hepatocyte paraffin-1 (HepPar-1). BSEP was expressed in 91% of HCCs and MDR3 in 83%. Although their sensitivities were slightly lower than those of ARG1 (96%) and HepPar-1 (93%), the 2 transporters appeared to be more specific for HCCs. ARG1 and HepPar-1 were expressed in intrahepatic cholangiocarcinomas (9% and 6%) and hepatoid carcinomas (22% and 44%, respectively), whereas BSEP and MDR3 were entirely negative in these neoplasms, except for 1 case of BSEP-positive hepatoid carcinoma of the esophagus. The highly specific expression of BSEP and MDR3 in hepatocytes was recapitulated in additional examinations of combined hepatocellular and cholangiocarcinomas, in which the expression of the transporters was restricted to morphologically hepatocellular areas. In contrast, ARG1 and HepPar-1 were also variably positive in areas of biliary or indeterminate differentiation. We also applied BSEP and MDR3 immunohistochemistry to 8 biopsy cases of poorly differentiated primary liver cancer, in which the original diagnosis was not conclusive. The diagnosis of HCC was retrospectively suggested in 2 cases expressing both BSEP and MDR3. In conclusion, given the highly specific expression of BSEP and MDR3 in HCCs, immunohistochemistry for these transporters will be useful not only for determining hepatocellular differentiation in primary liver cancers but also for discriminating HCCs from hepatoid carcinomas. PMID:26735860

  10. Primary hepatic tumors with myxoid change: morphologically unique hepatic adenomas and hepatocellular carcinomas.

    PubMed

    Salaria, Safia N; Graham, Rondell P; Aishima, Shinichi; Mounajjed, Taofic; Yeh, Matthew M; Torbenson, Michael S

    2015-03-01

    Mucin production in primary liver neoplasms is typically interpreted as evidence for biliary differentiation. However, we have observed benign and malignant liver tumors that have abundant extracellular myxoid/mucinous material, yet have only evidence of hepatocellular differentiation. To further characterize these unusual findings, 9 cases were identified and further studied. Four cases were hepatic adenomas, whereas 5 were hepatocellular carcinomas. Extracellular myxoid/mucinous material was diffuse in 7 cases and patchy in 2 cases. The extracellular myxoid/mucinous material was typically weakly mucicarmine positive (N=6) and Alcian blue positive (N=8). All tumors were well differentiated, and none had evidence for biliary differentiation by morphology or immunohistochemistry. The hepatic adenomas arose in nondiabetic and nonobese patients. Both the hepatic adenomas and the hepatocellular carcinomas were strongly and diffusely HepPar1 positive, CK19 negative, and showed loss of LFABP protein expression. These findings indicate that extracellular myxoid/mucinous material in isolation should not be interpreted as cholangiocarcinoma. Furthermore, the unique morphology, the clinical characteristics, and the immunophenotype results suggest that myxoid hepatic adenomas and hepatocellular carcinoma may be unique tumor variants. PMID:25602798

  11. Mutation of p53 Tumor Suppressor Gene in Hepatocellular Carcinoma.

    PubMed

    Tullo, A; Sbisà, E

    2000-01-01

    In recent years, the most commonly observed genetic alteration in hepatocellular carcinoma (HCC), as in many other tumors affecting man, has been reported to be the mutation of the p53 coding gene (1,2). This gene has the features of a recessive oncosuppressor in its wild-type form and can be a dominant oncogene in its mutated form. The gene (20 kb) is located in a single copy on the short arm of chromosome 17 and contains 11 exons interrupted by 10 introns. The mRNA (2.8 kb) codes for a protein of 393 amino acids, which is expressed at relatively low levels in all tissues. p53 product is a 53-kDa phosphoprotein involved in the regulation of cell cycle, in DNA synthesis and repair, and in cell differentiation and apoptosis (see refs. 3-6, for reviews). PMID:21341051

  12. Liver-Directed Radiotherapy for Hepatocellular Carcinoma

    PubMed Central

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

    2016-01-01

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

  13. Treatment of Hepatocellular Carcinoma: A Systematic Review

    PubMed Central

    Lin, Shibo; Hoffmann, Katrin; Schemmer, Peter

    2012-01-01

    Hepatocellular carcinoma (HCC) is one of the most common malignancies, with an increasing incidence. With advances in surgical techniques and instrumentation and the development of molecular-target drugs, a number of potentially curative treatments have become available. Management of HCC patients depends on the stage of their tumor. Liver resection remains the first choice for very early-stage HCC, but it is being challenged by local ablative therapy. For early-stage HCC that meet the Milan criteria, liver transplantation still offers a better outcome; however, local ablative therapy can be a substitute when transplantation is not feasible. Local ablation is also used as a bridging therapy toward liver transplantation. HCC recurrence is the main obstacle to successful treatment, and there is currently no effective means of preventing or treating HCC recurrence. Transarterial therapy is considered suitable for intermediate-stage HCC, while sorafenib is recommended for advanced-stage HCC. This stage-based approach to therapy not only provides acceptable outcomes but also improves the quality of life of HCC patients. Because of the complexity of HCC, therapeutic approaches must be adapted according to the characteristics of each individual patient. This review discusses the current standards and trends in the treatment of HCC. PMID:24159579

  14. Problem of hepatocellular carcinoma in West Africa

    PubMed Central

    Ladep, Nimzing G; Lesi, Olufunmilayo A; Mark, Pantong; Lemoine, Maud; Onyekwere, Charles; Afihene, Mary; Crossey, Mary ME; Taylor-Robinson, Simon D

    2014-01-01

    The incidence of hepatocellular carcinoma (HCC) is known to be high in West Africa with an approximate yearly mortality rate of 200000. Several factors are responsible for this. Early acquisition of risk factors; with vertical or horizontal transmission of hepatitis B (HBV), environmental food contaminants (aflatoxins), poor management of predisposing risk factors and poorly-managed strategies for health delivery. There has been a low uptake of childhood immunisation for hepatitis B in many West African countries. Owing to late presentations, most sufferers of HCC die within weeks of their diagnosis. Highlighted reasons for the specific disease pattern of HCC in West Africa include: (1) high rate of risk factors; (2) failure to identify at risk populations; (3) lack of effective treatment; and (4) scarce resources for timely diagnosis. This is contrasted to the developed world, which generally has sufficient resources to detect cases early for curative treatment. Provision of palliative care for HCC patients is limited by availability and affordability of potent analgesics. Regional efforts, as well as collaborative networking activities hold promise that could change the epidemiology of HCC in West Africa. PMID:25429316

  15. Aflatoxins, hepatocellular carcinoma and public health

    PubMed Central

    Magnussen, Arvin; Parsi, Mansour A

    2013-01-01

    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. PMID:23539499

  16. Hepatocellular carcinoma: modern image-guided therapies.

    PubMed

    Puppala, Sapna; Patel, Rafiuddin; Yap, Ki Sing; Patel, Jai; Wah, Tze; Snoddon, Andrew

    2016-03-01

    The most common primary malignancy of the liver and the third leading cause of cancer mortality worldwide is hepatocellular carcinoma (HCC), which presents a major global health problem due to its increasing incidence. Most cases of HCC are secondary to either infection (hepatitis B or C) or cirrhosis (alcohol being the most common cause). Clinical presentation is variable and the tumour can be an incidental finding. Treatment options for HCC and prognosis are dependent on many factors but most importantly tumour size and staging. The last two decades have revolutionised the treatment of HCC using image-guided techniques. The concepts of imaging and image-guided techniques are still young and not well described in standard textbooks and hence an up to date review article is essential. The clinical subspecialities may lack familiarity with image-guided techniques but are responsible for management of these patients before and after the treatment by interventional radiologists. This article reviews current image-guided techniques, evidence and outcomes and provides educational highlights and question and answers. The article provides an overview in a simple understandable manner to enable readers from various levels of practice and training to benefit from and apply in their practice. PMID:26787919

  17. 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

  18. Imaging of hepatocellular carcinoma: a practical approach.

    PubMed

    Coakley, F V; Schwartz, L H

    2001-10-01

    Imaging of hepatocellular carcinoma (HCC) is complicated because the tumor has a varied radiologic appearance and frequently coexists with cirrhotic regenerative and dysplastic nodules. In cirrhotic patients, any dominant solid nodule that is not clearly a hemangioma should be considered a HCC until proven otherwise, especially if the lesion is hypervascular, of high T2 signal intensity, or demonstrates venous invasion. Biopsy of HCC in cirrhosis is risky and surveillance is often preferable. The doubling time of HCC is 1 to 12 months, and a nodule that is stable over 4 months is very unlikely to be a HCC. However, stable nodules cannot be dismissed, since livers containing dysplastic nodules are at high risk to develop HCC. In noncirrhotic patients, any solid mass that is not clearly a hemangioma or focal nodular hyperplasia is potentially a HCC, and biopsy may be required. Venous invasion by tumor should be distinguished from bland thrombus. Imaging detection of nodal metastases is limited by the frequent finding of benign reactive lymphadenopathy in cirrhosis. Resection is the preferred treatment for HCC, but is contraindicated in the presence of tumors in both lobes, major venous invasion, invasion of adjacent organs other than the gallbladder, tumor rupture, nodal metastases, or distant metastases. PMID:11685739

  19. Interventional treatment for unresectable hepatocellular carcinoma.

    PubMed

    Murata, Satoru; Mine, Takahiko; Sugihara, Fumie; Yasui, Daisuke; Yamaguchi, Hidenori; Ueda, Tatsuo; Onozawa, Shiro; Kumita, Shin-ichiro

    2014-10-01

    Hepatocellular carcinoma (HCC) is the sixth most common cancer and third leading cause of cancer-related death in the world. The Barcelona clinic liver cancer classification is the current standard classification system for the clinical management of patients with HCC and suggests that patients with intermediate-stage HCC benefit from transcatheter arterial chemoembolization (TACE). Interventional treatments such as TACE, balloon-occluded TACE, drug-eluting bead embolization, radioembolization, and combined therapies including TACE and radiofrequency ablation, continue to evolve, resulting in improved patient prognosis. However, patients with advanced-stage HCC typically receive only chemotherapy with sorafenib, a multi-kinase inhibitor, or palliative and conservative therapy. Most patients receive palliative or conservative therapy only, and approximately 50% of patients with HCC are candidates for systemic therapy. However, these patients require therapy that is more effective than sorafenib or conservative treatment. Several researchers try to perform more effective therapies, such as combined therapies (TACE with radiotherapy and sorafenib with TACE), modified TACE for HCC with arterioportal or arteriohepatic vein shunts, TACE based on hepatic hemodynamics, and isolated hepatic perfusion. This review summarizes the published data and data on important ongoing studies concerning interventional treatments for unresectable HCC and discusses the technical improvements in these interventions, particularly for advanced-stage HCC. PMID:25309076

  20. Current and future treatments for hepatocellular carcinoma

    PubMed Central

    Schlachterman, Alexander; Craft Jr, Willie W; Hilgenfeldt, Eric; Mitra, Avir; Cabrera, Roniel

    2015-01-01

    Hepatocellular carcinoma (HCC) represents a unique challenge for physicians and patients. There is no definitively curative treatment. Rather, many treatment and management modalities exist with differing advantages and disadvantages. Both current guidelines and individual patient concerns must be taken into account in order to properly manage HCC. In addition, quality of life issues are particularly complex in patients with HCC and these concerns must also be factored into treatment strategies. Thus, considering all the options and their various pros and cons can quickly become complex for both clinicians and patients. In this review, we systematically discuss the current treatment modalities available for HCC, detailing relevant clinical data, risks and rewards and overall outcomes for each approach. Surgical options discussed include resection, transplantation and ablation. We also discuss the radiation modalities: conformal radiotherapy, yttrium 90 microspheres and proton and heavy ion radiotherapy. The biologic agent Sorafenib is discussed as a promising new approach, and recent clinical trials are reviewed. We then detail currently described molecular pathways implicated in the initiation and progression of HCC, and we explore the potential of each pathway as an avenue for drug exploitation. We hope this comprehensive and forward-looking review enables both clinicians and patients to understand various options and thereby make more informed decisions regarding this disease. PMID:26229392

  1. Laser Ablation for Small Hepatocellular Carcinoma

    PubMed Central

    Pacella, Claudio Maurizio; Francica, Giampiero; Di Costanzo, Giovanni Giuseppe

    2011-01-01

    Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and is increasingly detected at small size (<5 cm) owing to surveillance programmes in high-risk patients. For these cases, curative therapies such as resection, liver transplantation, or percutaneous ablation have been proposed. When surgical options are precluded, image-guided tumor ablation is recommended as the most appropriate therapeutic choice in terms of tumor local control, safety, and improvement in survival. Laser ablation (LA) represents one of currently available loco-ablative techniques: light is delivered via flexible quartz fibers of diameter from 300 to 600 μm inserted into tumor lesion through either fine needles (21g Chiba needles) or large-bore catheters. The thermal destruction of tissue is achieved through conversion of absorbed light (usually infrared) into heat. A range of different imaging modalities have been used to guide percutaneous laser ablation, but ultrasound and magnetic resonance imaging are most widely employed, according to local experience and resource availability. Available clinical data suggest that LA is highly effective in terms of tumoricidal capability with an excellent safety profile; the best results in terms of long-term survival are obtained in early HCC so that LA can be proposed not only in unresectable cases but, not differently from radiofrequency ablation, also as the first-line treatment. PMID:22191028

  2. Transplant benefit for patients with hepatocellular carcinoma.

    PubMed

    Vitale, Alessandro; Volk, Michael; Cillo, Umberto

    2013-12-28

    Although liver transplantation is theoretically the best treatment for hepatocellular carcinoma (HCC), it is limited by the realities of perioperative complications, and the shortage of donor organs. Furthermore, in many cases there are available alternative treatments such as resection or locoregional therapy. Deciding upon the best option for a patient with HCC is complicated, involving numerous ethical principles including: urgency, utility, intention-to-treat survival, transplant benefit, harm to candidates on waiting list, and harm to living donors. The potential contrast between different principles is particularly relevant for patients with HCC for several reasons: (1) HCC candidates to liver transplantation are increasing; (2) the great prognostic heterogeneity within the HCC population; (3) in HCC patients tumor progression before liver transplantation may significantly impair post transplant outcome; and (4) effective alternative therapies are often available for HCC candidates to liver transplantation. In this paper we suggest that allocating organs by transplant benefit could help balance these competing principles, and also introduce equity between patients with HCC and nonmalignant liver disease. We also propose a triangular equipoise model to help decide between deceased donor liver transplantation, living donor liver transplantation, or alternative therapies. PMID:24409046

  3. [Inspection of guidelines for hepatocellular carcinoma].

    PubMed

    Arii, Shigeki

    2010-04-01

    An evidence-based clinical guideline for diagnosing and treating hepatocellular carcinoma patients was published in 2005, based on 7,118 original English papers(published between 1966-2002)and edited by the executive members of the Liver Cancer Study Group of Japan (Chief Editor, Professor M. Makuuchi, MD). These were composed of 58 clinical questions which covered prevention, surveillance, diagnosis, surgery, transplantation, chemotherapy, radiotherapy, chemoembolization and ablation therapy. The surveys investigating the validity and usefulness of this guideline revealed that it is well worked out and considered useful by medical practitioners. This guideline changed the therapeutic strategy of 20% of the experts. However, 43% of experts and 30% of non experts believed that this guideline restricted their medical discretion. Moreover, the percentage of medical practitioners who felt that medical malpractice suits would increase exceeded those who did not. A revised 2009 version was published based on the evaluation of 2,950 original papers (published between 2002-2007). Major revisions were not made, but clinical questions and scientific statements were updated. However, this version of the guideline does not provide clear recommendations in about 40% of the clinical questions because of lack of evidence. The guideline must be utilized based on an appropriate understanding of medical science and medical practice, and not on dogmatism. PMID:20414014

  4. Biological features and biomarkers in hepatocellular carcinoma

    PubMed Central

    Chiba, Tetsuhiro; Suzuki, Eiichiro; Saito, Tomoko; Ogasawara, Sadahisa; Ooka, Yoshihiko; Tawada, Akinobu; Iwama, Atsushi; Yokosuka, Osamu

    2015-01-01

    Similar to other cancers, a multistep process of carcinogenesis is observed in hepatocellular carcinoma (HCC). Although the mechanisms underlying the development of HCC have been investigated in terms of oncology, virology, and stem cell biology, the whole picture of hepatocarcinogenesis remains to be elucidated. Recent progress in molecular biology has provided clues to the underlying cause of various diseases. In particular, sequencing technologies, such as whole genome and exome sequencing analyses, have made an impact on genomic research on a variety of cancers including HCC. Comprehensive genomic analyses have detected numerous abnormal genetic alterations, such as mutations and copy number alterations. Based on these findings, signaling pathways and cancer-related genes involved in hepatocarcinogenesis could be analyzed in detail. Simultaneously, a number of novel biomarkers, both from tissue and blood samples, have been recently reported. These biomarkers have been successfully applied to early diagnosis and prognostic prediction of patients with HCC. In this review, we focus on the recent developments in molecular cancer research on HCC and explain the biological features and novel biomarkers. PMID:26261691

  5. Treatment of hepatocellular carcinoma: beyond international guidelines.

    PubMed

    Sangiovanni, Angelo; Colombo, Massimo

    2016-01-01

    Treatment of hepatocellular carcinoma (HCC) is guided by the tumour stage. The Barcelona clinical liver cancer (BCLC) score endorsed by the European Society of the Liver EASL divides patients into five prognostic categories, each with a distinct treatment indication. Hepatic resection, orthotopic liver transplantation and percutaneous local ablation are strongly indicated in accurately selected patients with very early (BCLC 0) and early stage (BCLC A) tumours providing a survival rate of between 50 and 75% at year five. In patients with a large tumour burden such as those with intermediate stage BCLC B, repeated treatments with transarterial chemoembolization (TACE) are advocated with clinical benefits (from 16 to 22 months). Survival may also improve in patients who are in poor condition or who do not respond to TACE and those with an advanced HCC (BCLC C), following oral therapy with the multikinase inhibitor, sorafenib. However, most recommendations are based on uncontrolled studies and expert opinions rather than well-designed controlled trials, and up to one-third of patients do not fit recommendations because of advanced age, the presence of significant comorbidities or a strategic location of the nodule. For these patients, treatment of HCC beyond guidelines is often advocated. PMID:26725909

  6. Percutaneous Local Ablative Therapy for Hepatocellular Carcinoma

    PubMed Central

    Lau, W. Y.; Leung, Thomas W. T.; Yu, Simon C. H.; Ho, Stephen K. W.

    2003-01-01

    Objective To review and compare treatment result for percutaneous local ablative therapy (PLAT) with surgical resection in the treatment of small hepatocellular carcinoma (HCC). Summary Background Data PLAT is indicated for small unresectable HCC localized to the liver. From the use of ethanol to the latest technology of radiofrequency ablation, ablative techniques have been refined and their role in the management of HCC established. This review aims to give an overview of various ablative methods, including their efficacy, indications, and limitations, and also tries to look into the future of clinical trials in PLAT. Methods The authors reviewed recent papers in the English medical literature about the use of local ablative therapy for HCC. Focus was given to the results of treatment in terms of local control, progression-free survival, and overall survival, and to compare treatment results with those of surgery. Results PLAT for small HCC (<5 cm) with thermal ablation (radiofrequency ablation or microwave coagulation) can achieve effective local control of disease and is superior to ethanol injection. Progressive disease in untreated areas is a common reason for failure. Overall progression-free survival is similar to that of surgical resection. Conclusions Thermal ablation gives good local control of small HCC, is superior to ethanol, and may be comparable to surgical resection in long-term outcome. PMID:12560774

  7. Radiofrequency ablation of hepatocellular carcinoma: Current status

    PubMed Central

    Minami, Yasunori; Kudo, Masatoshi

    2010-01-01

    Ablation therapy is one of the best curative treatment options for malignant liver tumors, and can be an alternative to resection. Radiofrequency ablation (RFA) of primary and secondary liver cancers can be performed safely using percutaneous, laparoscopic, or open surgical techniques, and RFA has markedly changed the treatment strategy for small hepatocellular carcinoma (HCC). Percutaneous RFA can achieve the same overall and disease-free survival as surgical resection for patients with small HCC. The use of a laparoscopic or open approach allows repeated placements of RFA electrodes at multiple sites to ablate larger tumors. RFA combined with transcatheter arterial chemoembolization will make the treatment of larger tumors a clinically viable treatment alternative. However, an accurate evaluation of treatment response is very important to secure successful RFA therapy. Since a sufficient safety margin (at least 0.5 cm) can prevent local tumor recurrences, an accurate evaluation of treatment response is very important to secure successful RFA therapy. To minimize complications of RFA, clinicians should be familiar with the imaging features of each type of complication. Appropriate management of complications is essential for successful RFA treatment. PMID:21179308

  8. Management of hepatocellular carcinoma in the elderly

    PubMed Central

    Borzio, Mauro; Dionigi, Elena; Parisi, Giancarlo; Raguzzi, Ivana; Sacco, Rodolfo

    2015-01-01

    Mean age of hepatocellular carcinoma (HCC) patients has been progressively increasing over the last decades and ageing of these patients is becoming a real challenge in every day clinical practice. Unfortunately, international guidelines on HCC management do not address this problem exhaustively and do not provide any specific recommendation. We carried out a literature search in MEDLINE database for studies reporting on epidemiology, clinical characteristics and treatment outcome of HCC in elderly patients. Available data seem to indicate that in elderly patients the outcome of HCC is mostly influenced by liver function and tumor stage rather than by age and the latter should not influence treatment allocation. Age is not a risk for resection and older patients with resectable HCC and good liver function could gain benefit from surgery. Mild comorbidities do not seem a contraindication for surgery in aged patients. Conversely, major resection in elderly, even when performed in experienced high-volume centres, should be avoided. Both percutaneous ablation and transarterial chemoembolization are not contraindicated in aged patients and safety profile of these procedures is acceptable. Sorafenib is a viable option for advanced HCC in elderly provided that a careful evaluation of concomitant comorbidities, particularly cardiovascular ones, is taken into account. Available data seem to suggest that in either elderly and younger, treatment is a main predictor of outcome. Consequently, a nihilistic attitude of physicians towards under- or no-treatment of aged patients should not be longer justified. PMID:26085911

  9. Interventional treatment for unresectable hepatocellular carcinoma

    PubMed Central

    Murata, Satoru; Mine, Takahiko; Sugihara, Fumie; Yasui, Daisuke; Yamaguchi, Hidenori; Ueda, Tatsuo; Onozawa, Shiro; Kumita, Shin-ichiro

    2014-01-01

    Hepatocellular carcinoma (HCC) is the sixth most common cancer and third leading cause of cancer-related death in the world. The Barcelona clinic liver cancer classification is the current standard classification system for the clinical management of patients with HCC and suggests that patients with intermediate-stage HCC benefit from transcatheter arterial chemoembolization (TACE). Interventional treatments such as TACE, balloon-occluded TACE, drug-eluting bead embolization, radioembolization, and combined therapies including TACE and radiofrequency ablation, continue to evolve, resulting in improved patient prognosis. However, patients with advanced-stage HCC typically receive only chemotherapy with sorafenib, a multi-kinase inhibitor, or palliative and conservative therapy. Most patients receive palliative or conservative therapy only, and approximately 50% of patients with HCC are candidates for systemic therapy. However, these patients require therapy that is more effective than sorafenib or conservative treatment. Several researchers try to perform more effective therapies, such as combined therapies (TACE with radiotherapy and sorafenib with TACE), modified TACE for HCC with arterioportal or arteriohepatic vein shunts, TACE based on hepatic hemodynamics, and isolated hepatic perfusion. This review summarizes the published data and data on important ongoing studies concerning interventional treatments for unresectable HCC and discusses the technical improvements in these interventions, particularly for advanced-stage HCC. PMID:25309076

  10. Liver resection for intermediate hepatocellular carcinoma

    PubMed Central

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

    2016-01-01

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

  11. Diabetes mellitus and metformin in hepatocellular carcinoma

    PubMed Central

    Fujita, Koji; Iwama, Hisakazu; Miyoshi, Hisaaki; Tani, Joji; Oura, Kyoko; Tadokoro, Tomoko; Sakamoto, Teppei; Nomura, Takako; Morishita, Asahiro; Yoneyama, Hirohito; Masaki, Tsutomu

    2016-01-01

    Hepatocellular carcinoma (HCC) is the leading cause of cancer-related death worldwide. Diabetes mellitus, a risk factor for cancer, is also globally endemic. The clinical link between these two diseases has been the subject of investigation for a century, and diabetes mellitus has been established as a risk factor for HCC. Accordingly, metformin, a first-line oral anti-diabetic, was first proposed as a candidate anti-cancer agent in 2005 in a cohort study in Scotland. Several subsequent large cohort studies and randomized controlled trials have not demonstrated significant efficacy for metformin in suppressing HCC incidence and mortality in diabetic patients; however, two recent randomized controlled trials have reported positive data for the tumor-preventive potential of metformin in non-diabetic subjects. The search for biological links between cancer and diabetes has revealed intracellular pathways that are shared by cancer and diabetes. The signal transduction mechanisms by which metformin suppresses carcinogenesis in cell lines or xenograft tissues and improves chemoresistance in cancer stem cells have also been elucidated. This review addresses the clinical and biological links between HCC and diabetes mellitus and the anti-cancer activity of metformin in clinical studies and basic experiments. PMID:27468203

  12. Synchronous Hepatic Epithelioid Hemangioendothelioma and Hepatocellular Carcinoma

    PubMed Central

    Athanasopoulos, Panagiotis G.; Hadjittofi, Christopher; Luong, Tu Vinh; O’Beirne, James; Sharma, Dinesh

    2015-01-01

    Abstract We would like to report the first case in English literature, to the best of our knowledge, of a synchronous hepatic epithelioid hemangioendothelioma (HEHE) and hepatocellular carcinoma (HCC), as well as to address the current trends and challenges in the management of HEHE. An otherwise well 58-year-old man was referred to his local hepatology service with elevated serum γ-GT levels. Imaging revealed bilobar liver lesions consistent with HEHE, a discrete left lobe lesion suspected as HCC, and multiple pulmonary nodules. Biopsies confirmed HEHE with pulmonary metastases. After multidisciplinary team discussions, the patient was admitted under our team and underwent an uneventful laparoscopic left lateral hepatectomy for suspected HCC, which was confirmed histologically. As part of a watch-and-wait approach to metastatic HEHE, in the first follow-up (3 months postoperatively) the patient was clinically fine and the surveillance CT scan did not show recurrent disease. By presenting this case, we aim to raise awareness that this rare entity can coexist with others, potentially complicating their management. PMID:26313777

  13. Hepatocellular carcinoma: clinical frontiers and perspectives

    PubMed Central

    Bruix, Jordi; Gores, Gregory J; Mazzaferro, Vincenzo

    2015-01-01

    Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death and is currently the main event leading to death in patients with cirrhosis. Evolving information suggests that the metabolic syndrome with non-alcoholic liver disease may be an important cause of HCC in addition to viral hepatitis and alcohol-induced liver disease. The molecular pathogenesis is extremely complex and heterogeneous. To date the molecular information has not impacted on treatment decisions. Periodic surveillance imaging of patients with cirrhosis is widely practiced, especially because diagnostic, radiographic criteria for early-stage HCC have been defined (including nodules between 1 and 2 cm) and effective treatment is available for tumours detected at an early stage. Worldwide the approach to resection versus transplantation varies depending upon local resources, expertise and donor availability. The criteria for transplantation are discussed, and the controversial areas highlighted with evidence-based recommendations provided. Several approaches are available for intermediate stage disease, including radiofrequency ablation, transarterial chemoembolisation and radioembolisation; the rationale for these therapies is buttressed by appropriate outcome-based studies. For advanced disease, systemic therapy with sorafenib remains the option best supported by current data. Thus, while several trials have failed to improve the benefits of established therapies, studies assessing the sequential or combined application of those already known to be beneficial are needed. Also, new concepts are provided in regards to selecting and stratifying patients for second-line studies, which may help explain the failure of prior studies. PMID:24531850

  14. Hepatocellular carcinoma and cholangiocarcinoma: an update.

    PubMed

    Yazici, Cemal; Niemeyer, David J; Iannitti, David A; Russo, Mark W

    2014-01-01

    Hepatocellular carcinoma (HCC) is the third most common cause of cancer worldwide and is rising in incidence. Ultrasound is the preferred modality for screening high-risk patients for HCC because it detects clinically significant nodules, widespread availability and lower cost. HCC does not require a biopsy for diagnosis if specific imaging criteria are fulfilled. Transarterial chemoembolization (TACE) is the most common modality used to treat HCC followed by ablation. Cholangiocarcinoma (CCA) is increasing in incidence and the second most common primary malignancy of the liver. There is no effective screening strategy for CCA although magnetic resonance imaging and carbohydrate antigen 19-9 (CA 19-9) are commonly used without proven benefit. Therapy for CCA is challenging and resection, when possible, is the mainstay of therapy. Gemcitabine in combination with cisplatin or biologics may offer a modest survival benefit. Liver transplantation for CCA is associated with reasonable survival in select cases. Molecular diagnostics offer the potential to develop personalized approaches in the management of HCC and CCA. PMID:24245910

  15. Surveillance and Diagnosis of Hepatocellular Carcinoma

    PubMed Central

    Fitzmorris, Paul

    2015-01-01

    Hepatocellular carcinoma (HCC) is an important cause of cancer-related death worldwide. If the disease is detected early, the treatment is more likely to be curative. This article discusses the current evidence regarding the surveillance and diagnosis of HCC, focusing on recent articles and the recommendations of the American Association for the Study of Liver Diseases (AASLD), which are briefly compared with the recommendations of other liver disease organizations. HCC surveillance aims to detect disease at an early stage in order to augment the likelihood of curative treatment. According to AASLD recommendations, patients who have cirrhosis and those who do not have cirrhosis but are at high risk for HCC should be screened. Ultrasonogra-phy (USG) at 6-month intervals is recommended. The available serologic markers, including serum alpha-fetoprotein, are inadequate for surveillance, even when combined with USG. Despite achievements in HCC management, physicians continue to underutilize surveillance. Quadruple-phase, contrast-enhanced computed tomography scans or magnetic resonance images with characteristic radiologic findings are commonly used to diagnose HCC in suspicious cases. The available surveillance and diagnostic tests effectively identify HCC at an early stage, and as a result, the chances of cure are increased. Physicians caring for patients who have cirrhosis and chronic liver disease should be familiar with HCC surveillance recommendations and the prognostic importance of early diagnosis. PMID:27099571

  16. Local Ablation for Hepatocellular Carcinoma in Taiwan

    PubMed Central

    Lin, Shi-Ming

    2013-01-01

    Hepatocellular carcinoma (HCC) is the second commonest cancer in Taiwan. The national surveillance program can detect HCC in its early stages, and various curative modalities (including surgical resection, orthotopic liver transplantation, and local ablation) are employed for the treatment of small HCC. Local ablation therapies are currently advocated for early-stage HCC that is unresectable because of co-morbidities, the need to preserve liver function, or refusal of resection. Among the various local ablation therapies, the most commonly used modalities include percutaneous ethanol injection and radiofrequency ablation (RFA); percutaneous acetic acid injection and microwave ablation are used less often. RFA is more commonly employed than other local ablative modalities in Taiwan because the technique is highly effective, minimally invasive, and requires fewer sessions. RFA is therefore advocated in Taiwan as the first-line curative therapy for unresectable HCC or even for resectable HCC. However, current RFA procedures are less effective against tumors that are in high-risk or difficult-to-ablate locations, are poorly visualized on ultrasonography (US), or are large. Recent advancements in RFA in Taiwan can resolve these issues by the creation of artificial ascites or pleural effusion, application of real-time virtual US assistance, use of combination therapy before RFA, or use of switching RF controllers with multiple electrodes. This review article provides updates on the clinical outcomes and advances in local ablative modalities (mostly RFA) for HCC in Taiwan. PMID:24159599

  17. Senescence and immortality in hepatocellular carcinoma.

    PubMed

    Ozturk, Mehmet; Arslan-Ergul, Ayca; Bagislar, Sevgi; Senturk, Serif; Yuzugullu, Haluk

    2009-12-01

    Cellular senescence is a process leading to terminal growth arrest with characteristic morphological features. This process is mediated by telomere-dependent, oncogene-induced and ROS-induced pathways, but persistent DNA damage is the most common cause. Senescence arrest is mediated by p16(INK4a)- and p21(Cip1)-dependent pathways both leading to retinoblastoma protein (pRb) activation. p53 plays a relay role between DNA damage sensing and p21(Cip1) activation. pRb arrests the cell cycle by recruiting proliferation genes to facultative heterochromatin for permanent silencing. Replicative senescence that occurs in hepatocytes in culture and in liver cirrhosis is associated with lack of telomerase activity and results in telomere shortening. Hepatocellular carcinoma (HCC) cells display inactivating mutations of p53 and epigenetic silencing of p16(INK4a). Moreover, they re-express telomerase reverse transcriptase required for telomere maintenance. Thus, senescence bypass and cellular immortality is likely to contribute significantly to HCC development. Oncogene-induced senescence in premalignant lesions and reversible immortality of cancer cells including HCC offer new potentials for tumor prevention and treatment. PMID:19070423

  18. Hepatitis C virus-induced hepatocellular carcinoma

    PubMed Central

    Goossens, Nicolas

    2015-01-01

    Hepatitis C virus (HCV) is a leading etiology of hepatocellular carcinoma (HCC). The interaction of HCV with its human host is complex and multilayered; stemming in part from the fact that HCV is a RNA virus with no ability to integrate in the host's genome. Direct and indirect mechanisms of HCV-induced HCC include activation of multiple host pathways such as liver fibrogenic pathways, cellular and survival pathways, interaction with the immune and metabolic systems. Host factors also play a major role in HCV-induced HCC as evidenced by genomic studies identifying polymorphisms in immune, metabolic, and growth signaling systems associated with increased risk of HCC. Despite highly effective direct-acting antiviral agents, the morbidity and incidence of liver-related complications of HCV, including HCC, is likely to persist in the near future. Clinical markers to selectively identify HCV subjects at higher risk of developing HCC have been reported however they require further validation, especially in subjects who have experienced sustained virological response. Molecular biomarkers allowing further refinement of HCC risk are starting to be implemented in clinical platforms, allowing objective stratification of risk and leading to individualized therapy and surveillance for HCV individuals. Another role for molecular biomarker-based stratification could be enrichment of HCC chemoprevention clinical trials leading to smaller sample size, shorter trial duration, and reduced costs. PMID:26157746

  19. Hepatocellular carcinoma and hepatitis B surface protein

    PubMed Central

    Li, Yong-Wei; Yang, Feng-Cai; Lu, Hui-Qiong; Zhang, Jiong-Shan

    2016-01-01

    The tumorigenesis of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) has been widely studied. HBV envelope proteins are important for the structure and life cycle of HBV, and these proteins are useful for judging the natural disease course and guiding treatment. Truncated and mutated preS/S are produced by integrated viral sequences that are defective for replication. The preS/S mutants are considered “precursor lesions” of HCC. Different preS/S mutants induce various mechanisms of tumorigenesis, such as transactivation of transcription factors and an immune inflammatory response, thereby contributing to HCC. The preS2 mutants and type II “Ground Glass” hepatocytes represent novel biomarkers of HBV-associated HCC. The preS mutants may induce the unfolded protein response and endoplasmic reticulum stress-dependent and stress-independent pathways. Treatments to inhibit hepatitis B surface antigen (HBsAg) and damage secondary to HBsAg or the preS/S mutants include antivirals and antioxidants, such as silymarin, resveratrol, and glycyrrhizin acid. Methods for the prevention and treatment of HCC should be comprehensive. PMID:26877602

  20. 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. PMID:23539499

  1. Chemoembolization in patients with hepatocellular carcinoma.

    PubMed

    Lencioni, Riccardo

    2012-06-01

    Transcatheter arterial chemoembolization (TACE) is the standard of care for nonsurgical patients with preserved liver function with large or multinodular noninvasive hepatocellular carcinoma (HCC) confined to the liver. The administration of an anticancer-in-oil emulsion followed by embolic agents is the most popular TACE technique; however, the introduction of embolic, drug-eluting beads (DEB) has provided an alternative to conventional regimens. Experimental studies have shown that DEB-TACE results in a safe pharmacokinetic profile and effective tumor killing in animal models. Clinical experiences have confirmed that DEB-TACE provides a combined ischemic and cytotoxic effect locally, with significantly reduced drug-related toxicity and liver toxicity compared with conventional TACE. The addition of molecular targeted drugs to the therapeutic armamentarium for HCC has prompted the design of clinical trials aimed at investigating the synergies between TACE and systemic treatments. Combining TACE with antiangiogenic agents represents a promising strategy because TACE is thought to cause local hypoxia, resulting in a temporary increase in levels of vascular endothelial growth factor. Recently, a large phase 2, randomized, double-blind, placebo-controlled trial (the SPACE study) indicated that the concurrent administration of DEB-TACE and sorafenib has a manageable safety profile and suggested that the time to progression (TTP) and time to vascular invasion or extrahepatic spread may be improved compared with DEB-TACE alone. These data support the further evaluation of molecular targeted, systemically active agents in combination with DEB-TACE in a phase 3 setting. PMID:24159570

  2. Potentiality of immunotherapy against hepatocellular carcinoma

    PubMed Central

    Tsuchiya, Nobuhiro; Sawada, Yu; Endo, Itaru; Uemura, Yasushi; Nakatsura, Tetsuya

    2015-01-01

    Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, is the fifth most common cancer worldwide and the second leading cause of cancer-related death. Despite the high incidence, treatment options remain limited for advanced HCC, and as a result prognosis continues to be poor. Current therapeutic options, surgery, chemotherapy and radiotherapy, have only modest efficacy. New treatment modalities to prolong survival and to minimize the risk of adverse response are desperately needed for patients with advanced HCC. Tumor immunotherapy is a promising, novel treatment strategy that may lead to improvements in both treatment-associated toxicity and outcome. The strategies have developed in part through genomic studies that have yielded candidate target molecules and in part through basic biology studies that have defined the pathways and cell types regulating immune response. Here, we summarize the various types of HCC immunotherapy and argue that the newfound field of HCC immunotherapy might provide critical advantages in the effort to improve prognosis of patients with advanced HCC. Already several immunotherapies, such as tumor-associated antigen therapy, immune checkpoint inhibitors and cell transfer immunotherapy, have demonstrated safety and feasibility in HCC patients. Unfortunately, immunotherapy currently has low efficacy in advanced stage HCC patients; overcoming this challenge will place immunotherapy at the forefront of HCC treatment, possibly in the near future. PMID:26420958

  3. Local-regional treatment of hepatocellular carcinoma.

    PubMed

    Lencioni, Riccardo; Crocetti, Laura

    2012-01-01

    Local-regional treatments play a key role in the management of hepatocellular carcinoma (HCC). Image-guided tumor ablation is recommended in patients with early-stage HCC when surgical options are precluded and can replace resection in selected patients. Radiofrequency (RF) ablation has shown superior anticancer effects and greater survival benefit with respect to the seminal percutaneous technique, ethanol injection, in meta-analyses of randomized controlled trials and is currently established as the standard method for local tumor treatment. Novel thermal and nonthermal techniques for tumor ablation, including microwave ablation and irreversible electroporation, seem to have potential to overcome the limitations of RF ablation and warrant further clinical investigation. Transcatheter arterial chemoembolization (TACE) is the standard of care for patients with asymptomatic noninvasive multinodular tumors in intermediate-stage disease. Embolic microspheres that have the ability to release a drug in a controlled and sustained fashion have been shown to substantially increase the safety and efficacy of TACE in comparison to conventional ethiodized oil-based regimens. The available data for radioembolization with yttrium 90 suggest that this is a potential new option for patients with HCC, and future studies should be devoted to assessments of the role of radioembolization in the treatment algorithm for HCC. PMID:22190656

  4. Cancer-associated fibroblasts in hepatocellular carcinoma.

    PubMed

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

    2016-08-14

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

  5. Cancer-associated fibroblasts in hepatocellular carcinoma

    PubMed Central

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

    2016-01-01

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

  6. HEPATOCELLULAR CARCINOMA: CURRENT AND PROSPECTIVE IMMUNOTHERAPEUTIC STRATEGIES.

    PubMed

    Kikodze, N; Mazmishvili, K; Iobadze, M; Rekhviashvili, Kh; Nanava, N; Pantsulaia, I; Mizandari, M; Janikashvili, N; Chikovani, T

    2015-09-01

    Hepatocellular carcinoma (HCC) is a highly lethal and the most common primary liver cancer with increasing worldwide incidence. Pathogenesis of HCC is immune mediated, however, not completely understood. Chronic low-grade inflammation alters both innate and adaptive immune responses. As a result tolerogenic environment is established in damaged organ. Up to date, incomplete understanding of HCC pathogenesis and the extend of biomarker variability among patients represent the major obstacle for early diagnosis and for the choice of effective treatment. Among current treatment options for HCC, thermal ablation strategy, which in addition to cancer eradication provides adjuvant/"danger"signal to the patient's immune cells, has demonstrated its active immunotherapeutic effect. In ongoing phase I/II clinical trials, tumor antigen loaded dendritic cell (DC)-based vaccines as well as tumor-specific cytotoxic T cells are being tested. Genetically redirected T cell therapy and more refined autologous vaccines are still awaiting approaches in HCC. The topic of this review focuses on current and bench-to-bedside immunotherapeutic strategies for HCC and discusses their advantages and limitations in clinic. We also weight up several prospective immunotherapeutic approaches which in theory have the potential for further implication in HCC. Combination of the induction of effective antitumor immunity with the inhibition of the mechanisms of tumor-induced immunosuppression ought to be a key objective in these future developments. PMID:26355320

  7. Clonal Origin of Hepatocellular Carcinoma and Recurrence After Liver Transplantation.

    PubMed

    Wang, Zhenglu; Gong, Weihua; Shou, Dawei; Zhang, Luzhou; Gu, Xiangqian; Wang, Yuliang; Teng, Dahong; Zheng, Hong

    2016-01-01

    BACKGROUND This study aimed to determine whether patterns of tumor clonal origin in pluri-nodular hepatocellular carcinoma (PNHC) could serve as an indicator of tumor recurrence following liver transplantation. MATERIAL AND METHODS Tumor tissue samples from 60 PNHC patients who underwent liver transplantation were examined. The diagnosis of patients conformed to the University of California San Francisco (UCSF) standards for pluri-nodular hepatocellular carcinoma. We performed loss of heterozygosity tests at multiple microsatellite sites to determine the clonal origins of the tumors. Clinical information, pathological data, preoperative serum alpha-feto protein (AFP) and postoperative follow-ups were obtained and correlations between the clonal origin of the tumor, tumor-free survival, pathological characteristics, and AFP levels in serum were studied. RESULTS A total of 165 tumor nodules were collected. Tumor clonal origins were identified as intrahepatic metastasis (IM; 41.67%), multicentric occurrence (MO; 55%) or unidentified (3.33%). Three-year tumor-free survival for the IM group was 48% compared to 75.76% in the MO group (p<0.05), while the occurrence of microscopic tumor thrombus was 100% and 3.03% (p<0.05) for these groups, respectively. The degree of tumor differentiation was 80% for the IM group and 18.18% for the MO group (p<0.05), while the mean AFP concentration for these groups was 226.80 μg/L (2.78-3000 μg/L) and 24.59 μg/L (1.16-531. 30 μg/L; p<0.05), respectively. CONCLUSIONS Clonal origin patterns can serve as important indicators to predict the recurrence of PNHC following liver transplantation. Taken together with pathological characteristics and preoperative serum AFP levels, the risk of recurrence can be established in advance. PMID:27487734

  8. Transarterial chemoembolization and bland embolization for hepatocellular carcinoma.

    PubMed

    Tsochatzis, Emmanuel A; Fatourou, Evangelia; O'Beirne, James; Meyer, Tim; Burroughs, Andrew K

    2014-03-28

    Transarterial chemoembolization (TACE) is the first line treatment for patients with intermediate stage hepatocellular carcinoma but is also increasingly being used for patients on the transplant waiting list to prevent further tumor growth. Despite its widespread use, TACE remains an unstandardized procedure, with variation in type and size of embolizing particles, type and dose of chemotherapy and interval between therapies. Existing evidence from randomized controlled trials suggest that bland transarterial embolization (TAE) has the same efficacy with TACE. In the current article, we review the use of TACE and TAE for hepatocellular carcinoma and we focus on the evidence for their use. PMID:24695579

  9. Risk factors of hepatocellular carcinoma--current status and perspectives.

    PubMed

    Gao, Jing; Xie, Li; Yang, Wan-Shui; Zhang, Wei; Gao, Shan; Wang, Jing; Xiang, Yong-Bing

    2012-01-01

    Hepatocellular carcinoma is a common disorder worldwide which ranks 5th and 7th most common cancer among men and women. In recent years, different incidence trends have been observed in various regions, but the reasons are not completely understood. However, due to the great public efforts in HCC prevention and alternation of lifestyle, the roles of some well documented risk factors played in hepatocarcinogenesis might have changed. This paper summarizes both the environmental and host related risk factors of hepatocellular carcinoma including well established risk factors such as hepatitis virus infection, aflatoxin and alcohol, as well as possible risk factors such as coffee drinking and other dietary agents. PMID:22631642

  10. Coexistence of splenic marginal zone lymphoma with hepatocellular carcinoma: a case report

    PubMed Central

    Zhang, Shu-Hui; Xu, Ai-Min; Zheng, Jian-Ming; He, Miao-Xia

    2007-01-01

    Background Coexistence of splenic marginal zone lymphoma with hepatocellular carcinoma is rare. Although some reports have suggested the possible pathogenic role of HBV, HCV, chronic and persistent antigenic stimulation in lymphoma, their role in causing lymphomas is still unclear. Case presentation We describe a hepatocellular carcinoma with concomitant splenic marginal zone lymphoma in a 64-year-old Chinese man with cirrhosis. Serum hepatitis B virus surface antigen was positive and antihepatitis C virus antibody was negative. The resected liver mass measuring 4 × 3 × 3 cm was grey and soft with a small area of bleeding, necrosis and intact capsule. Cut surface of the spleen was red-purple and had a diffuse reticulonodular appearance indicative of prominent white pulp. On histologic sections, the liver mass was well and moderately differentiated hepatocellular carcinoma, and the splenic tumor was a specific low-grade small B-cell lymphoma. Immunohistochemical staining and gene rearrangement studies supported that the splenic tumor represents a clonal B-cell lymphoma. Therefore, the diagnosis of SMZL was made from the splenic specimen. Conclusion To our knowledge, this is the second case report describing coexistence of hepatocellular carcinoma and splenic marginal zone lymphoma in the course of chronic HBV infection. However, we cannot assert at present that hepatitis B virus is directly involved in splenic lymphomagenesis until more information is collected from more cases in the future. PMID:17284308

  11. 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. PMID:27471568

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

    SciTech Connect

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

    1989-05-01

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

  13. 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

  14. Risk Factors for Hepatocellular Carcinoma in India

    PubMed Central

    Kar, Premashis

    2014-01-01

    Hepatocellular carcinoma (HCC) is an important cause of death all over the world, more so in Asia and Africa. The representative data on epidemiology of HCC in India is very scanty and cancer is not a reportable disease in India and the cancer registries in India are mostly urban. 45 million people who are suffering from chronic Hepatitis B virus (HBV) infection and approximately 15 million people who are afflicted with chronic Hepatitis C virus (HCV) infection in India. HBV and HCV infection is considered an important etiologic factor in HCC. Positive association between HCC and consumption of alcohol where alcohol contribute as a cofactor for hepatotoxins and hepatitis viruses. Aflatoxin contamination in the diets, Hepatitis B virus infection and liver cirrhosis in Andhra Pradesh, India and direct chronic exposure to aflatoxins was shown to cause liver cirrhosis. Cirrhosis of liver of any cause lead to develop about 70%–90% of HCC. Aflatoxin interact synergistically with Hepatitis B virus (HBV)/Hepatitis C virus (HCV) infection which increase the risk of HCC. HBV infection, HBV infection with Aflatoxin exposure, viral infection and alcohol consumption leading to overt cirrhosis of the liver, alcohol consumption leading to cirrhosis of the liver with viral infection are the predominant risk factor for the development of HCC. HCV and alcohol are also associated with HCC in India. Indians develop diabetes at younger age, Asians have strong genetic susceptibility for type II diabetes. Diabetes mellitus is identified as a risk factor for HCC. Prevention of viral infection by universal vaccination against hepatitis virus, HCC surveillance program, preventing alcoholic liver diseases, fungal contamination of grains and ground crops to prevent basically Aflatoxin exposure are important measures to prevent liver diseases and HCC among those at risk. PMID:25755609

  15. Stereotactic Body Radiotherapy for Primary Hepatocellular Carcinoma

    SciTech Connect

    Andolino, David L.; Johnson, Cynthia S.; Maluccio, Mary; Kwo, Paul; Tector, A. Joseph; Zook, Jennifer; Johnstone, Peter A.S.; Cardenes, Higinia R.

    2011-11-15

    Purpose: To evaluate the safety and efficacy of stereotactic body radiotherapy (SBRT) for the treatment of primary hepatocellular carcinoma (HCC). Methods and Materials: From 2005 to 2009, 60 patients with liver-confined HCC were treated with SBRT at the Indiana University Simon Cancer Center: 36 Child-Turcotte-Pugh (CTP) Class A and 24 CTP Class B. The median number of fractions, dose per fraction, and total dose, was 3, 14 Gy, and 44 Gy, respectively, for those with CTP Class A cirrhosis and 5, 8 Gy, and 40 Gy, respectively, for those with CTP Class B. Treatment was delivered via 6 to 12 beams and in nearly all cases was prescribed to the 80% isodose line. The records of all patients were reviewed, and treatment response was scored according to Response Evaluation Criteria in Solid Tumors v1.1. Toxicity was graded according to the Common Terminology Criteria for Adverse Events v4.0. Local control (LC), time to progression (TTP), progression-free survival (PFS), and overall survival (OS) were calculated according to the method of Kaplan and Meier. Results: The median follow-up time was 27 months, and the median tumor diameter was 3.2 cm. The 2-year LC, PFS, and OS were 90%, 48%, and 67%, respectively, with median TTP of 47.8 months. Subsequently, 23 patients underwent transplant, with a median time to transplant of 7 months. There were no {>=}Grade 3 nonhematologic toxicities. Thirteen percent of patients experienced an increase in hematologic/hepatic dysfunction greater than 1 grade, and 20% experienced progression in CTP class within 3 months of treatment. Conclusions: SBRT is a safe, effective, noninvasive option for patients with HCC {<=}6 cm. As such, SBRT should be considered when bridging to transplant or as definitive therapy for those ineligible for transplant.

  16. Advances of imaging for hepatocellular carcinoma.

    PubMed

    Choi, Byung Ihn

    2010-07-01

    A variety of imaging modalities, including ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI), nuclear medicine, and angiography, are currently used in evaluating patients with chronic liver disease and suspected hepatocellular carcinoma (HCC). Further technological advancement will undoubtedly have a major impact on liver tumor imaging. Increased speed of data acquisition and consequently shorter scan times in CT and MRI show further improvement in resolution by further reducing motion artifacts. Development of new contrast materials for liver tumor imaging in US and MRI improve tumor detection and characterization by increasing the contrast resolution. Currently available advanced US techniques in the evaluation of HCC are various harmonic imaging techniques with contrast agents, volume imaging, and recently, US elastography, that has been developing and might play a role in characterizing liver nodules in the future. The latest advance in CT is the multidetector (MD) CT scanner where a 256- or 320-detector CT was introduced. Recent studies describe the high sensitivity of double arterial phase imaging in hepatic tumor detection and the usefulness of CT angiography by using MD CT in a detailed assessment of hepatic arterial anatomy using a three-dimensional dataset. In addition, perfusion CT imaging is also being developed and can be used for the characterization and treatment monitoring of HCC. Dual-energy CT with new technology is also continuously progressing. Advances in MR technology, including hardware and pulse sequence implementation, allow acquisition times to be reduced to the time frame of one breathhold, providing multiphasic dynamic MRI. Functional MRI including diffusion-weighted MRI, MR elastography, and new MR contrast agent with dual function have been investigated for the clinical utility of detection and characterization of HCCs. Functional MRI has a potential to be a promising technique for assessing HCC. PMID:20616584

  17. Angiogenic Blockade and Radiotherapy in Hepatocellular Carcinoma

    SciTech Connect

    Chi, Kwan-Hwa; Liao, Chao-Sheng; Chang, Chih-Chia; Ko, Hui-Ling; Tsang, Yuk-Wah; Yang, Kuo-Ching; Mehta, Minesh P.

