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Sample records for hepatocellular carcinoma detection

  1. Hepatocellular carcinoma.

    PubMed

    Llovet, Josep M; Zucman-Rossi, Jessica; Pikarsky, Eli; Sangro, Bruno; Schwartz, Myron; Sherman, Morris; Gores, Gregory

    2016-01-01

    Liver cancer is the second leading cause of cancer-related deaths globally and has an incidence of approximately 850,000 new cases per year. Hepatocellular carcinoma (HCC) represents approximately 90% of all cases of primary liver cancer. The main risk factors for developing HCC are well known and include hepatitis B and C virus infection, alcohol intake and ingestion of the fungal metabolite aflatoxin B1. Additional risk factors such as non-alcoholic steatohepatitis are also emerging. Advances in the understanding of the molecular pathogenesis of HCC have led to identification of critical driver mutations; however, the most prevalent of these are not yet druggable targets. The molecular classification of HCC is not established, and the Barcelona Clinic Liver Cancer staging classification is the main clinical algorithm for the stratification of patients according to prognosis and treatment allocation. Surveillance programmes enable the detection of early-stage tumours that are amenable to curative therapies - resection, liver transplantation or local ablation. At more developed stages, only chemoembolization (for intermediate HCC) and sorafenib (for advanced HCC) have shown survival benefits. There are major unmet needs in HCC management that might be addressed through the discovery of new therapies and their combinations for use in the adjuvant setting and for intermediate- and advanced-stage disease. Moreover, biomarkers for therapy stratification, patient-tailored strategies targeting driver mutations and/or activating signalling cascades, and validated measurements of quality of life are needed. Recent failures in the testing of systemic drugs for intermediate and advanced stages have indicated a need to refine trial designs and to define novel approaches. PMID:27158749

  2. Detection of epigenetic aberrations in the development of hepatocellular carcinoma.

    PubMed

    Zhang, Yujing

    2015-01-01

    Hepatocellular carcinoma (HCC) is the third most common cause of cancer death worldwide. Hepatocarcinogenesis is a complex, multistep process. It is now recognized that HCC is a both genetic and epigenetic disease; genetic and epigenetic components cooperate at all stages of hepatocarcinogenesis. Epigenetic changes involve aberrant DNA methylation, posttranslational histone modifications and aberrant expression of microRNAs all of which can affect the expression of oncogenes, tumor suppressor genes and other tumor-related genes and alter the pathways in cancer development. Several risk factors for HCC, including hepatitis B and C virus infections and exposure to the chemical carcinogen aflatoxin B1 have been found to influence epigenetic changes. Their interactions could play an important role in the initiation and progression of HCC. Discovery and detection of biomarkers for epigenetic changes is a promising area for early diagnosis and risk prediction of HCC.

  3. 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

  4. 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 ...

  5. [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

  6. Hepatocellular carcinoma.

    PubMed

    Okuda, K

    2000-01-01

    Hepatocellular carcinoma (HCC) is increasing in many countries as a result of an increase in hepatitis C virus (HCV) infection since World War II. The epidemiology of HCC varies with the global region. There have been conflicting observations from different parts of the world concerning the frequency of HCC in patients who in the distant past had post-transfusion non-A, non-B hepatitis. The genetic basis of hepatocarcinogenesis is still poorly understood. In hepatitis B virus (HVB) associated HCC, codon 249 mutation in the p 53 gene seems more related to exposure to aflatoxin B1 than to hepatocarcinogenesis itself. HCC that occurs in children in high HBV endemic regions could be associated with germ-line mutations, but little information is available; not much is known about chemical hepatocarcinogens in the environment other than aflatoxins. The X gene of HBV seems to play an important role in HBV-associated hepatocarcinogenesis. There are preliminary observations on the molecular mechanism of HCV-associated HCC, such as HCV core protein inducing HCC in transgenic mice and the NS3 genome transforming NIH 3T3 cells. Pathological distinction between preneoplastic and very early transformed lesions still depends on classical morphology, and a more genetically oriented differential diagnosis is required. Clinical diagnosis based on modern imaging has improved greatly, but is still unsatisfactory in the differential diagnosis of preneoplastic and early transformed nodules, because the vasculature changes that occur within the nodule are not accurately discerned with the current imaging. Use of sensitive des-gamma-carboxy prothrombin (PIVKA II) assay, and lectin affinity chromatography separating HCC specific subspecies of AFP molecules with a more practical biochemical technique will further improve diagnosis. Early diagnosis and transplantation are the best treatment at the moment, but transplantation is not widely available because of the donor shortage. Despite

  7. 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

  8. 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.

  9. 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

  10. [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

  11. Screening for hepatocellular carcinoma.

    PubMed

    Merican, I

    1996-03-01

    Hepatocellular carcinoma (HCC) is one of the commonest cancers in Asian males. In Malaysia, it is one of the ten most common cancers amongst the male population. Most of our patients with HCC present to us rather late and almost all die within 4 months of diagnosis. HCC occurs more commonly in patients with cirrhosis associated with hepatitis B and C infections. Screening for HCC can lead to early detection of small tumours (< 5 cm) that are more amenable to surgical resection, resulting in improved survival rates. The average 5-year survival rate for those who have undergone surgical resection is 68% (range, 22-73%). Better results are obtained with the smaller tumours (< 2 cm in diameter). Patients with chronic hepatitis B and C infection especially those who are > 45 years of age, who have concomitant cirrhosis or have a family history of HCC should be examined every 3-6 months with periodic serum alpha-fetoprotein (AFP) measurements and abdominal ultrasound examinations. Abdominal ultrasound is useful in the detection of small tumours. While mass screening for HCC is not cost-effective in countries of low incidence of HCC, screening of high risk groups may be justified in countries with a high endemicity of HBV infection. Screening for HCC in Japan, Taiwan and China appears to yield better results than those in the West. Nonetheless, primary prevention with mass hepatitis B vaccination and blood donor screening for anti-HCV is expected to make a much greater impact in the control of HCC in the years to come.

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

    SciTech Connect

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

    1989-02-01

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

  13. Computer-aided detection (CAD) of hepatocellular carcinoma on multiphase CT images

    NASA Astrophysics Data System (ADS)

    Tajima, Tetsuji; Zhang, Xuejun; Kitagawa, Teruhiko; Kanematsu, Masayuki; Zhou, Xiangrong; Hara, Takeshi; Fujita, Hiroshi; Yokoyama, Ryujiro; Kondo, Hiroshi; Hoshi, Hiroaki; Nawano, Shigeru; Shinozaki, Kenji

    2007-03-01

    Primary malignant liver tumor, including hepatocellular carcinoma (HCC), caused 1.25 million deaths per year worldwide. Multiphase CT images offer clinicians important information about hepatic cancer. The presence of HCC is indicated by high-intensity regions in arterial phase images and low-intensity regions in equilibrium phase images following enhancement with contrast material. We propose an automatic method for detecting HCC based on edge detection and subtraction processing. Within a liver area segmented according to our scheme, black regions are selected by subtracting the equilibrium phase images to the corresponding registrated arterial phase images. From these black regions, the HCC candidates are extracted as the areas without edges by using Sobel and LoG edge detection filters. The false-positive (FP) candidates are eliminated by using six features extracted from the cancer and liver regions. Other FPs are further eliminated by opening processing. Finally, an expansion process is applied to acquire the 3D shape of the HCC. The cases used in this experiment were from the CT images of 44 patients, which included 44 HCCs. We extracted 97.7% (43/44) HCCs successfully by our proposed method, with an average number of 2.1 FPs per case. The result demonstrates that our edge-detection-based method is effective in locating the cancer region by using the information obtained from different phase images.

  14. Hepatocellular Carcinoma and Diffusion-Weighted MRI: Detection and Evaluation of Treatment Response

    PubMed Central

    Gluskin, Jill S; Chegai, Fabrizio; Monti, Serena; Squillaci, Ettore; Mannelli, Lorenzo

    2016-01-01

    Differentiating between cancerous tissue and healthy liver parenchyma could represent a challenge with the only conventional Magnetic Resonance (MR) imaging. Diffusion weighted imaging (DWI) exploits different tissue characteristics to conventional Magnetic Resonance Imaging (MRI) sequences that enhance hepatocellular carcinoma (HCC) detection, characterization, and post-treatment evaluation. Detection of HCC is improved by DWI, infact this technology increases conspicuity of lesions that might otherwise not be identified due to obscuration by adjacent vessels or due to low contrast between the lesion and background liver. It is important to remember that DWI combined with contrast-enhanced MRI has higher sensitivity than DWI alone, and that some patients are not eligible for use of contrast on CT and MRI; in these patients DWI has a prominent role. MRI has advanced beyond structural anatomic imaging to now showing pathophysiologic processes. DWI is a promising way to characterize lesions utilizing the inherent contrast within the liver and has the benefit of not requiring contrast injection. DWI improves detection and characterization of HCC. Proposed clinical uses for DWI include: assessing prognosis, predicting response, monitoring response to therapy, and distinguishing tumor recurrence from treatment effect. Ideally, DWI will help risk stratify patients and will participate in prognostic modeling. PMID:27471573

  15. Hepatocellular Carcinoma and Diffusion-Weighted MRI: Detection and Evaluation of Treatment Response.

    PubMed

    Gluskin, Jill S; Chegai, Fabrizio; Monti, Serena; Squillaci, Ettore; Mannelli, Lorenzo

    2016-01-01

    Differentiating between cancerous tissue and healthy liver parenchyma could represent a challenge with the only conventional Magnetic Resonance (MR) imaging. Diffusion weighted imaging (DWI) exploits different tissue characteristics to conventional Magnetic Resonance Imaging (MRI) sequences that enhance hepatocellular carcinoma (HCC) detection, characterization, and post-treatment evaluation. Detection of HCC is improved by DWI, infact this technology increases conspicuity of lesions that might otherwise not be identified due to obscuration by adjacent vessels or due to low contrast between the lesion and background liver. It is important to remember that DWI combined with contrast-enhanced MRI has higher sensitivity than DWI alone, and that some patients are not eligible for use of contrast on CT and MRI; in these patients DWI has a prominent role. MRI has advanced beyond structural anatomic imaging to now showing pathophysiologic processes. DWI is a promising way to characterize lesions utilizing the inherent contrast within the liver and has the benefit of not requiring contrast injection. DWI improves detection and characterization of HCC. Proposed clinical uses for DWI include: assessing prognosis, predicting response, monitoring response to therapy, and distinguishing tumor recurrence from treatment effect. Ideally, DWI will help risk stratify patients and will participate in prognostic modeling. PMID:27471573

  16. Cutaneous metastases of hepatocellular carcinoma.

    PubMed

    Lazaro, M; Serrano, M L; Allende, I; Ratón, J A; Acebo, E; Diaz-Perez, J L

    2009-12-01

    Cutaneous metastases are an unusual finding that may present as the first sign of an internal neoplasia. A case of cutaneous metastases of hepatocellular carcinoma, which may often involve other organs but very rarely metastases to the skin, is reported.

  17. 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

  18. 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).

  19. Prevention of Hepatocellular Carcinoma

    PubMed Central

    Schütte, Kerstin; Balbisi, Fathi; Malfertheiner, Peter

    2016-01-01

    The epidemiology of hepatocellular carcinoma (HCC) has significantly changed throughout the past decade and will continue to do so in the future as a consequence of effective primary prevention and treatment of virus-related liver diseases. However, other risk factors for HCC are constantly on the rise, including alcoholic liver disease and nonalcoholic fatty liver disease. The knowledge on these and further risk factors associated with an increased risk of HCC provide the opportunity and chance for the development and implementation of successful preventive strategies to decrease the worldwide burden of HCC. This mini-review gives a short overview on current strategies in primary, secondary, and tertiary prevention of HCC. PMID:27722155

  20. Preparation of magnetic resonance probes using one-pot method for detection of hepatocellular carcinoma

    PubMed Central

    Li, You-Wei; Chen, Zheng-Guang; Zhao, Zhou-She; Li, Hong-Li; Wang, Ji-Chen; Zhang, Zong-Ming

    2015-01-01

    AIM: To prepare the specific magnetic resonance (MR) probes for detection of hepatocellular carcinoma (HCC) using one-pot method. METHODS: The carboxylated dextran-coated nanoparticles were conjugated with anti-α-fetoprotein (anti-AFP) or anti-glypican 3 (anti-GPC3) antibodies through 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride/N-hydroxysuccinimide (EDC/NHS)-mediated reaction to synthesize the probes. The physical and chemical properties of the probes were determined by transmission electron microscopy (TEM) and dynamic light scattering, and the relaxivity was compared to uncombined ultrasmall superparamagnetic iron oxide nanoparticles (USPIONs) using a 1.5T clinical MR scanner. The binding efficiency of the antibodies to nanoparticles was measured with an ultraviolet-visible spectrophotometer. In addition, the probes were incubated with targetable cells in vitro. RESULTS: The superparamagnetic MR probes (anti-GPC3-USPION probe and anti-AFP-USPION probe) were synthesized using one-pot method. Their mean hydrodynamic diameter was 47 nm with a broader slight size distribution. The coupling efficiency of carboxylated dextran-coated ultrasmall superparamagnetic iron oxide (USPIO) with anti-GPC3 or anti-AFP antibody was 15.9% and 88.8%, respectively. Each of the USPIO nanoparticles may bind 3 GPC3 antibodies or 12 AFP antibodies. The statistical analysis showed no significance (P > 0.05) in shortening the T1 and T2 values when comparing the USPIO-AFP or USPIO-GPC3 to USPIO. Analysis of TEM images revealed that anti-GPC3-USPION probes and anti-AFP-USPION probes could specifically enter into the HepG2 cell by combining with the GPC3 receptors or AFP receptors, whereas the HepG2 cell sample incubated with USPIONs showed no or few nanoparticles in the cytoplasm. CONCLUSION: The synthesized probes using one-pot method can be used for in vitro experimental study and have potential clinical application in MR imaging for detection of hepatocellular carcinomas

  1. Magnetic Resonance Elastography – A Novel Technique for Detection of Hepatic Fibrosis and Hepatocellular Carcinoma After the Fontan Operation

    PubMed Central

    Poterucha, Joseph T.; Johnson, Jonathan N.; Qureshi, Muhammad Y.; O’Leary, Patrick W.; Kamath, Patrick S.; Lennon, Ryan J.; Bonnichsen, Crystal R.; Young, Phillip M.; Venkatesh, Sudhakar K.; Ehman, Richard L.; Gupta, Sounak; Smyrk, Thomas C.; Dearani, Joseph A.; Warnes, Carole A.; Cetta, Frank

    2015-01-01

    Objective To evaluate the utility of magnetic resonance elastography (MRE) in screening patients for hepatic fibrosis, cirrhosis, and hepatocellular carcinoma after Fontan operation. Patients and Methods Hepatic MRE was performed in conjunction with cardiac magnetic resonance imaging in patients with prior Fontan operation between 2010-2014. Liver stiffness was calculated using previously reported techniques. Comparisons to available clinical, laboratory, imaging, and histopathologic data were made. Results Overall, 50 Fontan patients aged 25 (21-33) years were evaluated. The median interval between Fontan creation and MRE was 22 (16-26) years. Mean liver stiffness values were increased; 5.5±1.4 kilopascals relative to normal subjects. Liver stiffness directly correlated with liver biopsy total fibrosis score, time since operation; mean Fontan pressure; γ-glutamyl transferase (GGT); MELD score; creatinine; and pulmonary vascular resistance index (PVR). Liver stiffness was inversely correlated with cardiac index (CI). All 3 subjects with hepatic nodules exhibiting decreased contrast uptake on delayed post-contrast imaging and elevated nodule stiffness had biopsy-proven hepatocellular carcinoma. Conclusion The association between hepatic stiffness and fibrosis scores, MELD scores, and GGT, suggests that MRE may be useful to detect (and possibly quantify) hepatic cirrhosis in Fontan patients. Correlation between stiffness and post-Fontan time interval, mean Fontan pressure, PVR and reduced CI suggests a role for long term hepatic congestion in creating these hepatic abnormalities. MRE was useful in detecting abnormal nodules ultimately diagnosed as hepatocellular carcinoma. The relationship between stiffness with advanced fibrosis and hepatocellular carcinoma provides a strong argument for additional study and broader application of MRE in these patients. PMID:26059757

  2. [External radiotherapy for hepatocellular carcinoma].

    PubMed

    Girard, N; Mornex, F

    2011-02-01

    For a long time radiotherapy has been excluded from the therapeutic strategy for hepatocellular carcinoma, given its significant toxicity on the non-tumoral liver parenchyma. Conformal radiation is a recent advance in the field of radiotherapy, allowing dose escalation and combination with other therapeutic options for hepatocellular carcinoma, including trans-arterial chemo-embolization. Conformal radiotherapy is associated with interesting features, especially in cirrhotic patients: wide availability, non-invasiveness, possibility to target multiple localizations anywhere within the liver parenchyma, and favorable tolerance profile even in patients with cirrhosis and/or in a poor medical condition. Recently, radiation delivery has been optimized through several technical developments: respiratory gating and intensity-modulated radiotherapy, which allow a better focalization of the ballistics, stereotactic techniques and proton-beam radiotherapy, whose availability is currently limited in Europe. Given the high response rates of hepatocellular carcinoma to radiation, conformal radiotherapy may be regarded as a curative-intent treatment for hepatocellular carcinoma, similar to surgery and per-cutaneous techniques. Yet the impact of radiotherapy has to be evaluated in randomized trials to better integrate in the complex therapeutic algorithm of hepatocellular carcinoma.

  3. Hepatocellular carcinoma in India.

    PubMed

    Bhattacharyya, Gouri Shankar; Babu, K Govind; Malhotra, Hemant; Ranade, Anantbhushan A; Murshed, Shaiqua; Datta, Debasis

    2013-12-01

    Cancers of the liver are one of the commonest cancers that occur in the world, the commonest of which is the hepatocellular carcinoma (HCC). It is considered to be the 5th commonest cancer in the world. In the areas that are endemic for hepatitis B and C, it is extremely common. Unfortunately, India which is an endemic zone for hepatitis B, there has been no comprehensive analyzed data for HCC. Incidence of HCC in India occurs at two peaks, one at a young age between 40 to 55 years and another above 60 years. Eighty per cent of all HCCs occurring in India occur with cirrhosis of liver in the background and 60% of all these cases are hepatitis B positive carriers. Symptoms are reflective of late presentation with advanced disease. Surgery, the only curative modulus available, unfortunately is not possible in 95% of HCC patients. Majority of the patients are treated with palliative and supportive care and life spans are limited. Sorafenib is used in a small section of patients. Characterization of HCC with molecular sub-typing is the need of the hour.

  4. Tumor markers for hepatocellular carcinoma

    PubMed Central

    ZHAO, YAN-JIE; JU, QIANG; LI, GUAN-CHENG

    2013-01-01

    Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with a high rate of morbidity and mortality. HCC affects approximately one million individuals annually worldwide, with the incidence equal to the mortality rate. In 2008, HCC was listed as the third most lethal cancer. Thus, early diagnosis is crucial for improving the survival rate for patients. α-fetoprotein (AFP) together with iconography and pathology detection are commonly used in the clinical early diagnosis of liver cancer. However, the specificity and sensitivity of AFP used in screening for liver cancer are not satisfactory. Athough the development of molecular biology has led to the identification of new tumor markers, including proteantigens, cytokines, enzymes and isoenzymes, as well as related genes that can be used in the treatment and prognosis of liver cancer, more tumor markers are required for effective early diagnosis of diseases and monitoring of the curative effect. PMID:24649215

  5. Detection of mycoplasma infection in circulating tumor cells in patients with hepatocellular carcinoma

    SciTech Connect

    Choi, Hong Seo; Lee, Hyun Min; Kim, Won-Tae; Kim, Min Kyu; Chang, Hee Jin; Lee, Hye Ran; Joh, Jae-Won; Kim, Dae Shick; Ryu, Chun Jeih

    2014-04-04

    Highlights: • This study generates a monoclonal antibody CA27 against the mycoplasmal p37 protein. • CA27 isolates circulating tumor cells (CTCs) from the blood of liver cancer patients. • Results show the first evidence for mycoplasma infected-CTCs in cancer patients. - Abstract: Many studies have shown that persistent infections of bacteria promote carcinogenesis and metastasis. Infectious agents and their products can modulate cancer progression through the induction of host inflammatory and immune responses. The presence of circulating tumor cells (CTCs) is considered as an important indicator in the metastatic cascade. We unintentionally produced a monoclonal antibody (MAb) CA27 against the mycoplasmal p37 protein in mycoplasma-infected cancer cells during the searching process of novel surface markers of CTCs. Mycoplasma-infected cells were enriched by CA27-conjugated magnetic beads in the peripheral blood mononuclear cells in patients with hepatocellular carcinoma (HCC) and analyzed by confocal microscopy with anti-CD45 and CA27 antibodies. CD45-negative and CA27-positive cells were readily detected in three out of seven patients (range 12–30/8.5 ml blood), indicating that they are mycoplasma-infected circulating epithelial cells. CA27-positive cells had larger size than CD45-positive hematological lineage cells, high nuclear to cytoplasmic ratios and irregular nuclear morphology, which identified them as CTCs. The results show for the first time the existence of mycoplasma-infected CTCs in patients with HCC and suggest a possible correlation between mycoplasma infection and the development of cancer metastasis.

  6. Hepatocellular carcinoma: a review

    PubMed Central

    Balogh, Julius; Victor, David; Asham, Emad H; Burroughs, Sherilyn Gordon; Boktour, Maha; Saharia, Ashish; Li, Xian; Ghobrial, R Mark; Monsour, Howard P

    2016-01-01

    Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is a leading cause of cancer-related death worldwide. In the United States, HCC is the ninth leading cause of cancer deaths. Despite advances in prevention techniques, screening, and new technologies in both diagnosis and treatment, incidence and mortality continue to rise. Cirrhosis remains the most important risk factor for the development of HCC regardless of etiology. Hepatitis B and C are independent risk factors for the development of cirrhosis. Alcohol consumption remains an important additional risk factor in the United States as alcohol abuse is five times higher than hepatitis C. Diagnosis is confirmed without pathologic confirmation. Screening includes both radiologic tests, such as ultrasound, computerized tomography, and magnetic resonance imaging, and serological markers such as α-fetoprotein at 6-month intervals. Multiple treatment modalities exist; however, only orthotopic liver transplantation (OLT) or surgical resection is curative. OLT is available for patients who meet or are downstaged into the Milan or University of San Francisco criteria. Additional treatment modalities include transarterial chemoembolization, radiofrequency ablation, microwave ablation, percutaneous ethanol injection, cryoablation, radiation therapy, systemic chemotherapy, and molecularly targeted therapies. Selection of a treatment modality is based on tumor size, location, extrahepatic spread, and underlying liver function. HCC is an aggressive cancer that occurs in the setting of cirrhosis and commonly presents in advanced stages. HCC can be prevented if there are appropriate measures taken, including hepatitis B virus vaccination, universal screening of blood products, use of safe injection practices, treatment and education of alcoholics and intravenous drug users, and initiation of antiviral therapy. Continued improvement in both surgical and nonsurgical approaches has demonstrated

  7. Spontaneous regression of hepatocellular carcinoma.

    PubMed Central

    Ayres, R C; Robertson, D A; Dewbury, K C; Millward-Sadler, G H; Smith, C L

    1990-01-01

    A 63 year old white woman presented with abdominal discomfort, anorexia, and weight loss. Investigations showed hepatocellular carcinoma with pulmonary metastases. The primary and secondary tumours resolved without specific treatment. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 PMID:2165992

  8. Mandible metastasis of hepatocellular carcinoma.

    PubMed

    Niedzielska, Iwona; Langowska-Adamczyk, Helena; Pajak, Jacek; Kajor, Maciej; Niedzielski, Zbigniew; Gołka, Dariusz

    2004-01-01

    Metastases to oral cavity are very uncommon. We present a case of hepatocellular carcinoma (HCC) metastasis to the jaw. The x-ray examination and clinical picture of the lesion were not characteristic. The gingival metastasis may mimic other benign and malignant conditions which affect jaw and therefore the histopathological examination is necessary to make an ultimate diagnosis.

  9. Early detection of hepatocellular carcinoma co-occurring with hepatitis C virus infection: A mathematical model

    PubMed Central

    Zekri, Abdel-Rahman Nabawy; Youssef, Amira Salah El-Din; Bakr, Yasser Mabrouk; Gabr, Reham Mohamed; Ahmed, Ola Sayed; Elberry, Mostafa Hamed; Mayla, Ahmed Mahmoud; Abouelhoda, Mohamed; Bahnassy, Abeer A

    2016-01-01

    AIM: To develop a mathematical model for the early detection of hepatocellular carcinoma (HCC) with a panel of serum proteins in combination with α-fetoprotein (AFP). METHODS: Serum levels of interleukin (IL)-8, soluble intercellular adhesion molecule-1 (sICAM-1), soluble tumor necrosis factor receptor II (sTNF-RII), proteasome, and β-catenin were measured in 479 subjects categorized into four groups: (1) HCC concurrent with hepatitis C virus (HCV) infection (n = 192); (2) HCV related liver cirrhosis (LC) (n = 96); (3) Chronic hepatitis C (CHC) (n = 96); and (4) Healthy controls (n = 95). The R package and different modules for binary and multi-class classifiers based on generalized linear models were used to model the data. Predictive power was used to evaluate the performance of the model. Receiver operating characteristic curve analysis over pairs of groups was used to identify the best cutoffs differentiating the different groups. RESULTS: We revealed mathematical models, based on a binary classifier, made up of a unique panel of serum proteins that improved the individual performance of AFP in discriminating HCC patients from patients with chronic liver disease either with or without cirrhosis. We discriminated the HCC group from the cirrhotic liver group using a mathematical model (-11.3 + 7.38 × Prot + 0.00108 × sICAM + 0.2574 × β-catenin + 0.01597 × AFP) with a cutoff of 0.6552, which achieved 98.8% specificity and 89.1% sensitivity. For the discrimination of the HCC group from the CHC group, we used a mathematical model [-10.40 + 1.416 × proteasome + 0.002024 × IL + 0.004096 × sICAM-1 + (4.251 × 10-4) × sTNF + 0.02567 × β-catenin + 0.02442 × AFP] with a cutoff 0.744 and achieved 96.8% specificity and 89.7% sensitivity. Additionally, we derived an algorithm, based on a binary classifier, for resolving the multi-class classification problem by using three successive mathematical model predictions of liver disease status. CONCLUSION: Our

  10. Evaluation of HAAH/humbug quantitative detection in the diagnosis of hepatocellular carcinoma.

    PubMed

    Xue, Tian; Su, Jing; Li, Hongmin; Xue, Xiaoping

    2015-01-01

    Human aspartyl-(asparaginyl)-β-hydroxylase (HAAH) is a type 2 transmembrane protein and an α-ketoglutarate-dependent dioxygenase that can stereospecifically catalyze the post-translational hydroxylation reaction of β-carbon atoms of aspartic acid and asparagine residues present in epidermal growth factor-like domains of certain specific proteins. Humbug is a truncated isoform of aspartyl (asparaginyl) β-hydroxylase that lacks the catalytic domain. A series of reports demonstrated that overexpression of HAAH/humbug was identified in hepatocellular carcinoma (HCC) and various tumor tissues. However, the prognostic value of HAAH/humbug expression in HCC remains unclear. The purpose of this study was to investigate the expression of the HAAH/humbug gene at the mRNA and protein levels in HCC and to assess the overexpression of HAAH/humbug as a diagnostic and prognostic marker in HCC. HAAH/humbug mRNA levels were measured in 120 HCCs and 40 paired non-tumor liver tissues by molecular beacon (MB) quantitative RT-PCR. Immunohistochemical staining was used to detect the protein level of the HAAH/humbug in the same specimens. ROC analysis was performed based on the expression levels of the HAAH/humbug gene in 120 cases of HCC tissues and 40 cases of adjacent non-tumor liver tissues. The results showed that 117 (97.5%) of the 120 frozen sections of patients with HCCs had HAAH/humbug-positive immunoreactivity, whereas the 40 adjacent non-tumor liver tissues exhibited no staining. Higher levels of HAAH/humbug mRNA were found in 114 (95%) of the 120 HCC tissues relative to the adjacent cancer‑free tissue. ROC curve analysis exhibited that the sensitivity was 90.1%, specificity was 97.6% and ROC AUC was 0.986. The specific value of HAAH/β-actin abundance used as a cut‑off point was 0.315, while the gene copy number (7.35 copies/µl) was used a as cut‑off point, with sensitivity being 99.2%, specificity 96.7% and the ROC AUC used 0.990. No statistically significant

  11. Alpha-Fetoprotein Detection of Hepatocellular Carcinoma Leads to a Standardized Analysis of Dynamic AFP to Improve Screening Based Detection.

    PubMed

    Bird, Thomas G; Dimitropoulou, Polyxeni; Turner, Rebecca M; Jenks, Sara J; Cusack, Pearce; Hey, Shiying; Blunsum, Andrew; Kelly, Sarah; Sturgeon, Catharine; Hayes, Peter C; Bird, Sheila M

    2016-01-01

    Detection of hepatocellular carcinoma (HCC) through screening can improve outcomes. However, HCC surveillance remains costly, cumbersome and suboptimal. We tested whether and how serum Alpha-Fetoprotein (AFP) should be used in HCC surveillance. Record linkage, dedicated pathways for management and AFP data-storage identified i) consecutive highly characterised cases of HCC diagnosed in 2009-14 and ii) a cohort of ongoing HCC-free patients undergoing regular HCC surveillance from 2009. These two well-defined Scottish patient cohorts enabled us to test the utility of AFP surveillance. Of 304 cases of HCC diagnosed over 6 years, 42% (129) were identified by a dedicated HCC surveillance programme. Of these 129, 47% (61) had a detectable lesion first identified by screening ultrasound (US) but 38% (49) were prompted by elevated AFP. Despite pre-HCC diagnosis AFP >20kU/L being associated with poor outcome, 'AFP-detected' tumours were offered potentially curative management as frequently as 'US-detected' HCCs; and had comparable survival. Linearity of serial log10-transformed AFPs in HCC cases and in the screening 'HCC-free' cohort (n = 1509) provided indicators of high-risk AFP behaviour in HCC cases. An algorithm was devised in static mode, then tested dynamically. A case/control series in hepatitis C related disease demonstrated highly significant detection (p<1.72*10-5) of patients at high risk of developing HCC. These data support the use of AFP in HCC surveillance. We show proof-of-principle that an automated and further refine-able algorithmic interpretation of AFP can identify patients at higher risk of HCC. This approach could provide a cost-effective, user-friendly and much needed addition to US surveillance. PMID:27308823

  12. Alpha-Fetoprotein Detection of Hepatocellular Carcinoma Leads to a Standardized Analysis of Dynamic AFP to Improve Screening Based Detection

    PubMed Central

    Dimitropoulou, Polyxeni; Turner, Rebecca M.; Jenks, Sara J.; Hey, Shiying; Blunsum, Andrew; Kelly, Sarah; Sturgeon, Catharine; Hayes, Peter C.; Bird, Sheila M.

    2016-01-01

    Detection of hepatocellular carcinoma (HCC) through screening can improve outcomes. However, HCC surveillance remains costly, cumbersome and suboptimal. We tested whether and how serum Alpha-Fetoprotein (AFP) should be used in HCC surveillance. Record linkage, dedicated pathways for management and AFP data-storage identified i) consecutive highly characterised cases of HCC diagnosed in 2009–14 and ii) a cohort of ongoing HCC-free patients undergoing regular HCC surveillance from 2009. These two well-defined Scottish patient cohorts enabled us to test the utility of AFP surveillance. Of 304 cases of HCC diagnosed over 6 years, 42% (129) were identified by a dedicated HCC surveillance programme. Of these 129, 47% (61) had a detectable lesion first identified by screening ultrasound (US) but 38% (49) were prompted by elevated AFP. Despite pre-HCC diagnosis AFP >20kU/L being associated with poor outcome, ‘AFP-detected’ tumours were offered potentially curative management as frequently as ‘US-detected’ HCCs; and had comparable survival. Linearity of serial log10-transformed AFPs in HCC cases and in the screening ‘HCC-free’ cohort (n = 1509) provided indicators of high-risk AFP behaviour in HCC cases. An algorithm was devised in static mode, then tested dynamically. A case/control series in hepatitis C related disease demonstrated highly significant detection (p<1.72*10−5) of patients at high risk of developing HCC. These data support the use of AFP in HCC surveillance. We show proof-of-principle that an automated and further refine-able algorithmic interpretation of AFP can identify patients at higher risk of HCC. This approach could provide a cost-effective, user-friendly and much needed addition to US surveillance. PMID:27308823

  13. 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

  14. [Tumor markers for hepatocellular carcinoma].

    PubMed

    Tateishi, Ryosuke; Enooku, Kenichiro; Shiina, Shuichiro; Koike, Kazuhiko

    2012-05-01

    Three tumor markers for hepatocellular carcinoma (HCC) are available in Japan: alpha-fetoprotein (AFP), protein induced by vitamin K absence or antagonists-II (PIVKA-II), and Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3). Although AFP has drawbacks in its specificity, it is widely utilized in treatment evaluation and prognosis prediction. PIVKA-II is a unique marker that does not correlate with AFP value and can predict microvascular invasion. AFP-L3 is a highly specific marker and strong predictor of poor prognosis. These three markers are indispensable in every aspect of clinical practice of hepatocellular carcinoma including surveillance, diagnosis, treatment evaluation, and prognosis prediction.

  15. [Current management of hepatocellular carcinoma].

    PubMed

    Ruiz, I; Féray, C

    2015-10-01

    Hepatocellular carcinoma is the major complication of chronic liver diseases and particularly of cirrhosis whatever its etiology. Once encountered mainly in the endemic countries of hepatitis B and C, the incidence of hepatocellular carcinoma (6/100,000) is parallel to the global development of diabetes, overweight and alcohol consumption. Little progress has been made for this cancer, whose mortality is 100 % at 10 years. Liver transplantation is the only truly curative treatment (survival more than 50 % at 10 years) since it allows the eradication of hepatocellular carcinoma and its essential cause, cirrhotic liver. This is the only possible therapy when liver function is impaired. It has little impact since in the richest countries, less than 10 % of cases can be transplanted. Surgical resection and percutaneous destruction methods (uni- and multipolar radiofrequency, microwave, cryotherapy, electroporation) are the preferred treatments (survival less than 50 % at 5 years) but are only applicable for moderate tumour masses and in the absence of adjuvant therapy, are effective only in the medium term. Most patients received chemoembolization through hepatic artery, whose action is modest. Radiotherapy is widely used in Asia but almost non-existent in Western countries in this indication. Sorafenib is the only effective drug but its impact is modest. Therapies combining two modalities (embolization and radiotherapy; embolization and radiofrequency) seem promising and deserve wider testing. Screening and monitoring of cirrhosis is probably the major measure for potentially curative therapies. PMID:26337474

  16. 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

  17. 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

  18. A highly sensitive x-ray imaging modality for hepatocellular carcinoma detection in vitro

    NASA Astrophysics Data System (ADS)

    Rand, Danielle; Walsh, Edward G.; Derdak, Zoltan; Wands, Jack R.; Rose-Petruck, Christoph

    2015-01-01

    Innovations that improve sensitivity and reduce cost are of paramount importance in diagnostic imaging. The novel x-ray imaging modality called spatial frequency heterodyne imaging (SFHI) is based on a linear arrangement of x-ray source, tissue, and x-ray detector, much like that of a conventional x-ray imaging apparatus. However, SFHI rests on a complete paradigm reversal compared to conventional x-ray absorption-based radiology: while scattered x-rays are carefully rejected in absorption-based x-ray radiology to enhance the image contrast, SFHI forms images exclusively from x-rays scattered by the tissue. In this study we use numerical processing to produce x-ray scatter images of hepatocellular carcinoma labeled with a nanoparticle contrast agent. We subsequently compare the sensitivity of SFHI in this application to that of both conventional x-ray imaging and magnetic resonance imaging (MRI). Although SFHI is still in the early stages of its development, our results show that the sensitivity of SFHI is an order of magnitude greater than that of absorption-based x-ray imaging and approximately equal to that of MRI. As x-ray imaging modalities typically have lower installation and service costs compared to MRI, SFHI could become a cost effective alternative to MRI, particularly in areas of the world with inadequate availability of MRI facilities.

  19. A Highly Sensitive X-ray Imaging Modality for Hepatocellular Carcinoma Detection in Vitro

    PubMed Central

    Rand, Danielle; Walsh, Edward G.; Derdak, Zoltan; Wands, Jack R.; Rose-Petruck, Christoph

    2015-01-01

    Innovations that improve sensitivity and reduce cost are of paramount importance in diagnostic imaging. The novel x-ray imaging modality called Spatial Frequency Heterodyne Imaging (SFHI) is based on a linear arrangement of x-ray source, tissue, and x-ray detector, much like that of a conventional x-ray imaging apparatus. However, SFHI rests on a complete paradigm reversal compared to conventional x-ray absorption-based radiology: while scattered x-rays are carefully rejected in absorption-based x-ray radiology to enhance the image contrast, SFHI forms images exclusively from x-rays scattered by the tissue. In this study we use numerical processing to produce x-ray scatter images of Hepatocellular Carcinoma (HCC) labeled with a nanoparticle contrast agent. We subsequently compare the sensitivity of SFHI in this application to that of both conventional x-ray imaging and Magnetic Resonance Imaging (MRI). Although SFHI is still in the early stages of its development, our results show that the sensitivity of SFHI is an order of magnitude greater than that of absorption-based x-ray imaging and approximately equal to that of MRI. As x-ray imaging modalities typically have lower installation and service costs compared to MRI, SFHI could become a cost effective alternative to MRI, particularly in areas of the world with inadequate availability of MRI facilities. PMID:25559398

  20. Computer-assisted evaluation of contrast kinetics for detection of hepatocellular carcinoma on magnetic resonance imaging.

    PubMed

    Chaturvedi, Abhishek; Bhargava, Puneet; Kolokythas, Orpheus; Mitsumori, Lee M; Maki, Jeffrey H

    2015-01-01

    The purpose of this study was to assess the use of semiquantitative contrast-enhanced parameter analysis as an objective criteria for improving the magnetic resonance (MR) evaluation of hepatocellular carcinoma (HCC) in patients with cirrhosis. Contrast-enhanced MR examination findings from 19 patients with 21 pathologically proven HCC were evaluated using a dedicated liver image postprocessing workstation. Contrast-enhancement kinetic curves were created for each lesion, and 4 enhancement parameters (arterial wash-in slope, arterial-portal slope, arterial-equilibrium slope, and portal-equilibrium slope) were defined from the signal intensity-time plots. The accuracy of each enhancement parameter for the characterization of HCC was assessed. Statistical analysis revealed that an arterial-phase wash-in slope percentage value >1.35 per sec had a sensitivity of 86%, a specificity of 71%, and an accuracy of 79% for the correct characterization of HCC, whereas an arterial-equilibrium wash-out slope percentage value<0.05 per sec had a sensitivity of 86%, a specificity of 81%, and an accuracy of 83%. Although there were significant differences among all groups, the greatest accuracy for differentiation based on receiver operating curve analysis appears to be with arterial and arterial-equilibrium phases. Semiquantitative analysis of lesion contrast kinetics could provide objective parameters to improve the characterization of HCC on contrast-enhanced MR images.

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

    PubMed

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

    2003-01-01

    follows: hepatocyte growth factor activator was only detected in malignant tissue but not cirrhotic liver or normal liver. Although hepatocyte growth factor was detected in most samples, it was significantly elevated in 5/9 hepatocellular carcinomas. Furthermore, 8/9 fibrolamellar hepatocellular carcinomas demonstrated hepatocyte growth factor receptor levels similar to normal, whereas 8/9 hepatocellular carcinomas and 11/12 cirrhotic livers exhibited either an increase or decrease. In contrast, active matrix metalloproteinase-2, which was absent in normal liver, was elevated in fibrolamellar hepatocellular carcinoma as compared to cirrhotic liver and conventional hepatocellular carcinoma. Surprisingly, 10/12 cirrhotic livers and 2/4 fibrolamellar hepatocellular carcinomas but only 1/9 hepatocellular carcinomas were enriched for plasmin. The combined data suggest that the hepatocyte growth factor and plasmin systems tend to be operative in hepatocellular carcinoma and cirrhotic liver, more than fibrolamellar hepatocellular carcinoma. Furthermore, matrix turnover appears to be a more prominent feature of fibrolamellar hepatocellular carcinoma. These findings provide insight into the behavioral differences between hepatocellular carcinoma and the fibrolamellar variant.

  2. 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.

  3. 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.

  4. Serum anti-Ku86 is a potential biomarker for early detection of hepatitis C virus-related hepatocellular carcinoma

    SciTech Connect

    Nomura, Fumio; Sogawa, Kazuyuki; Noda, Kenta; Seimiya, Masanori; Matsushita, Kazuyuki; Miura, Toshihide; Tomonaga, Takeshi; Yoshitomi, Hideyuki; Imazeki, Fumio; Takizawa, Hirotaka; Mogushi, Kaoru; Miyazaki, Masaru; Yokosuka, Osamu

    2012-05-18

    Highlights: Black-Right-Pointing-Pointer Overexpression of Ku86 in human liver cancer was shown by immunohistochemistry. Black-Right-Pointing-Pointer Serum anti-Ku86 was significantly elevated in early hepatocellular carcinoma. Black-Right-Pointing-Pointer Anti-Ku86 may be more sensitive than the conventional markers for early detection. Black-Right-Pointing-Pointer Serum anti-Ku86 significantly decreased after surgical resection of liver tumors. Black-Right-Pointing-Pointer Elevation of serum anti-Ku86 in other non-liver solid tumors was minimal. -- Abstract: Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, is one of the most common cancers worldwide and the third most common cause of cancer-related death. Imaging studies including ultrasound and computed tomography are recommended for early detection of HCC, but they are operator dependent, costly and involve radiation. Therefore, there is a need for simple and sensitive serum markers for the early detection of hepatocellular carcinoma (HCC). In our recent proteomic studies, a number of proteins overexpressed in HCC tissues were identified. We thought if the serum autoantibodies to these overexpressed proteins were detectable in HCC patients. Of these proteins, we focused on Ku86, a nuclear protein involved in multiple biological processes and aimed to assess the diagnostic value of serum anti-Ku86 in the early detection of HCC. Serum samples were obtained prior to treatment from 58 consecutive patients with early or relatively early hepatitis C virus (HCV)-related HCC and 137 patients with HCV-related liver cirrhosis without evidence of HCC. Enzyme immunoassays were used to measure serum levels of autoantibodies. Serum levels of anti-Ku86 antibodies were significantly elevated in HCC patients compared to those in liver cirrhosis patients (0.41 {+-} 0.28 vs. 0.18 {+-} 0.08 Abs at 450 nm, P < 0001). Setting the cut-off level to give 90% specificity, anti-Ku86 was positive in 60.7% of

  5. Aptamer-based Sandwich Assay and its Clinical Outlooks for Detecting Lipocalin-2 in Hepatocellular Carcinoma (HCC)

    PubMed Central

    Lee, Kyeong-Ah; Ahn, Ji-Young; Lee, Sang-Hee; Singh Sekhon, Simranjeet; Kim, Dae-Ghon; Min, Jiho; Kim, Yang-Hoon

    2015-01-01

    We validated a single-stranded, DNA aptamer-based, diagnostic method capable of detecting Lipocalin-2 (LCN2), a biomarker from clinically relevant hepatocellular carcinoma (HCC) patient serum, in the sandwich assay format. Nine aptamers (LCN2_apta1 to LCN2_apta9) for LCN2 were screened with SELEX processes, and a sandwich pair (LCN2_apta2 and LCN2_apta4) was finally chosen using surface plasmon resonance (SPR) and dot blotting analysis. The result of the proposed aptamer sandwich construction shows that LCN2 was sensitively detected in the concentration range of 2.5–500 ng mL−1 with a limit of detection of 0.6 ng mL−1. Quantitative measurement tests in HCC patients were run on straight serum and were compared with the performance of the conventional antibody-based ELISA kit. The aptamer sandwich assay demonstrated an excellent dynamic range for LCN2 at clinically relevant serum levels, covering sub-nanogram per mL concentrations. The new approach offers a simple and robust method for detecting serum biomarkers that have low and moderate abundance. It consists of functionalization, hybridization and signal read-out, and no dilution is required. The results of the study demonstrate the capability of the aptamer sandwich assay platform for diagnosing HCC and its potential applicability to the point-of-care testing (POCT) system. PMID:26039737

  6. Mini-Array of Multiple Tumor-Associated Antigens to Enhance Autoantibody Detection for Immunodiagnosis of Hepatocellular Carcinoma

    PubMed Central

    Zhang, Jian-Ying

    2009-01-01

    Liver cancer, especially hepatocellular carcinoma (HCC), is particularly prevalent in Africa and Asia. HCC affects the Hispanic population of the United States at a rate double that of the white population. The majority of people with HCC will die within 1 year of its detection. This high case-fatality rate can in part be attributed to lack of diagnostic methods that allow early detection. How to establish a methodology to identify the high-risk individuals for HCC remains to be investigated. The multi-factorial and multi-step nature in the molecular pathogenesis of human cancers must be taken into account in both the design and interpretation of studies to identify markers which will be useful for early detection of cancer. Our recent studies demonstrated that a mini-array of multiple tumor-associated antigens (TAAs) might enhance autoantibody detection for diagnosis of HCC, especially for the alpha fetoprotein (AFP)-negative cases. It also suggested that different types of cancer might require different panels of TAAs to achieve the sensitivity and specificity required to make immunodiagnosis a feasible adjunct to tumor diagnosis. PMID:17289549

  7. Plasma abnormal prothrombin (PIVKA-II): a new and reliable marker for the detection of hepatocellular carcinoma.

    PubMed

    Takikawa, Y; Suzuki, K; Yamazaki, K; Goto, T; Madarame, T; Miura, Y; Yoshida, T; Kashiwabara, T; Sato, S

    1992-01-01

    We evaluated the clinical usefulness of a protein induced by vitamin K absence, antagonist-prothrombin (PIVKA-II), in detecting hepatocellular carcinoma (HCC) specifically in patients with liver cirrhosis, and the possible correlation between levels of PIVKA-II and pathological features of HCC. Plasma levels of PIVKA-II and alpha-fetoprotein (AFP) were measured in 628 patients with various diseases, including 253 with liver cirrhosis and 116 with HCC. PIVKA-II was detected (greater than or equal to 0.1 arbitrary unit/mL) in 54.3% of HCC and the concentration showed a positive correlation with the tumour size. As a screening test for the detection of HCC, PIVKA-II produced values comparable with those of AFP with a sensitivity, specificity and validity of 52.8, 98.8 and 51.6% respectively. Sixteen of 45 patients (37%) with HCC who had low AFP (less than 100 ng/mL) levels were positive for PIVKA-II. No apparent relationship, however, could be found between the levels of PIVKA-II and the aetiology or pathological findings of HCC. These results suggest that PIVKA-II can be a reliable marker for detecting HCC in patients with liver cirrhosis.