    2010-09-01

    Purpose: We report our preliminary experience of combining sunitinib and helical tomotherapy in patients with advanced HCC. Methods and Materials: Records of patients with advanced hepatocellular carcinoma (HCC) treated with helical tomotherapy and sunitinib after radiation therapy (RT) from March 2007 to August 2008 were retrospectively reviewed. We report acute toxicities, radiologic response, serial {alpha}-fetoprotein (AFP) kinetics, and survival. Results: Of 23 evaluable patients, 60% had {>=}2 hepatic lesions, extrahepatic disease was present in 5 (21.7%), and all received 2 tablets (25 mg) of sunitinib at least 1 week before, during, and 2 weeks after RT. Thirteen patients continued maintenance sunitinib after RT until disease progression. Hypofractionated RT with a median target dose of 52.5 Gy/15 fractions was delivered. An objective response was achieved in 74% of patients. The 1-year survival rate was 70%, with median survival of 16 months. Multivariate analysis showed that maintenance sunitinib was the most significant factor for survival. The time to progression was 10 months in the maintenance group compared with 4 months in the control group. Eighteen out of 21 patients with elevated AFP (85.7%) had {>=}50% decline of AFP within 2 months after RT. There were three episodes of upper gastrointestinal bleeding and one episode of pancreatitis; 10 patients had {>=}Grade 2 elevation of liver enzymes, and 15 had {>=}Grade 2 thrombocytopenia. Conclusions: These preliminary results suggest that sunitinib and helical tomotherapy yield high Response Evaluation Criteria in Solid Tumors (RECIST) and AFP response rates in advanced HCC with an acceptable safety profile. Maintenance sunitinib after RT potentially prolongs survival. A randomized trial is warranted.

  18. Quality of life and hepatocellular carcinoma

    PubMed Central

    Khubchandani, Sapna; Iyer, Renuka

    2014-01-01

    Hepatocellular carcinoma (HCC) is a common and rapidly fatal cancer ranking third among the leading causes of cancer-related deaths. Potentially curative therapies like surgery, transplant and ablation are not an option for most patients as they are often diagnosed when the disease is advanced. Liver directed therapy and oral targeted therapies are used in these patients to prolong life and palliate symptoms of the cancer and associated liver failure. Overall survival remains poor and hence health-related quality of life (HRQoL) is of paramount importance in these patients. As novel therapies are developed to improve outcomes, a comprehensive knowledge of available tools to assess impact on QoL is needed. Hence we reviewed all the studies in HCC patients published within the last 13 years from 2001-2013 which assessed HRQoL as a primary or secondary endpoint. A total of 45 studies and 4 meta-analysis were identified. Commonly used tools were European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) (15 studies) and the Functional Assessment of Cancer Therapy-Hepatobiliary Questionnaire (FACT-Hep) (14 studies). Of the 45 publications which incorporated HRQoL as end-point only 24 were clinical trials, 17/24 (71%) assessed systemic therapies while 7/24 (29%) assessed liver-directed therapies. Majority of the publications (trials + retrospective reviews) that had HRQoL as an endpoint in HCC patients were studies evaluating liver-directed therapies (23/45 or >50%). We discuss the measures included in the tools, their interpretation, and summarize existing QoL data that will help design future HCC trials. PMID:25083303

  19. The Eltrombopag antitumor effect on hepatocellular carcinoma.

    PubMed

    Kurokawa, Tomohiro; Murata, Soichiro; Zheng, Yun-Wen; Iwasaki, Kenichi; Kohno, Keisuke; Fukunaga, Kiyoshi; Ohkohchi, Nobuhiro

    2015-11-01

    Currently, sorafenib is the only available chemotherapeutic agent for advanced hepatocellular carcinoma (HCC), but it cannot be used in patients with liver cirrhosis (LC) or thrombocytopenia. In these cases, sorafenib is likely effective if given in combination with treatments that increase the number of platelets, such as thrombopoietin (TPO) receptor agonists. Increasing the platelet count via TPO treatment resulted in reduction of LC. Eltrombopag (EP), a TPO receptor agonist, has been reported to have antitumor effects against certain cancers, despite their lack of TPO receptor expression. We hypothesized that EP may possess antitumor activity against HCC in addition to its ability to suppress hepatic fibrosis by increasing the platelet count. In the present study, the antitumor activity of EP was examined by assessing the inhibition of cell proliferation and then ascertaining the ability of iron supplementation to reverse these effects in HepG2, Hep3B and Huh7 cells. In addition, a cell cycle assay was performed using flow cytometry, and signal transduction was evaluated by analyzing cell cycle-related protein expression. The results of EP were compared with those of the most common iron chelator, deferoxamine (DFO). The combined effect of EP and sorafenib was also assessed. The results revealed that EP exerts antitumor activity in HCC that is mediated by the modulation of intracellular iron content. EP suppressed the expression of the cell cycle-related protein cyclin D1 and elicited cell cycle arrest in the G0/G1 phase. The activity of EP was comparable to that of DFO in HCC, and EP did not compete with sorafenib at low concentrations. In conclusion, our findings suggest that EP is a good candidate chemotherapeutic agent for the treatment of HCC in patients with LC and thrombocytopenia. PMID:26397763

  20. The Eltrombopag antitumor effect on hepatocellular carcinoma

    PubMed Central

    KUROKAWA, TOMOHIRO; MURATA, SOICHIRO; ZHENG, YUN-WEN; IWASAKI, KENICHI; KOHNO, KEISUKE; FUKUNAGA, KIYOSHI; OHKOHCHI, NOBUHIRO

    2015-01-01

    Currently, sorafenib is the only available chemotherapeutic agent for advanced hepatocellular carcinoma (HCC), but it cannot be used in patients with liver cirrhosis (LC) or thrombocytopenia. In these cases, sorafenib is likely effective if given in combination with treatments that increase the number of platelets, such as thrombopoietin (TPO) receptor agonists. Increasing the platelet count via TPO treatment resulted in reduction of LC. Eltrombopag (EP), a TPO receptor agonist, has been reported to have antitumor effects against certain cancers, despite their lack of TPO receptor expression. We hypothesized that EP may possess antitumor activity against HCC in addition to its ability to suppress hepatic fibrosis by increasing the platelet count. In the present study, the antitumor activity of EP was examined by assessing the inhibition of cell proliferation and then ascertaining the ability of iron supplementation to reverse these effects in HepG2, Hep3B and Huh7 cells. In addition, a cell cycle assay was performed using flow cytometry, and signal transduction was evaluated by analyzing cell cycle-related protein expression. The results of EP were compared with those of the most common iron chelator, deferoxamine (DFO). The combined effect of EP and sorafenib was also assessed. The results revealed that EP exerts antitumor activity in HCC that is mediated by the modulation of intracellular iron content. EP suppressed the expression of the cell cycle-related protein cyclin D1 and elicited cell cycle arrest in the G0/G1 phase. The activity of EP was comparable to that of DFO in HCC, and EP did not compete with sorafenib at low concentrations. In conclusion, our findings suggest that EP is a good candidate chemotherapeutic agent for the treatment of HCC in patients with LC and thrombocytopenia. PMID:26397763

  1. Epidemiology of Hepatocellular Carcinoma in India

    PubMed Central

    Acharya, Subrat K.

    2014-01-01

    Indian data on epidemiology of HCC is not available. Cancer is not a reportable disease in India and the cancer registries in India are mostly urban. National cancer registry program of the Indian Council of Medical Research (ICMR) has been recently expanded to include 21 population based and 6 hospital based cancer registries. The last published registry data by ICMR available in the cancer registry website (www.ncrpindia.org) was in 2008 which provides information on various cancers from 2006 to 2008. The other source of information was the report published by International Agency for Research on Cancer (WHO). According to these available data the age adjusted incidence rate of hepatocellular carcinoma (HCC) in India for men ranges from 0.7 to 7.5 and for women 0.2 to 2.2 per 100,000 population per year. The male:female ratio for HCC in India is 4:1. The age of presentation varies from 40 to 70 years. According to a study conducted by verbal autopsy in 1.1 million homes representing the whole country, the age standardized mortality rate for HCC in India for men is 6.8/100,000 and for women is 5.1/100,000. According to another study the incidence of HCC in cirrhotics in India is 1.6% per year. The unpublished data from various tertiary care centers suggest that the incidence of HCC is increasing in India. There is a need for a multi-centric HCC registry under the aegis of INASL. PMID:25755607

  2. Epidemiology of hepatocellular carcinoma in India.

    PubMed

    Acharya, Subrat K

    2014-08-01

    Indian data on epidemiology of HCC is not available. Cancer is not a reportable disease in India and the cancer registries in India are mostly urban. National cancer registry program of the Indian Council of Medical Research (ICMR) has been recently expanded to include 21 population based and 6 hospital based cancer registries. The last published registry data by ICMR available in the cancer registry website (www.ncrpindia.org) was in 2008 which provides information on various cancers from 2006 to 2008. The other source of information was the report published by International Agency for Research on Cancer (WHO). According to these available data the age adjusted incidence rate of hepatocellular carcinoma (HCC) in India for men ranges from 0.7 to 7.5 and for women 0.2 to 2.2 per 100,000 population per year. The male:female ratio for HCC in India is 4:1. The age of presentation varies from 40 to 70 years. According to a study conducted by verbal autopsy in 1.1 million homes representing the whole country, the age standardized mortality rate for HCC in India for men is 6.8/100,000 and for women is 5.1/100,000. According to another study the incidence of HCC in cirrhotics in India is 1.6% per year. The unpublished data from various tertiary care centers suggest that the incidence of HCC is increasing in India. There is a need for a multi-centric HCC registry under the aegis of INASL. PMID:25755607

  3. The Transcriptional Profiling of Glycogenes Associated with Hepatocellular Carcinoma Metastasis

    PubMed Central

    Liu, Tianhua; Zhang, Shu; Chen, Jie; Jiang, Kai; Zhang, Qinle; Guo, Kun; Liu, Yinkun

    2014-01-01

    Background and objective Metastasis is one of the important reasons for the poor prognosis of hepatocellular carcinoma (HCC), abnormal glycosylation plays a pivotal role in HCC metastasis. The goal of this study was to screen and validate the transcriptional profiling of glycogenes associated with HCC metastasis. Methodology The differentially transcribed glycogenes were screened out by the Human Glycosylation RT2 Profiler PCR Array, and were identified by qRT-PCR in human HCC cell lines and their orthotopic xenograft tumors. Further analyses were performed with K-mean clustering, Gene Ontology (GO) and ingenuity pathways analysis (IPA). Four differentially transcribed glycogenes were validated in clinical cancer specimens by qRT-PCR. Results A total of thirty-three differentially transcribed glycogenes were obtained by comparison the transcription in the metastatic human HCC cell lines (MHCC97L, MHCC97H and HCCLM3) with the transcription in the non-metastatic HCC cell line Hep3B. Seven differentially transcribed glycogenes were selected to further identification in human HCC cell lines and their orthotopic xenograft tumors. According to their trends by K-mean clustering, all of the differentially transcribed glycogenes were classified in six clusters. GO analysis of the differentially transcribed glycogenes described them in biological process, subcellular location and molecular function. Furthermore, the partial regulatory network of the differentially transcribed glycogenes was acquired through the IPA. The transcription levels of galnt3, gcnt3, man1a1, mgat5b in non-metastatic and metastatic HCC clinical cancer specimens showed the same changing trends with the results in human HCC cell lines and their orthotopic xenograft tumors, and the divergent transcription levels of gcnt3 and mgat5b were statistically significant. Conclusions The transcriptional profiling of glycogenes associated with HCC metastasis was obtained and validated in this study and it might

  4. Identification of Driver Genes in Hepatocellular Carcinoma by Exome Sequencing

    PubMed Central

    Cleary, Sean P.; Jeck, William R.; Zhao, Xiaobei; Chen, Kui; Selitsky, Sara R.; Savich, Gleb L.; Tan, Ting-Xu; Wu, Michael C.; Getz, Gad; Lawrence, Michael S.; Parker, Joel S.; Li, Jinyu; Powers, Scott; Kim, Hyeja; Fischer, Sandra; Guindi, Maha; Ghanekar, Anand; Chiang, Derek Y.

    2013-01-01

    Genetic alterations in specific driver genes lead to disruption of cellular pathways and are critical events in the instigation and progression of hepatocellular carcinoma. As a prerequisite for individualized cancer treatment, we sought to characterize the landscape of recurrent somatic mutations in hepatocellular carcinoma. We performed whole exome sequencing on 87 hepatocellular carcinomas and matched normal adjacent tissues to anaverage coverage of 59x. The overall mutation rate was roughly 2 mutations per Mb, with a median of 45 non-synonymous mutations that altered the amino acid sequence (range 2 to 381). We found recurrent mutations in several genes with high transcript levels: TP53 (18%), CTNNB1 (10%), KEAP1 (8%), C16orf62 (8%), MLL4(7%) and RAC2 (5%). Significantly affected gene families include the nucleotide-binding domain and leucine rich repeat containing family, calcium channel subunits, and histone methyltransferases. In particular, the MLL family of methyltransferases for histone H3 lysine 4 were mutated in 20% of tumors. Conclusion The NFE2L2-KEAP1 and MLL pathways are recurrently mutated in multiple cohorts of hepatocellular carcinoma. PMID:23728943

  5. Hepatocellular carcinoma and suspected splenic hemangiosarcoma in a potbellied pig

    PubMed Central

    Morrow, Janet L.

    2002-01-01

    A 10-year-old, lethargic, potbellied pig presented with signs of abdominal discomfort and a palpable abdominal mass. Laparotomy revealed a 20 cm diameter mass on the spleen and smaller masses on the omentum and liver. After euthanasia and histologic examination of the hepatic mass, the diagnosis was hepatocellular carcinoma. PMID:12058574

  6. A Case of Sphenoid Sinus Metastasis in Hepatocellular Carcinoma.

    PubMed

    Lee, Tae Hoon; Rangan, Vikram; Khallafi, Hicham

    2016-06-01

    Sphenoid sinus metastasis from hepatocellular carcinoma (HCC) has been reported only rarely. We present a case of solitary sphenoid sinus metastasis of a 2.7 × 2.3 cm single HCC lesion. (Hepatology 2016;63:2050-2053). PMID:26928869

  7. UNIQUE GENOMIC PROFILE OF FIBROLAMELLAR HEPATOCELLULAR CARCINOMA

    PubMed Central

    Cornella, Helena; Alsinet, Clara; Sayols, Sergi; Zhang, Zhongyang; Hao, Ke; Cabellos, Laia; Hoshida, Yujin; Villanueva, Augusto; Thung, Swan; Ward, Stephen C.; Rodriguez-Carunchio, Leonardo; Vila-Casadesús, Maria; Imbeaud, Sandrine; Lachenmayer, Anja; Quaglia, Alberto; Nagorney, David M.; Minguez, Beatriz; Carrilho, Flair; Roberts, Lewis R.; Waxman, Samuel; Mazzaferro, Vincenzo; Schwartz, Myron; Esteller, Manel; Heaton, Nigel D.; Zucman-Rossi, Jessica; Llovet, Josep M.

    2015-01-01

    Background & Aims Fibrolamellar hepatocellular carcinoma (FLC) is a rare primary hepatic cancer that develops in children and young adults without cirrhosis. Little is known about its pathogenesis, and it can only be treated with surgery. We performed an integrative genomic analysis of a large series of patients with FLC to identify associated genetic factors. Methods Using 78 clinically annotated FLC samples, we performed whole-transcriptome (n=58), single-nucleotide polymorphism array (n=41), and next-generation sequencing (n=48) analyses; we also assessed the prevalence of the DNAJB1–PRKACA fusion transcript associated with this cancer (n=73). We performed class discovery using non-negative matrix factorization, and functional annotation using gene set enrichment analyses, nearest template prediction, ingenuity pathway analyses, and immunohistochemistry. The genomic identification of significant targets in cancer algorithm was used to identify chromosomal aberrations, MuTect and VarScan2 were used to identify somatic mutations, and the random survival forest was used to determine patient prognoses. Findings were validated in an independent cohort. Results Unsupervised gene expression clustering revealed 3 robust molecular classes of tumors: the proliferation class (51% of samples) had altered expression of genes that regulate proliferation and mTOR signaling activation; the inflammation class (26% of samples) had altered expression of genes that regulate inflammation and cytokine production; and the unannotated class (23% of samples) had a gene expression signature not previously associated with liver tumors. Expression of genes that regulate neuroendocrine function, as well has histologic markers of cholangiocytes and hepatocytes, were detected in all 3 classes. FLCs had few copy number variations; the most frequent were focal amplification at 8q24.3 (in 12.5% of samples) and deletions at 19p13 (in 28% of samples) and 22q13.32 (in 25% of samples). The DNAJB1

  8. Metabolism of Radiolabeled Methionine in Hepatocellular Carcinoma

    PubMed Central

    Kuang, Yu; Wang, Fangjing; Corn, David J.; Tian, Haibin; Lee, Zhenghong

    2015-01-01

    Purpose Radiolabeled methionine (Met) promises to be useful in the positron emission tomography (PET) imaging of hepatocellular carcinoma (HCC). However, its metabolic routes in HCC have not yet been fully understood. In this study, the metabolic pathway(s) of radiolabeled Met in HCC were investigated. Procedures To simulate the rapid blood clearance of radiolabeled Met, pulse–chase experiments were conducted. L-[methyl-3H]-Met or L-[1-14C]-Met was pulsed over control or cycloheximide- treated WCH17 cells and rat hepatocytes for 5 min and chased with cold media. The water-soluble, lipid-soluble, DNA, RNA, and protein phases were subsequently extracted and measured from the acid-precipitable and acid-soluble fractions of whole cells. The radioactive metabolites Met, S- adenosylmethionine (SAM), S-adenosylhomocysteine, Met sulfoxide, and Met sulfone were further separated by radio thin layer chromatography. Results (1) The uptake of L-[methyl-3H]-Met in both cell types was higher than that of L-[1-14C]-Met. In rat hepatocytes, the uptake of L-[methyl-3H]-Met was significantly higher than that of L-[1-14C]-Met, which may contribute to its physiologic accumulation in surrounding hepatic tissues seen in PET imaging of HCC using L-[methyl-11C]-Met. Compared to rat hepatocytes, WCH17 cells had significantly higher uptake of both radiotracers. (2) For L-[methyl-3H]-Met, the major intracellular uptake was found mostly in the protein phase and, to a lesser degree, in the phosphatidylethanolamine (PE) methylation pathway, which is fairly stabilized within the 55-min chase period (the main metabolites were SAM, Met, Met sulfoxide, and Met sulfone). In contrast, the uptake of Met in rat hepatocytes mainly points to phosphatidylcholine (PC) synthesis through the PE methylation pathway (the main metabolite was PC). (3) Both cell types incorporated L-[1-14C]-Met predominantly into protein synthesis. (4) Finally, when the protein synthesis pathway was inhibited, the incorporation

  9. Screening for hepatocellular carcinoma by Egyptian physicians

    PubMed Central

    Hassany, Sahar M; Moustafa, Ehab F Abdou; Taher, Mohamed El; Abdeltwab, Afaf Adel; Blum, Hubert E

    2015-01-01

    AIM: To assess the practice of Egyptian physicians in screening patients for hepatocellular carcinoma (HCC). METHODS: The study included 154 physicians from all over Egypt caring for patients at risk for HCC. The study was based on a questionnaire with 20 items. Each questionnaire consisted of two parts: (1) personal information regarding the physician (name, age, specialty and type of health care setting); and (2) professional experience in the care of patients at risk for HCC development (screening, knowledge about the cause and natural course of liver diseases and HCC risk). RESULTS: Sixty-eight percent of doctors with an MD degree, 48% of doctors with a master degree or a diploma and 40% of doctors with a Bachelor of Medicine, Bachelor of Surgery certificate considered the hepatitis C virus (HCV) genotype as risk factor for HCC development (P < 0.05). Ninety percent of physicians specialized in tropical medicine, internal medicine or gastroenterology and 67% of physicians in other specialties advise patients to undergo screening for HCV and hepatitis B virus infection as well as liver cirrhosis (P < 0.05). Eighty-six percent of doctors in University Hospitals and 69% of Ministry of Health (MOH) doctors consider HCV infection as the leading cause of HCC in Egypt (P < 0.05). Seventy-two percent of doctors with an MD degree, 55% of doctors with a master degree or a diploma, 56% of doctors with an MBBCH certificate, 74% of doctors in University Hospitals and 46% of MOH hospital doctors consider abdominal ultrasonography as the most important investigation in HCC screening (P < 0.05). Sixty-five percent of physicians in tropical medicine, internal medicine or gastroenterology and 37% of physicians in other specialties recommend as HCC screening interval of 3 mo (P < 0.05). Seventy-one percent of doctors with an MD degree, 50% of doctors with a master degree or diploma and 60% of doctors with an MBBCH certificate follow the same recommendation. CONCLUSION: In Egypt

  10. Treatment of hepatocellular carcinoma: beyond international guidelines.

    PubMed

    Colombo, Massimo; Sangiovanni, Angelo

    2015-01-01

    The management of hepatocellular carcinoma (HCC) is decided according to evidence-based recommendations generated by international societies: according to these recommendations, the tumour stage, as determined by the Barcelona clinical liver cancer (BCLC) score, divides patients into five prognostic categories, each with a distinct treatment indication. Radical therapies such as hepatic resection, orthotopic liver transplantation and percutaneous local ablation are strongly indicated in patients with very early and early stage tumours (BCLC O and A), a choice which mainly depends on a combination of tumour volume, status of underlying liver disease, the presence of comorbidities and the patient's age. Although radical therapies provide a survival rate of between 50% and 75% at year five in well selected patients, tumour recurrence is frequent following resection and ablation compared to transplantation (70% vs. 10% respectively), which has the additional advantage of preventing morbidity and mortality from portal hypertension. Generally, while radical therapies are contraindicated in patients with a large tumour burden, such as those with intermediate stage BCLC B, survival in the subset of these patients with well compensated cirrhosis may improve from 16 to 20 months, on average, following repeated treatments with transarterial chemoembolization (TACE). Survival may also improve in patients who are in poor condition or who do not respond to TACE and in those with an advanced HCC (BCLC C) following oral therapy with the multikinase inhibitor sorafenib. However, because most recommendations are based on uncontrolled studies and expert opinions rather than well designed, high powered randomized controlled trials, treatment criteria need to be adapted to special groups because real life cohorts do not match the selection criteria suggested by the guidelines. Indeed, up to one-third of patients with early stage tumours who are unfit for radical therapy because of

  11. [Comparative genomic classification of human hepatocellular carcinoma].

    PubMed

    Kaposi-Novák, Pál

    2009-03-01

    Global transcriptome analysis has been successfully applied to characterize various human tumors, including hepatocellular carcinomas. This novel technology can facilitate early diagnosis, as well as prognostic and therapeutic diversification of cancer patients. To enhance access to the genomic information buried in archived pathology samples, we assessed RT-PCR amplification rates in paraffin-embedded tissues preserved in three different fixatives. Reliable amplification could be achieved from all paraffin-embedded specimens, when the amplicon size did not exceed 225 bp. A longer amplicon size resulted in rapid decrease of yield and reproducibility. In addition, formalin provided superior morphology and better reactivity with claudin-4 and -7 immunohistochemistry. Amplification of the initial sample is often required before transcriptome analysis of clinical specimens could be performed. We introduced a random nonamer primed T3 polymerase reaction into the conventional linear RNA amplification protocol. The modified T3T7 method generated a sense strand product ideal for synthesizing indirectly labeled cDNA templates. Microarray analysis of amplified frozen and laser-microdissected Myc and Myc/TGFalpha mouse liver tumors confirmed good reproducibility (r=0.9) of the reaction and conservation of original transcriptional patterns (r=0.78). Finally, we tested the utility of expression profiling for the classification of human HCC samples. By comparing expression data from HGF-treated c-Met conditional knock-out and control primary mouse hepatocytes, we identified 690 HGF/c-Met target genes. Functional analysis of the significant gene set implicated c-Met as key regulator of hepatocyte motility and oxidative homeostasis. Cross comparison of the c-Met-induced transcription signature with human HCC expression profiles revealed a group of tumors (27%) with potentially activated c-Met signaling (MET+). These tumors were characterized by higher vascular invasion rate

  12. Subcellular tissue proteomics of hepatocellular carcinoma for molecular signature discovery.

    PubMed

    Lee, Yong-Yook; McKinney, Kimberly Q; Ghosh, Sriparna; Iannitti, David A; Martinie, John B; Caballes, F Ryan; Russo, Mark W; Ahrens, William A; Lundgren, Deborah H; Han, David K; Bonkovsky, Herbert L; Hwang, Sun-Il

    2011-11-01

    Hepatocellular carcinoma (HCC) is one of the leading causes of mortality from solid organ malignancy worldwide. Because of the complexity of proteins within liver cells and tissues, the discovery of therapeutic targets of HCC has been difficult. To investigate strategies for decreasing the complexity of tissue samples for detecting meaningful protein mediators of HCC, we employed subcellular fractionation combined with 1D-gel electrophoresis and liquid chromatography-tandem mass spectrometry analysis. Moreover, we utilized a statistical method, namely, the Power Law Global Error Model (PLGEM), to distinguish differentially expressed proteins in a duplicate proteomic data set. Mass spectrometric analysis identified 3045 proteins in nontumor and HCC from cytosolic, membrane, nuclear, and cytoskeletal fractions. The final lists of highly differentiated proteins from the targeted fractions were searched for potentially translocated proteins in HCC from soluble compartments to the nuclear or cytoskeletal compartments. This analysis refined our targets of interest to include 21 potential targets of HCC from these fractions. Furthermore, we validated the potential molecular targets of HCC, MATR3, LETM1, ILF2, and IQGAP2 by Western blotting, immunohistochemisty, and immunofluorescent microscopy. Here we demonstrate an efficient strategy of subcellular tissue proteomics toward molecular target discovery of one of the most complicated human disease, HCC. PMID:21913717

  13. Neuroendocrine differentiation in cervical carcinoma.

    PubMed Central

    Savargaonkar, P R; Hale, R J; Mutton, A; Manning, V; Buckley, C H

    1996-01-01

    AIMS: To examine neuroendocrine differentiation, as shown by chromogranin A (CGA) expression, in cervical carcinomas. METHODS: Sixty seven cervical carcinomas were studied and were classified as adenocarcinomas, adenosquamous carcinomas or squamous cell carcinomas based on the assessment of haematoxylin and eosin staining and stains for mucin. Where features of glandular differentiation were identified, sections were also stained for evidence of intestinal type mucin. CGA immunostaining was done and the results were graded on a three point scale: 0, + (1-5% of cells positive) and ++ (> 5% of cells positive). These findings were then analysed with respect to lymph node status, tumour differentiation and clinical outcome. RESULTS: There were 32 adenocarcinomas, 18 adenosquamous carcinomas and 17 squamous cell carcinomas. Positive staining was seen in 14 (20.9%) cases, of which four were strongly positive. All but one case were either adenocarcinomas or adenosquamous carcinomas. There was a trend for CGA positivity to be related to intestinal differentiation but this failed to reach statistical significance. No correlation could be demonstrated between CGA staining and lymph node status, tumour differentiation and clinical outcome. CONCLUSIONS: Neuroendocrine differentiation is common in cervical carcinomas where there is evidence of glandular differentiation. Whilst the numbers in this study are relatively small, the presence of neuroendocrine cells in otherwise typical carcinomas does not seem to have any association with clinical behaviour. Images PMID:8655680

  14. MicroRNA profiles in various hepatocellular carcinoma cell lines

    PubMed Central

    Morishita, Asahiro; Iwama, Hisakazu; Fujihara, Shintaro; Sakamoto, Teppei; Fujita, Koji; Tani, Joji; Miyoshi, Hisaaki; Yoneyama, Hirohito; Himoto, Takashi; Masaki, Tsutomu

    2016-01-01

    Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-associated mortality worldwide. Although surgery is considered the most effective treatment for patients with HCC, its indication is restricted by limited criteria and a high relapse rate following surgery; therefore, systemic chemotherapy is required for patients with advanced-stage HCC to prolong their survival. MicroRNAs (miRNAs) are endogenous non-coding RNAs of 18–22 nucleotides in length. It has been reported that aberrant expression of miRNAs is a feature shared by various types of human cancer. Previous studies have indicated that the modulation of non-coding RNAs, particularly miRNAs, may be a valuable therapeutic target for HCC. The aim of the present study was to elucidate the miRNA profiles associated with differentiation and hepatitis B virus (HBV) infection observed in HCC cell lines. The human Alex, Hep3B, HepG2, HuH1, HuH7, JHH1, JHH2, JHH5, JHH6, HLE, HLF and Li-7 HCC cell lines were used for an miRNA array. Replicate data were analyzed following their classification into: i) Poorly- and well-differentiated human HCC cells and ii) HBV-positive and -negative human HCC cells. Out of the 1,719 miRNAs, 4 were found to be significantly upregulated and 52 significantly downregulated in the poorly-differentiated cells, as compared with the well-differentiated cells. Conversely, in the HBV-positive cells 125 miRNAs were found to be upregulated and 2 downregulated, as compared with the HBV-negative cells. Unsupervised hierarchical clustering analysis with Pearson's correlation revealed that the miRNA expression levels were clustered both together and separately in each group. In conclusion, miRNA profile characterization based on various parameters may be a novel approach to determine the etiology of HCC.

  15. The immunosuppression role of alpha-fetoprotein in human hepatocellular carcinoma.

    PubMed

    Meng, Wenbo; Bai, Bing; Bai, Zhongtian; Li, Yan; Yue, Ping; Li, Xun; Qiao, Liang

    2016-06-01

    Human hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death. Alpha-fetoprotein (AFP) is perhaps the best-defined tumor marker for HCC, and as such, it is widely used in clinical settings as an adjuvant diagnostic and prognostic tool. Up to 70% of HCC cases exhibit elevated serum level of AFP, but its pathophysiological functions in HCC are poorly defined. It is now known that AFP is not just a fetal form of carrier protein and a tumor marker, it is also critically involved in the regulation of several important cellular functions, such as cell growth, differentiation, apoptosis, angiogenesis, and immune regulation. In this mini-review, we summarize the recent development of AFP in hepatocellular carcinoma. PMID:27448785

  16. Synchronously resected double primary hepatic cancers - hepatocellular carcinoma and cholangiolocellular carcinoma.

    PubMed

    Matsuda, Masanori; Hara, Michio; Suzuki, Tetsuya; Kono, Hiroshi; Fujii, Hideki

    2006-01-01

    The frequency of double primary cancers in the liver is very low. All reported cases are double cancers consisting of hepatocellular carcinoma (HCC) and intrahepatic cholangiocellular carcinoma (CCC). We herein report a surgical patient who had simultaneous double cancers consisting of HCC and cholangiolocellular carcinoma (CoCC). This is the first case report of such a patient. A 70-year-old Japanese man was admitted to our hospital for further examination of two hepatic nodules. He had a history of schistosomiasis japonica, idiopathic pulmonary fibrosis, and diabetes mellitus. Laboratory data revealed that hepatitis C virus (HCV) antibody was positive and hepatic enzymes were slightly elevated. The level of prothrombin induced by vitamin K absence or antagonist II was elevated. Computed tomography depicted two tumors; one, measuring 4.0 cm in diameter, was in the medial segment and the other, 2.2 cm in diameter, was in the posterior superior segment of the liver. The larger tumor showed contrast enhancement and the smaller one showed enhancement at the tumor periphery in the hepatic arterial phase. In the portal phase, the larger tumor became less dense than the liver parenchyma, but the periphery of the smaller one showed continuous enhancement. He underwent an operation under a diagnosis of double hepatic cancers, consisting of HCC and CCC. However, microscopic examination of the resected tumors revealed that the larger tumor was moderately differentiated HCC and the smaller one was CoCC. PMID:17139434

  17. Identification of Differential Protein Expression in Hepatocellular Carcinoma Induced Wistar Albino Rats by 2D Electrophoresis and MALDI-TOF-MS Analysis.

    PubMed

    Vedarethinam, Vadanasundari; Dhanaraj, Karthik; Soundherrajan, Ilavenil; Sivanesan, Ravikumar

    2016-04-01

    Hepato cellular carcinoma (HCC) is a type of malignant tumor. To investigate the proteins in cancer molecular mechanism and its role in HCC, we have used proteomic tools such as 2DE and MALDI-TOF-MS. Our investigation ravels that, plasma α-fetoprotein and carcinoembryonic antigen levels were elevated in DEN induced rats and gradually decreased after the treatment with 1,3BPMU. 2DE and MALDI-TOF-MS tool offers to identify the up and down regulation of proteins in HCC. Proteomic study reveals that, five differentially expressed proteins were identified in DEN induced rats and 1,3BPMU treated rats i.e. three up regulated protein such as T kininogen, NDPKB, PRMT1 (DEN induced rats), RGS19 and PAF (1,3BPMU treated rats) in 3BPMU treated rats, activation of transcription of a single gene from multiple promoters provides flexibility in the controlled gene expression. The regulations of hepatocyte stimulating factor were slow down the proliferation of hepatic cell and uncontrolled hepatic cell growth and also molecular signals strongly argue for a patho-physiological role in liver metastasis to control the cell aggression. This indicates that, anti cancer property of 1,3BPMU can be used as potent anti cancer agent. The present study also shows the proteomic approach helps to elucidate the tumor maker as well as regulatory marker proteins in HCC. PMID:27069327

  18. SIAH1 inactivation correlates with tumor progression in hepatocellular carcinomas.

    PubMed

    Matsuo, Koichi; Satoh, Seiji; Okabe, Hiroshi; Nomura, Akinari; Maeda, Toshiki; Yamaoka, Yoshio; Ikai, Iwao

    2003-03-01

    Accumulation of loss of heterozygosity (LOH) on chromosome 16 is frequently observed in human hepatocellular carcinomas (HCCs). To identify tumor-suppressor genes (TSGs) involved in hepatocarcinogenesis, we performed deletion mapping of chromosome 16 in 59 HCCs. Three commonly deleted regions, located in 16q12.1, 16q22.1, and 16q24.2, were observed. Because there has been no study on LOH at locus 16q12.1 in HCCs, we focused on this region. By searching the Human Genome Database at the National Center for Biotechnology Information web site, we identified 14 known genes in 16q12.1 as TSG candidates. Among these, the expression of SIAH1 was markedly downregulated in HCCs, and inactivation of SIAH1 expression was associated with LOH at 16q12.1. A mutation analysis of SIAH1 revealed no somatic mutations, but one single nucleotide polymorphism was found among the 35 HCCs investigated. Subsequently, we evaluated the relation between SIAH1 expression, confirmed by semiquantitative RT-PCR, and clinicopathological parameters in HCCs. SIAH1 was significantly downregulated in advanced HCCs, including poorly differentiated tumors, larger tumors, and tumors in advanced stages. These findings suggest that inactivation of SIAH1 plays an important role in HCC progression. PMID:12557228

  19. Integrating subpathway analysis to identify candidate agents for hepatocellular carcinoma

    PubMed Central

    Wang, Jiye; Li, Mi; Wang, Yun; Liu, Xiaoping

    2016-01-01

    Hepatocellular carcinoma (HCC) is the second most common cause of cancer-associated death worldwide, characterized by a high invasiveness and resistance to normal anticancer treatments. The need to develop new therapeutic agents for HCC is urgent. Here, we developed a bioinformatics method to identify potential novel drugs for HCC by integrating HCC-related and drug-affected subpathways. By using the RNA-seq data from the TCGA (The Cancer Genome Atlas) database, we first identified 1,763 differentially expressed genes between HCC and normal samples. Next, we identified 104 significant HCC-related subpathways. We also identified the subpathways associated with small molecular drugs in the CMap database. Finally, by integrating HCC-related and drug-affected subpathways, we identified 40 novel small molecular drugs capable of targeting these HCC-involved subpathways. In addition to previously reported agents (ie, calmidazolium), our method also identified potentially novel agents for targeting HCC. We experimentally verified that one of these novel agents, prenylamine, induced HCC cell apoptosis using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, an acridine orange/ethidium bromide stain, and electron microscopy. In addition, we found that prenylamine not only affected several classic apoptosis-related proteins, including Bax, Bcl-2, and cytochrome c, but also increased caspase-3 activity. These candidate small molecular drugs identified by us may provide insights into novel therapeutic approaches for HCC. PMID:27022281

  20. MicroRNAs: Emerging Novel Clinical Biomarkers for Hepatocellular Carcinomas

    PubMed Central

    Anwar, Sumadi Lukman; Lehmann, Ulrich

    2015-01-01

    The discovery of small non-coding RNAs known as microRNAs has refined our view of the complexity of gene expression regulation. In hepatocellular carcinoma (HCC), the fifth most frequent cancer and the third leading cause of cancer death worldwide, dysregulation of microRNAs has been implicated in all aspects of hepatocarcinogenesis. In addition, alterations of microRNA expression have also been reported in non-cancerous liver diseases including chronic hepatitis and liver cirrhosis. MicroRNAs have been proposed as clinically useful diagnostic biomarkers to differentiate HCC from different liver pathologies and healthy controls. Unique patterns of microRNA expression have also been implicated as biomarkers for prognosis as well as to predict and monitor therapeutic responses in HCC. Since dysregulation has been detected in various specimens including primary liver cancer tissues, serum, plasma, and urine, microRNAs represent novel non-invasive markers for HCC screening and predicting therapeutic responses. However, despite a significant number of studies, a consensus on which microRNA panels, sample types, and methodologies for microRNA expression analysis have to be used has not yet been established. This review focuses on potential values, benefits, and limitations of microRNAs as new clinical markers for diagnosis, prognosis, prediction, and therapeutic monitoring in HCC. PMID:26295264

  1. An Analysis of Immunoreactive Signatures in Early Stage Hepatocellular Carcinoma

    PubMed Central

    Hong, Yu; Long, Jiang; Li, Hai; Chen, Shuhong; Liu, Qiqi; Zhang, Bei; He, Xiaomin; Wang, Yan; Li, Hongyi; Li, Yimei; Zhang, Tao; Lu, Chenzhen; Yan, Hao; Zhang, Minli; Li, Qing; Cao, Bangwei; Bai, Zhigang; Wang, Jin; Zhang, Zhongtao; Zhu, Shengtao; Zheng, Jiasheng; Ou, Xiaojuan; Ma, Hong; Jia, Jidong; You, Hong; Wang, Shengqi; Huang, Jian

    2015-01-01

    Background Hepatocellular carcinoma (HCC) is prevalent worldwide and early diagnosis of HCC is critical for effective treatment and optimal prognosis. Methods Serum was screened first by immunoproteomic analysis for HCC-related tumor associated antigens (TAAs). Selected TAAs were clinically evaluated retrospectively in patients with HCC, liver cirrhosis, chronic hepatitis and healthy controls. Levels of autoantibody to the selected TAAs were measured by protein microarrays containing protein antigens of the candidate TAAs. Analyses were done by using receiver operating characteristics (ROC) to calculate diagnostic accuracy. Findings Twenty-two candidate TAAs were assessed by protein microarray analysis in 914 participants with serum α-fetoprotein (AFP) available. Twelve candidate TAAs were statistically different in signal intensity between HCC and controls. Among them, CENPF, HSP60 and IMP-2 showed AUC (area under the curve) values of 0.826, 0.764 and 0.796 respectively for early HCC. The highest prevalence of autoantibody positivity was observed in HCC cases with BCLC tumor stage A, well-differentiated histology and Child-Pugh grade C. Specifically, 73.6% or 79.3% cases of early HCC with negative AFP were positive for autoantibody to CENPF or HSP60. Interpretation Tumor-associated autoimmune reactions may be triggered by early stage HCCs. Measurement of serum autoantibody to TAAs may be complementary to AFP measurements and improve diagnosis of early HCC. PMID:26137588

  2. Integrating subpathway analysis to identify candidate agents for hepatocellular carcinoma.

    PubMed

    Wang, Jiye; Li, Mi; Wang, Yun; Liu, Xiaoping

    2016-01-01

    Hepatocellular carcinoma (HCC) is the second most common cause of cancer-associated death worldwide, characterized by a high invasiveness and resistance to normal anticancer treatments. The need to develop new therapeutic agents for HCC is urgent. Here, we developed a bioinformatics method to identify potential novel drugs for HCC by integrating HCC-related and drug-affected subpathways. By using the RNA-seq data from the TCGA (The Cancer Genome Atlas) database, we first identified 1,763 differentially expressed genes between HCC and normal samples. Next, we identified 104 significant HCC-related subpathways. We also identified the subpathways associated with small molecular drugs in the CMap database. Finally, by integrating HCC-related and drug-affected subpathways, we identified 40 novel small molecular drugs capable of targeting these HCC-involved subpathways. In addition to previously reported agents (ie, calmidazolium), our method also identified potentially novel agents for targeting HCC. We experimentally verified that one of these novel agents, prenylamine, induced HCC cell apoptosis using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, an acridine orange/ethidium bromide stain, and electron microscopy. In addition, we found that prenylamine not only affected several classic apoptosis-related proteins, including Bax, Bcl-2, and cytochrome c, but also increased caspase-3 activity. These candidate small molecular drugs identified by us may provide insights into novel therapeutic approaches for HCC. PMID:27022281

  3. Shp2 SUMOylation promotes ERK activation and hepatocellular carcinoma development

    PubMed Central

    Deng, Rong; Zhao, Xian; Qu, YingYing; Chen, Cheng; Zhu, Changhong; Zhang, Hailong; Yuan, Haihua; Jin, Hui; Liu, Xin; Wang, Yanli; Chen, Qin; Huang, Jian; Yu, Jianxiu

    2015-01-01

    Shp2, an ubiquitously expressed protein tyrosine phosphatase, is essential for regulation of Ras/ERK signaling pathway and tumorigenesis. Here we report that Shp2 is modified by SUMO1 at lysine residue 590 (K590) in its C-terminus, which is reduced by SUMO1-specific protease SENP1. Analysis of wild-type Shp2 and SUMOylation-defective Shp2K590R mutant reveals that SUMOylation of Shp2 promotes EGF-stimulated ERK signaling pathway and increases anchorage-independent cell growth and xenografted tumor growth of hepatocellular carcinoma (HCC) cell lines. Furthermore, we find that mutant Shp2K590R reduces its binding with the scaffolding protein Gab1, and consistent with this, knockdown of SENP1 increased the interaction between Shp2 and Gab1. More surprisingly, we show that human Shp2 (hShp2) and mouse Shp2 (mShp2) have differential effects on ERK activation as a result of different SUMOylation level, which is due to the event of K590 at hShp2 substituted by R594 at mShp2. In summary, our data demonstrate that SUMOylation of Shp2 promotes ERK activation via facilitating the formation of Shp2-Gab1 complex and thereby accelerates HCC cell and tumor growth, which presents a novel regulatory mechanism underlying Shp2 in regulation of HCC development. PMID:25823821

  4. Increased mRNA Levels of Sphingosine Kinases and S1P Lyase and Reduced Levels of S1P Were Observed in Hepatocellular Carcinoma in Association with Poorer Differentiation and Earlier Recurrence

    PubMed Central

    Uranbileg, Baasanjav; Ikeda, Hitoshi; Kurano, Makoto; Enooku, Kenichiro; Sato, Masaya; Saigusa, Daisuke; Aoki, Junken; Ishizawa, Takeaki; Hasegawa, Kiyoshi; Kokudo, Norihiro; Yatomi, Yutaka

    2016-01-01

    Although sphingosine 1-phosphate (S1P) has been reported to play an important role in cancer pathophysiology, little is known about S1P and hepatocellular carcinoma (HCC). To clarify the relationship between S1P and HCC, 77 patients with HCC who underwent surgical treatment were consecutively enrolled in this study. In addition, S1P and its metabolites were quantitated by LC-MS/MS. The mRNA levels of sphingosine kinases (SKs), which phosphorylate sphingosine to generate S1P, were increased in HCC tissues compared with adjacent non-HCC tissues. Higher mRNA levels of SKs in HCC were associated with poorer differentiation and microvascular invasion, whereas a higher level of SK2 mRNA was a risk factor for intra- and extra-hepatic recurrence. S1P levels, however, were unexpectedly reduced in HCC compared with non-HCC tissues, and increased mRNA levels of S1P lyase (SPL), which degrades S1P, were observed in HCC compared with non-HCC tissues. Higher SPL mRNA levels in HCC were associated with poorer differentiation. Finally, in HCC cell lines, inhibition of the expression of SKs or SPL by siRNA led to reduced proliferation, invasion and migration, whereas overexpression of SKs or SPL enhanced proliferation. In conclusion, increased SK and SPL mRNA expression along with reduced S1P levels were more commonly observed in HCC tissues compared with adjacent non-HCC tissues and were associated with poor differentiation and early recurrence. SPL as well as SKs may be therapeutic targets for HCC treatment. PMID:26886371

  5. [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. PMID:23092693

  6. Multiple skeletal metastases as unusual manifestations of hepatocellular carcinoma in a noncirrhotic liver.

    PubMed

    Shakya, V C; Agrawal, C S; Pandey, S R; Rauniyar, R K; Dhungel, K; Adhikary, S

    2010-09-01

    Hepatocellular carcinoma is the most frequent primary malignant tumor of the liver. Bony metastases of hepatocellular carcinoma are usually rare, in which most common sites involved are vertebra and pelvis. Still rarer are metastases to the chest wall and skull. We report a case of a 45-year old man with unusual metastases of hepatocellular carcinoma to skull, sternum and ribs. These combinations of metastases have rarely been reported in literature. PMID:21446373

  7. Distinct DNA methylation patterns in cirrhotic liver and hepatocellular carcinoma.

    PubMed

    Ammerpohl, Ole; Pratschke, Johann; Schafmayer, Clemens; Haake, Andrea; Faber, Wladimir; von Kampen, Oliver; Brosch, Mario; Sipos, Bence; von Schönfels, Witigo; Balschun, Katharina; Röcken, Christoph; Arlt, Alexander; Schniewind, Bodo; Grauholm, Jonas; Kalthoff, Holger; Neuhaus, Peter; Stickel, Felix; Schreiber, Stefan; Becker, Thomas; Siebert, Reiner; Hampe, Jochen

    2012-03-15

    Abberrant DNA methylation is one of the hallmarks of cancerogenesis. Our study aims to delineate differential DNA methylation in cirrhosis and hepatic cancerogenesis. Patterns of methylation of 27,578 individual CpG loci in 12 hepatocellular carcinomas (HCCs), 15 cirrhotic controls and 12 normal liver samples were investigated using an array-based technology. A supervised principal component analysis (PCA) revealed 167 hypomethylated loci and 100 hypermethylated loci in cirrhosis and HCC as compared to normal controls. Thus, these loci show a "cirrhotic" methylation pattern that is maintained in HCC. In pairwise supervised PCAs between normal liver, cirrhosis and HCC, eight loci were significantly changed in all analyses differentiating the three groups (p < 0.0001). Of these, five loci showed highest methylation levels in HCC and lowest in control tissue (LOC55908, CELSR1, CRMP1, GNRH2, ALOX12 and ANGPTL7), whereas two loci showed the opposite direction of change (SPRR3 and TNFSF15). Genes hypermethylated between normal liver to cirrhosis, which maintain this methylation pattern during the development of HCC, are depleted for CpG islands, high CpG content promoters and polycomb repressive complex 2 (PRC2) targets in embryonic stem cells. In contrast, genes selectively hypermethylated in HCC as compared to nonmalignant samples showed an enrichment of CpG islands, high CpG content promoters and PRC2 target genes (p < 0.0001). Cirrhosis and HCC show distinct patterns of differential methylation with regards to promoter structure, PRC2 targets and CpG islands. PMID:21500188

  8. MiR-940 inhibits hepatocellular carcinoma growth and correlates with prognosis of hepatocellular carcinoma patients.

    PubMed

    Yuan, Bo; Liang, Yasha; Wang, Duoning; Luo, Fengming

    2015-07-01

    Hepatocellular carcinoma (HCC) is among the leading causes of cancer-related death in China. Deregulation of microRNA (miRNA) contributes to HCC development by influencing cell growth, apoptosis, migration or invasion. It has been proved that miR-940 plays important roles in various cancers. Here we investigated the role of miR-940 in HCC. We found that miR-940 was remarkably decreased in HCC tissues and cell lines. Importantly, lower miR-940 expression in HCC tissues significantly correlated with the reduced patient's survival rate. Overexpression of miR-940 inhibited HCC cell line growth and induced cell apoptosis, and vice versa. Estrogen-related receptor gamma (ESRRG) was targeted by miR-940, and suppression of ESRRG inhibited HCC cell lines growth and induced cell apoptosis. In conclusion, we found that a lower level of miR-940 in HCC promoted cellular proliferation via ESRRG, which may lead to the short survival period of HCC patients. PMID:25940592

  9. MiR-940 inhibits hepatocellular carcinoma growth and correlates with prognosis of hepatocellular carcinoma patients

    PubMed Central

    Yuan, Bo; Liang, Yasha; Wang, Duoning; Luo, Fengming

    2015-01-01

    Hepatocellular carcinoma (HCC) is among the leading causes of cancer-related death in China. Deregulation of microRNA (miRNA) contributes to HCC development by influencing cell growth, apoptosis, migration or invasion. It has been proved that miR-940 plays important roles in various cancers. Here we investigated the role of miR-940 in HCC. We found that miR-940 was remarkably decreased in HCC tissues and cell lines. Importantly, lower miR-940 expression in HCC tissues significantly correlated with the reduced patient’s survival rate. Overexpression of miR-940 inhibited HCC cell line growth and induced cell apoptosis, and vice versa. Estrogen-related receptor gamma (ESRRG) was targeted by miR-940, and suppression of ESRRG inhibited HCC cell lines growth and induced cell apoptosis. In conclusion, we found that a lower level of miR-940 in HCC promoted cellular proliferation via ESRRG, which may lead to the short survival period of HCC patients. PMID:25940592

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

    PubMed

    Pár, Alajos; Pár, Gabriella

    2016-06-19

    In the past decade non-alcoholic liver disease became the most frequently diagnosed liver disease in developed countries. At the same time, the dramatic rise in the incidence of hepatocellular carcinoma is attributed to this common metabolic disorder, and mainly to its severe form, non-alcoholic steatohepatitis. The risk factors of these associated diseases are genetic predisposition, obesity and diabetes as well as chronic low grade necro-infammation, which often leads to liver fibrosis. Free fatty acids, cytokines, lipotoxicity, insulin resistance, microRNS dysregulation and alteration in intestinal microbiota play a pivotal role in the pathogenesis. Treatment of non-alcoholic fatty liver disease - weight reduction and physical exercise in obesity, metformin in diabetes, statins in dyslipidemia and, as a new option, obeticholic acid - may diminish the risk of the hepatocellular carcinoma related to this metabolic disease. PMID:27287838

  11. Simple Sugar Intake and Hepatocellular Carcinoma: Epidemiological and Mechanistic Insight

    PubMed Central

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

    2014-01-01

    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. PMID:25533006

  12. 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

  13. Diaphragmatic Hernia After Radiofrequency Ablation for Hepatocellular Carcinoma

    SciTech Connect

    Yamagami, Takuji Yoshimatsu, Rika; Matsushima, Shigenori; Tanaka, Osamu; Miura, Hiroshi; Nishimura, Tsunehiko

    2011-02-15

    We describe a 71-year-old woman with a hepatocellular carcinoma who underwent percutaneous radiofrequency ablation (RF) with a single internally cooled electrode under computed tomography (CT) fluoroscopic guidance. Nine months after the procedure, CT images showed herniation of the large intestine into the right pleural cavity. To our knowledge this complication of RF performed with a single internally cooled electrode under CT guidance has not been previously reported.

  14. Intraperitoneal seeding from hepatocellular carcinoma following percutaneous ethanol ablation therapy.

    PubMed

    Kurl, S; Farin, P; Rytkonen, H; Soimakallio, S

    1997-01-01

    We present a case of intraperitoneal seeding in a 36-year-old woman with a large primary hepatocellular carcinoma located superfically in the left lobe of the otherwise normal liver. The patient was treated with percutaneous ethanol ablation therapy. Eight months after the treatment computed tomography and ultrasonography (US) revealed an intraperitoneal seeding that was confirmed with US-guided percutaneous biopsy. PMID:9107646

  15. Imaging approach to hepatocellular carcinoma, cholangiocarcinoma, and metastatic colorectal cancer.

    PubMed

    Fowler, Kathryn J; Saad, Nael E; Linehan, David

    2015-01-01

    Liver imaging is a highly evolving field with new imaging contrast agents and modalities. Knowledge of the different imaging options and what they have to offer in primary and metastatic liver disease is essential for appropriate diagnosis, staging, and prognosis in patients. This review summarizes the major imaging modalities in liver neoplasms and provides specific discussion of imaging hepatocellular carcinoma, cholangiocarcinoma, and colorectal liver metastases. The final sections provide an overview of presurgical imaging relevant to planning hepatectomies and ablative procedures. PMID:25444467

  16. Pain Palliation by Percutaneous Acetabular Osteoplasty for Metastatic Hepatocellular Carcinoma

    SciTech Connect

    Hokotate, Hirofumi; Baba, Yasutaka; Churei, Hisahiko; Nakajo, Masayuki; Ohkubo, Kouichi; Hamada, Kenji

    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.

  17. Recent advances in the imaging of hepatocellular carcinoma

    PubMed Central

    You, Myung-Won; Kim, Kyoung Won; Lee, So Jung; Shin, Yong Moon; Kim, Jin Hee; Lee, Moon-Gyu

    2015-01-01

    The role of imaging is crucial for the surveillance, diagnosis, staging and treatment monitoring of hepatocellular carcinoma (HCC). Over the past few years, considerable technical advances were made in imaging of HCCs. New imaging technology, however, has introduced new challenges in our clinical practice. In this article, the current status of clinical imaging techniques for HCC is addressed. The diagnostic performance of imaging techniques in the context of recent clinical guidelines is also presented. PMID:25834808

  18. Quinacrine sensitizes hepatocellular carcinoma cells to TRAIL and chemotherapeutic agents.

    PubMed

    Wang, Wenge; Gallant, Jean-Nicolas; Katz, Sharyn I; Dolloff, Nathan G; Smith, Charles D; Abdulghani, Junaid; Allen, Joshua E; Dicker, David T; Hong, Bo; Navaraj, Arunasalam; El-Deiry, Wafik S

    2011-08-01

    Quinacrine has been widely explored in treatment of malaria, giardiasis, and rheumatic diseases. We find that quinacrine stabilizes p53 and induces p53-dependent and independent cell death. Treatment by quinacrine alone at concentrations of 10-20 mM for 1-2 d cannot kill hepatocellular carcinoma cells, such as HepG2, Hep3B, Huh7, which are also resistant to TRAIL. However, quinacrine renders these cells sensitive to treatment by TRAIL. Co-treatment of these cells with quinacrine and TRAIL induces overwhelming cell death within 3-4 h. Levels of DR5, a pro-apoptotic death receptor of TRAIL, are increased upon treatment with quinacrine, while levels of Mcl-1, an anti-apoptotic member of the Bcl-2 family, are decreased. While the synergistic effect of quinacrine with TRAIL appears to be in part independent of p53, knockdown of p53 in HepG2 cells by siRNA results in more cell death after treatment by quinacrine and TRAIL. The mechanism by which quinacrine sensitizes hepatocellular carcinoma cells to TRAIL and chemotherapies, and the potential for clinical application currently are being further explored. Lastly, quinacrine synergizes with chemotherapeutics, such as adriamycin, 5-FU, etoposide, CPT11, sorafenib, and gemcitabine, in killing hepatocellular carcinoma cells in vitro and the drug enhances the activity of sorafenib to delay tumor growth in vivo. PMID:21725212

  19. [A case of hepatocellular carcinoma with multiple lymph node metastases detected by FDG-PET].

    PubMed

    Ito, Tadao; Noguchi, Akinori; Shimizu, Takeshi; Tani, Naoki; Yamaguchi, Masahide; Okano, Shinji; Yamane, Tetsuro; Kawabata, Kenji

    2012-11-01

    We report a case of hepatocellular carcinoma (HCC) with multiple lymph node (LN) metastases. A 68-year-old man underwent hepatectomy at our hospital. Intrahepatic recurrence and swelling of multiple LNs were detected by enhanced CT 21 months later. FDG-PET was positive for multiple swollen LNs, but all were negative for the intrahepatic recurrences. Biopsy of para-aortic LNs was revealed LN metastases from HCC. Immunohistochemically, the LN metastases were composed of poorly differentiated HCC. The sensitivity of FDG-PET in patients with HCC varies in relation to degree of differentiation and decreased FDG uptake must be noted. PMID:23132040

  20. Probiotics modulated gut microbiota suppresses hepatocellular carcinoma growth in mice.

    PubMed

    Li, Jun; Sung, Cecilia Ying Ju; Lee, Nikki; Ni, Yueqiong; Pihlajamäki, Jussi; Panagiotou, Gianni; El-Nezami, Hani

    2016-03-01

    The beneficial roles of probiotics in lowering the gastrointestinal inflammation and preventing colorectal cancer have been frequently demonstrated, but their immunomodulatory effects and mechanism in suppressing the growth of extraintestinal tumors remain unexplored. Here, we adopted a mouse model and metagenome sequencing to investigate the efficacy of probiotic feeding in controlling s.c. hepatocellular carcinoma (HCC) and the underlying mechanism suppressing the tumor progression. Our result demonstrated that Prohep, a novel probiotic mixture, slows down the tumor growth significantly and reduces the tumor size and weight by 40% compared with the control. From a mechanistic point of view the down-regulated IL-17 cytokine and its major producer Th17 cells, whose levels decreased drastically, played critical roles in tumor reduction upon probiotics feeding. Cell staining illustrated that the reduced Th17 cells in the tumor of the probiotic-treated group is mainly caused by the reduced frequency of migratory Th17 cells from the intestine and peripheral blood. In addition, shotgun-metagenome sequencing revealed the crosstalk between gut microbial metabolites and the HCC development. Probiotics shifted the gut microbial community toward certain beneficial bacteria, including Prevotella and Oscillibacter, that are known producers of antiinflammatory metabolites, which subsequently reduced the Th17 polarization and promoted the differentiation of antiinflammatory Treg/Tr1 cells in the gut. Overall, our study offers novel insights into the mechanism by which probiotic treatment modulates the microbiota and influences the regulation of the T-cell differentiation in the gut, which in turn alters the level of the proinflammatory cytokines in the extraintestinal tumor microenvironment. PMID:26884164

  1. 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

  2. Activated macrophages down-regulate expression of E-cadherin in hepatocellular carcinoma cells via NF-κB/Slug pathway.

    PubMed

    Wang, Xianteng; Wang, Hao; Li, Guosheng; Song, Yonghong; Wang, Shurong; Zhu, Faliang; Guo, Chun; Zhang, Lining; Shi, Yongyu

    2014-09-01

    Hepatocellular carcinomas are an aggressive malignancy mainly due to metastasis or postsurgical recurrence. Expression of E-cadherin is strongly reduced in Hepatocellular carcinoma (HCC) tissues, and its downregulation is connected to invasiveness and metastasis in hepatocellular carcinomas. The previous study showed that the supernatant from activated macrophages can downregulate the expression of E-cadherin in HCC cells. The partial known molecular mechanism is that tyrosine kinases c-Src- and EGFR phosphorylate β-catenin and E-cadherin leading to destabilization of E-cadherin/β-catenin complex. The aim of this study is to clarify other mechanism by which activated macrophages downregulate the expression of E-cadherin. We detect the expression of E-cadherin and macrophage infiltration in hepatocellular carcinoma tissues by double-staining immunohistochemistry and evaluate the relationship between macrophages and E-cadherin expression in hepatocellular carcinoma cells in vitro experiments. We found that reduced expression of E-cadherin was associated with macrophage infiltration along the border between the tumor nest and stroma in hepatocellular carcinoma tissues. Besides, protein expression of E-cadherin was significantly decreased in hepatocellular carcinoma cells co-cultured with macrophages derived from THP-1 cells. Consistently, mRNA expression of E-cadherin was also decreased in cancer cells co-cultured with THP-1-differentiated macrophages. Moreover, the downregulation of E-cadherin expression was companied by upregulation of Slug expression in cancer cells with conditional medium from THP-1-differentiated macrophage culture. The change in expression of E-cadherin and Slug was abrogated when NF-κB signaling pathway was blocked. All the findings suggested that macrophages contributed to the decreased expression of E-cadherin by NF-κB/Slug pathway in hepatocellular carcinomas. PMID:24894673

  3. 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

  4. 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. PMID:26188280

  5. Transforming growth factor-β as a therapeutic target in hepatocellular carcinoma.

    PubMed

    Giannelli, Gianluigi; Villa, Erica; Lahn, Michael

    2014-04-01

    Hepatocellular carcinoma arises in patients as a consequence of long-standing preexisting liver illnesses, including viral hepatitis, alcohol abuse, or metabolic disease. In such preexisting liver diseases, TGF-β plays an important role in orchestrating a favorable microenvironment for tumor cell growth and promoting epithelial-mesenchymal transition (EMT). TGF-β signaling promotes hepatocellular carcinoma progression by two mechanisms: first, via an intrinsic activity as an autocrine or paracrine growth factor and, second, via an extrinsic activity by inducing microenvironment changes, including cancer-associated fibroblasts, T regulatory cells, and inflammatory mediators. Although there is an increasing understanding on how TGF-β signaling is associated with tumor progression in hepatocellular carcinoma, it is not clear whether TGF-β signaling is limited to a certain subgroup of patients with hepatocellular carcinoma or is a key driver of hepatocellular carcinoma during the entire tumorigenesis of hepatocellular carcinoma. Inhibitors of the TGF-β signaling have been shown to block hepatocellular carcinoma growth and progression by modulating EMT in different experimental models, leading to the clinical investigation of the TGF-β inhibitor LY2157299 monohydrate in hepatocellular carcinoma. Preliminary results from a phase II clinical trial have shown improved clinical outcome and also changes consistent with a reduction of EMT. PMID:24638984

  6. Elucidating the Landscape of Aberrant DNA Methylation in Hepatocellular Carcinoma

    PubMed Central

    Song, Min-Ae; Tiirikainen, Maarit; Kwee, Sandi; Okimoto, Gordon; Yu, Herbert; Wong, Linda L.

    2013-01-01

    Background Hepatocellular carcinoma (HCC) is one of the most common cancers and frequently presents with an advanced disease at diagnosis. There is only limited knowledge of genome-scale methylation changes in HCC. Methods and Findings We performed genome-wide methylation profiling in a total of 47 samples including 27 HCC and 20 adjacent normal liver tissues using the Illumina HumanMethylation450 BeadChip. We focused on differential methylation patterns in the promoter CpG islands as well as in various less studied genomic regions such as those surrounding the CpG islands, i.e. shores and shelves. Of the 485,577 loci studied, significant differential methylation (DM) was observed between HCC and adjacent normal tissues at 62,692 loci or 13% (p<1.03e-07). Of them, 61,058 loci (97%) were hypomethylated and most of these loci were located in the intergenic regions (43%) or gene bodies (33%). Our analysis also identified 10,775 differentially methylated (DM) loci (17% out of 62,692 loci) located in or surrounding the gene promoters, 4% of which reside in known Differentially Methylated Regions (DMRs) including reprogramming specific DMRs and cancer specific DMRs, while the rest (10,315) involving 4,106 genes could be potential new HCC DMR loci. Interestingly, the promoter-related DM loci occurred twice as frequently in the shores than in the actual CpG islands. We further characterized 982 DM loci in the promoter CpG islands to evaluate their potential biological function and found that the methylation changes could have effect on the signaling networks of Cellular development, Gene expression and Cell death (p = 1.0e-38), with BMP4, CDKN2A, GSTP1, and NFATC1 on the top of the gene list. Conclusion Substantial changes of DNA methylation at a genome-wide level were observed in HCC. Understanding epigenetic changes in HCC will help to elucidate the pathogenesis and may eventually lead to identification of molecular markers for liver cancer diagnosis, treatment and

  7. Impact of PIVKA-II in diagnosis of hepatocellular carcinoma.

    PubMed

    Zakhary, Nadia I; Khodeer, Sherif M; Shafik, Hanan E; Abdel Malak, Camelia A

    2013-11-01

    Liver cancer grows silently with mild or no symptoms until advanced. In the absence of an effective treatment for advanced stage of hepatic cancer hope lies in early detection, and screening for high-risk population. Among Egyptians viral hepatitis is the most common risk factor for hepatocellular carcinoma (HCC). The current work was designed to determine the level of prothrombin induced by vitamin K absence-II (PIVKA-II) in sera of patients suffering from HCC and hepatitis C virus (HCV) patients being the most common predisposing factor for HCC. Our ultimate goal is diagnosis of HCC at its early stage. The current study was carried out on 83 individuals within three groups; Normal control, HCV and HCC groups. Patients were subdivided into cirrhotic and non-cirrhotic. Complete clinicopathological examination was carried out for each individual to confirm diagnosis. Individuals' sera were subjected to quantitative determination of alpha-fetoprotein (AFP), PIVKA-II and other parameters. PIVKA-II proved to be superior to AFP for early detection of HCC patients being highly sensitive and specific. Furthermore it has the ability to discriminate between different histopathological grades of HCC and It has a powerful diagnostic validity to evaluate the thrombosis of portal vein and to differentiate between early and late stages of HCC. The direct relation between the level of PIVKA-II and the size of tumor makes it an attractive tool for early HCC diagnosis and surveillance. Using the best cut-off value of AFP (>28), showed a sensitivity of (44%) and specificity of (73.3%). While cut-off value of PIVKA-II (>53.7) showed 100% sensitivity and specificity. PMID:25685463

  8. Pivotal Role of mTOR Signaling in Hepatocellular Carcinoma

    PubMed Central

    Villanueva, Augusto; Chiang, Derek Y.; Newell, Pippa; Peix, Judit; Thung, Swan; Alsinet, Clara; Tovar, Victoria; Roayaie, Sasan; Minguez, Beatriz; Sole, Manel; Battiston, Carlo; van Laarhoven, Stijn; Fiel, Maria I; Di Feo, Analisa; Hoshida, Yujin; Yea, Steven; Toffanin, Sara; Ramos, Alex; Martignetti, John A.; Mazzaferro, Vincenzo; Bruix, Jordi; Waxman, Samuel; Schwartz, Myron; Meyerson, Matthew; Friedman, Scott L.; Llovet, Josep M.

    2008-01-01

    BACKGROUND The advent of targeted therapies in hepatocellular carcinoma (HCC) has underscored the importance of pathway characterization to identify novel molecular targets for treatment. Based on its role in cell growth and differentiation, we evaluated mTOR signaling activation in human HCC, as well as the anti-tumoral effect of a dual-level blockade of the mTOR pathway. METHODS The mTOR pathway was assessed using integrated data from mutation analysis (direct sequencing), DNA copy number changes (SNP-array), mRNA levels (qRT-PCR and gene expression microarray), and protein activation (immunostaining) in 351 human samples, including HCC (n=314), and non-tumoral tissue (n=37). Effects of dual blockade of mTOR signaling using a rapamycin analog (everolimus) and an EGFR/VEGFR inhibitor (AEE788) were evaluated in liver cancer cell lines, and in a tumor xenograft model. RESULTS Aberrant mTOR signaling (phosphorylated-RPS6) was present in half of the cases, associated with IGF pathway activation, EGF upregulation, and PTEN dysregulation. PTEN and PI3KCA-B mutations were rare events. Chromosomal gains in RICTOR (25% of patients) and positive pRPS6 staining correlated with recurrence. RICTOR-specific siRNA downregulation reduced tumor cell viability in vitro. Blockage of mTOR signaling with everolimus in vitro and in a xenograft model decelerated tumor growth and increased survival. This effect was enhanced in vivo after EGFR blockade. CONCLUSIONS MTOR signaling has a critical role in the pathogenesis of HCC, with evidence for the role of RICTOR in tumor oncogenesis. MTOR blockade with everolimus is effective in vivo. These findings establish a rationale for targeting mTOR pathway in clinical trials in HCC. PMID:18929564

  9. Expression and clinical significance of Nectin-4 in hepatocellular carcinoma

    PubMed Central

    Ma, Jie; Sheng, ZhiYong; Lv, Yang; Liu, WenBin; Yao, QiYang; Pan, TingTing; Xu, ZhiJun; Zhang, ChuanHai; Xu, GeLiang

    2016-01-01

    Objective Nectin-4 is a member of the Nectin family of four Ca+-independent immunoglobulin-like cell adhesion molecules and implicated in cell adhesion, movement, proliferation, differentiation, polarization, and survival. The aberrant expression of Nectin-4 has been found in a variety of tumors; however, its expression in hepatocellular carcinoma (HCC) is still poorly understood. This study was to investigate the expression of Nectin-4 and its clinical significance in the patients with HCC. Methods The expression of Nectin-4 was assessed at mRNA and protein levels by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting assays in 20 HCC specimens and adjacent non-tumor live tissues. Furthermore, the clinical significance of Nectin-4 in 87 cases of HCC was confirmed by immunohistochemistry. Results The mRNA and protein levels of Nectin-4 were higher in HCC tumor tissues than in the matched non-tumor tissues. Nectin-4 was located in the cytoplasm of tumor cells and over-expressed in 67.82% (59/87) HCC tissues by immunohistochemical staining. Positive Nectin-4 expression was significantly correlated with tumor size (P=0.029), status of metastasis (P=0.023), vascular invasion (P=0.018) and tumor-node-metastasis stage (P=0.003). In addition, Kaplan–Meier survival analysis indicated that positive Nectin-4 expression was associated with worse recurrence-free survival (RFS) and overall survival (OS) (P=0.006 and P=0.005, respectively). In multivariate analysis, Nectin-4 was an independent prognostic factor for RFS and OS in the patients with HCC. Conclusion Nectin-4 is upregulated in HCC and may be a novel prognostic biomarker for the patients after surgical resection. PMID:26793002

  10. Emerging role of Hpo signaling and YAP in hepatocellular carcinoma

    PubMed Central

    Valero, Vicente; Pawlik, Timothy M; Anders, Robert A

    2015-01-01

    Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most common cause of cancer-related mortality worldwide. Due to the poor prognosis and limited therapeutic options, there is great interest in further understanding better the molecular underpinnings and potential molecular targets associated with HCC. The Hippo (Hpo) signaling pathway and YAP, its principal downstream effector, represent an innovative area of research in HCC. Pioneered in Drosophila melanogaster, the Hpo cascade controls tissue homeostasis including organ size, cell proliferation, apoptosis, as well as cell-cycle regulation and differentiation. This conserved kinase cascade in mammals depends on central control by the tumor suppressor mammalian sterile 20-like kinase 1/2 (Mst1/2). The Mst1/2 commences the downstream kinase cascade, ultimately activating the oncoprotein YAP and allowing its physical association with downstream targets to enhance the gene expression signatures that are involved in proliferation and survival. Alterations in YAP expression and defective regulation of other key Hpo pathway members, such as Mst1/2, Salvador, neurofibromatosis and Mer (Nf2/mer), large tumor suppressor homolog 1/2 (Lats1/2), and Mps one binder kinase activator-like 1A and 1B (Mob1) drive carcinogenesis in animal models. The dysregulation of the Hpo pathway – resulting in an unchecked activation of YAP – culminates in the development of a broad range of human tumor types, including HCC. The abrogation of Mst1/2-mediated YAP phosphorylation permits YAP entry into the nucleus in murine models and functions similarly in human HCCs. Chemoresistance mechanisms displayed by HCC tumors occur in a YAP-dependent manner. The HCC specimens exhibit YAP overexpression, and YAP serves as an independent prognostic marker for disease-free survival and overall survival in patients with HCC. Recently, the small molecule inhibitor, verteporfin has been shown to attenuate YAP activity in murine

  11. Lesion in Scalp and Skull as the First Manifestation of Hepatocellular Carcinoma

    PubMed Central

    Vitorino-Araújo, J. L.; Veiga, J. C. E.

    2016-01-01

    Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver and the fifth most common cancer in the world. The lungs, bone, and lymph nodes are frequent sites of metastasis of HCC. The purpose of the present study is show that metastases, although rare, must be among the differential diagnosis of skin lesions and that a diagnostic research based on these findings can be conducted. The authors report a rare case of metastatic hepatocellular injury to the scalp and skull treated by a radical surgical approach. Excision of the lesion in the scalp was performed “en bloc.” The tumor was supplied by the frontal branch of the superficial temporal artery. There are few case reports of metastatic HCC to scalp and skull; treatment of these lesions should be individualized in order to control symptoms, improve quality of life, and promote an increase in survival. PMID:27403358

  12. Hepatocellular carcinoma in a patient with focal nodular hyperplasia

    PubMed Central

    Lowell, Jeffrey A; Hassan, Anjum; Howard, Todd K

    2002-01-01

    Background Focal nodular hyperplasia is an uncommon liver tumour that typically requires no therapeutic intervention. Case outline A 43-year-old woman with a 20-year history of oral contraceptive use presented with symptomatic bilateral liver masses. Biopsy revealed hepatocellular carcinoma in the right hemiliver and focal nodular hyperplasia in the left hemiliver.At operation,the patient was noted to have multiple liver nodules bilaterally, and all intraoperative biopsies were consistent with focal nodular hyperplasia including a biopsy taken from the region that demonstrated carcinoma preoperatively. Because of the earlier biopsy results and the patient's preoperative symptoms, a right hemihepatectomy was performed. Final pathology revealed hepatocellular carcinoma directly adjacent to an area of focal nodular hyperplasia, as well as multiple other areas of hyperplastic liver tumour. Discussion Although focal nodular hyperplasia is believed to be benign, few studies have followed patients with this tumour beyond three years. Longer-term follow-up studies are needed to determine the natural history of focal nodular hyperplasia, potentially focussing on a subset of patients with either diffuse tumours or prolonged oral contraceptive use. PMID:18332941

  13. Detection of the inferred interaction network in hepatocellular carcinoma from EHCO (Encyclopedia of Hepatocellular Carcinoma genes Online)

    PubMed Central

    Hsu, Chun-Nan; Lai, Jin-Mei; Liu, Chia-Hung; Tseng, Huei-Hun; Lin, Chih-Yun; Lin, Kuan-Ting; Yeh, Hsu-Hua; Sung, Ting-Yi; Hsu, Wen-Lian; Su, Li-Jen; Lee, Sheng-An; Chen, Chang-Han; Lee, Gen-Cher; Lee, DT; Shiue, Yow-Ling; Yeh, Chang-Wei; Chang, Chao-Hui; Kao, Cheng-Yan; Huang, Chi-Ying F

    2007-01-01

    Background The significant advances in microarray and proteomics analyses have resulted in an exponential increase in potential new targets and have promised to shed light on the identification of disease markers and cellular pathways. We aim to collect and decipher the HCC-related genes at the systems level. Results Here, we build an integrative platform, the Encyclopedia of Hepatocellular Carcinoma genes Online, dubbed EHCO , to systematically collect, organize and compare the pileup of unsorted HCC-related studies by using natural language processing and softbots. Among the eight gene set collections, ranging across PubMed, SAGE, microarray, and proteomics data, there are 2,906 genes in total; however, more than 77% genes are only included once, suggesting that tremendous efforts need to be exerted to characterize the relationship between HCC and these genes. Of these HCC inventories, protein binding represents the largest proportion (~25%) from Gene Ontology analysis. In fact, many differentially expressed gene sets in EHCO could form interaction networks (e.g. HBV-associated HCC network) by using available human protein-protein interaction datasets. To further highlight the potential new targets in the inferred network from EHCO, we combine comparative genomics and interactomics approaches to analyze 120 evolutionary conserved and overexpressed genes in HCC. 47 out of 120 queries can form a highly interactive network with 18 queries serving as hubs. Conclusion This architectural map may represent the first step toward the attempt to decipher the hepatocarcinogenesis at the systems level. Targeting hubs and/or disruption of the network formation might reveal novel strategy for HCC treatment. PMID:17326819

  14. Liver transplantation for hepatocellular carcinoma beyond the Milan criteria

    PubMed Central

    Xu, Xiao; Lu, Di; Ling, Qi; Wei, Xuyong; Wu, Jian; Zhou, Lin; Yan, Sheng; Wu, Liming; Geng, Lei; Ke, Qinghong; Gao, Feng; Tu, Zhenhua; Wang, Weilin; Zhang, Min; Shen, Yan; Xie, Haiyang; Jiang, Wenshi; Wang, Haibo; Zheng, Shusen

    2016-01-01

    Objective Liver transplantation is an optimal radical therapy for selected patients with hepatocellular carcinoma. The stringent organ allocation system driven by the Milan criteria has been challenged by alternative sets of expanded criteria. Careful analysis is needed to prove that the Milan criteria can be expanded safely and effectively. Design This study collectively reviewed 6012 patients of hepatocellular carcinoma from the China Liver Transplant Registry. Expanded criteria were evaluated to characterise an optimised expansion with acceptable outcomes beyond the Milan criteria. Results Compared with the Milan criteria, Valencia, University of California, San Francisco, University Clinic of Navarra and Hangzhou criteria provided an expansion of 12.4%, 16.3%, 19.6%, and 51.5%, respectively. The post-transplant survivals of patients fulfilling the expanded criteria were comparable to that of the Milan criteria. The analysis of net reclassification improvement and area under the receiver operating characteristic curves showed an excellent efficiency in recurrence prediction for the expanded criteria compared with the Milan criteria. In patients exceeding Milan but fulfilling the Hangzhou criteria (N=1352), α-fetoprotein (AFP) >100 ng/mL and tumour burden>8 cm were the only two independent prognostic factors (p<0.001). Accordingly, the Hangzhou criteria were stratified as type A (tumour burden ≤8 cm, or tumour burden >8 cm but AFP≤100 ng/mL) and type B (tumour burden >8 cm but AFP between 100 and 400 ng/mL). Type A showed significantly higher 5-year tumour-free survival rates compared with type B (p<0.001). Conclusions The Milan criteria can be expanded safely and effectively. The prognostic stratification system based on the Hangzhou criteria serves as a hierarchy of transplant candidates for hepatocellular carcinoma. PMID:25804634

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

    SciTech Connect

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

    2002-08-15

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

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

    PubMed Central

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

    2016-01-01

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

  17. Rhabdomyolysis developing after transcatheter arterial chemoembolization for hepatocellular carcinoma.

    PubMed

    Matake, Kunishige; Tajima, Tsuyoshi; Yoshimitsu, Kengo; Irie, Hiroyuki; Aibe, Hitoshi; Sugitani, Atsushi; Honda, Hiroshi

    2009-11-01

    A 25-year-old man with hepatocellular carcinoma developed severe muscular weakness and pain 15 days after transcatheter arterial chemoembolization (TACE). The diagnosis of rhabdomyolysis was made based on myalgia localized in the bilateral upper extremities (bilateral trapezius, deltoid, biceps brachii, and teres major muscles) on magnetic resonance imaging and increased levels of muscle-derived serum enzymes. In this case, some drugs administered during the clinical course of TACE (diclofenac, famotidine, and cefotiam dihydrochloride) were suspected to be involved in the rhabdomyolysis, but the exact cause of rhabdomyolysis was not identified. The symptoms were completely improved by right trisegmentectomy of the liver following conservative treatment. PMID:19680719

  18. Novel Investigations of Flavonoids as Chemopreventive Agents for Hepatocellular Carcinoma

    PubMed Central

    Liao, Chen-Yi; Lee, Ching-Chang; Tsai, Chi-chang; Hsueh, Chao-Wen; Wang, Chih-Chiang; Chen, I-Hung; Tsai, Ming-Kai; Liu, Mei-Yu; Hsieh, An-Tie; Su, Kuan-Jen; Wu, Hau-Ming; Huang, Shih-Chung; Wang, Yi-Chen; Wang, Chien-Yao; Huang, Shu-Fang; Yeh, Yen-Cheng; Ben, Ren-Jy; Chien, Shang-Tao; Hsu, Chin-Wen; Kuo, Wu-Hsien

    2015-01-01

    We would like to highlight the application of natural products to hepatocellular carcinoma (HCC). We will focus on the natural products known as flavonoids, which target this disease at different stages of hepatocarcinogenesis. In spite of the use of chemotherapy and radiotherapy in treating HCC, patients with HCC still face poor prognosis because of the nature of multidrug resistance and toxicity derived from chemotherapy and radiotherapy. Flavonoids can be found in many vegetables, fruits, and herbal medicines that exert their different anticancer effects via different intracellular signaling pathways and serve as antioxidants. In this review, we will discuss seven common flavonoids that exert different biological effects against HCC via different pathways. PMID:26858957

  19. Clostridium perfringens infection after transarterial chemoembolization for large hepatocellular carcinoma.

    PubMed

    Li, Jing-Huan; Yao, Rong-Rong; Shen, Hu-Jia; Zhang, Lan; Xie, Xiao-Ying; Chen, Rong-Xin; Wang, Yan-Hong; Ren, Zheng-Gang

    2015-04-14

    We report an unusual case of Clostridium perfringens liver abscess formation after transcatheter arterial chemoembolization (TACE) for large hepatocellular carcinoma. Severe deterioration in liver and renal function accompanied with hemocytolysis was found on the 2(nd) day after TACE. Blood culture found Clostridium perfringens and abdominal computed tomography revealed a gas-containing abscess in the liver. Following antibiotics administration and support care, the infection was controlled and the liver and renal function turned normal. The 2(nd) TACE procedure was performed 1.5 mo later and no recurrent Clostridium perfringens infection was found. PMID:25892893

  20. 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

  1. Clinical implications for imaging of vascular invasion in hepatocellular carcinoma.

    PubMed

    Baheti, Akshay D; Dunham, Gregor M; Ingraham, Christopher R; Moshiri, Mariam; Lall, Chandana; Park, James O; Li, David; Katz, Douglas S; Madoff, David C; Bhargava, Puneet

    2016-09-01

    Hepatocellular carcinoma (HCC) is the second largest cause of cancer mortality in the world, with vascular invasion being one of the most important prognostic factors. HCC with tumor thrombus was traditionally considered to have very limited treatment options. However, multiple promising treatment strategies have emerged in recent years, with diagnostic and interventional radiologists playing a major role in patient management. We provide a comprehensive update on the diagnosis and management of HCC with vascular invasion and the role of the radiologist in this condition. PMID:27142384

  2. Portal vein involvement in hepatocellular carcinoma: dynamic CT features

    SciTech Connect

    Mathieu, D.; Grenier, P.; Larde, D.; Vasile, N.

    1984-07-01

    The authors conducted a retrospective examination of 62 hepatocellular carcinomas, taking dynamic CT scans of selected sections after an intravenous contrast bolus. The proximal portal vein was involved in 40% of cases and distal segment in 16%. Angiographic correlation was available in 23 patients. The characteristic appearance of tumor within the portal vein was noted in many cases; in others, distinction between tumor and bland thrombus could not be made. Peripheral portal vein obstruction was suggested when a small, hypervascular tumor became hypodense during the portal phase of CT. The frequency and significance of these CT signs of portal vein involvement are discussed.

  3. Clostridium perfringens infection after transarterial chemoembolization for large hepatocellular carcinoma

    PubMed Central

    Li, Jing-Huan; Yao, Rong-Rong; Shen, Hu-Jia; Zhang, Lan; Xie, Xiao-Ying; Chen, Rong-Xin; Wang, Yan-Hong; Ren, Zheng-Gang

    2015-01-01

    We report an unusual case of Clostridium perfringens liver abscess formation after transcatheter arterial chemoembolization (TACE) for large hepatocellular carcinoma. Severe deterioration in liver and renal function accompanied with hemocytolysis was found on the 2nd day after TACE. Blood culture found Clostridium perfringens and abdominal computed tomography revealed a gas-containing abscess in the liver. Following antibiotics administration and support care, the infection was controlled and the liver and renal function turned normal. The 2nd TACE procedure was performed 1.5 mo later and no recurrent Clostridium perfringens infection was found. PMID:25892893

  4. Combining Locoregional Therapies in the Treatment of Hepatocellular Carcinoma

    PubMed Central

    Higgins, Mikhail C. S. S.; Soulen, Michael C.

    2013-01-01

    In an effort to promote more durable local control of larger lesions, thermal ablation has been combined with chemical ablative techniques and with vaso-occlusive procedures such as chemoembolization and bland embolization in an effort to mitigate the limitations inherent in the use of any single treatment for hepatocellular carcinoma (HCC) >3 cm. The heat-sink effect is the underlying principle for combining vaso-occlusive therapies with ablative techniques. Combination therapies do present viable options for abrogating tumor progression and potentially downsizing tumors to facilitate transplant. We discuss the two most commonly used combination locoregional therapies by the interventionalist and the evidence defining the best techniques in practice. PMID:24436520

  5. Hepatocellular carcinoma: Surgeon's view on latest findings and future perspectives

    PubMed Central

    Slotta, Jan Erik; Kollmar, Otto; Ellenrieder, Volker; Ghadimi, B Michael; Homayounfar, Kia

    2015-01-01

    Hepatocellular carcinoma (HCC) is the most common liver-derived malignancy with a high fatality rate. Risk factors for the development of HCC have been identified and are clearly described. However, due to the lack of tumor-specific symptoms, HCC are diagnosed at progressed tumor stages in most patients, and thus curative therapeutic options are limited. The focus of this review is on surgical therapeutic options which can be offered to patients with HCC with special regard to recent findings, not exclusively focused on surgical therapy, but also to other treatment modalities. Further, potential promising future perspectives for the treatment of HCC are discussed. PMID:26019733

  6. Hepatocellular carcinoma and the risk of occupational exposure.

    PubMed

    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

    2016-05-01

    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

  7. Induction of hepatocellular carcinoma in nonhuman primates by chemical carcinogens

    SciTech Connect

    Adamson, R.H. )

    1989-01-01

    Several compounds were evaluated in nonhuman primates for their potential to induce neoplasms, especially hepatocellular carcinoma (HCC). The compounds can be classified into three groups: food contaminants, model rodent carcinogens, and nitrosamines. All three compounds in the food contaminants group, namely, aflatoxin B1, sterigmatocystin, and methylazoxymethanol acetate, induced HCC. None of the model rodent carcinogens tested consistently induced HCC in rhesus and cynomolgus monkeys. Three of four nitrosamines evaluated induced HCC in rhesus and cynomolgus monkeys. One nitrosamine, diethylnitrosamine, is a predictable and potent inducer of HCC and is useful for establishment of a nonhuman primate model for numerous oncologic studies.

  8. Irreversible Electroporation in the Treatment of Hepatocellular Carcinoma.

    PubMed

    Lencioni, Riccardo; Crocetti, Laura; Narayanan, Govindarajan

    2015-09-01

    Irreversible electroporation (IRE) is a new nonthermal ablation modality that can be used to treat primary and metastatic lesions in the liver. This article describes the way IRE works, reviews safety and efficacy data, and presents strategies and recommendations for its use in everyday practice. In a series of liver lesions of various histologies, initial success was 100%; local recurrence rates were greater in larger lesions. In another series of hepatocellular carcinoma only, there was a 79% complete response rate overall and 93% in lesions less than 3 cm. Safety is comparable with those of other ablation modalities. IRE has advantages over other ablation modalities with comparable success rates. PMID:26365542

  9. Identification of specific protein markers in microdissected hepatocellular carcinoma.

    PubMed

    Melle, Christian; Ernst, Günther; Scheibner, Olaf; Kaufmann, Roland; Schimmel, Bettina; Bleul, Annett; Settmacher, Utz; Hommann, Merten; Claussen, Uwe; von Eggeling, Ferdinand

    2007-01-01

    At present, the molecular mechanisms of hepatocellular carcinogenesis are not well-understood, and hepatocellular carcinoma (HCC) stays one of the most frequent and high-risk metastatic visceral neoplasms worldwide. For the identification of tumor-relevant proteins, we analyzed microdissected cells from nontumorous liver tissue (n = 28) and tissue derived from hepatic tumor center (n = 25), as well as tumor margin (n = 23). We unequivocally identified 53 proteins from hepatic tumor tissues by peptide fingerprint mapping and SELDI mass spectrometry that were separated using two-dimensional gel electrophoresis. Among a number of signals that were detected as significantly different in the protein profiling analysis, we identified for the first time ferritin light subunit (FLS) and adenylate kinase 3 alpha-like 1 (AK3), showing decreased expressions in hepatic tumor, as well as biliverdin reductase B (BVRB) that was upregulated in HCC. The use of ProteinChip technology in combination with tissue microdissection gives insight of the complex changes occurring at the protein level in hepatocellular cancer associated with tumor development and progression and resulted in three new potential diagnostically useful markers. PMID:17203974

  10. 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

  11. Acetylcarnitine Is a Candidate Diagnostic and Prognostic Biomarker of Hepatocellular Carcinoma.

    PubMed

    Lu, Yonghai; Li, Ning; Gao, Liang; Xu, Yong-Jiang; Huang, Chong; Yu, Kangkang; Ling, Qingxia; Cheng, Qi; Chen, Shengsen; Zhu, Mengqi; Fang, Jinling; Chen, Mingquan; Ong, Choon Nam

    2016-05-15

    The identification of serum biomarkers to improve the diagnosis and prognosis of hepatocellular carcinoma has been elusive to date. In this study, we took a mass spectroscopic approach to characterize metabolic features of the liver in hepatocellular carcinoma patients to discover more sensitive and specific biomarkers for diagnosis and progression. Global metabolic profiling of 50 pairs of matched liver tissue samples from hepatocellular carcinoma patients was performed. A series of 62 metabolites were found to be altered significantly in liver tumors; however, levels of acetylcarnitine correlated most strongly with tumor grade and could discriminate between hepatocellular carcinoma tumors and matched normal tissues. Post hoc analysis to evaluate serum diagnosis and progression potential further confirmed the diagnostic capability of serum acetylcarnitine. Finally, an external validation in an independent batch of 58 serum samples (18 hepatocellular carcinoma patients, 20 liver cirrhosis patients, and 20 healthy individuals) verified that serum acetylcarnitine was a meaningful biomarker reflecting hepatocellular carcinoma diagnosis and progression. These findings present a strong new candidate biomarker for hepatocellular carcinoma with potentially significant diagnostic and prognostic capabilities. Cancer Res; 76(10); 2912-20. ©2016 AACR. PMID:26976432

  12. Control of oxidative stress in hepatocellular carcinoma: Helpful or harmful?

    PubMed Central

    Takaki, Akinobu; Yamamoto, Kazuhide

    2015-01-01

    Oxidative stress is becoming recognized as a key factor in the progression of chronic liver disease (CLD) and hepatocarcinogenesis. The metabolically important liver is a major reservoir of mitochondria that serve as sources of reactive oxygen species, which are apparently responsible for the initiation of necroinflammation. As a result, CLD could be a major inducer of oxidative stress. Chronic hepatitis C is a powerful generator of oxidative stress, causing a high rate of hepatocarcinogenesis among patients with cirrhosis. Non-alcoholic steatohepatitis is also associated with oxidative stress although its hepatocarcinogenic potential is lower than that of chronic hepatitis C. Analyses of serum markers and histological findings have shown that hepatocellular carcinoma correlates with oxidative stress and experimental data indicate that oxidative stress increases the likelihood of developing hepatocarcinogenesis. However, the results of antioxidant therapy have not been favorable. Physiological oxidative stress is a necessary biological response, and thus adequate control of oxidative stress and a balance between oxidative and anti-oxidative responses is important. Several agents including metformin and L-carnitine can reportedly control mechanistic oxidative stress. This study reviews the importance of oxidative stress in hepatocarcinogenesis and of control strategies for the optimal survival of patients with CLD and hepatocellular carcinoma. PMID:25954479

  13. Recombinant lipoproteins reinforce cytotoxicity of doxorubicin to hepatocellular carcinoma.

    PubMed

    Wang, Baolong; Yuan, Yuan; Han, Lei; Ye, Li; Shi, Xunlong; Feng, Meiqing

    2014-01-01

    Cancer nanotherapeutics are changing the landscape of tumor treatment and used to circumvent limitations of conventional chemotherapy, such as non-specificity and low bioavailability. Reconstituted high density lipoproteins (rHDL) system is one of the most promising targeting delivery systems of chemotherapeutic drugs toward tumors. Here, we developed recombined high-density lipoprotein which can be functionalized to deliver doxorubicin intracellular with a higher efficiency. The cellular viability assay showed that the rHDL/Dox nanovectors had an enhanced efficiency in inhibiting the cell viability of hepatocellular carcinoma cell lines HepG2 and SMMC-7721. FACS and confocal microscopy was used to observe the doxorubicin delivery into cancer cells. Intracellular drug accumulation analysis confirmed that treatment of rHDL/Dox nanovectors resulted in higher intracellular doxorubicin concentration to the levels exceeding that of free drug. On the premise of efficient drug delivery, rHDL/Dox nanovectors have been preliminarily demonstrated effective inducing of cytotoxic effect and cell apoptosis to both of the cell lines in vitro. Tissue distribution experiment showed that rHDL/Dox nanovectors could also deliver doxorubicin to liver effectively. So, we proposed that this lipoprotein-based strategy holds promise for a safer and more efficient delivery of chemotherapeutic agents in the treatment of hepatocellular carcinoma. PMID:24093636

  14. Hepatocellular Carcinoma: Novel Molecular Targets in Carcinogenesis for Future Therapies

    PubMed Central

    Bertino, Gaetano; Demma, Shirin; Ardiri, Annalisa; Proiti, Maria; Gruttadauria, Salvatore; Toro, Adriana; Malaguarnera, Giulia; Bertino, Nicoletta; Malaguarnera, Michele; Malaguarnera, Mariano; Di Carlo, Isidoro

    2014-01-01

    Background. Hepatocellular carcinoma is one of the most common and lethal malignant tumors worldwide. Over the past 15 years, the incidence of HCC has more than doubled. Due to late diagnosis and/or advanced underlying liver cirrhosis, only limited treatment options with marginal clinical benefit are available in up to 70% of patients. During the last decades, no effective conventional cytotoxic systemic therapy was available contributing to the dismal prognosis in patients with HCC. A better knowledge of molecular hepatocarcinogenesis provides today the opportunity for targeted therapy. Materials and Methods. A search of the literature was made using cancer literature, the PubMed, Scopus, and Web of Science (WOS) database for the following keywords: “hepatocellular carcinoma,” “molecular hepatocarcinogenesis,” “targeted therapy,” and “immunotherapy.” Discussion and Conclusion. Treatment decisions are complex and dependent upon tumor staging, presence of portal hypertension, and the underlying degree of liver dysfunction. The knowledge of molecular hepatocarcinogenesis broadened the horizon for patients with advanced HCC. During the last years, several molecular targeted agents have been evaluated in clinical trials in advanced HCC. In the future, new therapeutic options will be represented by a blend of immunotherapy-like vaccines and T-cell modulators, supplemented by molecularly targeted inhibitors of tumor signaling pathways. PMID:25089265

  15. Targeted disruption of fibrinogen like protein-1 accelerates hepatocellular carcinoma development

    SciTech Connect

    Nayeb-Hashemi, Hamed; Desai, Anal; Demchev, Valeriy; Bronson, Roderick T.; Hornick, Jason L.; Cohen, David E.; Ukomadu, Chinweike

    2015-09-18

    Fibrinogen like protein-1 (Fgl1) is a predominantly liver expressed protein that has been implicated as both a hepatoprotectant and a hepatocyte mitogen. Fgl1 expression is decreased in hepatocellular carcinoma (HCC) and its loss correlates with a poorly differentiated phenotype. To better elucidate the role of Fgl1 in hepatocarcinogenesis, we treated mice wild type or null for Fgl1 with diethyl nitrosamine and monitored for incidence of hepatocellular cancer. We find that mice lacking Fgl1 develop HCC at more than twice the rate of wild type mice. We show that hepatocellular cancers from Fgl1 null mice are molecularly distinct from those of the wild type mice. In tumors from Fgl1 null mice there is enhanced activation of Akt and downstream targets of the mammalian target of rapamycin (mTOR). In addition, there is paradoxical up regulation of putative hepatocellular cancer tumor suppressors; tripartite motif-containing protein 35 (Trim35) and tumor necrosis factor super family 10b (Tnfrsf10b). Taken together, these findings suggest that Fgl1 acts as a tumor suppressor in hepatocellular cancer through an Akt dependent mechanism and supports its role as a potential therapeutic target in HCC. - Highlights: • Fgl1 knockout mice (Fgl1KO) are more prone to carcinogen-induced liver cancer compared to wild type (WT) mates. • Tumors from the Fgl1KO are molecularly distinct with enhanced Akt and mTOR activity in comparison with Fgl1WT tumors. • Tumors from the Fgl1KO have enhanced expression of Trim35 and Tnfrsf10b, putative HCC tumor suppressors.

  16. Evaluation of hepatocellular carcinoma aggressiveness by a panel of extracellular matrix antigens.

    PubMed Central

    Grigioni, W. F.; Garbisa, S.; D'Errico, A.; Baccarini, P.; Stetler-Stevenson, W. G.; Liotta, L. A.; Mancini, A. M.

    1991-01-01

    Invasion and metastasis requires a series of interactions between malignant cells and the extracellular matrix (ECM). Antigen markers that relate to these interactions were evaluated for prognostic correlation in human hepatocellular carcinoma. Basement membrane type IV collagen (cIV), type IV collagenase (cIVase), laminin, and laminin receptors (LRs)--all ECM antigens previously proposed to be modulated in association with tumor aggressiveness--were immunohistochemically investigated in 30 cases of hepatocellular carcinomas (HCCs). The pattern of antigen expression was correlated with 1) 36 months' clinical follow-up and 2) the pathologic grade. As a means of estimating the proliferation fraction, an additional antigen, Ki67, was also studied in this series. There were major differences in the distribution of cIV and laminin, and in the quantity of cIVase-, LR-, and Ki67-positive cells associated with grade and prognosis. A smaller quantity of cIV and laminin and a higher number of cIVase-, LR-, and Ki67-positive cells were detected in the poorly differentiated compared with the well-differentiated HCCs. The tumors with lower immunoreactivity for cIV and laminin components accompanied by a higher number of cIVase-, LR-, and Ki67-positive cells fall into a group with the poorest overall survival (P less than 0.006). The panel of antigens is proposed as a useful prognostic tool for evaluating HCC tumor aggressiveness. Images Figure 2 Figure 3 Figure 4 PMID:1848041

  17. Recurrence of hepatocellular carcinoma with rapid growth after spontaneous regression

    PubMed Central

    Nakajima, Tomoki; Moriguchi, Michihisa; Watanabe, Tadashi; Noda, Masao; Fuji, Nobuaki; Minami, Masahito; Itoh, Yoshito; Okanoue, Takeshi

    2004-01-01

    We report an 80-year-old man who presented with sponta- neous regression of hepatocellular carcinoma (HCC). He complained of sudden right flank pain and low-grade fever. The level of protein induced by vitamin K antagonist (PIVKA)-II was 1137 mAU/mL. A computed tomography scan in November 2000 demonstrated a low-density mass located in liver S4 with marginal enhancement and a cystic mass of 68 mm × 55 mm in liver S6, with slightly high density content and without marginal enhancement. Angiography revealed that the tumor in S4 with a size of 25 mm × 20 mm was a typical hypervascular HCC, and transarterial chemoembolization was performed. However, the tumor in S6 was hypovascular and atypical of HCC, and thus no therapy was given. In December 2000, the cystic mass regressed spontaneously to 57 mm × 44 mm, and aspiration cytology revealed bloody fluid, and the mass was diagnosed cytologically as class I. The tumor in S4 was treated successfully with a 5 mm margin of safety around it. The PIVKA-II level normalized in February 2001. In July 2001, the tumor regressed further but presented with an enhanced area at the posterior margin. In November 2001, the enhanced area extended, and a biopsy revealed well-differentiated HCC, although the previous tumor in S4 disappeared. Angiography demonstrated two tumor stains, one was in S6, which was previously hypovascular, and the other was in S8. Subsequently, the PIVKA-II level started to rise with the doubling time of 2-3 wk, and the tumor grew rapidly despite repeated transarterial embolization with gel foam. In February 2003, the patient died of bleeding into the peritoneal cavity from the tumor that occupied almost the entire right lobe. Considering the acute onset of the symptoms, we speculate that local ischemia possibly due to rapid tumor growth, resulted in intratumoral bleeding and/or hemorrhagic necrosis, and finally spontaneous regression of the initial tumor in S6. PMID:15484326

  18. Altered expression of AT-rich interactive domain 1A in hepatocellular carcinoma.

    PubMed

    Abe, Hiroyuki; Hayashi, Akimasa; Kunita, Akiko; Sakamoto, Yoshihiro; Hasegawa, Kiyoshi; Shibahara, Junji; Kokudo, Norihiro; Fukayama, Masashi

    2015-01-01

    AT-rich interactive domain 1A (ARID1A) is a subunit of the Switch/Sucrose non-fermentable (SWI/SNF) chromatin remodeling complex. Recently, genome-wide whole exome sequencing revealed frequent mutations of ARID1A in hepatocellular carcinoma, but clinicopathological significance of ARID1A alteration has not been clarified yet. In this study, expression of ARID1A was investigated immunohistochemically in 290 cases of hepatocellular carcinomas. In the evaluation of tissue microarrays, cases of ARID1A alteration (63 total cases, 21.7%) consisted of 11 (3.8%) cases showing loss of expression and 52 (17.9%) with weak expression. Alteration of ARID1A was correlated with larger tumor size (P=0.034) and well or moderate differentiation of tumor histology (P=0.035). There was no significant correlation with age, sex, cirrhosis, TNM stage, tumor size, number of tumors, vascular invasion, patient survival, HBV infection, HCV infection, heavy use of alcohol, nor diabetes mellitus. EBER in situ hybridization was negative in all 11 cases with loss of ARID1A. Altered expression of ARID1A was inversely correlated with nuclear expression of p53 (P=0.018) or beta-catenin (P=0.025). There was some heterogeneity of ARID1A alteration within each case, and immunohistochemistry of the whole sections demonstrated that four of 11 cases with loss of ARID1A in TMA analysis showed localized positive area within the tumor. Alteration of ARID1A may accelerate tumor growth in a subset of hepatocellular carcinoma, and this pathway may be distinct from p53 and beta-catenin pathways. PMID:26045782

  19. Hepatocellular carcinoma in ground squirrels persistently infected with ground squirrel hepatitis virus.

    PubMed Central

    Marion, P L; Van Davelaar, M J; Knight, S S; Salazar, F H; Garcia, G; Popper, H; Robinson, W S

    1986-01-01

    Although persistent infection with hepatitis B virus and woodchuck hepatitis virus has been associated with development of hepatocellular carcinoma in the host, little has been known of such an association with ground squirrel hepatitis virus (GSHV), which is closely related to the woodchuck virus. Colonies of GSHV-infected and -uninfected Beechey ground squirrels were observed for tumors for a period of 5 years. Tumors developed in seven squirrels after a minimum of 2.4 years of observation per animal; each of the seven animals was over 4 years old when the tumor was detected. The predominant type of tumor was hepatocellular carcinoma, which appeared in 2 of 28 GSHV-bearing animals studied and in 1 of 23 squirrels with antibody to the virus. No hepatocellular carcinoma appeared in 24 GSHV marker-free squirrels. Integrated GSHV DNA was found in the hepatocellular carcinoma tissue of the one carrier animal examined, paralleling the frequent findings of integrated hepatitis B and woodchuck hepatitis viral DNA in human and woodchuck hepatocellular carcinoma. Although the incidence of liver carcinoma reported here in carrier ground squirrels is neither as great as that in carrier woodchucks nor statistically different from the incidence in noncarrier squirrels, the data presented suggest that persistent infection with GSHV may also be associated with hepatocellular carcinoma. Images PMID:3012572

  20. 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. PMID:26459734

  1. Fulminant hepatitis in a patient with hepatocellular carcinoma related to nonalcoholic steatohepatitis treated with sorafenib.