  8. 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

  9. 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

  10. Biomarker Discovery for Early Detection of Hepatocellular Carcinoma in Hepatitis C–infected Patients*

    PubMed Central

    Mustafa, Mehnaz G.; Petersen, John R.; Ju, Hyunsu; Cicalese, Luca; Snyder, Ned; Haidacher, Sigmund J.; Denner, Larry; Elferink, Cornelis

    2013-01-01

    Chronic hepatic disease damages the liver, and the resulting wound-healing process leads to liver fibrosis and the subsequent development of cirrhosis. The leading cause of hepatic fibrosis and cirrhosis is infection with hepatitis C virus (HCV), and of the patients with HCV-induced cirrhosis, 2% to 5% develop hepatocellular carcinoma (HCC), with a survival rate of 7%. HCC is one of the leading causes of cancer-related death worldwide, and the poor survival rate is largely due to late-stage diagnosis, which makes successful intervention difficult, if not impossible. The lack of sensitive and specific diagnostic tools and the urgent need for early-stage diagnosis prompted us to discover new candidate biomarkers for HCV and HCC. We used aptamer-based fractionation technology to reduce serum complexity, differentially labeled samples (six HCV and six HCC) with fluorescent dyes, and resolved proteins in pairwise two-dimensional difference gel electrophoresis. DeCyder software was used to identify differentially expressed proteins and spots picked, and MALDI-MS/MS was used to determine that ApoA1 was down-regulated by 22% (p < 0.004) in HCC relative to HCV. Differential expression quantified via two-dimensional difference gel electrophoresis was confirmed by means of 18O/16O stable isotope differential labeling with LC-MS/MS zoom scans. Technically independent confirmation was demonstrated by triple quadrupole LC-MS/MS selected reaction monitoring (SRM) assays with three peptides specific to human ApoA1 (DLATVYVDVLK, WQEEMELYR, and VSFLSALEEYTK) using 18O/16O-labeled samples and further verified with AQUA peptides as internal standards for quantification. In 50 patient samples (24 HCV and 26 HCC), all three SRM assays yielded highly similar differential expression of ApoA1 in HCC and HCV patients. These results validated the SRM assays, which were independently confirmed by Western blotting. Thus, ApoA1 is a candidate member of an SRM biomarker panel for early diagnosis

  11. 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

  12. Detecting Circulating Tumor DNA in Hepatocellular Carcinoma Patients Using Droplet Digital PCR Is Feasible and Reflects Intratumoral Heterogeneity

    PubMed Central

    Huang, Ao; Zhang, Xin; Zhou, Shao-Lai; Cao, Ya; Huang, Xiao-Wu; Fan, Jia; Yang, Xin-Rong; Zhou, Jian

    2016-01-01

    Purpose: Circulating tumor DNA (ctDNA) is increasingly recognized as liquid biopsy to profile tumor genome. Droplet digital PCR (ddPCR) is a highly sensitive and easily operable platform for mutant detection. Here, we tried to detect ctDNA in hepatocellular carcinoma (HCC) patients using ddPCR. Methods: Studies sequencing the genome of HCCs and COSMIC (Catalogue of Somatic Mutations in Cancer) database were reviewed to identify hotspot mutations. Circulating cell-free DNAs (cfDNAs) extracted from 1 ml preoperative plasma sample were analyzed to detect circulating mutants using ddPCR. The DNAs from matched tumor and adjacent liver tissues or peripheral blood mononuclear cells (PBMCs) were sequenced to identify the origin of circulating mutants. Results: Forty-eight HCC patients were enrolled and four gene loci, TP53 (c.747G>T), CTNNB1 (c.121A>G, c.133T>C), and TERT (c.1-124C>T) were chosen as targets for ddPCR assay. Serial dilution demonstrated the detection limit of ddPCR to be 0.01%. Twenty-seven patients (56.3%, 27/48) were found to have at least one kind of circulating mutants, with the mutant allele frequency ranging from 0.33% to 23.7%. Six patients (22.2%, 6/27) also had matched mutants in tumor tissues while none of the mutants were detected in adjacent liver tissues or PBMCs in all patients, which excluded the nonneoplastic origin of these circulating mutants and qualified them as ctDNA. Conclusions: ctDNA could be readily detected in HCC patients by targeting hotspot mutations using ddPCR and might reflect intratumoral heterogeneity. ctDNA detecting may serve as a promising liquid biopsy in HCC management.

  13. Detecting Circulating Tumor DNA in Hepatocellular Carcinoma Patients Using Droplet Digital PCR Is Feasible and Reflects Intratumoral Heterogeneity

    PubMed Central

    Huang, Ao; Zhang, Xin; Zhou, Shao-Lai; Cao, Ya; Huang, Xiao-Wu; Fan, Jia; Yang, Xin-Rong; Zhou, Jian

    2016-01-01

    Purpose: Circulating tumor DNA (ctDNA) is increasingly recognized as liquid biopsy to profile tumor genome. Droplet digital PCR (ddPCR) is a highly sensitive and easily operable platform for mutant detection. Here, we tried to detect ctDNA in hepatocellular carcinoma (HCC) patients using ddPCR. Methods: Studies sequencing the genome of HCCs and COSMIC (Catalogue of Somatic Mutations in Cancer) database were reviewed to identify hotspot mutations. Circulating cell-free DNAs (cfDNAs) extracted from 1 ml preoperative plasma sample were analyzed to detect circulating mutants using ddPCR. The DNAs from matched tumor and adjacent liver tissues or peripheral blood mononuclear cells (PBMCs) were sequenced to identify the origin of circulating mutants. Results: Forty-eight HCC patients were enrolled and four gene loci, TP53 (c.747G>T), CTNNB1 (c.121A>G, c.133T>C), and TERT (c.1-124C>T) were chosen as targets for ddPCR assay. Serial dilution demonstrated the detection limit of ddPCR to be 0.01%. Twenty-seven patients (56.3%, 27/48) were found to have at least one kind of circulating mutants, with the mutant allele frequency ranging from 0.33% to 23.7%. Six patients (22.2%, 6/27) also had matched mutants in tumor tissues while none of the mutants were detected in adjacent liver tissues or PBMCs in all patients, which excluded the nonneoplastic origin of these circulating mutants and qualified them as ctDNA. Conclusions: ctDNA could be readily detected in HCC patients by targeting hotspot mutations using ddPCR and might reflect intratumoral heterogeneity. ctDNA detecting may serve as a promising liquid biopsy in HCC management. PMID:27698932

  14. 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

  15. Molecular Pathogenesis of Hepatocellular Carcinoma

    PubMed Central

    Ho, Daniel Wai-Hung; Lo, Regina Cheuk-Lam; Chan, Lo-Kong; Ng, Irene Oi-Lin

    2016-01-01

    The pathogenesis of hepatocellular carcinoma (HCC) is a multistep process involving the progressive accumulation of molecular alterations pinpointing different molecular and cellular events. The next-generation sequencing technology is facilitating the global and systematic evaluation of molecular landscapes in HCC. There is emerging evidence supporting the importance of cancer metabolism and tumor microenvironment in providing a favorable and supportive niche to expedite HCC development. Moreover, recent studies have identified distinct surface markers of cancer stem cell (CSC) in HCC, and they also put forward the profound involvement of altered signaling pathways and epigenetic modifications in CSCs, in addition to the concomitant drug resistance and metastasis. Taken together, multiple key genetic and non-genetic factors, as well as liver CSCs, result in the development and progression of HCC. PMID:27781201

  16. [Hepatocellular Carcinoma: therapeutic options 2015].

    PubMed

    Schultheiß, Michael; Bettinger, Dominik; Neeff, Hannes P; Brunner, Thomas B; Thimme, Robert

    2015-07-01

    The incidence of hepatocellular carcinoma (HCC), a common neoplasm, is rising and the prognosis is poor. Many factors have to be taken into account when deciding on the best mode of therapy, like tumor size and number, liver function, sequelae of portal hypertension or other comorbidities. These factors are reflected in the Barcelona Clinic Liver Cancer (BCLC) classification. Resection, radiofrequency ablation (RFA) and liver transplantation can be seen as curative therapies for the early and localized HCC. For the intermediate state of the HCC, there are other therapeutic modalities in therapy available: transarterial chemoembolization (TACE), selective internal radiation therapy (SIRT, rarer occasions), off label: stereotactic body radiation therapy (SBRT). At the moment, Sorafenib is the only option in treating advanced stages of HCC. Alternative treatment strategies, like e.g. immunological therapies, are being investigated. PMID:26182255

  17. Cytoreductive surgery for hepatocellular carcinoma.

    PubMed

    Lau, W Y; Leung, T W; Leung, K L; Ho, S; Leung, N; Chan, M; Lin, J; Li, A K

    1994-06-01

    A prospective study was conducted on 26 patients for cytoreductive surgery of inoperable hepatocellular carcinoma. These patients underwent cytoreduction with liver resection, cryosurgery, microwave tissue coagulation and/or absolute alcohol injection. In-hospital mortality was 7.7%. The symptomatic relief and quality of survival were excellent. The median survival of patients after cytoreduction was 10.0 months and the survival was much better than those of 26 patients matched by sex, age, tumour size, Child-Pugh grading and Karnofsky scores who received systemic chemotherapy during the same period of the study (log rank test, P = 0.0001). There was no statistical difference between the survival curves of those patients who received (19 patients) and those who did not receive (7 patients) additional treatment by chemotherapy or selective internal radiation therapy after cytoreduction. This suggests that the gained survival benefit could have been derived mainly from the cytoreductive surgery rather than the additional treatments.

  18. Hepatocellular carcinoma and industrial epidemics

    PubMed Central

    Braillon, Alain; Dubois, Gérard

    2011-01-01

    Worldwide, the burden of the non viral causes of hepatocellular carcinoma (HCC) is usually underestimated. Clearly industrial goods, tobacco, alcohol and processed foods are the agents of new epidemics in modern times which far outscore the burden of infectious agents on morbidity and mortality. Smoking, a dose-related contributing factor for HCC, receives too little attention in clinical practice. In France, tobacco, hepatitis B and C virus and alcohol are the main risk factors for HCC mortality (33%, 31% and 26%, respectively). In developing countries, where tobacco consumption is dramatically increasing, this epidemic may soon surpass hepatitis B. Obesity and diabetes are the contributing factors too. The role of industrial processed foods in the increase of the prevalence of obesity and diabetes cannot be ignored. PMID:21734811

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

    PubMed

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

    2014-05-01

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

  20. Electrochemical Detection and Distribution Analysis of β-Catenin for the Evaluation of Invasion and Metastasis in Hepatocellular Carcinoma.

    PubMed

    Yu, Yue; Li, Hao; Wei, Luming; Li, Liudi; Ding, Yitao; Li, Genxi

    2016-04-01

    Pro-metastatic cell signaling controls the switch to distant metastasis and the final cancer death. In hepatocellular carcinoma (HCC), this death switch is turned on by the multiprotein interactions of β-catenin with many transcription factors, so a method to assay the bioactivity of β-catenin to participate in these pro-metastatic protein/protein interactions has been proposed in this work. This method employs cost-effective peptide-based protein targeting ligands, while the electrochemical catalytic cross-linking in this method also "finalize" the noncovalent molecular recognition, so that the robustness can be improved to enable detection of relatively more complex biosamples. In studying clinical samples with the proposed method, the cellular distribution and overall expression of β-catenin show a parallel with the pathological grade of the sample, particularly, nuclear translocation. The pro-metastatic activation of β-catenin can also be observed as evidently correlated with higher-grade cases, suggesting the active role of β-catenin in promoting metastasis. According to these results, the proposed method may have the prospective use as a prognostic tool for evaluating the potential of invasion and metastasis in cancer.

  1. Genome-scale detection of hypermethylated CpG islands in circulating cell-free DNA of hepatocellular carcinoma patients

    PubMed Central

    Wen, Lu; Li, Jingyi; Guo, Huahu; Liu, Xiaomeng; Zheng, Shengmin; Zhang, Dafang; Zhu, Weihua; Qu, Jianhui; Guo, Limin; Du, Dexiao; Jin, Xiao; Zhang, Yuhao; Gao, Yun; Shen, Jie; Ge, Hao; Tang, Fuchou; Huang, Yanyi; Peng, Jirun

    2015-01-01

    Despite advances in DNA methylome analyses of cells and tissues, current techniques for genome-scale profiling of DNA methylation in circulating cell-free DNA (ccfDNA) remain limited. Here we describe a methylated CpG tandems amplification and sequencing (MCTA-Seq) method that can detect thousands of hypermethylated CpG islands simultaneously in ccfDNA. This highly sensitive technique can work with genomic DNA as little as 7.5 pg, which is equivalent to 2.5 copies of the haploid genome. We have analyzed a cohort of tissue and plasma samples (n = 151) of hepatocellular carcinoma (HCC) patients and control subjects, identifying dozens of high-performance markers in blood for detecting small HCC (≤ 3 cm). Among these markers, 4 (RGS10, ST8SIA6, RUNX2 and VIM) are mostly specific for cancer detection, while the other 15, classified as a novel set, are already hypermethylated in the normal liver tissues. Two corresponding classifiers have been established, combination of which achieves a sensitivity of 94% with a specificity of 89% for the plasma samples from HCC patients (n = 36) and control subjects including cirrhosis patients (n = 17) and normal individuals (n = 38). Notably, all 15 alpha-fetoprotein-negative HCC patients were successfully identified. Comparison between matched plasma and tissue samples indicates that both the cancer and noncancerous tissues contribute to elevation of the methylation markers in plasma. MCTA-Seq will facilitate the development of ccfDNA methylation biomarkers and contribute to the improvement of cancer detection in a clinical setting. PMID:26516143

  2. Genome-scale detection of hypermethylated CpG islands in circulating cell-free DNA of hepatocellular carcinoma patients.

    PubMed

    Wen, Lu; Li, Jingyi; Guo, Huahu; Liu, Xiaomeng; Zheng, Shengmin; Zhang, Dafang; Zhu, Weihua; Qu, Jianhui; Guo, Limin; Du, Dexiao; Jin, Xiao; Zhang, Yuhao; Gao, Yun; Shen, Jie; Ge, Hao; Tang, Fuchou; Huang, Yanyi; Peng, Jirun

    2015-11-01

    Despite advances in DNA methylome analyses of cells and tissues, current techniques for genome-scale profiling of DNA methylation in circulating cell-free DNA (ccfDNA) remain limited. Here we describe a methylated CpG tandems amplification and sequencing (MCTA-Seq) method that can detect thousands of hypermethylated CpG islands simultaneously in ccfDNA. This highly sensitive technique can work with genomic DNA as little as 7.5 pg, which is equivalent to 2.5 copies of the haploid genome. We have analyzed a cohort of tissue and plasma samples (n = 151) of hepatocellular carcinoma (HCC) patients and control subjects, identifying dozens of high-performance markers in blood for detecting small HCC (≤ 3 cm). Among these markers, 4 (RGS10, ST8SIA6, RUNX2 and VIM) are mostly specific for cancer detection, while the other 15, classified as a novel set, are already hypermethylated in the normal liver tissues. Two corresponding classifiers have been established, combination of which achieves a sensitivity of 94% with a specificity of 89% for the plasma samples from HCC patients (n = 36) and control subjects including cirrhosis patients (n = 17) and normal individuals (n = 38). Notably, all 15 alpha-fetoprotein-negative HCC patients were successfully identified. Comparison between matched plasma and tissue samples indicates that both the cancer and noncancerous tissues contribute to elevation of the methylation markers in plasma. MCTA-Seq will facilitate the development of ccfDNA methylation biomarkers and contribute to the improvement of cancer detection in a clinical setting.

  3. Serum albumin and globulin analysis for hepatocellular carcinoma detection avoiding false-negative results from alpha-fetoprotein test negative subjects

    NASA Astrophysics Data System (ADS)

    Wang, Jing; Feng, Shangyuan; Lin, Juqiang; Zeng, Yongyi; Li, Ling; Huang, Zufang; Li, Buhong; Zeng, Haishan; Chen, Rong

    2013-11-01

    Surface-enhanced Raman spectroscopy (SERS) of serum albumin and globulin were employed to detect hepatocellular carcinoma (HCC). Tentative assignments of SERS bands show specific biomolecular changes associated with cancer development. These changes include a decrease in relative amounts of tryptophan, glutamine, glycine, and serine, indicating excessive consumption of amino acids for protein duplication. Principal component analysis was also introduced to analyze the obtained spectra, resulting in both diagnostic sensitivity and specificity of 100%. More importantly, it reveals that this method can detect HCC patients with alpha-fetoprotein negative test results, suggesting its great potential as a new alternative to detect HCC.

  4. Perspectives on using des-γ-carboxyprothrombin (DCP) as a serum biomarker: facilitating early detection of hepatocellular carcinoma in China.

    PubMed

    Song, Peipei; Feng, Xiaobin; Zhang, Keming; Song, Tianqiang; Ma, Kuansheng; Kokudo, Norihiro; Dong, Jiahong; Tang, Wei

    2013-08-01

    Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths in China. Evidence has shown that surgical resection and liver transplantation may offer the best potential for treating HCC but are only available to patients whose tumors are detected early. Over the past few decades, although a series of measures for standardized management of HCC has been implemented in China, most patients with HCC in China still present with advanced-stage disease, thus strategies to screen for and diagnose HCC at an earlier stage are urgently needed in China when curable interventions can be offered to achieve long-term disease-free survival for patients with HCC. In China, the serum biomarker α-fetoprotein (AFP) is considered a useful and feasible tool for HCC screening and early diagnosis. However, the sensitivity and specificity of AFP vary widely, and the total AFP is not always specific, especially when HCC is in its early stages. Globally, numerous studies have reported that the combination of des-γ-carboxyprothrombin (DCP) and AFP may have a higher sensitivity than AFP alone, and suggested DCP could also be used to assess the progression of HCC. However, DCP has not been approved in China until now. Differ from most of Western countries, people with HBV infection are the largest population at risk of developing HCC China. In order to assess the screening and diagnostic value of DCP in Chinese patients with HCC, a first large-scale, multi-center study was launched in China in 2012, results showed that DCP can help to detect HCC in its early stages and facilitate definitive treatment. The clinical use of DCP is urgently needed to facilitate early detection of HCC in China.

  5. 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

  6. Challenges of advanced hepatocellular carcinoma.

    PubMed

    Colagrande, Stefano; Inghilesi, Andrea L; Aburas, Sami; Taliani, Gian G; Nardi, Cosimo; Marra, Fabio

    2016-09-14

    Hepatocellular carcinoma (HCC) is an aggressive malignancy, resulting as the third cause of death by cancer each year. The management of patients with HCC is complex, as both the tumour stage and any underlying liver disease must be considered conjointly. Although surveillance by imaging, clinical and biochemical parameters is routinely performed, a lot of patients suffering from cirrhosis have an advanced stage HCC at the first diagnosis. Advanced stage HCC includes heterogeneous groups of patients with different clinical condition and radiological features and sorafenib is the only approved treatment according to Barcelona Clinic Liver Cancer. Since the introduction of sorafenib in clinical practice, several phase III clinical trials have failed to demonstrate any superiority over sorafenib in the frontline setting. Loco-regional therapies have also been tested as first line treatment, but their role in advanced HCC is still matter of debate. No single agent or combination therapies have been shown to impact outcomes after sorafenib failure. Therefore this review will focus on the range of experimental therapeutics for patients with advanced HCC and highlights the successes and failures of these treatments as well as areas for future development. Specifics such as dose limiting toxicity and safety profile in patients with liver dysfunction related to the underlying chronic liver disease should be considered when developing therapies in HCC. Finally, robust validated and reproducible surrogate end-points as well as predictive biomarkers should be defined in future randomized trials. PMID:27678348

  7. Challenges of advanced hepatocellular carcinoma

    PubMed Central

    Colagrande, Stefano; Inghilesi, Andrea L; Aburas, Sami; Taliani, Gian G; Nardi, Cosimo; Marra, Fabio

    2016-01-01

    Hepatocellular carcinoma (HCC) is an aggressive malignancy, resulting as the third cause of death by cancer each year. The management of patients with HCC is complex, as both the tumour stage and any underlying liver disease must be considered conjointly. Although surveillance by imaging, clinical and biochemical parameters is routinely performed, a lot of patients suffering from cirrhosis have an advanced stage HCC at the first diagnosis. Advanced stage HCC includes heterogeneous groups of patients with different clinical condition and radiological features and sorafenib is the only approved treatment according to Barcelona Clinic Liver Cancer. Since the introduction of sorafenib in clinical practice, several phase III clinical trials have failed to demonstrate any superiority over sorafenib in the frontline setting. Loco-regional therapies have also been tested as first line treatment, but their role in advanced HCC is still matter of debate. No single agent or combination therapies have been shown to impact outcomes after sorafenib failure. Therefore this review will focus on the range of experimental therapeutics for patients with advanced HCC and highlights the successes and failures of these treatments as well as areas for future development. Specifics such as dose limiting toxicity and safety profile in patients with liver dysfunction related to the underlying chronic liver disease should be considered when developing therapies in HCC. Finally, robust validated and reproducible surrogate end-points as well as predictive biomarkers should be defined in future randomized trials.

  8. Targeted therapies in hepatocellular carcinoma.

    PubMed

    Bronte, F; Bronte, G; Cusenza, S; Fiorentino, E; Rolfo, C; Cicero, G; Bronte, E; Di Marco, V; Firenze, A; Angarano, G; Fontana, T; Russo, A

    2014-01-01

    The onset of hepatocellular carcinoma (HCC) is related to the development of non-neoplastic liver disease, such as viral infections and cirrhosis. Even though patients with chronic liver diseases undergo clinical surveillance for early diagnosis of HCC, this cancer is often diagnosed in advanced stage. In this case locoregional treatment is not possible and systemic therapies are the best way to control it. Until now sorafenib, a Raf and multi-kinase inhibitor has been the best, choice to treat HCC systemically. It showed a survival benefit in multicenter phase III trials. However the proper patient setting to treat is not well defined, since the results in Child-Pugh B patients are conflicting. To date various new target drugs are under developed and other biological treatments normally indicated in other malignancies are under investigation also for HCC. These strategies aim to target the different biological pathways implicated in HCC development and progression. The target drugs studied in HCC include anti-VEGF and anti-EGFR monoclonal antibodies, tyrosine kinase inhibitors and mTOR inhibitors. The most important challenge is represented by the best integration of these drugs with standard treatments to achieve improvement in overall survival and quality of life.

  9. Challenges of advanced hepatocellular carcinoma

    PubMed Central

    Colagrande, Stefano; Inghilesi, Andrea L; Aburas, Sami; Taliani, Gian G; Nardi, Cosimo; Marra, Fabio

    2016-01-01

    Hepatocellular carcinoma (HCC) is an aggressive malignancy, resulting as the third cause of death by cancer each year. The management of patients with HCC is complex, as both the tumour stage and any underlying liver disease must be considered conjointly. Although surveillance by imaging, clinical and biochemical parameters is routinely performed, a lot of patients suffering from cirrhosis have an advanced stage HCC at the first diagnosis. Advanced stage HCC includes heterogeneous groups of patients with different clinical condition and radiological features and sorafenib is the only approved treatment according to Barcelona Clinic Liver Cancer. Since the introduction of sorafenib in clinical practice, several phase III clinical trials have failed to demonstrate any superiority over sorafenib in the frontline setting. Loco-regional therapies have also been tested as first line treatment, but their role in advanced HCC is still matter of debate. No single agent or combination therapies have been shown to impact outcomes after sorafenib failure. Therefore this review will focus on the range of experimental therapeutics for patients with advanced HCC and highlights the successes and failures of these treatments as well as areas for future development. Specifics such as dose limiting toxicity and safety profile in patients with liver dysfunction related to the underlying chronic liver disease should be considered when developing therapies in HCC. Finally, robust validated and reproducible surrogate end-points as well as predictive biomarkers should be defined in future randomized trials. PMID:27678348

  10. Environmental Exposures and Hepatocellular Carcinoma

    PubMed Central

    Wu, Hui-Chen

    2013-01-01

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

  11. Non-coding RNAs in hepatitis C-induced hepatocellular carcinoma: dysregulation and implications for early detection, diagnosis and therapy.

    PubMed

    Hou, Weihong; Bonkovsky, Herbert L

    2013-11-28

    Hepatitis C virus (HCV) infection is one of main causes of hepatocellular carcinoma (HCC) and the prevalence of HCV-associated HCC is on the rise worldwide. It is particularly important and helpful to identify potential markers for screening and early diagnosis of HCC among high-risk individuals with chronic hepatitis C, and to identify target molecules for the prevention and treatment of HCV-associated-HCC. Small non-coding RNAs, mainly microRNAs (miRNAs), and long non-coding RNAs (lncRNAs) with size greater than 200 nucleotides, are likely to play important roles in a variety of biological processes, including development and progression of HCC. For the most part their underlying mechanisms of action remain largely unknown. In recent years, with the advance of high-resolution of microarray and application of next generation sequencing techniques, a significant number of non-coding RNAs (ncRNAs) associated with HCC, particularly caused by HCV infection, have been found to be differentially expressed and to be involved in pathogenesis of HCV-associated HCC. In this review, we focus on recent studies of ncRNAs, especially miRNAs and lncRNAs related to HCV-induced HCC. We summarize those ncRNAs aberrantly expressed in HCV-associated HCC and highlight the potential uses of ncRNAs in early detection, diagnosis and therapy of HCV-associated HCC. We also discuss the limitations of recent studies, and suggest future directions for research in the field. miRNAs, lncRNAs and their target genes may represent new candidate molecules for the prevention, diagnosis and treatment of HCC in patients with HCV infection. Studies of the potential uses of miRNAs and lncRNAs as diagnostic tools or therapies are still in their infancy.

  12. Antiproliferative effects of cinobufacini on human hepatocellular carcinoma HepG2 cells detected by atomic force microscopy

    PubMed Central

    Wu, Qing; Lin, Wei-Dong; Liao, Guan-Qun; Zhang, Li-Guo; Wen, Shun-Qian; Lin, Jia-Ying

    2015-01-01

    AIM: To investigate the antiproliferative activity of cinobufacini on human hepatocellular carcinoma HepG2 cells and the possible mechanism of its action. METHODS: HepG2 cells were treated with different concentrations of cinobufacini. Cell viability was measured by methylthiazolyl tetrazolium (MTT) assay. Cell cycle distribution was analyzed by flow cytometry (FCM). Cytoskeletal and nuclear alterations were observed by fluorescein isothiocyanate-phalloidin and DAPI staining under a laser scanning confocal microscope. Changes in morphology and ultrastructure of cells were detected by atomic force microscopy (AFM) at the nanoscale level. RESULTS: MTT assay indicated that cinobufacini significantly inhibited the viability of HepG2 cells in a dose-dependent manner. With the concentration of cinobufacini increasing from 0 to 0.10 mg/mL, the cell viability decreased from 74.9% ± 2.7% to 49.41% ± 2.2% and 39.24% ± 2.1% (P < 0.05). FCM analysis demonstrated cell cycle arrest at S phase induced by cinobufacini. The immunofluorescence studies of cytoskeletal and nuclear morphology showed that after cinobufacini treatment, the regular reorganization of actin filaments in HepG2 cells become chaotic, while the nuclei were not damaged seriously. Additionally, high-resolution AFM imaging revealed that cell morphology and ultrastructure changed a lot after treatment with cinobufacini. It appeared as significant shrinkage and deep pores in the cell membrane, with larger particles and a rougher cell surface. CONCLUSION: Cinobufacini inhibits the viability of HepG2 cells via cytoskeletal destruction and cell membrane toxicity. PMID:25624718

  13. Early Detection, Curative Treatment, and Survival Rates for Hepatocellular Carcinoma Surveillance in Patients with Cirrhosis: A Meta-analysis

    PubMed Central

    Singal, Amit G.; Pillai, Anjana; Tiro, Jasmin

    2014-01-01

    Background Surveillance for hepatocellular carcinoma (HCC) has level I evidence among patients with hepatitis B but only level II evidence in patients with cirrhosis. This lack of randomized data has spurred questions regarding the utility of HCC surveillance in this patient population; however, lack of randomized data does not equate to a lack of data supporting the efficacy of surveillance. The aim of our study was to determine the effect of HCC surveillance on early stage tumor detection, receipt of curative therapy, and overall survival in patients with cirrhosis. Methods and Findings We performed a systematic literature review using Medline from January 1990 through January 2014 and a search of national meeting abstracts from 2009–2012. Two investigators identified studies that reported rates of early stage tumor detection, curative treatment receipt, or survival, stratified by HCC surveillance status, among patients with cirrhosis. Both investigators independently extracted data on patient populations, study methods, and results using standardized forms. Pooled odds ratios, according to HCC surveillance status, were calculated for each outcome using the DerSimonian and Laird method for a random effects model. We identified 47 studies with 15,158 patients, of whom 6,284 (41.4%) had HCC detected by surveillance. HCC surveillance was associated with improved early stage detection (odds ratio [OR] 2.08, 95% CI 1.80–2.37) and curative treatment rates (OR 2.24, 95% CI 1.99–2.52). HCC surveillance was associated with significantly prolonged survival (OR 1.90, 95% CI 1.67–2.17), which remained significant in the subset of studies adjusting for lead-time bias. Limitations of current data included many studies having insufficient duration of follow-up to assess survival and the majority not adjusting for liver function or lead-time bias. Conclusions HCC surveillance is associated with significant improvements in early tumor detection, receipt of curative

  14. 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

  15. 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

  16. 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.

  17. 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

  18. 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

  19. Primary prevention of hepatocellular carcinoma.

    PubMed

    Yu, S Z

    1995-01-01

    Hepatocellular carcinoma (HCC) is one of the major cancers in China. Accordingly, the mortality rates in 1990 (per 100,000) were 20.10 in certain cities and 24.32 in certain counties. More than 90% of HCC cases and 70% of controls were infected with the hepatitis B virus (HBV) (Odds Ratio (OR) = 10-50). In the same group of patients, 8-27% of those with HCC and 0-11% of the healthy controls were also infected with hepatitis C (HCV) (OR = 2.11-17.29). There appears to be some correlation between HBV markers and the OR. The government requires that 85% of infants be immunized with HBV vaccine. In 1992, there were 3 million infants inoculated with HB vaccines. Aflatoxins have been found as contaminants in food, particularly in corn, peanut oil, soya sauce and fermented soya beans. The intake of aflatoxin B1 (AFB1) by people of ten different villages correlated with HCC mortality rates (r = 0.55; P < 0.05). The concentration of AFB1-albumin adducts is an indicator of individual exposure to aflatoxins. These adducts are higher in hyperendemic HCC areas and cases. Most people have now changed their staple food and eat rice instead of corn. Six large epidemiological studies have confirmed that people who drink pond-ditch water experience higher HCC mortality rates than people who drink deep-well water. Recent research has found that the blue-green algal toxin microcystin (MCYST) was a contaminant of pond-ditch water. MCYST is a strong promoter of HCC and will induce severe intrahepatic haemorrhages and liver necrosis. More than 80% of people in Qidong County have already changed their sources of water from pond-ditches to deep wells. Therefore, a combined strategy of the prevention of hepatitis, control of crops and control of drinking water is advocated for the primary prevention of HCC in China.

  20. 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

  1. 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

  2. Targeted Therapies for Hepatocellular Carcinoma

    PubMed Central

    Villanueva, Augusto; Llovet, Josep M.

    2013-01-01

    Unlike most solid tumors, incidence and mortality of hepatocellular carcinoma (HCC) have increased in the US and Europe in the last decade. Most patients are diagnosed at advanced stages, so there is an urgent need for new systemic therapies. Sorafenib, a tyrosine kinase inhibitor (TKI), has demonstrated clinical efficacy in patients with HCC. Studies in patients with lung, breast, or colorectal cancers indicated that the genetic heterogeneity of cancer cells within a tumor affect its response to therapeutics designed to target specific molecules. When tumor progression requires alterations in specific oncogenes (oncogene addiction), drugs that selectively block their products might slow tumor growth. However, no specific oncogene alterations are yet known to be implicated in HCC progression, so it is important to improve our understanding of its molecular pathogenesis. There are currently many clinical trials evaluating TKIs for HCC, including those tested in combination with (e.g., erlotinib) or compared to (e.g., linifanib) sorafenib as a first-line therapy. For patients that do not respond or are intolerant to sorafenib, TKIs such as brivanib, everolimus, and monoclonal antibodies (e.g. ramucirumab) are being tested as second-line therapies. There are early-stage trials investigating the efficacy for up to 60 reagents for HCC. Together, these studies might change the management strategy for HCC, and combination therapies might be developed for patients with advanced HCC. Identification of oncogenes that mediate progression of HCC, and trials that monitor their products as biomarkers, might lead to personalized therapy; reagents that interfere with signaling pathways required for HCC progression might be used to treat selected populations, and thereby maximize the efficacy and cost-benefit. PMID:21406195

  3. 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

  4. Prognostic factors for hepatocellular carcinoma recurrence.

    PubMed

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

    2014-05-28

    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.

  5. 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

  6. Usefulness of serum des-γ-carboxy prothrombin in detection of hepatocellular carcinoma

    PubMed Central

    Wang, Chaur-Shine; Lin, Chih-Lin; Lee, Hsi-Chang; Chen, Kuan-Yang; Chiang, Ming-Feng; Chen, Hung-Sheng; Lin, Tsung-Jung; Liao, Li-Ying

    2005-01-01

    AIM: To evaluate whether DCP is better than AFP for differentiating HCC from nonmalignant liver disease and further evaluate the usefulness of DCP in early diagnosis of small HCC. METHODS: Serum DCP and AFP levels were determined in 127 patients. Among these patients, 32 were with non-cirrhotic chronic hepatitis, 34 were with compensated cirrhosis, and 61 were with HCC. The cut-off value for the DCP and AFP were set as 40 mAU/mL and 20 ng/mL, respectively. To compare the diagnostic value of DCP and AFP in distinguishing HCC from nonmalignant chronic liver disease, receiver operating characteristic (ROC) curves were constructed for each assay. RESULTS: The accuracy, sensitivity, and specificity of DCP were higher than AFP in detecting HCC (81.9%, 77%, and 86.4% vs 68.5%, 59%, and 77.3%, respectively). The area under the ROC (AUROC) curves revealed that DCP had a better accuracy than AFP in diagnosis of HCC (0.85 [95%CI, 0.78-0.91] vs 0.73 [95%CI, 0.65-0.81], P = 0.013). In 39 patients with solitary HCC, the positive rates of DCP were 100% in patients with tumor size larger than 3 cm, 66.7% in patients with tumor size 2-3 cm and 50% in patients with tumor size less than 2 cm. The positive rates of AFP in patients with tumor size larger than 3 cm, 2-3 cm and less than 2 cm were 55.6%, 50%, and 33.3%, respectively. The median level of DCP in HCC patients with tumor size larger than 3 cm was significantly higher than those with tumor size 2-3 cm and those with the size of less than 2 cm. CONCLUSION: Our study indicates that DCP has a better diagnostic value than AFP in differentiating HCC from nonmalignant chronic liver disease. DCP has not only a stronger correlation with HCC than AFP in tumor size but also more effectiveness than AFP in detecting small size of HCC. PMID:16273636

  7. 77 FR 24959 - Scientific Information Request on Local Therapies for Unresectable Primary Hepatocellular Carcinoma

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-04-26

    ... Therapies for Unresectable Primary Hepatocellular Carcinoma AGENCY: Agency for Healthcare Research and... local, minimally invasive, medical devices for unresectable primary hepatocellular carcinoma (e.g... Comparative Effectiveness Review of Local Therapies for Unresectable Primary Hepatocellular Carcinoma,...

  8. Screening process failures for hepatocellular carcinoma.

    PubMed

    Singal, Amit G; Marrero, Jorge A; Yopp, Adam

    2014-03-01

    More than 60% of patients with hepatocellular carcinoma (HCC) are diagnosed at a late stage, suggesting potential breakdowns in the HCC screening process. Understanding which steps in the screening process are not being performed is essential for designing effective interventions. To characterize HCC screening process failures, a retrospective cohort study of patients with cirrhosis diagnosed with HCC at a large urban safety-net hospital was conducted between 2005 and 2012. Screening process failures during the year before HCC diagnosis were characterized into 3 categories: absence of surveillance, failure of detection, and delayed follow-up. Univariate and multivariate analyses were performed to identify predictors of screening process failures. A total of 185 patients with cirrhosis and HCC were identified, of whom 91 (49%) were diagnosed at an early stage (Barcelona Clinic Liver Cancer system stage A). Only 16 (8.6%) patients successfully completed the screening process. Absence of surveillance was the most common screening process failure, found in 75.7% of all patients, and was associated with trends toward lower rates of early tumor detection (odds ratio, 0.51; 95% CI, 0.23-1.09) and worse overall survival (hazard ratio, 0.79; 95% CI, 0.49-1.25). Failure of detection and delayed follow-up were found in 11.4% and 2.7% of patients, respectively.

  9. Changing epidemiology of hepatocellular carcinoma in Asia.

    PubMed

    Goh, George Boon-Bee; Chang, Pik-Eu; Tan, Chee-Kiat

    2015-12-01

    Hepatocellular carcinoma is a major problem in Asia because of the presence of multiple risk factors in the region such as endemicity of hepatitis B and significant contamination of foodstuff by aflatoxin in some areas. Another risk factor for HCC, chronic hepatitis C infection, in Asia is most significant in Japan, the only Asian country with more HCV than HBV-related hepatocellular carcinoma. As these risk factors can and are being modified by measures such as universal hepatitis B immunisation, successful treatment of HCV infections, reduction and improved surveillance of aflatoxin contamination of foodstuff, it is not surprising that the epidemiology of HCC in Asia is changing. All these are offset by the rising importance of NAFLD and NASH as chronic liver diseases and risk factors for HCC which contributes to the changing epidemiology of HCC in Asia.

  10. Epidemiology of hepatocellular carcinoma (HCC) in hemophilia.

    PubMed

    Shetty, Shrimati; Sharma, Nitika; Ghosh, Kanjaksha

    2016-03-01

    Hepatocellular carcinoma (HCC) is an important cause of increasing mortality in elderly hemophilia population. Majority of the patients treated with virus non-inactivated factor concentrates prepared from large plasma pools prior to 1985 have been found to be infected with hepatitis C virus (HCV), a major risk factor for HCC. A PubMed search of articles published until February 2015 was performed utilizing the keywords hemophilia, malignancy, neoplasm, cancer, mortality, ageing hemophilia, epidemiology, hepatocellular carcinoma and liver cancer and the relevant articles were included. Contradictory reports are available in literature on the incidence of cancers in general in hemophilia population. Almost all the studies where the incidence of HCC or mortality due to HCC have been analyzed in hemophilia population show that a vast majority of these patients are HCV infected. The incidence of HCC though higher in hemophilic population is related to the higher incidence of HCV infection and not due to the hemophilia phenotype.

  11. 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

  12. Effect of superoxide and inflammatory factor on aflatoxin B1 triggered hepatocellular carcinoma

    PubMed Central

    Qin, Huimin; Li, Hongtao; Zhou, Xiaolin; Peng, Chen; Tan, Honghu; Wang, Minxin

    2016-01-01

    Presently, there have been a lot of documents confirmed that aflatoxin B1 could promote the incident rate of hepato-cellular carcinoma, but the specific mechanism is not completely clear. Some evidences showed that it might relate to oxidative stress and inflammatory reaction. So the rat hepato-cellular carcinoma model was applied in this study for being discussed. Aflatoxin B1 was applied for inducing the rats to produce hepato-cellular carcinoma model to evaluate the expression of histopathology and glutathione transferase. At the same time, we also detected the expression of antioxidase, pro-inflammatory cytokine, proliferating cell nuclear antigen and etc in rat hepato-cellular carcinoma tissues. The histo-pathological results showed that the necrosis of liver cells could be observed after being induced by Aflatoxin B1 for 4 weeks. We could observe obvious hepato-cellular carcinoma in 10th week. The level of reactive oxygen species in liver cancer rose obviously, and the activity of antioxidant enzymes reduced. At the same time, the expression level of pro-inflammatory cytokine, TNFα, IL-1α, proliferating cell nuclear antigen and etc all increased significantly. In conclusion, the histological characteristics of hepato-cellular carcinoma could be induced by aflatoxin B1, and the progression of hepato-cellular carcinoma related closely to inflammatory reaction. PMID:27725881

  13. 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

  14. 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

  15. 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

  16. 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

  17. MRI-detectable polymeric micelles incorporating platinum anticancer drugs enhance survival in an advanced hepatocellular carcinoma model

    PubMed Central

    Vinh, Nguyen Quoc; Naka, Shigeyuki; Cabral, Horacio; Murayama, Hiroyuki; Kaida, Sachiko; Kataoka, Kazunori; Morikawa, Shigehiro; Tani, Tohru

    2015-01-01

    Hepatocellular carcinoma (HCC) is one of the most intractable and lethal cancers; most cases are diagnosed at advanced stages with underlying liver dysfunction and are frequently resistant to conventional chemotherapy and radiotherapy. The development of tumor-targeting systems may improve treatment outcomes. Nanomedicine platforms are of particular interest for enhancing chemotherapeutic efficiency, and they include polymeric micelles, which enable targeting of multiple drugs to solid tumors, including imaging and therapeutic agents. This allows concurrent diagnosis, targeting strategy validation, and efficacy assessment. We used polymeric micelles containing the T1-weighted magnetic resonance imaging contrast agent gadolinium-diethylenetriaminpentaacetic acid (Gd-DTPA) and the parent complex of the anticancer drug oxaliplatin [(1,2-diaminocyclohexane)platinum(II) (DACHPt)] for simultaneous imaging and therapy in an orthotopic rat model of HCC. The Gd-DTPA/DACHPt-loaded micelles were injected into the hepatic artery, and magnetic resonance imaging performance and antitumor activity against HCC, as well as adverse drug reactions were assessed. After a single administration, the micelles achieved strong and specific tumor contrast enhancement, induced high levels of tumor apoptosis, and significantly suppressed tumor size and growth. Moreover, the micelles did not induce severe adverse reactions and significantly improved survival outcomes in comparison to oxaliplatin or saline controls. Our results suggest that Gd-DTPA/DACHPt-loaded micelles are a promising approach for effective diagnosis and treatment of advanced HCC. PMID:26203241

  18. Targeted Therapy for Hepatocellular Carcinoma.

    PubMed

    Ohri, Nitin; Kaubisch, Andreas; Garg, Madhur; Guha, Chandan

    2016-10-01

    Hepatocellular cancer (HCC) is a leading cause of cancer death worldwide, and most patients who are diagnosed with HCC are ineligible for curative local therapy. The targeted agent sorafenib provides modest survival benefits in the setting of advanced disease. Novel systemic treatment options for HCC are sorely needed. In this review, we identify and categorize the drugs and targets that are in various phases of testing for use against HCC. We also focus on the potential for combining these agents with radiotherapy. This would help identify directions for future study that are likely to yield positive findings and improve outcomes for patients with HCC. PMID:27619254

  19. Hepatocellular carcinoma in glycogen storage disease type IV

    PubMed Central

    de Moor, R A; Schweizer, J; van Hoek, B; Wasser, M; Vink, R; Maaswinkel-Mooy, P

    2000-01-01

    A 13 year old patient with juvenile type IV glycogen storage disease died of the complications of hepatocellular carcinoma. To our knowledge this is the first reported case of hepatocellular carcinoma in association with type IV glycogen storage disease.

 PMID:10833181

  20. 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

  1. 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

  2. Aflatoxins as a cause of hepatocellular carcinoma.

    PubMed

    Kew, Michael C

    2013-09-01

    Aflatoxins, metabolites of the fungi Aspergillus flavus and Aspergillus parasiticus, are frequent contaminants of a number of staple foods, particularly maize and ground nuts, in subsistence farming communities in tropical and sub-tropical climates in sub-Saharan Africa, Eastern Asia and parts of South America. Contamination of foods occurs during growth and as a result of storage in deficient or inappropriate facilities. These toxins pose serious public health hazards, including the causation of hepatocellular carcinoma by aflatoxin B1. Exposure begins in utero and is life-long. The innocuous parent molecule of the fungus is converted by members of the cytochrome p450 family into mutagenic and carcinogenic intermediates. Aflatoxin-B1 is converted into aflatoxin B1-8,9 exo-epoxide, which is in turn converted into 8,9-dihydroxy-8-(N7) guanyl-9-hydroxy aflatoxin B1 adduct. This adduct is metabolized into aflatoxin B1 formaminopyrimidine adduct. These adducts are mutagenic and carcinogenic. In addition, an arginine to serine mutation at codon 249 of the p53 tumor suppressor gene is produced, abrogating the function of the tumor suppressor gene, and contributing to hepatocarcinogenesis. Aflatoxin B1 acts synergistically with hepatitis B virus in causing hepatocellular carcinoma. A number of interactions between the two carcinogens may be responsible for this action, including integration of hepatitis B virus x gene and its consequences, as well as interference with nucleotide excision repair, activation of p21waf1/cip1, generation of DNA mutations, and altered methylation of genes. But much remains to be learnt about the precise pathogenetic mechanisms responsible for aflatoxin B1-induced hepatocellular carcinoma as well as the interaction between the toxin and hepatitis B virus in causing the tumor.