    PubMed

    Brandi, Giovanni; De Lorenzo, Stefania; Di Girolamo, Stefania; Bellentani, Stefano; Saccoccio, Gioconda; Biasco, Guido

    2015-01-01

    We describe a case of acute liver failure in a patient with advanced hepatocellular carcinoma related to nonalcoholic steatohepatitis during sorafenib treatment. A 74-year-old man with diabetes mellitus and hypertension was diagnosed with hepatocellular carcinoma associated with fatty liver. Three weeks after sorafenib therapy, at Eastern Cooperative Oncology Group performance status 3, he developed jaundice, general weakness, flapping tremor, nausea, and anorexia. Sorafenib was stopped: laboratory tests showed a relevant elevation of transaminases suggesting diagnosis of acute hepatitis. During hospital admission, the patient died of liver failure. Sorafenib is the first successful target therapy effective for advanced hepatocellular carcinoma. The most common adverse events are fatigue, hand-foot skin reaction, skin rash/desquamation, diarrhea, and hypertension, whereas liver dysfunction is uncommon. To our knowledge, this is the first patient reported in the literature with hepatocellular carcinoma related to nonalcoholic steatohepatitis who died of rapid worsening of liver function during sorafenib treatment. PMID:25702656

  2. Ultrasound guided fine needle biopsy of early hepatocellular carcinoma complicating liver cirrhosis: a multicentre study

    PubMed Central

    Caturelli, E; Solmi, L; Anti, M; Fusilli, S; Roselli, P; Andriulli, A; Fornari, F; Del Vecchio Blanco, C; de Sio, I

    2004-01-01

    Background: Because hepatic cirrhosis is a major risk factor for hepatocellular carcinoma, recent guidelines by the European Association for the Study of the Liver (EASL) on clinical management of hepatocellular carcinoma recommend periodic ultrasound surveillance of cirrhotic patients with immediate workup for nodules >1 cm; an increase in the frequency of screening is considered sufficient for smaller lesions. Aims: To determine the actual risk of hepatocellular carcinoma associated with the latter lesions and to assess the role of ultrasound guided-fine needle biopsy in their diagnosis Patients and methods: Data were analysed for 294 new nodular lesions <20 mm, including 48 that were <10 mm, detected during a prospective multicentre study involving ultrasound surveillance of 4375 patients with hepatic cirrhosis. In the absence of α fetoprotein (AFP) levels diagnostic of hepatocellular carcinoma, ultrasound guided-fine needle biopsy was performed (n = 274). AFP and fine needle biopsy diagnoses of malignancies (hepatocellular carcinoma and lymphoma) were considered definitive. Non-malignant fine needle biopsy diagnoses (dysplastic or regenerative nodule) were verified by a second imaging study. Diagnoses of hepatocellular carcinoma based on this study were considered definitive; non-malignant imaging diagnoses were considered definitive after at least one year of clinical and ultrasound follow up. Results: Overall, 258/294 (87.6%) nodules proved to be hepatocellular carcinoma, including 33/48 (68.7%) of those ⩽10 mm. Overall typing accuracy of ultrasound guided-fine needle biopsy was 89.4%, and 88.6% for lesions ⩽10 mm. Conclusions: In a screening population, well over half of very small nodules arising in cirrhotic livers may prove to be hepatocellular carcinoma, and approximately 90% of these malignancies can be reliably identified with ultrasound guided-fine needle biopsy. PMID:15306600

  3. Targeted Delivery of Peptide-Tagged DNA Lipoplexes to Hepatocellular Carcinoma Cells.

    PubMed

    Ariatti, Mario

    2016-01-01

    The application of homing peptides to direct DNA and RNA lipoplexes to target cells is a rapidly evolving area of study, which may find application in corrective gene therapy for the treatment of neoplasms and other disorders of a genetic origin. Here, a step-wise account of the assembly and characterization of hepatocellular carcinoma cell-specific DNA lipoplexes and their cytotoxicity assessment in and delivery to the human hepatocellular carcinoma cell line HepG2 is given. PMID:27436315

  4. Recent insights on risk factors of hepatocellular carcinoma

    PubMed Central

    Abdel-Hamid, Nabil Mohie

    2009-01-01

    Hepatocellular carcinoma (HCC) is a disease prevalent in many populations worldwide. It initiates many economic and health problems in management modalities and leads to increasing mortality rates. Worldwide, trials have attempted to discover specific early markers for detection and prediction of the disease, hoping to set a more precise strategy for liver cancer prevention. Unfortunately, many economic, cultural and disciplinary levels contribute to confounding preventive strategies. Many risk factors contribute to predisposition to HCC, which can present individually or simultaneously. Previous articles discussed many risk factors for hepatocellular carcinogenesis; however, most of them didn't consider collectively the most recent data relating to causes. In this article, the pathogenesis and risk factors of HCC are discussed. Most of the intermediary steps of HCC involve molecular and transcriptional events leading to hepatocyte malignant transformation. These steps are mainly triggered by hepatitis B, C or transfusion-transmitted virus, either alone, or with other factors. Diabetes seems to be a major contributing risk factor. Schistosomiasis, a blood infestation, mostly affects Nile basin inhabitants leading to bladder, renal and hepatic cancers. Alcoholism, food and water pollutants and some drugs can also lead to HCC. Additionally, some hereditary diseases, as hemochromatosis, α-1-antitrypsin deficiency and tyrosinaemia are known to lead to the development of HCC, if not well managed. PMID:21160959

  5. Genome-wide DNA Methylation Profiles in Hepatocellular Carcinoma

    PubMed Central

    Shen, Jing; Wang, Shuang; Zhang, Yu-Jing; Kappil, Maya; Wu, Hui-Chen; Kibriya, Muhammad G.; Wang, Qiao; Jasmine, Farzana; Ahsan, Habib; Lee, Po-Huang; Yu, Ming-Whei; Chen, Chien-Jen; Santella, Regina M.

    2012-01-01

    Alterations in DNA methylation frequently occur in hepatocellular cancer (HCC). We have previously demonstrated that hypermethylation in candidate genes can be detected in plasma DNA prior to HCC diagnosis. To identify with a genome-wide approach additional genes hypermethylated in HCC that could be used for more accurate analysis of plasma DNA for early diagnosis, we analyzed tumor and adjacent non-tumor tissues from 62 Taiwanese HCC cases using Illumina methylation arrays that screen 26,486 autosomal CpG sites. After Bonferroni adjustment, a total of 2,324 CpG sites significantly differed in methylation level, with 684 CpG sites significantly hypermethylated and 1,640 hypomethylated in tumor compared to non-tumor tissues. Array data were validated with pyrosequencing in a subset of 5 of these genes; correlation coefficients ranged from 0.92 to 0.97. Analysis of plasma DNA from 38 cases demonstrated that 37% to 63% of cases had detectable hypermethylated DNA (≥5% methylation) for these 5 genes individually. At least one of these genes was hypermethylated in 87% of cases, suggesting that measurement of DNA methylation in plasma samples is feasible. The panel of methylated genes indentified in the current study will be further tested in large cohort of prospectively collected samples to determine their utility as early biomarkers of hepatocellular carcinoma. PMID:22234943

  6. Progress in systemic therapy of advanced hepatocellular carcinoma

    PubMed Central

    Gong, Xin-Lei; Qin, Shu-Kui

    2016-01-01

    Primary liver cancer, mainly consisting of hepatocellular carcinoma (HCC), is one of common malignancies worldwide, and prevalent among the Chinese population. A diagnosis of early stage HCC has proven to be very difficult because of its insidious feature in onset and development. At the time of diagnosis, most HCC cases are locally advanced and/or distant metastatic, which results in difficulty to be treated and poor prognosis. For advanced HCC, systemic therapy is frequently adopted as an important palliative method. In recent years, clinical studies and observations have often reported about systemic anti-cancer therapy of advanced HCC, including molecular target therapy, systemic chemotherapy and immunotherapy. In this article, we review these treatment modalities to provide a reference for clinicians. PMID:27547002

  7. MRI Features of Hepatocellular Carcinoma Related to Biologic Behavior

    PubMed Central

    Cho, Eun-Suk

    2015-01-01

    Imaging studies including magnetic resonance imaging (MRI) play a crucial role in the diagnosis and staging of hepatocellular carcinoma (HCC). Several recent studies reveal a large number of MRI features related to the prognosis of HCC. In this review, we discuss various MRI features of HCC and their implications for the diagnosis and prognosis as imaging biomarkers. As a whole, the favorable MRI findings of HCC are small size, encapsulation, intralesional fat, high apparent diffusion coefficient (ADC) value, and smooth margins or hyperintensity on the hepatobiliary phase of gadoxetic acid-enhanced MRI. Unfavorable findings include large size, multifocality, low ADC value, non-smooth margins or hypointensity on hepatobiliary phase images. MRI findings are potential imaging biomarkers in patients with HCC. PMID:25995679

  8. MRI features of hepatocellular carcinoma related to biologic behavior.

    PubMed

    Cho, Eun-Suk; Choi, Jin-Young

    2015-01-01

    Imaging studies including magnetic resonance imaging (MRI) play a crucial role in the diagnosis and staging of hepatocellular carcinoma (HCC). Several recent studies reveal a large number of MRI features related to the prognosis of HCC. In this review, we discuss various MRI features of HCC and their implications for the diagnosis and prognosis as imaging biomarkers. As a whole, the favorable MRI findings of HCC are small size, encapsulation, intralesional fat, high apparent diffusion coefficient (ADC) value, and smooth margins or hyperintensity on the hepatobiliary phase of gadoxetic acid-enhanced MRI. Unfavorable findings include large size, multifocality, low ADC value, non-smooth margins or hypointensity on hepatobiliary phase images. MRI findings are potential imaging biomarkers in patients with HCC. PMID:25995679

  9. 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

  10. Proteomic and metabonomic biomarkers for hepatocellular carcinoma: a comprehensive review

    PubMed Central

    Kimhofer, T; Fye, H; Taylor-Robinson, S; Thursz, M; Holmes, E

    2015-01-01

    Hepatocellular carcinoma (HCC) ranks third in overall global cancer-related mortality. Symptomatic presentation often means advanced disease where potentially curative treatment options become very limited. Numerous international guidelines propose the routine monitoring of those with the highest risk factors for the condition in order to diagnose potential tumourigenesis early. To aid this, the fields of metabonomic- and proteomic-based biomarker discovery have applied advanced tools to identify early changes in protein and metabolite expression in HCC patients vs controls. With robust validation, it is anticipated that from these candidates will rise a high-performance non-invasive test able to diagnose early HCC and related conditions. This review gathers the numerous markers proposed by studies using mass spectrometry and proton nuclear magnetic resonance spectroscopy and evaluates areas of consistency as well as discordance. PMID:25826224

  11. Proteomic and metabonomic biomarkers for hepatocellular carcinoma: a comprehensive review.

    PubMed

    Kimhofer, T; Fye, H; Taylor-Robinson, S; Thursz, M; Holmes, E

    2015-03-31

    Hepatocellular carcinoma (HCC) ranks third in overall global cancer-related mortality. Symptomatic presentation often means advanced disease where potentially curative treatment options become very limited. Numerous international guidelines propose the routine monitoring of those with the highest risk factors for the condition in order to diagnose potential tumourigenesis early. To aid this, the fields of metabonomic- and proteomic-based biomarker discovery have applied advanced tools to identify early changes in protein and metabolite expression in HCC patients vs controls. With robust validation, it is anticipated that from these candidates will rise a high-performance non-invasive test able to diagnose early HCC and related conditions. This review gathers the numerous markers proposed by studies using mass spectrometry and proton nuclear magnetic resonance spectroscopy and evaluates areas of consistency as well as discordance. PMID:25826224

  12. Hepatocellular carcinoma in elderly patients: challenges and solutions

    PubMed Central

    Brunot, Angélique; Le Sourd, Samuel; Pracht, Marc; Edeline, Julien

    2016-01-01

    Hepatocellular carcinoma (HCC) is the second most common cause of death by cancer in the world. Due to the delayed HCC development in hepatitis C carriers and nonalcoholic fatty liver disease, the incidence of HCC in the elderly is increasing and is becoming a global health issue. Elderly patients with HCC should be assessed through proper oncologic approach, namely, screening tools for frailty (Geriatric-8 or Vulnerable Elders Survey-13) and comprehensive geriatric assessment. This review of the literature supports the same treatment options for elderly patients as for younger patients, in elderly patients selected as fit following proper oncogeriatric assessment. Unfit patients should be managed through a multidisciplinary team involving both oncological and geriatrician professionals. Specific studies and recommendations for HCC in the elderly should be encouraged. PMID:27574587

  13. A possible predictive marker of progression for hepatocellular carcinoma

    PubMed Central

    DI STASIO, MICHELE; VOLPE, MARIA GRAZIA; COLONNA, GIOVANNI; NAZZARO, MELISSA; POLIMENO, MIRIAM; SCALA, STEFANIA; CASTELLO, GIUSEPPE; COSTANTINI, SUSAN

    2011-01-01

    The correlation between decreased levels of selenium and increased DNA damage and oxidative stress shows the significance of this trace element. A number of studies have provided evidence for lower serum, plasma and tissue levels of selenium in patients with various diseases and types of cancer. In this study, liver selenium concentrations were measured in tissue samples of patients with hepatocellular carcinoma (HCC) by atomic absorption spectrometry. The results showed that the selenium concentrations decreased when the malignant grade increased. Furthermore, a significant correlation was found between selenium levels and human selenium binding protein-1 (SELENBP1) down-regulation in the liver. Therefore, we suggest that the evaluation of selenium and SELENBP1 concentrations can be used for improving the prognosis of HCC. PMID:22848296

  14. DNA markers in molecular diagnostics for hepatocellular carcinoma

    PubMed Central

    Su, Ying-Hsiu; Lin, Selena Y; Song, Wei; Jain, Surbhi

    2015-01-01

    Hepatocellular carcinoma (HCC) is the one of the leading causes of cancer mortality in the world, mainly due to the difficulty of early detection and limited therapeutic options. The implementation of HCC surveillance programs in well-defined, high-risk populations were only able to detect about 40–50% of HCC at curative stages (Barcelona Clinic Liver Cancer stages 0 & 1) due to the low sensitivities of the current screening methods. The advance of sequencing technologies has identified numerous modifications as potential candidate DNA markers for diagnosis/surveillance. Here we aim to provide an overview of the DNA alterations that result in activation of cancer pathways known to potentially drive HCC carcinogenesis and to summarize performance characteristics of each DNA marker in the periphery (blood or urine) for HCC screening. PMID:25098554

  15. Epigenetics in hepatocellular carcinoma: An update and future therapy perspectives

    PubMed Central

    Ma, Li; Chua, Mei-Sze; Andrisani, Ourania; So, Samuel

    2014-01-01

    Hepatocellular carcinoma (HCC), the predominant form of adult liver malignancies, is a global health concern. Its dismal prognosis has prompted recent significant advances in the understanding of its etiology and pathogenesis. The deregulation of epigenetic mechanisms, which maintain heritable gene expression changes and chromatin organization, is implicated in the development of multiple cancers, including HCC. This review summarizes the current knowledge of epigenetic mechanisms in the pathogenesis of HCC, with an emphasis on HCC mediated by chronic hepatitis B virus infection. This review also discusses the encouraging outcomes and lessons learnt from epigenetic therapies for hematological and other solid cancers, and highlights the future potential of similar therapies in the treatment of HCC. PMID:24574704

  16. Isolated duodenal varices as the initial presentation of hepatocellular carcinoma

    PubMed Central

    Okoli, Amara; Raymond, Pascale; Ammannagari, Nischala; Merrell, Nancy

    2013-01-01

    Duodenal varices are an uncommon, life-threatening cause of acute gastrointestinal (GI) bleeding commonly caused by portal hypertension. Though generally regarded as a complication of advanced cirrhosis and portal hypertension, often overlooked is that in about 2.7% of cases, it can be the first presenting symptom of advanced hepatocellular carcinoma (HCC). We report a case of an isolated, duodenal variceal bleeding as the first clinical manifestation of HCC, complicated by portal venous thrombosis. Diagnosis of HCC was established by a markedly elevated α-fetoprotein, hepatitis B surface and core antibody positivity and consistent radiological findings. Although not the first choice, variceal bleeding was successfully arrested with endoclips. The patient thereafter declined further evaluation and unsurprisingly died within a few weeks from a massive GI bleed. An initial bleed from a duodenal varix often confers a poor prognosis. Patients with HCC who present with variceal bleeding reportedly have a median survival of 71 days. PMID:24347452

  17. Hepatitis B virus infection and primary hepatocellular carcinoma.

    PubMed Central

    Feitelson, M

    1992-01-01

    For many years, epidemiological studies have demonstrated a strong link between chronic hepatitis B virus (HBV) infection and the development of primary hepatocellular carcinoma (PHC). Other hepatocarcinogens such as hepatitis C virus and aflatoxin also contribute to hepatocarcinogenesis either in conjunction with HBV infection or alone. Cellular and molecular biological studies are providing explanations for the HBV-PHC relationship, and models are now being formulated to further test the relative importance of various factors such as viral DNA integration, activation of oncogenes, genetic instability, loss of tumor suppressor genes, and trans-activating properties of HBV to the pathogenesis of PHC. Further research will probably define more than a single mechanism whereby chronic HBV infection results in PHC. PMID:1323384

  18. Management of Hepatocellular Carcinoma: Current Status and Future Directions

    PubMed Central

    Au, Jennifer S.; Frenette, Catherine T.

    2015-01-01

    Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide. This cancer commonly arises against a background of chronic liver disease. As a result, a patient with HCC requires multidisciplinary care. Treatment options vary widely based on tumor burden and metastases. The most widely utilized staging system is the Barcelona Clinic Liver Cancer staging system, which recommends treatments based on tumor size and the underlying liver disease and functional status of the patient. Treatment options range from surgical resection or transplantation to locoregional therapies with modalities such as radiofrequency ablation and transarterial chemoembolization to systemic chemotherapies. Future care involves the development of combination therapies that afford the best tumor response, further clarification of the patients best suited for therapies and the development of new oral chemotherapeutic agents. PMID:26087860

  19. Spontaneous Hepatocellular Carcinoma after the Combined Deletion of Akt Isoforms.

    PubMed

    Wang, Qi; Yu, Wan-Ni; Chen, Xinyu; Peng, Xiao-Ding; Jeon, Sang-Min; Birnbaum, Morris J; Guzman, Grace; Hay, Nissim

    2016-04-11

    Akt is frequently hyperactivated in human cancers and is targeted for cancer therapy. However, the physiological consequences of systemic Akt isoform inhibition were not fully explored. We showed that while combined Akt1 and Akt3 deletion in adult mice is tolerated, combined Akt1 and Akt2 deletion induced rapid mortality. Akt2(-/-) mice survived hepatic Akt1 deletion but all developed spontaneous hepatocellular carcinoma (HCC), which is associated with FoxO-dependent liver injury and inflammation. The gene expression signature of HCC-bearing livers is similar to aggressive human HCC. Consistently, neither Akt1(-/-) nor Akt2(-/-) mice are resistant to diethylnitrosamine-induced hepatocarcinogenesis, and Akt2(-/-) mice display a high incidence of lung metastasis. Thus, in contrast to other cancers, hepatic Akt inhibition induces liver injury that could promote HCC. PMID:26996309

  20. Hepatitis-related hepatocellular carcinoma: Insights into cytokine gene polymorphisms.

    PubMed

    Dondeti, Mahmoud Fathy; El-Maadawy, Eman Anwar; Talaat, Roba Mohamed

    2016-08-14

    Hepatocellular carcinoma (HCC) is a primary liver cancer, which is one of the most prevalent cancers among humans. Many factors are involved in the liver carcinogenesis as lifestyle and environmental factors. Hepatitis virus infections are now recognized as the chief etiology of HCC; however, the precise mechanism is still enigmatic till now. The inflammation triggered by the cytokine-mediated immune response, was reported to be the closest factor of HCC development. Cytokines are immunoregulatory proteins produced by immune cells, functioning as orchestrators of the immune response. Genes of cytokines and their receptors are known to be polymorphic, which give rise to variations in their genes. These variations have a great impact on the expression levels of the secreted cytokines. Therefore, cytokine gene polymorphisms are involved in the molecular mechanisms of several diseases. This piece of work aims to shed much light on the role of cytokine gene polymorphisms as genetic host factor in hepatitis related HCC. PMID:27570418

  1. Hepatocellular carcinoma review: current treatment, and evidence-based medicine.

    PubMed

    Raza, Ali; Sood, Gagan K

    2014-04-21

    Hepatocellular carcinoma (HCC) is the fifth most common tumor worldwide. Multiple treatment options are available for HCC including curative resection, liver transplantation, radiofrequency ablation, trans-arterial chemoembolization, radioembolization and systemic targeted agent like sorafenib. The treatment of HCC depends on the tumor stage, patient performance status and liver function reserve and requires a multidisciplinary approach. In the past few years with significant advances in surgical treatments and locoregional therapies, the short-term survival of HCC has improved but the recurrent disease remains a big problem. The pathogenesis of HCC is a multistep and complex process, wherein angiogenesis plays an important role. For patients with advanced disease, sorafenib is the only approved therapy, but novel systemic molecular targeted agents and their combinations are emerging. This article provides an overview of treatment of early and advanced stage HCC based on our extensive review of relevant literature. PMID:24764650

  2. 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

  3. Immunotherapy in hepatocellular carcinoma: Primed to make a difference?

    PubMed

    Harding, James J; El Dika, Imane; Abou-Alfa, Ghassan K

    2016-02-01

    Advanced hepatocellular carcinoma (HCC) carries a dismal prognosis and the current treatment is limited to sorafenib, an agent with modest benefit. Preclinical data have indicated that several immunologic mechanisms are at play to promote HCC development and growth while impairing effective antitumor immune surveillance. Several novel approaches geared toward manipulating the immune response to HCC have suggested a therapeutic benefit in early-stage clinical trials, indicating a real potential to augment tumor-specific immunity and improve outcomes in patients with this disease. In the current study, the authors reviewed the barriers to an effective immune response against HCC and contemporary clinical investigations that may be "primed" to alter the natural history of HCC. PMID:26540029

  4. Hepatitis-related hepatocellular carcinoma: Insights into cytokine gene polymorphisms

    PubMed Central

    Dondeti, Mahmoud Fathy; El-Maadawy, Eman Anwar; Talaat, Roba Mohamed

    2016-01-01

    Hepatocellular carcinoma (HCC) is a primary liver cancer, which is one of the most prevalent cancers among humans. Many factors are involved in the liver carcinogenesis as lifestyle and environmental factors. Hepatitis virus infections are now recognized as the chief etiology of HCC; however, the precise mechanism is still enigmatic till now. The inflammation triggered by the cytokine-mediated immune response, was reported to be the closest factor of HCC development. Cytokines are immunoregulatory proteins produced by immune cells, functioning as orchestrators of the immune response. Genes of cytokines and their receptors are known to be polymorphic, which give rise to variations in their genes. These variations have a great impact on the expression levels of the secreted cytokines. Therefore, cytokine gene polymorphisms are involved in the molecular mechanisms of several diseases. This piece of work aims to shed much light on the role of cytokine gene polymorphisms as genetic host factor in hepatitis related HCC. PMID:27570418

  5. Hypermethylation reduces the expression of PNPLA7 in hepatocellular carcinoma

    PubMed Central

    ZHANG, XIAOJIAO; ZHANG, JUN; WANG, RUI; GUO, SHICHENG; ZHANG, HUILU; MA, YANYUN; LIU, QINGMEI; CHU, HAIYAN; XU, XIANGHONG; ZHANG, YITONG; YANG, DONGQIN; WANG, JIUCUN; LIU, JIE

    2016-01-01

    Liver cancer has a high morbidity and mortality rate, and is one of the most common types of cancer in men. PNPLA7 is a member of the patatin-like phospholipase domain-containing protein family which is involved in triglyceride hydrolysis, energy metabolism and lipid droplet metabolism. The liver is the most important energy metabolism organ; whether PNPLA7 is deregulated in liver cancer has not been previously reported. In the present study, reverse transcription-quantitative polymerase chain reaction and subsequent methylation analysis provided evidence that PNPLA7 is down-regulated in hepatocellular carcinoma (HCC) cell lines and tissue samples, via the mechanism of transcriptional silencing by promoter hypermethylation. These results may provide novel insights for HCC diagnosis. PMID:27347198

  6. Management before hepatectomy for hepatocellular carcinoma with cirrhosis

    PubMed Central

    Nakayama, Hisashi; Takayama, Tadatoshi

    2015-01-01

    The global distribution of hepatocellular carcinoma (HCC) varies markedly among regions, and patients in East Asia and Central Africa account for about 80% of all cases. The risk factors are hepatitis B, hepatitis C, alcohol, and etc. The risk of carcinogenesis further increases with progression to hepatic cirrhosis in all liver disorders. Radical treatment of HCC by liver resection without causing liver failure has been established as a safe approach through selection of an appropriate range of resection of the damaged liver. This background indicates that both evaluation of hepatic functional reserve and measures against concomitant diseases such as thrombocytopenia accompanying portal hypertension, prevention of rupture of esophageal varices, reliable control of ascites, and improvement of hypoalbuminemia are important issues in liver resection in patients with hepatic cirrhosis. We review the latest information on perioperative management of liver resection in HCC patients with hepatic cirrhosis. PMID:26380653

  7. Development of MicroRNA Therapeutics for Hepatocellular Carcinoma

    PubMed Central

    Aravalli, Rajagopal N.

    2013-01-01

    Hepatocellular carcinoma (HCC) is the most common form of liver cancer and is the third leading cause of cancer-related deaths worldwide. Treatment options for HCC are very limited, as it is often diagnosed at a late stage. Recent studies have demonstrated that microRNAs (miRNAs), a class of non-coding RNAs, are aberrantly expressed in HCC. Some of these were shown to be functionally involved in carcinogenesis and tumor progression, suggesting that miRNAs can serve as novel molecular targets for HCC therapy. Several promising studies have recently demonstrated the therapeutic potential of miRNAs in animal models and in reducing the viral load in hepatitis C patients. In this review, these advances and strategies for modulating miRNAs for in vivo therapeutic delivery and replacement therapy are discussed. PMID:26835673

  8. Hepatocellular carcinoma review: Current treatment, and evidence-based medicine

    PubMed Central

    Raza, Ali; Sood, Gagan K

    2014-01-01

    Hepatocellular carcinoma (HCC) is the fifth most common tumor worldwide. Multiple treatment options are available for HCC including curative resection, liver transplantation, radiofrequency ablation, trans-arterial chemoembolization, radioembolization and systemic targeted agent like sorafenib. The treatment of HCC depends on the tumor stage, patient performance status and liver function reserve and requires a multidisciplinary approach. In the past few years with significant advances in surgical treatments and locoregional therapies, the short-term survival of HCC has improved but the recurrent disease remains a big problem. The pathogenesis of HCC is a multistep and complex process, wherein angiogenesis plays an important role. For patients with advanced disease, sorafenib is the only approved therapy, but novel systemic molecular targeted agents and their combinations are emerging. This article provides an overview of treatment of early and advanced stage HCC based on our extensive review of relevant literature. PMID:24764650

  9. SND1 overexpression deregulates cholesterol homeostasis in hepatocellular carcinoma.

    PubMed

    Navarro-Imaz, Hiart; Rueda, Yuri; Fresnedo, Olatz

    2016-09-01

    SND1 is a multifunctional protein participating, among others, in gene transcription and mRNA metabolism. SND1 is overexpressed in cancer cells and promotes viability and tumourigenicity of hepatocellular carcinoma cells. This study shows that cholesterol synthesis is increased in SND1-overexpressing hepatoma cells. Neither newly synthesised nor extracellularly supplied cholesterol are able to suppress this increase; however, inhibition of cholesterol esterification reverted the activated state of sterol-regulatory element-binding protein 2 (SREBP2) and cholesterogenesis. These results highlight SND1 as a potential regulator of cellular cholesterol distribution and homeostasis in hepatoma cells, and support the rationale for the therapeutic use of molecules that influence cholesterol management when SND1 is overexpressed. PMID:27238764

  10. Hepatocellular carcinoma--epidemiological trends and risk factors.

    PubMed

    Schütte, Kerstin; Bornschein, Jan; Malfertheiner, Peter

    2009-01-01

    Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide with about 600,000 patients dying from the disease annually. In 70-90%, HCC develops on the background of chronic liver cirrhosis or inflammation. Risk factors and etiologies vary among geographical regions. In regions with a high incidence the majority of cases are related to HBV and HCV hepatitis. In developed countries, in addition to virus-related HCC, high consumption of alcohol as well as non-alcoholic fatty liver disease often in the context of metabolic syndromes are the prevalent causes. Improvement in clinical management of patients with liver cirrhosis and the control of related complications are the key for the rising incidence of HCC. This review gives an overview on epidemiological trends and risk factors and their mechanisms involved in the hepatocarcinogenesis. Knowledge of these factors will help to improve current concepts for prevention, screening and treatment of this disease. PMID:19546545

  11. Hepatocellular carcinoma detected by iodized oil: use of anticancer agents

    SciTech Connect

    Ohishi, H.; Uchida, H.; Yoshimura, H.; Ohue, S.; Ueda, J.; Katsuragi, M.; Matsuo, N.; Hosogi, Y.

    1985-01-01

    Transcatheter arterial embolization (TAE) was performed in 97 patients with hepatocellular carcinoma. Ethiodol (iodized oil) containing an anticancer drug was infused via the hepatic artery followed by Gelfoam particles. The Ethiodol emulsion was selectively retained in the tumor vessels and also remained in the small daughter nodules that could not be detected by angiography or computed tomography (CT) prior to TAE. In most patients there was a reduction in the tumor size following TAE, and serum alpha-fetoprotein levels were reduced in all patients whose initial levels had exceeded 400 ng/ml. This method is considered to be effective not only for treatment of hepatic tumor but also useful for evaluation of post-TAE changes in the tumor and diagnosis of small daughter nodules, due to the long-term accumulation of Ethiodol in tumor vessels.

  12. The Role of Hypoxia Inducible Factor-1 in Hepatocellular Carcinoma

    PubMed Central

    Luo, Dongjun; Wang, Zhongxia; Wu, Junyi; Jiang, Chunping

    2014-01-01

    Hypoxia is a common feature of many solid tumors, including hepatocellular carcinoma (HCC). Hypoxia can promote tumor progression and induce radiation and chemotherapy resistance. As one of the major mediators of hypoxic response, hypoxia inducible factor-1 (HIF-1) has been shown to activate hypoxia-responsive genes, which are involved in multiple aspects of tumorigenesis and cancer progression, including proliferation, metabolism, angiogenesis, invasion, metastasis and therapy resistance. It has been demonstrated that a high level of HIF-1 in the HCC microenvironment leads to enhanced proliferation and survival of HCC cells. Accordingly, overexpression, of HIF-1 is associated with poor prognosis in HCC. In this review, we described the mechanism by which HIF-1 is regulated and how HIF-1 mediates the biological effects of hypoxia in tissues. We also summarized the latest findings concerning the role of HIF-1 in the development of HCC, which could shed light on new therapeutic approaches for the treatment of HCC. PMID:25101278

  13. Autophagy in hepatocellular carcinomas: from pathophysiology to therapeutic response

    PubMed Central

    Dash, Srikanta; Chava, Srinivas; Chandra, Partha K; Aydin, Yucel; Balart, Luis A; Wu, Tong

    2016-01-01

    Autophagy is an intracellular lysosomal degradation process performed by the cells to maintain energy balance. The autophagy response plays an important role in the progression of liver disease due to hepatitis virus infection, alcoholic liver disease, nonalcoholic fatty liver disease, liver cirrhosis, and hepatocellular carcinoma (HCC). An increased autophagy response also contributes to the pathogenesis of liver disease through modulation of innate and adaptive immune responses; a defective cellular autophagy response leads to the development of HCC. Recent progress in the field indicates that autophagy modulation provides a novel targeted therapy for human liver cancer. The purpose of this review is to update our understanding of how the cellular autophagy response impacts the pathophysiology of liver disease and HCC treatment. PMID:26955295

  14. Focal lesions in cirrhotic liver: what else beyond hepatocellular carcinoma?

    PubMed Central

    Galia, Massimo; Taibbi, Adele; Marin, Daniele; Furlan, Alessandro; Burgio, Marco Dioguardi; Agnello, Francesco; Cabibbo, Giuseppe; Van Beers, Bernard E.; Bartolotta, Tommaso Vincenzo; Midiri, Massimo; Lagalla, Roberto; Brancatelli, Giuseppe

    2014-01-01

    Detection and characterization of focal lesions in the cirrhotic liver may pose a diagnostic dilemma. Several benign and malignant lesions may be found in a cirrhotic liver along with hepatocellular carcinoma (HCC), and may exhibit typical or atypical imaging features. In this pictorial essay, we illustrate computed tomography and magnetic resonance imaging findings of lesions such as simple bile duct cysts, hemangioma, focal nodular hyperplasia-like nodules, peribiliary cysts, intrahepatic cholangiocarcinoma, lymphoma, and metastases, all of which occur in cirrhotic livers with varying prevalences. Pseudolesions, such as perfusion anomalies, focal confluent fibrosis, and segmental hyperplasia, will also be discussed. Imaging characterization of non-HCC lesions in cirrhosis is important in formulating an accurate diagnosis and triaging the patient towards the most appropriate management. PMID:24509186

  15. Telomerase activity and telomere length in human hepatocellular carcinoma.

    PubMed

    Huang, G T; Lee, H S; Chen, C H; Chiou, L L; Lin, Y W; Lee, C Z; Chen, D S; Sheu, J C

    1998-11-01

    Telomerase activity is activated and telomere length altered in various types of cancers, including hepatocellular carcinoma (HCC). A total of 39 HCC tissues and the corresponding non-tumour livers were analysed and correlated with clinical parameters. Telomere length was determined by terminal restriction fragment assay, and telomerase activity was assayed by telomeric repeat amplification protocol. Telomerase activity was positive in 24 of the 39 tumour tissues (1.15-285.13 total product generated (TPG) units) and in six of the 39 non-tumour liver tissues (1.05-1.73 TPG units). In the 28 cases analysed for telomere length, telomere length was shortened in 11 cases, lengthened in six cases, and unaltered in 11 cases compared with non-tumour tissues. Neither telomere length nor telomerase activity was correlated to any clinical parameters. PMID:10023320

  16. Long non-coding RNAs and hepatocellular carcinoma

    PubMed Central

    YU, FU-JUN; ZHENG, JIAN-JIAN; DONG, PEI-HONG; FAN, XIAO-MING

    2015-01-01

    Recent advances in next-generation sequencing technology in transcriptome analysis have helped identify numerous non-coding RNAs. The long non-coding RNA (lncRNA) is commonly defined as an RNA molecule with a length of 200 bp-100 kbp that lacks protein-coding potential. LncRNAs play a critical role in the regulation of gene expression, including chromatin modification, transcription and post-transcriptional processing. It has been confirmed that dysregulation of lncRNAs is associated with a number of human diseases, particularly tumors. In this study, we focused on the most extensively investigated lncRNAs in hepatocellular carcinoma (HCC). The biological functions and molecular mechanisms of the majority of lncRNAs have yet to be investigated. The improved knowledge on lncRNAs in HCC may help identify lncRNAs that may be used as novel prognostic markers and therapeutic targets. PMID:25469263

  17. Familial Hepatocellular Carcinoma- First Reported Case from India

    PubMed Central

    Kusum, Anuradha; Chandra, Harish; Yadav, Kanika; Verma, Sanjiv Kumar

    2016-01-01

    Familial clustering of Hepatocellular Carcinoma (HCC) is commonly observed in various parts of the world including China and Eastern Asia where HBV is endemic while in western world, genetic factors and metabolic disorders may play an important role. In India, HCC is considered to be a rare tumour and till date no case of familial HCC has been reported here. Therefore the present case demonstrates rare occurrence of familial HCC which is being reported for the first time from India on cytology. The case also highlights an unusual feature that it was not associated with any risk factor including HBV, HCV infection, alcoholism, obesity, diabetes or smoking suggesting its independent association with genetic factors. Cytology is uncomplicated diagnostic tool for HCC and may be useful for its early diagnosis. This case also highlights the importance of early surveillance and follow up of blood relatives for every case of HCC so that early diagnosis and management of familial HCC is possible. PMID:27134884

  18. Hepatocellular carcinoma: Review of disease and tumor biomarkers

    PubMed Central

    Kim, Jin Un; Shariff, Mohamed I F; Crossey, Mary M E; Gomez-Romero, Maria; Holmes, Elaine; Cox, I Jane; Fye, Haddy K S; Njie, Ramou; Taylor-Robinson, Simon D

    2016-01-01

    Hepatocellular carcinoma (HCC) is a common malignancy and now the second commonest global cause of cancer death. HCC tumorigenesis is relatively silent and patients experience late symptomatic presentation. As the option for curative treatments is limited to early stage cancers, diagnosis in non-symptomatic individuals is crucial. International guidelines advise regular surveillance of high-risk populations but the current tools lack sufficient sensitivity for early stage tumors on the background of a cirrhotic nodular liver. A number of novel biomarkers have now been suggested in the literature, which may reinforce the current surveillance methods. In addition, recent metabonomic and proteomic discoveries have established specific metabolite expressions in HCC, according to Warburg’s phenomenon of altered energy metabolism. With clinical validation, a simple and non-invasive test from the serum or urine may be performed to diagnose HCC, particularly benefiting low resource regions where the burden of HCC is highest. PMID:27057305

  19. Hepatocellular Carcinoma Radiation Therapy: Review of Evidence and Future Opportunities

    SciTech Connect

    Klein, Jonathan

    2013-09-01

    Hepatocellular carcinoma (HCC) is a leading cause of global cancer death. Curative therapy is not an option for most patients, often because of underlying liver disease. Experience in radiation therapy (RT) for HCC is rapidly increasing. Conformal RT can deliver tumoricidal doses to focal HCC with low rates of toxicity and sustained local control in HCC unsuitable for other locoregional treatments. Stereotactic body RT and particle therapy have been used with long-term control in early HCC or as a bridge to liver transplant. RT has also been effective in treating HCC with portal venous thrombosis. Patients with impaired liver function and extensive disease are at increased risk of toxicity and recurrence. More research on how to combine RT with other standard and novel therapies is warranted. Randomized trials are also needed before RT will be generally accepted as a treatment option for HCC. This review discusses the current state of the literature and opportunities for future research.

  20. Immunotherapy for hepatocellular carcinoma: From basic research to clinical use

    PubMed Central

    Hong, Yu-Peng; Li, Zi-Duo; Prasoon, Pankaj; Zhang, Qi

    2015-01-01

    Hepatocellular carcinoma (HCC) is a common cancer worldwide with a poor prognosis. Few strategies have been proven efficient in HCC treatment, particularly for those patients not indicated for curative resection or transplantation. Immunotherapy has been developed for decades for cancer control and is attaining more attention as a result of encouraging outcomes of new strategies such as chimeric antigen receptor T cells and immune checkpoint blockade. Right at the front of the new era of immunotherapy, we review the immunotherapy in HCC treatment, from basic research to clinical trials, covering anything from immunomodulators, tumor vaccines and adoptive immunotherapy. The mechanisms, efficacy and safety as well as the approach particulars are unveiled to assist readers to gain a concise but extensive understanding of immunotherapy of HCC. PMID:25954480

  1. A Peculiar Mutation Spectrum Emerging from Young Peruvian Patients with Hepatocellular Carcinoma

    PubMed Central

    Marchio, Agnès; Bertani, Stéphane; Rojas Rojas, Teresa; Doimi, Franco; Terris, Benoît; Deharo, Eric; Dejean, Anne; Ruiz, Eloy; Pineau, Pascal

    2014-01-01

    Hepatocellular carcinoma usually afflicts individuals in their later years following longstanding liver disease. In Peru, hepatocellular carcinoma exists in a unique clinical presentation, which affects patients around age 25 with a normal, healthy liver. In order to deepen our understanding of the molecular processes ongoing in Peruvian liver tumors, mutation spectrum analysis was carried out on hepatocellular carcinomas from 80 Peruvian patients. Sequencing analysis focused on nine genes typically altered during liver carcinogenesis, i.e. ARID2, AXIN1, BRAF, CTNNB1, NFE2L2, H/K/N-RAS, and TP53. We also assessed the transcription level of factors involved in the control of the alpha-fetoprotein expression and the Hippo signaling pathway that controls contact inhibition in metazoans. The mutation spectrum of Peruvian patients was unique with a major class of alterations represented by Insertions/Deletions. There were no changes at hepatocellular carcinoma-associated mutation hotspots in more than half of the specimens analyzed. Furthermore, our findings support the theory of a consistent collapse in the Hippo axis, as well as an expression of the stemness factor NANOG in high alpha-fetoprotein-expressing hepatocellular carcinomas. These results confirm the specificity of Peruvian hepatocellular carcinoma at the molecular genetic level. The present study emphasizes the necessity to widen cancer research to include historically neglected patients from South America, and more broadly the Global South, where cancer genetics and tumor presentation are divergent from canonical neoplasms. PMID:25502816

  2. Impact of mitochondrial telomerase over-expression on drug resistance of hepatocellular carcinoma

    PubMed Central

    Yan, Jing; Zhou, Yuan; Chen, Daixing; Li, Lili; Yang, Xin; You, Yang; Ling, Xianlong

    2015-01-01

    Background: The efficacy of chemotherapy in patients with hepatocellular carcinomas still poor due to multidrug resistance. This study aimed to investigate the impact of the over-expressed mitochondrial human telomerase reverse transcriptase on multidrug resistance of hepatocellular carcinomas. Methods: HepG2 and SK-Hep1 cell lines were used. And sensitivity to chemotherapeutic drugs was detected. Results: Mitochondrial human telomerase reverse transcriptase over-expression in hepatocellular carcinomas cells could significantly reduce its sensitivity to multiple chemotherapeutic drugs in vitro and in vivo. Hepatocellular carcinomas cells over-expressing mitochondrial human telomerase reverse transcriptase showed a significantly higher mitochondrial membrane potential, a markedly lower activated caspase-3 after drug treatment, and an increased mtDNA copy number, which explained the drastically decreased drug-induced apoptosis of hepatocellular carcinomas cells with mitochondrial human telomerase reverse transcriptase over-expression. Conclusion: Over-expressed mitochondrial human telomerase reverse transcriptase may increase the mtDNA copy number and inhibit the activation of mitochondrial apoptotic pathway to contribute to the multidrug resistance of hepatocellular carcinomas cells. PMID:25755831

  3. The cytotoxic and mechanistic effects of aaptamine on hepatocellular carcinoma.

    PubMed

    Li, Qiao-lu; Zhang, Ping-ping; Wang, Pei-qin; Yu, Hao-bing; Sun, Fan; Hu, Wen-zheng; Wu, Wen-hui; Zhang, Xin; Chen, Fei; Chu, Zhi-yong; Zhang, Jun-ping; Chen, Shun-shen; Lin, Hou-wen

    2015-01-01

    Hepatocellular carcinoma (HCC) is the fifth most common form of cancer and the third most frequent cause of cancer-associated mortality worldwide. We isolated aaptamine from the marine sponge Aaptos, and synthesized derivatives of this compound. Aaptamine and synthetic derivatives displayed various biological activities. This represents the first account of studies on the effects of aaptamine and its derivatives in hepatocarcinogenesis. In this study, Cell Counting Kit (CCK8) was used to evaluate the anti-proliferative effect of aaptamine on HCC in vitro. Additionally, a subcutaneous xenograft model was used to determine if aaptamine could inhibit hepatocellular carcinoma in vivo. We also used RT-PCR and Western blot to analyze the mechanisms behind these effects. Our results showed that aaptamine has anti-proliferation effects on the cell lines LM3 and HepG2. Aaptamine also suppressed the colony-formation ability of HCC cells. We found that aaptamine treatment led to cell cycle arrest in HCC cells, reduced the expression of SOX9 and CDK2. Significant anti-tumor effects were observed in aaptamine-administered tumor-bearing mice as compared to controls. However, structural changes made to aaptamine yielded two derivatives for which all the effects listed above were considerably reduced as compared to the original compound aaptamine. In conclusion, aaptamine is demonstrated for the first time to inhibit liver cancer progression. The aaptamine-induced cell cycle arrest was associated with the increased binding of p21 to Cdk2-cyclin D/E complexes, inhibition of Cdk2 kinase activity in HCC cells. Furthermore, aaptamine appears to be a promising and efficient treatment of liver cancer HCC-LM3 in vivo. We have also uncovered structural changes that might affect the biological activity. The work provides a promising drug candidate for HCC treatment. PMID:25403168

  4. Lactosylated liposomes for targeted delivery of doxorubicin to hepatocellular carcinoma

    PubMed Central

    Zhou, Xiaoju; Zhang, Mengzi; Yung, Bryant; Li, Hong; Zhou, Chenguang; Lee, L James; Lee, Robert J

    2012-01-01

    Background N-lactosyl-dioleoylphosphatidylethanolamine (Lac-DOPE) was synthesized and evaluated as a liver-specific targeting ligand via asialoglycoprotein receptors for liposomal delivery of doxorubicin. Methods Lactosylated liposomes encapsulating calcein (Lac-L-calcein) or doxorubicin (Lac-L-DOX) composed of egg phosphatidylcholine, cholesterol, monomethoxy polyethylene glycol 2000-distearoyl phosphatidylethanolamine, and Lac-DOPE at 50:35:5:10 (mol/mol) were prepared by polycarbonate membrane extrusion and evaluated in human hepatocellular carcinoma HepG2 cells. Cellular uptake of Lac-L-calcein was monitored by confocal microscopy and by flow cytometry. The cytotoxicity of Lac-L-DOX was evaluated by MTT assay. The pharmacokinetic properties of Lac-L-DOX were studied in normal mice, and its biodistribution and antitumor activity were studied in nude mice with HepG2 xenografts. Results The size of Lac-L-DOX was less than 100 nm and the liposomes demonstrated excellent colloidal stability. In vitro uptake of Lac-L-calcein by HepG2 cells was four times greater than that of non-targeted L-calcein. In the presence of 20 mM lactose, the uptake of Lac-L-calcein was inhibited, suggesting that asialoglycoprotein receptors mediated the observed cellular uptake. Lac-L-DOX exhibited enhanced in vivo cytotoxicity compared with the nontargeted liposomal doxorubicin (L-DOX), and its pharmacokinetic parameters indicate that Lac-L-DOX has a long blood circulation time (t1/2 8.73 hours). Tissue distribution and therapeutic efficacy studies in nude mice bearing HepG2 xenografts show that Lac-L-DOX had significantly stronger tumor inhibitory activity compared with L-DOX and free doxorubicin, along with a higher accumulation of drug within the tumor site and greater cellular uptake by tumor cells. Conclusion These data suggest that lactosylated liposomes are promising drug delivery vehicles for hepatocellular carcinoma. PMID:23093902

  5. Safety validation of decision trees for hepatocellular carcinoma

    PubMed Central

    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

    2015-01-01

    AIM: To evaluate a different decision tree for safe liver resection and verify its efficiency. METHODS: 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. RESULTS: 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. CONCLUSION: 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. PMID:26309366

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

    PubMed

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

    2015-01-01

    Reactive lymphoid hyperplasia is a rare disease that forms a mass-like lesion and is characterized by the proliferation of non-neoplastic, polyclonal lymphocytes forming follicles. We recently encountered 2 cases of reactive lymphoid hyperplasia of liver, both of which were asymptomatic and mimicked hepatocellular carcinoma by various imaging modalities. Based on the clinical impression of hepatocellular carcinoma, surgical resections were performed. Microscopic findings revealed that both lesions consisted of an aggregation of lymphocytes consisting of predominantly B-cells, with multiple lymphoid follicles positive for CD10 and negative for bcl-2, consistent with the diagnosis of reactive lymphoid hyperplasia. Polyclonality of both lesions was further confirmed by B cell receptor gene rearrangement study. The incidence of reactive lymphoid hyperplasia in the liver is exceedingly rare, and it is difficult to differentiate such lesions from hepatic malignancies based upon clinical grounds. The clinicopathological findings and literature review of this report may be helpful to improve the clinical decision-making. PMID:26191310

  7. Antiviral therapy for hepatitis B virus-related hepatocellular carcinoma after surgery: A comment for moving forward

    PubMed Central

    Zhong, Jian-Hong; Yang, Tian; Xiang, Bang-De; Li, Le-Qun; Ma, Liang

    2016-01-01

    Recurrence rate of hepatocellular carcinoma remains quite high even after surgery, and no postoperative therapies have been definitively shown to prevent hepatocellular carcinoma recurrence. A previous study showed that therapy with nucleos(t)ide analogues given to such patients after surgery significantly improved survival. However, many questions still exist about the usage of nucleos(t)ide analogues for patients with hepatocellular carcinoma after surgery. PMID:27168873

  8. Carcinoma with shared pathologic characteristics of both hepatocellular carcinoma and cholangiocarcinoma

    PubMed Central

    Hiraoka, Atsushi; Kurose, Kiyotaka; Kumagi, Teru; Hirooka, Masashi; Yokota, Tomoyuki; Fujiwara, Toshiteru; Utsunomiya, Sachiko; Hirata, Mami; Ohtani, Hiromi; Michitaka, Kojiro; Horiike, Norio; Kobayashi, Nobuaki; Onji, Morikazu

    2005-01-01

    Background: α-Fetoprotein (AFP) is a useful marker of hepatocellular carcinoma (HCC), and protein induced by vitamin K absence or antagonist II (PIVKA-II) and fucosylated AFP (AFP-L3) are specific tumor markers. Objective: The aim of this article was to report a case of intrahepatic cholangiocarcinoma (CC) with high levels of expression of AFP, AFP-L3, and PIVKA-II. Methods: A 70-year-old man weighing 66 kg with a diagnosis of intrahepatic CC presented with a liver tumor 4.0 cm in diameter and elevated concentrations of carbohydrate antigen 19-9 (575 U/mL), PIVKA-II (379 mAU/mL), and AFP (497 ng/mL; AFP-L3, 88.1%). On extended medial hepatic segmentectomy, microscopy showed that the tumor was a CC without HCC. The patient subsequently underwent immunohistochemical assessments using cytokeratin-19, epithelial membrane antigen (EMA), hepatocyte paraffin-1 (HP-1), PIVKA-II, and AFP. Results: In all specimens, desmoplasia was observed. However, results of immunohistochemistry showed positive results for cytokeratin-19 and EMA; HP-1 results were negative. Results of PIVKA-II and AFP testing in the tumor were positive. Conclusions: The case presented here showed characteristics of CC and HCC, whereas the histologic expression of the tumor suggested CC. Based on the literature search, this is the first known report of a case of a CC expressing AFP and PIVKA-II confirmed on immunohistochemical staining. This case is interesting with regard to the ability of the progenitor cells to differentiate HCC and CC. PMID:24678077

  9. Solid adenoma with exclusive hepatocellular differentiation: a new variant among pancreatic benign neoplasms?

    PubMed

    Cuilliere, Peggy; Lazure, Thierry; Bui, Matthieu; Fabre, Monique; Buffet, Catherine; Gayral, François; Bedossa, Pierre

    2002-11-01

    We report a unique, previously unreported pancreatic tumor with hepatoid differentiation associated with serous microcystic adenoma in a 70-year-old man. These two lesions localized, respectively, at the body and the tail of the pancreas, were found incidentally on abdominal ultrasonography. Serum alpha-fetoprotein was not increased and no hepatic lesion was displayed on computed tomography. A subtotal pancreatectomy with splenectomy was performed. The patient is alive and well 12 months after resection. Pathological examination showed a very unusual encapsulated solid tumor with hepatocytic differentiation, bile production and immunoreactivity for hepatocyte paraffin-1 antibody. The tumor cells were negative for endocrine (neuron-specific enolase, chromogranin A, synaptophysin) and acinar (amylase, trypsin) markers. Ultrastructurally, zymogen and neurosecretory granules were absent. The features of the tumor were almost indistinguishable from those of hepatocellular adenoma; therefore, we believe that this solid hepatoid tumor may represent a variant of pancreatic adenoma. Recognition of this entity is important because the only reported pancreatic hepatoid tumors to date have been malignant. The main differential diagnoses include hepatoid ductal adenocarcinoma, hepatoid acinar cell carcinoma, primitive hepatoid endocrine tumor, and metastatic hepatocellular carcinoma. PMID:12447684

  10. Polysaccharide from Lentinus edodes combined with oxaliplatin possesses the synergy and attenuation effect in hepatocellular carcinoma.

    PubMed

    Zhang, Yu; Li, Qiang; Wang, Junfeng; Cheng, Fang; Huang, Xiao; Cheng, Yao; Wang, Kaiping

    2016-07-28

    Despite the great progress in the treatment of hepatocellular carcinoma, combination chemotherapy is still the main choice of treatment for patients with unresectable metastatic or recurrent hepatocellular cancer. Lentinan, which has been used as an immunomodulator in the treatment of cancer, possesses anti-tumor activities. However, the mechanisms by which Lentinan inhibits hepatocellular carcinoma remain unknown. Our study showed that Lentinan has a significantly synergistic anti-tumor effect with oxaliplatin against HepG2 cells in vitro and in H22 tumor-bearing mice through the mitochondria pathway and for the inhibition of NF-κB, Stat3 and survivin signaling. Moreover, Lentinan moderated side effects induced by oxaliplatin. These findings suggested that Lentinan may be an ideal agent for the combination therapy of oxaliplatin against hepatocellular carcinoma. PMID:27130669

  11. New Oily Agents for Targeting Chemoembolization for Hepatocellular Carcinoma

    SciTech Connect

    Hamuro, Masao; Nakamura, Kenji; Sakai, Yukimasa; Nakata, Manabu; Ichikawa, Hideki; Fukumori, Yoshinobu; Yamada, Ryusaku

    1999-03-15

    Purpose: The evaluation of new oily agents for targeting chemoembolization for hepatocellular carcinoma. Methods: Five types of oily preparation were injected into the hepatic artery of 54 rabbits inoculated with VX2 carcinoma cells in order to evaluate (1) the safety of these preparations, (2) their histologic distribution and the amount of agents remaining at tumor sites, and (3) computed tomographic (CT) images obtained. Of these preparations, three were made by mixing non-iodinated poppy seed oil and a thickener and then adjusted to have a viscosity lower than, equal to, or higher than that of lipiodol. A fourth preparation was a mixture of lipiodol and a thickener with a higher viscosity than lipiodol alone, and the fifth preparation was lipiodol alone. Results: (1) No injury to the hepatic parenchyma was observed hematologically or histologically. (2) With increase in the viscosity, a significantly larger amount of agent remained at the tumor site. No agent was present at normal sites 14 days after intraarterial injection, regardless of which preparation was given. (3) On CT scans following intraarterial injection, tumor cells were visibly deeply stained in the non-iodinated preparation groups, while the lipiodol groups were not evaluable because of excessively high attenuation. Conclusion: The non-iodinated oily preparations and highly viscous oily preparations developed in the present study were more useful than lipiodol for treatment of hepatic tumors.

  12. The genomic landscape of fibrolamellar hepatocellular carcinoma: whole genome sequencing of ten patients

    PubMed Central

    Darcy, David G.; Chiaroni-Clarke, Rachel; Murphy, Jennifer M.; Honeyman, Joshua N.; Bhanot, Umesh; LaQuaglia, Michael P.; Simon, Sanford M.

    2015-01-01

    Fibrolamellar hepatocellular carcinoma is a rare, malignant liver tumor that often arises in the otherwise normal liver of adolescents and young adults. Previous studies have focused on biomarkers and comparisons to traditional hepatocellular carcinoma, and have yielded little data on the underlying pathophysiology. We performed whole genome sequencing on paired tumor and normal samples from 10 patients to identify recurrent mutations and structural variations that could predispose to oncogenesis. There are relatively few coding, somatic mutations in this cancer, putting it on the low end of the mutational spectrum. Aside from a previously described heterozygous deletion on chromosome 19 that encodes for a functional, chimeric protein, there were no other recurrent structural variations that contribute to the tumor genotype. The lack of a second-hit mutation in the genomic landscape of fibrolamellar hepatocellular carcinoma makes the DNAJB1-PRKACA fusion protein the best target for diagnostic and therapeutic advancements. The mutations, altered pathways and structural variants that characterized fibrolamellar hepatocellular carcinoma were distinct from those in hepatocellular carcinoma, further defining it as a distinct carcinoma. PMID:25605237

  13. [Delayed Tc-99m-PMT imaging in the specific diagnosis of hepatocellular carcinoma].

    PubMed

    Wu, Z M

    1988-09-01

    The results of Tc-99m-PMT imaging on 100 patients with various malignant and benign hepatic diseases verified histologically (73 hepatocellular carcinoma, 3 liver cell adenoma, 1 cholangiocarcinoma, 5 metastatic liver carcinoma, 2 liver cyst, 12 hemangioma, 1 fatty degeneration, 1 liver regeneration, 1 postoperative liver fibrosis and 1 liver cirrhosis) are reported. All lesions appeared as decreased radioactivity or "cold" defect region on early Tc-99m-PMT imaging, rendering it valuable for the diagnosis of tumor localization. In 92 (95.8%) of the 96 patients with various hepatic tumors and 25 (86.2%) of the 29 patients with small hepatocellular carcinoma (less than 5 cm), the tumors were localized by early Tc-99m-PMT imaging. In 14 of the 73 patients with established hepatocellular carcinoma, the tumors gave greater radioactivity than that of the surrounding liver tissues, whereas in 31 patients the radioactivity of the tumor equalled the normal liver on delayed Tc-99m-PMT imaging (positive rate 61.6%). There was no significant difference between the positive rates of serum AFP level and the tumor size shown by delayed Tc-99m-PMT imaging in hepatocellular carcinomas. The radioactivity in 3 liver cell adenoma patients was similar to the gallbladder. No false positive result was seen in the other malignant and benign hepatic tumors. This study indicates that delayed Tc-99m-PMT imaging is highly specific in the diagnosis of hepatocellular carcinoma. PMID:2854779

  14. A Collision Probability Model of Portal Vein Tumor Thrombus Formation in Hepatocellular Carcinoma

    PubMed Central

    Xiong, Fei

    2015-01-01

    Hepatocellular carcinoma is one of the most common malignancies worldwide, with a high risk of portal vein tumor thrombus (PVTT). Some promising results have been achieved for venous metastases of hepatocellular carcinoma; however, the etiology of PVTT is largely unknown, and it is unclear why the incidence of PVTT is not proportional to its distance from the carcinoma. We attempted to address this issue using physical concepts and mathematical tools. Finally, we discuss the relationship between the probability of a collision event and the microenvironment of the PVTT. Our formulae suggest that the collision probability can alter the tumor microenvironment by increasing the number of tumor cells. PMID:26131562

  15. Long noncoding RNAs in hepatocellular carcinoma: Novel insights into their mechanism

    PubMed Central

    Liu, Yong-Ru; Tang, Rui-Xue; Huang, Wen-Ting; Ren, Fang-Hui; He, Rong-Quan; Yang, Li-Hua; Luo, Dian-Zhong; Dang, Yi-Wu; Chen, Gang

    2015-01-01

    Hepatocellular carcinoma (HCC) is the predominant subject of liver malignancies which arouse global concern. Advanced studies have found that long noncoding RNAs (lncRNAs) are differentially expressed in HCC and implicate they may play distinct roles in the pathogenesis and metastasis of HCC. However, the underlying mechanisms remain largely unclear. In this review, we summarized the functions and mechanisms of those known aberrantly expressed lncRNAs identified in human HCC tissues. We hope to enlighten more comprehensive researches on the detailed mechanisms of lncRNAs and their application in clinic, such as being used as diagnostic and prognostic biomarkers and the targets for potential therapy. Although studies on lncRNAs in HCC are still deficient, an improved understanding of the roles played by lncRNAs in HCC will lead to a much more effective utilization of those lncRNAs as novel candidates in early detection, diagnosis, prevention and treatment of HCC. PMID:26668690

  16. Metabolic Inflammation-Associated IL-17A Causes Non-alcoholic Steatohepatitis and Hepatocellular Carcinoma.

    PubMed

    Gomes, Ana L; Teijeiro, Ana; Burén, Stefan; Tummala, Krishna S; Yilmaz, Mahmut; Waisman, Ari; Theurillat, Jean-Philippe; Perna, Cristian; Djouder, Nabil

    2016-07-11

    Obesity increases hepatocellular carcinoma (HCC) risks via unknown mediators. We report that hepatic unconventional prefoldin RPB5 interactor (URI) couples nutrient surpluses to inflammation and non-alcoholic steatohepatitis (NASH), a common cause of HCC. URI-induced DNA damage in hepatocytes triggers inflammation via T helper 17 (Th17) lymphocytes and interleukin 17A (IL-17A). This induces white adipose tissue neutrophil infiltration mediating insulin resistance (IR) and fatty acid release, stored in liver as triglycerides, causing NASH. NASH and subsequently HCC are prevented by pharmacological suppression of Th17 cell differentiation, IL-17A blocking antibodies, and genetic ablation of the IL-17A receptor in myeloid cells. Human hepatitis, fatty liver, and viral hepatitis-associated HCC exhibit increased IL-17A correlating positively with steatosis. IL-17A blockers may prevent IR, NASH, and HCC in high-risk patients. PMID:27411590

  17. Pathological evidence of the cause of spontaneous regression in a case of resected hepatocellular carcinoma.

    PubMed

    Matsuoka, Shunichi; Tamura, Akinori; Moriyama, Mitsuhiko; Fujikawa, Hirotoshi; Mimatsu, Kenji; Oida, Takatsugu; Sugitani, Masahiko

    2015-01-01

    A 67-year-old man presented for an evaluation after experiencing right hypochondrial pain lasting for two months. Abdominal ultrasonography showed a hepatic tumor in the right liver and extremely mild hepatic steatosis. The imaging findings indicated that the tumor (43 mm in size) was ischemic, and the lesion was surgically resected and examined. The histopathological findings demonstrated 95% necrosis with moderately differentiated hepatocellular carcinoma (HCC). The diagnosis was HCC with spontaneous regression. There was also pathological evidence of thrombus formation in the peripheral arteries and portal veins. In addition, the non-cancerous regions of the liver were diagnosed as exhibiting non-alcoholic steatohepatitis. The pathological findings obtained after resection of the HCC lesion showed spontaneous regression. PMID:25742889

  18. Ursodeoxycholic acid induces apoptosis in hepatocellular carcinoma xenografts in mice

    PubMed Central

    Liu, Hui; Xu, Hong-Wei; Zhang, Yu-Zhen; Huang, Ya; Han, Guo-Qing; Liang, Tie-Jun; Wei, Li-Li; Qin, Cheng-Yong; Qin, Cheng-Kun

    2015-01-01

    AIM: To evaluate the efficacy of ursodeoxycholic acid (UDCA) as a chemotherapeutic agent for the treatment of hepatocellular carcinoma (HCC). METHODS: BALB/c nude mice were randomized into four groups 24 h before subcutaneous injection of hepatocarcinoma BEL7402 cells suspended in phosphate buffered saline (PBS) into the right flank. The control group (n = 10) was fed a standard diet while treatment groups (n = 10 each) were fed a standard daily diet supplemented with different concentrations of UDCA (30, 50 and 70 mg/kg per day) for 21 d. Tumor growth was measured once each week, and tumor volume (V) was calculated with the following equation: V = (L × W2) × 0.52, where L is the length and W is the width of the xenograft. After 21 d, mice were killed under ether anesthesia, and tumors were excised and weighed. Apoptosis was evaluated through detection of DNA fragmentation with gel electrophoresis and the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay. Western blot analysis was performed to determine the expression of apoptosis-related proteins BAX, BCL2, APAF1, cleaved caspase-9, and cleaved caspase-3. RESULTS: UDCA suppressed tumor growth relative to controls. The mean tumor volumes were the following: control, 1090 ± 89 mm3; 30 mg/kg per day, 612 ± 46 mm3; 50 mg/kg per day, 563 ± 38 mm3; and 70 mg/kg per day, 221 ± 26 mm3. Decreased tumor volumes reached statistical significance relative to control xenografts (30 mg/kg per day, P < 0.05; 50 mg/kg per day, P < 0.05; 70 mg/kg per day, P < 0.01). Increasing concentrations of UDCA led to increased DNA fragmentation observed on gel electrophoresis and in the TUNEL assay (control, 1.6% ± 0.3%; 30 mg/kg per day, 2.9% ± 0.5%; 50 mg/kg per day, 3.15% ± 0.7%, and 70 mg/kg per day, 4.86% ± 0.9%). Western blot analysis revealed increased expression of BAX, APAF1, cleaved-caspase-9 and cleaved-caspase-3 proteins, which induce apoptosis, but decreased expression of BCL2

  19. The cell surface GRP78 facilitates the invasion of hepatocellular carcinoma cells.

    PubMed

    Zhang, Xiu-Xiu; Li, Hong-Dan; Zhao, Song; Zhao, Liang; Song, Hui-Juan; Wang, Guan; Guo, Qing-Jun; Luan, Zhi-Dong; Su, Rong-Jian

    2013-01-01

    Invasion is a major characteristic of hepatocellular carcinoma and one of the main causes of refractory to treatment. We have previously reported that GRP78 promotes the invasion of hepatocellular carcinoma although the mechanism underlying this change remains uncertain. In this paper, we explored the role of the cell surface GRP78 in the regulation of cancer cell invasion in hepatocellular carcinoma cells. We found that neutralization of the endogenous cell surface GRP78 with the anti-GRP78 antibody inhibited the adhesion and invasion in hepatocellular carcinoma cell lines Mahlavu and SMMC7721. However, forced expression of the cell surface GRP78 facilitated the adhesion and invasion in SMMC7721. We further demonstrated that inhibition of the endogenous cell surface GRP78 specifically inhibited the secretion and activity of MMP-2 but did not affect the secretion and activity of MMP-9. We also found that inhibition of the cell surface GRP78 increased E-Cadherin expression and decreased N-Cadherin level. On the contrary, forced expression of the cell surface GRP78 increased N-Cadherin expression and decreased E-Cadherin level, suggesting that the cell surface GRP78 plays critical role in the regulation of EMT process. These findings suggest that the cell surface GRP78 plays a stimulatory role in the invasion process and may be a potential anti-invasion target for the treatment of hepatocellular carcinoma. PMID:24383061

  20. 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. PMID:20084675

  1. Annexin A2 as a differential diagnostic marker of hepatocellular tumors.

    PubMed

    Longerich, Thomas; Haller, Maria Theresia; Mogler, Carolin; Aulmann, Sebastian; Lohmann, Volker; Schirmacher, Peter; Brand, Karsten

    2011-01-15

    While improved imaging techniques have made it possible to detect focal liver lesions smaller than 1cm in diameter, differentiating benign lesions from hepatocellular carcinoma (HCC) still remains a challenge. To address this problem and obtain a definite diagnosis, needle core biopsies are often performed, leading to an increased need for supportive ancillary techniques in the histopathological assessment of highly differentiated hepatocellular tumors. Here we evaluate the diagnostic value of immunohistologically detected Annexin A2 (ANXA2) expression in highly differentiated liver tumors. ANXA2 is a calcium-dependent phospholipid-binding protein that has been linked to malignant transformation and HCC development. Our data show that adding sinusoidal ANXA2 expression to the already established marker panel (GPC3, GS, and HSP70) increases the accuracy for the detection of well-differentiated HCC (74% sensitivity, 100% specificity). In addition, in our series, the combinations ANXA2-GPC3 and ANXA2-GS performed better compared to the other established marker combinations. In conclusion, we suggest that adding ANXA2 to the established diagnostic marker panel increases the reliability and objectivity of HCC diagnosis in liver biopsies. PMID:20971570

  2. Non-viral factors contributing to hepatocellular carcinoma

    PubMed Central

    Hamed, Manal A; Ali, Sanaa A

    2013-01-01

    Hepatocellular carcinoma (HCC) is a major cause of cancer death worldwide, accounting for over half a million deaths per year. The geographic pattern of HCC incidence is parallel to exposure to viral etiologic factors. Its incidence is increasing, ranging between 3% and 9% annually depending on the geographical location, and variability in the incidence rates correspond closely to the prevalence and pattern of the primary etiologic factors. Chronic infections with hepatitis B viruses or hepatitis C viruses have both been recognized as human liver carcinogens with a combined attributable fraction of at least 75% of all HCC cases. Multiple non-viral factors have been implicated in the development of HCC. Increased body mass index and diabetes with subsequent development of non-alcoholic steatohepatitis represent significant risk factors for HCC. Other non-viral causes of HCC include iron overload syndromes, alcohol use, tobacco, oral contraceptive, aflatoxin, pesticides exposure and betel quid chewing, a prevalent habit in the developing world. Wilson disease, α-1 antitrypsin deficiency, Porphyrias, autoimmune hepatitis, Schistosoma japonicum associated with positive hepatitis B surface antigen, and thorotrast-ray are also contributing hepatocellualar carcinoma. In addition, primary biliary cirrhosis, congestive liver disease and family history of liver cancer increase the risk of HCC incident. In conclusion, clarification of relevant non-viral causes of HCC will help to focus clinicians on those risk factors that are modifiable. The multilevel preventative approach will hopefully lead to a reduction in incidence of non-viral HCC, and a decrease in the patient morbidity and mortality as well as the societal economic burden associated with HCC. PMID:23805355

  3. Technical advances in external radiotherapy for hepatocellular carcinoma

    PubMed Central

    Park, Shin-Hyung; Kim, Jae-Chul; Kang, Min Kyu

    2016-01-01

    Radiotherapy techniques have substantially improved in the last two decades. After the introduction of 3-dimensional conformal radiotherapy, radiotherapy has been increasingly used for the treatment of hepatocellular carcinoma (HCC). Currently, more advanced techniques, including intensity-modulated radiotherapy (IMRT), stereotactic ablative body radiotherapy (SABR), and charged particle therapy, are used for the treatment of HCC. IMRT can escalate the tumor dose while sparing the normal tissue even though the tumor is large or located near critical organs. SABR can deliver a very high radiation dose to small HCCs in a few fractions, leading to high local control rates of 84%-100%. Various advanced imaging modalities are used for radiotherapy planning and delivery to improve the precision of radiotherapy. These advanced techniques enable the delivery of high dose radiotherapy for early to advanced HCCs without increasing the radiation-induced toxicities. However, as there have been no effective tools for the prediction of the response to radiotherapy or recurrences within or outside the radiation field, future studies should focus on selecting the patients who will benefit from radiotherapy. PMID:27621577

  4. Effects of Statins on the Risk of Hepatocellular Carcinoma

    PubMed Central

    Mansourian, Pejman G.; Yoneda, Masato; Krishna Rao, M.; Martinez, Fernando J.; Schiff, Eugene R.

    2014-01-01

    Hepatocellular carcinoma (HCC) is one of the leading causes of cancer morbidity and mortality worldwide and is one of the few cancers that is increasing in incidence. This cancer often arises in the setting of hepatic cirrhosis; however, it can also occur in patients with chronic hepatitis B virus infection without cirrhosis. Statins have been used for many years for the prevention and treatment of cardiovascular disease. Based on recent meta-analy-ses, these lipid-lowering agents are now being investigated for a class effect observed in the prevention of carcinogenesis. There are robust data suggesting that statins can alter biochemical pathways involved in tumorigenesis and cell survival and, thus, have a protective effect by reducing the risk of development of several types of cancer. In recent years, several studies have demonstrated that statins also can specifically decrease the risk of HCC development. Because statins are underutilized in patients with preexisting liver disease, understanding the role of statins in the prevention of HCC is important, and changes in practice guidelines supporting the use of statins as chemoprotective agents may be warranted. PMID:25904829

  5. Imaging of hepatocellular carcinoma: diagnosis, staging and treatment monitoring

    PubMed Central

    Hennedige, Tiffany

    2012-01-01

    Abstract Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Imaging is important for establishing a diagnosis of HCC. Several imaging modalities including ultrasonography (US), computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET) and angiography are used in evaluating patients with chronic liver disease and suspected HCC. CT, MRI and contrast-enhanced US have replaced biopsy for diagnosis of HCC. Dynamic multiphase contrast-enhanced CT or MRI is the current standard for imaging diagnosis of HCC. Functional imaging techniques such as perfusion CT and diffusion-weighted MRI provide additional information about tumor angiogenesis that may be useful for treatment. Techniques evaluating tissue mechanical properties such as magnetic resonance elastography, and acoustic radiation force impulse imaging are being explored for characterizing liver lesions. The role of PET in the evaluation of HCC is evolving with promise seen especially with the use of a hepatocyte-specific PET tracer. Imaging is also critical for assessment of treatment response and detection of recurrence following locoregional treatment. Knowledge of the post-treatment appearance of HCC is essential for correct interpretation. This review article provides an overview of the role of imaging in the diagnosis, staging and post-treatment follow-up of HCC. PMID:23400006

  6. Three-dimensional Organotypic Culture Models of Human Hepatocellular Carcinoma.

    PubMed

    Takai, Atsushi; Fako, Valerie; Dang, Hien; Forgues, Marshonna; Yu, Zhipeng; Budhu, Anuradha; Wang, Xin Wei

    2016-01-01

    Three-dimensional cell culture methods are viable in vitro approaches that facilitate the examination of biological features cancer cells present in vivo. In this study, we demonstrate that hepatocellular carcinoma (HCC) cells in porous alginate scaffolds can generate organoid-like spheroids that mimic numerous features of glandular epithelium in vivo, such as acinar morphogenesis and apical expression patterns of EpCAM, a hepatic stem/progenitor cell marker highly expressed in a subset of HCC with stemness features. We show that the activation of Wnt/β-catenin signaling, an essential pathway for maintaining HCC stemness, is required for EpCAM(+) HCC spheroid formation as well as the maintenance of the acinous structure. Furthermore, we demonstrate that EpCAM(+) HCC cells cultured as spheroids are more sensitive to TGF/β-induced epithelial-mesenchymal transition with highly tumorigenic and metastatic potential in vivo compared to conventional two-dimensional (2D) culture. In addition, HCC cells in EpCAM(+) spheroids are more resistant to chemotherapeutic agents than 2D-cultured cells. The alginate scaffold-based organotypic culture system is a promising, reliable, and easy system that can be configured into a high throughput fashion for the identification of critical signaling pathways and screening of molecular drug targets specific for HCC. PMID:26880118

  7. Stratification of Hepatocellular Carcinoma Patients Based on Acetate Utilization.

    PubMed

    Björnson, Elias; Mukhopadhyay, Bani; Asplund, Anna; Pristovsek, Nusa; Cinar, Resat; Romeo, Stefano; Uhlen, Mathias; Kunos, George; Nielsen, Jens; Mardinoglu, Adil

    2015-12-01

    Hepatocellular carcinoma (HCC) is a deadly form of liver cancer that is increasingly prevalent. We analyzed global gene expression profiling of 361 HCC tumors and 49 adjacent noncancerous liver samples by means of combinatorial network-based analysis. We investigated the correlation between transcriptome and proteome of HCC and reconstructed a functional genome-scale metabolic model (GEM) for HCC. We identified fundamental metabolic processes required for cell proliferation using the network centric view provided by the GEM. Our analysis revealed tight regulation of fatty acid biosynthesis (FAB) and highly significant deregulation of fatty acid oxidation in HCC. We predicted mitochondrial acetate as an emerging substrate for FAB through upregulation of mitochondrial acetyl-CoA synthetase (ACSS1) in HCC. We analyzed heterogeneous expression of ACSS1 and ACSS2 between HCC patients stratified by high and low ACSS1 and ACSS2 expression and revealed that ACSS1 is associated with tumor growth and malignancy under hypoxic conditions in human HCC. PMID:26655911

  8. Glutamine synthetase predicts adjuvant TACE response in hepatocellular carcinoma

    PubMed Central

    Zhang, Bo; Liu, Kai; Zhang, Jian; Dong, Liwei; Jin, Zhichao; Zhang, Xinji; Xue, Feng; He, Jia

    2015-01-01

    Background: Adjuvant transcatheter arterial chemoembolization (TACE) is associated with better outcome and reduced tumor recurrence in hepatocellular carcinoma (HCC) patients. This study aimed to investigate the relationship between glutamine synthetase (GS) expression and survival of HCC patients after postoperative adjuvant TACE. Methods: We retrospectively analyzed 554 HCC patients in two independent cohorts who underwent curative resection. Immunohistochemistry assay was used to investigate the expression of GS protein and evaluate the association with survival and the response to adjuvant TACE. Results: In training cohort, patients with low GS expression who received postoperative adjuvant TACE showed a better overall survival (OS) (P<0.001) and less early phase recurrence (P=0.016). Adjuvant TACE was an independent prognostic factor for 5-year OS (HR=0.408, 95% CI 0.261-0.639, P<0.001) and early phase recurrence (HR=0.592, 95% CI 0.376-0.931, P=0.023). The same result was confirmed in validation cohort. Patients with high GS expression in both cohorts did not have a significant response to adjuvant TACE in OS and early phase recurrence. Conclusions: GS status in tumor might be a useful tool in the selection of HCC patients who would be likely to benefit from postoperative adjuvant TACE. PMID:26884995

  9. Role of hepatectomy for recurrent or initially unresectable hepatocellular carcinoma

    PubMed Central

    Kishi, Yoji; Shimada, Kazuaki; Nara, Satoshi; Esaki, Minoru; Kosuge, Tomoo

    2014-01-01

    As a result of donor shortage and high postoperative morbidity and mortality after liver transplantation, hepatectomy is the most widely applicable and reliable option for curative treatment of hepatocellular carcinoma (HCC). Because intrahepatic tumor recurrence is frequent after loco-regional therapy, repeated treatments are advocated provided background liver function is maintained. Among treatments including local ablation and transarterial chemoembolization, hepatectomy provides the best long-term outcomes, but studies comparing hepatectomy with other nonsurgical treatments require careful review for selection bias. In patients with initially unresectable HCC, transarterial chemo-or radio-embolization, and/or systemic chemotherapy can down-stage the tumor and conversion to resectable HCC is achieved in approximately 20% of patients. However, complete response is rare, and salvage hepatectomy is essential to help prolong patients’ survival. To counter the short recurrence-free survival, excellent overall survival is obtained by combining and repeating different treatments. It is important to recognize hepatectomy as a complement, rather than a contraindication, to other nonsurgical treatments in a multidisciplinary approach for patients with HCC, including recurrent or unresectable tumors. PMID:25544870

  10. Causes of and prevention strategies for hepatocellular carcinoma.

    PubMed

    Cabibbo, Giuseppe; Maida, Marcello; Genco, Chiara; Antonucci, Michela; Cammà, Calogero

    2012-08-01

    Hepatocellular carcinoma (HCC) is a challenging malignancy of global importance. It is associated with a high rate of mortality and its prevalence in the United States and in Western Europe is increasing. Cirrhosis is the strongest and the most common known risk factor for HCC, usually due to hepatitis C virus (HCV) and hepatitis B virus (HBV) infections. However, different lines of evidence identify in non-alcoholic fatty liver disease (NAFLD) a possible relevant risk factor for occurrence of HCC. Given the continuing increase in the prevalence of obesity and diabetes, the incidence of non-alcoholic steatohepatitis-related HCC may also be expected to increase, and a potential role of behavior treatment and/or insulin-sensitizing drugs can be envisaged. Vaccination against HBV is the most efficient primary prevention measure currently available to reduce the HCC incidence and mortality in high-incidence areas, while data on the role of interferon (IFN) and nucleos(t)ide analogues (NUC) are still controversial. The pooling of data from the literature suggests a slight preventive effect of antiviral therapy on HCC development in patients with HCV-related cirrhosis, but the preventive effect is limited to sustained virological responders. PMID:22846856

  11. Androgen receptor roles in hepatocellular carcinoma, cirrhosis, and hepatitis

    PubMed Central

    Ma, Wen-Lung; Lai, Hsueh-Chou; Yeh, Shuyuan; Cai, Xiujun; Chang, Chawnshang

    2014-01-01

    Summary Androgen/androgen receptor (AR) signaling plays important roles in normal liver function and in progression of liver diseases. In studies of non-cancerous liver diseases, AR knockout mouse models of liver disease have revealed that androgen/AR signaling suppresses the development of steatosis, virus-related hepatitis, and cirrhosis. In addition, studies have shown that targeting AR in bone marrow-derived mesenchymal stem cells (BM-MSCs) improves their self-renewal and migration potentials, thereby increasing the efficacy of BM-MSC transplantation as a way to control the progression of cirrhosis. Androgen/AR signaling is known to be involved in the initiation of carcinogen- or Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). However, studies have demonstrated that AR, rather than androgen, plays the dominant role in cancer initiation. Therefore, targeting AR might be an appropriate therapy for patients with early-stage HCC. In contrast, androgen/AR signaling has been shown to suppress metastasis of HCC in patients with late-stage disease. In addition, there is evidence that therapy comprising Sorafenib and agents that enhance the functional expression of AR may suppress the progression of late-stage HCC. PMID:24424503

  12. Management strategies for hepatocellular carcinoma: old certainties and new realities.

    PubMed

    Mazzoccoli, Gianluigi; Tarquini, Roberto; Valoriani, Alice; Oben, Jude; Vinciguerra, Manlio; Marra, Fabio

    2016-08-01

    Hepatocellular carcinoma (HCC) is a highly prevalent disease ranking among the ten most common cancers worldwide with increasing trend of incidence in most developed countries. The great healthcare costs and economic burden of HCC dictate proper preventive interventions as well as surveillance and screening programs to decrease disease incidence and allow early diagnosis. HCC treatment outcomes are affected by several variables, including liver function, patient's performance status, and tumor stage. In line with the Barcelona Clinic Liver Cancer (BCLC) staging curative treatments, such as surgery or radio-frequency ablation, are indicated in early-stage HCC (BCLC-A), and the noncurative treatments are indicated in intermediate and advanced stages of HCC (BCLC-B, C). Transarterial chemoembolization (TACE) represents the treatment of choice for intermediate-stage HCC with Child-Pugh A cirrhosis, and the long-term survival after liver transplantation is inferior to that of early-stage HCCs. In advanced-stage HCC or when complete necrosis is not achieved or early recurrence after TACE develops, individualized treatments such as systemic treatment or combined radiation therapy are indicated. The increasing knowledge of the genomic landscape of HCC and the development of molecular-targeted therapies is heading toward expanding the armamentarium for HCC management. PMID:26077653

  13. Hepatocellular carcinoma: Advances in diagnosis, management, and long term outcome

    PubMed Central

    Bodzin, Adam S; Busuttil, Ronald W

    2015-01-01

    Hepatocellular carcinoma (HCC) remains a common and lethal malignancy worldwide and arises in the setting of a host of diseases. The incidence continues to increase despite multiple vaccines and therapies for viruses such as the hepatitis B and C viruses. In addition, due to the growing incidence of obesity in Western society, there is anticipation that there will be a growing population with HCC due to non-alcoholic fatty liver disease. Due to the growing frequency of this disease, screening is recommended using ultrasound with further imaging using magnetic resonance imaging and multi-detector computed tomography used for further characterization of masses. Great advances have been made to help with the early diagnosis of small lesions leading to potential curative resection or transplantation. Resection and transplantation maybe used in a variety of patients that are carefully selected based on underlying liver disease. Using certain guidelines and clinical acumen patients may have good outcomes with either resection or transplantation however many patients are inoperable at time of presentation. Fortunately, the use of new locoregional therapies has made down staging patients a potential option making them potential surgical candidates. Despite a growing population with HCC, new advances in viral therapies, chemotherapeutics, and an expanding population of surgical and transplant candidates might all contribute to improved long-term survival of these patients. PMID:26019732

  14. Guadecitabine (SGI-110) priming sensitizes hepatocellular carcinoma cells to oxaliplatin.

    PubMed

    Kuang, Yuting; El-Khoueiry, Anthony; Taverna, Pietro; Ljungman, Mats; Neamati, Nouri

    2015-11-01

    Promoter DNA hypermethylation is an important biomarker of hepatocellular carcinoma (HCC), supporting the potential utility of demethylating agents in this disease. Guadecitabine (SGI-110) is a second-generation hypomethylating agent formulated as a dinucleotide of decitabine and deoxyguanosine that yields longer half-life and more extended decitabine exposure than decitabine IV infusion. Here we performed preclinical evaluation of SGI-110 in HCC models to guide the design of a phase I/II clinical trial. HCC cell lines and xenograft models were used to determine the antitumor activity of SGI-110 as a single agent and in combination with oxaliplatin. Pretreatment with low doses of SGI-110 significantly synergized with oxaliplatin yielding enhanced cytotoxicity. The combination of SGI-110 and oxaliplatin was well tolerated and significantly delayed tumor growth in mice compared to oxaliplatin alone. Bromouridine-labeled RNA sequencing (Bru-seq) was employed to elucidate the effects of SGI-110 and/or oxaliplatin on genome-wide transcription. SGI-110 and the combination treatment inhibited the expression of genes involved in WNT/EGF/IGF signaling. DNMT1 and survivin were identified as novel PD markers to monitor the efficacy of the combination treatment. In conclusion, SGI-110 priming sensitizes HCC cells to oxaliplatin by inhibiting distinct signaling pathways. We expect that this combination treatment will show low toxicity and high efficacy in patients. Our study supports the use of the combination of low doses of SGI-110 and oxaliplatin in HCC patients. PMID:26160429

  15. Hepatitis B vaccination and prevention of hepatocellular carcinoma.

    PubMed

    Kao, Jia-Horng

    2015-12-01

    Hepatitis B virus (HBV) infection is a global health threat; with 240 million people are chronic carriers of the virus. The infection can cause acute and chronic liver disease including liver cirrhosis and hepatocellular carcinoma (HCC). On the basis of disease burden and the availability of safe and effective vaccines, World Health Organization has recommended that hepatitis B vaccine be incorporated into routine infant and childhood immunization programs for all countries. The efficacy of universal immunization has been proven in many countries, with substantial reductions of the prevalence of HBV carriage in children, adolescents and young adults. Most important, hepatitis B vaccination can protect them from HCC, as has been demonstrated in Taiwan and other countries. Nevertheless, the implementation of worldwide vaccination against HBV indeed requires more effort to overcome the social and economic challenges. To have a global control of HBV infection, we have to continue the universal HBV vaccination, interrupt the possible transmission routes and treat eligible patients with antiviral agents. However, current treatments are still far from ideal as they cannot eradicate intrahepatic HBV cccDNA, and lifelong administration of these agents will pose a major economic burden, especially in the endemic Asia-Pacific region. Thus we need innovative treatment strategies and novel agents with difference modes of action to overcome the unmet medical need for an efficient HBV cure with subsequent global eradication of HBV infection, hopefully by the first half of 21st century. PMID:26651252

  16. Epidemiology of Hepatocellular Carcinoma in the Asia-Pacific Region.

    PubMed

    Zhu, Ran Xu; Seto, Wai-Kay; Lai, Ching-Lung; Yuen, Man-Fung

    2016-05-23

    Hepatocellular carcinoma (HCC) is the predominant primary liver cancer in many countries and is the third most common cause of cancer-related death in the Asia-Pacific region. The incidence of HCC is higher in men and in those over 40 years old. In the Asia-Pacific region, chronic hepatitis B virus and hepatitis C virus infections are the main etiological agents; in particular, chronic hepatitis B infection (CHB) is still the major cause in all Asia-Pacific countries except for Japan. Over the past two decades, the incidence of HCC has remained stable in countries in the region except for Singapore and Hong Kong, where the incidence for both sexes is currently decreasing. Chronic hepatitis C infection (CHC) is an important cause of HCC in Japan, representing 70% of HCCs. Over the past several decades, the prevalence of CHC has been increasing in many Asia-Pacific countries, including Australia, New Zealand, and India. Despite advancements in treatment, HCC is still an important health problem because of the associated substantial mortality. An effective surveillance program could offer early diagnosis and hence better treatment options. Antiviral treatment for both CHB and CHC is effective in reducing the incidence of HCC. PMID:27114433

  17. Computed tomography predictors of hepatocellular carcinoma tumour necrosis after chemoembolization

    PubMed Central

    Bryant, Mary K; Dorn, David P; Zarzour, Jessica; Smith, J Kevin; Redden, David T; Saddekni, Souheil; Aal, Ahmed Kamel Abdel; Gray, Stephen H; Eckhoff, Devin E; DuBay, Derek A

    2014-01-01

    Background Radiographical features associated with a favourable response to trans-arterial chemoembolization (TACE) are poorly defined for patients with hepatocellular carcinoma (HCC). Methods From 2008 to 2012, all first TACE interventions for HCC performed at the University of Alabama at Birmingham (UAB) were retrospectively reviewed. Only patients with a pre-TACE and a post-TACE computed tomography (CT) scan were included in the analyses (n = 115). HCC tumour response to TACE was quantified via the the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria. Univariate and multivariable analyses were constructed. Results The index HCC tumours experienced a > 90% or complete tumour necrosis in 59/115 (51%) of patients after the first TACE intervention. On univariate analysis, smaller tumour size, peripheral tumour location and arterial enhancement were associated with a > 90% or complete tumour necrosis, whereas, only smaller tumour size [odds ratio (OR) 0.62; 95% confidence interval (CI) 0.48, 0.81] and peripheral location (OR 6.91; 95% CI 1.75, 27.29) were significant on multivariable analysis. There was a trend towards improved survival in the patients that experienced a > 90% or complete tumour necrosis (P = 0.08). Conclusions Peripherally located smaller HCC tumours are most likely to experience a > 90% or complete tumour necrosis after TACE. Surprisingly, arterial-phase enhancement and portal venous-phase washout were not significantly predictive of TACE-induced tumour necrosis. The TACE response was not statistically associated with improved survival. PMID:23980917

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

    SciTech Connect

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

    1986-06-01

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

  19. Tumor Heterogeneity in Hepatocellular Carcinoma: Facing the Challenges

    PubMed Central

    Lu, Li-Chun; Hsu, Chih-Hung; Hsu, Chiun; Cheng, Ann-Lii

    2016-01-01

    Tumor heterogeneity in hepatocellular carcinoma (HCC), such as that found in second primary tumors after curative treatment, synchronous multifocal tumors of different clonality, or intratumor heterogeneity, poses severe challenges for the development and administration of systemic molecular targeted therapies. Various methodologies, including historical DNA ploidy analysis, integrated hepatitis B virus DNA analysis, DNA fingerprinting, and next-generation sequencing technologies, are used to explore tumor heterogeneity in HCC. It is estimated that 30%-60% of recurrent or metastatic tumors harbor clones different from the primary tumor, 22%-79% of synchronous tumors vary clonally, and 12%-66% of single tumors contain intratumor heterogeneity. Substantial intertumor and intratumor heterogeneity renders biomarker identification, which is critical for the development and administration of molecular targeted therapy, challenging when applied to a single tumor biopsy specimen. The use of circulating tumor cells or circulating tumor DNA to evaluate overall tumor heterogeneity may help resolve this problem. This article reviews previous studies of tumor heterogeneity and discusses the implications and future opportunities regarding tumor heterogeneity in HCC.

  20. Development and novel therapeutics in hepatocellular carcinoma: a review.

    PubMed

    Ingle, Pravinkumar Vishwanath; Samsudin, Sarah Zakiah; Chan, Pei Qi; Ng, Mei Kei; Heng, Li Xuan; Yap, Siu Ching; Chai, Amy Siaw Hui; Wong, Audrey San Ying

    2016-01-01

    This review summarizes the epidemiological trend, risk factors, prevention strategies such as vaccination, staging, current novel therapeutics, including the drugs under clinical trials, and future therapeutic trends for hepatocellular carcinoma (HCC). As HCC is the third most common cause of cancer-related death worldwide, its overall incidence remains alarmingly high in the developing world and is steadily rising across most of the developed and developing world. Over the past 15 years, the incidence of HCC has more than doubled and it increases with advancing age. Chronic infection with hepatitis B virus is the leading cause of HCC, closely followed by infection with hepatitis C virus. Other factors contributing to the development of HCC include alcohol abuse, tobacco smoking, and metabolic syndrome (including obesity, diabetes, and fatty liver disease). Treatment options have improved in the past few years, particularly with the approval of several molecular-targeted therapies. The researchers are actively pursuing novel therapeutic targets as well as predictive biomarker for treatment of HCC. Advances are being made in understanding the mechanisms underlying HCC, which in turn could lead to novel therapeutics. Nevertheless, there are many emerging agents still under clinical trials and yet to show promising results. Hence, future therapeutic options may include different combination of novel therapeutic interventions. PMID:27042086

  1. Risk Factors for the Development of Hepatocellular Carcinoma in Thailand

    PubMed Central

    Chitapanarux, Taned; Phornphutkul, Kannika

    2015-01-01

    Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide. The incidence of HCC is on the rise in Thailand, where it has become the most common malignancy in males and the third most common in females. Here, we review some of the risk factors that have contributed to this increase in HCC incidence in the Thai population. Hepatitis B virus (HBV) is the main etiologic risk factor for HCC, followed by hepatitis C virus (HCV). Patients with HBV genotype C have a higher positive rate of hepatitis B early antigen (HBeAg) and progress to cirrhosis and HCC earlier than genotype B. For HCV patients, 16% developed HCC associated cirrhosis by year 5 after diagnosis, and the cumulative risk for death from HCC at year 10 was 60%. Dietary exposure to the fungal hepatocarcinogen aflatoxin B1 has been shown to interact synergistically with HBV infection to increase the risk of early onset HCC. Chronic alcohol abuse remains an important risk factor for malignant transformation of hepatocytes, frequently in association with alcohol-induced cirrhosis. In recent years, obesity and metabolic syndrome have markedly increased the incidence of HCC and are important causes of HCC in some resource-rich regions. PMID:26623264

  2. Staging systems for hepatocellular carcinoma: Current status and future perspectives

    PubMed Central

    Kinoshita, Akiyoshi; Onoda, Hiroshi; Fushiya, Nao; Koike, Kazuhiko; Nishino, Hirokazu; Tajiri, Hisao

    2015-01-01

    Hepatocellular carcinoma (HCC) is a major health concern worldwide and the third cause of cancer-related death. Despite advances in treatment as well as careful surveillance programs, the mortality rates in most countries are very high. In contrast to other cancers, the prognosis and treatment of HCC depend on the tumor burden in addition to patient’s underlying liver disease and liver functional reserve. Moreover, there is considerable geographic and institutional variation in both risk factors attributable to the underlying liver diseases and the management of HCC. Therefore, although many staging and/or scoring systems have been proposed, there is currently no globally accepted system for HCC due to the extreme heterogeneity of the disease. The aim of this review is to focus on currently available staging systems as well as those newly reported in the literatures since 2012. Moreover, we describe problems with currently available staging systems and attempts to modify and/or add variables to existing staging systems. PMID:25848467

  3. Adjuvant Iodine131 Lipiodol after Resection of Hepatocellular Carcinoma

    PubMed Central

    Furtado, Ruelan V.; Ha, Leo; Clarke, Stephen; Sandroussi, Charbel

    2015-01-01

    Background. Survival after liver resection for HCC is compromised by a high rate of intrahepatic recurrence. Adjuvant treatment with a single, postoperative dose of intra-arterial I131 lipiodol has shown promise, as a means of prolonging disease-free survival (DFS). Methodology. DFS and overall survival (OS) after a single dose of postoperative I131 lipiodol were compared to liver resection alone, for treatment of hepatocellular carcinoma (HCC). Data were collected retrospectively for patients who had a curative resection for HCC between December 1993 and September 2011. Seventy-two patients were given I131 lipiodol after surgery and 70 patients had surgery alone. Results. The DFS at 1, 3, and 5 years was 72%, 43%, and 26% in the surgery group and 70%, 39%, and 29% in the adjuvant I131 lipiodol group (p = 0.75). The 1-, 3-, and 5-year OS was 83%, 64%, and 52% in the surgery group and 96%, 72%, and 61% in the adjuvant I131 lipiodol group (p = 0.16). Conclusion. This retrospective study has found no significant benefit to survival, after adjuvant treatment with I131 lipiodol. PMID:26713092

  4. Natural history of hepatocellular carcinoma and current treatment options.

    PubMed

    Raoul, Jean-Luc

    2008-03-01

    Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer and the most severe complication of chronic liver disease. The annual number of new cases worldwide is approximately 550,000, representing more than 5% of human cancers and is the third leading cause of cancer-related deaths. The stages of the malignancy as well as the severity of the underlying liver disease are essential factors in planning the therapeutic approach. Curative treatment options are represented mainly by surgery (ie, resection or transplantation), but most patients are not candidates for a curative option, and only palliative treatment could be given to these patients. Among palliative treatments, only chemoembolization has been proven to be effective, but other options are currently being investigated. Major risk factors for HCC are well known and are dependent on the geographic area. In Europe, the United States, and Japan, the main risk factors are liver cirrhosis, hepatitis B and C virus, alcohol, and tobacco; in contrast, in Africa and Asia, these factors are hepatitis B and C virus, tobacco use, and aflatoxin exposure. Cirrhosis from any cause is a predisposing factor for HCC and could be considered as a premalignant condition. The present concept of carcinogenesis in HCC is a multistage process. This article describes the natural history of HCC and discusses the various treatment options available at present. PMID:18243838

  5. Multidisciplinary management of hepatocellular carcinoma: where are we today?

    PubMed

    Marrero, Jorge A

    2013-02-01

    Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide, and the incidence of HCC continues to rise. Improved understanding of risk factors for HCC has allowed the development of more effective prevention and surveillance strategies to reduce the global burden of this malignancy. Because of the complex nature of HCC, arising in a background of chronic liver dysfunction and often associated with viral infection, appropriate treatment requires a multidisciplinary approach designed to control the cancer and treat the underlying liver disease. Treatment approaches vary based on disease stage and severity, making accurate diagnosis and staging of disease critical. This has been aided by the development of new staging criteria, such as the Barcelona Clinic Liver Cancer Staging System. For earlier-stage disease, resection, radiofrequency ablation, transplantation, and transarterial chemoembolization (TACE) are preferred treatment modalities that provide optimal outcome. Until recently, few treatment options existed for patients with more advanced disease. Improved understanding of the underlying biology of the disease and the development of molecularly targeted therapies, including the multitargeted angiokinase inhibitor sorafenib, has improved outcomes in this patient population. Research into therapeutic targets and novel agents continues for more advanced disease. PMID:23457037

  6. Therapeutic inhibition of phospholipase D1 suppresses hepatocellular carcinoma.

    PubMed

    Xiao, Junjie; Sun, Qi; Bei, Yihua; Zhang, Ling; Dimitrova-Shumkovska, Jasmina; Lv, Dongchao; Yang, Yuefeng; Cao, Yan; Zhao, Yingying; Song, Meiyi; Song, Yang; Wang, Fei; Yang, Changqing

    2016-07-01

    Hepatocellular carcinoma (HCC) represents a leading cause of deaths worldwide. Novel therapeutic targets for HCC are needed. Phospholipase D (PD) is involved in cell proliferation and migration, but its role in HCC remains unclear. In the present study, we show that PLD1, but not PLD2, was overexpressed in HCC cell lines (HepG2, Bel-7402 and Bel-7404) compared with the normal human L-02 hepatocytes. PLD1 was required for the proliferation, migration and invasion of HCC cells without affecting apoptosis and necrosis, and PLD1 overexpression was sufficient to promote those effects. By using HCC xenograft models, we demonstrated that therapeutic inhibition of PLD1 attenuated tumour growth and epithelial-mesenchymal transition (EMT) in HCC mice. Moreover, PLD1 was found to be highly expressed in tumour tissues of HCC patients. Finally, mTOR (mechanistic target of rapamycin) and Akt (protein kinase B) were identified as critical pathways responsible for the role of PLD1 in HCC cells. Taken together, the present study indicates that PLD1 activation contributes to HCC development via regulation of the proliferation, migration and invasion of HCC cells, as well as promoting the EMT process. These observations suggest that inhibition of PLD1 represents an attractive and novel therapeutic modality for HCC. PMID:27129182

  7. 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

  8. Involvement of DNA Damage Response Pathways in Hepatocellular Carcinoma

    PubMed Central

    Yang, Sheau-Fang; Wei, Ren-Jie; Shiue, Yow-Ling; Wang, Shen-Nien

    2014-01-01

    Hepatocellular carcinoma (HCC) has been known as one of the most lethal human malignancies, due to the difficulty of early detection, chemoresistance, and radioresistance, and is characterized by active angiogenesis and metastasis, which account for rapid recurrence and poor survival. Its development has been closely associated with multiple risk factors, including hepatitis B and C virus infection, alcohol consumption, obesity, and diet contamination. Genetic alterations and genomic instability, probably resulted from unrepaired DNA lesions, are increasingly recognized as a common feature of human HCC. Dysregulation of DNA damage repair and signaling to cell cycle checkpoints, known as the DNA damage response (DDR), is associated with a predisposition to cancer and affects responses to DNA-damaging anticancer therapy. It has been demonstrated that various HCC-associated risk factors are able to promote DNA damages, formation of DNA adducts, and chromosomal aberrations. Hence, alterations in the DDR pathways may accumulate these lesions to trigger hepatocarcinogenesis and also to facilitate advanced HCC progression. This review collects some of the most known information about the link between HCC-associated risk factors and DDR pathways in HCC. Hopefully, the review will remind the researchers and clinicians of further characterizing and validating the roles of these DDR pathways in HCC. PMID:24877058

  9. Prognostic significance of Dicer expression in hepatocellular carcinoma

    PubMed Central

    ZHANG, LI; WANG, CUIJU; LIU, SHUFENG; ZHAO, YUFEI; LIU, CHAO; GUO, ZHANJUN

    2016-01-01

    Dicer is a RNaseIII endonuclease of the microRNA processing pathway, which is implicated in carcinogenesis of various types of human cancer. The present study assessed the expression level of Dicer in hepatocellular carcinoma (HCC) tissue to evaluate its association with HCC tumorigenesis. A low expression of Dicer was significantly associated with a shorter postoperative survival time of patients with HCC, which was assessed using the log-rank test with Kaplan-Meier survival analysis. Multivariate analysis identified that Dicer expression was an independent predictor for HCC outcome (relative risk, 0.660; 95% confidence interval, 0.506–0.861; P=0.002). A functional assay demonstrated that Dicer overexpression inhibited the proliferation and promoted the apoptosis of HCC cells. In addition, a Transwell assay revealed that Dicer markedly inhibited the migration and invasion of HCC cells. The present findings indicate that Dicer expression modified the outcomes of HCC patients by inhibiting proliferation, promoting apoptosis and inhibiting metastasis of HCC cells. PMID:27313724

  10. Downregulation of CCR1 inhibits human hepatocellular carcinoma cell invasion

    SciTech Connect

    Wu Xiaofeng; Fan Jia; E-mail: jiafan99@yahoo.com; Wang Xiaoying; Zhou Jian; Qiu Shuangjian; Yu Yao; Liu Yinkun; Tang Zhaoyou

    2007-04-20

    CC chemokine receptor 1 (CCR1) has an important role in the recruitment of leukocytes to the site of inflammation. The migration and metastasis of tumor cells shares many similarities with leukocyte trafficking, which is mainly regulated by chemokine receptor-ligand interactions. CCR1 is highly expressed in hepatocellular carcinoma (HCC) cells and tissues with unknown functions. In this study, we silenced CCR1 expression in the human HCC cell line HCCLM3 using artificial microRNA (miRNA)-mediated RNA interference (RNAi) and examined the invasiveness and proliferation of CCR1-silenced HCCLM3 cells and the matrix metalloproteinase (MMP) activity. The miRNA-mediated knockdown expression of CCR1 significantly inhibited the invasive ability of HCCLM3 cells, but had only a minor effect on the cellular proliferation rate. Moreover, CCR1 knockdown significantly reduced the secretion of MMP-2. Together, these findings indicate that CCR1 has an important role in HCCLM3 invasion and that CCR1 might be a new target of HCC treatment.