  3. Hepatocellular carcinoma and African iron overload.

    PubMed Central

    Gangaidzo, I T; Gordeuk, V R

    1995-01-01

    Both hepatocellular carcinoma (HCC) and iron overload are important health problems in Africa. Chronic hepatitis B virus (HBV) infection is recognised as a major risk factor for HCC, but iron overload in Africans has not been considered in pathogenesis. Up to half the patients with HCC in Africa do not have any recognised risk factors such as preceding chronic HBV infection, and other risk factors remain unidentified. HCC is an important complication of HLA-linked haemochromatosis, an iron loading disorder found in Europeans. It is proposed that African iron overload might also be a risk factor for HCC. PMID:8549953

  4. 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

  5. Hepatitis C virus replication in hepatocellular carcinoma.

    PubMed Central

    Niu, J; Kumar, U; Monjardino, J; Goldin, R; Rosin, D; Thomas, H C

    1995-01-01

    Hepatitis C virus (HCV) replication is reported in both tumour and non-tumour tissue in a case of hepatocellular carcinoma. Viral replication was established by showing the presence of minus strand HCV RNA by PCR amplification, after excluding residual reverse transcriptase activity of Taq polymerase. No minus strand was found in serum derived virion RNA. PCR amplified products from both tumour and non-tumour parenchyma were sequenced in the 5' non-coding region and shown to be identical. The genotype of this Indonesian patient was found to be 1b (or II), the most prevalent type in the Far East. Images PMID:7490330

  6. 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

  7. 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

  8. 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

  9. 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

  10. Biofunctionalized magnetic nanospheres-based cell sorting strategy for efficient isolation, detection and subtype analyses of heterogeneous circulating hepatocellular carcinoma cells.

    PubMed

    Chen, Lan; Wu, Ling-Ling; Zhang, Zhi-Ling; Hu, Jiao; Tang, Man; Qi, Chu-Bo; Li, Na; Pang, Dai-Wen

    2016-11-15

    Hepatocellular carcinoma (HCC) is an awful threat to human health. Early-stage HCC may be detected by isolation of circulating tumor cells (CTCs) from peripheral blood samples, which is beneficial to the diagnosis and therapy. However, the extreme rarity and high heterogeneity of HCC CTCs have been restricting the relevant research. To achieve an efficient isolation, reliable detection and subtype analyses of heterogeneous HCC CTCs, herein, we present a cell sorting strategy based on anti-CD45 antibody-modified magnetic nanospheres. By this strategy, leukocyte depletion efficiency was up to 99.9% within 30min in mimic clinical samples, and the purity of the spiked HCC cells was improved 265-317-fold. Besides, the isolated HCC cells remained viable at 92.3% and could be directly recultured. Moreover, coupling the convenient, fast and effective cell sorting strategy with specific ICC identification via biomarkers AFP and GPC3, HCC CTCs were detectable in peripheral blood samples, showing the potential for HCC CTC detection in clinic. Notably, this immunomagnetic cell sorting strategy enabled isolating more heterogeneous HCC cells compared with the established EpCAM-based methods, and further achieved characterization of three different CTC subtypes from one clinical HCC blood sample, which may assist clinical HCC analyses such as prognosis or personalized treatment. PMID:27240010

  11. Hepatic miR-126 is a potential plasma biomarker for detection of hepatitis B virus infected hepatocellular carcinoma.

    PubMed

    Ghosh, Amit; Ghosh, Alip; Datta, Somenath; Dasgupta, Debanjali; Das, Soumyajit; Ray, Sukanta; Gupta, Subash; Datta, Simanti; Chowdhury, Abhijit; Chatterjee, Raghunath; Mohapatra, Saroj Kant; Banerjee, Soma

    2016-06-01

    Controversies about the origin of circulating miRNAs have encouraged us to identify organ specific circulating miRNAs as disease biomarkers. To identify liver-specific miRNAs for hepatocellular carcinoma (HCC), global expression profiling of miRNAs in liver tissue of HBV-HCC and HBV-control with no or mild fibrosis was evaluated. A total of 40 differentially expressed miRNAs were identified in HCC. Among ten highly altered miRNAs, six miRNAs were successfully validated in tissues, whereas only two miRNAs, miR-126 and miR-142-3p showed increased expression in plasma of HBV-HCC compared to HBV-non-HCC patients. Subsequently, ROC curve analysis revealed that neither miR-126 nor miR-142-3p performed better than AFP in discriminating HCC from non-HCC while combination of each with AFP showed significantly higher efficiency rather than AFP alone (AUC: 0.922, 0.908 vs. 0.88; sensitivity: 0.84, 0.86 vs. 0.82 and specificity: 0.92, 0.94 vs. 0.86 respectively). Interestingly, triple combination of markers (miR-126 + miR-142-3p + AFP) showed no additive effect on efficiency (AUC: 0.925) over the dual combination. Again, the expression of only miR-126 was noticed significantly higher in HBV-HCC patients with low-AFP [<250 ng/ml] compared to either non-HCC or liver cirrhosis (AUC: 0.77, 0.64, respectively). Furthermore, no alteration in expression of mir-126 in HCV-HCC or non-viral-HCC revealed that miR-126 + AFP might be specific to HBV-HCC. To understand the physiological role of these two miRNAs in hepato-carcinogenesis, target genes related to cancer pathways (APAF1, APC2, CDKN2A, IRS1, CRKL, LIFR, EGR2) were verified. Thus, combination of circulating miR-126 + AFP is a promising noninvasive diagnostic biomarker for HBV-HCC and may be useful in the management of HCC patients. PMID:26756996

  12. 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

  13. 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

  14. Hepatocellular carcinoma: epidemiology, biology, diagnosis, and therapies.

    PubMed

    Gomes, Marcos António; Priolli, Denise Gonçalves; Tralhão, José Guilherme; Botelho, Maria Filomena

    2013-01-01

    Hepatocellular carcinoma is the fifth most common cancer in men and the seventh in women, as is diagnosed in more than half a million individuals worldwide every year. In Portugal, its incidence and mortality rates are low compared to other types of cancers. In Brazil, in the city of São Paulo, according to data released by the Brazilian Unified Health System (Sistema Único de Saúde - SUS), the incidence of primary liver cancer was 2.07/100,000 inhabitants. Although the vast majority of cases (85%) mainly affect developing countries, especially where infection by hepatitis B virus (HBV) is endemic, the incidence in developed countries is increasing. This pathology is associated with several risk factors, not only environmental but also genetic, generating an increasing interest in attaining a better understanding of this disease, which is still associated with very late diagnosis and poor prognosis. Of the available treatments, few patients benefit from their scanty advantages, increasingly stimulating research of new forms of treatment against this disease. This review aimed to briefly but fully identify risk factors, molecular and biochemical pathways, pathophysiology, diagnosis, and possible clinical approaches of hepatocellular carcinoma.

  15. 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

  16. Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is a tissue biomarker for detection of early Hepatocellular carcinoma in patients with cirrhosis

    PubMed Central

    2012-01-01

    Background Hepatocellular carcinoma (HCC) is one of the most common malignant tumors occurring mainly in patients with chronic liver disease. Detection of early HCC is critically important for treatment of these patients. Methods We employed a proteomic profiling approach to identify potential biomarker for early HCC detection. Based on Barcelona Clinic Liver Cancer (BCLC) staging classification, 15 early HCC and 25 late HCC tissue samples from post-operative HCC patients and their clinicopathological data were used for the discovery of biomarkers specific for the detection of early HCC. Differential proteins among cirrhotic, early, and late tissue samples were separated by two-dimensional gel electrophoresis (2-DE) and subsequently identified by mass spectrometry (MS). Receiver operating characteristic (ROC) curves analysis were performed to find potential biomarkers associated with early HCC. Diagnosis performance of the biomarker was obtained from diagnosis test. Results Protein spot SSP2215 was found to be significantly overexpressed in HCC, particularly in early HCC, and identified as heterogeneous nuclear ribonucleoprotein K (hnRNP K) by tandem mass spectrometry (MALDI TOF/TOF). The overexpression in HCC was subsequently validated by western blot and immunohistochemistry. ROC curve analysis showed that hnRNP K intensity could detect early HCC at 66.67 % sensitivity and 84 % specificity, which was superior to serum α-fetoprotein (AFP) in detection of early HCC. Furthermore, the diagnosis test demonstrated, when combined with hnRNP K and serum AFP as biomarker panel to detect early HCC at different cut-off value, the sensitivity and specificity could be enhanced to 93.33 % and 96 %, respectively. Conclusions hnRNP K is a potential tissue biomarker, either alone or in combination with serum AFP, for detection of early HCC. High expression of hnRNP K could be helpful to discriminate early HCC from a nonmalignant nodule, especially for patients with liver

  17. Comparison of the Number of Image Acquisitions and Procedural Time Required for Transarterial Chemoembolization of Hepatocellular Carcinoma with and without Tumor-Feeder Detection Software.

    PubMed

    Iwazawa, Jin; Ohue, Shoichi; Hashimoto, Naoko; Mitani, Takashi

    2013-01-01

    Purpose. To compare the number of image acquisitions and procedural time required for transarterial chemoembolization (TACE) with and without tumor-feeder detection software in cases of hepatocellular carcinoma (HCC). Materials and Methods. We retrospectively reviewed 50 cases involving software-assisted TACE (September 2011-February 2013) and 84 cases involving TACE without software assistance (January 2010-August 2011). We compared the number of image acquisitions, the overall procedural time, and the therapeutic efficacy in both groups. Results. Angiography acquisition per session reduced from 6.6 times to 4.6 times with software assistance (P < 0.001). Total image acquisition significantly decreased from 10.4 times to 8.7 times with software usage (P = 0.004). The mean procedural time required for a single session with software-assisted TACE (103 min) was significantly lower than that for a session without software (116 min, P = 0.021). For TACE with and without software usage, the complete (68% versus 63%, resp.) and objective (78% versus 80%, resp.) response rates did not differ significantly. Conclusion. In comparison with software-unassisted TACE, automated feeder-vessel detection software-assisted TACE for HCC involved fewer image acquisitions and could be completed faster while maintaining a comparable treatment response.

  18. 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

  19. Latest developments in targeted therapy for hepatocellular carcinoma.

    PubMed

    Montella, Liliana; Addeo, Raffaele; Caraglia, Michele; Del Prete, Salvatore

    2010-10-01

    The advent of sorafenib can be considered as a turning point in the history of advanced hepatocellular carcinoma. After unfortunate attempts at using chemotherapy, drugs targeting key pathways have generated new perspectives in this field. This means not only killing both tumor cells and cirrhotic fragile tissue, but killing them selectively; more than was previously possible. This seems like the Copernican Revolution. However, hepatocellular carcinoma is pathogenetically complicated, resulting from the number of mutations. Until now, there has not been a single drug able to block and reverse abnormally activated signaling in hepatocellular carcinoma cells. In this article, we describe the most promising targeted drugs being studied in hepatocellular carcinoma and depict the possible future scenarios. PMID:20942634

  20. Efficacy of PIVKA-II in prediction and early detection of hepatocellular carcinoma: a nested case-control study in Chinese patients

    PubMed Central

    Yu, Rentao; Xiang, Xiaomei; Tan, Zhaoxia; Zhou, Yi; Wang, Haoliang; Deng, Guohong

    2016-01-01

    Prognosis of hepatocellular carcinoma (HCC) remains unsatisfying due to a lack of early detecting methods. Protein Induced by Vitamin K Absence or Antagonist-II (PIVKA-II) has been proved to be an efficient biomarker for HCC. However, the predicting efficacy of PIVKA-II has barely been reported. In the Hepatitis Biobank of Southwest Hospital (HBS) cohort at Southwest Hospital, we did a two-stage nested case-control study. Totally, 45 HCC cases versus 138 matched controls were enrolled to compare levels of α-fetoprotein (AFP) and PIVKA-II in sequential sera at −12, −9, −6, −3 and 0 months before imaging diagnosis. Levels of both PIVKA-II and AFP in HCC cases elevated significantly at all time points compared with controls. In validation stage, the sensitivity and specificity of PIVKA-II at baseline were 58.3% and 92.6%, and AFP were 75.0% and 91.7%. AFP-/PIVKA-II+ patients covered 27.4%, 29.4% and 19.6% at M-12, M-6 and M-0, respectively, while AFP+/PIVKA-II- patients covered 25.5%, 19.6% and 17.7%, respectively. Both PIVKA-II and AFP have the potential for HCC prediction, while PIVKA-II has a better positive rate than AFP before diagnosis. PMID:27731353

  1. Epidemiology and carcinogenesis of hepatocellular carcinoma

    PubMed Central

    Leong, Trishe Y.-M.

    2005-01-01

    The incidence of hepatocellular carcinoma (HCC) shows marked variation worldwide but the magnitude of this tumor is reflected by the occurrence of at least 1 million new cases annually and the uniformly dismal outlook with median survivals of <25 months after resection and <6 months with symptomatic treatment. The strikingly uneven distribution of this tumor parallels the prevalence of hepatitis B infection with rising incidence in western countries attributed to hepatitis C infection. Chronic hepatitis and cirrhosis constitute the major preneoplastic conditions in the majority of HCCs and may be related to other etiologic agents such as environmental chemical carcinogens including nitrites, hydrocarbons, solvents, organochlorine pesticides, and the chemicals in processed foods, cleaning agents, cosmetics and pharmaceuticals, as well as plant toxins such as anatoxins produced by fungi that cause spoilage of grain and food in the tropics. Genetic diseases such as genetic hematochromatosis, Wilson's disease, α-1-antitrypsin deficiency, and the inborn errors of metabolism including hereditary tyrosinemia and hepatic porphyria, are known to be associated with HCC. Numerous genetic alterations and the modulation of DNA methylation are recognized in HCC and it is likely that these genetic and epigenetic changes combine with factors involved in chronic hepatocyte destruction and regeneration to result in neoplastic growth and multiple molecular pathways may be involved in the production of subsets of hepatocellular tumors. PMID:18333156

  2. Detection of Corona Enhancement of Hypervascular Hepatocellular Carcinoma by C-Arm Dual-Phase Cone-Beam CT During Hepatic Arteriography

    SciTech Connect

    Miyayama, Shiro Yamashiro, Masashi; Okuda, Miho; Yoshie, Yuichi; Nakashima, Yoshiko; Ikeno, Hiroshi; Orito, Nobuaki; Matsui, Osamu

    2011-02-15

    The purpose of this study was to evaluate the detectability of corona enhancement around the hypervascular hepatocellular carcinoma (HCC) by dual-phase cone-beam computed tomography during hepatic arteriography (CBCTHA). Dual-phase CBCTHA was performed for 71 HCC lesions (mean {+-} SD 1.7 {+-} 0.9 cm), including seven presenting a nodule-in-nodule appearance and nine hypervascular pseudolesions. The first scan was performed during injection of 30-40 ml half-diluted contrast material at a rate of 1.5-2 ml/s through the hepatic artery. Scanning was initiated 7 s after the beginning of contrast material injection. The second scan was started 30 s after the end of the first scan. Detectability of corona enhancement on second-phase CBCTHA was evaluated. Thickness of corona enhancement was also analyzed as thin ({<=}2 mm) or thick (>2 mm). Corona enhancement was detected in 63 (88.7%) of 71 tumors (1.8 {+-} 0.9 cm), but it was not detected in eight tumors (1.0 {+-} 0.2 cm). Thin corona enhancement was seen in 18 tumors (1.2 {+-} 0.5 cm), and thick corona enhancement was seen in 45 tumors (2.0 {+-} 0.9 cm). There was a significant difference in tumor diameter between tumors with and those without corona enhancement (P = 0.0157) and between thin and thick corona enhancement (P = 0.001). In all seven early-stage tumors, corona enhancement was demonstrated around the hypervascular focus within the hypovascular tumor portion. None of the nine pseudolesions showed any corona enhancement. Dual-phase CBCTHA depicted corona enhancement in 88.7% of hypervascular HCC lesions. This technique may improve the diagnostic accuracy of HCC.

  3. Hepatocellular carcinoma metastatic to the mandible.

    PubMed

    Miller, Mia E; McCall, Andrew A; Juillard, Guy F; Nadelman, Celina M; Wang, Marilene B; Nabili, Vishad

    2013-02-01

    We describe the case of a 55-year-old man with known multifocal hepatocellular carcinoma (HCC) who presented with a painful mandibular mass. Fine-needle aspiration cytology of the mass revealed the presence of bile canaliculi and bile formation, an extremely rare finding. Findings on immunoperoxidase staining of the aspirate were consistent with an HCC. Since the patient was known to have multiorgan metastatic disease, he was administered palliative radiation therapy to the mandibular metastasis for pain control, which was achieved. One year after presentation, the patient died as a result of disease progression. HCC rarely metastasizes to the mandible, as only about 70 such cases have been reported in the literature. We discuss the histopathologic appearance of HCC metastatic to the mandible, the radiologic findings, and the established treatment modalities.

  4. 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

  5. Metastatic Hepatocellular Carcinoma Responsive to Pembrolizumab.

    PubMed

    Truong, Phu; Rahal, Ahmad; Kallail, K James

    2016-06-04

    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.

  6. Hepatocellular carcinoma from an immunological perspective

    PubMed Central

    Greten, Tim F.; Duffy, Austin G.; Korangy, Firouzeh

    2013-01-01

    Hepatocellular carcinoma is the 3rd most common cancer worldwide. It is an inflammation-associated cancer. Multiple investigators have demonstrated that analysis of the tumor microenvironment may be used to predict patient outcome indicating the importance of local immune responses in this disease. In contrast to other types of cancer, in which surgery, radiation and systemic cytotoxic chemotherapies dominate the treatment options, in HCC loco-regional treatments are widely applied. Such treatments induce rapid tumor cell death and anti-tumor immune responses, which may favor or impair patients’ outcome. Recent immunotherapy studies demonstrating promising results include trials evaluating intra-tumoral injection of an oncolytic virus expressing GM-CSF, glypican-3 targeting treatments and anti-CTLA4 treatment. While some of these novel approaches may provide benefit as single agents, there is a clear opportunity in HCC to evaluate these in combination with the standard modalities to more effectively harness the immune response. PMID:24030702

  7. 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

  8. Hepatocellular Carcinoma-Cause, Treatment and Metastasis

    PubMed Central

    Tang, Zhao-You

    2001-01-01

    In the recent decades, the incidence of hepatocellular carcinoma (HCC) has been found to be increasing in males in some countries. In China, HCC ranked second of cancer mortality since 1990s. Hepatitis B and C viruses (HBV and HCV) and dietary aflatoxin intake remain the major causative factors of HCC. Surgery plays a major role in the treatment of HCC, particularly for small HCC. Down-staging unresectable huge HCC to smaller HCC and followed by resection will probably be a new approach for further study. Liver transplantation is indicated for small HCC, however, some issues remain to be solved. Different modes of “regional cancer therapy for HCC” have been tried. Systemic chemotherapy has been disappointing in the past but the future can be promising. Biotherapy, such as cytokines, differentiation inducers, anti-angiogenic agents, gene therapy and tumor vaccine will probably play a role, particularly in the prevention of tumor recurrence. HCC invasiveness is currently the major target of study. Tremendous works have been done at the molecular level, which will provide clues for biomarker of HCC progression as well as targets for intervention. Abbreviation: HCC-hepatocellular carcinoma, HBV-hepatitis B virus, HCV-hepatitis C virus, HGV-hepatitis G virus, TTV-transfusion transmitted virus, AFB1-aflatoxin B1, IFN-interferon, OLT-orthotopic liver transplantation, PH-partial hepatectomy, RCT-randomized controlled trial, TACE-transcatheter arterial chemoembolization, PEI-percutaneous ethanol injection, PMCT-percutaneous microwave coagulation therapy, RF-radiofrequency, AFP-alpha fetoprotein, VEGF-vascular endothelial growth factor. PMID:11819809

  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. Epidemiology, risk factors, and natural history of hepatocellular carcinoma.

    PubMed

    Montalto, Giuseppe; Cervello, Melchiorre; Giannitrapani, Lydia; Dantona, Fabio; Terranova, Angela; Castagnetta, Luigi A M

    2002-06-01

    The incidence of hepatocellular carcinoma is increasing in many countries. The estimated number of new cases annually is over 500,000, and the yearly incidence comprises between 2.5 and 7% of patients with liver cirrhosis. The incidence varies between different geographic areas, being higher in developing areas; males are predominantly affected, with a 2:3 male/female ratio. The heterogeneous geographic distribution reflects the epidemiologic impact of the main etiologic factors and environmental risk, which are the hepatitis B (HBV) and hepatitis C (HCV) viruses. The percentage of cases of hepatocellular carcinoma attributable to HBV worldwide is 52.3% and is higher in Asia where the seroprevalence of HBsAg in the population is high. However, the vaccination campaign against this virus in some eastern countries has tended to lower the incidence of new cases of hepatocellular carcinoma. The percentage of cases of hepatocellular carcinoma attributable to HCV is 25%, and it is more prevalent in Japan, Spain, and Italy where the association between hepatocellular carcinoma and antibodies to HCV ranges between 50 and 70%. In most cases hepatocellular carcinoma develops in cirrhotic livers, where the persistent proliferation of liver cells represents the key factor of progression to hepatocellular carcinoma independent of the etiology. Another minor risk factor is aflatoxin B1 consumption, which is responsible for most cases of hepatocellular carcinoma in Africa, where the consumption of contaminated foods is common. Other known risk factors are some hereditary diseases, such as hemochromatosis, porphyria cutanea tarda, hereditary tyrosinemia, and alpha1 anti-trypsin deficiency. The natural history of hepatocellular carcinoma is heterogeneous and is influenced by nodule dimension, the mono- or plurifocality of lesions at diagnosis, the growth rate of the tumor, and the stage of the underlying cirrhosis. Available data to date suggest that tumor growth in a cirrhotic

  11. Paraneoplastic alopecia associated with hepatocellular carcinoma in a cat.

    PubMed

    Marconato, Laura; Albanese, Francesco; Viacava, Paolo; Marchetti, Veronica; Abramo, Francesca

    2007-08-01

    A 15-year-old spayed female domestic shorthair cat presented with alopecia associated with hepatocellular carcinoma. Clinical signs, which had commenced 6 months previously, included loss of appetite, loss of weight, and depression. As reported by the owner, the cat developed alopecia a week before referral. The hair loss was localized to the ventral aspect of the thorax and abdomen, medial aspect of front and hind limbs, and ventral aspect of the tail, and was associated with histological features consistent with paraneoplastic alopecia. At necropsy, multiple hepatic nodules were observed, and subsequent histopathological investigation showed cords and sheets of hepatocyte-like neoplastic cells positive for the hepatocyte marker (Hep Par 1), thereby demonstrating the hepatocellular origin of the tumour, which was diagnosed as a hepatocellular carcinoma. This is the first report of feline paraneoplastic alopecia associated with hepatocellular carcinoma confirmed by the Hep Par 1 marker.

  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. 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

  14. 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

  15. 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

  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. Activins and activin antagonists in hepatocellular carcinoma

    PubMed Central

    Deli, Alev; Kreidl, Emanuel; Santifaller, Stefan; Trotter, Barbara; Seir, Katja; Berger, Walter; Schulte-Hermann, Rolf; Rodgarkia-Dara, Chantal; Grusch, Michael

    2008-01-01

    In many parts of the world hepatocellular carcinoma (HCC) is among the leading causes of cancer-related mortality but the underlying molecular pathology is still insufficiently understood. There is increasing evidence that activins, which are members of the transforming growth factor β (TGFβ) superfamily of growth and differentiation factors, could play important roles in liver carcinogenesis. Activins are disulphide-linked homo- or heterodimers formed from four different β subunits termed βA, βB, βC, and βE, respectively. Activin A, the dimer of two βA subunits, is critically involved in the regulation of cell growth, apoptosis, and tissue architecture in the liver, while the hepatic function of other activins is largely unexplored so far. Negative regulators of activin signals include antagonists in the extracellular space like the binding proteins follistatin and FLRG, and at the cell membrane antagonistic co-receptors like Cripto or BAMBI. Additionally, in the intracellular space inhibitory Smads can modulate and control activin activity. Accumulating data suggest that deregulation of activin signals contributes to pathologic conditions such as chronic inflammation, fibrosis and development of cancer. The current article reviews the alterations in components of the activin signaling pathway that have been observed in HCC and discusses their potential significance for liver tumorigenesis. PMID:18350601

  18. 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

  19. 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

  20. 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

  1. 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

  2. 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.

  3. 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

  4. Occult hepatitis B virus and hepatocellular carcinoma.

    PubMed

    Pollicino, Teresa; Saitta, Carlo

    2014-05-28

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

  5. 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

  6. 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

  7. 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

  8. 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.

  9. 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

  10. 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

  11. Advances in Management of Hepatocellular Carcinoma.

    PubMed

    Intaraprasong, Pongphob; Siramolpiwat, Sith; Vilaichone, Ratha-Korn

    2016-01-01

    Hepatocellular carcinoma (HCC) is the most frequent type of malignant liver tumor and a high impact health problem worldwide. The prevalence of HCC is particularly high in many Asian and African countries. Some HCC patients have no symptoms prior to diagnosis and many of them therefore present at late stage and have a grave prognosis. The well-established causes of HCC are chronic hepatitis B virus (HBV) or chronic hepatitis C virus (HCV) infection or alcoholic cirrhosis and nonalcoholic steatohepatitis. The Barcelona Clinic Liver Cancer (BCLC) Staging System remains the most widely used for HCC management guidelines. To date, the treatments for HCC are still very challenging for physicians due to limited resources in many parts of the world, but many options of management have been proposed, including hepatic resection, liver transplantation, ablative therapy, chemoembolization, sora nib and best supportive care. This review article describes the current evidence-based management of HCC with focus on early to advance stages that impact on patient overall survival. PMID:27644603

  12. Mechanisms of HBV-induced hepatocellular carcinoma.

    PubMed

    Levrero, Massimo; Zucman-Rossi, Jessica

    2016-04-01

    Hepatitis B virus (HBV) contributes to hepatocellular carcinoma (HCC) development through direct and indirect mechanisms. HBV DNA integration into the host genome occurs at early steps of clonal tumor expansion and induces both genomic instability and direct insertional mutagenesis of diverse cancer-related genes. Prolonged expression of the viral regulatory protein HBx and/or altered versions of the preS/S envelope proteins dysregulates cell transcription and proliferation control and sensitizes liver cells to carcinogenic factors. Accumulation of preS1 large envelope proteins and/or preS2/S mutant proteins activates the unfold proteins response, that can contribute to hepatocyte transformation. Epigenetic changes targeting the expression of tumor suppressor genes occur early in the development of HCC. A major role is played by the HBV protein, HBx, which is recruited on cellular chromatin and modulates chromatin dynamics at specific gene loci. Compared with tumors associated with other risk factors, HBV-related tumors have a higher rate of chromosomal alterations, p53 inactivation by mutations and overexpression of fetal liver/hepatic progenitor cells genes. The WNT/β-catenin pathway is also often activated but HBV-related tumors display a low rate of activating β-catenin mutations. HBV-related HCCs may arise on non-cirrhotic livers, further supporting the notion that HBV plays a direct role in liver transformation by triggering both common and etiology specific oncogenic pathways in addition to stimulating the host immune response and driving liver chronic necro-inflammation.

  13. Cellular reprogramming and hepatocellular carcinoma development

    PubMed Central

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

    2013-01-01

    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

  14. Potentiality of immunotherapy against hepatocellular carcinoma.

    PubMed

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

    2015-09-28

    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 new-found 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.

  15. Bone marrow metastasis presenting as bicytopenia originating from hepatocellular carcinoma

    PubMed Central

    Hong, Young Mi; Yoon, Ki Tae; Cho, Mong; Kang, Dae Hwan; Kim, Hyung Wook; Choi, Cheol Woong; Park, Su Bum; Heo, Jeong; Woo, Hyun Young; Lim, Won; Bakhtiar UI Islam, SM

    2016-01-01

    The bone is a common site for metastasis in hepatocellular carcinoma (HCC). However, bone marrow metastasis from HCC is rarely reported, and its frequency is unclear. Here we report a rare case of bone marrow metastasis that presented as bicytopenia originating from HCC without bone metastasis. A 58-year-old man was admitted for investigation of a liver mass with extensive lymph node enlargement that was detected when examining his general weakness and weight loss. Laboratory findings revealed anemia, thrombocytopenia, mild elevated liver enzymes, normal prothrombin time percentage and high levels of tumor markers (α-fetoprotein and des-γ-carboxyprothrombin). Abdominal computed tomography showed multiple enhanced masses in the liver and multiple enlarged lymph nodes in the abdomen. A bone marrow biopsy revealed only a few normal hematopoietic cells and abundant tumor cells. Despite its rarity, bone marrow metastasis should always be suspected in HCC patients even if accompanied by cirrhosis. PMID:27184470

  16. Modeling Gene Regulation in Liver Hepatocellular Carcinoma with Random Forests

    PubMed Central

    2016-01-01

    Liver hepatocellular carcinoma (HCC) remains a leading cause of cancer-related death. Poor understanding of the mechanisms underlying HCC prevents early detection and leads to high mortality. We developed a random forest model that incorporates copy-number variation, DNA methylation, transcription factor, and microRNA binding information as features to predict gene expression in HCC. Our model achieved a highly significant correlation between predicted and measured expression of held-out genes. Furthermore, we identified potential regulators of gene expression in HCC. Many of these regulators have been previously found to be associated with cancer and are differentially expressed in HCC. We also evaluated our predicted target sets for these regulators by making comparison with experimental results. Lastly, we found that the transcription factor E2F6, one of the candidate regulators inferred by our model, is predictive of survival rate in HCC. Results of this study will provide directions for future prospective studies in HCC.

  17. Immunological Studies in Ugandan Patients with Hepatocellular Carcinoma

    PubMed Central

    Primack, Aron; Vogel, Charles L.; Barker, Lewellys F.

    1973-01-01

    Immunological studies were performed on Ugandan patients with hepatocellular carcinoma to test the hypothesis that the high rate of persistence of hepatitis-associated antigen in these patients is the result of defects in host immune response. The responses to 1-chloro-2,4-dinitrobenzene sensitization and to a battery of recall skin test antigens were normal, as was the humoral antibody response to tularaemia antigen. Neither hypogammaglobulinaemia nor specific immunoglobulin deficiencies were found. Thus it appears unlikely that generalized defects in host immune responses can account for the high incidence of persistent hepatitis B virus infection found in Ugandan patients with hepatocellular carcinoma. PMID:4345903

  18. 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

  19. Epigenetic inactivation of SLIT2 in human hepatocellular carcinomas.

    PubMed

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

    2009-01-30

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

  20. Specific diagnosis of hepatocellular carcinoma by delayed hepatobiliary imaging

    SciTech Connect

    Hasegawa, Y.; Nakano, S.; Ibuka, K.; Hashizume, T.; Noguchi, A.; Sasaki, Y.; Imaoka, S.; Fujita, M.; Kawamoto, S.; Kasugai, H.

    1986-01-15

    For assessment of the value of delayed hepatobiliary imaging with technetium 99m (/sup 99m/Tc)-(Sn)-N-pyridoxyl-5-methyltryptophan (/sup 99m/Tc-PMT) for specific diagnosis of hepatocellular carcinoma, 88 patients with various malignant and benign liver diseases (49 with hepatocellular carcinoma, 4 with cholangiocellular carcinoma, 10 with metastatic liver carcinoma, 2 with liver cysts, 2 with liver hemangioma, 1 with liver abscess, 2 with intrahepatic lithiasis, 12 with liver cirrhosis, and 6 with chronic hepatitis) were studied. In 20 (41%) of the 49 patients with hepatocellular carcinoma, greater uptake of /sup 99m/Tc-PMT by the tumor than by the surrounding liver tissue was seen in delayed hepatobiliary images, whereas in eight patients (16%), equilibrated uptake was seen. No increased uptake of the radioisotope by hepatic lesions was seen in 21 patients with localized liver diseases other than hepatoma. Moreover, in 18 patients with diffuse liver diseases, no focal accumulation of the radioisotope was seen in delayed /sup 99m/Tc-PMT images. In addition, of 28 patients with hepatocellular carcinoma in whom the serum alpha-fetoprotein level showed little or no increase, 12 showed increased uptake of /sup 99m/Tc-PMT by the tumor. In assessing delayed /sup 99m/Tc-PMT images, however, it was necessary to consider following complications: accumulation of tracer in obstructed and dilated biliary trees; retention of radioactivity in nonneoplastic liver tissues; difficulties in evaluating /sup 99m/Tc-PMT uptake by small hepatic tumors; overlapping of radioactivity in the gut and gallbladder in delayed /sup 99m/Tc-PMT images of tumors. This study indicates that delayed /sup 99m/Tc-PMT images can be useful in the diagnosis of hepatocellular carcinoma.

  1. 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

  2. Metabolic syndrome and hepatocellular carcinoma risk

    PubMed Central

    Turati, F; Talamini, R; Pelucchi, C; Polesel, J; Franceschi, S; Crispo, A; Izzo, F; La Vecchia, C; Boffetta, P; Montella, M

    2013-01-01

    Background: Hepatocellular carcinoma (HCC) has been associated to diabetes and obesity, but a possible association with the metabolic syndrome (MetS) and its potential interaction with hepatitis is open to discussion. Methods: We analysed data from an Italian case–control study, including 185 HCC cases and 404 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed from unconditional logistic regression models. Results: Among the MetS components, diabetes and obesity (i.e, body mass index (BMI)⩾30 kg m−2) were positively associated to HCC risk, with ORs of 4.33 (95% CI, 1.89–9.86) and 1.97 (95% CI, 1.03–3.79), respectively. The ORs for the MetS were 4.06 (95% CI, 1.33–12.38) defining obesity as BMI⩾25, and 1.92 (95% CI, 0.38–9.76) defining it as BMI⩾30. The risk increased with the number of MetS components, up to an almost four-fold excess risk among subjects with ⩾2 MetS factors. Among subjects without chronic infection with hepatitis B and/or C, the OR for those with ⩾2 MetS components was over six-fold elevated. There was no consistent association in subjects with serological evidence of hepatitis B and/or C infection. Conclusion: This study found that the risk of HCC increases with the number of MetS components in subjects not chronically infected with hepatitis viruses. PMID:23169288

  3. 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

  4. 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.

  5. 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

  6. HLA expression in hepatocellular carcinoma cell lines.

    PubMed

    Wadee, A A; Paterson, A; Coplan, K A; Reddy, S G

    1994-08-01

    The present study undertook to investigate the biological significance of human leucocyte antigen expression in hepatocellular carcinoma and to elucidate the role of potential modulating agents on human leucocyte antigen expression. These studies used several hepatic tumour-derived cell lines as in vitro model systems. The cell lines included PLC/PRF/5 (Alexander cell line), Hep3B, HepG2, TONG PHC, HA22T/VGH, HA59T/VGH and Mahlavu. The cell lines K562 and Raji were used as negative and positive controls, respectively. K562, a B lymphoid-derived cell line, was shown to express negligible amounts of human leucocyte antigens, while Raji, an erythromyeloid-derived cell line, expressed both class I and class II human leucocyte antigens as well as their respective invariant chains, beta 2-microglobulin and Ii. Using an ELISA, experiments performed on these cell lines confirmed the natural expression of class I and class II antigens by the HA22T/VGH and HA59T/VGH cell lines, whereas PLC/PRF/5 displayed class II surface antigens only. The effects of modulating agents such as interferon-gamma sodium butyrate and clofazimine on human leucocyte antigen expression were investigated using the HA22T/VGH, HA59T/VGH and TONG PHC cell lines. These agents increased class II and class II human leucocyte antigen expression on HA22T/VGH and TONG PHC cells, but had no effect on the HA59T/VGH cell line. The results suggest a potential use for these agents as modulators of human leucocyte antigen expression by human heptocellular cell lines.

  7. Survival of Hepatocellular Carcinoma in Puerto Rico

    PubMed Central

    MARRERO, CARLOS ROMERO; ORTIZ, ANA P.; PÉREZ, CYNTHIA M.; PÉREZ, JAVIER; TORRES, ESTHER A.

    2013-01-01

    Background Blacks and Hispanics in the United States (US) have the lowest survival rates of hepatocellular carcinoma (HCC), mainly associated to the presence of advanced disease at diagnosis when intervention is least beneficial. This study compared the survival distribution and relative survival of HCC in Puerto Rico (PR) during 1988-1992 and 1998-2002. Methods All HCC cases in the PR Central Cancer Registry database for 1988-1992 (n=306) and 1998-2002 (n=333) were identified. Patient characteristics and clinical variables were compared between study periods. Survival by age at diagnosis, sex, tumor stage and treatment was estimated using the Kaplan-Meier method, and survival curves were compared using the Wilcoxon test. A Cox proportional hazards model was employed to assess the effect of period of diagnosis on survival, after adjusting for confounders. One- and three-year survival rates were also calculated. Results Patients diagnosed during 1998-2002 (median: 3.08 months, 95% CI: 2.30-4.16) had a longer observed survival than those diagnosed from 1988-1992 (median: 1.80 months, 95% CI: 1.44-2.52). A significant interaction was observed between the variables age and period of diagnosis, where only among persons aged ≥ 60 years the risk of HCC death was lower (sex-adjusted HR=O.72; 95%CI: 0.59-0.88) in patients diagnosed during 1998-2002 as compared to those diagnosed during 1988-1992. The overall one- and three-year relative survival during 1998-2002 was approximately 6% (22.4% vs.16.6%) and 2% higher (9.0% vs. 6.7%) respectively, as compared to 1988-1992. Conclusion We observed a temporal improvement in the survival of HCC in PR during the last decade. However, this survival is inferior to the one observed in the US population. Further studies are needed to identify factors that explain these disparities. PMID:19530551

  8. 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

  9. 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.

  10. 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

  11. 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

  12. 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

  13. Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease

    PubMed Central

    Ur Rahman, Zia; Hurairah, Abu

    2016-01-01

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

  14. 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.

  15. 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

  16. Abnormal plasma prothrombin (PIVKA-II) levels in hepatocellular carcinoma.

    PubMed

    Kawaguchi, Y

    1989-05-01

    The concentration of abnormal prothrombin, or the protein induced by vitamin K absence or antagonist II (PIVKA-II) in 102 patients with hepatic disorders was measured by an enzyme immunoassay method. The concentration of PIVKA-II in the plasma was elevated in 11 out of 18 patients with hepatocellular carcinoma and also in a patient with hepatoblastoma. There was no correlation between serum alpha-fetoprotein and plasma PIVKA-II levels. The PIVKA-II level was normal in 11 patients who had metastatic carcinoma or cholangiocellular carcinoma. Moreover, benign diseases of the liver did not cause an elevation in PIVKA-II. PIVKA-II might be an useful marker of hepatocellular carcinoma because, like alpha-fetoprotein, its level changes in close relation to the effects of treatment.

  17. Detection of Endogenous Iron Reduction during Hepatocarcinogenesis at Susceptibility-Weighted MR Imaging: Value for Characterization of Hepatocellular Carcinoma and Dysplastic Nodule in Cirrhotic Liver

    PubMed Central

    Li, Ruo-kun; Palmer, Suzanne L.; Zeng, Meng-su; Qiang, Jin-wei; Chen, Frank; Rao, Sheng-xiang; Chen, Ling-li; Dai, Yong-ming

    2015-01-01

    Objective To investigate the value of susceptibility-weighted imaging (SWI) for characterization of hepatocellular carcinoma (HCC) and dysplastic nodule (DN). Materials and Methods Sixty-eight cirrhotic patients with 89 hepatocellular nodules underwent SWI. The radiological features of hepatocellular nodules on SWI were classified into three types: type A (iso- or hypointensity, and background liver siderosis), type B (hyperintensity, and background liver siderosis), or type C (hyperintensity, and no background liver siderosis). Intranodular and background liver iron content was quantified and correlated with SWI pattern. Prussian blue staining was performed to quantify intranodular and background liver iron content. Results Type A pattern (n = 12) contained 11 (91.7%) DNs and 1 (8.3%) HCC, Type B pattern (n = 66) comprised 1 (1.5%) DN and 65 (98.5%) HCCs (including 12 DN-HCCs and 53 overt HCCs), and type C pattern (n = 11) was exclusively seen in HCCs. The iron scores of DN-HCCs and overt HCCs were significantly lower than those of background livers [(0.091±0.30) VS (2.18±0.87), P = 0.000; (0.11±0.41) VS (2.16±0.97), P = 0.000; respectively]. There was no significant difference between iron scores of DNs and those of background livers [(1.92±0.29) VS (2.17±039), P = 0.191]. For lesion-based and patient-based analysis of HCCs (DN-HCCs and overt HCCs), type B pattern showed a sensitivity, specificity, accuracy, positive predicative value (PPV), and negative predicative value (NPV) of 84.4% and 84.4%, 91.7% and 75%, 85.4% and 83.8%, 98.5% and 98.2%, 47.8% and 23.1%, respectively. Conclusion SWI can provide valuable information for characterization of HCC and DN based on endogenous iron reduction during hepatocarcinogenesis. PMID:26605946

  18. Translating the molecular diversity of hepatocellular carcinoma into clinical practice

    PubMed Central

    Schulze, Kornelius; Zucman-Rossi, Jessica

    2016-01-01

    abstract Deciphering genomic diversity could improve clinical care for patients with hepatocellular carcinoma. Recently, our study group identified 161 putative driver genes and 2 new mutational signatures, and demonstrated that 28% of patients harbor targetable alterations. This could be the first promising step in the development of genome-based clinical trials. PMID:27652310

  19. Translating the molecular diversity of hepatocellular carcinoma into clinical practice.

    PubMed

    Schulze, Kornelius; Zucman-Rossi, Jessica

    2016-07-01

    Deciphering genomic diversity could improve clinical care for patients with hepatocellular carcinoma. Recently, our study group identified 161 putative driver genes and 2 new mutational signatures, and demonstrated that 28% of patients harbor targetable alterations. This could be the first promising step in the development of genome-based clinical trials. PMID:27652310

  20. 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

  1. [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

  2. Hyponatremia in Hepatocellular Carcinoma Complicating with Cirrhosis

    PubMed Central

    Nishikawa, Hiroki; Kita, Ryuichi; Kimura, Toru; Ohara, Yoshiaki; Sakamoto, Azusa; Saito, Sumio; Nishijima, Norihiro; Nasu, Akihiro; Komekado, Hideyuki; Osaki, Yukio

    2015-01-01

    Background and aims: We aimed to investigate the effect of serum sodium level on survival in hepatocellular carcinoma (HCC) patients complicating with liver cirrhosis (LC). Methods: A total of 1170 HCC patients with LC were analysed. We classified these patients into three groups according to serum sodium level at HCC diagnosis: group A (n=96); serum sodium ≤135 mmol/L, group B (n=520); 135 mmol/L < serum sodium ≤140 mmol/L, group C (n=554); serum sodium >140 mmol/L. We compared the baseline characteristics and overall survival (OS) among these three groups. Furthermore, we examined the factors linked to OS using univariate and multivariate analyses. Results: In our results, decreased baseline serum sodium level was significantly associated with Child-Pugh classification and HCC stage along with several laboratory parameters in groups A, B and C. The median follow-up period was 1.1 years in group A, 2.4 years in group B and 3.3 years in group C. The 1-, 3- and 5-year cumulative OS rates in groups A, B and C were 64.8%, 46.9% and 25.7%, respectively, in group A, 85.5%, 60.5% and 41.1%, respectively, in group B and 90.7%, 66.6% and 48.2%, respectively, in group C (P<0.001). The multivariate analyses showed that Child-Pugh classification (P<0.001), HCC stage (P<0.001), serum sodium (P<0.001), aspartate aminotransferase ≥57 IU/L (P=0.002), alkaline phosphatase ≥348 IU/L (P<0.001), alpha-fetoprotein ≥29.2 ng/mL (P=0.019) and des-γ-carboxy prothrombin ≥55 mAU/mL (P<0.001) were significant independent predictors linked to OS. Conclusion: Lower serum sodium concentration is a useful predictor in HCC patients complicating with LC. PMID:25874013

  3. Fibrolamellar Hepatocellular Carcinoma: a Case Report with Distinct Radiological Features

    PubMed Central

    Haritanti, Afrodite; Economou, Ipoliti

    2010-01-01

    Introduction We report a rare case of a 23-year-old male who presented with abdominal discomfort for 15 days. An ultrasound was performed which showed a hypoechoic, heterogenous mass in the left lobe of the liver and distended portal vein, followed by further investigation with computed tomography (CT), MRI, and MRA. Serum alpha-fetoprotein was not elevated and hepatitis B antigen was negative. Methods CT scan depicted a nodular mass in left liver lobe with occlusion of both the central part and the two main branches of intrahepatic portal vein. Result Biopsy of the liver mass led to a diagnosis of fibrolamellar hepatocellular carcinoma. Conclusion Fibrolamellar carcinoma is an uncommon variant of hepatocellular carcinoma. The diagnosis is suggested by radiographic studies and is confirmed by histological examination. PMID:19960280

  4. Armc8 regulates the invasive ability of hepatocellular carcinoma through E-cadherin/catenin complex.

    PubMed

    Zhao, Yang; Peng, Songlin; Jia, Changjun; Xu, Feng; Xu, Yongqing; Dai, Chaoliu

    2016-08-01

    Armc8 (armadillo-repeat-containing protein 8) was proved to promote disruption of E-cadherin complex through regulating α-catenin degradation. In this study, we investigated Armc8 expression in hepatocellular carcinoma using immunohistochemistry (IHC). The positive rate of Armc8 expression in hepatocellular carcinoma was 53.9 % and higher than that in normal hepatic tissues (9.2 %) (p < 0.05). Clinicopathological analysis shows that Armc8 expression in hepatocellular carcinoma was significantly associated with larger tumor size (≥5 cm), multiple tumor numbers, higher pathological grade (media and poor), advanced TNM stages (II/III), and advanced BCLC stages (B/C). Western blot study also detected higher Armc8 expression in hepatocellular carcinoma cells including HepG2, HCC97L, and SMMC-7721 than in human hepatic cell Bel-7402. We further use specific small interfering RNAs (siRNAs) to knock down Armc8 expression in HepG2 cells and found that knockdown of Armc8 expression significantly inhibited the invasive ability of HepG2 cells. Downregulation of Armc8 expression significantly upregulated α-catenin, β-catenin, and E-cadherin expression in HepG2 cells. Immunofluorescent study shows that knockdown of Armc8 expression restored E-cadherin expression in membrane of HepG2 cells. These results indicate that Armc8 may be a potential cancer marker in hepatocellular carcinoma and may regulate cancer invasion through E-cadherin/catenin complex. PMID:26944057

  5. Hepatoid adenocarcinoma of the gallbladder: a mimicker of hepatocellular carcinoma.

    PubMed

    van den Bos, I C; Hussain, S M; Dwarkasing, R S; Stoop, H; Zondervan, P E; Krestin, G P; de Man, R A

    2007-12-01

    We present a case of a large gallbladder tumour in a patient with no known liver disease and elevated alpha-fetoprotein (AFP), in whom a differential diagnosis from hepatocellular carcinoma (HCC) in a non-cirrhotic liver was particularly difficult given the combination of the size of the tumour, solitary nature, elevated AFP and striking resemblance with HCC at histology. In presenting this patient, we would like to emphasise the role of MRI as a problem-solving tool for analysis of rare tumours of non-hepatocellular origin, including hepatoid adenocarcinoma of the gallbladder. PMID:18065642

  6. 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

  7. 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.

  8. Knockdown of Histone Methyltransferase hSETD1A Inhibits Progression, Migration, and Invasion in Human Hepatocellular Carcinoma.

    PubMed

    Cheng, Xin-Sheng; Sun, Shi-Bo; Zhong, Feng; He, Kun; Zhou, Jie

    2016-01-01

    Our aim was to study the expression of human SET domain containing protein 1A (hSETD1A) in hepatocellular carcinoma patients and its relationship with human hepatocellular carcinoma cell function. A total of 30 patients with hepatocellular carcinoma were enrolled in this study. The expression of hSETD1A was detected by real-time polymerase chain reaction (PCR) and Western blotting. The immortalized normal human liver cell line including SMMC-7721 was subjected to real-time PCR for hSETD1A mRNA. Furthermore, hSETD1A-small hairpin RNA (shRNA) was used to knock down hSETD1A expression in SMMC-7721 cells. Cell proliferation, cell apoptosis, and cell migration were determined by CCK8, flow cytometry, and Transwell assays. The positive expression rate level of hSETD1A mRNA and protein in liver carcinoma tissues was 73.33%. hSETD1A knockdown using a specific hSETD1A-shRNA inhibited cell proliferation and promoted cell apoptosis in SMMC-7721 cells. It was also found that downregulation of hSETD1A inhibited cell migration ability but did not affect cell invasion. In conclusion, the expression of hSETD1A occurs at a high rate in hepatocellular carcinoma patients. The expression state of hSETD1A may be a prognostic factor in hepatocellular carcinoma. PMID:27656834

  9. New Paradigm for Management of Hepatocellular Carcinoma by Imaging

    PubMed Central

    Joo, Ijin; Choi, Byung Ihn

    2012-01-01

    Based on recent clinical practice guidelines, imaging is largely replacing pathology as the preferred diagnostic method for determination of hepatocellular carcinoma (HCC). A variety of imaging modalities, including ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI), nuclear medicine, and angiography, are currently used to examine patients with chronic liver disease and suspected HCC. Advancements in imaging techniques such as perfusion imaging, diffusion imaging, and elastography along with the development of new contrast media will further improve the ability to detect and characterize HCC. Early diagnosis of HCC is essential for prompt treatment, which may in turn improve prognosis. Considering the process of hepatocarcinogenesis, it is important to evaluate sequential changes via imaging which would help to differentiate HCC from premalignant or benign lesions. Recent innovations including multiphasic examinations, high-resolution imaging, and the increased functional capabilities available with contrast-enhanced US, multidetector row CT, and MRI have raised the standards for HCC diagnosis. Although hemodynamic features of nodules in the cirrhotic liver remain the main diagnostic criterion, newly developed cellspecific contrast agents have shown great possibilities for improved HCC diagnosis and may overcome the diagnostic dilemma associated with small or borderline hepatocellular lesions. In the 20th century paradigm of medical imaging, radiological diagnosis was based on morphological characteristics, but in the 21st century, a paradigm shift to include biomedical, physiological, functional, and genetic imaging is needed. A multidisciplinary team approach is necessary to foster an integrated approach to HCC imaging. By developing and combining new imaging modalities, all phases of HCC patient care, including screening, diagnosis, treatment, and therapy, can be dramatically improved. PMID:24159577

  10. [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.

  11. 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

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

    PubMed

    Yin, Chang-Qing; Yuan, Chun-Hui; Qu, Zhen; Guan, Qing; Chen, Hao; Wang, Fu-Bing

    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

  13. 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

  14. 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

  15. 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

  16. Tissue- and Serum-Associated Biomarkers of Hepatocellular Carcinoma.

    PubMed

    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

  17. 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

  18. Detection of the hepatitis B virus X protein (HBx) antigen and anti-HBx antibodies in cases of human hepatocellular carcinoma.

    PubMed

    Hwang, Guang-Yuh; Lin, Chuang-Yu; Huang, Li-Mei; Wang, Yan-Hsiung; Wang, Jing-Chyi; Hsu, Ching-Ting; Yang, Sheng-Shun; Wu, Cheng-Chung

    2003-12-01

    Hepatitis B virus X protein (HBx) expressed in Escherichia coli DH5alpha by recombinant DNA technology was purified to homogeneity by use of glutathione-Sepharose beads. Immunological characterization of the recombinant HBx protein was performed. Specific binding between the anti-HBx monoclonal antibody and HBx protein showed the specificity of the recombinant HBx protein. The intact HBx protein of the factor Xa-digested glutathione S-transferase-HBx fusion protein was further purified and was used as an antigen for screening the titers of anti-HBx antibodies in sera. Titers of anti-HBx in sera from 20 patients with hepatocellular carcinoma (HCC), 20 patients with chronic hepatitis (CH), and 20 healthy individuals were evaluated by Western blotting and a quantitative enzyme-linked immunosorbent assay. The results indicated that 70% of sera from HCC patients and 5% of sera from CH patients contained antibodies with significant binding to the HBx protein. Western blotting of HBx protein in liver extracts from 20 HCC patients was also performed by using the anti-HBx monoclonal antibody. Results showed that 85% of HCC patients' liver tissues contained a specific HBx protein with the same molecular size as the purified intact HBx. Full correlation was found between anti-HBx antibody positivity in serum and HBx protein positivity in HCC tissues. The data demonstrated that the etiology of HCC is involved with hepatitis B virus (HBV) infection and that HBx in particular plays a role in the development of HBV-related HCC.

  19. Detection of small hepatocellular carcinoma: comparison of conventional gadolinium-enhanced MRI with gadolinium-enhanced MRI after the administration of ferucarbotran.

    PubMed

    Kim, Y K; Kim, C S; Han, Y M

    2009-06-01

    We compared the diagnostic efficacy of gadolinium (Gd)-enhanced MRI with that of Gd-enhanced MRI after administration of ferucarbotran for revealing small hypervascular hepatocellular carcinomas (HCCs). 24 patients with 34 HCCs (ranging in size from 0.6-2.0 cm) underwent Gd-enhanced three-dimensional dynamic MRI followed, after an interval of 5-11 days (mean, 7 days), by Gd-enhanced three-dimensional dynamic MRI after administration of ferucarbotran. The two Gd-enhanced arterial-phase MRI scans were compared quantitatively by measuring the tumour-liver contrast-to-noise ratio (CNR) and qualitatively by evaluating the tumour-liver contrast using matched-pairs analysis. The tumour-liver CNR with Gd-enhanced arterial-phase imaging after ferucarbotran (250.3 +/- 103.7) was higher than that with Gd-enhanced arterial-phase imaging (221.1 +/- 96.1) (p < 0.001). Matched-pairs analysis indicated that, for three lesions, the relative tumour-liver contrast was slightly better with Gd-enhanced arterial-phase imaging after ferucarbotran than with conventional Gd-enhanced arterial-phase imaging; however, in the case of the remaining 31 lesions, the two images were equivalent. We concluded that, although Gd-enhanced arterial-phase imaging after ferucarbotran results in better tumour-liver CNR than Gd-enhanced arterial-phase imaging, the ability of the two techniques to reveal small hypervascular HCCs is the same.

  20. The evolving epidemiology of hepatocellular carcinoma: a global perspective.

    PubMed

    Wallace, Michael C; Preen, David; Jeffrey, Gary P; Adams, Leon A

    2015-06-01

    Primary liver cancer, the majority of which are hepatocellular carcinomas, is now the second leading cause of cancer death worldwide. Hepatocellular carcinoma is a unique cancer that typically arises in the setting of chronic liver disease at a rate dependent upon the complex interplay between the host, disease and environmental factors. Infection with chronic hepatitis B or C virus is currently the dominant risk factor worldwide. However, changing lifestyle and environmental factors in western countries plus rising neonatal hepatitis B vaccination rates and decreasing exposure to dietary aflatoxins in developing countries are driving an evolution of the epidemiology of this cancer. An understanding of this change is crucial in combating the rising incidence currently being seen in western regions and will underpin the efforts to reduce the mortality rates associated with this cancer.

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

    PubMed

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

    2014-12-01

    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

  2. [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

  3. 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

  4. [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.

  5. Surveillance and diagnosis of hepatocellular carcinoma in patients with cirrhosis

    PubMed Central

    Andreana, Lorenzo; Isgrò, Graziella; Pleguezuelo, Maria; Germani, Giacomo; Burroughs, Andrew K

    2009-01-01

    Early identification of hepatocellular carcinoma (HCC) is more frequent because of surveillance programs for HCC worldwide. The optimal strategy of surveillance in cirrhosis is a current topical issue. In terms of diagnosis, recent advances in non-invasive imaging technology, including various techniques of harmonic ultrasound, new ultrasound contrast agents, multi-slice helical computed tomography and rapid high quality magnetic resonance, have all improved the accuracy of diagnosis. Consequently the role of liver biopsy in diagnosis of HCC has declined. The imaging diagnosis relies on the hallmark of arterial hypervascularity with portal venous washout. However, with recent advances in genomics and proteomics a great number of potential serum and tissue markers have been identified and are being developed as new candidate markers for both diagnosis and prognosis of hepatocellular carcinoma, and may increase the need for liver biopsy. PMID:21160965

  6. 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.

  7. 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.

  8. 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

  9. Indication of liver transplantation for hepatocellular carcinoma in Japan.

    PubMed

    Tanikawa, K

    1992-01-01

    Approximately 20,000 patients die of hepatocellular carcinoma (HCC) annually in Japan and most of them are hepatitis B virus (HBV) or hepatitis C virus (HCV) carriers. Recently, small HCC, less than 3 cm in diameter, have frequently been found by ultrasonography in the follow-up of patients with chronic liver diseases. Such cases are mainly treated by either surgical resection or percutaneous ethanol injection therapy (PEIT) with a satisfactory 5 year survival rate of 50%. In addition, the survival rate of advanced cases has gradually improved thanks to transcatheter arterial chemo-embolization combined with PEIT, radiation, hyperthermia, or immune therapy. On the other hand, our autopsy study has indicated a high frequency of extrahepatic metastasis in advanced cases. From these results, liver transplantation for HCC does not seem to be the treatment of first choice, at present, in Japan. In the future, the means to control the underlying infection of HBV or HCV as well as making an accurate imaging diagnosis for the detection of extrahepatic metastasis will become inevitably more important for successful liver transplantation in HCC.

  10. Hepatocellular Carcinoma From Epidemiology to Prevention: Translating Knowledge into Practice.

    PubMed

    Singal, Amit G; El-Serag, Hashem B

    2015-11-01

    The epidemiology of hepatocellular carcinoma (HCC) is characterized by dynamic temporal trends, several major established (i.e., HCV, HBV, alcohol) and emerging (i.e., diabetes, obesity, NAFLD) risk factors. Epidemiologic studies and clinical trials have identified additional demographic, clinical, pharmacological, genetic and life style factors that further affect or modify the likelihood of HCC and can be used in clinical practice to identify at-risk patients (i.e., risk stratification or prognostic algorithms) that can be targeted for prevention and early detection programs. These studies have also paved the way toward several well established preventive measures including HBV vaccination, HBV treatment, HCV treatment and HCC surveillance, and potential chemoprevention using statins, metformin or coffee. However, the effectiveness of HCC prevention in clinical practice and at the population level has lagged behind due to patient, provider, system, and societal factors. The Quality in the Continuum of Cancer Care model provides a framework for evaluating the HCC prevention processes, including potential failures that create a gap between efficacy and effectiveness. PMID:26284591

  11. Hepatocellular Carcinoma from Epidemiology to Prevention: Translating Knowledge into Practice

    PubMed Central

    Singal, Amit G.; El-Serag, Hashem B

    2015-01-01

    Hepatocellular carcinoma (HCC) is the 3rd leading cause of cancer-related death worldwide and one of the leading causes of death in patients with cirrhosis.1]HCC incidence in the United States (US) has more than doubled over the past 2 decades and is anticipated to continue increasing over the next 20 y, due to the growing number of patients with advanced hepatitis C virus (HCV) and/or non-alcoholic steatohepatitis (NASH). At its current pace, HCC is projected to surpass breast and colorectal cancer to become the 3rd leading cause of cancer-related death in the US by 2030.2 Currently only 46% of HCC cases are diagnosed at an early stage and most do not receive curative therapy.2 Epidemiologic and clinical studies have identified many factors that affect risk for HCC and can be used to identify at-risk patients and implement prevention measures. Although several advances in HCC prevention, early detection, and diagnosis are efficacious and could reduce the incidence and mortality of HCC, widespread dissemination and successful implementation are essential for these strategies to be effective in clinical practice. Challenges include limited recognition of at-risk patients, availability of well-validated risk stratification measures, and surveillance in high-risk groups. PMID:26284591

  12. 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

  13. Recent Advances in Tumor Ablation for Hepatocellular Carcinoma.

    PubMed

    Kang, Tae Wook; Rhim, Hyunchul

    2015-09-01

    Image-guided tumor ablation for early stage hepatocellular carcinoma (HCC) is an accepted non-surgical treatment that provides excellent local tumor control and favorable survival benefit. This review summarizes the recent advances in tumor ablation for HCC. Diagnostic imaging and molecular biology of HCC has recently undergone marked improvements. Second-generation ultrasonography (US) contrast agents, new computed tomography (CT) techniques, and liver-specific contrast agents for magnetic resonance imaging (MRI) have enabled the early detection of smaller and inconspicuous HCC lesions. Various imaging-guidance tools that incorporate imaging-fusion between real-time US and CT/MRI, that are now common for percutaneous tumor ablation, have increased operator confidence in the accurate targeting of technically difficult tumors. In addition to radiofrequency ablation (RFA), various therapeutic modalities including microwave ablation, irreversible electroporation, and high-intensity focused ultrasound ablation have attracted attention as alternative energy sources for effective locoregional treatment of HCC. In addition, combined treatment with RFA and chemoembolization or molecular agents may be able to overcome the limitation of advanced or large tumors. Finally, understanding of the biological mechanisms and advances in therapy associated with tumor ablation will be important for successful tumor control. All these advances in tumor ablation for HCC will result in significant improvement in the prognosis of HCC patients. In this review, we primarily focus on recent advances in molecular tumor biology, diagnosis, imaging-guidance tools, and therapeutic modalities, and refer to the current status and future perspectives for tumor ablation for HCC.

  14. Nilotinib induces autophagy in hepatocellular carcinoma through AMPK activation.

    PubMed

    Yu, Hui-Chuan; Lin, Chen-Si; Tai, Wei-Tien; Liu, Chun-Yu; Shiau, Chung-Wai; Chen, Kuen-Feng

    2013-06-21

    Hepatocellular carcinoma (HCC) is the most common liver cancer and the third-leading cause of cancer death worldwide. Nilotinib is an orally available receptor tyrosine kinase inhibitor approved for chronic myelogenous leukemia. This study investigated the effect of nilotinib on HCC. Nilotinib did not induce cellular apoptosis. Instead, staining with acridine orange and microtubule-associated protein 1 light chain 3 revealed that nilotinib induced autophagy in a dose- and time-dependent manner in HCC cell lines, including PLC5, Huh-7, and Hep3B. Moreover, nilotinib up-regulated the phosphryaltion of AMP-activated kinase (AMPK) and protein phosphatase PP2A inactivation were detected after nilotinib treatment. Up-regulating PP2A activity suppressed nilotinib-induced AMPK phosphorylation and autophagy, suggesting that PP2A mediates the effect of nilotinib on AMPK phosphorylation and autophagy. Our data indicate that nilotinib-induced AMPK activation is mediated by PP2A, and AMPK activation and subsequent autophagy might be a major mechanism of action of nilotinib. Growth of PLC5 tumor xenografts in BALB/c nude mice was inhibited by daily oral treatment with nilotinib. Western blot analysis showed both increased phospho-AMPK expression and decreased PP2A activity in vivo. Together, our results reveal that nilotinib induces autophagy, but not apoptosis in HCC, and that the autophagy-inducing activity is associated with PP2A-regulated AMPK phosphorylation.

  15. 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

  16. Hepatocellular Carcinoma-propagating Cells are Detectable by Side Population Analysis and Possess an Expression Profile Reflective of a Primitive Origin

    PubMed Central

    Xia, Honghai; Cao, Jun; Li, Qing; Lv, Yang; Jia, Weidong; Ren, Weihua; Cheng, Qingyu; Song, Xiaoyuan; Xu, Geliang

    2016-01-01

    The recent identification of “Side Population” (SP) cells in a number of unrelated human cancers has renewed interests in the hypothesis of cancer stem cells. Here we isolated SP cells from HepG2 cells and 18 of the 21 fresh hepatocellular carcinoma (HCC) tissue samples. These SP cells have higher abilities of forming spheroids, invasion and migration. Tumors could generate only from SP, not non-SP (NSP), cells in a low dose of subcutaneous injection to the NOD/SCID mice (5 × 102 cells/mouse). The mRNA microarray analysis of the SP vs. NSP cells isolated from HepG2 cells revealed that the SP cells express higher levels of pluripotency- and stem cell-associated transcription factors including Klf4, NF-Ya, SALL4 and HMGA2. Some of the known hepatobiliary progenitor/stem cell markers, such as Sox9 was also up-regulated. RT-qPCR analysis of the gene expression between SP cells and NSP cells isolated from both HepG2 cells and HCC tissue samples showed that most of the tested mRNAs’ changes were in consistent with the microarray data, including the general progenitor/stem cells markers such as Klf4, NF-Ya, SALL4 and HMGA2, which were up-regulated in SP cells. Our data indicates that HCC cancer stem cells exist in HepG2 and HCC fresh tissue samples and can be isolated by SP assay. PMID:27725724

  17. Transcriptomic Characterization of Hepatocellular Carcinoma with CTNNB1 Mutation

    PubMed Central

    Du, Chengzhi; Xu, Naiqing; Huang, Huanwei; Cai, Tao; Zhang, Aiqun; Han, Ze-Guang; Zhou, Weiping; Chen, Liang

    2014-01-01

    Purpose Hepatocellular carcinoma (HCC) is the sixth most common solid tumor worldwide and the third leading cause of cancer-related death. HCC is a particularly serious threat to the Chinese population. Although many molecular alterations are known to be involved in the tumorigenesis of hepatocytes, no systemic survey has examined the somatic mutations in HCC samples from Chinese patients. Our goal was to elucidate somatic mutations in Chinese HCC patients and investigate the possible molecular mechanisms involved in tumorigenesis. Experimental Design A total of 110 hepatitis B virus (HBV)-positive HCC samples and 46 HBV-negative HCC samples were genotyped for hot-spot mutations in the CSF1R, CTNNB1, KRAS, BRAF, NRAS, ERBB2, MET, PIK3CA, JAK1, and SMO genes. The transcriptomes of the CTNNB1 mutation-positive HCC samples from the HBV-positive patients (CB+ HCC) were compared to adjacent non-cancerous livers, and significantly altered genes were functionally validated in vitro. Results CTNNB1 mutations accounted for the majority of the mutations detected in our study. A slightly higher mutation rate was found in the HBV-positive patients than in their negative counterparts. A distinct pattern of CTNNB1 mutation was detected in these two populations, and drastic changes at the transcriptomic level were detected in the CB+ tumors compared to adjacent non-cancerous livers. Potential tumor suppressors (FoxA3 and Onecut1) and oncogenes (MAFG and SSX1) were functionally validated. Conclusions Our work is the first systemic characterization of oncogenic mutations in HCC samples from Chinese patients. Targeting the Wnt-β-catenin pathway may represent a valid treatment option for Chinese HCC patients. Our work also suggests that targeting ONECUT1, FOXA3, SSX1, and MAFG may be a valid treatment option for CTNNB1 mutation positive HCC patients. PMID:24798046

  18. Quantitative Contrast-Enhanced Ultrasonic Imaging Reflects Microvascularization in Hepatocellular Carcinoma and Prognosis after Resection.

    PubMed

    Zou, Ru-Hai; Lin, Qing-Guang; Huang, Wei; Li, Xiao-Ling; Cao, Yun; Zhang, Jing; Zhou, Jian-Hua; Li, An-Hua; Beretta, Laura; Qian, Chao-Nan

    2015-10-01

    Our aim was to evaluate the correlation between tumor vasculature detected by pre-surgical contrast-enhanced ultrasonography and the post-surgical prognosis of patients with hepatocellular carcinoma. One hundred ninety-five patients with hepatocellular carcinoma who had undergone curative resection and pre-operative contrast-enhanced ultrasonography were enrolled. Intra-tumoral microvessels were evaluated by immunohistochemical staining for anti-CD31 and anti-CD34. On the basis of the immunohistochemical staining and morphology patterns, tumors were divided into capillary-like and sinusoid-like microvessel subtypes. The rise time of tumors was shorter in the capillary-like microvessel subtype than in the sinusoid-like microvasculature subtype (p = 0.026). Intra-tumor microvascular density (p < 0.001, hazard ratio = 0.137) and rise time (p = 0.006, hazard ratio = 2.475) were independent factors corresponding to different microvasculature types. Microvascular density, vascular invasion and wash-in perfusion index were determined to be independent factors in recurrence-free survival and overall survival. In conclusion, contrast-enhanced ultrasonography may serve as a means of non-invasive assessment of tumor angiogenesis and may be associated with the survival of patients with hepatocellular carcinoma after resection. PMID:26210785

  19. Current status and perspectives of immune-based therapies for hepatocellular carcinoma

    PubMed Central

    Aerts, Maridi; Benteyn, Daphné; Van Vlierberghe, Hans; Thielemans, Kris; Reynaert, Hendrik

    2016-01-01

    Hepatocellular carcinoma (HCC) is a frequent cancer with a high mortality. For early stage cancer there are potentially curative treatments including local ablation, resection and liver transplantation. However, for more advanced stage disease, there is no optimal treatment available. Even in the case of a “curative” treatment, recurrence or development of a new cancer in the precancerous liver is common. Thus, there is an urgent need for novel and effective (adjuvant) therapies to treat HCC and to prevent recurrence after local treatment in patients with HCC. The unique immune response in the liver favors tolerance, which remains a genuine challenge for conventional immunotherapy in patients with HCC. However, even in this “immunotolerant” organ, spontaneous immune responses against tumor antigens have been detected, although they are insufficient to achieve significant tumor death. Local ablation therapy leads to immunogenic tumor cell death by inducing the release of massive amounts of antigens, which enhances spontaneous immune response. New immune therapies such as dendritic cell vaccination and immune checkpoint inhibition are under investigation. Immunotherapy for cancer has made huge progress in the last few years and clinical trials examining the use of immunotherapy to treat hepatocellular carcinoma have shown some success. In this review, we discuss the current status of and offer some perspectives on immunotherapy for hepatocellular carcinoma, which could change disease progression in the near future. PMID:26755874

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

    PubMed Central

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

    2016-01-01

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

  1. 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.

  2. Improved method increases sensitivity for circulating hepatocellular carcinoma cells

    PubMed Central

    Liu, Hui-Ying; Qian, Hai-Hua; Zhang, Xiao-Feng; Li, Jun; Yang, Xia; Sun, Bin; Ma, Jun-Yong; Chen, Lei; Yin, Zheng-Feng

    2015-01-01

    AIM: To improve an asialoglycoprotein receptor (ASGPR)-based enrichment method for detection of circulating tumor cells (CTCs) of hepatocellular carcinoma (HCC). METHODS: Peripheral blood samples were collected from healthy subjects, patients with HCC or various other cancers, and patients with hepatic lesions or hepatitis. CTCs were enriched from whole blood by extracting CD45-expressing leukocytes with monoclonal antibody coated-beads following density gradient centrifugation. The remaining cells were cytocentrifuged on polylysine-coated slides. Isolated cells were treated by triple immunofluorescence staining with CD45 antibody and a combination of antibodies against ASGPR and carbamoyl phosphate synthetase 1 (CPS1), used as liver-specific markers, and costained with DAPI. The cell slide was imaged and stained tumor cells that met preset criteria were counted. Recovery, sensitivity and specificity of the detection methods were determined and compared by spiking experiments with various types of cultured human tumor cell lines. Expression of ASGPR and CPS1 in cultured tumor cells and tumor tissue specimens was analyzed by flow cytometry and triple immunofluorescence staining, respectively. RESULTS: CD45 depletion of leukocytes resulted in a significantly greater recovery of multiple amounts of spiked HCC cells than the ASGPR+ selection (Ps < 0.05). The expression rates of either ASGPR or CPS1 were different in various liver cancer cell lines, ranging between 18% and 99% for ASGPR and between 9% and 98% for CPS1. In both human HCC tissues and liver cancer cell lines, there were a few HCC cells that did not stain positive for ASGPR or CPS1. The mixture of monoclonal antibodies against ASGPR and CPS1 identified more HCC cells than either antibody alone. However, these antibodies did not detect any tumor cells in blood samples spiked with the human breast cancer cell line MCF-7 and the human renal cancer cell line A498. ASGPR+ or/and CPS1+ CTCs were detected in 29

  3. 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

  4. 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

  5. Intermediate hepatocellular carcinoma: the role of transarterial therapy

    PubMed Central

    Chegai, Fabrizio; Orlacchio, Antonio; Merolla, Stefano; Monti, Serena; Mannelli, Lorenzo

    2015-01-01

    According to Barcelona Clinic Liver Cancer, the recommended first-line treatment for patients with intermediate stage of hepatocellular carcinoma (HCC) is transarterial chemoembolization. Patients with intermediate stage of HCC represent 20% with a 2-year survival of approximately 50%. Nowadays, transarterial therapies have proved precious in the treatment of hepatic malignancies. During the last years, there were important developments in practiced transarterial therapies and their efficacy is still controversial. The purpose of this review is to discuss in further details these transarterial therapies that have been used to treat cases of HCC. PMID:26998220

  6. New agents on the horizon in hepatocellular carcinoma

    PubMed Central

    2013-01-01

    Despite the successful approval and extensive application of sorafenib, the prognosis for patients with advanced hepatocellular carcinoma (HCC) remains poor. Fortunately, there have been renewed and continued interests and active research in developing other molecularly targeted agents in HCC during the past few years. While there is early evidence of antitumor activity of several agents in phase I/II studies, phase III efforts with a few targeted agents have failed, highlighting the challenges of new drug development in HCC. This review summarizes the current status of other molecularly targeted agents under development in advanced HCC. PMID:23323146

  7. 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

  8. Frequency of elevated biomarkers in patients with cryptogenic hepatocellular carcinoma

    PubMed Central

    Taura, Naota; Ichikawa, Tatsuki; Miyaaki, Hisamitsu; Ozawa, Eisuke; Tsutsumi, Takuya; Tsuruta, Shotaro; Kato, Yuji; Goto, Takashi; Kinoshita, Noboru; Fukushima, Masanori; Kato, Hiroyuki; Ohata, Kazuyuki; Ohba, Kazuo; Masuda, Junichi; Hamasaki, Keisuke; Yatsuhashi, Hiroshi; Nakao, Kazuhiko

    2013-01-01

    Background The incidence of hepatocellular carcinoma (HCC) continues to increase in Japan, but the clinical characteristics of Japanese patients with HCC have not been well described. The aim of this study was to determine the frequencies and utilities of elevated α-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) levels as biomarkers in cryptogenic HCC. Material/Methods A total of 2638 patients with HCC diagnosed between 1999 and 2010 in the Nagasaki Association Study of Liver (NASLD) were recruited for this study. The cause of HCC was categorized into 4 groups; HCC-B, HCC-C, HCC-BC, and HCC-nonBC. The significance of factors was examined for HCC-nonBC using logistic regression analysis in all patients. Results Multivariate analysis identified age, sex, BMI, alcohol consumption, platelet count, AST, ALT, AFP, DCP, and TNM stage as independent and significant risk factors for HCC-nonBC. According to TNM stage, the median AFP levels in HCC-nonBC with TNM stages I, II, and III were significantly lower than in either HCC-B or HCC-C. In TNM stage IV, the median AFP level in HCC-nonBC was significantly lower than in either HCC-B or HCC-BC. The median DCP levels in HCC-nonBC with TNM stages I and II were significantly higher than those in either HCC-B or HCC-C. In TNM stage III, the median DCP level in HCC-nonBC was significantly higher than that in HCC-C. Conclusions DCP was more sensitive than AFP for the diagnosis of early stage cryptogenic HCC. DCP should be used as the main serum test for cryptogenic HCC detection. PMID:24008520

  9. Recent Advances in Tumor Ablation for Hepatocellular Carcinoma.

    PubMed

    Kang, Tae Wook; Rhim, Hyunchul

    2015-09-01

    Image-guided tumor ablation for early stage hepatocellular carcinoma (HCC) is an accepted non-surgical treatment that provides excellent local tumor control and favorable survival benefit. This review summarizes the recent advances in tumor ablation for HCC. Diagnostic imaging and molecular biology of HCC has recently undergone marked improvements. Second-generation ultrasonography (US) contrast agents, new computed tomography (CT) techniques, and liver-specific contrast agents for magnetic resonance imaging (MRI) have enabled the early detection of smaller and inconspicuous HCC lesions. Various imaging-guidance tools that incorporate imaging-fusion between real-time US and CT/MRI, that are now common for percutaneous tumor ablation, have increased operator confidence in the accurate targeting of technically difficult tumors. In addition to radiofrequency ablation (RFA), various therapeutic modalities including microwave ablation, irreversible electroporation, and high-intensity focused ultrasound ablation have attracted attention as alternative energy sources for effective locoregional treatment of HCC. In addition, combined treatment with RFA and chemoembolization or molecular agents may be able to overcome the limitation of advanced or large tumors. Finally, understanding of the biological mechanisms and advances in therapy associated with tumor ablation will be important for successful tumor control. All these advances in tumor ablation for HCC will result in significant improvement in the prognosis of HCC patients. In this review, we primarily focus on recent advances in molecular tumor biology, diagnosis, imaging-guidance tools, and therapeutic modalities, and refer to the current status and future perspectives for tumor ablation for HCC. PMID:26674766

  10. Expression and clinical significance of aquaglyceroporins in human hepatocellular carcinoma.

    PubMed

    Chen, Xiao-Feng; Li, Chuan-Fei; Lü, Lin; Mei, Zhe-Chuan

    2016-06-01

    Aquaglyceroporins (AQPs) are a subset of the aquaporin family, and are permeable to water and glycerol. The aim of the present study was to determine the expression and clinical significance of three AQPs, AQP3, 7 and 9 in hepatocellular carcinoma (HCC). Fresh HCC and adjacent non‑tumorous liver tissues were collected from 68 patients diagnosed with HCC. The expression levels of AQP3, 7 and 9 were detected by reverse transcription‑quantitative polymerase chain reaction, western blotting and immunohistochemical analysis. The association between the expression of AQPs and clinicopathological parameters of HCC were investigated. Compared with non‑tumorous liver tissue, HCC tissues exhibited a significant (P<0.05) increase in the expression of AQP3 and a concomitant reduction in the expression levels of AQP7 and AQP9, at both the mRNA and protein levels. Immunohistochemistry revealed that AQP9 was dominantly localized on the plasma membrane of hepatocytes, while AQP3 and AQP7 exhibited a predominantly cytoplasmic and nuclear distribution. High expression of AQP3 was significantly (P<0.05) associated with low expression levels of AQP7 and AQP9. High expression of AQP3 was correlated with tumor grade (P=0.017), tumor stage (P=0.010) and lymphatic metastasis (P=0.031). Low expression of AQP7 was correlated with tumor grade (P=0.043). AQP3 was upregulated, and AQP7 and AQP9 were downregulated in HCC. A high expression of AQP3 and low expression of AQP7 was significantly associated with the aggressive features of HCC. PMID:27121567

  11. RGD-FasL Induces Apoptosis in Hepatocellular Carcinoma

    PubMed Central

    Liu, Zhongchen; Wang, Juan; Yin, Ping; Qiu, Jinhua; Liu, Ruizhen; Li, Wenzhu; Fan, Xin; Cheng, Xiaofeng; Chen, Caixia; Zhang, Jiakai; Zhuang, Guohong

    2009-01-01

    Despite impressive results obtained in animal models, the clinical use of Fas ligand (FasL) as an anticancer drug is limited by severe toxicity. Systemic toxicity of death ligands may be prevented by using genes encoding membrane-bound death ligands and by targeted transgene expression through either targeted transduction or targeted transcription. Selective induction of tumor cell death is a promising anticancer strategy. A fusion protein is created by fusing the extracellular domain of Fas ligand (FasL) to the peptide arginine-glycine-aspartic acid (RGD) that selectively targets avβ3-integrins on tumor endothelial cells. The purpose of this study is to evaluate the effects of RGD-FasL on tumor growth and survival in a murine hepatocellular carcinoma (HCC) tumor model. Treatment with RGD-FasL displaying an obvious suppressive effect on the HCC tumor model as compared to that with FasL (p < 0.05) and resulted in a more additive effect on tumor growth delay in this model. RGD-FasL treatment significantly enhanced mouse survival and caused no toxic effect, such as weight loss, organ failure, or other treatment-related toxicities. Apoptosis was detected by flow cytometric analysis and TUNEL assays; those results also showed that RGD-FasL is a more potent inducer of cell apoptosis for H22 and H9101 cell lines than FasL (p < 0.05). In conclusion, RGD-FasL appears to be a low-toxicity selective inducer of tumor cell death, which merits further investigation in preclinical and clinical studies. Furthermore, this approach offers a versatile technology for complexing target ligands with therapeutic recombinant proteins. To distinguish the anti-tumor effects of FasL in vivo, tumor and liver tissues were harvested to examine for evidence of necrotic cells, tumor cells, or apoptotic cells by Hematoxylin and eosin (H&E) staining. PMID:19728930

  12. Maotai Ameliorates Diethylnitrosamine-Initiated Hepatocellular Carcinoma Formation in Mice

    PubMed Central

    Yi, Xu; Long, Li; Yang, Chunzhang; Lu, Yingying; Cheng, Mingliang

    2014-01-01

    Consumption of alcohol is closely related to liver disease, such as hepatic fibrosis or even hepatocellular carcinoma (HCC). However, epidemiological and experimental studies indicated that consumption of Maotai, one of the famous liquors in China, exhibits no significant correlation with hepatic fibrosis or cirrhosis as other beverage sources do. This study detected the relationship of Maotai consumption and HCC development in a diethylnitrosamine (DEN)-initiated HCC animal model. DEN was given to mice at a dose of 100 mg/kg, ip, and 50 mg/kg, ip in the following week. Mice were simultaneously given Maotai or an equal amount of ethanol (53%, 5 ml/kg/day, 5days/week for up to 35weeks). At 3-week and 35- week of the experiment, serum and livers were collected for biochemical and histopathological examination of liver injury and incidence of HCC. Real-time RT-PCR, immunohistochemistry and Western blotting were used to examine the expression of metallothionein-1/2 (MT-1/2), NF-E2-related factor 2 (Nrf2), glutamate-cysteine ligase catalytic subunit (GCLC) and modified subunit (GCLM). We identified tissue damage and dysfunction of liver in ethanol + DEN-treated mice, whereas the extent of injury was reduced in Maotai+ DEN –treated mice. Significant Glypican-3(GPC3) expression and precancerous injury or HCC were seen in approximately 50% of mice with ethanol+ DEN, but barely be seen in Maotai + DEN-treated mice. A higher expression of MT-1/2, Nrf2 and GCLC could be seen in Maotai + DEN-treated mice. Thus, Maotai liquor ameliorates the formation of DEN-induced HCC in mice, and the protection mechanism is possibly related with the activation of anti-oxidation factors, such as MTs, Nrf2 and GCLC. PMID:24690765

  13. 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.

  14. Multiple Primary Malignancies in Patients With Hepatocellular Carcinoma

    PubMed Central

    Xu, Wei; Liao, Wenjun; Ge, Penglei; Ren, Jinjun; Xu, Haifeng; Yang, Huayu; Sang, Xinting; Lu, Xin; Mao, Yilei

    2016-01-01

    Abstract Multiple primary malignancies (MPMs) are defined as 2 or more malignancies without subordinate relationship detected in different organs of an individual patient. Reports addressing MPM patients with hepatocellular carcinoma (HCC) are rare. We perform a 26-year follow-up study to investigate characteristics and prognosis of MPM patients associated with HCC due to the scarcity of relative researches. We retrospectively analyzed records of 40 patients who were diagnosed with MPM including HCC at the Departments of Surgery at Peking Union Medical College Hospital during 1989 to 2010. Their clinical characteristics and postoperative survival were compared with those of 448 patients who had HCC only during the study period. Among the 40 MPM patients, 11 were diagnosed synchronously and 29 metachronously. The most common extra-hepatic malignancies were lung cancer (15%), colorectal (12.5%), and thyroid carcinoma (12.5%). MPM patients had a negative hepatitis B virus infection rate (P = 0.013) and lower median alfa-fetoprotein (AFP) level (P = 0.001). Post-operative 1-, 3-, and 5-year overall survival (OS) rates for MPM patients were 82.5%, 64.5%, and 38.6% respectively, and showed no significant difference with those of HCC-only patients (84.7%, 54.2%, and 38.3% P = 0.726). During follow-up, 24 MPM patients died, including 17 (70.8%) who died of HCC-related causes. In univariate analysis, synchronous diagnosis, higher gamma glutamyltransferase (GGT) and/or AFP levels, tumor >5 cm and vascular invasion were significantly associated with shorter OS, but only tumor size was an independent OS factor in Cox modeling analysis. HCC should be considered as a potential second primary for all cancer survivors. Most MPM patients died of HCC-related causes and showed no significant difference in OS compared with HCC-only patients. Tumor size of HCC, rather than MPMs itself, was the only independent OS predictor for the MPM patients. PMID:27124050

  15. Safrole-DNA adduct in hepatocellular carcinoma associated with betel quid chewing.

    PubMed

    Chung, Yu-Ting; Chen, Chiu-Lan; Wu, Cheng-Chung; Chan, Shan-An; Chi, Chin-Wen; Liu, Tsung-Yun

    2008-12-15

    Betel quid chewing, which contributes high concentration of safrole in saliva, is a popular oral habit in Taiwan. Safrole is a documented rodent hepatocarcinogen, yet its hepatocarcinogenic potential in human is not known. Here, we used LC/ESI-ITMS(n) and LC/QTOF-MS confirmed safrole-dGMP as reference standard to detect the safrole-DNA adduct in hepatic tissues from HBsAg-/HCV-seronegative hepatocellular carcinoma patients by (32)P-postlabeling. We first synthesized and confirmed safrole-dGMP by LC/MS. Two isomeric safrole-dGMPs were characterized as N(2)-(trans-isosafrol-3'-yl) deoxyguanosine and N(2)-(safrol-1'-yl) deoxyguanosine. This technique was able to detect hepatic safrole-DNA adduct in mice that were treated with safrole but not sensitive enough to detect safrole-DNA adduct in human samples. Using the nuclease P1 version of the (32)P-postlabeling technique, we detected the presence of safrole-DNA adduct in two out of 28 hepatic tissues from hepatocellular carcinoma patients, and only these two patients had a history of betel quid chewing lasting more than 10 years. From co-chromatography with the mass confirmed safrole-dGMPs, this safrole-DNA adduct was identified as N(2)-(trans-isosafrol-3'-yl) deoxyguanosine. These results suggest that betel quid-containing safrole might be involved in the pathogenesis of hepatocellular carcinoma in human beings and LC/MS has the potential to identify DNA adducts in clinical samples.

  16. 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

  17. Knockdown of TMEM16A suppressed MAPK and inhibited cell proliferation and migration in hepatocellular carcinoma

    PubMed Central

    Deng, Liang; Yang, Jihong; Chen, Hongwu; Ma, Bo; Pan, Kangming; Su, Caikun; Xu, Fengfeng; Zhang, Jihong

    2016-01-01

    TMEM16A plays an important role in cell proliferation in various cancers. However, less was known about the expression and role of TMEM16A in hepatocellular carcinoma. We screened the expression of TMEM16A in patients’ hepatocellular carcinoma tissues, and also analyzed the biological function of hepatocellular carcinoma cells by knockdown of TMEM16A, as well as the expression of MAPK signaling proteins, including p38, p-p38, ERK1/2, p-ERK1/2, JNK, and p-JNK, and cell cycle regulatory protein cyclin D1 in TMEM16A siRNA-transfected SMMC-7721 cells by Western blot. Our results showed that TMEM16A was overexpressed in hepatocellular carcinoma tissues. Inhibition of TMEM16A suppressed the cell proliferation, migration, and invasion, and cell cycle progression but did not influence the cell apoptosis. TMEM16A siRNA-suppressed cancer cell proliferation and tumor growth were accompanied by a reduction of p38 and ERK1/2 activation and cyclin D1 induction, and were not influenced by other tested MAPK signaling proteins. In addition, inhibition of TMEM16A suppressed tumorigenicity in vivo. TMEM16A is overexpressed in hepatocellular carcinoma, and that inhibition of TMEM16A suppressed MAPK and growth of hepatocellular carcinoma. TMEM16A could be a potentially novel therapeutic target for human cancers, including hepatocellular carcinoma. PMID:26834491

  18. Evaluation of five DNA extraction methods for detection of H. pylori in formalin-fixed paraffin-embedded (FFPE) liver tissue from patients with hepatocellular carcinoma.

    PubMed

    Rabelo-Gonçalves, Elizabeth; Roesler, Bruna; Guardia, Ana Carolina; Milan, Arlete; Hara, Natalicia; Escanhoela, Cecília; Almeida, Jazon; Boin, Ilka; Zeitune, José Murilo

    2014-03-01

    Since Helicobacter spp. DNA was identified in liver tissue resected from patients with hepatocelullar carcinoma (HCC), researchers have suggested a role of this bacterium in hepatic carcinogenesis. Archives of formalin-fixed, paraffin-embedded (FFPE) tissues represent an extraordinary source for clinical studies providing many advantages. However, DNA extraction from FFPE tissues is laborious, time-consuming and still remains a challenge. The aim of this study was to evaluate five protocols for DNA extraction from FFPE liver obtained from patients with HCC in order to detect Helicobacter pylori DNA. These methods were: (1) QIAamp FFPE Tissue Kit, (2) QIAamp DNA Mini Kit, (3) Wizard SV Genomic DNA Purification System, (4) RealiaPrep FFPE gDNA Miniprep System and (5) phenol-chloroform. H. pylori detection was performed using 16S rRNA gene amplification by PCR. The highest total amount of DNA was obtained using the phenol-chloroform method. Analyses of 16S rRNA gene amplification did not show statistically significant differences among the methods (p=0.466), although the highest percentage of positive cases (70%) was found in samples extracted with phenol-chloroform. We suggest that of the five methods evaluated, phenol/chloroform is the most suitable for detection of H. pylori in FFPE liver from patients with HCC.

  19. Metastatic hepatocellular carcinoma in a juvenile rhesus macaque (Macaca mulatta).

    PubMed

    Laing, Steven T; Lemoy, Marie J; Sammak, Rebecca L; Tarara, Ross P

    2013-10-01

    Neoplasia in juvenile (younger than 5 y) rhesus macaques has been estimated to represent only approximately 1.4% of all occurrences of spontaneous neoplasia. Here we report an unusual case of a 3.75-y-old primiparous female rhesus macaque that was euthanized due to poor prognosis associated with progressive anemia, marked hepatomegaly, and radiographic evidence of meta- static neoplasia. Postmortem examination revealed an invasive, hemorrhagic hepatic mass that effaced approximately 70% of the liver parenchyma and had evidence of metastatic spread to multiple abdominal organs, the lungs, and the pituitary gland. Neoplastic polygonal cells lined large necrohemorrhagic cavities and exhibited marked anisocytosis and anisokaryosis, with frequent multinucleate cells. There was no desmoplasia associated with the primary neoplasm or metastases. Immunohistochemical studies revealed the neoplastic cells to be diffusely reactive with pancytokeratin, cytokeratin 7, and cytokeratin 8/18 antibodies and rarely reactive with carcinoembryonic antigen antibodies. The cells did not react with vimentin, S100, CD31, or factor VIII antibodies. Tumor morphology and immunophenotype led to the diagnosis of anaplastic hepatocellular carcinoma. This report represents the first known case of metastatic liver neoplasia in a rhesus macaque. The young age of this animal and the aggressive nature of the neoplasm are highly unusual and reminiscent of adolescent onset hepatocellular carcinoma in humans.

  20. Nanosecond pulsed electric field ablation of hepatocellular carcinoma.

    PubMed

    Beebe, Stephen J; Chen, Xinhua; Liu, Jie A; Schoenbach, Karl H

    2011-01-01

    Hepatocellular carcinoma often evades effective therapy and recurrences are frequent. Recently, nanosecond pulsed electric field (nsPEF) ablation using pulse power technology has emerged as a local-regional, non-thermal, and non-drug therapy for skin cancers. In the studies reported here we use nsPEFs to ablate murine, rat and human HCCs in vitro and an ectopic murine Hepa 1-6 HCC in vivo. Using pulses with 60 or 300 ns and electric fields as high as 60 kV/cm, murine Hepa 1-6, rat N1S1 and human HepG2 HCC are readily eliminated with changes in caspase-3 activity. Interestingly caspase activities increase in the mouse and human model and decrease in the rat model as electric field strengths are increased. In vivo, while sham treated control mice survived an average of 15 days after injection and before humane euthanasia, Hepa 1-6 tumors were eliminated for longer than 50 days with 3 treatments using one hundred pulses with 100 ns at 55 kV/cm. Survival was 40% in mice treated with 30 ns pulses at 55 kV/cm. This study demonstrates that nsPEF ablation is not limited to effectively treating skin cancers and provides a rationale for treating orthotopic hepatocellular carcinoma in pre-clinical applications and ultimately in clinical trials.