  11. Hepatocellular carcinoma in non-cirrhotic liver: a reappraisal.

    PubMed

    Trevisani, Franco; Frigerio, Marta; Santi, Valentina; Grignaschi, Alice; Bernardi, Mauro

    2010-05-01

    Although not frequently, hepatocellular carcinoma (HCC) can ensue in a non-cirrhotic liver. As compared to cirrhotic HCC, this kind of tumour has some peculiarities, such as: (a) a lower male preponderance and a bimodal age distribution; (b) a lower prevalence of the three main risk factors (hepatitis B and C virus infections and alcohol abuse), with an increased prevalence of other etiologic factors, such as exposure to genotoxic substances and sex hormones, inherited diseases, genetic mutations; (c) a more advanced tumour stage at the time of diagnosis, as it is usually detected due to the occurrence of cancer-related symptoms, outside any scheduled surveillance program; (d) a much higher amenability to hepatic resection, due to the low risk of liver failure even after extended parenchymal mutilation; (e) overall and disease-free survivals after resection of non-advanced tumours (meeting the Milano criteria) comparable to that obtained with liver transplantation in cirrhotic patients carrying an early tumour; (f) overall survival strictly dependent on tumour burden (and its recurrence) and barely influenced by liver function. PMID:19828388

  12. Prognostic value of DNA repair based stratification of hepatocellular carcinoma.

    PubMed

    Lin, Zhuo; Xu, Shi-Hao; Wang, Hai-Qing; Cai, Yi-Jing; Ying, Li; Song, Mei; Wang, Yu-Qun; Du, Shan-Jie; Shi, Ke-Qing; Zhou, Meng-Tao

    2016-01-01

    Aberrant activation of DNA repair is frequently associated with tumor progression and response to therapy in hepatocellular carcinoma (HCC). Bioinformatics analyses of HCC data in the Cancer Genome Atlas (TCGA) were performed to define DNA repair based molecular classification that could predict the prognosis of patients with HCC. Furthermore, we tested its predictive performance in 120 independent cases. Four molecular subgroups were identified on the basis of coordinate DNA repair cluster (CDRC) comprising 15 genes in TCGA dataset. Increasing expression of CDRC genes were significantly associated with TP53 mutation. High CDRC was significantly correlated with advanced tumor grades, advanced pathological stage and increased vascular invasion rate. Multivariate Cox regression analysis indicated that the molecular subgrouping was an independent prognostic parameter for both overall survival (p = 0.004, hazard ratio (HR): 2.989) and tumor-free survival (p = 0.049, HR: 3.366) in TCGA dataset. Similar results were also obtained by analyzing the independent cohort. These data suggest that distinct dysregulation of DNA repair constituents based molecular classes in HCC would be useful for predicting prognosis and designing clinical trials for targeted therapy. PMID:27174663

  13. Lactate Dehydrogenase in Hepatocellular Carcinoma: Something Old, Something New

    PubMed Central

    Faloppi, Luca; Bianconi, Maristella; Memeo, Riccardo; Casadei Gardini, Andrea; Giampieri, Riccardo; Bittoni, Alessandro; Andrikou, Kalliopi; Del Prete, Michela; Cascinu, Stefano; Scartozzi, Mario

    2016-01-01

    Hepatocellular carcinoma (HCC) is the most common primary liver tumour (80–90%) and represents more than 5.7% of all cancers. Although in recent years the therapeutic options for these patients have increased, clinical results are yet unsatisfactory and the prognosis remains dismal. Clinical or molecular criteria allowing a more accurate selection of patients are in fact largely lacking. Lactic dehydrogenase (LDH) is a glycolytic key enzyme in the conversion of pyruvate to lactate under anaerobic conditions. In preclinical models, upregulation of LDH has been suggested to ensure both an efficient anaerobic/glycolytic metabolism and a reduced dependence on oxygen under hypoxic conditions in tumour cells. Data from several analyses on different tumour types seem to suggest that LDH levels may be a significant prognostic factor. The role of LDH in HCC has been investigated by different authors in heterogeneous populations of patients. It has been tested as a potential biomarker in retrospective, small, and nonfocused studies in patients undergoing surgery, transarterial chemoembolization (TACE), and systemic therapy. In the major part of these studies, high LDH serum levels seem to predict a poorer outcome. We have reviewed literature in this setting trying to resume basis for future studies validating the role of LDH in this disease. PMID:27314036

  14. Optimal combination of antiangiogenic therapy for hepatocellular carcinoma

    PubMed Central

    Ch’ang, Hui-Ju

    2015-01-01

    The success of sorafenib in prolonging survival of patients with hepatocellular carcinoma (HCC) makes therapeutic inhibition of angiogenesis a component of treatment for HCC. To enhance therapeutic efficacy, overcome drug resistance and reduce toxicity, combination of antiangiogenic agents with chemotherapy, radiotherapy or other targeted agents were evaluated. Nevertheless, the use of antiangiogenic therapy remains suboptimal regarding dosage, schedule and duration of therapy. The issue is further complicated by combination antiangiogenesis to other cytotoxic or biologic agents. There is no way to determine which patients are most likely respond to a given form of antiangiogenic therapy. Activation of alternative pathways associated with disease progression in patients undergoing antiangiogenic therapy has also been recognized. There is increasing importance in identifying, validating and standardizing potential response biomarkers for antiangiogenesis therapy for HCC patients. In this review, biomarkers for antiangiogenesis therapy including systemic, circulating, tissue and imaging ones are summarized. The strength and deficit of circulating and imaging biomarkers were further demonstrated by a series of studies in HCC patients receiving radiotherapy with or without thalidomide. PMID:26261692

  15. Prognostic value of DNA repair based stratification of hepatocellular carcinoma

    PubMed Central

    Lin, Zhuo; Xu, Shi-Hao; Wang, Hai-Qing; Cai, Yi-Jing; Ying, Li; Song, Mei; Wang, Yu-Qun; Du, Shan-Jie; Shi, Ke-Qing; Zhou, Meng-Tao

    2016-01-01

    Aberrant activation of DNA repair is frequently associated with tumor progression and response to therapy in hepatocellular carcinoma (HCC). Bioinformatics analyses of HCC data in the Cancer Genome Atlas (TCGA) were performed to define DNA repair based molecular classification that could predict the prognosis of patients with HCC. Furthermore, we tested its predictive performance in 120 independent cases. Four molecular subgroups were identified on the basis of coordinate DNA repair cluster (CDRC) comprising 15 genes in TCGA dataset. Increasing expression of CDRC genes were significantly associated with TP53 mutation. High CDRC was significantly correlated with advanced tumor grades, advanced pathological stage and increased vascular invasion rate. Multivariate Cox regression analysis indicated that the molecular subgrouping was an independent prognostic parameter for both overall survival (p = 0.004, hazard ratio (HR): 2.989) and tumor-free survival (p = 0.049, HR: 3.366) in TCGA dataset. Similar results were also obtained by analyzing the independent cohort. These data suggest that distinct dysregulation of DNA repair constituents based molecular classes in HCC would be useful for predicting prognosis and designing clinical trials for targeted therapy. PMID:27174663

  16. Gold Nanoparticles and Radiofrequency in Experimental Models for Hepatocellular Carcinoma

    PubMed Central

    Raoof, Mustafa; Corr, Stuart J.; Zhu, Cihui; Cisneros, Brandon T.; Kaluarachchi, Warna D; Phounsavath, Sophia; Wilson, Lon J.; Curley, Steven A.

    2015-01-01

    Hepatocellular carcinoma (HCC) is one of the most lethal and chemo-refractory cancers, clearly, alternative treatment strategies are needed. We utilized 10nm gold nanoparticles as a scaffold to synthesize nanoconjugates bearing a targeting antibody (cetuximab, C225) and gemcitabine. Loading efficiency of gemcitabine on the gold nanoconjugates was 30%. Targeted gold nanoconjugates in combination with RF were selectively cytotoxic to EGFR expressing Hep3B and SNU449 cells when compared to isotype particles with/without RF (p<0.05). In animal experiments, targeted gold nanoconjugates halted the growth of subcutaneous Hep3B xenografts in combination with RF exposure (p<0.05). These xenografts also demonstrated increased apoptosis, necrosis and decreased proliferation compared to controls. Normal tissues were unharmed. We have demonstrated that non-invasive RF-induced hyperthermia when combined with targeted delivery of gemcitabine is more effective and safe at dosages ~275-fold lower than the current clinically-delivered systemic dose of gemcitabine. PMID:24650884

  17. Hepatocellular carcinoma: Exploring the impact of ethnicity on molecular biology.

    PubMed

    Lamarca, Angela; Mendiola, Marta; Barriuso, Jorge

    2016-09-01

    Hepatocellular carcinoma (HCC) is the sixth most common cancer in the world and the third leading cause of cancer-related death. The high rate of diagnosis in non-curable stages and the lack of novel active treatments make it necessary to review all the possible sources of misleading results in this scenario. The incidence of HCC shows clear geographical variation with higher annual incidence in Asia and Africa than in Western countries; we aimed to review the literature to find if there are different trends in the main activated molecular pathways. Hyperactivation of RAS/RAF/MEK/ERK and PI3K/AKT/mTOR signalling and epithelial to mesenchymal transition (EMT) process are more prevalent in the Western population; however, fibroblast growth factor (FGF), transforming growth factor β (TGFβ) and Notch pathways seems to be more relevant in Asian population. Whether these variations just reflect the distinct distribution of known causes of HCC or proper ethnical differences remain to be elucidated. Nevertheless, these clearly different patterns are relevant to regional or worldwide clinical trial design. If this information is neglected by sponsors and researchers the rate of failure in HCC trials will not improve. PMID:27372199

  18. Hepatocellular carcinoma beyond Milan criteria: Management and transplant selection criteria.

    PubMed

    Elshamy, Mohammed; Aucejo, Federico; Menon, K V Narayanan; Eghtesad, Bijan

    2016-07-28

    Liver transplantation (LT) for hepatocellular carcinoma (HCC) has been established as a standard treatment in selected patients for the last two and a half decades. After initially dismal outcomes, the Milan criteria (MC) (single HCC ≤ 5 cm or up to 3 HCCs ≤ 3 cm) have been adopted worldwide to select HCC patients for LT, however cumulative experience has shown that MC can be too strict. This has led to the development of numerous expanded criteria worldwide. Morphometric expansions on MC as well as various criteria which incorporate biomarkers as surrogates of tumor biology have been described. HCC that presents beyond MC initially can be downstaged with locoregional therapy (LRT). Post-LRT monitoring aims to identify candidates with favorable tumor behavior. Similarly, tumor marker levels as response to LRT has been utilized as surrogate of tumor biology. Molecular signatures of HCC have also been correlated to outcomes; these have yet to be incorporated into HCC-LT selection criteria formally. The ongoing discrepancy between organ demand and supply makes patient selection the most challenging element of organ allocation. Further validation of extended HCC-LT criteria models and pre-LT treatment strategies are required. PMID:27478537

  19. Changes in arginase isoenzymes pattern in human hepatocellular carcinoma

    SciTech Connect

    Chrzanowska, Alicja; Krawczyk, Marek; Baranczyk-Kuzma, Anna

    2008-12-12

    Hepatocellular carcinoma (HCC) is one of the most common tumors worldwide affecting preferentially patients with liver cirrhosis. The studies were performed on tissues obtained during surgery from 50 patients with HCC, 40 with liver cirrhosis and 40 control livers. It was found that arginase activity in HCC was nearly 5- and 15-fold lower than in cirrhotic and normal livers, respectively. Isoenzymes AI (so-called liver-type arginase) and AII (extrahepatic arginase) were identified by Western blotting in all studied tissues, however the amount of AI, as well as the expression of AI-mRNA were lower in HCC, in comparison with normal liver, and those of AII were significantly higher. Since HCC is arginine-dependent, and arginine is essential for cells growth, the decrease of AI may preserve this amino acid within tumor cells. Concurrently, the rise of AII can increase the level of polyamines, compounds crucial for cells proliferation. Thus, both arginase isoenzymes seem to participate in liver cancerogenesis.

  20. Current surgical treatment strategies for hepatocellular carcinoma in North America.

    PubMed

    Khan, Adeel S; Fowler, Kathryn J; Chapman, William C

    2014-11-01

    Hepatocellular carcinoma (HCC) is an aggressive tumor that often occurs in the setting of chronic liver disease. Many patients do not initially manifest any symptoms of HCC and present late when cure with surgical resection or transplantation is no longer possible. For this reason, patients at high risk for developing HCC are subjected to frequent screening processes. The surgical management of HCC is complex and requires an inter-disciplinary approach. Hepatic resection is the treatment of choice for HCC in patients without cirrhosis and is indicated in some patients with early cirrhosis (Child-Pugh A). Liver transplantation has emerged in the past decade as the standard of care for patients with cirrhosis and HCC meeting Milan criteria and in select patients with HCC beyond Milan criteria. Loco-regional therapy with transarterial chemoembolization, transarterial embolization, radiofrequency ablation and other similar local treatments can be used as neo-adjuvant therapy to downstage HCC to within Milan criteria or as a bridge to transplantation in patients on transplant wait list. PMID:25386049

  1. Liquid Biopsy of Hepatocellular Carcinoma: Circulating Tumor-Derived Biomarkers

    PubMed Central

    Yuan, Chun-Hui; Qu, Zhen; Guan, Qing; Chen, Hao

    2016-01-01

    Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide due to latent liver disease, late diagnosis, and nonresponse to systemic treatments. Till now, surgical and/or biopsy specimens are still generally used as a gold standard by the clinicians for clinical decision-making. However, apart from their invasive characteristics, tumor biopsy only mirrors a single spot of the tumor, failing to reflect current cancer dynamics and progression. Therefore, it is imperative to develop new diagnostic strategies with significant effectiveness and reliability to monitor high-risk populations and detect HCC at an early stage. In the past decade, the potent utilities of “liquid biopsy” have attracted intense concern and were developed to evaluate cancer progression in several clinical trials. “Liquid biopsies” represent a series of noninvasive tests that detect cancer byproducts easily accessible in peripheral blood, mainly including circulating tumor cells (CTCs) and cell-free nucleic acids (cfNAs) that are shed into the blood from the tumor sites. In this review, we focus on the recent developments in the field of “liquid biopsy” as well as the diagnostic and prognostic significance of CTCs and cfNAs in HCC patients. PMID:27403030

  2. FXR induces SOCS3 and suppresses hepatocellular carcinoma.

    PubMed

    Guo, Fei; Xu, Zhizhen; Zhang, Yan; Jiang, Peng; Huang, Gang; Chen, Shan; Lyu, Xilin; Zheng, Ping; Zhao, Xin; Zeng, Yijun; Wang, Shuguang; He, Fengtian

    2015-10-27

    Suppressor of cytokine signaling 3 (SOCS3) is regarded as a vital repressor in the liver carcinogenesis mainly by inhibiting signal transducer and activator of transcription 3 (STAT3) activity. Farnesoid X Receptor (FXR), highly expressed in liver, has an important role in protecting against hepatocellular carcinoma (HCC). However, it is unclear whether the tumor suppressive activity of FXR involves the regulation of SOCS3. In the present study, we found that activation of FXR by its specific agonist GW4064 in HCC cells inhibited cell growth, induced cell cycle arrest at G1 phase, elevated p21 expression and repressed STAT3 activity. The above anti-tumor effects of FXR were dramatically alleviated by knockdown of SOCS3 with siRNA. Reporter assay revealed that FXR activation enhanced the transcriptional activity of SOCS3 promoter. Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay displayed that FXR directly bound to IR9 DNA motif within SOCS3 promoter region. The in vivo study in nude mice showed that treatment with FXR ligand GW4064 could decelerate the growth of HCC xenografts, up-regulate SOCS3 and p21 expression and inhibit STAT3 phosphorylation in the xenografts. These results suggest that induction of SOCS3 may be a novel mechanism by which FXR exerts its anti-HCC effects, and the FXR-SOCS3 signaling may serve as a new potential target for the prevention/treatment of HCC. PMID:26416445

  3. Effect of saracatinib on pulmonary metastases from hepatocellular carcinoma.

    PubMed

    Xiong, Ju; Wu, Jin-Sheng; Mao, Shan-Shan; Yu, Xiang-Nan; Huang, Xiao-Xi

    2016-09-01

    Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Src is involved in multiple processes of cancer metastasis; however, its significance in HCC is not well defined. In the present study, overexpression of Src phosphorylation (Y416) was observed in the highly metastatic MHCC97H cell line; additionally, through inhibition of Src kinase activation, HCC cell proliferation, migration, invasion and colony formation were significantly reduced in vitro. Tumour growth was not affected in the orthotopic xenograft HCC model, but the metastasic potential was inhibited as revealed by reduced lung metastasic foci after administration of saracatinib. Phosphorylation level of Src pathway signalling molecules, such as Src, FAK and Stat3, were also reduced in vitro and in vivo, as a result of the anti-metastasic effects caused by saracatinib treatment. In conclusion, we demonstrated the pro-metastasic role of Src in HCC, and further experiments suggest the use of the Src inhibitor in combination with cytotoxic agents and other anticancer treatments to improve HCC prognosis. PMID:27460949

  4. Hepatocellular Carcinoma in Obesity, Type 2 Diabetes, and NAFLD.

    PubMed

    Reeves, Helen L; Zaki, Marco Y W; Day, Christopher P

    2016-05-01

    Hepatocellular carcinoma (HCC) is the second commonest cause of cancer death worldwide. Rather than falling as a result of prevention and treatments for viral hepatitis, an increase is evident in developed nations consequent to the rising prevalence of obesity and type 2 diabetes mellitus (T2DM)-the two major risk factors for nonalcoholic fatty liver disease (NAFLD). The majority of patients with HCC complicating these conditions present with advanced disease as the tools for surveillance are inadequate, and the "at-risk" population is not well characterized. This review will summarize the epidemiological evidence linking obesity, T2DM, and NAFLD with HCC, what is known about the pathogenic mechanisms involved, as well as their relevance for clinicians managing patients at risk. There will also be an overview of the "unmet needs" surrounding this topic, with suggestions for the direction translational research should take in order to prevent progression of NAFLD to HCC, to improve early detection of HCC in those with NAFLD, as well as to improve outcomes for those affected. PMID:26921078

  5. Multidisciplinary perspective of hepatocellular carcinoma: A Pacific Northwest experience

    PubMed Central

    Yeh, Matthew M; Yeung, Raymond S; Apisarnthanarax, Smith; Bhattacharya, Renuka; Cuevas, Carlos; Harris, William P; Hon, Tony Lim Kiat; Padia, Siddharth A; Park, James O; Riggle, Kevin M; Daoud, Sayed S

    2015-01-01

    Hepatocellular carcinoma (HCC) is the most rapidly increasing type of cancer in the United States. HCC is a highly malignant cancer, accounting for at least 14000 deaths in the United States annually, and it ranks third as a cause of cancer mortality in men. One major difficulty is that most patients with HCC are diagnosed when the disease is already at an advanced stage, and the cancer cannot be surgically removed. Furthermore, because almost all patients have cirrhosis, neither chemotherapy nor major resections are well tolerated. Clearly there is need of a multidisciplinary approach for the management of HCC. For example, there is a need for better understanding of the fundamental etiologic mechanisms that are involved in hepatocarcinogenesis, which could lead to the development of successful preventive and therapeutic modalities. It is also essential to define the cellular and molecular bases for malignant transformation of hepatocytes. Such knowledge would: (1) greatly facilitate the identification of patients at risk; (2) prompt efforts to decrease risk factors; and (3) improve surveillance and early diagnosis through diagnostic imaging modalities. Possible benefits extend also to the clinical management of this disease. Because there are many factors involved in pathogenesis of HCC, this paper reviews a multidisciplinary perspective of recent advances in basic and clinical understanding of HCC that include: molecular hepatocarcinogenesis, non-invasive diagnostics modalities, diagnostic pathology, surgical modality, transplantation, local therapy and oncological/target therapeutics. PMID:26085907

  6. MicroRNA-429 Modulates Hepatocellular Carcinoma Prognosis and Tumorigenesis

    PubMed Central

    Huang, Xiao-Ying; Yao, Jin-Guang; Wang, Chao; Ma, Yun; Xia, Qiang

    2013-01-01

    MicroRNA-429 (miR-429) may modify the development and progression of cancers; however, the role of this microRNA in the hepatocellular carcinoma (HCC) has not been well elaborated. Here, we tested miR-429 expression in 138 pathology-diagnosed HCC cases and SMMC-7721 cells. We found that miR-429 was upregulated in HCC tumor tissues and that the high expression of miR-429 was significantly correlated with larger tumor size (odd ratio (OR), 2.70; 95% confidence interval (CI), 1.28–5.56) and higher aflatoxin B1-DNA adducts (OR = 3.13, 95% CI = 1.47–6.67). Furthermore, this microRNA overexpression modified the recurrence-free survival and overall survival of HCC patients. Functionally, miR-429 overexpression progressed tumor cells proliferation and inhibited cell apoptosis. These results indicate for the first time that miR-429 may modify HCC prognosis and tumorigenesis and may be a potential tumor therapeutic target. PMID:24204382

  7. Role of sex steroid receptors in pathobiology of hepatocellular carcinoma

    PubMed Central

    Kalra, Mamta; Mayes, Jary; Assefa, Senait; Kaul, Anil K; Kaul, Rashmi

    2008-01-01

    The striking gender disparity observed in the incidence of hepatocellular carcinoma (HCC) suggests an important role of sex hormones in HCC pathogenesis. Though the studies began as early as in 1980s, the precise role of sex hormones and the significance of their receptors in HCC still remain poorly understood and perhaps contribute to current controversies about the potential use of hormonal therapy in HCC. A comprehensive review of the existing literature revealed several shortcomings associated with the studies on estrogen receptor (ER) and androgen receptor (AR) in normal liver and HCC. These shortcomings include the use of less sensitive receptor ligand binding assays and immunohistochemistry studies for ERα alone until 1996 when ERβ isoform was identified. The animal models of HCC utilized for studies were primarily based on chemical-induced hepatocarcinogenesis with less similarity to virus-induced HCC pathogenesis. However, recent in vitro studies in hepatoma cells provide newer insights for hormonal regulation of key cellular processes including interaction of ER and AR with viral proteins. In light of the above facts, there is an urgent need for a detailed investigation of sex hormones and their receptors in normal liver and HCC. In this review, we systematically present the information currently available on androgens, estrogens and their receptors in normal liver and HCC obtained from in vitro, in vivo experimental models and clinical studies. This information will direct future basic and clinical research to bridge the gap in knowledge to explore the therapeutic potential of hormonal therapy in HCC. PMID:18932272

  8. Hormonal control of the metabolic machinery of hepatocellular carcinoma.

    PubMed

    Wong, Carmen Chak-Lui; Wong, Chun-Ming; Ng, Irene Oi-Lin

    2016-06-01

    Hepatocellular carcinoma (HCC) is one of the most fatal malignancies worldwide. It is an aggressive cancer with low cure rate, frequent metastasis, and highly resistant to conventional chemotherapies. Better knowledge regarding the molecular and metabolic alterations in HCC will be instrumental to the development of novel therapeutic interventions against HCC. In the August 2015 issue of Hepatology, Nie et al. reports an important molecular pathway that contributes to the Warburg Effect in HCC. They have beautifully demonstrated that the loss of a component of a hormonal system, the mineralocorticoid receptor (MR), reprogrammed the metabolic machinery of HCC cells to aerobic glycolysis through the miR-338-3p-PKL/R axis. The implication could be that in addition to drugs that directly target the metabolic enzymes in cancer cells, more translational efforts could be focused on the development of drugs that involve the activation of the MR-aldosterone system or other hormonal systems to target the Warburg effect. PMID:27275458

  9. Novel hepatocellular carcinoma molecules with prognostic and therapeutic potentials

    PubMed Central

    Scaggiante, Bruna; Kazemi, Maryam; Pozzato, Gabriele; Dapas, Barbara; Farra, Rosella; Grassi, Mario; Zanconati, Fabrizio; Grassi, Gabriele

    2014-01-01

    Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, is the sixth most common cancer worldwide and the third leading cause of cancer-related death. The difficulty to diagnose early cancer stages, the aggressive behaviors of HCC, and the poor effectiveness of therapeutic treatments, represent the reasons for the quite similar deaths per year and incidence number. Considering the fact that the diagnosis of HCC typically occurs in the advanced stages of the disease when the therapeutic options have only modest efficacy, the possibility to identify early diagnostic markers could be of significant benefit. So far, a large number of biomarkers have been associated to HCC progression and aggressiveness, but many of them turned out not to be of practical utility. This is the reason why active investigations are ongoing in this field. Given the huge amount of published works aimed at the identification of HCC biomarkers, in this review we mainly focused on the data published in the last year, with particular attention to the role of (1) molecular and biochemical cellular markers; (2) micro-interfering RNAs; (3) epigenetic variations; and (4) tumor stroma. It is worth mentioning that a significant number of the HCC markers described in the present review may be utilized also as targets for novel therapeutic approaches, indicating the tight relation between diagnosis and therapy. In conclusion, we believe that integrated researches among the different lines of investigation indicated above should represent the winning strategies to identify effective HCC markers and therapeutic targets. PMID:24574801

  10. Three-dimensional Organotypic Culture Models of Human Hepatocellular Carcinoma

    PubMed Central

    Takai, Atsushi; Fako, Valerie; Dang, Hien; Forgues, Marshonna; Yu, Zhipeng; Budhu, Anuradha; Wang, Xin Wei

    2016-01-01

    Three-dimensional cell culture methods are viable in vitro approaches that facilitate the examination of biological features cancer cells present in vivo. In this study, we demonstrate that hepatocellular carcinoma (HCC) cells in porous alginate scaffolds can generate organoid-like spheroids that mimic numerous features of glandular epithelium in vivo, such as acinar morphogenesis and apical expression patterns of EpCAM, a hepatic stem/progenitor cell marker highly expressed in a subset of HCC with stemness features. We show that the activation of Wnt/β-catenin signaling, an essential pathway for maintaining HCC stemness, is required for EpCAM+ HCC spheroid formation as well as the maintenance of the acinous structure. Furthermore, we demonstrate that EpCAM+ HCC cells cultured as spheroids are more sensitive to TGF/β-induced epithelial-mesenchymal transition with highly tumorigenic and metastatic potential in vivo compared to conventional two-dimensional (2D) culture. In addition, HCC cells in EpCAM+ spheroids are more resistant to chemotherapeutic agents than 2D-cultured cells. The alginate scaffold-based organotypic culture system is a promising, reliable, and easy system that can be configured into a high throughput fashion for the identification of critical signaling pathways and screening of molecular drug targets specific for HCC. PMID:26880118

  11. MPHOSPH1: a potential therapeutic target for hepatocellular carcinoma.

    PubMed

    Liu, Xinran; Zhou, Yafan; Liu, Xinyuan; Peng, Anlin; Gong, Hao; Huang, Lizi; Ji, Kaige; Petersen, Robert B; Zheng, Ling; Huang, Kun

    2014-11-15

    MPHOSPH1 is a critical kinesin protein that functions in cytokinesis. Here, we show that MPHOSPH1 is overexpressed in hepatocellular carcinoma (HCC) cells, where it is essential for proliferation. Attenuating MPHOSPH1 expression with a tumor-selective shRNA-expressing adenovirus (Ad-shMPP1) was sufficient to arrest HCC cell proliferation in a manner associated with an accumulation of multinucleated polyploid cells, induction of postmitotic apoptosis, and increased sensitivity to taxol cytotoxicity. Mechanistic investigations showed that attenuation of MPHOSPH1 stabilized p53, blocked STAT3 phosphorylation, and prolonged mitotic arrest. In a mouse subcutaneous xenograft model of HCC, tumoral injection of Ad-shMPP1 inhibited MPHOSPH1 expression and tumor growth in a manner correlated with induction of apoptosis. Combining Ad-shMPP1 injection with taxol administration enhanced antitumor efficacy relative to taxol alone. Furthermore, Ad-shMPP1 tail vein injection suppressed formation of orthotopic liver nodules and prevented hepatic dysfunction. Taken together, our results identify MPHOSPH1 as an oncogenic driver and candidate therapeutic target in HCC. PMID:25269478

  12. Epidemiology of Hepatocellular Carcinoma in the Asia-Pacific Region

    PubMed Central

    Zhu, Ran Xu; Seto, Wai-Kay; Lai, Ching-Lung; Yuen, Man-Fung

    2016-01-01

    Hepatocellular carcinoma (HCC) is the predominant primary liver cancer in many countries and is the third most common cause of cancer-related death in the Asia-Pacific region. The incidence of HCC is higher in men and in those over 40 years old. In the Asia-Pacific region, chronic hepatitis B virus and hepatitis C virus infections are the main etiological agents; in particular, chronic hepatitis B infection (CHB) is still the major cause in all Asia-Pacific countries except for Japan. Over the past two decades, the incidence of HCC has remained stable in countries in the region except for Singapore and Hong Kong, where the incidence for both sexes is currently decreasing. Chronic hepatitis C infection (CHC) is an important cause of HCC in Japan, representing 70% of HCCs. Over the past several decades, the prevalence of CHC has been increasing in many Asia-Pacific countries, including Australia, New Zealand, and India. Despite advancements in treatment, HCC is still an important health problem because of the associated substantial mortality. An effective surveillance program could offer early diagnosis and hence better treatment options. Antiviral treatment for both CHB and CHC is effective in reducing the incidence of HCC. PMID:27114433

  13. National Cancer Centre Singapore Consensus Guidelines for Hepatocellular Carcinoma

    PubMed Central

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

    2016-01-01

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

  14. Tumor information extraction in radiology reports for hepatocellular carcinoma patients.

    PubMed

    Yim, Wen-Wai; Denman, Tyler; Kwan, Sharon W; Yetisgen, Meliha

    2016-01-01

    Hepatocellular carcinoma (HCC) is a deadly disease affecting the liver for which there are many available therapies. Targeting treatments towards specific patient groups necessitates defining patients by stage of disease. Criteria for such stagings include information on tumor number, size, and anatomic location, typically only found in narrative clinical text in the electronic medical record (EMR). Natural language processing (NLP) offers an automatic and scale-able means to extract this information, which can further evidence-based research. In this paper, we created a corpus of 101 radiology reports annotated for tumor information. Afterwards we applied machine learning algorithms to extract tumor information. Our inter-annotator partial match agreement scored at 0.93 and 0.90 F1 for entities and relations, respectively. Based on the annotated corpus, our sequential labeling entity extraction achieved 0.87 F1 partial match, and our maximum entropy classification relation extraction achieved scores 0.89 and 0. 74 F1 with gold and system entities, respectively. PMID:27570686

  15. Multimodal treatment of hepatocellular carcinoma on cirrhosis: An update

    PubMed Central

    Vivarelli, Marco; Montalti, Roberto; Risaliti, Andrea

    2013-01-01

    Hepatocellular carcinoma (HCC) is the most frequent primary liver tumor, and overall, it is one of the most frequent cancers. The association of HCC with chronic liver disease, and cirrhosis in particular, is well known, making treatment complex and challenging. The treatment of HCC must take into account the presence and stage of chronic liver disease, with the aim of preserving hepatic function that is often already impaired, the stage of HCC and the clinical condition of the patient. The different treatment options include surgical resection, transplantation, local ablation, chemoembolization, radioembolization and molecular targeted therapies; these treatments can be combined in various ways to achieve different goals. Ideally, liver transplantation is best treatment for early stage HCC on cirrhosis because it removes both the tumor and the chronic disease that produced it; however, the application of this powerful tool is limited by the scarcity of donors. Downstaging and bridging are different strategies for the management of HCC patients who will undergo liver transplantation. Several professionals, including gastroenterologists, radiologists and surgeons, are involved in the choice of the most appropriate treatment for a single case, and a multidisciplinary approach is necessary to optimize the outcome. The purpose of this review is to provide a comprehensive description of the current treatment options for patients with HCC by analyzing the advantages, disadvantages and rationale for their use. PMID:24259963

  16. Liver Stem Cells and Molecular Signaling Pathways in Hepatocellular Carcinoma

    PubMed Central

    Kitisin, Krit; Pishvaian, Michael J.

    2007-01-01

    Hepatocellular carcinoma (HCC) is one of the most lethal cancers. Surgical intervention is the only curative option, with only a small fraction of patients being eligible. Conventional chemotherapy and radiotherapy have not been effective in treating this disease, thus leaving patients with an extremely poor prognosis. In viral, alcoholic, and other chronic hepatitis, it has been shown that there is an activation of the progenitor/stem cell population, which has been found to reside in the canals of Hering. In fact, the degree of inflammation and the disease stage have been correlated with the degree of activation. Dysregulation of key regulatory signaling pathways such as transforming growth factor-beta/transforming growth factor-beta receptor (TGF-β/TBR), insulin-like growth factor/IGF-1 receptor (IGF/IGF-1R), hepatocyte growth factor (HGF/MET), Wnt/β-catenin/FZD, and transforming growth factor-α/epidermal growth factor receptor (TGF-α/EGFR) in this progenitor/stem cell population could give rise to HCC. Further understanding of these key signaling pathways and the molecular and genetic alterations associated with HCC could provide major advances in new therapeutic and diagnostic modalities. PMID:19360142

  17. The Epidemiological Investigation on the Risk Factors of Hepatocellular Carcinoma

    PubMed Central

    Niu, Jianjun; Lin, Yong; Guo, Zhinan; Niu, Mu; Su, Chenghao

    2016-01-01

    Abstract Incidence of hepatocellular carcinoma (HCC) ranked the fifth in male and ninth in the female counterparts, and 50% of incidence HCC cases were occurred in China with high hepatitis B virus (HBV) prevalence. HCC has seriously compromised the health status of general population in China. A case–control study of 314 HCC cases and 346 controls was conducted in Xiamen, which is an epidemic area in China for both hepatitis B infection and HCC. Face-to-face interview was conducted to gather information on demographic characteristics as well as exposure of environmental factors. Commercial enzyme-linked immunosorbent assay kits were used to determine the status of serological markers of HBV infection. Odds ratios and 95% confidence intervals were estimated by using unconditional logistic regression. Multivariate unconditional logistic regression analysis was applied to evaluate the potential interactions of variables or confounders. As expected, HBV and alcohol intake still are the major risk factors of HCC. Liver disease history and passive smoking are also associated with elevated HCC risk. Indoor air pollution and pesticide exposure have newly identified as risk factors of HCC. Fruit and tea intake can significantly lower the HCC risk. The application of HBV vaccine and reduction on alcohol intake should be further promoted in high-risk population. Fruit and tea can be served as chemoprevention in daily life due to their high accessibility. PMID:26871825

  18. Wnt-/-β-catenin pathway signaling in human hepatocellular carcinoma

    PubMed Central

    Waisberg, Jaques; Saba, Gabriela Tognini

    2015-01-01

    The molecular basis of the carcinogenesis of hepatocellular carcinoma (HCC) has not been adequately clarified, which negatively impacts the development of targeted therapy protocols for this overwhelming neoplasia. The aberrant activation of signaling in the HCC is primarily due to the deregulated expression of the components of the Wnt-/-β-catenin. This leads to the activation of β-catenin/T-cell factor-dependent target genes that control cell proliferation, cell cycle, apoptosis, and cell motility. The deregulation of the Wnt pathway is an early event in hepatocarcinogenesis. An aggressive phenotype was associated with HCC, since this pathway is implicated in the proliferation, migration, and invasiveness of cancer cells, regarding the cell’s own survival. The disruption of the signaling cascade Wnt-/-β-catenin has shown anticancer properties in HCC’s clinical evaluations of therapeutic molecules targeted for blocking the Wnt signaling pathway for the treatment of HCC, and it represents a promising perspective. The key to bringing this strategy in to clinical practice is to identify new molecules that would be effective only in tumor cells with aberrant signaling β-catenin. PMID:26609340

  19. Wnt-/-β-catenin pathway signaling in human hepatocellular carcinoma.

    PubMed

    Waisberg, Jaques; Saba, Gabriela Tognini

    2015-11-18

    The molecular basis of the carcinogenesis of hepatocellular carcinoma (HCC) has not been adequately clarified, which negatively impacts the development of targeted therapy protocols for this overwhelming neoplasia. The aberrant activation of signaling in the HCC is primarily due to the deregulated expression of the components of the Wnt-/-β-catenin. This leads to the activation of β-catenin/T-cell factor-dependent target genes that control cell proliferation, cell cycle, apoptosis, and cell motility. The deregulation of the Wnt pathway is an early event in hepatocarcinogenesis. An aggressive phenotype was associated with HCC, since this pathway is implicated in the proliferation, migration, and invasiveness of cancer cells, regarding the cell's own survival. The disruption of the signaling cascade Wnt-/-β-catenin has shown anticancer properties in HCC's clinical evaluations of therapeutic molecules targeted for blocking the Wnt signaling pathway for the treatment of HCC, and it represents a promising perspective. The key to bringing this strategy in to clinical practice is to identify new molecules that would be effective only in tumor cells with aberrant signaling β-catenin. PMID:26609340

  20. Recent progress in radiofrequency ablation therapy for hepatocellular carcinoma.

    PubMed

    Ikeda, Kenji; Osaki, Yukio; Nakanishi, Hiroyuki; Nasu, Akihiro; Kawamura, Yusuke; Jyoko, Koji; Sano, Takatomo; Sunagozaka, Hajime; Uchino, Koji; Minami, Yasunori; Saito, Yu; Nagai, Kazumasa; Inokuchi, Ryosuke; Kokubu, Shigehiro; Kudo, Masatoshi

    2014-01-01

    In order to attain better ablation and more effective management of hepatocellular carcinoma (HCC), new approaches and devices in radiofrequency ablation (RFA) therapy were presented and discussed in a workshop at the 50th Annual Meeting of the Liver Cancer Study Group of Japan. A novel bipolar RFA apparatus was introduced in Japan in January 2013. Hundreds of subjects with HCC were treated with multipolar RFA with varied devices and plans. Among these, no-touch ablation was one of the most useful procedures in the treatment of HCC with the apparatus. In RFA therapy, a few assisting devices and techniques were applied for convenience and improvement of the thermal ablation procedure. Contrast-enhanced ultrasonography and three-dimensional fusion imaging technique using volume data of CT or MRI could improve exact targeting and shorten the treatment time for RFA procedures under ultrasonographic guidance. A more complicated method using a workstation was also reported as being helpful in planning the ablated shape and volume in multineedle RFA. The effective use of sedatives and antianalgesics as well as a novel microwave apparatus with a cooled-tip electrode was also discussed. PMID:25427736

  1. Induction of hepatocellular carcinoma by in vivo gene targeting

    PubMed Central

    Wang, Pei-Rong; Xu, Mei; Toffanin, Sara; Li, Yi; Llovet, Josep M.; Russell, David W.

    2012-01-01

    The distinct phenotypic and prognostic subclasses of human hepatocellular carcinoma (HCC) are difficult to reproduce in animal experiments. Here we have used in vivo gene targeting to insert an enhancer-promoter element at an imprinted chromosome 12 locus in mice, thereby converting ∼1 in 20,000 normal hepatocytes into a focus of HCC with a single genetic modification. A 300-kb chromosomal domain containing multiple mRNAs, snoRNAs, and microRNAs was activated surrounding the integration site. An identical domain was activated at the syntenic locus in a specific molecular subclass of spontaneous human HCCs with a similar histological phenotype, which was associated with partial loss of DNA methylation. These findings demonstrate the accuracy of in vivo gene targeting in modeling human cancer and suggest future applications in studying various tumors in diverse animal species. In addition, similar insertion events produced by randomly integrating vectors could be a concern for liver-directed human gene therapy. PMID:22733778

  2. National Cancer Centre Singapore Consensus Guidelines for Hepatocellular Carcinoma.

    PubMed

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

    2016-04-01

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

  3. Update in management of hepatocellular carcinoma in Eastern population.

    PubMed

    Chu, Kevin Ka Wan; Cheung, Tan To

    2015-06-18

    Hepatocellular carcinoma (HCC) is one of the commonest malignant tumours in the East. Although the management of HCC in the West is mainly based on the Barcelona Clinic for Liver Cancer staging, it is considered too conservative by Asian countries where the number of HCC patients is huge. Scientific and clinical advances were made in aspects of diagnosis, staging, and treatment of HCC. HCC is well known to be associated with cirrhosis and the treatment of HCC must take into account the presence and stage of chronic liver disease. The major treatment modalities of HCC include: (1) surgical resection; (2) liver transplantation; (3) local ablation therapy; (4) transarterial locoregional treatment; and (5) systemic treatment. Among these, resection, liver transplantation and ablation therapy for small HCC are considered as curative treatment. Portal vein embolisation and the associating liver partition with portal vein ligation for staged hepatectomy may reduce dropout in patients with marginally resectable disease but the midterm and long-term results are still to be confirmed. Patient selection for the best treatment modality is the key to success of treatment of HCC. The purpose of current review is to provide a description of the current advances in diagnosis, staging, pre-operative liver function assessment and treatment options for patients with HCC in the east. PMID:26085915

  4. Management of hepatocellular carcinoma with portal vein thrombosis.

    PubMed

    Quirk, Matthew; Kim, Yun Hwan; Saab, Sammy; Lee, Edward Wolfgang

    2015-03-28

    Management of hepatocellular carcinoma (HCC) with portal vein thrombosis (PVT) is complex and requires an understanding of multiple therapeutic options. PVT is present in 10%-40% of HCC at the time of diagnosis, and is an adverse prognostic factor. Management options are limited, as transplantation is generally contraindicated, and surgical resection is only rarely performed in select centers. Systemic medical therapy with sorafenib has been shown to modestly prolong survival. Transarterial chemoembolization has been performed in select cases but has shown a high incidence of complications. Emerging data on treatment of PVT with Y-90 radioembolization suggest that this modality is well-tolerated and associated with favorable overall survival. Current society guidelines do not yet specifically recommend radioembolization for patients with PVT, but this may change with the development of newer staging systems and treatment algorithms. In this comprehensive literature review, we present current and available management options with the relative advantages, disadvantages and contraindications of these treatment options with summarized data on overall survival. PMID:25834310

  5. Tumor Heterogeneity in Hepatocellular Carcinoma: Facing the Challenges.

    PubMed

    Lu, Li-Chun; Hsu, Chih-Hung; Hsu, Chiun; Cheng, Ann-Lii

    2016-04-01

    Tumor heterogeneity in hepatocellular carcinoma (HCC), such as that found in second primary tumors after curative treatment, synchronous multifocal tumors of different clonality, or intratumor heterogeneity, poses severe challenges for the development and administration of systemic molecular targeted therapies. Various methodologies, including historical DNA ploidy analysis, integrated hepatitis B virus DNA analysis, DNA fingerprinting, and next-generation sequencing technologies, are used to explore tumor heterogeneity in HCC. It is estimated that 30%-60% of recurrent or metastatic tumors harbor clones different from the primary tumor, 22%-79% of synchronous tumors vary clonally, and 12%-66% of single tumors contain intratumor heterogeneity. Substantial intertumor and intratumor heterogeneity renders biomarker identification, which is critical for the development and administration of molecular targeted therapy, challenging when applied to a single tumor biopsy specimen. The use of circulating tumor cells or circulating tumor DNA to evaluate overall tumor heterogeneity may help resolve this problem. This article reviews previous studies of tumor heterogeneity and discusses the implications and future opportunities regarding tumor heterogeneity in HCC. PMID:27386431

  6. 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

  7. The effect of LOXL2 in hepatocellular carcinoma.

    PubMed

    Wu, Linghong; Zhang, Yuan; Zhu, Ying; Cong, Qingwei; Xiang, Yan; Fu, Linlin

    2016-09-01

    Lysyl oxidase-like 2 (LOXL2) is key in the hepatocellular carcinoma (HCC) tumor microenvironment and metastatic niche formation. However, its effect on proliferation and clinical parameters in HCC require further elucidation. The present study aimed to investigate LOXL2 expression in HCC from in vitro and clinical aspects. The present study constructed LOXL2‑small interfering RNA with a lentiviral vector, investigated the effect of LOXL2 on proliferation using HCC cell lines via a series of assays, including reverse transcription‑quantitative polymerase chain reaction, cell counting, colony formation, assessment of cell cycle and apoptosis using flow cytometry, MTT and BrdU. Furthermore, 80 tissue samples from HCC patients at The First Affiliated Hospital of Dalian Medical University (Dalian, China) from 2007 to 2010. Immunohistochemical staining was used to clinically verify LOXL2 expression. The results of the present study demonstrate that LOXL2 silencing decreased cell numbers, proliferation, colony formations and cell growth, induced cell cycle arrest and increased apoptosis. Clinically, expression levels of LOXL2 was markedly increased in matched adjacent non‑tumor tissue (ANT) samples compared with levels in tumor tissue (TT) samples, and this gradually increased with higher histological grade and more advanced TNM classification in the matched ANT and TT samples. LOXL2 was determined to promote proliferation of HCC and demonstrated to be highly expressed in HCC ANT samples compared with TT samples. PMID:27430160

  8. Targeting Wnt/β-catenin pathway in hepatocellular carcinoma treatment

    PubMed Central

    Vilchez, Valery; Turcios, Lilia; Marti, Francesc; Gedaly, Roberto

    2016-01-01

    Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide. Liver cancer is generally related to hepatitis B or C infection and cirrhosis. Usually, patients with HCC are asymptomatic and are diagnosed at late stages when surgical treatment is no longer suitable. Limited treatment options for patients with advanced HCC are a major concern. Therefore, there is an urge for finding novel therapies to treat HCC. Liver cancer is highly heterogeneous and involved deregulation of several signaling pathways. Wnt/β-catenin pathway is frequently upregulated in HCC and it is implicated in maintenance of tumor initiating cells, drug resistance, tumor progression, and metastasis. A great effort in developing selective drugs to target components of the β-catenin pathway with anticancer activity is underway but only a few of them have reached phase I clinical trials. We aim to review the role of β-catenin pathway on hepatocarcinogenesis and liver cancer stem cell maintenance. We also evaluated the use of small molecules targeting the Wnt/β-catenin pathway with potential application for treatment of HCC. PMID:26811628

  9. Preoperative portal vein embolization for hepatocellular carcinoma: Consensus and controversy

    PubMed Central

    Aoki, Taku; Kubota, Keiichi

    2016-01-01

    Thirty years have passed since the first report of portal vein embolization (PVE), and this procedure is widely adopted as a preoperative treatment procedure for patients with a small future liver remnant (FLR). PVE has been shown to be useful in patients with hepatocellular carcinoma (HCC) and chronic liver disease. However, special caution is needed when PVE is applied prior to subsequent major hepatic resection in cases with cirrhotic livers, and volumetric analysis of the liver segments in addition to evaluation of the liver functional reserve before PVE is mandatory in such cases. Advances in the embolic material and selection of the treatment approach, and combined use of PVE and transcatheter arterial embolization/chemoembolization have yielded improved outcomes after PVE and major hepatic resections. A novel procedure termed the associating liver partition and portal vein ligation for staged hepatectomy has been gaining attention because of the rapid hypertrophy of the FLR observed in patients undergoing this procedure, however, application of this technique in HCC patients requires special caution, as it has been shown to be associated with a high morbidity and mortality even in cases with essentially healthy livers. PMID:27028706

  10. Dysregulated serum response factor triggers formation of hepatocellular carcinoma

    PubMed Central

    Ohrnberger, Stefan; Thavamani, Abhishek; Braeuning, Albert; Lipka, Daniel B; Kirilov, Milen; Geffers, Robert; Authenrieth, Stella E; Römer, Michael; Zell, Andreas; Bonin, Michael; Schwarz, Michael; Schütz, Günther; Schirmacher, Peter; Plass, Christoph; Longerich, Thomas; Nordheim, Alfred

    2015-01-01

    The ubiquitously expressed transcriptional regulator serum response factor (SRF) is controlled by both Ras/MAPK (mitogen-activated protein kinase) and Rho/actin signaling pathways, which are frequently activated in hepatocellular carcinoma (HCC). We generated SRF-VP16iHep mice, which conditionally express constitutively active SRF-VP16 in hepatocytes, thereby controlling subsets of both Ras/MAPK- and Rho/actin-stimulated target genes. All SRF-VP16iHep mice develop hyperproliferative liver nodules that progresses to lethal HCC. Some murine (m)HCCs acquire Ctnnb1 mutations equivalent to those in human (h)HCC. The resulting transcript signatures mirror those of a distinct subgroup of hHCCs, with shared activation of oncofetal genes including Igf2, correlating with CpG hypomethylation at the imprinted Igf2/H19 locus. Conclusion: SRF-VP16iHep mHCC reveal convergent Ras/MAPK and Rho/actin signaling as a highly oncogenic driver mechanism for hepatocarcinogenesis. This suggests simultaneous inhibition of Ras/MAPK and Rho/actin signaling as a treatment strategy in hHCC therapy. (Hepatology 2015;61:979–989) PMID:25266280

  11. Management of hepatocellular carcinoma with portal vein thrombosis

    PubMed Central

    Quirk, Matthew; Kim, Yun Hwan; Saab, Sammy; Lee, Edward Wolfgang

    2015-01-01

    Management of hepatocellular carcinoma (HCC) with portal vein thrombosis (PVT) is complex and requires an understanding of multiple therapeutic options. PVT is present in 10%-40% of HCC at the time of diagnosis, and is an adverse prognostic factor. Management options are limited, as transplantation is generally contraindicated, and surgical resection is only rarely performed in select centers. Systemic medical therapy with sorafenib has been shown to modestly prolong survival. Transarterial chemoembolization has been performed in select cases but has shown a high incidence of complications. Emerging data on treatment of PVT with Y-90 radioembolization suggest that this modality is well-tolerated and associated with favorable overall survival. Current society guidelines do not yet specifically recommend radioembolization for patients with PVT, but this may change with the development of newer staging systems and treatment algorithms. In this comprehensive literature review, we present current and available management options with the relative advantages, disadvantages and contraindications of these treatment options with summarized data on overall survival. PMID:25834310

  12. Transcatheter Arterial Chemoembolization Based on Hepatic Hemodynamics for Hepatocellular Carcinoma

    PubMed Central

    Murata, Satoru; Mine, Takahiko; Ueda, Tatsuo; Nakazawa, Ken; Onozawa, Shiro; Yasui, Daisuke; Kumita, Shin-ichiro

    2013-01-01

    Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer-related deaths in the world. The Barcelona Clinic Liver Cancer (BCLC) classification has recently emerged as the standard classification system for clinical management of patients with HCC. According to the BCLC staging system, curative therapies (resection, transplantation, and percutaneous ablation) can improve survival in HCC patients diagnosed at an early stage and offer potential long-term curative effects. Patients with intermediate-stage HCC benefit from transcatheter arterial chemoembolization (TACE), and those diagnosed at an advanced stage receive sorafenib, a multikinase inhibitor, or conservative therapy. Most patients receive palliative or conservative therapy only, and approximately 50% of patients with HCC are candidates for systemic therapy. TACE is often recommended for advanced-stage HCC patients all over the world because these patients desire therapy that is more effective than systemic chemotherapy or conservative treatment. This paper aims to summarize both the published data and important ongoing studies for TACE and to discuss technical improvements in TACE for advanced-stage HCC. PMID:23606815

  13. Risk prediction models for hepatocellular carcinoma in different populations

    PubMed Central

    Ma, Xiao; Yang, Yang; Tu, Hong; Gao, Jing; Tan, Yu-Ting; Zheng, Jia-Li; Bray, Freddie; Xiang, Yong-Bing

    2016-01-01

    Hepatocellular carcinoma (HCC) is a malignant disease with limited therapeutic options due to its aggressive progression. It places heavy burden on most low and middle income countries to treat HCC patients. Nowadays accurate HCC risk predictions can help making decisions on the need for HCC surveillance and antiviral therapy. HCC risk prediction models based on major risk factors of HCC are useful and helpful in providing adequate surveillance strategies to individuals who have different risk levels. Several risk prediction models among cohorts of different populations for estimating HCC incidence have been presented recently by using simple, efficient, and ready-to-use parameters. Moreover, using predictive scoring systems to assess HCC development can provide suggestions to improve clinical and public health approaches, making them more cost-effective and effort-effective, for inducing personalized surveillance programs according to risk stratification. In this review, the features of risk prediction models of HCC across different populations were summarized, and the perspectives of HCC risk prediction models were discussed as well. PMID:27199512

  14. MDM2-p53 Pathway in Hepatocellular Carcinoma

    PubMed Central

    Meng, Xuan; Franklin, Derek A; Dong, Jiahong; Zhang, Yanping

    2015-01-01

    Abnormalities in the TP53 gene and overexpression of MDM2, a transcriptional target and negative regulator of p53, are commonly observed in cancers. The MDM2-p53 feedback loop plays an important role in tumor progression and thus, increased understanding of the pathway has the potential to improve clinical outcomes for cancer patients. Hepatocellular carcinoma (HCC) has emerged as one of the most commonly diagnosed forms of human cancer; yet, the current treatment for HCC is less effective than those used against other cancers. We review the current studies of the MDM2-p53 pathway in cancer with a focus on HCC, and specifically discuss the impact of p53 mutations along with other alterations of the MDM2-p53 feedback loop in HCC. We also discuss the potential diagnostic and prognostic applications of p53 and MDM2 in malignant tumors as well as therapeutic avenues that are being developed to target the MDM2-p53 pathway. PMID:25477334

  15. Liver transplantation as a management of hepatocellular carcinoma

    PubMed Central

    Azzam, Ayman Zaki

    2015-01-01

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

  16. Polymorphisms of FGFR1 in HBV-related hepatocellular carcinoma.

    PubMed

    Xie, Haiyang; Xing, Chunyang; Wei, Bajin; Xu, Xiao; Wu, Liming; Wu, Jian; Chen, Leiming; Cao, Guoqiang; Chen, Hai; Meng, Xueqin; Yin, Shengyong; Zhou, Lin; Zheng, Shusen

    2015-11-01

    Hepatitis B virus (HBV)-induced hepatocellular carcinoma (HCC) is one of the most commonly diagnosed cancers in China. It is important to understand the genetic mechanisms underlying the development and progression of HBV-related HCC and to identify new biomarkers for clinical treatment. The important role of fibroblast growth factor receptors (FGFRs) has been widely recognized in many types of cancers, but the association between FGFR polymorphisms and HCC carcinogenesis has been rarely reported. In this study, 199 patients with HBV-associated cirrhosis, 203 with HBV-associated HCC, and 184 healthy controls with no liver diseases were enrolled as participants. Using SNaPshot assays, five SNPs (rs13317, rs7825208, rs1047057, rs1047111, and rs1966265) of growth factor receptor genes were genotyped. Our results showed that the G/A and G/G genotypes at rs7825208 of FGFR1 were negatively correlated with HBV-related HCC (odds ratio (OR) = 0.45, 95% confidence interval (CI) = 0.22-0.93, P = 0.027). However, after Bonferroni correction, these significant differences no longer existed (P > 0.05). Our results indicated that these five polymorphisms of fibroblast growth factor receptor genes do not play any independent roles in the tumorigenesis and progression of HBV-related HCC in Han Chinese patients. PMID:26069105

  17. Biomarkers for hepatocellular carcinoma: diagnostic and therapeutic utility

    PubMed Central

    Ferrín, Gustavo; Aguilar-Melero, Patricia; Rodríguez-Perálvarez, Manuel; Montero-Álvarez, José Luis; de la Mata, Manuel

    2015-01-01

    Because of the high prevalence and associated-mortality of hepatocellular carcinoma (HCC), early diagnosis of the disease is vital for patient survival. In this regard, tumor size is one of the two main prognostic factors for surgical resection, which constitutes the only curative treatment for HCC along with liver transplantation. However, techniques for HCC surveillance and diagnosis that are currently used in clinical practice have certain limitations that may be inherent to the tumor development. Thus, it is important to continue efforts in the search for biomarkers that increase diagnostic accuracy for HCC. In this review, we focus on different biological sources of candidate biomarkers for HCC diagnosis. Although those biomarkers identified from biological samples obtained by noninvasive methods have greater diagnostic value, we have also considered those obtained from liver tissue because of their potential therapeutic value. To date, sorafenib is the only US Food and Drug Administration-approved antineoplastic for HCC. However, this therapeutic agent shows very low tumor response rates and frequently causes acquired resistance in HCC patients. We discuss the use of HCC biomarkers as therapeutic targets themselves, or as targets to increase sensitivity to sorafenib treatment. PMID:25926760

  18. [Needle tract seeding of hepatocellular carcinoma after liver transplantation].