  1. 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

  2. Comparing the Detectability of Hepatocellular Carcinoma by C-Arm Dual-Phase Cone-Beam Computed Tomography During Hepatic Arteriography With Conventional Contrast-Enhanced Magnetic Resonance Imaging

    SciTech Connect

    Loffroy, Romaric; Lin, MingDe; Rao, Pramod; Bhagat, Nikhil; Noordhoek, Niels; Radaelli, Alessandro; Blijd, Jaerl; Geschwind, Jean-Francois

    2012-02-15

    Purpose: To evaluate the sensitivity of dual-phase cone-beam computed tomography during hepatic arteriography (CBCTHA) for the detection of hepatocellular carcinoma (HCC) by comparing it with the diagnostic imaging 'gold standard': contrast-enhanced magnetic resonance imaging (CE-MRI) of the liver. Materials and Methods: Eighty-eight HCC lesions (mean diameter 3.9 {+-} 3.3 cm) in 20 patients (13 men, mean age 61.4 years [range 50 to 80]), who sequentially underwent baseline diagnostic liver CE-MRI and then underwent early arterial- and delayed portal venous-phase CBCTHA during drug eluting-bead transarterial chemoembolization, were evaluated. Dual-phase CBCTHA findings of each tumor in terms of conspicuity were compared with standard CE-MR images and classified into three grades: optimal, suboptimal, and nondiagnostic. Results: Seventy-seven (mean diameter 4.2 {+-} 3.4 cm [range 0.9 to 15.9]) (93.9%) of 82 tumors were detected. Sensitivity of arterial-phase (71.9%) was lower than that of venous-phase CBCTHA (86.6%) for the detection of HCC lesions. Of the 82 tumors, 33 (40.2%) and 52 (63.4%), 26 (31.7%) and 19 (23.2%), and 23 (28%) and 11 (13.4%) nodules were classed as optimal, suboptimal, and nondiagnostic on arterial- and venous-phase CBCTHA images, respectively. Seventeen (73.9%) of the 23 tumors that were not visible on arterial phase were detected on venous phase. Six (54.5%) of the 11 tumors that were not visible on venous phase were detected on arterial phase. Conclusions: Dual-phase CBCTHA has sufficient image quality to detect the majority of HCC lesions compared with the imaging 'gold standard': CE-MRI of the liver. Moreover, dual-phase CBCTHA is more useful and reliable than single-phasic imaging to depict HCC nodules.

  3. Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa.

    PubMed

    Bressac, B; Kew, M; Wands, J; Ozturk, M

    1991-04-01

    Hepatocellular carcinoma (HCC) is a prevalent cancer in sub-Saharan Africa and eastern Asia. Hepatitis B virus and aflatoxins are risk factors for HCC, but the molecular mechanism of human hepatocellular carcinogenesis is largely unknown. Abnormalities in the structure and expression of the tumour-suppressor gene p53 are frequent in HCC cell lines, and allelic losses from chromosome 17p have been found in HCCs from China and Japan. Here we report on allelic deletions from chromosome 17p and mutations of the p53 gene found in 50% of primary HCCs from southern Africa. Four of five mutations detected were G----T substitutions, with clustering at codon 249. This mutation specificity could reflect exposure to a specific carcinogen, one candidate being aflatoxin B1 (ref. 7), a food contaminant in Africa, which is both a mutagen that induces G to T substitution and a liver-specific carcinogen.

  4. A biochemical comparison of normal human liver and hepatocellular carcinoma ferritins.

    PubMed

    Bullock, S; Bomford, A; Williams, R

    1980-03-01

    1. The iron contents, gel migration rates and isoelectric-focusing patterns of normal liver and hepatocellular carcinoma ferritins from the same patients were compared. 2. Sucrose-density-gradient centrifugation showed that the number of iron atoms per ferritin molecule was decreased to approximately half in carcinoma tissue when compared with normal liver. 3. On electrophoresis, hepatocellular carcinoma ferritin migrates faster and is therefore more negatively charged than normal liver ferritin, thus refuting the general view that the more negatively charged a ferritin molecule the greater its iron content. 4. Comparison of tumour and normal liver ferritin subunit compositions on acid/urea/polyacrylamide gels showed hepatocellular carcinoma ferritin to contain an additional, more negatively charged, subunit to normal liver ferritin. 5. Isoelectric focusing showed that hepatocellular carcinoma tissue contains isoferritins with isoelectric points intermediate between the ranges of normal liver and normal heart isoferritins. PMID:6248028

  5. Unusual Presentation of Hepatocellular Carcinoma into Right iliac fossa: A Rare Entity

    PubMed Central

    Periyasamy, Karthikumaran

    2015-01-01

    Hepatocellular carcinoma (HCC) is the most common primary malignant hepatic tumour. Hepatocellular carcinoma presenting itself or extending into the right iliac fossa (RIF) is a very rare entity. We report on a rare case of hepatocellular carcinoma in a 60-year-old lady, presented with a mobile mass in the lower abdomen without cirrhosis, with normal α-feto protein levels (AFP) or any known risk factors for liver disease. HCC in this case was unusual in its presentation both in the patient as well as a disease. PMID:26672490

  6. Unusual Presentation of Hepatocellular Carcinoma into Right iliac fossa: A Rare Entity.

    PubMed

    Uthamalingam, Murali; Periyasamy, Karthikumaran

    2015-11-01

    Hepatocellular carcinoma (HCC) is the most common primary malignant hepatic tumour. Hepatocellular carcinoma presenting itself or extending into the right iliac fossa (RIF) is a very rare entity. We report on a rare case of hepatocellular carcinoma in a 60-year-old lady, presented with a mobile mass in the lower abdomen without cirrhosis, with normal α-feto protein levels (AFP) or any known risk factors for liver disease. HCC in this case was unusual in its presentation both in the patient as well as a disease.

  7. Chemotherapeutic Agents for the Treatment of Hepatocellular Carcinoma: Efficacy and Mode of Action

    PubMed Central

    Shaaban, Saad; Negm, Amr; Ibrahim, Elsayed E.; Elrazak, Ahmed A.

    2014-01-01

    Hepatocellular carcinoma (HCC) is a dreaded malignancy that every year causes half a million deaths worldwide. Being an aggressive cancer, its incidence exceeds 700,000 new cases per year worldwide with a median survival of 6-8 months. Despite advances in prognosis and early detection, effective HCC chemoprevention or treatment strategies are still lacking, therefore its dismal survival rate remains largely unchanged. This review will characterize currently available chemotherapeutic drugs used in the treatment of HCC. The respective mode(s) of action, side effects and recommendations will be also described for each drug. PMID:25992234

  8. [Hepatic adenoma and hepatocellular carcinoma in 3 brothers with type I glycogenosis].

    PubMed

    Kharsa, G; Degott, C; Filoche, B; Hedde, J P; Potet, F; Benhamou, J P

    1990-01-01

    We report 2 cases of type I glycogen storage disease (Von Gierke's disease) discovered in 2 brothers at the age of 7 and 5 years, respectively. Both developed hepatic adenoma at the age of 19 and 17. Hepatocellular carcinoma occurred in the older brother the discovery of adenoma 4 years after. The frequency of these tumors in patients with type I glycogen storage disease raises problems concerning the treatment and modality of regular surveillance of the liver in these patients. The policy for the detection and treatment of these tumors, and particularly the indications for liver transplantation are discussed. PMID:2155841

  9. A genomic case study of mixed fibrolamellar hepatocellular carcinoma

    PubMed Central

    Griffith, O. L.; Griffith, M.; Krysiak, K.; Magrini, V.; Ramu, A.; Skidmore, Z. L.; Kunisaki, J.; Austin, R.; McGrath, S.; Zhang, J.; Demeter, R.; Graves, T.; Eldred, J. M.; Walker, J.; Larson, D. E.; Maher, C. A.; Lin, Y.; Chapman, W.; Mahadevan, A.; Miksad, R.; Nasser, I.; Hanto, D. W.; Mardis, E. R.

    2016-01-01

    Background Mixed fibrolamellar hepatocellular carcinoma (mFL-HCC) is a rare liver tumor defined by the presence of both pure FL-HCC and conventional HCC components, represents up to 25% of cases of FL-HCC, and has been associated with worse prognosis. Recent genomic characterization of pure FL-HCC identified a highly recurrent transcript fusion (DNAJB1:PRKACA) not found in conventional HCC. Patients and Methods We performed exome and transcriptome sequencing of a case of mFL-HCC. A novel BAC-capture approach was developed to identify a 400 kb deletion as the underlying genomic mechanism for a DNAJB1:PRKACA fusion in this case. A sensitive Nanostring Elements assay was used to screen for this transcript fusion in a second case of mFL-HCC, 112 additional HCC samples and 44 adjacent non-tumor liver samples. Results We report the first comprehensive genomic analysis of a case of mFL-HCC. No common HCC-associated mutations were identified. The very low mutation rate of this case, large number of mostly single-copy, long-range copy number variants, and high expression of ERBB2 were more consistent with previous reports of pure FL-HCC than conventional HCC. In particular, the DNAJB1:PRKACA fusion transcript specifically associated with pure FL-HCC was detected at very high expression levels. Subsequent analysis revealed the presence of this fusion in all primary and metastatic samples, including those with mixed or conventional HCC pathology. A second case of mFL-HCC confirmed our finding that the fusion was detectable in conventional components. An expanded screen identified a third case of fusion-positive HCC, which upon review, also had both conventional and fibrolamellar features. This screen confirmed the absence of the fusion in all conventional HCC and adjacent non-tumor liver samples. Conclusion These results indicate that mFL-HCC is similar to pure FL-HCC at the genomic level and the DNAJB1:PRKACA fusion can be used as a diagnostic tool for both pure and m

  10. Circulating Tumor Cells Measurements in Hepatocellular Carcinoma

    PubMed Central

    Chiappini, Franck

    2012-01-01

    Liver cancer is the fifth most common cancer in men and the seventh in women. During the past 20 years, the incidence of HCC has tripled while the 5-year survival rate has remained below 12%. The presence of circulating tumor cells (CTC) reflects the aggressiveness nature of a tumor. Many attempts have been made to develop assays that reliably detect and enumerate the CTC during the development of the HCC. In this case, the challenges are (1) there are few markers specific to the HCC (tumor cells versus nontumor cells) and (2) they can be used to quantify the number of CTC in the bloodstream. Another technical challenge consists of finding few CTC mixed with million leukocytes and billion erythrocytes. CTC detection and identification can be used to estimate prognosis and may serve as an early marker to assess antitumor activity of treatment. CTC can also be used to predict progression-free survival and overall survival. CTC are an interesting source of biological information in order to understand dissemination, drug resistance, and treatment-induced cell death. Our aim is to review and analyze the different new methods existing to detect, enumerate, and characterize the CTC in the peripheral circulation of patients with HCC. PMID:22690340

  11. Expression of Girdin in primary hepatocellular carcinoma and its effect on cell proliferation and invasion.

    PubMed

    Cao, Ke; Lu, Can; Han, Shuang; Zou, Qiong; Li, Jingjing; Xie, Dingfang; He, Siqi; Yu, Li; Zhou, Jianda; Peng, Xiaowei; Cao, Peiguo

    2015-01-01

    Girdin has been proven to play a vital role in the process of proliferation, apoptosis, and invasion in various cancer cells, yet the underlying molecular mechanism in primary hepatocellular carcinoma (HCC) has not yet been clarified. Thereafter, we performed immunohistochemistry to detect the expression of Girdin in 40 primary HCC tissues and 30 matched adjacent tissues using hepatic carcinoma tissue microarray. Our data showed that the positive expression rate of Girdin in hepatocellular carcinoma tissues was 67.5%, higher than that found in adjacent tissues of 16.7% (P < 0.05). It closely correlates to tumor size, T stage, TNM stage and Edmondson-Steiner stage (P < 0.05) of HCC patients. After specific small interfering RNA of Girdin was transfected into HepG2 and Huh7.5.1 cells, the proliferation and invasion ability of tumor cells were significantly inhibited. In summary, we suggest that the oncogenic role of Girdin could provide new molecular target for the treatment of HCC.

  12. 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

  13. 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

  14. 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

    2015-04-28

    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.

  15. 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

  16. Hepatocellular carcinoma in tyrosinemia type 1 without clear increase of AFP.

    PubMed

    van Ginkel, Willem G; Gouw, Annette S H; van der Jagt, Eric J; de Jong, Koert P; Verkade, Henkjan J; van Spronsen, Francjan J

    2015-03-01

    Patients with hereditary tyrosinemia type 1 have an elevated risk of developing hepatocellular carcinoma, especially if initiation of treatment with 2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3-cyclohexanedione is delayed. Hepatocellular carcinoma can usually be suspected when there are increased α1-fetoprotein levels and characteristic imaging features. The present case shows that a lack of a clear increase in α1-fetoprotein should still lead to consideration of liver transplantation when imaging features change.

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

    PubMed

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

    2011-03-01

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

  18. 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

  19. 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

  20. UHRF1 overexpression drives DNA hypomethylation and hepatocellular carcinoma

    PubMed Central

    Mudbhary, Raksha; Hoshida, Yujin; Chernyavskaya, Yelena; Jacob, Vinitha; Villanueva, Augusto; Fiel, M. Isabel; Chen, Xintong; Kojima, Kensuke; Thung, Swan; Bronson, Roderick T.; Lachenmayer, Anja; Revill, Kate; Alsinet, Clara; Sachidanandam, Ravi; Desai, Anal; SenBanerjee, Sucharita; Ukomadu, Chinweike; Llovet, Josep M.; Sadler, Kirsten C.

    2014-01-01

    SUMMARY UHRF1 is an essential regulator of DNA methylation that is highly expressed in many cancers. Here, we use transgenic zebrafish, cultured cells and human tumors to demonstrate that UHRF1 is an oncogene. UHRF1 overexpression in zebrafish hepatocytes destabilizes and delocalizes DNMT1, causes DNA hypomethylation and Tp53-mediated senescence. Hepatocellular carcinoma (HCC) emerges when senescence is bypassed. tp53 mutation both alleviates senescence and accelerates tumor onset. Human HCCs recapitulate this paradigm, as UHRF1 overexpression defines a subclass of aggressive HCCs characterized by genomic instability, TP53 mutation and abrogation of the TP53-mediated senescence program. We propose that UHRF1 overexpression is a mechanism underlying DNA hypomethylation in cancer cells and that senescence is a primary means of restricting tumorigenesis due to epigenetic disruption. PMID:24486181

  1. 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

  2. Non alcoholic steatohepatitis a precursor for hepatocellular carcinoma development

    PubMed Central

    Jiang, Chun-Meng; Pu, Chun-Wen; Hou, Ya-Hui; Chen, Zhe; Alanazy, Mohammed; Hebbard, Lionel

    2014-01-01

    Hepatocellular carcinoma (HCC) is increasing in prevalence and is one of the most common cancers in the world. Chief amongst the risks of attaining HCC are hepatitis B and C infection, aflatoxin B1 ingestion, alcoholism and obesity. The later has been shown to promote non alcoholic fatty liver disease, which can lead to the inflammatory form non alcoholic steatohepatitis (NASH). NASH is a complex metabolic disorder that can impact greatly on hepatic function. The mechanisms by which NASH promotes HCC are only beginning to be characterized. Here in this review, we give an overview of the recent novel mechanisms published that have been associated with NASH and subsequent HCC progression. We will focus our discussion on inflammation and gut derived inflammation and how they contribute to NASH driven HCC. PMID:25469014

  3. Computed tomography and magnetic resonance imaging in diagnosing hepatocellular carcinoma.

    PubMed

    Dalla Palma, L; Pozzi-Mucelli, R S

    1992-02-01

    The evaluation of hepatocellular carcinoma (HCC) is based upon ultrasonography (US) which has proved to have a high sensitivity and is also extremely useful in guiding the percutaneous needle biopsy. The main role of computed tomography (CT) and magnetic resonance imaging (MRI) is to supplement US in evaluating the extent of HCC. The Authors discuss the different techniques of examinations of the liver both for CT and MRI as far as the modalities of contrast enhancement, site of injection, and type of contrast agents are concerned. The differences between low field and high field magnets are also discussed. The main CT and MRI findings are illustrated, depending upon the technique of examination. Finally the role of these techniques is discussed. Based upon personal experience and the data in CT literature, and if performed with updated technology and intraarterial injection (lipiodol), CT is the method of choice in order to supplement US in the evaluation of HCC.

  4. Targeting gut flora to prevent progression of hepatocellular carcinoma.

    PubMed

    Darnaud, Marion; Faivre, Jamila; Moniaux, Nicolas

    2013-02-01

    Increased translocation of intestinal bacteria is a hallmark of chronic liver disease and contributes to hepatic inflammation and fibrosis. Here we tested the hypothesis that the intestinal microbiota and Toll-like receptors (TLRs) promote hepatocellular carcinoma(HCC), a long-term consequence of chronic liver injury, inflammation,and fibrosis. Hepatocarcinogenesis in chronically injured livers depended on the intestinal microbiota and TLR4 activation in nonbone-marrow-derived resident liver cells. TLR4 and the intestinal microbiota were not required for HCC initiation but for HCC promotion, mediating increased proliferation, expression of the hepatomitogen epiregulin, and prevention of apoptosis. Gut sterilization restricted to late stages of hepatocarcinogenesis reduced HCC, suggesting that the intestinal microbiota and TLR4 represent therapeutic targets for HCC prevention in advanced liver disease.

  5. 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

  6. Next big threat for Pakistan Hepatocellular Carcinoma (HCC).

    PubMed

    Parkash, Om; Hamid, Saeed

    2016-06-01

    In our country, world hepatitis day (28th May 2013) was observed as a liver cancer day to draw global attention on the global health menace caused by Hepatocellular carcinoma (HCC). This is the right time to write a review article to apprise the nation of this growing burden of HCC caused most commonly by viruses in our country. Pakistan is also recognized as one of the countries of the world where hepatitis C virus (HCV) is endemic. Recent large national surveys suggest an overall HCV prevalence of 4.8% and that of HBV as 2.5%. There are however communities where the sero-prevalence of HCV can be as high as 23%. No wonder that chronic liver disease is the fifth most common reason for morbidity and mortality in the country and Pakistan has been perhaps accurately called a "cirrhotic state". Hence majority of such patients are at risk of developing HCC.

  7. Interplay of genetic and epigenetic alterations in hepatocellular carcinoma.

    PubMed

    Lee, Sun-Min; Kim-Ha, Jeongsil; Choi, Won-Young; Lee, Jungwoo; Kim, Dawon; Lee, Jinyoung; Choi, Eunji; Kim, Young-Joon

    2016-07-01

    Genetic and epigenetic alterations play prominent roles in hepatocarcinogenesis and their appearance varies depending on etiological factors, race and tumor progression. Intriguingly, distinct patterns of these genetic and epigenetic mutations are coupled not only to affect each other, but to trigger different types of tumorigenesis. The patterns and frequencies of somatic variations vary depending on the nature of the surrounding chromatin. On the other hand, epigenetic alterations often induce genomic instability prone to mutation. Therefore, genetic mutations and epigenetic alterations in hepatocellular carcinoma appear to be inseparable factors that accelerate tumorigenesis synergistically. We have summarized recent findings on genetic and epigenetic modifications, their influences on each other's alterations and putative roles in liver tumorigenesis.

  8. 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.

  9. 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

  10. PPAR Could Contribute to the Pathogenesis of Hepatocellular Carcinoma.

    PubMed

    Kimura, Osamu; Kondo, Yasuteru; Shimosegawa, Tooru

    2012-01-01

    Viral hepatitis with hepatitis C virus or hepatitis B virus and chronic liver disease such as alcoholic or nonalcoholic steatohepatitis are critical factors in the development of hepatocellular carcinoma (HCC). Furthermore, diabetes is known as an independent risk factor for HCC. Peroxisome proliferator-activated receptor (PPAR) is known to have an important role in fatty liver, and the mechanism of carcinogenesis has been clarified. PPAR controls ligand-dependent transcription, and three subtypes (α, δ, and γ) in humans are known. PPARs could contribute to the mechanisms of cell cycling, anti-inflammatory responses, and apoptosis. Therefore, to clarify the pathogenesis of HCC, we should examine PPAR signaling. In this paper, we have summarized the relevance of PPARs to the pathogenesis of HCC and cancer stem cells and possible therapeutic options through modifying PPAR signaling. PMID:23316217

  11. PPAR Could Contribute to the Pathogenesis of Hepatocellular Carcinoma

    PubMed Central

    Kimura, Osamu; Kondo, Yasuteru; Shimosegawa, Tooru

    2012-01-01

    Viral hepatitis with hepatitis C virus or hepatitis B virus and chronic liver disease such as alcoholic or nonalcoholic steatohepatitis are critical factors in the development of hepatocellular carcinoma (HCC). Furthermore, diabetes is known as an independent risk factor for HCC. Peroxisome proliferator-activated receptor (PPAR) is known to have an important role in fatty liver, and the mechanism of carcinogenesis has been clarified. PPAR controls ligand-dependent transcription, and three subtypes (α, δ, and γ) in humans are known. PPARs could contribute to the mechanisms of cell cycling, anti-inflammatory responses, and apoptosis. Therefore, to clarify the pathogenesis of HCC, we should examine PPAR signaling. In this paper, we have summarized the relevance of PPARs to the pathogenesis of HCC and cancer stem cells and possible therapeutic options through modifying PPAR signaling. PMID:23316217

  12. [Occult hepatitis B virus infection and hepatocellular carcinoma].

    PubMed

    Lee, Jong Joon; Kwon, Oh Sang

    2013-09-01

    Many studies have suggested that occult HBV infection has a substantial clinical relevance to hepatocellular carcinoma (HCC). Occult HBV infection is an important risk factor for the development of cirrhosis and HCC in patients without HBsAg. As a matter of fact, occult HBV infection is one of the most common causes of crytogenic HCC in endemic areas of HBV. However, there still are controversial issues about the association between occult HBV infection and HCC according to the underlying liver disease. In alcoholic cirrhosis, occult HBV infection may exert synergistic effect on the development of HCC. However, there is insufficient evidence to relate occult HBV infection to hepatocarcinogenesis in non-alcoholic fatty liver disease. In cryptogenic HCC, occult HBV infection may play a direct role in the development of HCC. In order to elucidate the assocciation between occult HBV infection and HCC, underlying liver disease must be specified and larger number of cases must be included in future studies.

  13. 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

  14. 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

  15. Magnetic Nanoparticles for Hepatocellular Carcinoma Diagnosis and Therapy.

    PubMed

    Ungureanu, Bogdan Silviu; Teodorescu, Cristian-Mihail; Săftoiu, Adrian

    2016-09-01

    Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver, ranking as the second most common cause of death from cancer worldwide. Magnetic nanoparticles (MNPs) have been used so far in tumor diagnosis and treatment, demonstrating great potential and promising results. In principle, three different approaches can be used in the treatment of tumors with superparamagnetic iron oxide nanoparticles: magnetically induced hyperthermia, drug targeting and selective suppression of tumor growth. This review focuses on the use of iron oxide nanoparticles for the diagnosis and treatment of liver cancer and offers a walkthrough from the MNPs imaging applicability to further therapeutic options, including their potential flaws. The MNP unique physical and biochemical properties will be mentioned in close relationship to their subsequent effects on the human body, and, also, their toxic potential will be noted. A presentation of what barriers the MNPs should overcome to be more successful will conclude this review. PMID:27689203

  16. 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

  17. AAV vector integration sites in mouse hepatocellular carcinoma.

    PubMed

    Donsante, Anthony; Miller, Daniel G; Li, Yi; Vogler, Carole; Brunt, Elizabeth M; Russell, David W; Sands, Mark S

    2007-07-27

    Adeno-associated viruses (AAV) are promising gene therapy vectors that have little or no acute toxicity. We show that normal mice and mice with mucopolysaccharidosis VII (MPS VII) develop hepatocellular carcinoma (HCC) after neonatal injection of an AAV vector expressing b-glucuronidase. AAV proviruses were isolated from four tumors and were all located within a 6-kilobase region of chromosome 12. This locus encodes several imprinted transcripts, small nucleolar RNAs (snoRNAs), and microRNAs. Transcripts from adjacent genes encoding snoRNAs and microRNAs were overexpressed in tumors. Our findings implicate this locus in the development of HCC and raise concerns over the clinical use of AAV vectors. PMID:17656716

  18. Long non-coding RNAs and hepatocellular carcinoma.

    PubMed

    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.

  19. [Pathogenesis of hepatitis B virus-related hepatocellular carcinoma].

    PubMed

    Zhang, Yuanqing; Guo, Jinsheng

    2016-02-01

    Hepatocellular carcinoma (HCC) is one of the most common cancer worldwide. Most of the HCC occur in developing countries. Chronic hepatitis B virus (HBV) infection is an important risk factor for HCC development. HBV induces immune-mediated chronic hepatitis, liver injury, regeneration and scar forming responses, leading to an inflammatory, fibrotic and immune deficient microenvironment. HBV may integrate into host genome, inducing genetic abnormality and altering the expression of HCC-related genes. HBV also expresses active proteins such as X (HBx) and S proteins, which may trans-activate HCC-related proteins expression, interact with intracellular specific proteins, activate a variety of signaling pathways, and induce aberrant epigenetic modifications. HBV mutation also has impact on HBV related HCC development. PMID:26983488

  20. A lymphotoxin-driven pathway to hepatocellular carcinoma

    PubMed Central

    Haybaeck, Johannes; Zeller, Nicolas; Wolf, Monika Julia; Weber, Achim; Wagner, Ulrich; do Kurrer, Michael O; Bremer, Juliane; Iezzi, Giandomenica; Graf, Rolf; Clavien, Pierre-Alain; Thimme, Robert; Blum, Hubert; Nedospasov, Sergei A.; Zatloukal, Kurt; Ramzan, Muhammad; Ciesek, Sandra; Pietschmann, Thomas; Marche, Patrice N.; Karin, Michael; Kopf, Manfred; Browning, Jeffrey L.; Aguzzi, Adriano; Heikenwalder, Mathias

    2015-01-01

    Summary Hepatitis B and C viruses (HBV, HCV) cause chronic hepatitis and hepatocellular carcinoma (HCC) by poorly understood mechanisms. We show that cytokines lymphotoxin (LT) α, β and their receptor (LTβR) are upregulated in HBV- or HCV-induced hepatitis and HCC. Liver-specific LTαβ expression in mice induces liver inflammation and HCC causally linking hepatic LT overexpression to hepatitis and HCC. Development of HCC, composed in part of A6+ oval cells, depends on lymphocytes and IKappa B kinase β expressed by hepatocytes but is independent of TNFR1. In vivo LTβR stimulation implicates hepatocytes as the major LT-responsive liver cells and LTβR inhibition in LTαβ-transgenic mice with hepatitis suppresses HCC formation. Thus, sustained LT signaling represents a pathway involved in hepatitis-induced HCC. PMID:19800575

  1. 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

  2. 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

  3. 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

  4. Experimental models of hepatocellular carcinoma: developments and evolution.

    PubMed

    Wu, Long; Tang, Zhao-You; Li, Yan

    2009-08-01

    Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world. The biological mechanisms of hepatocarcinogenesis and progression are poorly understood. Experimental models of HCC provide valuable tools to evaluate the risk factors, new treatment modalities and biologic characteristics. Under the constant evolution in model design and technology development, new experimental models continue to emerge, including spontaneous models, induced models, viral models, transplantable models, and genetically engineered models. These models are used as tools to investigate basic biological mechanisms of growth and differentiation, oncogene function, and as systems to test new diagnostic and therapeutic approaches. Each model has its own advantages and disadvantages. The progress in HCC model construction and studies are summarized in this review. PMID:19399516

  5. 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

  6. HBx Gene Mutations in Hepatitis B Virus and Hepatocellular Carcinoma

    PubMed Central

    Mathew M, Anumol; Kurian, Sumitha C; Varghese, Atul Philip; Oommen, Seema; G, Manoj

    2014-01-01

    Hepatocellular carcinoma (HCC) is one of the most prevalent cancers which are found in many Asian and African countries. There are several risk factors that may develop to HCC. Along with several other factors contributing to HCC, hepatitis B virus (HBV) infection also accounts for a major cause. HBV infection represents a major health problem worldwide. Among all of HBV genes, HBx is believed to play a prominent role in carcinogenesis, although the actual mechanism is not yet fully understood. The HBx gene of HBV is the most common open reading frame that may undergo mutations and may develop into HCC. This review summarizes the current knowledge about the most important roles of HBx gene that may lead to the development of HCC.

  7. 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

  8. Immune-based Therapy Clinical Trials in Hepatocellular Carcinoma

    PubMed Central

    Liu, Dai; Staveley-O’Carroll, Kevin F.; Li, Guangfu

    2016-01-01

    Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality and continues to increase. Current standard of care for patients with HCC only provides limited therapeutic benefit. Development of innovative strategies is urgently needed. Experience with immunotherapy in HCC is quite early, but rapidly rise in the recent 15 years. Multifaceted immune-based approaches have shown efficacy in achieving disease regression, representing the most promising new treatment approach. Here, we classify the ongoing or completed clinical trials in HCC in terms of the immune strategies to be used and assess their clinical outcomes. The generated information may be helpful in the design of future immune-based therapies for achieving ideal tumor control and maximizing anti-tumor immunity. PMID:26877890

  9. Next big threat for Pakistan Hepatocellular Carcinoma (HCC).

    PubMed

    Parkash, Om; Hamid, Saeed

    2016-06-01

    In our country, world hepatitis day (28th May 2013) was observed as a liver cancer day to draw global attention on the global health menace caused by Hepatocellular carcinoma (HCC). This is the right time to write a review article to apprise the nation of this growing burden of HCC caused most commonly by viruses in our country. Pakistan is also recognized as one of the countries of the world where hepatitis C virus (HCV) is endemic. Recent large national surveys suggest an overall HCV prevalence of 4.8% and that of HBV as 2.5%. There are however communities where the sero-prevalence of HCV can be as high as 23%. No wonder that chronic liver disease is the fifth most common reason for morbidity and mortality in the country and Pakistan has been perhaps accurately called a "cirrhotic state". Hence majority of such patients are at risk of developing HCC. PMID:27339578

  10. Minimally invasive image-guided therapies for hepatocellular carcinoma

    PubMed Central

    Abdelsalam, Mohamed E; Murthy, Ravi; Avritscher, Rony; Mahvash, Armeen; Wallace, Michael J; Kaseb, Ahmed O; Odisio, Bruno C

    2016-01-01

    Hepatocellular carcinoma (HCC) is the fifth most frequently occurring cancer globally and predominantly develops in the setting of various grades of underlying chronic liver disease, which affects management decisions. Image-guided percutaneous ablative or transarterial therapies have acquired wide acceptance in HCC management as a single treatment modality or combined with other treatment options in patients who are not amenable for surgery. Recently, such treatment modalities have also been used for bridging or downsizing before definitive treatment (ie, surgical resection or liver transplantation). This review focuses on the use of minimally invasive image-guided locoregional therapies for HCC. Additionally, it highlights recent advancements in imaging and catheter technology, embolic materials, chemotherapeutic agents, and delivery techniques; all lead to improved patient outcomes, thereby increasing the interest in these invasive techniques. PMID:27785450

  11. Artesunate obliterates experimental hepatocellular carcinoma in rats through suppression of IL-6-JAK-STAT signalling.

    PubMed

    Ilamathi, M; Prabu, P C; Ayyappa, K Ashok; Sivaramakrishnan, V

    2016-08-01

    Activation of the IL-6 mediated JAK-STAT (Janus associated kinase-signal transducer and activator of transcription) oncogenic signalling plays a major role in hepatocellular carcinoma pathogenesis. The aim of this study is to assess the anti-tumour, anti-proliferative and apoptotic potential of artesunate and its capacity to modulate JAK-STAT pathway in a nitrosodiethylamine mediated experimental hepatocellular carcinoma model. Administration of nitrosodiethylamine (200mg/kg body weight by i.p. Injections) to rats resulted in alterations of liver pathophysiological parameters such as increased relative liver weight, and increased tumour nodule occurrence. It also increased the levels of serum marker enzymes (AST, ALT, ALP, LDH, and γGT) and tumour biomarker (AFP) levels suggestive of its capacity to cause liver tumourigenesis. Additionally, the immunohistochemistry of liver sections pertaining to nitrosodiethylamine administered animals showed increased detection of AgNOR, PCNA, and GST-Pi positive cells suggestive of its capacity to promote liver proliferation associated tumourigenesis. On the contrary, artesunate (25mg/kg bodyweight) supplementation to nitrosodiethylamine administered animals decreased all the above mentioned pathophysiological, biochemical, and immunohistochemistry parameters suggesting its anti-tumour and anti-proliferative potential. Furthermore, immunoblot analysis showed significant up-regulation of IL-6, GP130, JAK-2, STAT-3 (pY705), Bcl-xL, Bcl-2 and simultaneous down-regulation of Caspase-3, PARP and SOCS-3 in nitrosodiethylamine administered animals. Nevertheless, the immunoblot analysis revealed vice-versa on artesunate supplementation to nitrosodiethylamine administered animals, indicating promotion of the feedback loop inhibition mechanism through SOCS3 up-regulation thereby leading to suppression of JAK-STAT signalling. Overall all these findings substantiate that artesunate promotes anti-tumour, anti-proliferation and apoptosis

  12. Hepatocellular carcinoma in Central Europe: prognostic features and survival

    PubMed Central

    Schoniger-Hekele, M; Muller, C; Kutilek, M; Oesterreicher, C; Ferenci, P; Gangl, A

    2001-01-01

    BACKGROUND AND AIMS—We investigated the influence of baseline characteristics of patients with hepatocellular carcinoma (HCC) on prognosis and developed a multivariate Cox model predicting survival. All patients were from Central Europe.
METHODS—All 245 patients seen at the Department of Gastroenterology and Hepatology at the University of Vienna, Austria, from July 1991 to March 1998 were included in this retrospective study. Nineteen different clinical characteristics and survival time from date of diagnosis were noted. Factors determining survival time were analysed by univariate and multivariate analysis using Cox proportional hazard regression models and a new classification model was constructed. The validity of this model was tested on an independent group of 89 patients, seen from April 1998 to September 1999.
RESULTS—Median survival in patients with HCC was 8.0 months. In a multivariate analysis bilirubin (>2 mg/dl), portal vein thrombosis, prothrombin time (<70%), alpha fetoprotein (>180 µg/l), tumour mass >50%, and enlarged lymph nodes were independent predictors of survival. A newly constructed Cox proportional hazard model (Vienna survival model for HCC=VISUM-HCC) identified three disease stages with different durations of survival (median survival stage 1, 15.2 months; stage 2, 7.2 months; and stage 3, 2.6 months; p=0.00001). Applying the VISUM-HCC survival model to patients in Okuda stage 2 identified subgroups with an excellent and very poor prognosis for which different treatment modalities should be offered.
CONCLUSIONS—Our patients with HCC had a poor median survival of eight months. Six easily measurable clinical variables were significant predictors of survival in patients with HCC. The new VISUM-HCC survival model may be useful for stratifying patients with HCC for various clinical treatment modalities.


Keywords: hepatocellular carcinoma; clinical presentation; prognostic model PMID:11115830

  13. 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

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

    PubMed

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

    2016-05-01

    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

  15. 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.

  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. Induction of Human Hepatocellular Carcinoma HepG2 Cell Apoptosis by Naringin.

    PubMed

    Banjerdpongchai, Ratana; Wudtiwai, Benjawan; Khawon, Patompong

    2016-01-01

    Naringin, a bioflavonoid found in Citrus seeds, inhibits proliferation of cancer cells. The objectives of this study were to investigate the mode and mechanism(s) of hepatocellular carcinoma HepG2 cell death induced by naringin. The cytotoxicity of naringin towards HepG2 cells proved dosedependent, measured by MTT assay. Naringintreated HepG2 cells underwent apoptosis also in a concentration related manner, determined by annexin Vfluorescein isothiocyanate (FITC) and propidium iodide (PI) employing flow cytometry. Mitochondrial transmembrane potential (MTP) measured using 3,3'dihexyloxacarbocyanine iodide (DiOC6) and flow cytometer was reduced concentrationdependently, which indicated influence on the mitochondrial signaling pathway. Caspase3, 8 and 9 activities were enhanced as evidenced by colorimetric detection of paranitroaniline tagged with a substrate for each caspase. Thus, the extrinsic and intrinsic pathways were linked in human naringintreated HepG2 cell apoptosis. The expression levels of proapoptotic Bax and Bak proteins were increased whereas that of the antiapoptotic BclxL protein was decreased, confirming the involvement of the mitochondrial pathway by immunoblotting. There was an increased expression of truncated Bid (tBid), which indicated caspase8 proteolysis activity in Bid cleavage as its substrate in the extrinsic pathway. In conclusion, naringin induces human hepatocellular carcinoma HepG2 cell apoptosis via mitochondriamediated activation of caspase9 and caspase8mediated proteolysis of Bid. Naringin anticancer activity warrants further investigation for application in medical treatment. PMID:27509965

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

    PubMed Central

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

    2012-01-01

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

  19. 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

  20. Circulating microRNAs (cmiRNAs) as novel potential biomarkers for hepatocellular carcinoma

    PubMed Central

    Qi, Jiahui; Wang, Jin; Katayama, Hiroshi; Sen, Subrata; Liu, Song-mei

    2013-01-01

    Incidence and mortality associated with hepatocellular carcinoma (HCC) is rising throughout the world. Accurate, noninvasive biomarkers for the early detection of HCC are urgently needed to reduce worldwide morbidity and mortality related to HCC. MicroRNAs (miRNAs), 17- to 25-nucleotide noncoding RNAs that are frequently dysregulated in HCC, have shown great promise as tissue-based markers for HCC diagnosis and prognosis. Moreover, they are stably expressed in serum and urine, and these circulating microRNAs (cmiRNAs) are emerging as novel noninvasive biomarkers for the early detection and prognosis of HCC. This article summarizes the latest findings on the role of circulating miRNAs as potential minimally invasive diagnostic and prognostic biomarkers for HCC. PMID:23259781

  1. Hepatocellular carcinoma in variegate porphyria: a case report and literature review.

    PubMed

    Luvai, Ahai; Mbagaya, Wycliffe; Narayanan, Deepa; Degg, Tim; Toogood, Giles; Wyatt, Judith I; Swinson, Daniel; Hall, Claire J; Barth, Julian H

    2015-05-01

    Variegate porphyria is an autosomal dominant acute hepatic porphyria characterized by photosensitivity and acute neurovisceral attacks. Hepatocellular carcinoma has been described as a potential complication of variegate porphyria in case reports. We report a case of a 48-year-old woman who was diagnosed with hepatocellular carcinoma following a brief history of right upper quadrant pain which was preceded by a few months of blistering lesions in sun-exposed areas. She was biochemically diagnosed with variegate porphyria, and mutational analysis confirmed the presence of a heterozygous mutation in the protoporphyrinogen oxidase gene. Despite two hepatic resections, she developed pulmonary metastases. She responded remarkably well to Sorafenib and remains in remission 16 months after treatment. A review of the literature revealed that hepatocellular carcinoma in variegate porphyria has been described in at least eight cases. Retrospective and prospective cohort studies have suggested a plausible association between hepatocellular carcinoma and acute hepatic porphyrias. Hepatic porphyrias should be considered in the differential diagnoses of hepatocellular carcinoma of uncertain aetiology. Patients with known hepatic porphyrias may benefit from periodic monitoring for this complication.

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

    PubMed

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

    2014-04-01

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

  3. 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.

  4. Peritoneal lavage with distilled water during liver resection in patients with spontaneously ruptured hepatocellular carcinomas.

    PubMed

    Lin, Chien-Hua; Hsieh, Huan-Fa; Yu, Jyh-Cherng; Chen, Teng-Wei; Yu, Chih-Yung; Hsieh, Chung-Bao

    2006-09-01

    Spontaneously rupture of hepatocellular carcinoma is a life threatening and worse prognosis. Not only the lower rate of resection and hemodynamic unstable, but also the hepatic failure and recurrence. Distilled water irrigation had been applied in several cancer surgeries including colon, stomach, breast, ovary, and bladder; thus had good results in lowering the tumor spreading. We applied distilled water peritoneal lavage after liver resection in patients with spontaneous rupture of hepatocellular carcinoma to define the influence of prognosis. Thirteen patients with spontaneous ruptured hepatocellular carcinoma underwent distilled water peritoneal lavage after curative liver resection (Group A). Nineteen patients with spontaneous ruptured hepatocellular carcinoma did not undergo distilled water peritoneal lavage after curative liver resection (Group B). There were 11 patients of tumor recurrence in Group B; 2 in Group A. The mean disease-free time of Group B was 2.05 +/- 0.74 years; for Group A it was 3.59 +/- 0.60 (P = 0.045). Peritoneal lavage in this series resulted in significantly better survival time for the patients in Group A (P = 0.0158). That implies distilled water peritoneal lavage during liver resection would retard the tumor recurrence and further improve the survival rate in patients with spontaneously ruptured hepatocellular carcinoma. PMID:16900516

  5. 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

  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. 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

  8. 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

  9. 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

  10. Infiltrative hepatocellular carcinoma: what radiologists need to know.

    PubMed

    Reynolds, Arich R; Furlan, Alessandro; Fetzer, David T; Sasatomi, Eizaburo; Borhani, Amir A; Heller, Matthew T; Tublin, Mitchell E

    2015-01-01

    Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. The macroscopic growth pattern of HCC is subdivided into three categories: nodular, massive, and infiltrative. Infiltrative HCC accounts for 7%-20% of HCC cases and is confirmed at pathologic analysis on the basis of the spread of minute tumor nodules throughout large regions of the liver. Infiltrative HCC may represent a diagnostic challenge because it is often difficult to distinguish from background changes in cirrhosis at imaging. Infiltrative HCC usually spreads over multiple hepatic segments, occupying an entire hepatic lobe or the entire liver, and it is frequently associated with portal vein tumor thrombosis. The tumor is usually ill defined at ultrasonography and shows minimal and inconsistent arterial enhancement and heterogeneous washout at contrast material-enhanced computed tomography and magnetic resonance (MR) imaging. The tumor may be more visible among the surrounding liver parenchyma at diffusion-, T1-, and T2-weighted MR imaging. Several liver diseases can mimic the infiltrative appearance of this malignancy, including focal confluent fibrosis, hepatic fat deposition, hepatic microabscesses, intrahepatic cholangiocarcinoma, and diffuse metastatic disease (pseudocirrhosis). The prognosis for patients with infiltrative HCC is poor because the tumor is often markedly advanced and associated with vascular invasion at presentation. Survival after surgical resection is decreased; thus, infiltrative HCC is a contraindication for resection and transplantation. Knowledge of the key tumor characteristics and imaging findings will help radiologists formulate a correct and timely diagnosis to improve patient management.

  11. 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

  12. Does herbal medicine reduce the risk of hepatocellular carcinoma?

    PubMed Central

    Rino, Yasushi; Yukawa, Norio; Yamamoto, Naoto

    2015-01-01

    Many herbal medicines are effective anti-inflammatory agents and may therefore suppress the development of hepatocellular carcinoma (HCC). Recently, treatment with a single-tablet regimen containing ledipasvir and sofosbuvir resulted in high rates of sustained virologic response among patients with hepatitis C virus genotype 1 infection who did not respond to prior interferon-based treatment. Patients with chronic hepatitis C are expected to receive this treatment worldwide. However, many patients have hepatitis-like fatty liver and nonalcoholic steatohepatitis. A strategy to prevent the development of HCC in this subgroup of patients is urgently required. Whether herbal medicines can suppress the development of HCC remains to be established. However, herbal medicines are effective anti-inflammatory agents and may inhibit the development of HCC. Clinical trials exploring the effectiveness of herbal medicines in the prevention and treatment of HCC are therefore warranted. The current lack of knowledge and of educational programs is a barrier to increasing the use of potentially effective herbal medicines and performing prospective clinical trials. PMID:26457019

  13. 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

  14. 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

  15. 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

  16. Untreated hepatocellular carcinoma in Egypt: outcome and prognostic factors

    PubMed Central

    Zeeneldin, Ahmed Abdelmabood; Salem, Salem Eid; Darwish, Amira Diaa; El-Gammal, Mosaad Mahmoud; Hussein, Marwa Mahmoud; Saadeldin, Mohamed

    2015-01-01

    Background Hepatocellular carcinoma (HCC) is a common cancer worldwide as well as in Egypt with hepatitis C and B, alcohol and aflatoxins being the commonest risk factors. Aim The objective of this study was to assess the prognostic factors affecting overall survival (OS) of untreated HCC in Egypt. Methods This retrospective study was conducted at Tanta Cancer Center, Egypt where 288 HCC cases who received no specific therapy and were followed-up until death were identified. The impact of possible prognostic factors on OS was assessed using the log-rank test (univariate analyses) and Cox regression method (multivariate analysis). Results The median OS of untreated HCC was 2.3 months (95% confidence interval: 1.9–2.6). The 1, 3, 6, 12, 24 months OS rates were 84%, 42%, 21%, 9%, and 3%, respectively. All cases had died by 46 months. Male sex, advanced Child-Pugh class, the clinical presentation of ascites, cough, fatigue, and the presence of metastases were associated with poor survival (P<0.05 for all). In multivariate analysis; cough, presence of ascites, and Child-Pugh class were independent predictors of poor survival. Conclusion OS in untreated HCC in Egypt is very short. Many factors interact to produce this dismal survival. PMID:27508189

  17. 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

  18. Aberrant regulation of Wnt signaling in hepatocellular carcinoma

    PubMed Central

    Liu, Li-Juan; Xie, Shui-Xiang; Chen, Ya-Tang; Xue, Jing-Ling; Zhang, Chuan-Jie; Zhu, Fan

    2016-01-01

    Hepatocellular carcinoma (HCC) is one of the most lethal malignancies in the world. Several signaling pathways, including the wingless/int-1 (Wnt) signaling pathway, have been shown to be commonly activated in HCC. The Wnt signaling pathway can be triggered via both catenin β1 (CTNNB1)-dependent (also known as “canonical”) and CTNNB1-independent (often referred to as “non-canonical”) pathways. Specifically, the canonical Wnt pathway is one of those most frequently reported in HCC. Aberrant regulation from three complexes (the cell-surface receptor complex, the cytoplasmic destruction complex and the nuclear CTNNB1/T-cell-specific transcription factor/lymphoid enhancer binding factor transcriptional complex) are all involved in HCC. Although the non-canonical Wnt pathway is rarely reported, two main non-canonical pathways, Wnt/planar cell polarity pathway and Wnt/Ca2+ pathway, participate in the regulation of hepatocarcinogenesis. Interestingly, the canonical Wnt pathway is antagonized by non-canonical Wnt signaling in HCC. Moreover, other signaling cascades have also been demonstrated to regulate the Wnt pathway through crosstalk in HCC pathogenesis. This review provides a perspective on the emerging evidence that the aberrant regulation of Wnt signaling is a critical mechanism for the development of HCC. Furthermore, crosstalk between different signaling pathways might be conducive to the development of novel molecular targets of HCC. PMID:27672271

  19. 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

  20. 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

  1. 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

  2. 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

  3. 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

  4. Hepatocellular Carcinoma in Pakistan: National Trends and Global Perspective.

    PubMed

    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

  5. 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.

  6. 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

  7. 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.

  8. Surveillance for Hepatocellular Carcinoma in Patients with NASH.

    PubMed

    Kolly, Philippe; Dufour, Jean-François

    2016-01-01

    European and American guidelines recommend surveillance for hepatocellular carcinoma (HCC) by performing ultrasonography on a six-month basis on an at risk population, defined by presence of cirrhosis. HCC, due to non-alcoholic steatohepatitis (NASH), is rising. Patients with NASH have a high risk of developing HCC and, therefore, have to be enrolled in a screening program. One of the challenges with NASH-induced HCC is that half of the cases arise in non-cirrhotic patients. There is a need to identify those patients in order to screen them for HCC. The obesity of these patients is another challenge, it makes ultrasound screening more difficult. Other radiological methods, such as computer tomography (CT) scans or magnetic resonance imaging (MRI), are available, but the surveillance program would no longer be cost-effective. There is a need to prospectively acquire information on cohorts of patients with NASH in order to improve the tools we have to diagnose early tumors in these patients. PMID:27338480

  9. 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

  10. 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

  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. 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

  13. 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.

  14. The effect of LOXL2 in hepatocellular carcinoma

    PubMed Central

    Wu, Linghong; Zhang, Yuan; Zhu, Ying; Cong, Qingwei; Xiang, Yan; Fu, Linlin

    2016-01-01

    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

  15. 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.

  16. 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

  17. Clinical Implications of Cancer Stem Cell Biology in Hepatocellular Carcinoma

    PubMed Central

    Ji, Junfang; Wang, Xin Wei

    2012-01-01

    Solid tumors are thought to contain cancer stem cells (CSCs) as a distinct population responsible for tumor relapse and metastasis due to their abilities to self renew, differentiate and give rise to a new tumor in local or distant organs. CSCs have been identified in many tumor types, including hepatocellular carcinoma (HCC), the fifth most common and third most deadly malignancy with observable heterogeneity. Numerous studies have shown that hepatic CSCs could be enriched via different cell surface markers, e.g., CD13, CD24, CD44, CD90, CD133, EpCAM (CD326), and OV6. They could also be identified through functional assays such as isolating the side population cells by Hoechst dye staining or screening cells with a high activity of aldehyde dehydrogenase. Functional characterization of hepatic CSCs has revealed several deregulated signaling pathways, such as Wnt/β-catenin, AKT, TGF-beta, IL-6/STAT3 pathways to be critical in inducing “stemness” of HCC and in promoting self-renewal, tumorigenicity and chemoresistance. An increased understanding of the hepatic CSC biology shed light on the development of new diagnostic, prognostic therapeutic strategies in improving HCC clinical management. In this review, we summarized recent evidence including the identification of hepatic CSCs and its underlying biological mechanisms, and discussed potential clinical implications in HCC. PMID:22846863

  18. 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

  19. 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

  20. 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

  1. 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

  2. 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

  3. 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.

  4. 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

  5. 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

  6. Astrocyte elevated gene-1 regulates hepatocellular carcinoma development and progression

    PubMed Central

    Yoo, Byoung Kwon; Emdad, Luni; Su, Zao-zhong; Villanueva, Augusto; Chiang, Derek Y.; Mukhopadhyay, Nitai D.; Mills, Alan Scott; Waxman, Samuel; Fisher, Robert A.; Llovet, Josep M.; Fisher, Paul B.; Sarkar, Devanand

    2009-01-01

    Hepatocellular carcinoma (HCC) is a highly aggressive vascular cancer characterized by diverse etiology, activation of multiple signal transduction pathways, and various gene mutations. Here, we have determined a specific role for astrocyte elevated gene-1 (AEG1) in HCC pathogenesis. Expression of AEG1 was extremely low in human hepatocytes, but its levels were significantly increased in human HCC. Stable overexpression of AEG1 converted nontumorigenic human HCC cells into highly aggressive vascular tumors, and inhibition of AEG1 abrogated tumorigenesis by aggressive HCC cells in a xenograft model of nude mice. In human HCC, AEG1 overexpression was associated with elevated copy numbers. Microarray analysis revealed that AEG1 modulated the expression of genes associated with invasion, metastasis, chemoresistance, angiogenesis, and senescence. AEG1 also was found to activate Wnt/β-catenin signaling via ERK42/44 activation and upregulated lymphoid-enhancing factor 1/T cell factor 1 (LEF1/TCF1), the ultimate executor of the Wnt pathway, important for HCC progression. Inhibition studies further demonstrated that activation of Wnt signaling played a key role in mediating AEG1 function. AEG1 also activated the NF-κB pathway, which may play a role in the chronic inflammatory changes preceding HCC development. These data indicate that AEG1 plays a central role in regulating diverse aspects of HCC pathogenesis. Targeted inhibition of AEG1 might lead to the shutdown of key elemental characteristics of HCC and could lead to an effective therapeutic strategy for HCC. PMID:19221438

  7. Aberrant regulation of Wnt signaling in hepatocellular carcinoma.

    PubMed

    Liu, Li-Juan; Xie, Shui-Xiang; Chen, Ya-Tang; Xue, Jing-Ling; Zhang, Chuan-Jie; Zhu, Fan

    2016-09-01

    Hepatocellular carcinoma (HCC) is one of the most lethal malignancies in the world. Several signaling pathways, including the wingless/int-1 (Wnt) signaling pathway, have been shown to be commonly activated in HCC. The Wnt signaling pathway can be triggered via both catenin β1 (CTNNB1)-dependent (also known as "canonical") and CTNNB1-independent (often referred to as "non-canonical") pathways. Specifically, the canonical Wnt pathway is one of those most frequently reported in HCC. Aberrant regulation from three complexes (the cell-surface receptor complex, the cytoplasmic destruction complex and the nuclear CTNNB1/T-cell-specific transcription factor/lymphoid enhancer binding factor transcriptional complex) are all involved in HCC. Although the non-canonical Wnt pathway is rarely reported, two main non-canonical pathways, Wnt/planar cell polarity pathway and Wnt/Ca(2+) pathway, participate in the regulation of hepatocarcinogenesis. Interestingly, the canonical Wnt pathway is antagonized by non-canonical Wnt signaling in HCC. Moreover, other signaling cascades have also been demonstrated to regulate the Wnt pathway through crosstalk in HCC pathogenesis. This review provides a perspective on the emerging evidence that the aberrant regulation of Wnt signaling is a critical mechanism for the development of HCC. Furthermore, crosstalk between different signaling pathways might be conducive to the development of novel molecular targets of HCC. PMID:27672271

  8. Downregulation of FOXP2 promoter human hepatocellular carcinoma cell invasion.

    PubMed

    Yan, Xia; Zhou, Huiling; Zhang, Tingting; Xu, Pan; Zhang, Shusen; Huang, Wei; Yang, Linlin; Gu, Xingxing; Ni, Runzhou; Zhang, Tianyi

    2015-12-01

    Hepatocellular carcinoma (HCC) is a major health concern with a high morbidity and mortality rate worldwide. However, the mechanism underlying hepatocarcinogenesis remains unclear. Forkhead box P2 (FOXP2) has been implicated in various human cancer types. However, the role of FOXP2 in HCC remains unknown. Western blot and immunohistochemistry were used to measure the expression of FOXP2 protein in HCC and adjacent normal tissues in 50 patients. Wound healing and transwell assays were used to determine the cell invasion ability. We showed that the level of FOXP2 was significantly reduced in HCC compared with the adjacent non-tumorous tissue. There was statistical significance between the expression of FOXP2 and vein invasion (P = 0.017), number of tumor nodes (P = 0.028), and AFP (P = 0.033). Low expression of FOXP2 correlated with poor survival. Moreover, wound healing and transwell assays showed that FOXP2 could decrease cell invasion and affect the expression of vimentin and E-cadherin. Our results suggested that FOXP2 expression was downregulated in HCC tumor tissues, and reduced FOXP2 expression was associated with poor overall survival. In addition, downregulation of FOXP2 significantly enhanced cell invasiveness. These findings uncover that FOXP2 might be a new prognostic factor and be closely correlated with HCC cell invasion.

  9. FXR induces SOCS3 and suppresses hepatocellular carcinoma

    PubMed Central

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

    2015-01-01

    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

  10. 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.

  11. Promoter Methylation of SFRP3 Is Frequent in Hepatocellular Carcinoma

    PubMed Central

    Shih, Yu-Lueng; Lien, Gi-Shih; Suk, Fat-Moon; Hsieh, Chung-Bao; Yan, Ming-De

    2014-01-01

    Oncogenic activation of the Wnt/β-catenin signaling pathway is common in human cancers. The secreted frizzled-related proteins (SFRPs) function as negative regulators of Wnt signaling and have important implications in carcinogenesis. Because there have been no reports about the role of SFRP3 in hepatocellular carcinoma (HCC), we investigated the level of methylation and transcription of SFRP3. Four HCC cell lines, 60 HCCs, 23 cirrhosis livers, 37 chronic hepatitis livers, and 30 control livers were prescreened for SFRP3 promoter methylation by methylation-specific polymerase chain reaction (MS-PCR) and bisulfite sequencing. SFRP3 promoter methylation was observed in 100%, 60%, 39.1%, 16.2%, and 0% in HCC cell lines, primary HCCs, cirrhosis livers, chronic hepatitis livers, and control livers, respectively. Demethylation treatment with 5-aza-2′-deoxycytidine in HCC cells restored or increased the SFRP3 mRNA expression. We next used quantitative MS-PCR (QMSP) to analyze the methylation level of SFRP3 in 60 HCCs and their corresponding nontumor tissues. Methylation of SFRP3 promoter region in HCCs increased significantly compared with control tissues. There is a positive correlation between promoter hypermethylation and SFRP3 mRNA downregulation. Our data suggest that promoter hypermethylation of SFRP3 is a common event in HCCs and plays an important role in regulation of SFRP3 mRNA expression. PMID:24591760

  12. 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

  13. 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

  14. 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.

  15. Personalized Clinical Trials in Hepatocellular Carcinoma Based on Biomarker Selection

    PubMed Central

    Zhang, Bingnan; Finn, Richard S.

    2016-01-01

    Background Since the approval of sorafenib there have been numerous failures of new agents in Phase III studies for treatment of advanced hepatocellular carcinoma (HCC). These studies have generally ignored the molecular heterogeneity of HCC and they have not enrolled patients based on predictive markers of response. The development of molecular targeted therapeutics in HCC needs to model the approach that has been taken with great success in other solid tumors, to decrease the likelihood of failure in future studies. Summary Here we review the paradigm taken with novel targeted agents in other solid tumors and highlight ongoing studies in HCC that are incorporating biomarkers in clinical development. Key Messages With the appreciation of the molecular diversity of HCC, clinical development of new agents in HCC will need to be targeted towards those patients who are most likely to benefit. This strategy, based on biomarkers for patient selection, is more likely to yield positive results and mitigate the risk of continued negative Phase III studies. PMID:27493897

  16. 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

  17. 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

  18. 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.

  19. 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

  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. 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

  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. 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

  4. 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

  5. Role of stereotactic body radiation therapy for hepatocellular carcinoma

    PubMed Central

    Sanuki, Naoko; Takeda, Atsuya; Kunieda, Etsuo

    2014-01-01

    The integration of new technologies has raised an interest in liver tumor radiotherapy, with literature evolving to support its efficacy. These advances, particularly stereotactic body radiation therapy (SBRT), have been critical in improving local control or potential cure in liver lesions not amenable to first-line surgical resection or radiofrequency ablation. Active investigation of SBRT, particularly for hepatocellular carcinoma (HCC), has recently started, yielding promising local control rates. In addition, data suggest a possibility that SBRT can be an alternative option for HCC unfit for other local therapies. However, information on optimal treatment indications, doses, and methods remains limited. In HCC, significant differences in patient characteristics and treatment availability exist by country. In addition, the prognosis of HCC is greatly influenced by underlying liver dysfunction and treatment itself in addition to tumor stage. Since they are closely linked to treatment approach, it is important to understand these differences in interpreting outcomes from various reports. Further studies are required to validate and maximize the efficacy of SBRT by a large, multi-institutional setting. PMID:24696597

  6. Does herbal medicine reduce the risk of hepatocellular carcinoma?

    PubMed

    Rino, Yasushi; Yukawa, Norio; Yamamoto, Naoto

    2015-10-01

    Many herbal medicines are effective anti-inflammatory agents and may therefore suppress the development of hepatocellular carcinoma (HCC). Recently, treatment with a single-tablet regimen containing ledipasvir and sofosbuvir resulted in high rates of sustained virologic response among patients with hepatitis C virus genotype 1 infection who did not respond to prior interferon-based treatment. Patients with chronic hepatitis C are expected to receive this treatment worldwide. However, many patients have hepatitis-like fatty liver and nonalcoholic steatohepatitis. A strategy to prevent the development of HCC in this subgroup of patients is urgently required. Whether herbal medicines can suppress the development of HCC remains to be established. However, herbal medicines are effective anti-inflammatory agents and may inhibit the development of HCC. Clinical trials exploring the effectiveness of herbal medicines in the prevention and treatment of HCC are therefore warranted. The current lack of knowledge and of educational programs is a barrier to increasing the use of potentially effective herbal medicines and performing prospective clinical trials.

  7. 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

  8. 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

  9. 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

  10. 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.

  11. 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

  12. 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

  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. Aberrant regulation of Wnt signaling in hepatocellular carcinoma

    PubMed Central

    Liu, Li-Juan; Xie, Shui-Xiang; Chen, Ya-Tang; Xue, Jing-Ling; Zhang, Chuan-Jie; Zhu, Fan

    2016-01-01

    Hepatocellular carcinoma (HCC) is one of the most lethal malignancies in the world. Several signaling pathways, including the wingless/int-1 (Wnt) signaling pathway, have been shown to be commonly activated in HCC. The Wnt signaling pathway can be triggered via both catenin β1 (CTNNB1)-dependent (also known as “canonical”) and CTNNB1-independent (often referred to as “non-canonical”) pathways. Specifically, the canonical Wnt pathway is one of those most frequently reported in HCC. Aberrant regulation from three complexes (the cell-surface receptor complex, the cytoplasmic destruction complex and the nuclear CTNNB1/T-cell-specific transcription factor/lymphoid enhancer binding factor transcriptional complex) are all involved in HCC. Although the non-canonical Wnt pathway is rarely reported, two main non-canonical pathways, Wnt/planar cell polarity pathway and Wnt/Ca2+ pathway, participate in the regulation of hepatocarcinogenesis. Interestingly, the canonical Wnt pathway is antagonized by non-canonical Wnt signaling in HCC. Moreover, other signaling cascades have also been demonstrated to regulate the Wnt pathway through crosstalk in HCC pathogenesis. This review provides a perspective on the emerging evidence that the aberrant regulation of Wnt signaling is a critical mechanism for the development of HCC. Furthermore, crosstalk between different signaling pathways might be conducive to the development of novel molecular targets of HCC.

  15. Management of hepatocellular carcinoma: Enlightening the gray zones

    PubMed Central

    Mancuso, Andrea

    2013-01-01

    Management of hepatocellular carcinoma (HCC) has been continuously evolving during recent years. HCC is a worldwide clinical and social issue and typically a complicates cirrhosis. The incidence of HCC is increasing, not only in the general population of patients with cirrhosis, but particularly in some subgroups of patients, like those with human immunodeficiency virus infection or thalassemia. Since a 3% annual HCC incidence has been estimated in cirrhosis, a bi-annual screening is generally suggested. The diagnostic criteria of HCC has recently had a dramatic evolution during recent years. HCC diagnosis is now made only on radiological criteria in the majority of the cases. In the context of cirrhosis, the universally accepted criteria for HCC diagnosis is contrast enhancement in arterial phase and washout in venous/late phase at imaging, the so called “typical pattern”. However, recently updated guidelines slightly differ in diagnostic criteria. Apart from liver transplantation, the only cure of both HCC and underlying liver cirrhosis, all the other treatments have to match with higher rate of HCC recurrence. The latter can be classified into curative (resection and percutaneous ablation) and palliative treatments. The aim of this paper was to review the current knowledge on management of HCC and to enlighten the areas of uncertainty. PMID:23805354

  16. 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.

  17. Alpha 1-antitrypsin and survival in hepatocellular carcinoma.

    PubMed Central

    Tzonou, A.; Sparos, L.; Kalapothaki, V.; Zavitsanos, X.; Rebelakos, A.; Trichopoulos, D.

    1990-01-01

    The association between serum levels of alpha 1-antitrypsin (alpha 1 AT) at the time of diagnosis and survival was studied in a group of 78 patients with confirmed hepatocellular carcinoma (HCC). All 78 patients were followed until the time of death, which occurred in all instances from HCC, with a median time of 6 months and a range of 1-117 months. Cox's proportional hazards model was utilised in the analysis controlling for sex, age, HBsAg status and logarithmically transformed values of alpha-fetoprotein (alpha-FP). Older patients and patients positive for HBsAg have suggestively higher fatality rates (0.05 less than P less than 0.10) whereas in these data sex and AFP levels were not important prognostic factors. Increased levels of serum at alpha 1AT at the time of diagnosis of HCC were statistically significantly (P less than 0.05) related with shorter survival, patients with higher serum alpha 1AT by 200 mg 100 ml-1 having an expected survival time shorter by about 25%. PMID:2153397

  18. 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

  19. 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

  20. 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.

  1. 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

  2. Identification of drivers from cancer genome diversity in hepatocellular carcinoma.

    PubMed

    Takai, Atsushi; Dang, Hien T; Wang, Xin W

    2014-01-01

    Hepatocellular carcinoma (HCC) is one of the most common cancers with a dismal outcome. The complicated molecular pathogenesis of HCC caused by tumor heterogeneity makes it difficult to identify druggable targets useful for treating HCC patients. One approach that has a potential for the improvement of patient prognosis is the identification of cancer driver genes that play a critical role in the development of HCC. Recent technological advances of high-throughput methods, such as gene expression profiles, DNA copy number alterations and somatic mutations, have expanded our understanding of the comprehensive genetic profiles of HCC. Integrative analysis of these omics profiles enables us to classify the molecular subgroups of HCC patients. As each subgroup classified according to genetic profiles has different clinical features, such as recurrence rate and prognosis, the tumor subclassification tools are useful in clinical practice. Furthermore, a global genetic analysis, including genome-wide RNAi functional screening, makes it possible to identify cancer vulnerable genes. Identification of common cancer driver genes in HCC leads to the development of an effective molecular target therapy.

  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.

  4. Hepatocellular Carcinoma Management in Nonalcoholic Fatty Liver Disease Patients

    PubMed Central

    Oliveira, Claudia P.; Alvares-da-Silva, Mario R.; Tani, Claudia M.; Diniz, Marcio A.; Stefano, Jose T.; Chagas, Aline L.; Alencar, Regiane S.S.M.; Vezozzo, Denise C.P.; Santos, Gilmar R.; Campos, Priscila B.; Alves, Venancio AF.; Ratziu, Vlad; Carrilho, Flair J.

    2016-01-01

    Background/Aims: Nonalcoholic fatty liver disease (NAFLD) has emerged as an important cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC). The Barcelona Clinic Liver Cancer (BCLC) system is the preferred staging system to evaluate patients with HCC and links prognosis assessment with treatment recommendation. The aim of this retrospective study was to evaluate whether the BCLC staging system and its treatment algorithm are suitable for patients with HCC arising from NAFLD. Methods: Forty-two patients with HCC related to either to NAFLD or cryptogenic cirrhosis were retrieved retrospectively from 2 centers in Brazil. Patients were classified according to BCLC staging system. If the proposed HCC therapy could not be applied, the case was considered to represent deviations from the recommended BCLC guideline. Causes of treatment deviations were investigated. Results: There were 4 patients without evidence of cirrhosis according to liver biopsy and/or clinical evaluation. One (2%), 21 (50%), 10 (24%), 5 (12%), and 5 patients (12%) were classified initially to the very early (0), early (A), intermediate (B), advanced (C), and terminal (D) BCLC stages, respectively. Thirty-five patients (83%) were treated according to BCLC recommendations. There were 3 cases (of 5) of protocol deviation in BCLC C patients. The 1- and 2-year overall survival rates were 81% and 66%, respectively. Conclusions: The BCLC system is applied in most cases of NAFLD-related HCC cases. Deviation of BCLC is found more frequently in BCLC C stage patients. PMID:25268068

  5. A study on the flip angle for an optimal T1-weighted image based on the 3D-THRIVE MRI technique: Focusing on the detection of a hepatocellular carcinoma (HCC)

    NASA Astrophysics Data System (ADS)

    Dong, Kyung-Rae; Goo, Eun-Hoe; Lee, Jae-Seung; Chung, Woon-Kwan; Kim, Young-Jae

    2014-04-01

    This study examined the optimal flip angle (FA) for a T1-weighted image in the detection of a hepatocellular carcinoma (HCC). A 3D-T1-weighted high-resolution isotropic volume examination (THRIVE) technique was used to determine the dependence of the signal to noise ratio (SNR) and the contrast-to-noise ratio (CNR) on the change in FA. This study targeted 40 liver cancer patients (25 men and 15 women aged 50 to 70 years with a mean age of 60.32 ± 6.2 years) who visited this hospital to undergo an abdominal MRI examination from January to June 2013. A 3.0 Tesla MRI machine (Philips, Medical System, Achieva) and a MRI receiver coil for data reception with a 16-channel multicoil were used in this study. The THRIVE (repetition time (TR): 8.1 ms, echo time (TE): 3.7 ms, matrix: 172 × 172, slice thickness: 4 mm, gap: 2 mm, field of view (FOV): 350 mm, and band width (BW): 380.1 Hz) technique was applied as a pulse sequence. The time required for the examination was 19 seconds, and the breath-hold technique was used. Axial images were obtained at five FAs: 5, 10, 15, 20 and 25°. The signal intensities of the liver, the lesion and the background noise were measured based on the acquired images before the SNR and the CNR were calculated. To evaluate the image at the FA, we used SPSS for Windows ver. 17.0 to conduct a one-way ANOVA test. A Bonferroni test was conducted as a post-hoc test. The SNRs of the hemorrhagic HCC in the 3D-THRIVE technique were 35.50 ± 4.12, 97.00 ± 10.24, 66.09 ± 7.29, 53.84 ± 5.43, and 42.92 ± 5.11 for FAs of 5, 10, 15, 20, and 25°, respectively (p = 0.0430), whereas the corresponding CNRs were 30.50 ± 3.84, 43.00 ± 5.42, 36.54 ± 4.09, 32.30 ± 2.79, and 31.69 ± 3.21 (p = 0.0003). At a small FA of 10, the SNR and the CNR showed the highest values. As the FA was increased, the SNR and the CNR values showed a decreasing tendency. In conclusion, the optimal T1-weighted image FA should be set to 10° to detect a HCC by using the 3D

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

    SciTech Connect

    Duan, J

    2015-06-15

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

  7. Recent Advances in CT and MR Imaging for Evaluation of Hepatocellular Carcinoma

    PubMed Central

    Lee, Jeong Min; Yoon, Jeong-Hee; Joo, Ijin; Woo, Hyun Sik

    2012-01-01

    Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Accurate diagnosis and assessment of disease extent are crucial for proper management of patients with HCC. Imaging plays a crucial role in early detection, accurate staging, and the planning of management strategies. A variety of imaging modalities are currently used in evaluating patients with suspected HCC; these include ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), nuclear medicine, and angiography. Among these modalities, dynamic MRI and CT are regarded as the best imaging techniques available for the noninvasive diagnosis of HCC. Recent improvements in CT and MRI technology have made noninvasive and reliable diagnostic assessment of hepatocellular nodules possible in the cirrhotic liver, and biopsy is frequently not required prior to treatment. Until now, the major challenge for radiologists in imaging cirrhosis has been the characterization of small cirrhotic nodules smaller than 2 cm in diameter. Further technological advancement will undoubtedly have a major impact on liver tumor imaging. The increased speed of data acquisition in CT and MRI has allowed improvements in both spatial and temporal resolution, which have made possible a more precise evaluation of the hemodynamics of liver nodules. Furthermore, the development of new, tissue-specific contrast agents such as gadoxetic acid has improved HCC detection on MRI. In this review, we discuss the role of CT and MRI in the diagnosis and staging of HCC, recent technological advances, and the strengths and limitations of these imaging modalities. PMID:24159569

  8. Budd-Chiari syndrome as an initial presentation of hepatocellular carcinoma: a case report.

    PubMed

    Bălăceanu, Lavinia Alice; Diaconu, Camelia Cristina; Aron, Gheorghiţa

    2014-06-01

    We report the case of a 84-year-old admitted with symptoms of congestive heart failure. Ultrasonography revealed a hyperechoic nodule in the left lobe of the liver, with a peripheral hypoechoic rim, multiple irregular hypoechoic nodules in both hepatic lobes, portal vein, inferior vena cava, and right atrium thrombosis. On ultrasonographic and alpha-fetoprotein criteria the case was interpreted as hepatocellular carcinoma with Budd-Chiari syndrome. The particularity of the case is the initial presentation of the hepatocellular carcinoma as Budd-Chiari syndrome. The inferior vena cava and right atrium thrombosis, as a cause of secondary Budd-Chiari syndrome in a patient with hepatocellular carcinoma, has been rarely reported.

  9. 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

  10. 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

  11. LincRNA-p21 activates endoplasmic reticulum stress and inhibits hepatocellular carcinoma

    PubMed Central

    Haibin, Zhang; Hui, Sima; Nan, Zhu; Guangshun, Yang

    2015-01-01

    LincRNA-p21 is a downstream long non-coding RNA (lncRNA) transcript of p53. LincRNA-p21 serves as a repressor in p53-dependent transcriptional responses and participates in diverse biological processes, including apoptosis, cell cycle, metabolism and pluripotency. However, the role of lincRNA-p21 in human hepatocellular carcinoma remains to be defined. Here in this work, we demonstrated that lincRNA-p21 acted as a tumor suppressive lncRNA in human hepatocellular carcinoma. We firstly found the downregulation of lincRNA-p21 level in human hepatocellular carcinoma tissues, and showed that low expression of lincRNA-p21 was associated with high disease stage and predicted poor survival. Further we showed that lincRNA-p21 knockdown promoted proliferation and colony formation of HepG2, Huh7 and Bel-7042 cells in vitro, while lincRNA-p21 overexpression obtained oppose results. Using tumor xenograft experiments, we also demonstrated that lincRNA-p21 inhibited HepG2 cell growth in vivo and lincRNA-p21 contributed to sorafenib-induced growth regression of HepG2 cell in vivo. Further mechanism analysis revealed that lincRNA-p21 promoted ER stress both in vitro and in vivo, which facilitated apoptosis of hepatocellular carcinoma cells. Finally, we demonstrated that ER stress accounted for lincRNA-p21 effects on apoptosis, proliferation and in vivo growth of hepatocellular carcinoma. These findings implicate that lincRNA-p21 is a potential prognostic factor and therapeutic target for human hepatocellular carcinoma. PMID:26305675

  12. 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

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

    PubMed

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

    2013-08-01

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

  14. LincRNA-p21 activates endoplasmic reticulum stress and inhibits hepatocellular carcinoma.

    PubMed

    Yang, Ning; Fu, Yong; Zhang, Haibin; Sima, Hui; Zhu, Nan; Yang, Guangshun

    2015-09-29

    LincRNA-p21 is a downstream long non-coding RNA (lncRNA) transcript of p53. LincRNA-p21 serves as a repressor in p53-dependent transcriptional responses and participates in diverse biological processes, including apoptosis, cell cycle, metabolism and pluripotency. However, the role of lincRNA-p21 in human hepatocellular carcinoma remains to be defined. Here in this work, we demonstrated that lincRNA-p21 acted as a tumor suppressive lncRNA in human hepatocellular carcinoma. We firstly found the downregulation of lincRNA-p21 level in human hepatocellular carcinoma tissues, and showed that low expression of lincRNA-p21 was associated with high disease stage and predicted poor survival. Further we showed that lincRNA-p21 knockdown promoted proliferation and colony formation of HepG2, Huh7 and Bel-7042 cells in vitro, while lincRNA-p21 overexpression obtained oppose results. Using tumor xenograft experiments, we also demonstrated that lincRNA-p21 inhibited HepG2 cell growth in vivo and lincRNA-p21 contributed to sorafenib-induced growth regression of HepG2 cell in vivo. Further mechanism analysis revealed that lincRNA-p21 promoted ER stress both in vitro and in vivo, which facilitated apoptosis of hepatocellular carcinoma cells. Finally, we demonstrated that ER stress accounted for lincRNA-p21 effects on apoptosis, proliferation and in vivo growth of hepatocellular carcinoma. These findings implicate that lincRNA-p21 is a potential prognostic factor and therapeutic target for human hepatocellular carcinoma. PMID:26305675

  15. LS-CAP: an algorithm for identifying cytogenetic aberrations in hepatocellular carcinoma using microarray data.

    PubMed

    He, Xianmin; Wei, Qing; Sun, Meiqian; Fu, Xuping; Fan, Sichang; Li, Yao

    2006-05-01

    Biological techniques such as Array-Comparative genomic hybridization (CGH), fluorescent in situ hybridization (FISH) and affymetrix single nucleotide pleomorphism (SNP) array have been used to detect cytogenetic aberrations. However, on genomic scale, these techniques are labor intensive and time consuming. Comparative genomic microarray analysis (CGMA) has been used to identify cytogenetic changes in hepatocellular carcinoma (HCC) using gene expression microarray data. However, CGMA algorithm can not give precise localization of aberrations, fails to identify small cytogenetic changes, and exhibits false negatives and positives. Locally un-weighted smoothing cytogenetic aberrations prediction (LS-CAP) based on local smoothing and binomial distribution can be expected to address these problems. LS-CAP algorithm was built and used on HCC microarray profiles. Eighteen cytogenetic abnormalities were identified, among them 5 were reported previously, and 12 were proven by CGH studies. LS-CAP effectively reduced the false negatives and positives, and precisely located small fragments with cytogenetic aberrations.

  16. Are we getting closer to understanding intratumor heterogeneity in hepatocellular carcinoma?

    PubMed

    Hammoud, Ghassan M; Ibdah, Jamal A

    2016-04-01

    Hepatocellular carcinoma (HCC) is a highly heterogenous disease and intratumor heterogeneity is a well-known fact within each individual tumor, and may involve morphological, immunohistochemical, and molecular heterogeneities. Understanding of intratumor heterogeneity of HCC should provide critical knowledge about prognosis of the disease and response to therapy. In a recent article by Friemel and colleagues, the investigators utilized a comprehensive approach in linking immunohistochemical markers and molecular changes to morphological intratumor heterogeneity in HCC. The study found that intratumor heterogeneity was detectable in 87% of HCC cases. Combined heterogeneities with respect to morphologic, immunohistochemical, and mutational status of the two most important driver mutations CTNNB1 and TP53 were seen in 22% of HCC cases. The study demonstrates the challenges facing therapeutic strategies targeting single molecules and may explain the limited success so far in developing molecular targeted therapy for HCC. PMID:27115014

  17. Are we getting closer to understanding intratumor heterogeneity in hepatocellular carcinoma?

    PubMed Central

    Hammoud, Ghassan M.

    2016-01-01

    Hepatocellular carcinoma (HCC) is a highly heterogenous disease and intratumor heterogeneity is a well-known fact within each individual tumor, and may involve morphological, immunohistochemical, and molecular heterogeneities. Understanding of intratumor heterogeneity of HCC should provide critical knowledge about prognosis of the disease and response to therapy. In a recent article by Friemel and colleagues, the investigators utilized a comprehensive approach in linking immunohistochemical markers and molecular changes to morphological intratumor heterogeneity in HCC. The study found that intratumor heterogeneity was detectable in 87% of HCC cases. Combined heterogeneities with respect to morphologic, immunohistochemical, and mutational status of the two most important driver mutations CTNNB1 and TP53 were seen in 22% of HCC cases. The study demonstrates the challenges facing therapeutic strategies targeting single molecules and may explain the limited success so far in developing molecular targeted therapy for HCC. PMID:27115014

  18. Role of biomarkers in the prediction and diagnosis of hepatocellular carcinoma

    PubMed Central

    Khattab, Mahmoud; Fouad, Magdy; Ahmed, Elham

    2015-01-01

    The prevalence of hepatocellular carcinoma (HCC) has progressively increased in recent years and is now the fifth and the second most common cancer in the World and in Egypt, respectively. Much work has focused in the development of assays for detecting hepatic carcinogensis before the observance of hepatic focal lesions. Particular attention has been directed towards HCC-specific biomarkers for use in the early diagnosis of HCC and in the confirmation of radiological studies. Although a number of biomarkers have been identified, none have been considered reliable indicators of early HCC lesions. This review presents a few of the most relevant HCC biomarkers and suggests improvements to the accuracy of diagnostic assays through their combined use. Furthermore, we present an algorithm for the biomarker-based diagnosis of HCC and highlight its important role in the early prediction of HCC. PMID:26483869

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

    PubMed Central

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

    2016-01-01

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

  20. 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

  1. [Clinical evaluation of PIVKA-II as a marker of hepatocellular carcinoma].

    PubMed

    Arima, K; Kodama, T; Suga, M; Sakamoto, H; Ohe, Y; Yachi, A

    1989-08-01

    PIVKA-II (protein induced vitamin K absence or antagonist-II) levels in plasma were measured using ELISA in patients with hepatocellular carcinoma (HCC). PIVKA-II was detected in 53 of 97 patients (54.6%) of HCC, and the combination assay of PIVKA-II and AFP identified 69 of 97 patients (71.1%) with HCC. However, the positive rate of PIVKA-II (6.1%) was lower than that of AFP (37.5%) in patients with HCC less than 2 cm in diameter. The concentration of PIVKA-II was markedly reduced within 2 weeks after treatment in patients with HCC showing a favorable response to Lp-TAE or Lp-TAI. Although PIVKA-II is a valuable marker for the diagnosis and follow-up of patients with HCC, it must be noted that the change to negative concentration of PIVKA-II after treatment does not mean complete necrosis of the tumor.

  2. 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

  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. 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.

  5. 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.

  6. 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

  7. Growth Inhibition and Apoptosis Induction by (+)-Cyanidan-3-ol in Hepatocellular Carcinoma

    PubMed Central

    Monga, Jitender; Pandit, Saurabh; Chauhan, Rajinder Singh; Chauhan, Chetan Singh; Chauhan, Shailender Singh; Sharma, Manu

    2013-01-01

    The objective of this study was to evaluate the cytotoxicity of (+)-cyanidan-3-ol (CD-3) in human hepatocellular carcinoma cell line (HepG2) and chemopreventive potential against hepatocellular carcinoma (HCC) in Balb/c mice. The HepG2 cell line was treated with CD-3 at various concentrations and the proliferation of the HepG2 cells was measure by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT), sulforhodamine B (SRB) and lactate dehydrogenase (LDH) assays. Cell apoptosis was detected by Hoechst 33258 (HO), Acridine orange/ethylene dibromide (AO/EB) staining, DNA fragmentation analysis and the apoptosis rate was detected by flow cytometry. The HCC tumor model was established in mice by injecting N-nitrosodiethylamine/carbon tetrachloride (NDEA/CCl4) and the effect of CD-3 on tumor growth in-vivo was studied. The levels of liver injury markers, tumor markers, and oxidative stress were measured. The expression levels of apoptosis-related genes in in-vitro and in vivo models were determined by RT-PCR and ELISA. The CD-3 induced cell death was considered to be apoptotic by observing the typical apoptotic morphological changes under fluorescent microscopy and DNA fragmentation analysis. Annexin V/PI assay demonstrated that apoptosis increased with increase in the concentration of CD-3. The expression levels of apoptosis-related genes that belong to bcl-2 and caspase family were increased and AP-1 and NF-κB activities were significantly suppressed by CD-3. Immunohistochemistry data revealed less localization of p53, p65 and c-jun in CD-3 treated tumors as compared to localization in NDEA/CCl4 treated tumors. Taken together, our data demonstrated that CD-3 could significantly inhibit the proliferation of HepG2 cells in-vitro and suppress HCC tumor growth in-vivo by apoptosis induction. PMID:23894334

  8. 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 imaging, and has become an indispensable imaging modality in the treatment of HCC. Early HCCs have been detected more frequently since the introduction of EOB-MRI into daily clinical practice. Early HCC is known to progress to conventional hypervascular HCC, and many risk factors have been identified for the hypervascularization of early HCC including the diameter of the tumor, presence of fat, and imaging findings of EOB-MRI. The rate of the development of hypervascular HCC was previously reported to be high in patients with chronic liver disease and early HCC. The presence of early HCC is regarded as a predictor for the recurrence of HCC following hepatic resection. On the other hand, although early HCC itself is currently not regarded as a target lesion for hepatic resection, early HCC at high risk of hypervascularity needs to be treated by local ablation therapy. If concomitant early HCC with progressed HCC is at high risk of hypervascularization and the functional liver reserve of a patient is sufficient, its simultaneous treatment at the time of hepatic resection for progressed HCC is recommended. Further studies on larger numbers of patients are needed before this strategy is adopted. PMID:26730272

  9. Clinical value of gadoxetic acid-enhanced magnetic resonance imaging in surgery for hepatocellular carcinoma - with a special emphasis on early hepatocellular carcinoma.

    PubMed

    Matsuda, Masanori

    2015-12-28

    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 imaging, and has become an indispensable imaging modality in the treatment of HCC. Early HCCs have been detected more frequently since the introduction of EOB-MRI into daily clinical practice. Early HCC is known to progress to conventional hypervascular HCC, and many risk factors have been identified for the hypervascularization of early HCC including the diameter of the tumor, presence of fat, and imaging findings of EOB-MRI. The rate of the development of hypervascular HCC was previously reported to be high in patients with chronic liver disease and early HCC. The presence of early HCC is regarded as a predictor for the recurrence of HCC following hepatic resection. On the other hand, although early HCC itself is currently not regarded as a target lesion for hepatic resection, early HCC at high risk of hypervascularity needs to be treated by local ablation therapy. If concomitant early HCC with progressed HCC is at high risk of hypervascularization and the functional liver reserve of a patient is sufficient, its simultaneous treatment at the time of hepatic resection for progressed HCC is recommended. Further studies on larger numbers of patients are needed before this strategy is adopted.

  10. Agitated saline sonography: a simple technique for intraprocedural feeder identification during transcatheter arterial chemoembolization of hepatocellular carcinoma.

    PubMed

    Krishna Prasad, B P; Ray, Brijesh

    2016-01-01

    Transcatheter arterial chemoembolization (TACE) is the most widely used treatment modality for patients with hepatocellular carcinoma who are not eligible for surgery. Selective tumor embolization is very important, more so in patients with mild to moderate liver cell failure, but determining feeder vessels could be difficult with two-dimensional angiogram alone. Cone beam computed tomography and detection software are available for intraprocedural accurate feeder vessel detection; however, these facilities are not widely available. We have evaluated and successfully applied a very simple technique using only a portable ultrasonography machine to ensure superselective feeder cannulation prior to embolization. PMID:27015444

  11. 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

  12. Giant pedunculated hepatocellular carcinoma with hemangioma mimicking intestinal obstruction

    PubMed Central

    2011-01-01

    Background Pedunculated hepatocellular carcinoma (P-HCC) has rarely been reported and is characteristically large and encapsulated. Only sporadic cases have been published, in which P-HCC was combined with other liver tumors (mostly benign), making the diagnosis difficult. Case presentation We report a patient who was admitted to our hospital with clinical features of intestinal obstruction and a palpable mass in the right iliac fossa. Ultrasound, computed tomography and magnetic resonance imaging demonstrated an encapsulated mass of unclear origin and characteristics of liver hemangioma. Laboratory tests revealed elevated α-fetoprotein (> 800 ng/ml) and cancer antigen 125 (> 51.2 U/ml). With a possible diagnosis of giant liver hemangioma, we proceeded to surgery. During surgery, a giant pedunculated tumor was discovered on the inferior surface of the right lobe of the liver, hanging free in the right abdominal cavity towards the right iliac fossa. The macroscopic appearance of the tumor was compatible with liver hemangioma. Tumor resection was performed at a safe distance, including the pedicle. The rest of the liver appeared normal. Histopathological examination revealed grade II and III HCC (according to Edmondson-Steiner's classification) with nodular configuration, central necrosis, and infiltration of the capsule. Underneath the tumor capsule, residual tissue of a cavernous hemangioma was recognized. The resection margins were free of neoplastic tissue. Conclusion This rare presentation of a giant P-HCC combined with a hemangioma with features of intestinal obstruction confirmed the diagnostic difficulties of similar cases, and required prompt surgical treatment. Therefore, patients benefit from surgical resection because both the capsule and the pedicle prevent vascular invasion, therefore improving prognosis. PMID:21939543

  13. Bland Embolization of Hepatocellular Carcinoma Using Superabsorbent Polymer Microspheres

    SciTech Connect

    Osuga, Keigo; Hori, Shinichi; Hiraishi, Kumiko; Sugiura, Takashi; Hata, Yasuhiro; Higashihara, Hiroki; Maeda, Noboru; Tomoda, Kaname; Nakamura, Hironobu

    2008-11-15

    The purpose of this study was to investigate the clinical outcomes of bland embolization using superabsorbent polymer microspheres (SAP-TAE) as an initial therapeutic option for previously untreated hepatocellular carcinoma (HCC) ineligible for resection or ablation. Fifty-nine patients with previously untreated HCC unamenable to surgery or ablation underwent bland embolization using 100- to 200-{mu}m reconstituted SAP particles (SAP-TAE) as the initial treatment. SAP-TAE was repeated as needed based on tumor response but was switched to chemoembolization when necessary to control residual or progressive tumor. Early tumor response was assessed by contrast-enhanced CT according to RECIST and EASL criteria 1 month after the initial SAP-TAE. The overall survival was calculated using the Kaplan-Meier method. The overall mean follow-up period was 30.6 months (range, 7-59 months). A total of 121 sessions of SAP-TAE were performed, with 1-5 sessions per patient (mean, 2.1 sessions). The mean period of repeated SAP-TAE was 15.6 months (range, 1-51 months), and it exceeded 1 and 2 years in 32 (54%) and 15 (25%) patients, respectively. Thirteen (22%) patients underwent repeated SAP-TAE alone, and the remaining 46 (78%) patients underwent subsequent chemoembolization. No major complication was observed and postembolization syndrome was minimal after SAP-TAE in all patients. Response rate was 14% and 66% by RECIST and EASL criteria, respectively. Overall survival rates were 100% and 83% at 1 and 2 years, respectively, and median survival time was 30 months. In conclusion, SAP-TAE was a safe and repeatable option as the induction therapy for HCC unamenable to surgery or ablation, despite the high incidence of converting to TACE during the total course.

  14. 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

  15. Risk factors for early mortality after hepatectomy for hepatocellular carcinoma.

    PubMed

    Lee, Chao-Wei; Tsai, Hsin-I; Sung, Chang-Mu; Chen, Chun-Wei; Huang, Shu-Wei; Jeng, Wen-Juei; Wu, Tsung-Han; Chan, Kun-Ming; Yu, Ming-Chin; Lee, Wei-Chen; Chen, Miin-Fu

    2016-09-01

    Despite advances in surgical technique and medical care, liver resection for hepatocellular carcinoma (HCC) remains a high-risk major operation. The present study evaluated the risk factors for early mortality after hepatectomy.We retrospectively reviewed records of patients undergoing liver resection for HCC between 1983 and 2015. A point score (Risk Assessment for early Mortality (RAM) score) for hepatectomy was developed based on multivariate analyses.Three hundred eighty-three patients (11.3%) expired within 6 months after the operation. Logistic regression analyses identified that operative duration >270 minutes and blood loss >800 cc were significant predictors of major surgical complications (P = 0.013 and 0.002, respectively). On the other hand, diabetes mellitus, albumin ≤3.5 g/dL, α-fetoprotein (AFP) >200 ng/mL, major surgical procedure, blood loss >800 cc, and major surgical complications were independent risk factors for early mortality after hepatectomy (P = 0.019, <0.001, <0.001, 0.006, 0.018, and <0.001, respectively). Risk Assessment for early Mortality score (RAM score) identified 3 subgroups of patients with distinct 6-month mortality rate, with Class III (score 10) having highest risk of early mortality.Our study demonstrated that meticulous surgical techniques to minimize blood loss and avoid prolonged operative time may help decrease the occurrence of major surgical complications. In addition to major surgical complications, diabetes mellitus, hypoalbuminemia, high AFP, massive blood loss, and major surgical procedure are also associated with early mortality after liver resection. Further study is warranted to validate the utility of RAM score as a bedside scoring system to predict postoperative outcome. PMID:27684875

  16. Dosimetric Analysis of Respiratory-Gated Radiotherapy for Hepatocellular Carcinoma

    SciTech Connect

    Xi Mian; Zhang Li; Liu Mengzhong; Deng Xiaowu; Huang Xiaoyan; Liu Hui

    2011-07-01

    The purpose of this study was to define individualized internal target volume (ITV) for hepatocellular carcinoma (HCC) using 4D computed tomography (4DCT), and to determine the geometric and dosimetric benefits of respiratory gating. Gross tumor volumes (GTVs) were contoured on 10 respiratory phases of 4DCT images for 12 patients with HCC. Three treatment plans were prepared using different planning target volumes (PTVs): (1) PTV{sub 3D}, derived from a single helical clinical target volume (CTV) plus conventional margins; (2) PTV{sub 10phases}, derived from ITV{sub 10phases}, which encompassed all 10 CTVs plus an isotropic margin of 0.8 cm; (3) PTV{sub gating}, derived from ITV{sub gating}, which encompassed three CTVs within gating-window at end-expiration plus an isotropic margin of 0.8 cm. The PTV{sub 3D} was the largest volume for all patients. The ITV-based plans and gating plans spared more normal tissues than 3D plans, especially the liver. Without increasing normal tissue complication probability of the 3D plans, the ITV-based plans allowed for increasing the calculated dose from 50.8 Gy to 54.7 Gy on average, and the gating plans could further escalate the dose to 58.5 Gy. Compared with ITV-based plans, the dosimetric gains with gating plan strongly correlated with GTV mobility in the craniocaudal direction. The ITV-based plans can ensure target coverage with less irradiation of normal tissues compared with 3D plans. Respiratory-gated radiotherapy can further reduce the target volumes to spare more surrounding tissues and allow dose escalation, especially for patients with tumor mobility >1 cm.