    PubMed

    Mrzljak, Anna; Kardum-Skelin, Ika; Blasković, Darko; Skegro, Dinko; Jadrijević, Stipislav; Colić-Cvrlje, Vesna

    2011-09-01

    Ultrasound guided fine needle aspiration cytology (FNAC) and core needle biopsy (CNB) are effective methods for the diagnosis of focal hepatic lesions. In case of neoplastic lesions, however, this may be followed by the seeding of malignant cells along the needle tract. We report a case of subcutaneous needle tract seeding of hepatocellular carcinoma (HCC) 25 months after liver transplantation. A 57-year-old man with compensated hepatitis-B-related liver cirrhosis was diagnosed with HCC by CNB, and the lesion was resected. Ten months after the procedure, FNAC of a small hepatic lesion confirmed tumor recurrence. The patient was successfully transplanted and 25 months later, a subcutaneous tumor appeared on the abdominal wall over the previous site of puncture without further dissemination of the disease. Total resection of the lesion confirmed HCC. It remains undetermined whether the seeding appeared after FNAC or CNB. After 18-month follow-up the patient was uneventful. The objectives of this report are to present clinical aspects and outcome of HCC needle tract seeding in a transplanted patient, discussing the problems and pitfalls of diagnostic workup and management of HCC. PMID:23126051

  19. Mechanical Stress Promotes Cisplatin-Induced Hepatocellular Carcinoma Cell Death

    PubMed Central

    Riad, Sandra; Bougherara, Habiba

    2015-01-01

    Cisplatin (CisPt) is a commonly used platinum-based chemotherapeutic agent. Its efficacy is limited due to drug resistance and multiple side effects, thereby warranting a new approach to improving the pharmacological effect of CisPt. A newly developed mathematical hypothesis suggested that mechanical loading, when coupled with a chemotherapeutic drug such as CisPt and immune cells, would boost tumor cell death. The current study investigated the aforementioned mathematical hypothesis by exposing human hepatocellular liver carcinoma (HepG2) cells to CisPt, peripheral blood mononuclear cells, and mechanical stress individually and in combination. HepG2 cells were also treated with a mixture of CisPt and carnosine with and without mechanical stress to examine one possible mechanism employed by mechanical stress to enhance CisPt effects. Carnosine is a dipeptide that reportedly sequesters platinum-based drugs away from their pharmacological target-site. Mechanical stress was achieved using an orbital shaker that produced 300 rpm with a horizontal circular motion. Our results demonstrated that mechanical stress promoted CisPt-induced death of HepG2 cells (~35% more cell death). Moreover, results showed that CisPt-induced death was compromised when CisPt was left to mix with carnosine 24 hours preceding treatment. Mechanical stress, however, ameliorated cell death (20% more cell death). PMID:25685789

  20. [Role of environmental factors in the etiology of hepatocellular carcinoma].

    PubMed

    Tornai, István

    2010-07-11

    Chronic B and C virus hepatitis (HBV and HCV) are the most important risk factors in the development of hepatocellular carcinoma (HCC). About 40-50% of HCC is induced by these two chronic viral infections. Prevalence of HCC is slowly increasing in the United States and in Western-Europe, whereas alcohol consumption is gradually decreasing in the majority of these countries. However, the most important environmental risk factor for HCC is still the heavy long-term alcohol use. The risk of cirrhosis and HCC increases linearly, wherever ethanol intake is greater than 60 g/day for men and women. Aflatoxin, which contaminates grains, mostly in China and Africa, is a well-known mycotoxin. Since geographical distribution of aflatoxin as well as HBV overlaps with each other, they have a synergistic effect on inducing HCC. Cigarette smoking has also hepatocarcinogenic effect, which is significantly enhanced by the concomitant alcohol use or chronic viral hepatitis. Obesity, non-alcoholic fatty liver and steatohepatitis as well as diabetes mellitus together also form a significant risk for HCC, due to the gradually increasing number of patients. Insulin resistance and oxidative stress are the major pathogenetic mechanisms leading to hepatic cell injury in these patients. Oral contraceptive drugs may also play a role in the development of HCC. The long-term exposure to organic solvents is also a risk factor for HCC. Dietary antioxidants, selenium, statins and coffee drinking have protective effect against HCC. PMID:20570793

  1. Transcriptional modules related to hepatocellular carcinoma survival: coexpression network analysis.

    PubMed

    Xu, Xinsen; Zhou, Yanyan; Miao, Runchen; Chen, Wei; Qu, Kai; Pang, Qing; Liu, Chang

    2016-06-01

    We performed weighted gene coexpression network analysis (WGCNA) to gain insights into the molecular aspects of hepatocellular carcinoma (HCC). Raw microarray datasets (including 488 samples) were downloaded from the Gene Expression Omnibus (GEO) website. Data were normalized using the RMA algorithm. We utilized the WGCNA to identify the coexpressed genes (modules) after non-specific filtering. Correlation and survival analyses were conducted using the modules, and gene ontology (GO) enrichment was applied to explore the possible mechanisms. Eight distinct modules were identified by the WGCNA. Pink and red modules were associated with liver function, whereas turquoise and black modules were inversely correlated with tumor staging. Poor outcomes were found in the low expression group in the turquoise module and in the high expression group in the red module. In addition, GO enrichment analysis suggested that inflammation, immune, virus-related, and interferon-mediated pathways were enriched in the turquoise module. Several potential biomarkers, such as cyclin-dependent kinase 1 (CDK1), topoisomerase 2α (TOP2A), and serpin peptidase inhibitor clade C (antithrombin) member 1 (SERPINC1), were also identified. In conclusion, gene signatures identified from the genome-based assays could contribute to HCC stratification. WGCNA was able to identify significant groups of genes associated with cancer prognosis. PMID:27052251

  2. Development and novel therapeutics in hepatocellular carcinoma: a review

    PubMed Central

    Ingle, Pravinkumar Vishwanath; Samsudin, Sarah Zakiah; Chan, Pei Qi; Ng, Mei Kei; Heng, Li Xuan; Yap, Siu Ching; Chai, Amy Siaw Hui; Wong, Audrey San Ying

    2016-01-01

    This review summarizes the epidemiological trend, risk factors, prevention strategies such as vaccination, staging, current novel therapeutics, including the drugs under clinical trials, and future therapeutic trends for hepatocellular carcinoma (HCC). As HCC is the third most common cause of cancer-related death worldwide, its overall incidence remains alarmingly high in the developing world and is steadily rising across most of the developed and developing world. Over the past 15 years, the incidence of HCC has more than doubled and it increases with advancing age. Chronic infection with hepatitis B virus is the leading cause of HCC, closely followed by infection with hepatitis C virus. Other factors contributing to the development of HCC include alcohol abuse, tobacco smoking, and metabolic syndrome (including obesity, diabetes, and fatty liver disease). Treatment options have improved in the past few years, particularly with the approval of several molecular-targeted therapies. The researchers are actively pursuing novel therapeutic targets as well as predictive biomarker for treatment of HCC. Advances are being made in understanding the mechanisms underlying HCC, which in turn could lead to novel therapeutics. Nevertheless, there are many emerging agents still under clinical trials and yet to show promising results. Hence, future therapeutic options may include different combination of novel therapeutic interventions. PMID:27042086

  3. Prevention of hepatocellular carcinoma: Focusing on antioxidant therapy.

    PubMed

    Miyanishi, Koji; Hoki, Toshifumi; Tanaka, Shingo; Kato, Junji

    2015-03-27

    Oxidative stress has been investigated in the context of alcoholic liver injury for many years and shown to be a causal factor of chronic hepatitis C (CHC), nonalcoholic steatohepatitis (NASH), drug-induced liver injury, Wilson's disease, and hemochromatosis. In CHC, it has been demonstrated that oxidative stress plays an important role in hepatocarcinogenesis. In cases with persistent hepatitis due to failure of hepatitis C virus eradication, or chronic liver disease, such as NASH, the treatment of which remains unestablished, it is important to reduce serum alanine aminotransferase levels and prevent liver fibrosis and development of hepatocellular carcinoma. This also suggests the importance of antioxidant therapy. Among treatment options where it would be expected that anti-inflammatory activity plays a role in their confirmed efficacy for chronic hepatitis, iron depletion therapy, glycyrrhizin, ursodeoxycholic acid, Sho-Saiko-To, and vitamin E can all be considered antioxidant therapies. To date, however, the ability of these treatments to prevent cancer has been confirmed only in CHC. Nevertheless, anti-inflammatory and anti-fibrotic effects have been demonstrated in other liver diseases and these therapies may potentially be effective for cancer prevention. PMID:25848483

  4. Molecular imaging and therapy targeting copper metabolism in hepatocellular carcinoma.

    PubMed

    Wachsmann, Jason; Peng, Fangyu

    2016-01-01

    Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Significant efforts have been devoted to identify new biomarkers for molecular imaging and targeted therapy of HCC. Copper is a nutritional metal required for the function of numerous enzymatic molecules in the metabolic pathways of human cells. Emerging evidence suggests that copper plays a role in cell proliferation and angiogenesis. Increased accumulation of copper ions was detected in tissue samples of HCC and many other cancers in humans. Altered copper metabolism is a new biomarker for molecular cancer imaging with position emission tomography (PET) using radioactive copper as a tracer. It has been reported that extrahepatic mouse hepatoma or HCC xenografts can be localized with PET using copper-64 chloride as a tracer, suggesting that copper metabolism is a new biomarker for the detection of HCC metastasis in areas of low physiological copper uptake. In addition to copper modulation therapy with copper chelators, short-interference RNA specific for human copper transporter 1 (hCtr1) may be used to suppress growth of HCC by blocking increased copper uptake mediated by hCtr1. Furthermore, altered copper metabolism is a promising target for radionuclide therapy of HCC using therapeutic copper radionuclides. Copper metabolism has potential as a new theranostic biomarker for molecular imaging as well as targeted therapy of HCC. PMID:26755872

  5. Targeting the Raft-Associated Akt Signaling in Hepatocellular Carcinoma

    PubMed Central

    Liu, Yuan; Lv, Ji-Yun; Shi, Jian-Fei; Yang, Mei; Liu, Shu-Hong; Li, Zhi-Wei; Wang, Hong-Bo; Zhang, Shao-Geng; Liu, Zhen-Wen; Ding, Jin-Biao; Xu, Dong-Ping; Zhao, Jing-Min

    2014-01-01

    Caveolin-1 and flotillin-1 are considered as markers of lipid rafts which can be regarded as sorting platforms for targeted transport of transmembrane proteins and are involved in fundamental cellular events such as signal transduction, cell adhesion, lipid/protein sorting, and human cancer. We addressed caveolin-1 and flotillin-1 expression in 90 human hepatocellular carcinoma (HCC) and adjacent noncancerous tissues (ANT) samples by SDS-PAGE and immunoblotting with specific antibodies. Significant caveolin-1 and flotillin-1 overexpression was found in HCC tissues compared to ANT and was confirmed by immunohistochemistry. Raft-associated Akt signaling pathway components involved in the regulation of cell survival were altered by western blotting in HCC microdomain-enriched subcellular fractions purified from paired HCC and ANT samples. Our results demonstrated that the activity of raft-associated but not total membrane Akt determines its cellular functions. Lipid rafts differ in different types of tissues, which allows for the possibility of tissue-type-specific targeting for cell survival. PMID:25243186

  6. Management of recurrent hepatocellular carcinoma after liver transplant.

    PubMed

    Chok, Kenneth Sh

    2015-05-18

    Hepatocellular carcinoma (HCC) is the leading cause of deaths in patients with hepatitis B or C, and its incidence has increased considerably over the past decade and is still on the rise. Liver transplantation (LT) provides the best chance of cure for patients with HCC and liver cirrhosis. With the implementation of the MELD exception system for patients with HCC waitlisted for LT, the number of recipients of LT is increasing, so is the number of patients who have recurrence of HCC after LT. Treatments for intrahepatic recurrence after transplantation and after other kinds of surgery are more or less the same, but long-term cure of posttransplant recurrence is rarely seen as it is a "systemic" disease. Nonetheless, surgical resection has been shown to be effective in prolonging patient survival despite the technical difficulty in resecting graft livers. Besides surgical resection, different kinds of treatment are also in use, including transarterial chemoembolization, radiofrequency ablation, high-intensity focused ultrasound ablation, and stereotactic body radiation therapy. Targeted therapy and modulation of immunosuppressants are also adopted to treat the deadly disease. PMID:26052403

  7. The significance of Brf1 overexpression in human hepatocellular carcinoma

    PubMed Central

    Shi, Ganggang; Huang, Yi; Zhang, Yanmei; Levy, Daniel; Zhong, Shuping

    2016-01-01

    Brf1 (TFIIB-related factor 1) plays a crucial role in cell transformation and tumorigenesis. However, the significance of Brf1 expression in human HCC (hepatocellular carcinoma) cases remains to be addressed. In this study, biopsies of human HCC, liver tumor samples of mice and cell lines of normal and tumor liver were utilized to determine the alteration of Brf1 expression using cytological and molecular biological approaches. Brf1 expression is increased in human HCC cases, which is correlated with shorter survival times. Levels of Brf1 and Pol III (RNA polymerase III-dependent) gene transcription in HCC patients with alcohol consumption are higher than the cases of non-HCC with or without alcohol intake. Induction of Brf1 and Pol III genes by ethanol in hepatoma cells is higher than in non-tumor cells. Ethanol increases the rate of cell transformation. Repression of Brf1 inhibits alcohol-promoted cell transformation. Alcohol consumption enhances Brf1 expression to promote cell transformation. These studies demonstrate that Brf1 is a new biomarker of HCC. PMID:26701855

  8. A splicing variant of Merlin promotes metastasis in hepatocellular carcinoma

    PubMed Central

    Luo, Zai-Li; Cheng, Shu-Qun; Shi, Jie; Zhang, Hui-Lu; Zhang, Cun-Zhen; Chen, Hai-Yang; Qiu, Bi-Jun; Tang, Liang; Hu, Cong-Li; Wang, Hong-Yang; Li, Zhong

    2015-01-01

    Merlin, which is encoded by the tumour suppressor gene Nf2, plays a crucial role in tumorigenesis and metastasis. However, little is known about the functional importance of Merlin splicing forms. In this study, we show that Merlin is present at low levels in human hepatocellular carcinoma (HCC), particularly in metastatic tumours, where it is associated with a poor prognosis. Surprisingly, a splicing variant of Merlin that lacks exons 2, 3 and 4 (Δ2–4Merlin) is amplified in HCC and portal vein tumour thrombus (PVTT) specimens and in the CSQT2 cell line derived from PVTT. Our studies show that Δ2–4Merlin interferes with the capacity of wild-type Merlin to bind β-catenin and ERM, and it is expressed in the cytoplasm rather than at the cell surface. Furthermore, Δ2–4Merlin overexpression increases the expression levels of β-catenin and stemness-related genes, induces the epithelium–mesenchymal-transition phenotype promoting cell migration in vitro and the formation of lung metastasis in vivo. Our results indicate that the Δ2–4Merlin variant disrupts the normal function of Merlin and promotes tumour metastasis. PMID:26443326

  9. Molecular imaging and therapy targeting copper metabolism in hepatocellular carcinoma

    PubMed Central

    Wachsmann, Jason; Peng, Fangyu

    2016-01-01

    Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Significant efforts have been devoted to identify new biomarkers for molecular imaging and targeted therapy of HCC. Copper is a nutritional metal required for the function of numerous enzymatic molecules in the metabolic pathways of human cells. Emerging evidence suggests that copper plays a role in cell proliferation and angiogenesis. Increased accumulation of copper ions was detected in tissue samples of HCC and many other cancers in humans. Altered copper metabolism is a new biomarker for molecular cancer imaging with position emission tomography (PET) using radioactive copper as a tracer. It has been reported that extrahepatic mouse hepatoma or HCC xenografts can be localized with PET using copper-64 chloride as a tracer, suggesting that copper metabolism is a new biomarker for the detection of HCC metastasis in areas of low physiological copper uptake. In addition to copper modulation therapy with copper chelators, short-interference RNA specific for human copper transporter 1 (hCtr1) may be used to suppress growth of HCC by blocking increased copper uptake mediated by hCtr1. Furthermore, altered copper metabolism is a promising target for radionuclide therapy of HCC using therapeutic copper radionuclides. Copper metabolism has potential as a new theranostic biomarker for molecular imaging as well as targeted therapy of HCC. PMID:26755872

  10. The imprint of radiofrequency in the management of hepatocellular carcinoma

    PubMed Central

    Bramis, Ioannis; Triantopoulou, Charikleia; Madariaga, Juan; Dervenis, Christos

    2006-01-01

    Background. This article reviews the current results of radiofrequency application in the management of hepatocellular carcinoma (HCC) with reference to the comparison between the different surgical modalities. Method. An electronic search was performed for studies on the treatment of HCC. Results. Thermoablation by means of radiofrequency (RFA), microwave coagulation therapy (MCT) and laser-induced thermotherapy (LITT) provides tumor necrosis with a low complication rate. These methods are still not predictable and it is difficult to monitor the extent of necrosis in a real-time manner. Combined transarterial embolization and RF ablation is a promising strategy for large HCCs. Radiofrequency-assisted liver resection is unique and has become very popular recently because it permits parenchymal transection with minimal blood loss. Conclusion. Many alternative techniques have been applied recently for the management of HCC but their exact roles need to be defined by randomized studies. Advances in technology and refinements in technique may provide an effective and predictable way to ablate liver tumors using radiofrequency devices. PMID:18333136

  11. Multidisciplinary Management of Hepatocellular Carcinoma in Clinical Practice

    PubMed Central

    Cannita, Katia; Giordano, Aldo Victor; Manetta, Rosa; Vicentini, Roberto; Carducci, Sergio; Saltarelli, Patrizia; Iapadre, Nerio; Coletti, Gino; Ficorella, Corrado; Ricevuto, Enrico

    2014-01-01

    Background. Hepatocellular carcinoma (HCC) patients require different treatment strategies according to disease extension, liver function, and patient's fitness. We evaluated HCC multidisciplinary management in clinical practice. Methods. Consecutive patients were followed and treated with tailored medical, locoregional, and surgical treatments, according to disease stage and patient's fitness (age, Cumulative Illness Rating Scale (CIRS)). Activity, efficacy, and safety were evaluated. Results. Thirty-eight patients were evaluated: median age, 74; elderly 92%; CIRS secondary 28 (74%); Child-Pugh A 20 (53%), B 11 (29%); and Barcelona Clinic Liver Cancer (BCLC) 0 2 (5%), A 9 (24%), B 10 (26%), C 13 (34%), and D 4 (11%). Overall survival (OS) was 30 months. At 9 months median follow-up, among 25 unresectable HCC, OS was 10 months; BCLC B–D unfit for sorafenib showed OS 3 months. Ten patients (40%) received sorafenib: Child-Pugh A 5 (50%) and B 5 (50%) and disease control rate 89%, progression-free survival 7 months, and OS 9 months. G3-4 toxicities: anorexia, hypertransaminaemia, hyperbilirubinemia, and hypercreatininemia. Limiting toxicity syndromes were 40%, all multiple sites. Conclusion. HCC patients require multidisciplinary clinical management to properly select tailored treatments according to disease stage, fitness, and liver function. Patients suitable for sorafenib should be carefully selected, monitored for individual safety, and prevalently characterized by limiting toxicity syndromes multiple sites. PMID:24900987

  12. Prevention of hepatocellular carcinoma: Focusing on antioxidant therapy

    PubMed Central

    Miyanishi, Koji; Hoki, Toshifumi; Tanaka, Shingo; Kato, Junji

    2015-01-01

    Oxidative stress has been investigated in the context of alcoholic liver injury for many years and shown to be a causal factor of chronic hepatitis C (CHC), nonalcoholic steatohepatitis (NASH), drug-induced liver injury, Wilson’s disease, and hemochromatosis. In CHC, it has been demonstrated that oxidative stress plays an important role in hepatocarcinogenesis. In cases with persistent hepatitis due to failure of hepatitis C virus eradication, or chronic liver disease, such as NASH, the treatment of which remains unestablished, it is important to reduce serum alanine aminotransferase levels and prevent liver fibrosis and development of hepatocellular carcinoma. This also suggests the importance of antioxidant therapy. Among treatment options where it would be expected that anti-inflammatory activity plays a role in their confirmed efficacy for chronic hepatitis, iron depletion therapy, glycyrrhizin, ursodeoxycholic acid, Sho-Saiko-To, and vitamin E can all be considered antioxidant therapies. To date, however, the ability of these treatments to prevent cancer has been confirmed only in CHC. Nevertheless, anti-inflammatory and anti-fibrotic effects have been demonstrated in other liver diseases and these therapies may potentially be effective for cancer prevention. PMID:25848483

  13. Tissue- and Serum-Associated Biomarkers of Hepatocellular Carcinoma

    PubMed Central

    Chauhan, Ranjit; Lahiri, Nivedita

    2016-01-01

    Hepatocellular carcinoma (HCC), one of the leading causes of cancer deaths in the world, is offering a challenge to human beings, with the current modes of treatment being a palliative approach. Lack of proper curative or preventive treatment methods encouraged extensive research around the world with an aim to detect a vaccine or therapeutic target biomolecule that could lead to development of a drug or vaccine against HCC. Biomarkers or biological disease markers have emerged as a potential tool as drug/vaccine targets, as they can accurately diagnose, predict, and even prevent the diseases. Biomarker expression in tissue, serum, plasma, or urine can detect tumor in very early stages of its development and monitor the cancer progression and also the effect of therapeutic interventions. Biomarker discoveries are driven by advanced techniques, such as proteomics, transcriptomics, whole genome sequencing, micro- and micro-RNA arrays, and translational clinics. In this review, an overview of the potential of tissue- and serum-associated HCC biomarkers as diagnostic, prognostic, and therapeutic targets for drug development is presented. In addition, we highlight recently developed micro-RNA, long noncoding RNA biomarkers, and single-nucleotide changes, which may be used independently or as complementary biomarkers. These active investigations going on around the world aimed at conquering HCC might show a bright light in the near future. PMID:27398029

  14. Hepatocellular carcinoma beyond Milan criteria: Management and transplant selection criteria

    PubMed Central

    Elshamy, Mohammed; Aucejo, Federico; Menon, K V Narayanan; Eghtesad, Bijan

    2016-01-01

    Liver transplantation (LT) for hepatocellular carcinoma (HCC) has been established as a standard treatment in selected patients for the last two and a half decades. After initially dismal outcomes, the Milan criteria (MC) (single HCC ≤ 5 cm or up to 3 HCCs ≤ 3 cm) have been adopted worldwide to select HCC patients for LT, however cumulative experience has shown that MC can be too strict. This has led to the development of numerous expanded criteria worldwide. Morphometric expansions on MC as well as various criteria which incorporate biomarkers as surrogates of tumor biology have been described. HCC that presents beyond MC initially can be downstaged with locoregional therapy (LRT). Post-LRT monitoring aims to identify candidates with favorable tumor behavior. Similarly, tumor marker levels as response to LRT has been utilized as surrogate of tumor biology. Molecular signatures of HCC have also been correlated to outcomes; these have yet to be incorporated into HCC-LT selection criteria formally. The ongoing discrepancy between organ demand and supply makes patient selection the most challenging element of organ allocation. Further validation of extended HCC-LT criteria models and pre-LT treatment strategies are required. PMID:27478537

  15. Biomarkers for the early diagnosis of hepatocellular carcinoma

    PubMed Central

    Tsuchiya, Nobuhiro; Sawada, Yu; Endo, Itaru; Saito, Keigo; Uemura, Yasushi; Nakatsura, Tetsuya

    2015-01-01

    Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer-related deaths worldwide. Although the prognosis of patients with HCC is generally poor, the 5-year survival rate is > 70% if patients are diagnosed at an early stage. However, early diagnosis of HCC is complicated by the coexistence of inflammation and cirrhosis. Thus, novel biomarkers for the early diagnosis of HCC are required. Currently, the diagnosis of HCC without pathological correlation is achieved by analyzing serum α-fetoprotein levels combined with imaging techniques. Advances in genomics and proteomics platforms and biomarker assay techniques over the last decade have resulted in the identification of numerous novel biomarkers and have improved the diagnosis of HCC. The most promising biomarkers, such as glypican-3, osteopontin, Golgi protein-73 and nucleic acids including microRNAs, are most likely to become clinically validated in the near future. These biomarkers are not only useful for early diagnosis of HCC, but also provide insight into the mechanisms driving oncogenesis. In addition, such molecular insight creates the basis for the development of potentially more effective treatment strategies. In this article, we provide an overview of the biomarkers that are currently used for the early diagnosis of HCC. PMID:26457017

  16. Biomarkers for the early diagnosis of hepatocellular carcinoma.

    PubMed

    Tsuchiya, Nobuhiro; Sawada, Yu; Endo, Itaru; Saito, Keigo; Uemura, Yasushi; Nakatsura, Tetsuya

    2015-10-01

    Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer-related deaths worldwide. Although the prognosis of patients with HCC is generally poor, the 5-year survival rate is > 70% if patients are diagnosed at an early stage. However, early diagnosis of HCC is complicated by the coexistence of inflammation and cirrhosis. Thus, novel biomarkers for the early diagnosis of HCC are required. Currently, the diagnosis of HCC without pathological correlation is achieved by analyzing serum α-fetoprotein levels combined with imaging techniques. Advances in genomics and proteomics platforms and biomarker assay techniques over the last decade have resulted in the identification of numerous novel biomarkers and have improved the diagnosis of HCC. The most promising biomarkers, such as glypican-3, osteopontin, Golgi protein-73 and nucleic acids including microRNAs, are most likely to become clinically validated in the near future. These biomarkers are not only useful for early diagnosis of HCC, but also provide insight into the mechanisms driving oncogenesis. In addition, such molecular insight creates the basis for the development of potentially more effective treatment strategies. In this article, we provide an overview of the biomarkers that are currently used for the early diagnosis of HCC. PMID:26457017

  17. Significant biomarkers for the management of hepatocellular carcinoma.

    PubMed

    Kondo, Yasuteru; Kimura, Osamu; Shimosegawa, Tooru

    2015-06-01

    Surveillance of hepatocellular carcinoma (HCC) is important for early detection. Imaging tests including computed tomography, magnetic resonance imaging and ultrasonography with or without various kinds of contrast medium are important options for detecting HCC. In addition to the imaging tests, various kinds of biomarkers including alpha-fetoprotein (AFP), lectin-bound AFP (AFP-L3) and protein induced by vitamin K absence or antagonist II (PIVKA-II) have been widely used to detect HCC and analyze treatment response. Recently, various kinds of novel biomarkers (proteins and miRNA) have been found to predict the malignancy potential of HCC and treatment response to specific therapies. Moreover, various combinations of well-established biomarkers and novel biomarkers have been tested to improve sensitivity and specificity. In practical terms, biomarkers that can be analyzed using peripheral blood samples might be more useful than immunohistochemical techniques. It has been reported that quantification of cytokines in peripheral blood and the analysis of peripheral immune subsets could be good biomarkers for managing HCC. Here, we describe the usefulness of and update well-established and novel biomarkers for the management of HCC. PMID:25855582

  18. Genome-wide DNA methylation analysis in hepatocellular carcinoma.

    PubMed

    Yamada, Nobuhisa; Yasui, Kohichiroh; Dohi, Osamu; Gen, Yasuyuki; Tomie, Akira; Kitaichi, Tomoko; Iwai, Naoto; Mitsuyoshi, Hironori; Sumida, Yoshio; Moriguchi, Michihisa; Yamaguchi, Kanji; Nishikawa, Taichiro; Umemura, Atsushi; Naito, Yuji; Tanaka, Shinji; Arii, Shigeki; Itoh, Yoshito

    2016-04-01

    Epigenetic changes as well as genetic changes are mechanisms of tumorigenesis. We aimed to identify novel genes that are silenced by DNA hypermethylation in hepatocellular carcinoma (HCC). We screened for genes with promoter DNA hypermethylation using a genome-wide methylation microarray analysis in primary HCC (the discovery set). The microarray analysis revealed that there were 2,670 CpG sites that significantly differed in regards to the methylation level between the tumor and non-tumor liver tissues; 875 were significantly hypermethylated and 1,795 were significantly hypomethylated in the HCC tumors compared to the non‑tumor tissues. Further analyses using methylation-specific PCR, combined with expression analysis, in the validation set of primary HCC showed that, in addition to three known tumor-suppressor genes (APC, CDKN2A, and GSTP1), eight genes (AKR1B1, GRASP, MAP9, NXPE3, RSPH9, SPINT2, STEAP4, and ZNF154) were significantly hypermethylated and downregulated in the HCC tumors compared to the non-tumor liver tissues. Our results suggest that epigenetic silencing of these genes may be associated with HCC. PMID:26883180

  19. MRI of hepatocellular carcinoma: an update of current practices

    PubMed Central

    Arif-Tiwari, Hina; Kalb, Bobby; Chundru, Surya; Sharma, Puneet; Costello, James; Guessner, Rainner W.; Martin, Diego R.

    2014-01-01

    Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and liver transplantation is the optimal treatment for selected patients with HCC and chronic liver disease (CLD). Accurate selection of patients for transplantation is essential to maximize patient outcomes and ensure optimized allocation of donor organs. Magnetic resonance imaging (MRI) is a powerful tool for the detection, characterization, and staging of HCC. In patients with CLD, the MRI findings of an arterial-enhancing mass with subsequent washout and enhancing capsule on delayed interstitial phase images are diagnostic for HCC. Major organizations with oversight for organ donor distribution, such as The Organ Procurement and Transplantation Network (OPTN), accept an imaging diagnosis of HCC, no longer requiring tissue biopsy. In patients that are awaiting transplantation, or are not candidates for liver transplantation, localized therapies such as transarterial chemoembolization and radiofrequency ablation may be offered. MRI can be used to monitor treatment response. The purpose of this review article is to describe the role of imaging methods in the diagnosis, staging, and follow-up of HCC, with particular emphasis on established and evolving MRI techniques employing nonspecific gadolinium chelates, hepatobiliary contrast agents, and diffusion weighted imaging. We also briefly review the recently developed Liver Imaging Reporting and Data System (LI-RADS) formulating a standardized terminology and reporting structure for evaluation of lesions detected in patients with CLD. PMID:24808419

  20. Transarterial chemoembolization for hepatocellular carcinoma: A review of techniques

    PubMed Central

    Imai, Norihiro; Ishigami, Masatoshi; Ishizu, Yoji; Kuzuya, Teiji; Honda, Takashi; Hayashi, Kazuhiko; Hirooka, Yoshiki; Goto, Hidemi

    2014-01-01

    Hepatocellular carcinoma (HCC) is one of the most common malignant diseases worldwide. While curative therapies, including resection, liver transplantation, and percutaneous ablation (percutaneous ethanol injection and radiofrequency ablation), are applicable for only a portion of the HCC population, transcatheter arterial chemoembolization (TACE) has been recognized as an effective palliative treatment option for patients with advanced HCC. TACE is also used even for single HCCs in which it is difficult to perform surgical resection or locoregional treatment due to systemic co-morbidities or anatomical problems. TACE has become widely adopted in the treatment of HCC. By using computed tomography-angiography, TACE is capable of performing diagnosis and treatment at the same time. Furthermore, TACE plays an important role in the multidisciplinary treatment for HCC when combined with other treatment. In this review, we first discuss the history of TACE, and then review the previous findings about techniques of achieving a locoregional treatment effect (liver infarction treatment, e.g., ultra-selective TACE, balloon-occluded TACE), and the use of TACE as a drug delivery system for anti-cancer agents (palliative, e.g., platinum complex agents, drug-eluting beads) for multiple lesions. PMID:25544871

  1. Update in management of hepatocellular carcinoma in Eastern population

    PubMed Central

    Chu, Kevin Ka Wan; Cheung, Tan To

    2015-01-01

    Hepatocellular carcinoma (HCC) is one of the commonest malignant tumours in the East. Although the management of HCC in the West is mainly based on the Barcelona Clinic for Liver Cancer staging, it is considered too conservative by Asian countries where the number of HCC patients is huge. Scientific and clinical advances were made in aspects of diagnosis, staging, and treatment of HCC. HCC is well known to be associated with cirrhosis and the treatment of HCC must take into account the presence and stage of chronic liver disease. The major treatment modalities of HCC include: (1) surgical resection; (2) liver transplantation; (3) local ablation therapy; (4) transarterial locoregional treatment; and (5) systemic treatment. Among these, resection, liver transplantation and ablation therapy for small HCC are considered as curative treatment. Portal vein embolisation and the associating liver partition with portal vein ligation for staged hepatectomy may reduce dropout in patients with marginally resectable disease but the midterm and long-term results are still to be confirmed. Patient selection for the best treatment modality is the key to success of treatment of HCC. The purpose of current review is to provide a description of the current advances in diagnosis, staging, pre-operative liver function assessment and treatment options for patients with HCC in the east. PMID:26085915

  2. Transarterial radioembolization for hepatocellular carcinoma: An update and perspectives

    PubMed Central

    Sacco, Rodolfo; Mismas, Valeria; Marceglia, Sara; Romano, Antonio; Giacomelli, Luca; Bertini, Marco; Federici, Graziana; Metrangolo, Salvatore; Parisi, Giuseppe; Tumino, Emanuele; Bresci, Giampaolo; Corti, Ambra; Tredici, Manuel; Piccinno, Michele; Giorgi, Luigi; Bartolozzi, Carlo; Bargellini, Irene

    2015-01-01

    In the last decade trans-arterial radioembolization has given promising results in the treatment of patients with intermediate or advanced stage hepatocellular carcinoma (HCC), both in terms of disease control and tolerability profile. This technique consists of the selective intra-arterial administration of microspheres loaded with a radioactive compound (usually Yttrium90), and exerts its therapeutic effect through the radiation carried by these microspheres. A careful and meticulous selection of patients is crucial before performing the radioembolization to correctly perform the procedure and reduce the incidence of complications. Radioembolization is a technically complex and expensive technique, which has only recently entered clinical practice and is supported by scant results from phase III clinical trials. Nevertheless, it may represent a valid alternative to transarterial chemoembolization (TACE) in the treatment of intermediate-stage HCC patients, as shown by a comparative retrospective assessment that reported a longer time to progression, but not of overall survival, and a more favorable safety profile for radioembolization. In addition, this treatment has reported a higher percentage of tumor shrinkage, if compared to TACE, for pre-transplant downsizing and it represents a promising therapeutic option in patients with large extent of disease and insufficient residual liver volume who are not immediately eligible for surgery. Radioembolization might also be a suitable companion to sorafenib in advanced HCC or it can be used as a potential alternative to this treatment in patients who are not responding or do not tolerate sorafenib. PMID:26074690

  3. Association of abnormal plasma bilirubin with aggressive hepatocellular carcinoma phenotype.

    PubMed

    Carr, Brian I; Guerra, Vito; Giannini, Edoardo G; Farinati, Fabio; Ciccarese, Francesca; Ludovico Rapaccini, Gian; Di Marco, Maria; Benvegnù, Luisa; Zoli, Marco; Borzio, Franco; Caturelli, Eugenio; Chiaramonte, Maria; Trevisani, Franco

    2014-04-01

    Cirrhosis-related abnormal liver function is associated with predisposition to hepatocellular carcinoma (HCC). It features in several HCC classification systems and is an HCC prognostic factor. The aim of the present study was to examine the phenotypic tumor differences in HCC patients with normal or abnormal plasma bilirubin levels. A 2,416-patient HCC cohort was studied and dichotomized into normal and abnormal plasma bilirubin groups. Their HCC characteristics were compared for tumor aggressiveness features, namely, blood alpha-fetoprotein (AFP) levels, tumor size, presence of portal vein thrombosis (PVT) and tumor multifocality. In the total cohort, elevated bilirubin levels were associated with higher AFP levels, increased PVT and multifocality, and lower survival, despite similar tumor sizes. When different tumor size terciles were compared, similar results were found, even among patients with small tumors. A multiple logistic regression model for PVT or tumor multifocality showed increased odds ratios for elevated levels of gamma glutamyl transpeptidase (GGTP), bilirubin, and AFP and for larger tumor sizes. We conclude that HCC patients with abnormal bilirubin levels had worse prognosis than patients with normal bilirubin. They also had an increased incidence of PVT and tumor multifocality, and higher AFP levels, in patients with both small and larger tumors. The results show an association between bilirubin levels and indices of HCC aggressiveness. PMID:24787296

  4. Vitamin K and hepatocellular carcinoma: The basic and clinic

    PubMed Central

    Jinghe, Xia; Mizuta, Toshihiko; Ozaki, Iwata

    2015-01-01

    Vitamin K (VK), which was originally identified as a cofactor involved in the production of functional coagulation factors in the liver, has been shown to be involved in various aspects of physiological and pathological events, including bone metabolism, cardiovascular diseases and tumor biology. The mechanisms and roles of VK are gradually becoming clear. Several novel enzymes involved in the VK cycle were identified and have been shown to be linked to tumorigenesis. The VKs have been shown to suppress liver cancer cell growth through multiple signaling pathways via the transcription factors and protein kinases. A VK2 analog was applied to the chemoprevention of hepatocellular carcinoma (HCC) recurrence after curative therapy and was shown to have beneficial effects, both in the suppression of HCC recurrence and in patient survival. Although a large scale randomized control study failed to demonstrate the suppression of HCC recurrence, a meta-analysis suggested a beneficial effect on the long-term survival of HCC patients. However, the beneficial effects of VK administration alone were not sufficient to prevent or treat HCC in clinical settings. Thus its combination with other anti-cancer reagents and the development of more potent novel VK derivatives are the focus of ongoing research which seeks to achieve satisfactory therapeutic effects against HCC. PMID:26380822

  5. Latest developments in precancerous lesions of hepatocellular carcinoma

    PubMed Central

    Niu, Zhao-Shan; Niu, Xiao-Jun; Wang, Wen-Hong; Zhao, Jing

    2016-01-01

    Hepatocarcinogenesis in human chronic liver diseases is a multi-step process in which hepatic precancerous lesions progress into early hepatocellular carcinoma (HCC) and progressed HCC, and the close surveillance and treatment of these lesions will help improve the survival rates of patients with HCC. The rapid development and extensive application of imaging technology have facilitated the discovery of nodular lesions of ambiguous significance, such as dysplastic nodules. Further investigations showed that these nodules may be hepatic precancerous lesions, and they often appear in patients with liver cirrhosis. Although the morphology of these nodules is not sufficient to support a diagnosis of malignant tumor, these nodules are closely correlated with the occurrence of HCC, as indicated by long-term follow-up studies. In recent years, the rapid development and wide application of pathology, molecular genetics and imaging technology have elucidated the characteristics of precancerous lesions. Based on our extensive review of the relevant literature, this article focuses on evidence indicating that high-grade dysplastic nodules are more likely to transform into HCC than low-grade dysplastic nodules based on clinical, pathological, molecular genetic and radiological assessments. In addition, evidence supporting the precancerous nature of large cell change in hepatitis B virus-related HCC is discussed. PMID:27022212

  6. [Molecular mechanisms of hepatitis B virus-associated hepatocellular carcinoma].

    PubMed

    Park, Neung Hwa; Chung, Young Hwa

    2007-09-01

    Hepatocellular carcinoma (HCC) is one of the most common malignant diseases in the world. The hepatitis B virus (HBV) replicates non-cytopathically in hepatocytes, and most of the liver injury associated with this infection reflects the immune response. Epidemiological studies have clearly demonstrated that a chronic HBV infection is a major etiological factor in the development of HCC. The pathogenesis of HBV-associated HCC has been studied extensively, and the molecular changes during the malignant transformation have been identified. The main carcinogenic mechanism of HBV-associated HCC is related to the long term-inflammatory changes caused by a chronic hepatitis B infection, which might involve the integration of the HBV. Integration of the HBV DNA into the host genome occurs at the early steps of clonal tumorous expansion. The hepatitis B x protein (HBx) is a multifunctional regulatory protein that communicates directly or indirectly with a variety of host targets, and mediates many opposing cellular functions, including its function in cell cycle regulation, transcriptional regulation, signaling, encoding of the cytoskeleton and cell adhesion molecules, as well as oncogenes and tumor suppressor genes. Continued study of the mechanisms of hepatocarcinogenesis will refine our current understanding of the molecular and cellular basis for neoplastic transformations in the liver. This review summarizes the current knowledge of the mechanisms involved in HBV-associated hepatocarcinogenesis. PMID:17898549

  7. Technical advances in external radiotherapy for hepatocellular carcinoma.

    PubMed

    Park, Shin-Hyung; Kim, Jae-Chul; Kang, Min Kyu

    2016-08-28

    Radiotherapy techniques have substantially improved in the last two decades. After the introduction of 3-dimensional conformal radiotherapy, radiotherapy has been increasingly used for the treatment of hepatocellular carcinoma (HCC). Currently, more advanced techniques, including intensity-modulated radiotherapy (IMRT), stereotactic ablative body radiotherapy (SABR), and charged particle therapy, are used for the treatment of HCC. IMRT can escalate the tumor dose while sparing the normal tissue even though the tumor is large or located near critical organs. SABR can deliver a very high radiation dose to small HCCs in a few fractions, leading to high local control rates of 84%-100%. Various advanced imaging modalities are used for radiotherapy planning and delivery to improve the precision of radiotherapy. These advanced techniques enable the delivery of high dose radiotherapy for early to advanced HCCs without increasing the radiation-induced toxicities. However, as there have been no effective tools for the prediction of the response to radiotherapy or recurrences within or outside the radiation field, future studies should focus on selecting the patients who will benefit from radiotherapy. PMID:27621577

  8. Novel Fucosylated Biomarkers for the Early Detection of Hepatocellular Carcinoma

    PubMed Central

    Wang, Mengjun; Long, Ronald E.; Comunale, Mary Ann; Junaidi, Omer; Marrero, Jorge; Di Bisceglie, Adrian M.; Block, Timothy M.; Mehta, Anand S.

    2009-01-01

    Changes in glycosylation, most notably fucosylation, have been associated with the development of hepatocellular carcinoma (HCC). In this report, the levels of fucosylated kininogen (Fc-Kin) and fucosylated α-1-antitrypsin were analyzed individually and in combination with the currently used marker, α-fetoprotein, and a previously identified biomarker, Golgi protein 73 (GP73), for the ability to distinguish between a diagnosis of cirrhosis and HCC. This analysis was done on serum from 113 patients with cirrhosis and 164 serum samples from patients with cirrhosis plus HCC. The levels of Fc-Kin and fucosylated α-1-antitrypsin were significantly higher in patients with HCC compared with those with cirrhosis (P < 0.0001). Greatest performance was achieved through the combination of Fc-Kin, α-fetoprotein, and GP73, giving an optimal sensitivity of 95%, a specificity of 70%, and an area under the receiver operating characteristic of 0.94. In conclusion, the altered glycosylation of serum glycoproteins can act as potential biomarkers of primary HCC when used independently or in combination with other markers of HCC. PMID:19454616

  9. Long Non-Coding RNAs: Critical Players in Hepatocellular Carcinoma

    PubMed Central

    Sun, Jin; Bie, Beibei; Zhang, Shu; Yang, Jun; Li, Zongfang

    2014-01-01

    Hepatocellular carcinoma (HCC) is a complex disease with multiple underlying pathogenic mechanisms caused by a variety of etiologic factors. Emerging evidence showed that long non-coding RNAs (lncRNAs), with size larger than 200 nucleotides (nt), play important roles in various types of cancer development and progression. In recent years, some dysregulated lncRNAs in HCC have been revealed and roles for several of them in HCC have been characterized. All these findings point to the potential of lncRNAs as prospective novel therapeutic targets in HCC. In this review, we summarize known dysregulated lncRNAs in HCC, and review potential biological roles and underlying molecular mechanisms of lncRNAs in HCC. Additionally, we discussed prospects of lncRNAs as potential biomarker and therapeutic target for HCC. In conclusion, this paper will help us gain better understanding of molecular mechanisms by which lncRNAs perform their function in HCC and also provide general strategies and directions for future research. PMID:25387074

  10. Vitamin K and hepatocellular carcinoma: The basic and clinic.

    PubMed

    Jinghe, Xia; Mizuta, Toshihiko; Ozaki, Iwata

    2015-09-16

    Vitamin K (VK), which was originally identified as a cofactor involved in the production of functional coagulation factors in the liver, has been shown to be involved in various aspects of physiological and pathological events, including bone metabolism, cardiovascular diseases and tumor biology. The mechanisms and roles of VK are gradually becoming clear. Several novel enzymes involved in the VK cycle were identified and have been shown to be linked to tumorigenesis. The VKs have been shown to suppress liver cancer cell growth through multiple signaling pathways via the transcription factors and protein kinases. A VK2 analog was applied to the chemoprevention of hepatocellular carcinoma (HCC) recurrence after curative therapy and was shown to have beneficial effects, both in the suppression of HCC recurrence and in patient survival. Although a large scale randomized control study failed to demonstrate the suppression of HCC recurrence, a meta-analysis suggested a beneficial effect on the long-term survival of HCC patients. However, the beneficial effects of VK administration alone were not sufficient to prevent or treat HCC in clinical settings. Thus its combination with other anti-cancer reagents and the development of more potent novel VK derivatives are the focus of ongoing research which seeks to achieve satisfactory therapeutic effects against HCC. PMID:26380822

  11. Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas.