  17. MTBP inhibits migration and metastasis of hepatocellular carcinoma.

    PubMed

    Bi, Qian; Ranjan, Atul; Fan, Rui; Agarwal, Neeraj; Welch, Danny R; Weinman, Steven A; Ding, Jie; Iwakuma, Tomoo

    2015-04-01

    Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide with increasing incidence. Despite curative surgical resection and advanced chemotherapy, its survival rate remains low. The presence of microvascular invasion and occult metastasis is one of the major causes for this poor outcome. MDM2 Binding Protein (MTBP) has been implicated in the suppression of cell migration and cancer metastasis. However, clinical significance of MTBP, particularly in human cancer, is poorly understood. Specifically, clinical relevance of MTBP in human HCC has never been investigated. Here we demonstrated that expression of MTBP was significantly reduced in human HCC tissues compared to adjacent non-tumor tissues. MTBP expression was negatively correlated with capsular/vascular invasion and lymph node metastasis. Overexpression of MTBP resulted in the suppression of the migratory and metastatic potential of HCC cells, while its downregulation increased the migration. Consistent with the previous report, MTBP endogenously bound to alpha-actinin 4 (ACTN4) and suppressed ACTN4-mediated cell migration in multiple HCC cell lines. However, MTBP also inhibited migratory potential of PLC/PRF/5 HCC cells whose migration was not altered by manipulation of ACTN4 expression. These results suggest that mechanisms behind MTBP-mediated migration suppression may not be limited to the pathway involving ACTN4 in certain cellular contexts. Additionally, as a potential mechanism for reduced MTBP expression in tumors, we found that MTBP expression was increased following the treatment with histone deacetylase inhibitors (HDIs). Our study, for the first time, provides clinical relevance of MTBP in the suppression of HCC metastasis.

  18. Interconnections between autophagy and the coagulation cascade in hepatocellular carcinoma

    PubMed Central

    Chen, K-D; Wang, C-C; Tsai, M-C; Wu, C-H; Yang, H-J; Chen, L-Y; Nakano, T; Goto, S; Huang, K-T; Hu, T-H; Chen, C-L; Lin, C-C

    2014-01-01

    Autophagy has an important role in tumor biology of hepatocellular carcinoma (HCC). Recent studies demonstrated that tissue factor (TF) combined with coagulation factor VII (FVII) has a pathological role by activating a G-protein-coupled receptor called protease-activated receptor 2 (PAR2) for tumor growth. The present study aimed to investigate the interactions of autophagy and the coagulation cascade in HCC. Seventy HCC patients who underwent curative liver resection were recruited. Immunohistochemical staining and western blotting were performed to determine TF, FVII, PAR2 and light chain 3 (LC3A/B) expressions in tumors and their contiguous normal regions. We found that the levels of autophagic marker LC3A/B-II and coagulation proteins (TF, FVII and PAR2) were inversely correlated in human HCC tissues. Treatments with TF, FVII or PAR2 agonist downregulated LC3A/B-II with an increased level of mTOR in Hep3B cells; in contrast, knockdown of TF, FVII or PAR2 increased LC3A/B. Furthermore, mTOR silencing restored the impaired expression of LC3A/B-II in TF-, FVII- or PAR2-treated Hep3B cells and activated autophagy. Last, as an in vivo correlate, we administered TF, FVII or PAR2 agonist in a NOD/severe combined immunodeficiency xenograft model and showed decreased LC3A/B protein levels in HepG2 tumors with treatments. Overall, our present study demonstrated that TF, FVII and PAR2 regulated autophagy mainly via mTOR signaling. The interaction of coagulation and autophagic pathways may provide potential targets for further therapeutic application in HCC. PMID:24853422

  19. Development of a prognostic scoring system for resectable hepatocellular carcinoma

    PubMed Central

    Sposito, Carlo; Di Sandro, Stefano; Brunero, Federica; Buscemi, Vincenzo; Battiston, Carlo; Lauterio, Andrea; Bongini, Marco; De Carlis, Luciano; Mazzaferro, Vincenzo

    2016-01-01

    AIM To develop a prognostic scoring system for overall survival (OS) of patients undergoing liver resection (LR) for hepatocellular carcinoma (HCC). METHODS Consecutive patients who underwent curative LR for HCC between 2000 and 2013 were identified. The series was randomly divided into a training and a validation set. A multivariable Cox model for OS was fitted to the training set. The beta coefficients derived from the Cox model were used to define a prognostic scoring system for OS. The survival stratification was then tested, and the prognostic scoring system was compared with the European Association for the Study of the Liver (EASL)/American Association for the Study of Liver Diseases (AASLD) surgical criteria by means of Harrell’s C statistics. RESULTS A total of 917 patients were considered. Five variables independently correlated with post-LR survival: Model for End-stage Liver Disease score, hepatitis C virus infection, number of nodules, largest diameter and vascular invasion. Three risk classes were identified, and OS for the three risk classes was significantly different both in the training (P < 0.0001) and the validation set (P = 0.0002). Overall, 69.4% of patients were in the low-risk class, whereas only 37.8% were eligible to surgery according to EASL/AASLD. Survival of patients in the low-risk class was not significantly different compared with surgical indication for EASL/AASLD guidelines (77.2 mo vs 82.5 mo respectively, P = 0.22). Comparison of Harrell’s C statistics revealed no significant difference in predictive power between the two systems (-0.00999, P = 0.667). CONCLUSION This study established a new prognostic scoring system that may stratify HCC patients suitable for surgery, expanding surgical eligibility with respect to EASL/AASLD criteria with no harm on survival. PMID:27688661

  20. Diagnostic imaging and interventional therapy of hepatocellular carcinoma.

    PubMed

    Palma, L D

    1998-08-01

    Diagnostic imaging has many important roles in the management of patients with hepatocellular carcinoma (HCC). In diagnosis, lipiodol CT (LCT) has been shown to be the most sensitive imaging modality (90-97%) for all sizes of lesions; all other modalities have high sensitivities for lesions 1-3 cm but low sensitivities for lesions < 1 cm (ultrasound 33-37%, conventional CT 20-42% and digital subtraction angiography 40-55%). All imaging modalities understage HCC. Once again LCT is the most accurate method of evaluating the extent of tumour, but even this method does not identify all satellite nodules. Ultrasound has been proposed as a screening method, but this cannot be justified on the basis of its results or cost benefit analysis. Both CT and dynamic MRI play useful roles in evaluating the efficacy and follow-up of patients undergoing chemoembolization (TACE) and percutaneous ethanol injection (PEI). Although surgery remains the best treatment of HCC, it is unsuitable in most of the cases which would be better treated with interventional therapy. This article presents a review of the literature regarding the use of TACE, PEI or a combination of both procedures in the treatment of HCC. A multicentric study has shown that patients with monofocal lesions less than 5 cm in diameter are better treated with PEI, which is therefore a good alternative to the surgical treatment; patients with multifocal lesions (maximum of three lesions) show a better survival with TACE. Combined treatment with TACE and PEI proves to be effective in patients with large HCC.

  1. 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

  2. Hepatocellular Carcinoma Supplied by the Right Lumbar Artery

    SciTech Connect

    Miyayama, Shiro Yamashiro, Masashi; Okuda, Miho; Yoshie, Yuichi; Sugimori, Natsuki; Igarashi, Saya; Nakashima, Yoshiko; Matsui, Osamu

    2010-02-15

    This study evaluated the clinical features of hepatocellular carcinoma (HCC) supplied by the right lumbar artery. Eleven patients with HCC supplied by the right lumbar artery were treated with chemoembolization. The patients' medical records were retrospectively analyzed. All patients underwent 6.7 {+-} 3.7 (mean {+-} SD) chemoembolization sessions, and the hepatic arterial branches were noted as being attenuated. The right inferior phrenic artery (IPA) was also embolized in 10 patients. The interval between initial chemoembolization and chemoembolization of the lumbar artery supply was 53.2 {+-} 26.9 months. Mean tumor diameter was 3.1 {+-} 2.4 cm and was located at the surface of S7 and S6. The feeding-branch arose proximal to the bifurcation of the dorsal ramus and muscular branches (n = 8) or from the muscular branches (n = 3) of the right first (n = 10) or second lumbar artery (n = 1). The anterior spinal artery originated from the tumor-feeding lumbar artery in one patient. All feeders were selected, and embolization was performed after injection of iodized oil and anticancer drugs (n = 10) or gelatin sponge alone in a patient with anterior spinal artery branching (n = 1). Eight patients died from tumor progression 10.1 {+-} 4.6 months later, and two patients survived 2 and 26 months, respectively. The remaining patient died of bone metastases after 32 months despite liver transplantation 10 months after chemoembolization. The right lumbar artery supplies HCC located in the bare area of the liver, especially in patients who undergo repeated chemoembolization, including chemoembolization by way of the right IPA. Chemoembolization by way of the right lumbar artery may be safe when the feeder is well selected.

  3. MTBP inhibits migration and metastasis of hepatocellular carcinoma.

    PubMed

    Bi, Qian; Ranjan, Atul; Fan, Rui; Agarwal, Neeraj; Welch, Danny R; Weinman, Steven A; Ding, Jie; Iwakuma, Tomoo

    2015-04-01

    Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide with increasing incidence. Despite curative surgical resection and advanced chemotherapy, its survival rate remains low. The presence of microvascular invasion and occult metastasis is one of the major causes for this poor outcome. MDM2 Binding Protein (MTBP) has been implicated in the suppression of cell migration and cancer metastasis. However, clinical significance of MTBP, particularly in human cancer, is poorly understood. Specifically, clinical relevance of MTBP in human HCC has never been investigated. Here we demonstrated that expression of MTBP was significantly reduced in human HCC tissues compared to adjacent non-tumor tissues. MTBP expression was negatively correlated with capsular/vascular invasion and lymph node metastasis. Overexpression of MTBP resulted in the suppression of the migratory and metastatic potential of HCC cells, while its downregulation increased the migration. Consistent with the previous report, MTBP endogenously bound to alpha-actinin 4 (ACTN4) and suppressed ACTN4-mediated cell migration in multiple HCC cell lines. However, MTBP also inhibited migratory potential of PLC/PRF/5 HCC cells whose migration was not altered by manipulation of ACTN4 expression. These results suggest that mechanisms behind MTBP-mediated migration suppression may not be limited to the pathway involving ACTN4 in certain cellular contexts. Additionally, as a potential mechanism for reduced MTBP expression in tumors, we found that MTBP expression was increased following the treatment with histone deacetylase inhibitors (HDIs). Our study, for the first time, provides clinical relevance of MTBP in the suppression of HCC metastasis. PMID:25759210

  4. Platelets contribute to growth and metastasis in hepatocellular carcinoma.

    PubMed

    Bihari, Chhagan; Rastogi, Archana; Shasthry, Saggere Muralikrishna; Bajpai, Meenu; Bhadoria, Ajeet Singh; Rajesh, S; Mukund, Amar; Kumar, Anupam; Sarin, Shiv K

    2016-09-01

    To determine the association of platelets with hepatocellular carcinoma (HCC) growth and its metastasis. We examined platelets, laboratory, and radiological data of consecutive 420 HCC and 1008 cirrhosis cases. Follow-up information of platelet count in cirrhosis to HCC, pre- to post-therapy, and post-therapy to HCC outcome was analyzed. Cytokine profiling was performed in HCC and cirrhosis (n = 10 each). On the basis of imaging, HCC was divided into six subgroups. Cytosmears of HCC were assessed for platelet clustering around tumor cells. An in vitro Matrigel invasion assay was performed on human HCC cell lines using graded concentration of platelets. Baseline platelet numbers and platelet/lymphocyte ratios (PLRs) were significantly higher (p < 0.001) in HCC than cirrhosis. IL-1, IL-6, FGF, G-CSF, thrombopoietin, and VEGF were higher in HCC than cirrhosis. Platelet counts were increased after HCC conversion of cirrhosis (p < 0.001) and decreased (p < 0.001) after therapy. Platelets and PLR in recurrence cases were higher than in responders at baseline. AFP, PIVKAII, platelets, and PLR increase (p < 0.001 each) with advancement in HCC growth. Multivariate analysis showed platelets (p = 0.002), PLR (p = 0.004), and AFP (p < 0.001) associated with distant metastasis. Platelet clustering seen in 75.7% of HCC group 3, 45% in group 2, and 12.5% in group 1 cases (p < 0.001). Invaded cells in Matrigel assay positively correlated with platelet concentration. Platelets can contribute to the development, growth, invasion, and metastasis of HCC. Rising platelet count after HCC therapy is indicative of incomplete response or recurrence. PMID:27457354

  5. Liver transplantation for non-hepatocellular carcinoma malignancy.

    PubMed

    Castaldo, Eric T; Pinson, C Wright

    2007-01-01

    Liver transplantation (LT) for hepatocellular carcinoma is effective for selected patients. LT for other malignancies like cholangiocarcinoma (CCA), hepatoblastoma (HB), hepatic epithelioid hemangioepithelioma (HEHE), angiosarcoma (AS), and neuroendocrine tumors (NET) is being defined. For CCA, series that did not emphasize highly selected early stage disease and neoadjuvant or adjuvant chemoradiation had an average 5-year survival of 10%. However, emphasizing neoadjuvant radiation and chemosensitization in operatively confirmed stage I or II hilar CCA has led to improved 5-year survival, up to 82%. LT is indicated under strict research protocols at selected centers, for patients with early stage CCA and anatomically unresectable (Bismuth type IV) lesions. HB is typically sensitive to cisplatin-based chemotherapy. LT plays a role as primary surgical therapy for those individuals in whom tumors remain unresectable after chemotherapy or as rescue therapy for those who are incompletely resected, recur after resection, or develop hepatic insufficiency after chemotherapy and/or resection. Long-term survival is reported at 58-88%. HEHE is a multifocal tumor that lies somewhere between benign hemangiomas and malignant AS. The extensive multifocal nature makes resection difficult and LT an attractive option. Series on LT for HEHE report overall survival of 71-78% at 5 years. However, AS is an aggressive tumor and LT is contraindicated. For NET, resection of the primary tumor and all gross metastatic disease is reported to provide 5-year survival of 70-85%. LT has been employed for some patients for unresectable tumors or for palliation of medically uncontrollable symptoms with 5-year survival reported between 36% and 80%. PMID:18333123

  6. Liver transplantation for non-hepatocellular carcinoma malignancy1

    PubMed Central

    Castaldo, Eric T.

    2007-01-01

    Liver transplantation (LT) for hepatocellular carcinoma is effective for selected patients. LT for other malignancies like cholangiocarcinoma (CCA), hepatoblastoma (HB), hepatic epithelioid hemangioepithelioma (HEHE), angiosarcoma (AS), and neuroendocrine tumors (NET) is being defined. For CCA, series that did not emphasize highly selected early stage disease and neoadjuvant or adjuvant chemoradiation had an average 5-year survival of 10%. However, emphasizing neoadjuvant radiation and chemosensitization in operatively confirmed stage I or II hilar CCA has led to improved 5-year survival, up to 82%. LT is indicated under strict research protocols at selected centers, for patients with early stage CCA and anatomically unresectable (Bismuth type IV) lesions. HB is typically sensitive to cisplatin-based chemotherapy. LT plays a role as primary surgical therapy for those individuals in whom tumors remain unresectable after chemotherapy or as rescue therapy for those who are incompletely resected, recur after resection, or develop hepatic insufficiency after chemotherapy and/or resection. Long-term survival is reported at 58–88%. HEHE is a multifocal tumor that lies somewhere between benign hemangiomas and malignant AS. The extensive multifocal nature makes resection difficult and LT an attractive option. Series on LT for HEHE report overall survival of 71–78% at 5 years. However, AS is an aggressive tumor and LT is contraindicated. For NET, resection of the primary tumor and all gross metastatic disease is reported to provide 5-year survival of 70–85%. LT has been employed for some patients for unresectable tumors or for palliation of medically uncontrollable symptoms with 5-year survival reported between 36% and 80%. PMID:18333123

  7. Chemoembolization for Hepatocellular Carcinoma Supplied by a Lumbar Artery

    SciTech Connect

    Kim, Han Myun; Kim, Hyo-Cheol Woo, Sungmin; Son, Kyu Ri; Cho, Seong Whi; Chung, Jin Wook

    2015-02-15

    PurposeTo describe the radiologic findings and imaging response of hepatocellular carcinoma (HCC) supplied by the lumbar artery.MethodsBetween April 2004 and December 2012, we encountered HCC supplied by a lumbar artery in 21 patients. Two investigators retrospectively reviewed clinical and radiological findings of HCC supplied by the lumbar artery using computed tomography (CT) scans and digital subtraction angiograms.ResultsPatients had received 1–27 sessions of previous chemoembolization procedures (mean 7.7 sessions, median 4 sessions). Mean tumor size was 5.3 cm. The locations of HCC supplied by lumbar artery were the bare area (n = 14, 67 %) and segment VI (n = 7, 33 %). Tumor-feeding arteries arose from the main lumbar artery (n = 7), proximal anterior division (n = 4), and distal anterior division (n = 14). In 20 patients, selective chemoembolization through the tumor-feeding arteries of the lumbar artery was achieved. In 1 patient, nonselective embolization at the main lumbar artery was performed. There was no complication such as skin necrosis or paralysis. On the first follow-up enhanced CT scan, target tumors fed by the lumbar artery showed complete response (n = 6), partial response (n = 4), stable disease (n = 3), and progressive disease (n = 8), but overall tumor response was partial response (n = 1) and progressive disease (n = 20).ConclusionWhen HCC is located in the inferior tip or bare area of the liver, a lumbar artery may supply the tumor. Although selective chemoembolization via the tumor-feeding vessel of the lumbar artery can be achieved in most cases, overall tumor response is commonly unfavorable.

  8. Intermediate hepatocellular carcinoma: How to choose the best treatment modality?

    PubMed

    Di Costanzo, Giovan Giuseppe; Tortora, Raffaella

    2015-05-28

    Intermediate stage, or stage B according to Barcelona Clinic Liver Cancer classification, of hepatocellular carcinoma (HCC) comprises a heterogeneous population with different tumor burden and liver function. This heterogeneity is confirmed by the large variability of treatment choice and disease-relate survival. The aim of this review was to highlight the existing evidences regarding this specific topic. In a multidisciplinary evaluation, patients with large (> 5 cm) solitary HCC should be firstly considered for liver resection (LR). When LR is unfeasible, locoregional treatments are evaluable therapeutic options, being transarterial chemoembolization (TACE), the most used procedure. Percutaneous ablation can be an evaluable treatment for large HCC. However, the efficacy of all ablative procedures decrease as tumor size increases over 3 cm. In clinical practice, a combination treatment strategy [TACE or transarterial radioembolization (TARE)-plus percutaneous ablation] is "a priori" preferred in a relevant percentage of these patients. On the other hands, sorafenib is the treatment of choice in patients who are unsuitable to surgery and/or with a contraindication to locoregional treatments. In multifocal HCC, TACE is the first-line treatment. The role of TARE is still undefined. Surgery may have also a role in the treatment of multifocal HCC in selected cases (patients with up to three nodules, multifocal HCC involving 2-3 adjacent liver segments). In some patients with bilobar disease the combination of LR and ablative treatment may be a valuable option. The choice of the best treatment in the patient with intermediate stage HCC should be "patient-tailored" and made by a multidisciplinary team.

  9. Intermediate hepatocellular carcinoma: How to choose the best treatment modality?

    PubMed Central

    Di Costanzo, Giovan Giuseppe; Tortora, Raffaella

    2015-01-01

    Intermediate stage, or stage B according to Barcelona Clinic Liver Cancer classification, of hepatocellular carcinoma (HCC) comprises a heterogeneous population with different tumor burden and liver function. This heterogeneity is confirmed by the large variability of treatment choice and disease-relate survival. The aim of this review was to highlight the existing evidences regarding this specific topic. In a multidisciplinary evaluation, patients with large (> 5 cm) solitary HCC should be firstly considered for liver resection (LR). When LR is unfeasible, locoregional treatments are evaluable therapeutic options, being transarterial chemoembolization (TACE), the most used procedure. Percutaneous ablation can be an evaluable treatment for large HCC. However, the efficacy of all ablative procedures decrease as tumor size increases over 3 cm. In clinical practice, a combination treatment strategy [TACE or transarterial radioembolization (TARE)-plus percutaneous ablation] is “a priori” preferred in a relevant percentage of these patients. On the other hands, sorafenib is the treatment of choice in patients who are unsuitable to surgery and/or with a contraindication to locoregional treatments. In multifocal HCC, TACE is the first-line treatment. The role of TARE is still undefined. Surgery may have also a role in the treatment of multifocal HCC in selected cases (patients with up to three nodules, multifocal HCC involving 2-3 adjacent liver segments). In some patients with bilobar disease the combination of LR and ablative treatment may be a valuable option. The choice of the best treatment in the patient with intermediate stage HCC should be “patient-tailored” and made by a multidisciplinary team. PMID:26019734

  10. Development of a prognostic scoring system for resectable hepatocellular carcinoma

    PubMed Central

    Sposito, Carlo; Di Sandro, Stefano; Brunero, Federica; Buscemi, Vincenzo; Battiston, Carlo; Lauterio, Andrea; Bongini, Marco; De Carlis, Luciano; Mazzaferro, Vincenzo

    2016-01-01

    AIM To develop a prognostic scoring system for overall survival (OS) of patients undergoing liver resection (LR) for hepatocellular carcinoma (HCC). METHODS Consecutive patients who underwent curative LR for HCC between 2000 and 2013 were identified. The series was randomly divided into a training and a validation set. A multivariable Cox model for OS was fitted to the training set. The beta coefficients derived from the Cox model were used to define a prognostic scoring system for OS. The survival stratification was then tested, and the prognostic scoring system was compared with the European Association for the Study of the Liver (EASL)/American Association for the Study of Liver Diseases (AASLD) surgical criteria by means of Harrell’s C statistics. RESULTS A total of 917 patients were considered. Five variables independently correlated with post-LR survival: Model for End-stage Liver Disease score, hepatitis C virus infection, number of nodules, largest diameter and vascular invasion. Three risk classes were identified, and OS for the three risk classes was significantly different both in the training (P < 0.0001) and the validation set (P = 0.0002). Overall, 69.4% of patients were in the low-risk class, whereas only 37.8% were eligible to surgery according to EASL/AASLD. Survival of patients in the low-risk class was not significantly different compared with surgical indication for EASL/AASLD guidelines (77.2 mo vs 82.5 mo respectively, P = 0.22). Comparison of Harrell’s C statistics revealed no significant difference in predictive power between the two systems (-0.00999, P = 0.667). CONCLUSION This study established a new prognostic scoring system that may stratify HCC patients suitable for surgery, expanding surgical eligibility with respect to EASL/AASLD criteria with no harm on survival.

  11. Current management of hepatocellular carcinoma: an Eastern perspective.

    PubMed

    Yim, Hyung Joon; Suh, Sang Jun; Um, Soon Ho

    2015-04-01

    Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death, especially in Eastern areas. With advancements in diagnosis and treatment modalities for HCC, the survival and prognosis of HCC patients are improving. However, treatment patterns are not uniform between areas despite efforts to promote a common protocol. Although many hepatologists in Asian countries may adopt the principles of the Barcelona Clinic Liver Cancer staging system, they are also independently making an effort to expand the indications of each treatment and to combine therapies for better outcomes. Several expanded criteria for liver transplantation in HCC have been developed in Asian countries. Living donor liver transplantation is much more commonly performed in these countries than deceased donor liver transplantation, and it may be preceded by other treatments such as the down-staging of tumors. Local ablation therapies are often combined with transarterial chemoembolization (TACE) and the outcome is comparable to that of surgical resection. The indications of TACE are expanding, and there are new types of transarterial therapies. Although data on drug-eluting beads, TACE, and radioembolization in Asian countries are still relatively sparse compared with Western countries, these methods are gradually gaining popularity because of better tolerability and the possibility of improved response rates. Hepatic arterial infusion chemotherapy and radiotherapy are not included in Western guidelines, but are currently being used actively in several Asian countries. For more advanced HCCs, appropriate combinations of TACE, radiotherapy, and sorafenib can be considered, and emerging data indicate improved outcomes of combination therapies compared with single therapies. To include these paradigm shifts into newer treatment guidelines, more studies may be needed, but they are certainly in progress.

  12. New insights in hepatocellular carcinoma: from bench to bedside

    PubMed Central

    Marzioni, Marco; Benedetti, Antonio; Svegliati-Baroni, Gianluca

    2013-01-01

    Hepatocarcinogenesis is a multistep process involving different genetic alterations that ultimately lead to malignant transformation of the hepatocyte. The liver is one of the main targets for different metastatic foci, but it represents an important and frequent locus of degeneration in the course of chronic disease. In fact, Hepatocellular carcinoma (HCC) represents the outcome of the natural history of chronic liver diseases, from the condition of fibrosis, to cirrhosis and finally to cancer. HCC is the sixth most common cancer in the world, some 630,000 new cases being diagnosed each year. Furthermore, about the 80% of people with HCC, have seen their clinical history developing from fibrosis, to cirrhosis and finally to cancer. The three main causes of HCC development are represented by HBV, HCV infection and alcoholism. Moreover, metabolic disease [starting from Non Alcoholic Fatty Liver Disease (NAFLD), Non Alcoholic Steatohepatitis (NASH)] and, with reduced frequency, some autoimmune disease may lead to HCC development. An additional rare cause of carcinogenetic degeneration of the liver, especially developed in African and Asian Countries, is represented by aflatoxin B1. The mechanisms by which these etiologic factors may induce HCC development involve a wide range of pathway and molecules, currently under investigation. In summary, the hepatocarcionogenesis results from a multifactorial process leading to the common condition of genetic changes in mature hepatocytes mainly characterized by uncontrolled proliferation and cell death. Advances in understanding the mechanism of action are fundamental for the development of new potential therapies and results primarily from the association of the research activities coming from basic and clinical science. This review article analyzes the current models used in basic research to investigate HCC activity, and the advances obtained from a basic and clinical point of view. PMID:25332959

  13. Functional and Topological Properties in Hepatocellular Carcinoma Transcriptome

    PubMed Central

    Wex, Thomas; Valeyev, Najl V.; Tsoka, Sophia; Malfertheiner, Peter

    2012-01-01

    Hepatocellular carcinoma (HCC) is a leading cause of global cancer mortality. However, little is known about the precise molecular mechanisms involved in tumor formation and pathogenesis. The primary goal of this study was to elucidate genome-wide molecular networks involved in development of HCC with multiple etiologies by exploring high quality microarray data. We undertook a comparative network analysis across 264 human microarray profiles monitoring transcript changes in healthy liver, liver cirrhosis, and HCC with viral and alcoholic etiologies. Gene co-expression profiling was used to derive a consensus gene relevance network of HCC progression that consisted of 798 genes and 2,012 links. The HCC interactome was further confirmed to be phenotype-specific and non-random. Additionally, we confirmed that co-expressed genes are more likely to share biological function, but not sub-cellular localization. Analysis of individual HCC genes revealed that they are topologically central in a human protein-protein interaction network. We used quantitative RT-PCR in a cohort of normal liver tissue (n = 8), hepatitis C virus (HCV)-induced chronic liver disease (n = 9), and HCC (n = 7) to validate co-expressions of several well-connected genes, namely ASPM, CDKN3, NEK2, RACGAP1, and TOP2A. We show that HCC is a heterogeneous disorder, underpinned by complex cross talk between immune response, cell cycle, and mRNA translation pathways. Our work provides a systems-wide resource for deeper understanding of molecular mechanisms in HCC progression and may be used further to define novel targets for efficient treatment or diagnosis of this disease. PMID:22539975

  14. Hepatocellular carcinoma and dietary aflatoxin in Mozambique and Transkei.

    PubMed Central

    Van Rensburg, S. J.; Cook-Mozaffari, P.; Van Schalkwyk, D. J.; Van der Watt, J. J.; Vincent, T. J.; Purchase, I. F.

    1985-01-01

    Estimations of the incidence of hepatocellular carcinoma (HCC) for the period 1968-74 in the Province of Inhambane, Mozambique, have been calculated and together with rates observed in South Africa among mineworkers from the same Province indicate very high levels of incidence in certain districts of Inhambane. Exceptionally high incidence levels in adolescents and young adults are not sustained at older ages and suggest the existence of a subgroup of highly susceptible individuals. A sharp decline in incidence occurred during the period of study. Concurrently with the studies of incidence, 2183 samples of prepared food were randomly collected from 6 districts of Inhambane as well as from Manhica-Magude, a region of lower HCC incidence to the south. A further 623 samples were taken during 1976-77 in Transkei, much further south, where an even lower incidence had been recorded. The mean aflatoxin dietary intake values for the regions studied were significantly related to HCC rates. Furthermore, data on aflatoxin B1 contamination of prepared food from 5 different countries showed overall a highly significant relationship with crude HCC rates. In view of the evidence that chronic hepatitis B virus (HBV) infection may be a prerequisite for the development of virtually all cases of HCC and given the merely moderate prevalence of carrier status that has been observed in some high incidence regions, it is likely that an interaction between HBV and aflatoxin is responsible for the exceptionally high rates evident in parts of Africa and Asia. Various indications from Mozambique suggest that aflatoxin may have a late stage effect on the development of HCC. This points to avenues for intervention that could be more rapidly implemented than with vaccination alone. PMID:2986667

  15. Recent advances in the surgical treatment of hepatocellular carcinoma.

    PubMed

    Morise, Zenichi; Kawabe, Norihiko; Tomishige, Hirokazu; Nagata, Hidetoshi; Kawase, Jin; Arakawa, Satoshi; Yoshida, Rie; Isetani, Masashi

    2014-10-21

    Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. The treatment of HCC is complex and complicated by the severity of associated chronic liver disease, the stage of HCC, and the clinical condition of the patient. Liver resection (LR) is one of the most efficient treatments for patients with HCC, with an expected 5-year survival of 38%-61% depending on the stage of the disease. Improved liver function assessment, increased understanding of segmental liver anatomy from advanced imaging studies, and surgical technical progress are important factors that have led to reduced mortality in patients with HCC. The indication for LR may be expanded due to emerging evidences from laparoscopic hepatectomies and combined treatments with newly developed chemotherapies. Liver transplantation (LT) is considered as an ideal treatment for removal of existing tumors and the injured/preneoplastic underlying liver tissue with impaired liver function and the risk of multicentric carcinogenesis that results from chronically injured liver. However, LT is restricted to patients with minimal risk of tumor recurrence under immunosuppression. The expansion of criteria for LT in HCC patients is still under trial and discussion. Limited availability of grafts, as well as the risk and the cost of transplantation have led to considerable interest in expansion of the donor pool, living donor-related transplantation, and combined treatment involving LR and LT. This highlight presents evidence concerning recent studies evaluating LR and LT in HCC patients. In addition, alternative therapies for the treatment of early stage tumors and the management of patients on transplant waiting lists are discussed. PMID:25339825

  16. 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. PMID:27588118

  17. Proton Beam Therapy for Aged Patients With Hepatocellular Carcinoma

    SciTech Connect

    Hata, Masaharu Tokuuye, Koichi; Sugahara, Shinji; Tohno, Eriko; Nakayama, Hidetsugu; Fukumitsu, Nobuyoshi; Mizumoto, Masashi; Abei, Masato; Shoda, Junichi; Minami, Manabu; Akine, Yasuyuki

    2007-11-01

    Purpose: To investigate the safety and efficacy of proton beam therapy for aged patients with hepatocellular carcinoma (HCC). Methods and Materials: Twenty-one patients aged {>=}80 years with HCC underwent proton beam therapy. At the time of irradiation, patient age ranged from 80 to 85 years (median, 81 years). Hepatic tumors were solitary in 17 patients and multiple in 4. Tumor size ranged from 10 to 135 mm (median, 40 mm) in maximum diameter. Ten, 5, and 6 patients received proton beam irradiation with total doses of 60 Gy in 10 fractions, 66 Gy in 22 fractions, and 70 Gy in 35 fractions, respectively, according to tumor location. Results: All irradiated tumors were controlled during the follow-up period of 6-49 months (median, 16 months). Five patients showed new hepatic tumors outside the irradiated volume, 2-13 months after treatment, and 1 of them also had lung metastasis. The local progression-free and disease-free rates were 100% and 72% at 3 years, respectively. Of 21 patients, 7 died 6-49 months after treatment; 2 patients each died of trauma and old age, and 1 patient each died of HCC, pneumonia, and arrhythmia. The 3-year overall, cause-specific, and disease-free survival rates were 62%, 88%, and 51%, respectively. No therapy-related toxicity of Grade {>=} 3 but thrombocytopenia in 2 patients was observed. Conclusions: Proton beam therapy seems to be tolerable, effective, and safe for aged patients with HCC. It may contribute to prolonged survival due to tumor control.

  18. Inflammatory microenvironment and expression of chemokines in hepatocellular carcinoma

    PubMed Central

    Han, Ke-Qi; He, Xue-Qun; Ma, Meng-Yu; Guo, Xiao-Dong; Zhang, Xue-Min; Chen, Jie; Han, Hui; Zhang, Wei-Wei; Zhu, Quan-Gang; Nian, Hua; Ma, Li-Jun

    2015-01-01

    AIM: To study the inflammatory microenvironment and expression of chemokines in hepatocellular carcinoma (HCC) in nude mice. METHODS: CBRH-7919 HCC cells were injected into the subcutaneous region of nude mice. Beginning two weeks after the challenge, tumor growth was measured every week for six weeks. The stromal microenvironment and inflammatory cell infiltration was assessed by immunohistochemistry in paired tumor and adjacent peritumoral samples, and macrophage phenotype was assessed using double-stain immunohistochemistry incorporating expression of an intracellular enzyme. A chemokine PCR array, comprised of 98 genes, was used to screen differential gene expressions, which were validated by Western blotting. Additionally, expression of identified chemokines was knocked-down by RNA interference, and the effect on tumor growth was assessed. RESULTS: Inflammatory cell infiltrates are a key feature of adjacent peritumoral tissues with increased macrophage, neutrophil, and T cell (specifically helper and activated subsets) infiltration. Macrophages within adjacent peritumoral tissues express inducible nitric oxide synthase, suggestive of a proinflammatory phenotype. Fifty-one genes were identified in tumor tissues during the progression period, including 50 that were overexpressed (including CXCL1, CXCL2 and CXCL3) and three that were underexpressed (CXCR1, Ifg and Actb). RNA interference of CXCL1 in the CBRH-7919 cells decreased the growth of tumors in nude mice and inhibited expression of CXCL2, CXCL3 and interleukin-1β protein. CONCLUSION: These findings suggest that CXCL1 plays a critical role in tumor growth and may serve as a potential molecular target for use in HCC therapy. PMID:25944999

  19. Multicentric occurrence of hepatocellular carcinoma with nonalcoholic steatohepatitis

    PubMed Central

    Kawai, Hirokazu; Nomoto, Minoru; Suda, Takeshi; Kamimura, Kenya; Tsuchiya, Atsunori; Tamura, Yasushi; Yano, Masahiko; Takamura, Masaaki; Igarashi, Masato; Wakai, Toshifumi; Yamagiwa, Satoshi; Matsuda, Yasunobu; Ohkoshi, Shogo; Kurosaki, Isao; Shirai, Yoshio; Okada, Masahiko; Aoyagi, Yutaka

    2011-01-01

    AIM: To reveal the manner of hepatocellular carcinoma (HCC) development in patients with nonalcoholic steatohepatitis (NASH) focusing on multicentric occurrence (MO) of HCC. METHODS: We compared clinicopathological characteristics between patients with and without MO of HCC arising from NASH background. The clinical features were implicated with reference to the literature available. RESULTS: MO of HCC was identified with histological proof in 4 out of 12 patients with NASH-related HCC (2 males and 2 females). One patient had synchronous MO; an advanced HCC, two well-differentiated HCCs and a dysplastic nodule, followed by the development of metachronous MO of HCC. The other three patients had multiple advanced HCCs accompanied by a well-differentiated HCC or a dysplastic nodule. Of these three patients, one had synchronous MO, one had metachronous MO and the other had both synchronous and metachronous MO. There were no obvious differences between the patients with or without MO in terms of liver function tests, tumor markers and anatomical extent of HCC. On the other hand, all four patients with MO of HCC were older than 70 years old and had the comorbidities of obesity, type 2 diabetes mellitus (T2DM), hypertension and cirrhosis. Although these conditions were not limited to MO of HCC, all the conditions were met in only one of eight patients without MO of HCC. Thus, concurrence of these conditions may be a predisposing situation to synchronous MO of HCC. In particular, old age, T2DM and cirrhosis were suggested to be prerequisite for MO because these factors were depicted in common among two other cases with MO of HCC under NASH in the literature. CONCLUSION: The putative predisposing factors and necessary preconditions for synchronous MO of HCC in NASH were suggested in this study. Further investigations are required to clarify the accurate prevalence and predictors of MO to establish better strategies for treatment and prevention leading to the prognostic

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

    PubMed Central

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

    2016-01-01

    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. Significant Association Between Adiponutrin and Hepatocellular Carcinoma Risk

    PubMed Central

    Li, Hong-Guang; Liu, Fang-Feng; Zhu, Hua-Qiang; Zhou, Xu; Lu, Jun; Chang, Hong; Hu, Jin-Hua

    2015-01-01

    Abstract ADPN I148M polymorphism has been consistently reported to play a role in liver-associated diseases, such as alcoholic liver disease, chronic hepatitis C, and liver fat and fibrosis in nonalcoholic fatty liver disease. This significant association was also indicated in a series of hepatocellular carcinoma (HCC) studies, where the significance may be affected due to the small sample sizes. The aim of this study was to reexamine the ADPN-HCC association by use of meta-analysis. Biweekly computer-based literature searches plus manual screening were undertaken in an effort to identify all studies that met the predefined inclusion criteria. The Mantel–Haenszel method was selected to estimate risk effects (odds ratio [OR] and 95% confidence interval [CI]). To examine reliability of the pooled risk effects, we additionally performed sensitivity analysis and publication bias tests. Ten studies (1335 HCC patients and 2927 HCC-free controls) were identified for the meta-analysis. We found significantly increased risk of HCC attributable to presence of ADPN I148M polymorphism, with the highest risk associated with the M/M genotype under the recessive model of inheritance (OR = 2.23, 95% CI = 1.87–2.67, between-study heterogeneity: P = 0.468). The significant increase persisted in Caucasian and African when data were stratified by ethnicity. Subgroup analysis according to source of controls revealed similar risk effects. Our meta-analysis indicates that I148M polymorphism in the ADPN gene may independently contribute to the progression of HCC irrespective of the etiologies. PMID:26632699

  2. Surgical Therapy for Early Hepatocellular Carcinoma in the Modern Era

    PubMed Central

    Nathan, Hari; Hyder, Omar; Mayo, Skye C.; Hirose, Kenzo; Wolfgang, Christopher L.; Choti, Michael A.; Pawlik, Timothy M.

    2014-01-01

    Objective We sought to quantify the use of and analyze factors predictive of receipt of surgical therapy for early hepatocellular carcinoma (HCC). Background The incidence of HCC is increasing, and the options for surgical therapy for early HCC have expanded, but the use of surgical therapy for early HCC has not been examined in a modern cohort. Methods A retrospective cohort study was performed using data from the 1998–2007 Surveillance, Epidemiology, and End Results-Medicare linked database. Data were analyzed for patients 66 years of age and older with early HCC (tumors ≤5 cm without metastatic disease, nodal metastasis, extrahepatic extension, or major vascular invasion). Both Surveillance, Epidemiology, and End Results and Medicare data were used to ascertain receipt of therapy as well as comorbidity burden and other patient and hospital variables. Multivariable logistic regression models were used to analyze factors associated with receipt of therapy. Results Our selection criteria identified 1745 patients for this study. Most patients had tumors between 2 and 5 cm in size (n = 1440, 83%). Solitary tumors (n = 1121, 64%) were more common than multiple tumors (n = 624, 36%). A total of 820 patients (47%) with early HCC received no surgical therapy. Among 741 patients with solitary, unilobar tumors and microscopic confirmation of HCC, 246 (33%) received no surgical therapy. Of 535 patients with no liver-related comorbidities, 273 (51%) did not receive surgical therapy. In multivariable analysis, patient age, income, tumor factors, liver-related comorbidities, and hospital factors were associated with receipt of surgical therapy. Conclusions Although some patients with early HCC may not be candidates for surgical therapy, these data suggest that there is a significant missed opportunity to improve survival of patients with early HCC through the use of surgical therapy. PMID:23299519

  3. Hypoxia inducible factor in hepatocellular carcinoma: A therapeutic target

    PubMed Central

    Lin, Daniel; Wu, Jennifer

    2015-01-01

    Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed and deadly cancers worldwide; its incidence has been rising in the United States due to the increase in hepatitis C associated cirrhosis and the growing epidemic of obesity. There have been no effective therapeutic options in the advanced disease setting beyond sorafenib, a multi-targeted tyrosine kinase inhibitor that showed significant survival benefit. Because of this, there is an urgent need to search for novel pathways in sorafenib experienced patients. This review will focus on the role of hypoxia and hypoxia-inducible factor alpha (HIF-1α) in cancer development, specifically in HCC. We will discuss the biology of HIF-1α, the pathways with which it interacts, and the function of HIF-1α in HCC. Furthermore, we will review studies highlighting the relevance of HIF-1α in the clinical setting, as well as the pre-clinical data supporting its further investigation. Finally, we will conclude with a discussion of the potential role of a HIF-1α mRNA antagonist for the treatment of HCC, and hypothesize the ways in which such an inhibitor may be best utilized in the management of advanced HCC. Hypoxia plays a significant role in the development of HCC. HIF-1α is a key transcription factor involved in the hypoxic response of cancer cells. It activates transcription of genes responsible for angiogenesis, glucose metabolism, proliferation, invasion and metastasis in HCC. Its involvement in multiple, essential tumor pathways makes it an attractive potential therapeutic target in HCC. PMID:26576101

  4. NRAGE promotes the malignant phenotype of hepatocellular carcinoma

    PubMed Central

    SHIMIZU, DAI; KANDA, MITSURO; SUGIMOTO, HIROYUKI; SUEOKA, SATOSHI; TAKAMI, HIDEKI; EZAKA, KAZUHIRO; TANAKA, YURI; HASHIMOTO, RYOJI; OKAMURA, YUKIYASU; IWATA, NAOKI; TANAKA, CHIE; YAMADA, SUGURU; FUJII, TSUTOMU; NAKAYAMA, GORO; KOIKE, MASAHIKO; NOMOTO, SHUJI; FUJIWARA, MICHITAKA; KODERA, YASUHIRO

    2016-01-01

    Hepatocellular carcinoma (HCC) is a fatal disease, primarily due to the limited effective therapies available for patients with advanced or recurrent stages of the disease. Therefore, in order to improve patient prognosis, it is important to identify an informative biomarker for HCC progression, as well as a molecular target for therapy. Neurotrophin receptor-interacting melanoma antigen-encoding protein (NRAGE), a member of the type II melanoma-associated antigen family, mediates apoptosis and cell death through interactions with a wide range of proteins, and is implicated as a tumor suppressor or oncoprotein depending on cell type. However, the role of NRAGE in HCC is currently unknown, therefore, the present study aimed to identify the underlying function of NRAGE in HCC tumorigenesis. Resected tumor and non-cancerous liver tissues from 151 patients with HCC, alongside HCC cell lines, were analyzed by polymerase chain reaction and immunohistochemical techniques to determine NRAGE expression levels, as well as the expression levels of potential genes encoding interacting proteins. It was demonstrated that the expression levels of NRAGE mRNA correlated significantly with those of apoptosis-antagonizing transcription factor (AATF), and were not affected by cirrhosis in non-cancerous liver tissues when compared to elevated levels in HCC tissues. The expression patterns of NRAGE protein and mRNA were consistent among 30 representative specimen pairs. Furthermore, increased NRAGE expression in patients with HCC correlated significantly with a shorter disease-specific survival time, and was identified as an independent prognostic factor via multivariate analysis (hazard ratio, 2.23; 95% confidence interval, 1.06–3.83; P=0.020). Therefore, the results of the present study indicated that increased NRAGE expression affects HCC progression via its interaction with AATF, and may represent a novel biomarker and molecular target for the treatment of HCC. PMID:26998088

  5. Stereotactic Body Radiation Therapy in Recurrent Hepatocellular Carcinoma

    SciTech Connect

    Huang, Wen-Yen; Jen, Yee-Min; Lee, Meei-Shyuan; Chang, Li-Ping; Chen, Chang-Ming; Ko, Kai-Hsiung; Lin, Kuen-Tze; Lin, Jang-Chun; Chao, Hsing-Lung; Lin, Chun-Shu; Su, Yu-Fu; Fan, Chao-Yueh; Chang, Yao-Wen

    2012-10-01

    Purpose: To examine the safety and efficacy of Cyberknife stereotactic body radiation therapy (SBRT) and its effect on survival in patients of recurrent hepatocellular carcinoma (HCC). Methods and Materials: This was a matched-pair study. From January 2008 to December 2009, 36 patients with 42 lesions of unresectable recurrent HCC were treated with SBRT. The median prescribed dose was 37 Gy (range, 25 to 48 Gy) in 4-5 fractions over 4-5 consecutive working days. Another 138 patients in the historical control group given other or no treatments were selected for matched analyses. Results: The median follow-up time was 14 months for all patients and 20 months for those alive. The 1- and 2-year in-field failure-free rates were 87.6% and 75.1%, respectively. Out-field intrahepatic recurrence was the main cause of failure. The 2-year overall survival (OS) rate was 64.0%, and median time to progression was 8.0 months. In the multivariable analysis of all 174 patients, SBRT (yes vs. no), tumor size ({<=}4 cm vs. >4 cm), recurrent stage (stage IIIB/IV vs. I) and Child-Pugh classification (A vs. B/C) were independent prognostic factors for OS. Matched-pair analysis revealed that patients undergoing SBRT had better OS (2-year OS of 72.6% vs. 42.1%, respectively, p = 0.013). Acute toxicities were mild and tolerable. Conclusion: SBRT is a safe and efficacious modality and appears to be well-tolerated at the dose fractionation we have used, and its use correlates with improved survival in this cohort of patients with recurrent unresectable HCC. Out-field recurrence is the major cause of failure. Further studies of combinations of SBRT and systemic therapies may be reasonable.