    PubMed

    Nault, Jean-Charles; Datta, Shalini; Imbeaud, Sandrine; Franconi, Andrea; Mallet, Maxime; Couchy, Gabrielle; Letouzé, Eric; Pilati, Camilla; Verret, Benjamin; Blanc, Jean-Frédéric; Balabaud, Charles; Calderaro, Julien; Laurent, Alexis; Letexier, Mélanie; Bioulac-Sage, Paulette; Calvo, Fabien; Zucman-Rossi, Jessica

    2015-10-01

    Hepatocellular carcinomas (HCCs) are liver tumors related to various etiologies, including alcohol intake and infection with hepatitis B (HBV) or C (HCV) virus. Additional risk factors remain to be identified, particularly in patients who develop HCC without cirrhosis. We found clonal integration of adeno-associated virus type 2 (AAV2) in 11 of 193 HCCs. These AAV2 integrations occurred in known cancer driver genes, namely CCNA2 (cyclin A2; four cases), TERT (telomerase reverse transcriptase; one case), CCNE1 (cyclin E1; three cases), TNFSF10 (tumor necrosis factor superfamily member 10; two cases) and KMT2B (lysine-specific methyltransferase 2B; one case), leading to overexpression of the target genes. Tumors with viral integration mainly developed in non-cirrhotic liver (9 of 11 cases) and without known risk factors (6 of 11 cases), suggesting a pathogenic role for AAV2 in these patients. In conclusion, AAV2 is a DNA virus associated with oncogenic insertional mutagenesis in human HCC. PMID:26301494

  12. Risk prediction models for hepatocellular carcinoma in different populations.

    PubMed

    Ma, Xiao; Yang, Yang; Tu, Hong; Gao, Jing; Tan, Yu-Ting; Zheng, Jia-Li; Bray, Freddie; Xiang, Yong-Bing

    2016-04-01

    Hepatocellular carcinoma (HCC) is a malignant disease with limited therapeutic options due to its aggressive progression. It places heavy burden on most low and middle income countries to treat HCC patients. Nowadays accurate HCC risk predictions can help making decisions on the need for HCC surveillance and antiviral therapy. HCC risk prediction models based on major risk factors of HCC are useful and helpful in providing adequate surveillance strategies to individuals who have different risk levels. Several risk prediction models among cohorts of different populations for estimating HCC incidence have been presented recently by using simple, efficient, and ready-to-use parameters. Moreover, using predictive scoring systems to assess HCC development can provide suggestions to improve clinical and public health approaches, making them more cost-effective and effort-effective, for inducing personalized surveillance programs according to risk stratification. In this review, the features of risk prediction models of HCC across different populations were summarized, and the perspectives of HCC risk prediction models were discussed as well. PMID:27199512

  13. FRZB up-regulated in hepatocellular carcinoma bone metastasis

    PubMed Central

    Huang, Jia; Hu, Wenhao; Lin, Xiangjin; Wang, Xuanwei; Jin, Ketao

    2015-01-01

    The clinical relevance of frizzled-related protein (FRZB) in hepatocellular carcinoma (HCC) bone metastasis remains uncertain. The aim of this study was to assess the clinical relationship of FRZB in patients with HCC bone metastasis after surgical resection. FRZB expression was evaluated by immunohistochemistry in formalin-fixed paraffin embedded (FFPE) HCC and paired bone metastasis tissues from 13 patients that underwent surgical resection. The clinical characteristics of 13 HCC patients with synchronous or metachronous bone metastasis received surgery were retrospectively reviewed. We found that FRZB was positive in 9 HCC tissues (69.2%) and in 11 paired bone metastatic tissues (84.6%) among these 13 paired samples. The expression of FRZB in the bone metastases was noticeably higher than that in the paired HCC tissues. The expression of FRZB was up-regulated in 10 (76.9%) paired bone metastases tissues. FRZB expression was up-regulated in HCC bone metastasis tissue, which suggested that FRZB might play a key role in the HCC bone metastasis. PMID:26722540

  14. Tumor information extraction in radiology reports for hepatocellular carcinoma patients

    PubMed Central

    Yim, Wen-wai; Denman, Tyler; Kwan, Sharon W.; Yetisgen, Meliha

    2016-01-01

    Hepatocellular carcinoma (HCC) is a deadly disease affecting the liver for which there are many available therapies. Targeting treatments towards specific patient groups necessitates defining patients by stage of disease. Criteria for such stagings include information on tumor number, size, and anatomic location, typically only found in narrative clinical text in the electronic medical record (EMR). Natural language processing (NLP) offers an automatic and scale-able means to extract this information, which can further evidence-based research. In this paper, we created a corpus of 101 radiology reports annotated for tumor information. Afterwards we applied machine learning algorithms to extract tumor information. Our inter-annotator partial match agreement scored at 0.93 and 0.90 F1 for entities and relations, respectively. Based on the annotated corpus, our sequential labeling entity extraction achieved 0.87 F1 partial match, and our maximum entropy classification relation extraction achieved scores 0.89 and 0. 74 F1 with gold and system entities, respectively. PMID:27570686

  15. Prevention of hepatocellular carcinoma in patients with chronic hepatitis B

    PubMed Central

    Fernández-Rodríguez, Conrado M; Gutiérrez-García, María Luisa

    2014-01-01

    Patients with chronic hepatitis B are at significant risk for hepatocellular carcinoma (HCC). Globally, over half a million people each year are diagnosed with HCC, with marked geographical variations. Despite overwhelming evidence for a causal role of hepatitis B virus (HBV) infection in the development of HCC and a well-established relationship between high baseline hepatitis B viral load and cumulative risk of HCC, the molecular basis for this association has not been fully elucidated. In addition, a beneficial role for antiviral therapy in preventing the development of HCC has been difficult to establish. This review examines the biological and molecular mechanisms of HBV-related hepatocarcinogenesis, recent results on the effect of modern nucleos(t)ides on the rate of HCC development in high risk HBV cohorts and the potential mechanisms by which long-term antiviral therapy with potent inhibitors of HBV replication might reduce the risk of HCC in patients with chronic hepatitis B. Although evidence from randomized controlled trials shows the favourable effects of antiviral agents in achieving profound and durable suppression of HBV DNA levels while improving liver function and histology, robust evidence of other long-term clinical outcomes, such as prevention of HCC, are limited. PMID:25133046

  16. Current approach in the treatment of hepatocellular carcinoma

    PubMed Central

    Rossi, Luigi; Zoratto, Federica; Papa, Anselmo; Iodice, Francesca; Minozzi, Marina; Frati, Luigi; Tomao, Silverio

    2010-01-01

    Hepatocellular carcinoma (HCC) is the most common malignant hepatobiliary disease; it is responsible for about 1 million deaths per year. Risk factors include hepatitis B and C, hepatic cirrhosis, including alcohol related hepatitis, metabolic and nutritional hepatic damage. The main modality of diffusion is intrahepatic in the natural course of the disease. There are two leading types of treatment: local and systemic. Surgical resection and liver transplantation constitute the most appropriate local treatments and are considered the only real possibility for recovery. Other local approaches include: radiofrequency ablation, percutaneous ethanol ablation, hepatic endoarterial chemoembolization and intrahepatic radiotherapy (SIRT: selective internal radiation therapy). These last treatments are used to control the disease when surgery or transplantation is not achievable; in some cases they are able to prolong survival while they constitute mainly a palliative treatment. Systemic treatments include: chemotherapy, immunological and hormonal therapies and, more recently, the introduction of new specific molecular target drugs. At the moment, in this group, the only drug that has given positive results during phase III trials (SHARP study) is Sorafenib. Sorafenib represents the only primary systemic therapy that has demonstrated, unlike the other treatments previously described, an increase in survival rate in patients affected with advanced HCC. Currently, other studies are taking place that are further developing the potential of this drug. These studies, including phase III trials, are directed in order to test the activity and safety of new emerging drugs with targeted activity. Examples of these new agents are: Sunitinib, Gefitinib, Cetuximab, Bevacizumab and Erlotinib. PMID:21160806

  17. Hepatocellular carcinoma tumor board: making sense of the technologies.

    PubMed

    Abou-Alfa, Ghassan K; Marrero, Jorge; Renz, John; Lencioni, Riccardo

    2015-01-01

    Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death, with a rising global incidence. The vast majority of HCC cases occur in the setting of liver cirrhosis, mainly due to chronic hepatitis C (HCV) or hepatitis B (HBV) viral infections, alcohol consumption, and nonalcoholic fatty liver disease. The new approval of curative therapy with two NS5A inhibitors, ledipasvir and sofosbuvir, for the treatment of HCV will no doubt affect HCC incidence and outcome. No studies have evaluated the use of the new antivirals in patients with HCC. Staging and scoring remain an integral part of the management of patients with advanced HCC. Curative therapies for the treatment of HCC are evolving. Improvements in surgical techniques and risk stratification for orthotopic liver transplantation (OLT) have expanded access and improved the outlook for patients suffering from HCC. Interventional locoregional treatments continue to play a key role in the management of HCC. Transarterial chemoembolization is considered the standard of care for patients with noninvasive multinodular tumors at the intermediate stage. Bland embolization appears to have similar virtues in some studies. Y90 radioembolization represents a promising treatment option for patients unfit or refractory to transarterial chemoembolization. The advent of sorafenib as a standard of care with an improvement in survival sadly remain the only major breakthrough in the treatment of advanced HCC, with mounting negative data from multiple clinical trials. Advances in immunotherapy and customized therapy may hopefully help reverse this tide. PMID:25993176

  18. Chemotherapy for advanced hepatocellular carcinoma in the sorafenib age

    PubMed Central

    Miyahara, Koji; Nouso, Kazuhiro; Yamamoto, Kazuhide

    2014-01-01

    The kinase inhibitor sorafenib is the only systemic therapy proven to have a positive effect on survival of patients with advanced hepatocellular carcinoma (HCC). After development of sorafenib and its introduction as a therapeutic agent used in the clinic, several critical questions have been raised. Clinical parameters and biomarkers predicting sorafenib efficacy are the most important issues that need to be elucidated. Although it is difficult to know the responders in advance using conventional characteristics of patients, there are specific serum cytokines and/or gene amplification in tumor tissues that have been reported to predict efficacy of sorafenib. Risk and benefits of continuation of sorafenib beyond radiological progression is another issue to consider because no other standard therapy for advanced HCC as yet exists. In addition, effectiveness of the expanded application of sorafenib is still controversial, although a few studies have shed some light on combinational treatment with sorafenib for intermediate-stage HCC. Recently, over 50 relevant drugs have been developed and are currently under investigation. The efficacy of some of these drugs has been extensively examined, but none have demonstrated any superiority over sorafenib, so far. However, there are several drugs that have shown efficacy for treatment after sorafenib failure, and these are proceeding to further studies. To address these issues and questions, we have done extensive literature review and summarize the most current status of therapeutic application of sorafenib. PMID:24764653

  19. Treatment Response Evaluation and Follow-up in Hepatocellular Carcinoma

    PubMed Central

    Arora, Anil; Kumar, Ashish

    2014-01-01

    Hepatocellular carcinoma (HCC) is one of the major causes of morbidity, mortality and healthcare expenditure in patients with chronic liver disease. The management of HCC is evolving because of recently introduced novel therapeutic approaches. Optimal outcome requires an early and accurate assessment of tumor response to therapy. Current imaging modalities, such as computed tomography (CT) and magnetic resonance (MR) imaging; provide reliable and reproducible anatomical data in order to demonstrate tumor burden changes. However, in the setting of novel targeted therapies and liver directed treatments, simple tumor anatomical changes can be less informative and usually appear later than biological changes. There has been a growing interest to monitor the therapeutic response, at an early phase of treatment, by measuring tumor viability and/or perfusion. Therefore the importance of tumor viability assessment is increasingly being recognized. The tumor viability measurement guidelines have recently been amended to include the measurement of only the longest diameter of the enhancing tumors to formally amend RECIST to modified RECIST (mRECIST). Viable tumor should be defined as uptake of contrast agent in the arterial phase. In this review, we discuss criteria of response evaluation in HCC and further follow-up of patients receiving curative and palliative treatment. PMID:25755604

  20. Recent advances in multidisciplinary management of hepatocellular carcinoma

    PubMed Central

    Gomaa, Asmaa I; Waked, Imam

    2015-01-01

    The incidence of hepatocellular carcinoma (HCC) is increasing, and it is currently the second leading cause of cancer-related death worldwide. Potentially curative treatment options for HCC include resection, transplantation, and percutaneous ablation, whereas palliative treatments include trans-arterial chemoembolization (TACE), radioembolization, and systemic treatments. Due to the diversity of available treatment options and patients’ presentations, a multidisciplinary team should decide clinical management of HCC, according to tumor characteristics and stage of liver disease. Potentially curative treatments are suitable for very-early- and early-stage HCC. However, the vast majority of HCC patients are diagnosed in later stages, where the tumor characteristics or progress of liver disease prevent curative interventions. For patients with intermediate-stage HCC, TACE and radioembolization improve survival and are being evaluated in addition to potentially curative therapies or with systemic targeted therapy. There is currently no effective systemic chemotherapy, immunologic, or hormonal therapy for HCC, and sorafenib is the only approved molecular-targeted treatment for advanced HCC. Other targeted agents are under investigation; trials comparing new agents in combination with sorafenib are ongoing. Combinations of systemic targeted therapies with local treatments are being evaluated for further improvements in HCC patient outcomes. This article provides an updated and comprehensive overview of the current standards and trends in the treatment of HCC. PMID:25866604

  1. Zebrafish as a disease model for studying human hepatocellular carcinoma

    PubMed Central

    Lu, Jeng-Wei; Ho, Yi-Jung; Yang, Yi-Ju; Liao, Heng-An; Ciou, Shih-Ci; Lin, Liang-In; Ou, Da-Liang

    2015-01-01

    Liver cancer is one of the world’s most common cancers and the second leading cause of cancer deaths. Hepatocellular carcinoma (HCC), a primary hepatic cancer, accounts for 90%-95% of liver cancer cases. The pathogenesis of HCC consists of a stepwise process of liver damage that extends over decades, due to hepatitis, fatty liver, fibrosis, and cirrhosis before developing fully into HCC. Multiple risk factors are highly correlated with HCC, including infection with the hepatitis B or C viruses, alcohol abuse, aflatoxin exposure, and metabolic diseases. Over the last decade, genetic alterations, which include the regulation of multiple oncogenes or tumor suppressor genes and the activation of tumorigenesis-related pathways, have also been identified as important factors in HCC. Recently, zebrafish have become an important living vertebrate model organism, especially for translational medical research. In studies focusing on the biology of cancer, carcinogen induced tumors in zebrafish were found to have many similarities to human tumors. Several zebrafish models have therefore been developed to provide insight into the pathogenesis of liver cancer and the related drug discovery and toxicology, and to enable the evaluation of novel small-molecule inhibitors. This review will focus on illustrative examples involving the application of zebrafish models to the study of human liver disease and HCC, through transgenesis, genome editing technology, xenografts, drug discovery, and drug-induced toxic liver injury. PMID:26576090

  2. Genome-wide identification of RNA editing in hepatocellular carcinoma.

    PubMed

    Kang, Lin; Liu, Xiaoqiao; Gong, Zhoulin; Zheng, Hancheng; Wang, Jun; Li, Yingrui; Yang, Huanming; Hardwick, James; Dai, Hongyue; Poon, Ronnie T P; Lee, Nikki P; Mao, Mao; Peng, Zhiyu; Chen, Ronghua

    2015-02-01

    We did whole-transcriptome sequencing and whole-genome sequencing on nine pairs of Hepatocellular carcinoma (HCC) tumors and matched adjacent tissues to identify RNA editing events. We identified mean 26,982 editing sites with mean 89.5% canonical A→G edits in each sample using an improved bioinformatics pipeline. The editing rate was significantly higher in tumors than adjacent normal tissues. Comparing the difference between tumor and normal tissues of each patient, we found 7 non-synonymous tissue specific editing events including 4 tumor-specific edits and 3 normal-specific edits in the coding region, as well as 292 edits varying in editing degree. The significant expression changes of 150 genes associated with RNA editing were found in tumors, with 3 of the 4 most significant genes being cancer related. Our results show that editing might be related to higher gene expression. These findings indicate that RNA editing modification may play an important role in the development of HCC. PMID:25462863

  3. Prevention of hepatocellular carcinoma in nonviral-related liver diseases.

    PubMed

    Fan, Jian-Gao; Farrell, Geoffrey C

    2009-05-01

    Although chronic infection with hepatitis B virus and/or hepatitis C virus are the most important risk factors for hepatocellular carcinoma (HCC) worldwide, other causes of cirrhosis can also lead to HCC. Given the high prevalence of alcoholism and the worldwide obesity epidemic, the relevant importance of nonviral liver disease-related HCC is expected to increase in the future. Some evidence supports mechanistic interactions between host or environmental factors and chronic viral hepatitis in the development of HCC. For example, food- and water-borne carcinogens have contributed to unusually high rates of HCC in parts of China and sub-Saharan Africa. With some of these conditions, appropriate public health measures to reduce the population's exposure to known etiologic agents, or early therapeutic intervention for 'at-risk' individuals before development of cirrhosis (e.g. hereditary hemochromatosis) can prevent HCC. Community-based programs to discourage and deal with excessive alcohol intake, to promote tobacco smoking awareness, to avoid exposure to aflatoxin and other food toxins, and measures to reduce the pandemic of obesity and diabetes are vital for effective interruption of the rising tide of HCC from nonviral liver disease. PMID:19646014

  4. Transarterial radioembolization for hepatocellular carcinoma: An update and perspectives.

    PubMed

    Sacco, Rodolfo; Mismas, Valeria; Marceglia, Sara; Romano, Antonio; Giacomelli, Luca; Bertini, Marco; Federici, Graziana; Metrangolo, Salvatore; Parisi, Giuseppe; Tumino, Emanuele; Bresci, Giampaolo; Corti, Ambra; Tredici, Manuel; Piccinno, Michele; Giorgi, Luigi; Bartolozzi, Carlo; Bargellini, Irene

    2015-06-01

    In the last decade trans-arterial radioembolization has given promising results in the treatment of patients with intermediate or advanced stage hepatocellular carcinoma (HCC), both in terms of disease control and tolerability profile. This technique consists of the selective intra-arterial administration of microspheres loaded with a radioactive compound (usually Yttrium(90)), and exerts its therapeutic effect through the radiation carried by these microspheres. A careful and meticulous selection of patients is crucial before performing the radioembolization to correctly perform the procedure and reduce the incidence of complications. Radioembolization is a technically complex and expensive technique, which has only recently entered clinical practice and is supported by scant results from phase III clinical trials. Nevertheless, it may represent a valid alternative to transarterial chemoembolization (TACE) in the treatment of intermediate-stage HCC patients, as shown by a comparative retrospective assessment that reported a longer time to progression, but not of overall survival, and a more favorable safety profile for radioembolization. In addition, this treatment has reported a higher percentage of tumor shrinkage, if compared to TACE, for pre-transplant downsizing and it represents a promising therapeutic option in patients with large extent of disease and insufficient residual liver volume who are not immediately eligible for surgery. Radioembolization might also be a suitable companion to sorafenib in advanced HCC or it can be used as a potential alternative to this treatment in patients who are not responding or do not tolerate sorafenib. PMID:26074690

  5. Current status of laparoscopic liver resection for hepatocellular carcinoma

    PubMed Central

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

    2016-01-01

    Laparoscopic liver resection (LLR) is becoming widely accepted for the treatment of hepatocellular carcinoma (HCC). Laparoscopic left lateral sectionectomy and minor laparoscopic liver resection are now considered standard approaches, especially for tumors located in the anterolateral segments of the liver. Laparoscopic left lateral sectionectomy in adult donors is also gaining acceptance for child liver transplantation in many centers. Major LLRs, including left hepatectomy and right hepatectomy, have been recently attempted. Laparoscopic donor hepatectomy is becoming more popular owing to increasing demand from young living donors who appreciate its minimal invasiveness and excellent cosmetic outcomes. Several centers have performed total laparoscopic donor right hepatectomy in adult-to-adult living donor liver transplantation. Many meta-analyses have shown that LLR is better than open liver resection in terms of short-term outcomes, principally cosmetic outcomes. Although no randomized control trials have compared LLR with open liver resection, the long-term oncologic outcomes were similar for both procedures in recent case-matched studies. PMID:27304550

  6. Galectin-1-Induced Autophagy Facilitates Cisplatin Resistance of Hepatocellular Carcinoma.

    PubMed

    Su, Yu-Chi; Davuluri, Goutham Venkata Naga; Chen, Cheng-Hao; Shiau, Dong-Che; Chen, Chien-Chin; Chen, Chia-Ling; Lin, Yee-Shin; Chang, Chih-Peng

    2016-01-01

    Hepatocellular carcinoma (HCC) is one of the most common cancers in Taiwan. Although chemotherapy is the primary treatment for HCC patients, drug resistance often leads to clinical failure. Galectin-1 is a beta-galactoside binding lectin which is up-regulated in HCC patients and promotes tumor growth by mediating cancer cell adhesion, migration and proliferation, but its role in chemoresistance of HCC is poorly understood. In this study we found that galectin-1 is able to lead to chemoresistance against cisplatin treatment, and subsequent inhibition has reversed the effect of cell death in HCC cells. Moreover, galectin-1 was found to induce autophagic flux in HCC cells. Inhibition of autophagy by inhibitors or knockdown of Atg5 cancels galectin-1-induced cisplatin resistance in HCC cells. Increase of mitophagy triggered by galectin-1 was found to reduce the mitochondrial potential loss and apoptosis induced by cisplatin treatment. Finally, using an in situ hepatoma mouse model, we clearly demonstrated that inhibition of galectin-1 by thiodigalactoside could significantly augment the anti-HCC effect of cisplatin. Taken together, our findings offer a new insight into the chemoresistance galectin-1 causes against cisplatin treatment, and points to a potential approach to improve the efficacy of cisplatin in the treatment of HCC patients. PMID:26859293

  7. Diagnosis and treatment of hepatocellular carcinoma: An update

    PubMed Central

    Tejeda-Maldonado, Javier; García-Juárez, Ignacio; Aguirre-Valadez, Jonathan; González-Aguirre, Adrián; Vilatobá-Chapa, Mario; Armengol-Alonso, Alejandra; Escobar-Penagos, Francisco; Torre, Aldo; Sánchez-Ávila, Juan Francisco; Carrillo-Pérez, Diego Luis

    2015-01-01

    Hepatocellular carcinoma (HCC) is one of the most common malignancies leading to high mortality rates in the general population; in cirrhotic patients, it is the primary cause of death. The diagnosis is usually delayed in spite of at-risk population screening recommendations, i.e., patients infected with hepatitis B or C virus. Hepatocarcinogenesis hinges on a great number of genetic and molecular abnormalities that lead to tumor angiogenesis and foster their dissemination potential. The diagnosis is mainly based on imaging studies such as computed tomography and magnetic resonance, in which lesions present a characteristic classical pattern of early arterial enhancement followed by contrast medium “washout” in late venous phase. On occasion, when imaging studies are not conclusive, biopsy of the lesion must be performed to establish the diagnosis. The Barcelona Clinic Liver Cancer staging method is the most frequently used worldwide and recommended by the international guidelines of HCC management. Currently available treatments include tumor resection, liver transplant, sorafenib and loco-regional therapies (alcoholization, radiofrequency ablation, chemoembolization). The prognosis of hepatocarcinoma is determined according to the lesion’s stage and in cirrhotic patients, on residual liver function. Curative treatments, such as liver transplant, are sought in patients diagnosed in early stages; patients in more advanced stages, were not greatly benefitted by chemotherapy in terms of survival until the advent of target molecules such as sorafenib. PMID:25848464

  8. Hormonal control of the metabolic machinery of hepatocellular carcinoma

    PubMed Central

    Wong, Carmen Chak-Lui; Wong, Chun-Ming

    2016-01-01

    Hepatocellular carcinoma (HCC) is one of the most fatal malignancies worldwide. It is an aggressive cancer with low cure rate, frequent metastasis, and highly resistant to conventional chemotherapies. Better knowledge regarding the molecular and metabolic alterations in HCC will be instrumental to the development of novel therapeutic interventions against HCC. In the August 2015 issue of Hepatology, Nie et al. reports an important molecular pathway that contributes to the Warburg Effect in HCC. They have beautifully demonstrated that the loss of a component of a hormonal system, the mineralocorticoid receptor (MR), reprogrammed the metabolic machinery of HCC cells to aerobic glycolysis through the miR-338-3p-PKL/R axis. The implication could be that in addition to drugs that directly target the metabolic enzymes in cancer cells, more translational efforts could be focused on the development of drugs that involve the activation of the MR-aldosterone system or other hormonal systems to target the Warburg effect. PMID:27275458

  9. Computational hepatocellular carcinoma tumor grading based on cell nuclei classification

    PubMed Central

    Atupelage, Chamidu; Nagahashi, Hiroshi; Kimura, Fumikazu; Yamaguchi, Masahiro; Tokiya, Abe; Hashiguchi, Akinori; Sakamoto, Michiie

    2014-01-01

    Abstract. Hepatocellular carcinoma (HCC) is the most common histological type of primary liver cancer. HCC is graded according to the malignancy of the tissues. It is important to diagnose low-grade HCC tumors because these tissues have good prognosis. Image interpretation-based computer-aided diagnosis (CAD) systems have been developed to automate the HCC grading process. Generally, the HCC grade is determined by the characteristics of liver cell nuclei. Therefore, it is preferable that CAD systems utilize only liver cell nuclei for HCC grading. This paper proposes an automated HCC diagnosing method. In particular, it defines a pipeline-path that excludes nonliver cell nuclei in two consequent pipeline-modules and utilizes the liver cell nuclear features for HCC grading. The significance of excluding the nonliver cell nuclei for HCC grading is experimentally evaluated. Four categories of liver cell nuclear features were utilized for classifying the HCC tumors. Results indicated that nuclear texture is the dominant feature for HCC grading and others contribute to increase the classification accuracy. The proposed method was employed to classify a set of regions of interest selected from HCC whole slide images into five classes and resulted in a 95.97% correct classification rate. PMID:26158066

  10. Annexin A6 protein is downregulated in human hepatocellular carcinoma.

    PubMed

    Meier, Elisabeth M; Rein-Fischboeck, Lisa; Pohl, Rebekka; Wanninger, Josef; Hoy, Andrew J; Grewal, Thomas; Eisinger, Kristina; Krautbauer, Sabrina; Liebisch, Gerhard; Weiss, Thomas S; Buechler, Christa

    2016-07-01

    Annexin A6 (AnxA6) is a lipid-binding protein highly expressed in the liver, regulating cholesterol homeostasis and signaling pathways with a role in liver physiology. Here, we analyzed whether hepatic AnxA6 levels are affected by pathological conditions that are associated with liver dysfunction and liver injury. AnxA6 levels in the fatty liver of mice fed a high-fat diet, in ob/ob and db/db animals and in human fatty liver are comparable to controls. Similarly, AnxA6 levels appear unaffected in murine nonalcoholic steatohepatitis and human liver fibrosis. Accordingly, adiponectin, lysophosphatidylcholine, palmitate, and TGFbeta, all of which have a role in liver injury, do not affect AnxA6 expression in human hepatocytes. Likewise, adiponectin and IL8 do not alter AnxA6 levels in primary human hepatic stellate cells. However, in hepatic tumors of 18 patients, AnxA6 protein levels are substantially reduced compared to nontumorous tissues. AnxA6 mRNA is even increased in the tumors suggesting that posttranscriptional mechanisms are involved herein. Lipidomic analysis shows trends toward elevated cholesteryl ester and sphingomyelin in the tumor samples, yet the ratio of tumor to nontumorous AnxA6 does not correlate with these lipids. The current study shows that AnxA6 is specifically reduced in human hepatocellular carcinoma suggesting a role of this protein in hepatocarcinogenesis. PMID:27334756

  11. Immunostains Used to Subtype Hepatic Adenomas Do Not Distinguish Hepatic Adenomas From Hepatocellular Carcinomas.

    PubMed

    Liu, Liping; Shah, Sejal S; Naini, Bita V; French, Samuel; Wu, Tsung-Teh; Torbenson, Michael S; Chandan, Vishal S

    2016-08-01

    Immunostains are used to subtype hepatic adenomas to stratify for the risk of malignant transformation. The most common panel of immunostains used for this purpose includes liver fatty acid-binding protein (LFABP), serum amyloid A (SAA) protein, C-reactive protein (CRP), and glutamine synthetase (GS). Importantly, some pathologists use these stains in an attempt to distinguish hepatocellular carcinomas (HCC) from hepatic adenomas. However, there are limited data on the performance of these stains in HCCs. To investigate the staining characteristics of HCCs, we studied 159 HCCs (92 well-differentiated, 67 moderately differentiated, and 7 poorly differentiated) and 7 fibrolamellar carcinomas for the expression of LFABP, SAA, CRP, and GS. All of the stains were positive in at least a subset of HCCs: SAA was positive in 27 of 159 (17%), CRP in 86 of 159 (54%), and GS in 23 of 47 (49%) cases; LFABP showed loss of staining in 36 of 159 (23%) cases. Fibrolamellar carcinomas were consistently CRP positive (7 of 7 cases) and frequently showed loss of LFABP (4 of 7 cases). There was no association between expression of SAA, CRP, and GS as well as loss of LFABP expression and other clinicopathologic features. HCCs with loss of LFABP were more frequently associated with negative GS expression (11 of 14 cases, P=0.02). These data show that immunostains used to subtype hepatic adenomas are not useful for distinguishing HCCs from hepatic adenomas and should be used only after a diagnosis of hepatic adenoma has been made using other criteria. PMID:26927891

  12. Long Noncoding RNA Plays a Key Role in Metastasis and Prognosis of Hepatocellular Carcinoma

    PubMed Central

    Li, Guangbing; Zhang, Haohai; Wan, Xueshuai; Yang, Xiaobo; Zhu, Chengpei; Wang, Anqiang; He, Lian; Miao, Ruoyu; Chen, Shuguang; Zhao, Haitao

    2014-01-01

    Long noncoding RNAs (lncRNAs) have been attracting immense research interests. However, only a handful of lncRNAs had been thoroughly characterized. They were involved in fundamental cellular processes including regulation of gene expression at epigenetics as well as tumorogenesis. In this paper, we give a systematic and comprehensive review of existing literature about lncRNA involvement in hepatocellular carcinoma. This review exhibited that lncRNAs played important roles in tumorigenesis and subsequent prognosis and metastasis of hepatocellular carcinoma and elucidated the role of some specific lncRNAs such as MALAT1 and HOTAIR in the pathophysiology of hepatocellular carcinoma and their potential of being therapeutic targets. PMID:24757675

  13. Radioembolisation and portal vein embolization before resection of large hepatocellular carcinoma.

    PubMed

    Bouazza, Fikri; Poncelet, Arthur; Garcia, Camilo Alejandro; Delatte, Philippe; Engelhom, Jean Luc; Gomez Galdon, Maria; Deleporte, Amélie; Hendlisz, Alain; Vanderlinden, Bruno; Flamen, Patrick; Donckier, Vincent

    2015-08-28

    Resectability of hepatocellular carcinoma in patients with chronic liver disease is dramatically limited by the need to preserve sufficient remnant liver in order to avoid postoperative liver insufficiency. Preoperative treatments aimed at downsizing the tumor and promoting hypertrophy of the future remnant liver may improve resectability and reduce operative morbidity. Here we report the case of a patient with a large hepatocellular carcinoma arising from chronic liver disease. Preoperative treatment, including tumor downsizing with transarterial radioembolization and induction of future remnant liver hypertrophy with right portal vein embolization, resulted in a 53% reduction in tumor volume and compensatory hypertrophy in the contralateral liver. The patient subsequently underwent extended right hepatectomy with no postoperative signs of liver decompensation. Pathological examination demonstrated a margin-free resection and major tumor response. This new therapeutic sequence, combining efficient tumor targeting and subsequent portal vein embolization, could improve the feasibility and safety of major liver resection for hepatocellular carcinoma in patients with liver injury. PMID:26327775

  14. Promising Urinary Protein Biomarkers for the Early Detection of Hepatocellular Carcinoma among High-Risk Hepatitis C Virus Egyptian Patients.

    PubMed

    Abdalla, Moemen Ak; Haj-Ahmad, Yousef

    2012-01-01

    Hepatocellular Carcinoma is a major healthcare problem, representing the third most common cause of cancer-related mortality worldwide. There are 130 million Hepatitis C virus infected patients worldwide who are at a high-risk for developing Hepatocellular Carcinoma. Due to the fact that reliable parameters and/or tools for the early detection of Hepatocellular Carcinoma among high-risk individuals are severely lacking, Hepatocellular Carcinoma patients are always diagnosed at a late stage where surgical solutions or effective treatment are not possible. Urine was collected from 106 Hepatitis C infected patients patients, 32 of whom had already developed Hepatocellular Carcinoma and 74 patients who were diagnosed as Hepatocellular Carcinoma -free at the time of initial sample collection. In addition to these patients, urine samples were also collected from 12 healthy control individuals. Total urinary proteins were isolated from the urine samples and LC-MS/MS was used to identify potential protein HCC biomarker candidates. This was followed by validating relative expression levels of proteins present in urine among all the patients using quantitative real time-PCR. This approach revealed that significant over-expression of three proteins: DJ-1, Chromatin Assembly Factor-1 (CAF-1) and Heat Shock Protein 60 (HSP60), was a characteristic event among Hepatocellular Carcinoma - post Hepatitis C virus infected patients. As a single-based Hepatocellular Carcinoma biomarker, CAF-1 over-expression identified Hepatocellular Carcinoma among Hepatitis C virus infected patients with a specificity of 90%, sensitivity of 66% and with an overall diagnostic accuracy of 78%. Moreover, the CAF-1/HSP60 tandem identified Hepatocellular Carcinoma among Hepatitis C virus infected patients with a specificity of 92%, sensitivity of 61% and with an overall diagnostic accuracy of 77%. PMID:23074380

  15. Nek7 is overexpressed in hepatocellular carcinoma and promotes hepatocellular carcinoma cell proliferation in vitro and in vivo

    PubMed Central

    Zhou, Lei; Wang, Zhixin; Xu, Xinsen; Wan, Yong; Qu, Kai; Fan, Haining; Chen, Qiangpu; Sun, Xuejun; Liu, Chang

    2016-01-01

    NIMA-related kinase-7 (Nek7) is a serine/threonine kinase involved in cell-cycle progression via mitotic spindle formation and cytokinesis. In this study, we investigated whether Nek7 involves in hepatocellular carcinoma (HCC). Interestingly, we found that Nek7 was significantly overexpressed in HCC than in liver tissues. In HCC patients, high Nek7 expression was significantly correlated with tumor numbers, tumor diameter, adjacent organs invasion, tumor grade and TNM stage. Furthermore, Nek7 expression pattern showed close relationship with that of Ki-67, a well-stablished cell proliferation marker. More importantly, patients with higher expression levels of Nek7 had significantly lower 5-years survival rate. Likewise, Nek7 expression was significantly higher in HCC cell lines than normal hepatic cell line. By Nek7 silencing using lentivirus-mediated Nek7 interference approach, the growth of HCC cell lines was inhibited and the tumor growth in xenograft mouse model was also suppressed. Mechanistic studies showed that silencing of Nek7 resulted in decreasing cyclinB1 level both in vitro and in vivo. In conclusion, this study highlights for the first time the possible role of Nek7 in HCC progression. Nek7 would be a useful biomarker that early predicts HCC patients at higher risk of poor prognosis. Also, Nek7 could be a novel HCC therapeutic target. PMID:26921196

  16. Proton Beam Therapy for Hepatocellular Carcinoma Located Adjacent to the Alimentary Tract;Proton beam therapy; Hepatocellular carcinoma; Gastrointestinal bleeding

    SciTech Connect

    Nakayama, Hidetsugu; Sugahara, Shinji; Fukuda, Kuniaki; Abei, Masato; Shoda, Junichi; Sakurai, Hideyuki; Tsuboi, Koji; Matsuzaki, Yasushi; Tokuuye, Koichi

    2011-07-15

    Purpose: To evaluate the safety and effectiveness of proton beam therapy for hepatocellular carcinoma (HCC) located adjacent to the alimentary tract. Patients and Methods: Forty-seven patients (median age, 69 years; range, 43-82 years) who had HCC located within 2 cm of the alimentary tract underwent proton beam therapy. Liver damage according to the Child-Pugh classification was Class A in 35 patients, Class B in 9, and Class C in 3. Treatment protocols of the early 16 patients and the late 31 patients were 72.6 GyE in 22 fractions and 77 GyE in 35 fractions, respectively. Results: During the median follow-up period of 23 months, 24 patients died; the remaining 23 patients were alive until September 2008. The median overall survival was 33.9 months (95% confidence interval [CI], 10.8-57.0 months). Actuarial overall and local progression-free survival rates at 3 years were 50.0% and 88.1%, respectively. Grade 2 and 3 alimentary tract hemorrhage was observed in 3 (6.4%) and 1 (2.1%) patients, respectively. Conclusions: Our proton beam therapy strategy for HCC located adjacent to the alimentary tract seems to be effective but should be performed with caution.

  17. A new cluster-based oversampling method for improving survival prediction of hepatocellular carcinoma patients.

    PubMed

    Santos, Miriam Seoane; Abreu, Pedro Henriques; García-Laencina, Pedro J; Simão, Adélia; Carvalho, Armando

    2015-12-01

    Liver cancer is the sixth most frequently diagnosed cancer and, particularly, Hepatocellular Carcinoma (HCC) represents more than 90% of primary liver cancers. Clinicians assess each patient's treatment on the basis of evidence-based medicine, which may not always apply to a specific patient, given the biological variability among individuals. Over the years, and for the particular case of Hepatocellular Carcinoma, some research studies have been developing strategies for assisting clinicians in decision making, using computational methods (e.g. machine learning techniques) to extract knowledge from the clinical data. However, these studies have some limitations that have not yet been addressed: some do not focus entirely on Hepatocellular Carcinoma patients, others have strict application boundaries, and none considers the heterogeneity between patients nor the presence of missing data, a common drawback in healthcare contexts. In this work, a real complex Hepatocellular Carcinoma database composed of heterogeneous clinical features is studied. We propose a new cluster-based oversampling approach robust to small and imbalanced datasets, which accounts for the heterogeneity of patients with Hepatocellular Carcinoma. The preprocessing procedures of this work are based on data imputation considering appropriate distance metrics for both heterogeneous and missing data (HEOM) and clustering studies to assess the underlying patient groups in the studied dataset (K-means). The final approach is applied in order to diminish the impact of underlying patient profiles with reduced sizes on survival prediction. It is based on K-means clustering and the SMOTE algorithm to build a representative dataset and use it as training example for different machine learning procedures (logistic regression and neural networks). The results are evaluated in terms of survival prediction and compared across baseline approaches that do not consider clustering and/or oversampling using the

  18. 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

  19. Novel Changes in Glycosylation of Serum Apo-J in Patients with Hepatocellular Carcinoma

    PubMed Central

    Comunale, Mary Ann; Wang, Mengjun; Rodemich-Betesh, Lucy; Hafner, Julie; Lamontagne, Anne; Klein, Andrew; Marrero, Jorge; Di Bisceglie, Adrian M.; Gish, Robert; Block, Timothy; Mehta, Anand

    2011-01-01

    Background Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and the occurrence of HCC has more than doubled in the United States (USA) in the last decade. Early detection is considered key to reducing the mortality of HCC. Methods Using two-dimensional gel electrophoresis and high performance liquid chromatography (HPLC) we have analyzed the glycosylation of Apo-J from healthy controls, patients with liver cirrhosis or with hepatocellular carcinoma. Results Apo-J in the serum from patients with HCC had decreased levels of (β-1,4) triantennary N-linked glycan compared with the healthy controls or patients with liver cirrhosis. We analyzed this change in an independent cohort of 76 patients with HCC, 32 with cirrhosis, and 43 infected with hepatitis C virus using the Datura stramonium lectin (DSL), which binds to (β-1,4) triantennary N-linked glycan. The level of DSL-reactive Apo-J allowed us to differentiate HCC from cirrhosis with an area under the receiver operating characteristic curve (AUROC) of 0.852. When Apo-J was combined with other serum biomarkers such as alpha-fetoprotein or fucosylated kininogen using a multivariate logistic regression model, the AUROC increased to 0.944, a value much greater than that observed with AFP alone (AUROC of 0.765). Conclusions The glycosylation of Apo-J is a useful marker when used alone or in combination with outer makers for the early detection of HCC. Impact The potential use of a combination of alpha-fetoprotein, DLS-reactive Apo-J, and fucosylated kininogen as a biomarker of HCC would have great value in the management of patients with liver disease. PMID:21467232

  20. Cyclin-dependent kinase inhibitor 3 is overexpressed in hepatocellular carcinoma and promotes tumor cell proliferation

    SciTech Connect

    Xing, Chunyang; Xie, Haiyang; Zhou, Lin; Zhou, Wuhua; Zhang, Wu; Ding, Songming; Wei, Bajin; Yu, Xiaobo; Su, Rong; Zheng, Shusen

    2012-03-30

    Highlights: Black-Right-Pointing-Pointer CDKN3 is commonly overexpressed in HCC and is associated with poor clinical outcome. Black-Right-Pointing-Pointer Overexpression of CDKN3 could stimulate the proliferation of HCC cells by promoting G1/S transition. Black-Right-Pointing-Pointer CDKN3 could inhibit the expression of p21 in HCC cells. Black-Right-Pointing-Pointer Overexpression of CDKN3 has no effect on apoptosis and invasion of HCC cells. Black-Right-Pointing-Pointer We identified 61 genes co-expressed with CDKN3, and BIRC5 was located at the center of the co-expression network. -- Abstract: Cyclin-dependent kinase inhibitor 3 (CDKN3) belongs to the protein phosphatases family and has a dual function in cell cycling. The function of this gene has been studied in several kinds of cancers, but its role in human hepatocellular carcinoma (HCC) remains to be elucidated. In this study, we found that CDKN3 was frequently overexpressed in both HCC cell lines and clinical samples, and this overexpression was correlated with poor tumor differentiation and advanced tumor stage. Functional studies showed that overexpression of CDKN3 could promote cell proliferation by stimulating G1-S transition but has no impact on cell apoptosis and invasion. Microarray-based co-expression analysis identified a total of 61 genes co-expressed with CDKN3, with most of them involved in cell proliferation, and BIRC5 was located at the center of CDKN3 co-expression network. These results suggest that CDKN3 acts as an oncogene in human hepatocellular carcinoma and antagonism of CDKN3 may be of interest for the treatment of HCC.

  1. Glycogenotic hepatocellular carcinoma with glycogen-ground-glass hepatocytes: A heuristically highly relevant phenotype

    PubMed Central

    Bannasch, Peter

    2012-01-01

    Glycogenotic hepatocellular carcinoma (HCC) with glycogen-ground-glass hepatocytes has recently been described as an allegedly “novel variant” of HCC, but neither the historical background nor the heuristic relevance of this observation were put in perspective. In the present contribution, the most important findings in animal models and human beings related to the emergence and further evolution of excessively glycogen storing (glycogenotic) hepatocytes with and without ground glass features during neoplastic development have been summarized. Glycogenotic HCCs with glycogen-ground-glass hepatocytes represent highly differentiated neoplasms which contain subpopulations of cells phenotypically resembling those of certain types of preneoplastic hepatic foci and benign hepatocellular neoplasms. It is questionable whether the occurrence of glycogen-ground-glass hepatocytes in a glycogenotic HCC justifies its classification as a specific entity. The typical appearance of ground-glass hepatocytes is due to a hypertrophy of the smooth endoplasmic reticulum, which is usually associated with an excessive storage of glycogen and frequently also with an expression of the hepatitis B surface antigen. Sequential studies in animal models and observations in humans indicate that glycogen-ground-glass hepatocytes are a facultative, integral part of a characteristic cellular sequence commencing with focal hepatic glycogenosis potentially progressing to benign and malignant neoplasms. During this process highly differentiated glycogenotic cells including ground-glass hepatocytes are gradually transformed via various intermediate stages into poorly differentiated glycogen-poor, basophilic (ribosome-rich) cancer cells. Histochemical, microbiochemical, and molecular biochemical studies on focal hepatic glycogenosis and advanced preneoplastic and neoplastic lesions in tissue sections and laser-dissected specimens in rat and mouse models have provided compelling evidence for an early

  2. Fine needle aspiration biopsy of the liver: Algorithmic approach and current issues in the diagnosis of hepatocellular carcinoma

    PubMed Central

    Wee, Aileen

    2005-01-01

    The role of fine needle aspiration biopsy (FNAB) in the evaluation of focal liver lesions has evolved. Guided FNAB is still useful to procure a tissue diagnosis if clinical, biochemical and radiologic findings are inconclusive. Major diagnostic issues include: (i) Distinction of benign hepatocellular nodular lesions from reactive hepatocytes, (ii) Distinction of well-differentiated hepatocellular carcinoma (WD-HCC) from benign hepatocellular nodular lesions, (iii) Distinction of poorly differentiated HCC from cholangiocarcinoma and metastatic carcinomas, (iv) Determination of histogenesis of malignant tumor, and (v) Determination of primary site of origin of malignant tumor. This review gives a general overview of hepatic FNAB; outlines an algorithmic approach to cytodiagnosis with emphasis on HCC, its variants and their mimics; and addresses current diagnostic issues. Close radiologic surveillance of high-risk cirrhotic patients has resulted in the increasing detection of smaller lesions with many subjected to biopsy for tissue characterization. The need for tissue confirmation in clinically obvious HCC is questioned due to risk of malignant seeding. When a biopsy is indicated, core needle biopsy is favored over FNAB. The inherent difficulty of distinguishing small/early HCC from benign hepatocellular nodular lesions has resulted in indeterminate reports. Changing concepts in the understanding of the biological behavior and morphologic evolution of HCC and its precursors; and the current lack of agreement on the morphologic criteria for distinguishing high-grade dysplastic lesions (with small cell change) from WD-HCC, have profound impact on nomenclature, cytohistologic interpretation and management. Optimization of hepatic FNAB to enhance the yield and accuracy of diagnoses requires close clinicopathologic correlation; combined cytohistologic approach; judicious use of ancillary tests; and skilled healthcare teams. PMID:15941489

  3. Transcatheter Arterial Embolization for Tumor Seeding in the Chest Wall After Radiofrequency Ablation for Hepatocellular Carcinoma

    SciTech Connect

    Shibata, Toshiya Shibata, Toyomichi; Maetani, Yoji; Kubo, Takeshi; Nishida, Naoshi; Itoh, Kyo

    2006-06-15

    Tumor seeding in the chest wall was depicted at follow-up CT obtained 9 months after radiofrequency ablation for hepatocellular carcinoma. Transcatheter arterial embolization was successfully performed, injecting emulsion of 10 mg of epirubicin and 1 ml of iodized oil followed by gelatin sponge particles via the microcatheter placed in the right eleventh intercostal artery. The patient died of tumor growth in the liver one year after the embolization, but no progression of the tumor seeding was noted during the follow-up period. We conclude that transcatheter arterial embolization was effective for the control of tumor seeding after radiofrequency ablation for hepatocellular carcinoma.

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

    SciTech Connect

    Matsumoto, Koichi Nojiri, Junichi; Takase, Yukinori; Egashira, Yoshikazu; Azama, Shinichi; Kato, Akira; Kitahara, Kenji; Miyazaki, Koji; Kudo, Sho

    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.

  5. Potential molecular, cellular and microenvironmental mechanism of sorafenib resistance in hepatocellular carcinoma.

    PubMed

    Chen, Jiang; Jin, Renan; Zhao, Jie; Liu, Jinghua; Ying, Hanning; Yan, Han; Zhou, Senjun; Liang, Yuelong; Huang, Diyu; Liang, Xiao; Yu, Hong; Lin, Hui; Cai, Xiujun

    2015-10-10

    Sorafenib, an orally-available kinase inhibitor, is the only standard clinical treatment against advanced hepatocellular carcinoma. However, development of resistance to sorafenib has raised concern in recent years due to the high-level heterogeneity of individual response to sorafenib treatment. The resistance mechanism underlying the impaired sensitivity to sorafenib is still elusive though some researchers have made great efforts. Here, we provide a systemic insight into the potential molecular, cellular and microenvironmental mechanism of sorafenib resistance in hepatocellular carcinoma depending on abundant previous studies and reports. PMID:26170167

  6. Combined approach to hepatocellular carcinoma: a new treatment concept for nonresectable disease.

    PubMed

    Strebel, Bruno M; Dufour, Jean-François

    2008-11-01

    Depending on tumor burden, hepatic function and patients' performance status, hepatocellular carcinoma is treated by surgery, local procedures, systemic therapy or palliation. The majority of patients are diagnosed at a stage where local therapy is the treatment of choice. Recently, the multikinase inhibitor sorafenib was found to improve the survival of patients with advanced hepatocellular carcinoma and conserved liver function. In this manuscript, we summarize the experimental evidence supporting the combination of a systemic targeted therapy with a local therapy. We also discuss the pros and cons of different schedules of combining such treatments. We conclude that there is enough of a theoretical argument to design clinical trials testing this strategy. PMID:18983234

  7. 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

  8. Hepatocellular carcinoma with extension to the diaphragm, falciform ligament, rectus abdominis and paraumbilical vein

    PubMed Central

    Kaur, R; Abdullah, BJJ; Rajasingam, V

    2008-01-01

    Hepatocellular carcinoma is the most common primary tumour of the liver. The most common extrahepatic metastatic sites are the lung, lymph nodes, bones and adrenal glands. All forms of HCC demonstrate a tendency for vascular invasion, producing extensive intrahepatic metastases and, occasionally, portal vein or inferior vena cava extension with spread into the right atrium in extreme cases. Tumour spread of abdominal diseases via hepatic ligaments has also been previously reported. We report a rare case of hepatocellular carcinoma with extension into the falciform ligament, overlying rectus sheath and adjacent diaphragm with concomitant infiltration into the recanalised paraumbilical vein. PMID:21611019

  9. Multimodality imaging of fat-containing adrenal metastasis from hepatocellular carcinoma.

    PubMed

    Tariq, Umar; Poder, Liina; Carlson, David; Courtier, Jesse; Joe, Bonnie N; Coakley, Fergus V

    2012-06-01

    A biopsy-proven fat-containing metastasis to the adrenal gland in a patient with hepatocellular carcinoma demonstrated low density on nonenhanced CT, heterogeneity on contrast-enhanced CT, and marked signal loss on opposed-phase gradient-echo MRI, mimicking an adrenal adenoma. However, the mass was not present on older studies and showed increased FDG uptake on PET. The possibility of a fat-containing metastasis should be considered for an apparent adrenal adenoma in a patient with a primary hepatocellular carcinoma. PMID:22614216

  10. GRAM domain-containing protein 1A (GRAMD1A) promotes the expansion of hepatocellular carcinoma stem cell and hepatocellular carcinoma growth through STAT5.

    PubMed

    Fu, Binsheng; Meng, Wei; Zhao, Hui; Zhang, Bing; Tang, Hui; Zou, Ying; Yao, Jia; Li, Heping; Zhang, Tong

    2016-01-01

    Hepatocellular carcinoma (HCC) is the leading cause for cancer death worldwide, new prognostic factors and targets are critical for HCC treatment. Here, we found GRAMD1A was upregulated in HCC tissues, patients with high GRAMD1A levels had poor outcome, statistical analyses found GRAMD1A expression was positively correlated with pathologic differentiation and survival or mortality. It was an unfavorable prognostic factor for HCC patients. Functional analyses revealed GRAMD1A contributed to the self-renewal of HCC stem cells, resistance to chemotherapy and tumor growth of HCC determined by hepatosphere formation assay, side population (SP) analysis, TUNEL assay, soft agar growth ability assay and tumor growth model in vivo. Mechanism analyses found signal transducer and activator of transcription 5 (STAT5) was the target of GRAMD1A, GRAMD1A regulated the target genes of STAT5 and the transcriptional activity of STAT5. Inhibition of STAT5 in indicated HCC cells overexpressing GRAMD1A suppressed the effects of GRAMD1A on the self-renewal of HCC stem cell, resistance to chemotherapy and tumor growth, suggesting GRAMD1A promoted the self-renewal of HCC stem cells and the development of HCC by increasing STAT5 level. GRAMD1A might be a useful biomarker and target for HCC. PMID:27585821

  11. GRAM domain-containing protein 1A (GRAMD1A) promotes the expansion of hepatocellular carcinoma stem cell and hepatocellular carcinoma growth through STAT5

    PubMed Central

    Fu, Binsheng; Meng, Wei; Zhao, Hui; Zhang, Bing; Tang, Hui; Zou, Ying; Yao, Jia; Li, Heping; Zhang, Tong

    2016-01-01

    Hepatocellular carcinoma (HCC) is the leading cause for cancer death worldwide, new prognostic factors and targets are critical for HCC treatment. Here, we found GRAMD1A was upregulated in HCC tissues, patients with high GRAMD1A levels had poor outcome, statistical analyses found GRAMD1A expression was positively correlated with pathologic differentiation and survival or mortality. It was an unfavorable prognostic factor for HCC patients. Functional analyses revealed GRAMD1A contributed to the self-renewal of HCC stem cells, resistance to chemotherapy and tumor growth of HCC determined by hepatosphere formation assay, side population (SP) analysis, TUNEL assay, soft agar growth ability assay and tumor growth model in vivo. Mechanism analyses found signal transducer and activator of transcription 5 (STAT5) was the target of GRAMD1A, GRAMD1A regulated the target genes of STAT5 and the transcriptional activity of STAT5. Inhibition of STAT5 in indicated HCC cells overexpressing GRAMD1A suppressed the effects of GRAMD1A on the self-renewal of HCC stem cell, resistance to chemotherapy and tumor growth, suggesting GRAMD1A promoted the self-renewal of HCC stem cells and the development of HCC by increasing STAT5 level. GRAMD1A might be a useful biomarker and target for HCC. PMID:27585821

  12. Clinical value of gadoxetic acid-enhanced magnetic resonance imaging in surgery for hepatocellular carcinoma - with a special emphasis on early hepatocellular carcinoma

    PubMed Central

    Matsuda, Masanori

    2015-01-01

    Gadoxetic acid- or gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) achieves excellent lesion detection and characterization for both hypervascular hepatocellular carcinoma (HCC) in arterial phase imaging and hypovascular early HCC (small well-differentiated HCC of the vaguely nodular type) in hepatobiliary phase im