  6. Coffee consumption and risk of hepatocellular carcinoma: a meta-analysis of eleven epidemiological studies

    PubMed Central

    Bai, Kai; Cai, Qiucheng; Jiang, Yi; Lv, Lizhi

    2016-01-01

    Growing evidence has shown that coffee consumption is inversely related with the risk of hepatocellular carcinoma. It is suggested that caffeine maintains strong antioxidative activity. With this property, coffee intake may lead to the inhibition of cell proliferation of liver cancer cells; also, some compounds contained in coffee can reduce the genotoxicity of aflatoxin B1 in vitro and lower the damage caused by some carcinogens. A computerized search was performed in PubMed to identify relevant articles published before August 2015. Eleven relevant studies were included with a total of 2,795 cases and 340,749 control subjects. According to the meta-analysis we performed, the pooled odds ratio (OR) from all included studies was 0.49 (95% confidence interval [CI] =0.46–0.52). The subgroup analysis indicated that the pooled ORs for Asian studies and other populations were 0.27 (95% CI =0.23–0.31) and 0.82 (95% CI =0.77–0.87), respectively. The overall pooled OR for high consumption was decreased to 0.21 (95% CI =0.18–0.25) and significance was observed. Among other populations, the pooled OR of subjects with high coffee consumption was 0.65 (95% CI =0.56–0.73) compared to the nondrinker. The corresponding OR of five Asian studies was 0.13 (95% CI =0.09–0.17). The findings from this meta-analysis further confirmed the inverse association between the coffee consumption and hepatocellular carcinoma risk with quantitative evidence. The protective effect can be detected among healthy population and patients with chronic liver diseases, and the consumption can also prevent the development of liver cirrhosis. PMID:27499631

  7. Up-to-seven criteria for hepatocellular carcinoma liver transplantation: A single center analysis

    PubMed Central

    Lei, Jian-Yong; Wang, Wen-Tao; Yan, Lu-Nan

    2013-01-01

    AIM: To detect whether the up-to-seven should be used as inclusion criteria for liver transplantation for hepatocellular carcinoma. METHODS: Between April 2002 and July 2008, 220 hepatocellular carcinoma (HCC) patients who were diagnosed with HCC and underwent liver transplantation (LT) at our liver transplantation center were included. These patients were divided into three groups according to the characteristics of their tumors (tumor diameter, tumor number): the Milan criteria group (Group 1), the in up-to-seven group (Group 2) and the out up-to-seven group (Group 3). Then, we compared long-term survival and tumor recurrence of these three groups. RESULTS: The baseline characteristics of transplant recipients were comparable among these three groups, except for the type of liver graft (deceased donor liver transplant or live donor liver transplantation). There were also no significant differences in the pre-operative α-fetoprotein level. The 1-, 3-, and 5-year overall survival and tumor-free survival rate for the Milan criteria group were 94.8%, 91.4%, 89.7% and 91.4%, 86.2%, and 86.2% respectively; in the up-to-seven criteria group, these rates were 87.8%, 77.8%, and 76.6% and 85.6%, 75.6%, and 75.6% respectively (P < 0.05). However, the advanced HCC patients’ (in the group out of up-to-seven criteria) overall and tumor-free survival rates were much lower, at 75%, 53.3%, and 50% and 65.8%, 42.5%, and 41.7%, respectively (P < 0.01). CONCLUSION: Considering that patients in the up-to-seven criteria group exhibited a considerable but lower survival rate compared with the Milan criteria group, the up-to-seven criteria should be used carefully and selectively. PMID:24106409

  8. Hepatocellular Carcinoma, Fibrolamellar Variant: Diagnostic Pathologic Criteria and Molecular Pathology Update. A Primer

    PubMed Central

    Sergi, Consolato M.

    2015-01-01

    Fibrolamellar hepatocellular carcinoma (FL-HCC) is generally a fairly rare event in routine pathology practice. This variant of hepatocellular carcinoma (HCC) is peculiarly intriguing and,in addition, poorly understood. Young people or children are often the target individuals with this type of cancer. Previously, I highlighted some pathology aspects of FL-HCC, but in this review, the distinctive clinico-pathologic features of FL-HCC and the diagnostic pathologic criteria of FL-HCC are fractionally reviewed and expanded upon. Further, molecular genetics update data with reference to this specific tumor are particularly highlighted as a primer for general pathologists and pediatric histopathologists. FL-HCC may present with metastases, and regional lymph nodes may be sites of metastatic spread. However, peritoneal and pulmonary metastatic foci have also been reported. To the best of our knowledge, FL-HCC was initially considered having an indolent course, but survival outcomes have recently been updated reconsidering the prognosis of this tumor. Patients seem to respond well to surgical resection, but recurrences are common. Thus, alternative therapies, such as chemotherapy and radiation, are ongoing. Overall, it seems that this aspect has not been well-studied for this variant of HCC and should be considered as target for future clinical trials. Remarkably, FL-HCC data seem to point to a liver neoplasm of uncertain origin and unveiled outcome. A functional chimeric transcript incorporating DNAJB1 and PRKACA was recently added to FL-HCC. This sensational result may give remarkable insights into the understanding of this rare disease and potentially provide the basis for its specific diagnostic marker. Detection of DNAJB1-PRKACA seems to be, indeed, a very sensitive and specific finding in supporting the diagnosis of FL-HCC. In a quite diffuse opinion, prognosis of this tumor should be reconsidered following the potentially mandatory application of new molecular

  9. Coffee consumption and risk of hepatocellular carcinoma: a meta-analysis of eleven epidemiological studies.

    PubMed

    Bai, Kai; Cai, Qiucheng; Jiang, Yi; Lv, Lizhi

    2016-01-01

    Growing evidence has shown that coffee consumption is inversely related with the risk of hepatocellular carcinoma. It is suggested that caffeine maintains strong antioxidative activity. With this property, coffee intake may lead to the inhibition of cell proliferation of liver cancer cells; also, some compounds contained in coffee can reduce the genotoxicity of aflatoxin B1 in vitro and lower the damage caused by some carcinogens. A computerized search was performed in PubMed to identify relevant articles published before August 2015. Eleven relevant studies were included with a total of 2,795 cases and 340,749 control subjects. According to the meta-analysis we performed, the pooled odds ratio (OR) from all included studies was 0.49 (95% confidence interval [CI] =0.46-0.52). The subgroup analysis indicated that the pooled ORs for Asian studies and other populations were 0.27 (95% CI =0.23-0.31) and 0.82 (95% CI =0.77-0.87), respectively. The overall pooled OR for high consumption was decreased to 0.21 (95% CI =0.18-0.25) and significance was observed. Among other populations, the pooled OR of subjects with high coffee consumption was 0.65 (95% CI =0.56-0.73) compared to the nondrinker. The corresponding OR of five Asian studies was 0.13 (95% CI =0.09-0.17). The findings from this meta-analysis further confirmed the inverse association between the coffee consumption and hepatocellular carcinoma risk with quantitative evidence. The protective effect can be detected among healthy population and patients with chronic liver diseases, and the consumption can also prevent the development of liver cirrhosis. PMID:27499631

  10. 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

  11. Evidence for the stem cell origin of hepatocellular carcinoma and cholangiocarcinoma.

    PubMed Central

    Sell, S.; Dunsford, H. A.

    1989-01-01

    A review of the morphologic, autoradiographic, and phenotypic analysis of the cellular changes seen during induction of cancer of the liver in rats by chemical carcinogens is used to develop an alternative to the established hypothesis that chemically induced hepatocellular carcinoma arises from premalignant nodules. The authors propose that hepatocellular and ductular carcinomas arise from a pluripotent liver stem cell and that enzyme-altered foci and nodular changes are adaptive non-oncogenic responses to the toxic effects of carcinogens. It is further postulated that persistent nodules may provide an environment that nurtures development of neoplastic cells other than the altered hepatocytes that originally form the nodule. It is possible, however, that there may be more than one cellular lineage to hepatocellular cancer and that persistent nodules contain these different lineages. Images Figure 2 Figure 6 Figure 8 Figure 11 Figure 13 PMID:2474256

  12. Liver transplantation for hepatocellular carcinoma - factors influencing outcome and disease-free survival

    PubMed Central

    Fahrner, René; Dondorf, Felix; Ardelt, Michael; Dittmar, Yves; Settmacher, Utz; Rauchfuß, Falk

    2015-01-01

    Hepatocellular carcinoma is one of the leading causes of cancer-related death worldwide. Liver transplantation can be a curative treatment in selected patients. However, there are several factors that influence disease-free survival after transplantation. This review addresses the pre-, intra- and postoperative factors that influence the risk of tumor recurrence after liver transplantation. PMID:26576092

  13. Granulocyte colony-stimulating factor-producing hepatocellular carcinoma with abrupt changes

    PubMed Central

    Nagata, Hiroaki; Komatsu, Shuhei; Takaki, Wataru; Okayama, Tokunari; Sawabe, Yasunori; Ishii, Michiaki; Kishimoto, Mitsuo; Otsuji, Eigo; Konosu, Hiroshi

    2016-01-01

    Granulocyte colony-stimulating factor (G-CSF)-producing tumor is one of the rare types of cancer clinically characterized by an elevated fever and white blood cell (WBC) increment. Although G-CSF producing tumors have been reported in several types of cancer including those of the lungs, cervix and bladder, G-CSF producing hepatocellular carcinoma is extremely rare. Here, we report the case of a rapidly growing and poorly differentiated hepatocellular carcinoma producing G-CSF. The patient showed symptoms of continuous high fever, stomach pain and cough, and high serum WBC counts, C-reactive protein (CRP) and G-CSF levels were found in laboratory tests. After a radical hepatectomy, the patient completely recovered from the above symptoms and inflammatory state. The serum levels of G-CSF were reduced to normal levels after radical surgery. An immunohistochemical analysis revealed the overexpression of G-CSF in the cytoplasm of certain hepatocellular carcinoma (HCC) cell. The patient’s serum WBC, CRP and G-CSF levels remained within normal levels in the six months after surgery without recurrence. This is the 9th case report of G-CSF producing hepatocellular carcinoma in English literature. We review the clinical characteristics of the G-CSF producing HCC and discuss a possible treatment strategy. PMID:27777880

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

    SciTech Connect

    Jeon, Ung Bae Lee, Jun Woo Baik, Seung Kug Kim, Tae Un Choo, Ki Seok Kim, Kun Il Kim, Yong-Woo Moon, Tae-Yong

    2012-12-15

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

  15. 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

  16. 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

  17. Rationale for clinical trials of coagulation: reactive drugs in hepatocellular carcinoma.

    PubMed

    Zacharski, Leo R; Hommann, Merten; Kaufmann, Roland

    2004-09-01

    Evidence for the regulation of cancer growth by components of the blood coagulation mechanism provides abundant opportunity for the development of novel hypotheses for the experimental treatment of malignancy. Information available on the heterogeneity in mechanisms of interaction between various cancer cell types, and procoagulant and fibrinolytic pathways, platelets, glycosaminoglycan-regulated growth factors and cell-adhesion molecules indicates that insightful clinical trial design may allow targeting of individual cancer cell types with agents capable of intercepting mechanisms of growth control that are relevant to specific tumor types. This paper reviews the evidence that the common anticoagulant, heparin, inhibits hepatocellular carcinoma cell proliferation and hepatocellular carcinoma tumor dissemination in experimental animals. Clinical trials of heparin performed to date have shown increased tumor response rates and survival in other tumor types. Expression of urokinase-type plasminogen activator by hepatocellular carcinoma cells enhances tumor cell proliferation, motility, invasiveness and metastatic dissemination. Inhibition of the urokinase-type plasminogen activator/plasmin system by protease inhibitors such as aprotinin (Trasylol, Bayer) have shown improvement in the clinical course of certain tumor types. These data suggest that drugs that are well-known in the field of vascular medicine may find a role in the treatment of hepatocellular carcinoma, a common tumor type that has resisted containment by other means. PMID:15350179

  18. Targeting the insulin-like growth factor pathway in hepatocellular carcinoma

    PubMed Central

    Enguita-Germán, Mónica; Fortes, Puri

    2014-01-01

    Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Only 30%-40% of the patients with HCC are eligible for curative treatments, which include surgical resection as the first option, liver transplantation and percutaneous ablation. Unfortunately, there is a high frequency of tumor recurrence after surgical resection and most HCC seem resistant to conventional chemotherapy and radiotherapy. Sorafenib, a multi-tyrosine kinase inhibitor, is the only chemotherapeutic option for patients with advanced hepatocellular carcinoma. Patients treated with Sorafenib have a significant increase in overall survival of about three months. Therefore, there is an urgent need to develop alternative treatments. Due to its role in cell growth and development, the insulin-like growth factor system is commonly deregulated in many cancers. Indeed, the insulin-like growth factor (IGF) axis has recently emerged as a potential target for hepatocellular carcinoma treatment. To this aim, several inhibitors of the pathway have been developed such as monoclonal antibodies, small molecules, antisense oligonucleotides or small interfering RNAs. However recent studies suggest that, unlike most tumors, HCC development requires increased signaling through insulin growth factor II rather than insulin growth factor I. This may have great implications in the future treatment of HCC. This review summarizes the role of the IGF axis in liver carcinogenesis and the current status of the strategies designed to target the IGF-I signaling pathway for hepatocellular carcinoma treatment. PMID:25349643

  19. Cerebellar stroke in a low cardiovascular risk patient associated with sorafenib treatment for fibrolamellar hepatocellular carcinoma

    PubMed Central

    Vandewynckel, Yves-Paul; Geerts, Anja; Verhelst, Xavier; Van Vlierberghe, Hans

    2014-01-01

    Key Clinical Message Sorafenib is the standard treatment of hepatocellular carcinoma (HCC). However, fibrolamellar HCC was not included in sorafenib trials. The case is a 26-year-old man with fibrolamellar HCC, who had a cerebrovascular accident (CVA) while being treated with sorafenib. This illustrates a probable relationship between use of sorafenib and CVA in low cardiovascular risk patients. PMID:25356226

  20. Radioembolization After Portal Vein Embolization in a Patient with Multifocal Hepatocellular Carcinoma

    SciTech Connect

    Burgmans, Mark C. Irani, Farah G. Chan, Wan Ying Teo, Terence K.; Kao, Yung Hsiang Goh, Anthony S.W.; Chow, Pierce K.; Lo, Richard H.

    2012-12-15

    Radioembolization is an effective locoregional therapy for patients with intermediate or advanced stage hepatocellular carcinoma (HCC). It has been shown that radioembolization is safe in patients with portal vein thrombosis. This case report describes safe radioembolization after portal vein embolization in a patient with multifocal HCC.

  1. X-ray Scatter Imaging of Hepatocellular Carcinoma in a Mouse Model Using Nanoparticle Contrast Agents

    NASA Astrophysics Data System (ADS)

    Rand, Danielle; Derdak, Zoltan; Carlson, Rolf; Wands, Jack R.; Rose-Petruck, Christoph

    2015-10-01

    Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide and is almost uniformly fatal. Current methods of detection include ultrasound examination and imaging by CT scan or MRI; however, these techniques are problematic in terms of sensitivity and specificity, and the detection of early tumors (<1 cm diameter) has proven elusive. Better, more specific, and more sensitive detection methods are therefore urgently needed. Here we discuss the application of a newly developed x-ray imaging technique called Spatial Frequency Heterodyne Imaging (SFHI) for the early detection of HCC. SFHI uses x-rays scattered by an object to form an image and is more sensitive than conventional absorption-based x-radiography. We show that tissues labeled in vivo with gold nanoparticle contrast agents can be detected using SFHI. We also demonstrate that directed targeting and SFHI of HCC tumors in a mouse model is possible through the use of HCC-specific antibodies. The enhanced sensitivity of SFHI relative to currently available techniques enables the x-ray imaging of tumors that are just a few millimeters in diameter and substantially reduces the amount of nanoparticle contrast agent required for intravenous injection relative to absorption-based x-ray imaging.

  2. X-ray Scatter Imaging of Hepatocellular Carcinoma in a Mouse Model Using Nanoparticle Contrast Agents

    PubMed Central

    Rand, Danielle; Derdak, Zoltan; Carlson, Rolf; Wands, Jack R.; Rose-Petruck, Christoph

    2015-01-01

    Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide and is almost uniformly fatal. Current methods of detection include ultrasound examination and imaging by CT scan or MRI; however, these techniques are problematic in terms of sensitivity and specificity, and the detection of early tumors (<1 cm diameter) has proven elusive. Better, more specific, and more sensitive detection methods are therefore urgently needed. Here we discuss the application of a newly developed x-ray imaging technique called Spatial Frequency Heterodyne Imaging (SFHI) for the early detection of HCC. SFHI uses x-rays scattered by an object to form an image and is more sensitive than conventional absorption-based x-radiography. We show that tissues labeled in vivo with gold nanoparticle contrast agents can be detected using SFHI. We also demonstrate that directed targeting and SFHI of HCC tumors in a mouse model is possible through the use of HCC-specific antibodies. The enhanced sensitivity of SFHI relative to currently available techniques enables the x-ray imaging of tumors that are just a few millimeters in diameter and substantially reduces the amount of nanoparticle contrast agent required for intravenous injection relative to absorption-based x-ray imaging. PMID:26511147

  3. X-ray scatter imaging of hepatocellular carcinoma in a mouse model using nanoparticle contrast agents

    SciTech Connect

    Rand, Danielle; Derdak, Zoltan; Carlson, Rolf; Wands, Jack R.; Rose-Petruck, Christoph

    2015-10-29

    Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide and is almost uniformly fatal. Current methods of detection include ultrasound examination and imaging by CT scan or MRI; however, these techniques are problematic in terms of sensitivity and specificity, and the detection of early tumors (<1 cm diameter) has proven elusive. Better, more specific, and more sensitive detection methods are therefore urgently needed. Here we discuss the application of a newly developed x-ray imaging technique called Spatial Frequency Heterodyne Imaging (SFHI) for the early detection of HCC. SFHI uses x-rays scattered by an object to form an image and is more sensitive than conventional absorption-based x-radiography. We show that tissues labeled in vivo with gold nanoparticle contrast agents can be detected using SFHI. We also demonstrate that directed targeting and SFHI of HCC tumors in a mouse model is possible through the use of HCC-specific antibodies. As a result, the enhanced sensitivity of SFHI relative to currently available techniques enables the x-ray imaging of tumors that are just a few millimeters in diameter and substantially reduces the amount of nanoparticle contrast agent required for intravenous injection relative to absorption-based x-ray imaging.

  4. X-ray scatter imaging of hepatocellular carcinoma in a mouse model using nanoparticle contrast agents

    DOE PAGES

    Rand, Danielle; Derdak, Zoltan; Carlson, Rolf; Wands, Jack R.; Rose-Petruck, Christoph

    2015-10-29

    Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide and is almost uniformly fatal. Current methods of detection include ultrasound examination and imaging by CT scan or MRI; however, these techniques are problematic in terms of sensitivity and specificity, and the detection of early tumors (<1 cm diameter) has proven elusive. Better, more specific, and more sensitive detection methods are therefore urgently needed. Here we discuss the application of a newly developed x-ray imaging technique called Spatial Frequency Heterodyne Imaging (SFHI) for the early detection of HCC. SFHI uses x-rays scattered by an object to form anmore » image and is more sensitive than conventional absorption-based x-radiography. We show that tissues labeled in vivo with gold nanoparticle contrast agents can be detected using SFHI. We also demonstrate that directed targeting and SFHI of HCC tumors in a mouse model is possible through the use of HCC-specific antibodies. As a result, the enhanced sensitivity of SFHI relative to currently available techniques enables the x-ray imaging of tumors that are just a few millimeters in diameter and substantially reduces the amount of nanoparticle contrast agent required for intravenous injection relative to absorption-based x-ray imaging.« less

  5. Cyberknife treatment for advanced or terminal stage hepatocellular carcinoma

    PubMed Central

    Kato, Hiroyuki; Yoshida, Hideo; Taniguch, Hiroyoshi; Nomura, Ryutaro; Sato, Kengo; Suzuki, Ichiro; Nakata, Ryo

    2015-01-01

    AIM: To investigate the safety and efficacy of the Cyberknife treatment for patients with advanced or terminal stage hepatocellular carcinoma (HCC). METHODS: Patients with HCC with extrahepatic metastasis or vascular or bile duct invasion were enrolled between May 2011 and June 2015. The Cyberknife was used to treat each lesion. Treatment response scores were based on Response Evaluation Criteria in Solid Tumors v1.1. The trends of tumor markers, including alpha fetoprotein (AFP) and proteins induced by vitamin K absence II (PIVKA II) were assessed. Prognostic factors for tumor response and tumor markers were evaluated with Fisher’s exact test and a logistic regression model. Survival was evaluated with the Kaplan-Meier method and multivariate analysis was performed using the Cox proportional hazards model. RESULTS: Sixty-five patients with 95 lesions were enrolled. Based on the Barcelona Clinic Liver Cancer classification, all patients were either in the advanced or terminal stage of the disease. The target lesions were as follows: 52 were bone metastasis; 9, lung metastasis; 7, brain metastasis; 9, portal vein invasion; 4, hepatic vein invasion; 4, bile duct invasion; and 10 other lesion types. The response rate and disease control rate were 34% and 53%, respectively. None of the clinical factors correlated significantly with tumor response. Fiducial marker implantation was associated with better control of both AFP (HR = 0.152; 95%CI: 0.026-0.887; P = 0.036) and PIVKA II (HR = 0.035; 95%CI: 0.003-0.342; P = 0.004). The median survival time was 9 mo (95%CI: 5-15 mo). Terminal stage disease (HR = 9.809; 95%CI: 2.589-37.17, P < 0.001) and an AFP of more than 400 ng/mL (HR = 2.548; 95%CI: 1.070-6.068, P = 0.035) were associated with worse survival. A radiation dose higher than 30 Gy (HR = 0.274; 95%CI: 0.093-0.7541, P = 0.012) was associated with better survival. In the 52 cases of bone metastasis, 36 patients (69%) achieved pain relief. One patient had cerebral

  6. Hepatocellular carcinoma in Asia: Prevention strategy and planning

    PubMed Central

    Ashtari, Sara; Pourhoseingholi, Mohamad Amin; Sharifian, Afsaneh; Zali, Mohamad Reza

    2015-01-01

    AIM: To review all of epidemiological and etiological aspects of hepatocellular carcinoma (HCC) and examined the prevention of this disease in Asia. METHODS: We conducted a systematic review according to the PRISMA guidelines. We were chosen articles that published previously, from PubMed (MEDLINE), the Cochrane database and Scopus. The key words used in this research were as follows: HCC in Asia and the way of prevention of this disease, with no language limitations. We selected those papers published before 2014 that we considered to be most important and appropriate. All relevant articles were accessed in full text and all relevant materials was evaluated and reviewed. RESULTS: More than 70% of all new cases of liver cancer were diagnosed in Asia, a region that 75% of all those chronically infected with hepatitis B virus (HBV) in the world. Chronic HBV infection is the main cause of HCC in Asia, where the virus is endemic and vertical transmission is common. Japan, Saudi Arabia, Egypt and Pakistan are exception because of high prevalence of HCV infection in these regions. The prevalence of this cancer is high in Eastern and South-Eastern Asia, But Middle Eastern countries are characterized as moderate prevalence rate of HCC region and Central Asia and some part of Middle Eastern countries are known as low prevalence rate of HCC. In addition of HBV and HCV the other factors such as aflatoxin, alcohol, obesity, diabetes and non-alcoholic fatty liver disease (NAFLD) might be responsible for a low prevalence of HCC in Asian countries. Currently available HCC therapies, chemotherapy, surgical are inefficient, mainly due to usually late diagnosis and high recurrence rates after surgical resection, and usually end with treatment failure. Liver transplantation also remains as a difficult strategy in patients with HCC. Thus prevention of HCC by treating and prevention HBV and HCV infection, the major causative agents of HCC, and the other risk factors such as aflatoxin

  7. Plasma Osteopontin Level in Chronic Liver Disease and Hepatocellular Carcinoma

    PubMed Central

    Fouad, Shawky Abdelhamid; Mohamed, Nagwa Abdel Ghaffar; Fawzy, Mary Wadie; Moustafa, Doaa Ali

    2015-01-01

    Background Osteopontin (OPN) is a secreted glycoprotein and is frequently associated with various tumors. Objectives We sought to investigate the clinical usefulness of the level of plasma OPN, compared to α-fetoprotein (AFP), as a biomarker for hepatocellular carcinoma (HCC) and to evaluate its diagnostic value in nonalcoholic fatty liver disease (NAFLD) and its relationship with clinical and laboratory features of HCC and NAFLD. Patients and Methods The study was performed on 120 subjects classified into 5 groups: Group I included 25 chronic non-cirrhotic hepatitis C virus (HCV)-infected patients; Group II encompassed 25 patients with chronic HCV infection with liver cirrhosis; Group III comprised 25 patients with chronic HCV with liver cirrhosis and HCC; Group IV was comprised of 25 patients with NAFLD; and Group V consisted of 20 healthy age- and sex-matched controls. All the participants were subjected to history taking and clinical and abdominal ultrasonographic examinations as well as the following laboratory investigations: liver function tests, complete blood count, blood sugar, hepatitis B surface antigen, hepatitis C virus antibodies, HCV-RNA by qualitative polymerase chain reaction (for Groups I, II, and III) and serum AFP and plasma OPN levels. Results There were statistically significant differences in plasma OPN levels between the HCC group (401 ± 72 ng/mL) and the other groups, between the cirrhotic group (258.3 ± 35 ng/mL) and the non-cirrhotic group (HCV group, 168.7 ± 41 ng/mL; fatty liver group, 106.7 ± 35 ng/mL), and between the chronic non-cirrhotic HCV group and the fatty liver group (I and IV) and the controls (35.1 ± 6 ng/mL). In the HCC group, the diagnostic value of OPN was comparable to that of AFP at a cutoff value of 280 ng/mL, achieving sensitivity, specificity, and overall accuracy of 100%, 98%, and 96%, respectively. Regarding the validity of plasma OPN as a predictor of fatty change, our results revealed a diagnostic accuracy

  8. Multimodality Treatment for Hepatocellular Carcinoma With Portal Vein Tumor Thrombus

    PubMed Central

    Wang, Kang; Guo, Wei Xing; Chen, Min Shan; Mao, Yi Lei; Sun, Bei Cheng; Shi, Jie; Zhang, Yao Jun; Meng, Yan; Yang, Ye Fa; Cong, Wen Ming; Wu, Meng Chao; Lau, Wan Yee; Cheng, Shu Qun

    2016-01-01

    Abstract The optimal treatment for hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) remains controversial. We aimed to investigate the best treatment for patients with HCC with PVTT. From January 2002 to January 2014, the data from all consecutive patients with HCC with PVTT who underwent surgical treatment (ST),TACE,TACE combined with sorafenib (TACE-Sor), or TACE combined with radiotherapy (TACE-RT) in the 4 largest tertiary hospitals in China were analyzed retrospectively. The patients were divided into 3 subtypes according to the extent of PVTT in the portal vein (type I-III). The primary endpoint was overall survival (OS). A total of 1580 patients with HCC with PVTT were included in the study. The median survival times (MST) for ST (n = 745) for type I, II, and III patients (95% CI) were 15.9 (13.3–18.5), 12.5 (10.7–14.3), and 6.0 (4.3–7.7) months, respectively. The corresponding figures for patients after TACE (n = 604) were 9.3 (5.6–12.9), 4.9 (4.1–5.7), and 4.0 (3.1–4.9), respectively; for patients after TACE-Sor (n = 113) 12.0 (6.6–17.4), 8.9 (6.7–11.1), and 7.0 (3.0–10.9), respectively; and for patients after TACE-RT (n = 118) 12.2 (0–24.7), 10.6 (6.8–14.5), and 8.9 (5.2–12.6), respectively. Comparison among the different treatments for the 3 subtypes of PVTT patients after propensity score (PS) matching showed the effectiveness of ST to be the best for type I and type II PVTT patients, and TACE-RT was most beneficial for type III patients. Treatment was an independent risk factor of OS. ST was the best treatment for type I and II PVTT patients with Child-Pugh A and selected B liver function. TACE-RT should be given to type III PVTT patients. PMID:26986115

  9. Transport and Metabolism of Radiolabeled Choline in Hepatocellular Carcinoma

    PubMed Central

    Kuang, Yu; Salem, Nicolas; Corn, David J.; Erowku, Bernadette; Tian, Haibin; Wang, Fangjing; Lee, Zhenghong

    2010-01-01

    Objectives Altered choline (Cho) metabolism in cancerous cells can be used as a basis for molecular imaging with PET using radiolabeled Cho. In this study, the metabolism of tracer Cho was investigated in a woodchuck hepatocellular carcinoma (HCC) cell line (WCH17) and in freshly-derived rat hepatocytes. The transporter responsible for [11C]-Cho uptake in HCC was also characterized in WCH17 cells. The study helped to define the specific mechanisms responsible for radio-Cho uptake seen on the PET images of primary liver cancer such as HCC. Methods Cells were pulsed with [14C]-Cho for 5 min and chased for varying durations in cold media to simulate the rapid circulation and clearance of [11C]-Cho. Radioactive metabolites were extracted and analyzed by radio-HPLC and radio-TLC. The Cho transporter (ChoT) was characterized in WCH17 cells. Results WCH17 cells showed higher 14C uptake than rat primary hepatocytes. [14C]-Phosphocholine (PC) was the major metabolite in WCH17. In contrast, the intracellular Cho in primary hepatocytes was found to be oxidized to betaine (partially released into media) and to a less degree, phosphorylated to PC. [14C]-Cho uptake by WCH17 cells was found to have both facilitative transport and non-facilitative diffusion components. The facilitative transport was characterized by Na+ dependence and low affinity (Km = 28.59 ± 6.75 μM) with partial energy dependence. In contrast, ChoT in primary hepatocytes is Na+ independent and low affinity. Conclusions Our data suggest that transport and phosphorylation of Cho are responsible for the tracer accumulation during [11C]-Cho PET imaging of HCC. WCH17 cells incorporate [14C]-Cho preferentially into PC. Conversion of [14C]-PC into phosphatidylcholine occurred slowly in vitro. Basal oxidation and phosphorylation activities in surrounding hepatic tissue contribute to the background seen in [11C]-Cho PET images. PMID:20698576

  10. 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

  11. Hepatocellular carcinoma: cost-effectiveness of screening. A systematic review.

    PubMed

    Ruggeri, Matteo

    2012-01-01

    Hepatocellular carcinoma (HCC) is one of the most common tumors worldwide. HCC is a potential target for cancer surveillance (or screening) as it occurs in well-defined, at-risk populations. Curative therapy is possible only for small tumors and screening strategy has been recommended by the US, Italian, and other international liver societies and is practiced widely, but its benefits are not clearly established. The objective of this study was to review the available evidence with respect to the cost-effectiveness of key technologies in the prevention HCC. The literature search was conducted with the support of PubMed. Firstly we selected articles by reading the abstracts. Secondly, we read the articles and the revision was further restricted, with the following as inclusion criteria: (1) full economic evaluation of HCC screening programs; (2) comparison between HCC techniques; (3) outcome measures expressed in terms of quality adjusted life years (QALY); (4) full text availability. The initial review of the literature yielded 346 articles. Of those, 288 were excluded at the first stage. Of those excluded, 108 did not meet the target, 106 did not present the cost analysis, 33 did not analyze the treatment of the disease, and in 41 the abstract was not available. Of the 58 included in the first step, seven examined the cost-effectiveness of different HCC screening techniques, seven investigated the cost-effectiveness of HCC screening versus no screening, and one looked at the cost-effectiveness of timing for HCC surveillance and monitoring, while 43 were about HBV vaccination and screening. We included only the seven articles examining the cost-effectiveness of different HCC screening techniques. In general, incidence is the key parameter which determines the cost-effectiveness of HCC screening. Discrepancies in the results exist when determining the type of technology to be used. Ultrasound (US) alone or in association with alpha fetoprotein (AFP) technology is

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

    PubMed Central

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

    2016-01-01

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

  13. Hepatocellular Carcinoma with Cervical Spine and Pelvic Bone Metastases Presenting as Unknown Primary Neoplasm.

    PubMed

    Hwang, Sea Won; Lee, Ji Eun; Lee, Jung Min; Hong, Sook Hee; Lee, Myung Ah; Chun, Hoo Geun; Chun, Ho Jong; Lee, Sung Hak; Jung, Eun Sun

    2015-07-01

    The occurrence of hepatocellular carcinoma (HCC) is closely associated with viral hepatitis or alcoholic hepatitis. Although active surveillance is ongoing in Korea, advanced or metastatic HCC is found at initial presentation in many patients. Metastatic HCC presents with a hypervascular intrahepatic tumor and extrahepatic lesions such as lung or lymph node metastases. Cases of HCC presenting as carcinoma of unknown primary have been rarely reported. The authors experienced a case of metastatic HCC in a patient who presented with a metastatic bone lesion but no primary intrahepatic tumor. This case suggests that HCC should be considered as a differential diagnosis when evaluating the primary origin of metastatic carcinoma.

  14. Metastatic colorectal cancer in a cirrhotic liver with synchronous hepatocellular carcinoma.

    PubMed

    Karass, Michael; Grossniklaus, Emily; Seoud, Talal; Kamel, Ralph; Teniola, Oluwadamilola; Oprea, Gabriela; Goldstein, Daniel A; Jain, Sanjay

    2015-11-01

    We are reporting a case of a patient with a previous history of colorectal cancer (CRC) and cirrhosis, who developed concurrent liver lesions consistent with hepatocellular carcinoma (HCC); a case which is unique due to the low incidence of multiple cancers, particularly HCC in the setting of previous advanced colorectal carcinoma along, in a cirrhotic liver. We will review the known literature on multiple cancer rates found in patients with known colorectal carcinoma. We will then outline this particular patient's presentation, followed by a discussion as to why the particular concurrent development of HCC in the setting of previous CRC is of note.

  15. Role of IL-33 expression in oncogenesis and development of human hepatocellular carcinoma

    PubMed Central

    YANG, YAN; WANG, JUN-BIN; LI, YU-MEI; ZHAO, YU; WANG, RUI; WU, QIONG; ZHENG, RONG-SHENG; OU, YU-RONG

    2016-01-01

    Interleukin-33 (IL-33), a newly-discovered cytokine belonging to the IL-1 family, serves an important role in inflammation. However, it is not clear whether IL-33 is of clinical significance in hepatocarcinogenesis. The present study was designed to investigate the role of IL-33 during oncogenesis and development of hepatocellular carcinoma (HCC). IL-33 protein expression was detected in 76 HCC (including 36 para-carcinoma), 33 cirrhosis, 30 hepatitis, and 20 normal liver tissues using immunohistochemistry. IL-33 mRNA expression in carcinoma and para-carcinoma tissues was evaluated by reverse transcription-polymerase chain reaction (RT-PCR). The possible correlation between IL-33 and clinicopathological parameters of HCC was also analyzed. Significant differences in IL-33 expression were not observed among normal, hepatic, and cirrhotic tissues (P>0.05), whereas the level of protein positive rate was markedly reduced in HCC tissues (P<0.01). Positive staining of IL-33 in non-cancerous liver (NCL) tissues (i.e. normal, hepatitis, and liver cirrhosis) was located predominantly in the nucleus and occasionally in the cytoplasm of hepatocytes; however, the expression in HCC tissues was mostly restricted to the cytoplasm. A significant alteration in protein localization was observed in HCC tissues as compared with NCL tissues (P<0.01). In comparison with HCC tissues, cytoplasmic staining of IL-33 was increased in para-carcinoma tissues. RT-PCR assay further confirmed relatively high mRNA expression levels of IL-33 in para-carcinoma tissues. IL-33 expression was significantly negatively associated with tumor histological grade (r=−0.279, P=0.015), but not with year, gender, tumor size, clinical stage, HCC with hepatitis and cirrhosis background, lymph node metastasis or intrahepatic vascular embolism (P>0.05). Therefore, the aberrant expression of IL-33 is associated with oncogenesis and progression of HCC and the cytoplasmic accumulation of the protein may serve a role

  16. HBV integrants of hepatocellular carcinoma cell lines contain an active enhancer.

    PubMed

    Shamay, M; Agami, R; Shaul, Y

    2001-10-18

    Hepatitis B virus (HBV) infection is a major risk factor worldwide for the development of hepatocellular carcinoma (HCC). Integrated HBV DNA fragments, often highly rearranged, are frequently detected in HCC. In woodchuck, the viral enhancer plays a central role in hepatocarcinogenesis, but in humans the mechanism of HBV oncogenesis has not been established. In this study we investigated the status of the viral enhancer in two human HCC cell lines, Hep3B and PLC/PRF/5 each containing one or more integrated HBV DNA fragments. Active enhancer was defined by virtue of its protein occupancy as determined by genomic in vivo DMS footprinting. In PLC/PRF/5 cells, the HBV DNA was integrated in a cellular gene at chromosome 11q13, at a locus reported to be amplified in many tumors. We show here that in both cell lines, the integrated HBV DNA fragments contain an active enhancer-I. In particular, the occupation of the two previously defined basic enhancer elements, E and EP, was prominent. While in both cell lines the same protein binds to the EP elements, the E element, however, is occupied in a cell-line specific manner. In PLC/PRF/5 but not Hep3B, the prominent binding of an undefined protein was detected. Our data suggest that this protein is likely to be the fetoprotein transcription factor (FTF). The finding that enhancer sequences are conserved and functional in different cell lines suggests a selection pressure for their long-term maintenance. We therefore propose that the HBV enhancer-I might play a role in hepatocellular carcinogenesis. PMID:11687960

  17. 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

  18. Meta-analysis: therapeutic effect of transcatheter arterial chemoembolization combined with compound kushen injection in hepatocellular carcinoma.

    PubMed

    Sun, Qizhe; Ma, Wenli; Gao, Yuan; Zheng, Wenling; Zhang, Bao; Peng, Yifei

    2012-01-01

    Compound Kushen Injection (CKI) is Sophora Flavescens and Heterosmilacis Japonicae extract. Meta-analysis confirmed that CKI plus transcatheter arterial chemoembolization (TACE) is more superior to TACE alone for unresectable hepatocellular carcinoma (UHCC) patients. PMID:23983333

  19. Single-domain GPC-3 Monoclonal Antibodies for the Treatment of Hepatocellular Carcinoma | NCI Technology Transfer Center | TTC

    Cancer.gov

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

  20. Protective altruistic phlebotomy: hereditary haemochromatosis presenting as hepatocellular carcinoma in a non-cirrhotic 83-year-old man.

    PubMed

    Ooka, Kohtaro; Onyiuke, Ifeyinwa; Zhang, Xuchen; Taddei, Tamar Hamosh

    2016-01-01

    Hereditary haemochromatosis is a multisystem disorder of iron metabolism. Hepatic manifestations include hepatomegaly, cirrhosis and hepatocellular carcinoma. Hepatocellular carcinoma is almost always preceded by cirrhosis. We present a case of an 83-year-old man without history of liver disease or iron overload who presented with abdominal pain. Workup revealed mildly elevated transaminases, ferritin of 3996 and a solitary liver tumour. Biopsy was consistent with hepatocellular carcinoma in a background of haemosiderosis without cirrhosis. He was diagnosed with hereditary haemochromatosis and hepatocellular carcinoma. He underwent a partial hepatectomy and was started on routine phlebotomy and surveillance imaging. He has improved and has not had signs of recurrence or new complications of haemochromatosis. We suggest a possible reason for his unique and late presentation. PMID:27591041

  1. MDCT Anatomic Assessment of Right Inferior Phrenic Artery Origin Related to Potential Supply to Hepatocellular Carcinoma and its Embolization

    SciTech Connect

    Basile, Antonio Tsetis, Dimitrios; Montineri, Arturo; Puleo, Stefano; Massa Saluzzo, Cesare; Runza, Giuseppe; Coppolino, Francesco; Ettorre, Giovanni Carlo; Patti, Maria Teresa

    2008-03-15

    Purpose. To prospectively assess the anatomic variation of the right inferior phrenic artery (RIPA) origin with multidetector computed tomography (MDCT) scans in relation to the technical and angiographic findings during transcatheter arterial embolization of hepatocellular carcinoma (HCC). Methods. Two hundred patients with hepatocellular carcinomas were examined with 16-section CT during the arterial phase. The anatomy of the inferior phrenic arteries was recorded, with particular reference to their origin. All patients with subcapsular HCC located at segments VII and VIII underwent arteriography of the RIPA with subsequent embolization if neoplastic supply was detected. Results. The RIPA origin was detected in all cases (sensitivity 100%), while the left inferior phrenic artery origin was detected in 187 cases (sensitivity 93.5%). RIPAs originated from the aorta (49%), celiac trunk (41%), right renal artery (5.5%), left gastric artery (4%), and proper hepatic artery (0.5%), with 13 types of combinations with the left IPA. Twenty-nine patients showed subcapsular HCCs in segments VII and VIII and all but one underwent RIPA selective angiography, followed by embolization in 7 cases. Conclusion. MDCT assesses well the anatomy of RIPAs, which is fundamental for planning subsequent cannulation and embolization of extrahepatic RIPA supply to HCC.

  2. Molecular imaging of hepatocellular carcinoma xenografts with epidermal growth factor receptor targeted affibody probes.

    PubMed

    Zhao, Ping; Yang, Xiaoyang; Qi, Shibo; Liu, Hongguang; Jiang, Han; Hoppmann, Susan; Cao, Qizhen; Chua, Mei-Sze; So, Samuel K; Cheng, Zhen

    2013-01-01

    Hepatocellular carcinoma (HCC) is a highly aggressive and lethal cancer. It is typically asymptomatic at the early stage, with only 10%-20% of HCC patients being diagnosed early enough for appropriate surgical treatment. The delayed diagnosis of HCC is associated with limited treatment options and much lower survival rates. Therefore, the early and accurate detection of HCC is crucial to improve its currently dismal prognosis. The epidermal growth factor receptor (EGFR) has been reported to be involved in HCC tumorigenesis and to represent an attractive target for HCC imaging and therapy. In this study, an affibody molecule, Ac-Cys-ZEGFR:1907, targeting the extracellular domain of EGFR, was used for the first time to assess its potential to detect HCC xenografts. By evaluating radio- or fluorescent-labeled Ac-Cys-ZEGFR:1907 as a probe for positron emission tomography (PET) or optical imaging of HCC, subcutaneous EGFR-positive HCC xenografts were found to be successfully imaged by the PET probe. Thus, affibody-based PET imaging of EGFR provides a promising approach for detecting HCC in vivo. PMID:23710458

  3. Norcantharidin combined with ABT-737 for hepatocellular carcinoma: Therapeutic effects and molecular mechanisms

    PubMed Central

    Ren, Jing; Li, Gang; Zhao, Wen; Lin, Ling; Ye, Tao

    2016-01-01

    AIM: To study the therapeutic effect of norcantharidin (NCTD) combined with ABT-737 on hepatocellular carcinoma cells and the molecular mechanism. METHODS: Two hepatocellular carcinoma (HCC) cell lines, HepG2 and SMMC-7721, were selected. ABT-737 and NCTD were allocated into groups to be used alone or in combination. HepG2 and SMMC-7721 cells were cultured in vitro. Liver cancer cells in the logarithmic phase of growth were vaccinated and cultured to the cell wall stage; these cells were treated for 48 h with different concentrations of NCTD, or ABT-737, or NCTD combined with ABT-737. The cell proliferation inhibition rate was detected by methyl thiazolyl tetrazolium. The expression of Mcl in HCC cells was detected by Western Blotting, and the cells in each group after treatment had apoptosis detected by flow cytometry. The proliferation inhibition rate, the expression of Mcl-1 in cells and the apoptosis inducing effect of treatment were observed in each group, and the effect of NCTD on ABT-737 in the treatment of HCC and its mechanism of action were analyzed. RESULTS: As the concentration of NCTD increased, the cell proliferation inhibition rate gradually decreased; and the treatment effect of ABT-737 1-3 μm combined with NCTD on cell proliferation inhibition was stronger than that of ABT-737 alone. The difference was statistically significant (P < 0.05). In observing the expression of Mcl-1 in cells after the treatment of different concentrations of NCTD, this was partially inhibited after treatment with NCTD 15 μm, and the expression of Mcl-1 was almost undetectable after treatment with NCTD 30 μm and 60 μm. The effect on inducing apoptosis with the treatment of ABT-737 or NCTD alone for 48 h was lower than that of the control group. The difference was not statistically significant (P > 0.05). The effect on inducing apoptosis in HepG2 and SMMC-7721 cells with the treatment of ABT-737 combined with NCTD for 48 h was greater than that of ABT-737 or NCTD alone

  4. Inhibiting ROS-STAT3-dependent autophagy enhanced capsaicin-induced apoptosis in human hepatocellular carcinoma cells.

    PubMed

    Chen, Xun; Tan, Miduo; Xie, Zhiqin; Feng, Bin; Zhao, Zhijian; Yang, Kaiqing; Hu, Chen; Liao, Ni; Wang, Taoli; Chen, Dongliang; Xie, Feng; Tang, Caixi

    2016-07-01

    Capsaicin, which is the pungent ingredient of red hot chili peppers, has been reported to possess anticancer activity, including that against hepatocellular carcinoma. However, the precise molecular mechanisms by which capsaicin exerts its anticancer effects remain poorly understood. Herein, we have tested the involvement of autophagy in the capsaicin mechanism of action in human hepatocellular carcinoma. HepG2 cancer cells were treated with different doses of capsaicin (50, 100 and 200μmol/L) for 6, 12, and 24 h. Flow cytometry and Caspase-3 activity assay were performed to determine cell apoptosis. Immunofluorescence was performed to visualize LC3-positive puncta. Western