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Shariare MH, Pinky NJK, Abedin J, Kazi M, Aldughaim MS, Uddin MN. Liposomal Drug Delivery of Blumea lacera Leaf Extract: In-Vivo Hepatoprotective Effects. NANOMATERIALS 2022; 12:nano12132262. [PMID: 35808096 PMCID: PMC9268469 DOI: 10.3390/nano12132262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 06/14/2022] [Accepted: 06/20/2022] [Indexed: 12/04/2022]
Abstract
Background: Blumea lacera (B. lacera) is a herbaceous plant commonly found in south-east Asia. It shows significant therapeutic activities against various diseases. The objectives of this study were to evaluate hepatoprotective effects of Blumea lacera leaf extract and also to investigate the comparative effectiveness between a liposomal preparation and a suspension of B. lacera leaf extract against carbon tetrachloride (CCl4)-induced liver damage. Methods: B. lacera leaf extract was characterized using a GC-MS method. A liposomal preparation of B. lacera leaf extract was developed using an ethanol injection method and characterized using dynamic light scattering (DLS) and electronic microscopic systems. The hepatoprotective effects of B. lacera leaf extracts and its liposomal preparation were investigated using CCl4-induced liver damage in Long Evan rats. Results: GC-MS data showed the presence of different components (e.g., phytol) in the B. lacera leaf extract. DLS and microscopic data showed that a liposomal preparation of B. lacera leaf extracts was in the nano size range. In vivo study results showed that liposomal preparation and a suspension of B. lacera leaf extract normalized liver biochemical parameters, enzymes and oxidative stress markers which were elevated due to CCl4 administration. However, a liposomal formulation of B. lacera leaf extract showed significantly better hepatoprotective effects compared to a suspension of leaf extract. In addition, histopathological evaluation showed that B. lacera leaf extract and its liposomal preparation treatments decreased the extent of CCl4-induced liver inflammations. Conclusion: Results demonstrated that B. lacera leaf extract was effective against CCl4-induced liver injury possibly due to the presence of components such as phytol. A liposomal preparation exhibited significantly better activity compared to a B. lacera suspension, probably due to improved bioavailability and stability of the leaf extract.
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Affiliation(s)
- Mohammad Hossain Shariare
- Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh; (M.H.S.); (N.J.K.P.); (J.A.)
| | - Nusrat Jahan Khan Pinky
- Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh; (M.H.S.); (N.J.K.P.); (J.A.)
| | - Joynal Abedin
- Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh; (M.H.S.); (N.J.K.P.); (J.A.)
| | - Mohsin Kazi
- Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
- Correspondence: (M.K.); (M.N.U.)
| | | | - Mohammad N. Uddin
- College of Pharmacy, Mercer University, 3001 Mercer University Drive, Atlanta, GA 30341, USA
- Correspondence: (M.K.); (M.N.U.)
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Bredt LC, Felisberto IBG, Felisberto DEG. Is there a role for liver transplantation in the treatment of hepatocellular carcinoma in non-cirrhotic liver? World J Meta-Anal 2022; 10:46-51. [DOI: 10.13105/wjma.v10.i2.46] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 03/21/2022] [Accepted: 04/28/2022] [Indexed: 02/06/2023] Open
Abstract
Whether liver transplantation (LT) plays a role in the treatment of patients with hepatocellular carcinoma (HCC) in non-cirrhotic liver (NCL) is a matter of debate. The recommendations for LT in this setting are extremely fragile and less well-defined than for cirrhosis-associated HCC. All reports of LT for NCL-HCC revealed that long-term outcomes of these patients are poor, and these dismal figures are justified by the advanced tumor stage at the time of LT, suggesting the presence of systemic micrometastatic disease. The decision-making regarding LT for NCL-HCC is difficult, since specific selection criteria are scarce, and basically the potential candidates are those with unresectable only-liver tumor at admission, or unresectable intrahepatic recurrence post-resection. Besides the surgical aspects regarding the tumor resectability, other phenotypic and genetic characteristics of the tumor should be considered for the indication of LT in this scenario. The present minireview aims to discuss and analyze the last series of LT for NCL-HCC, in order to help clinicians in the decision-making process regarding the role of LT in NCL-HCC treatment.
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Affiliation(s)
- Luis Cesar Bredt
- Surgical Oncology and Hepatobiliary Surgery, Unioeste University, Cascavel 85819-110, Paraná, Brazil
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Hepatocellular carcinoma clinical update: Current standards and therapeutic strategies. LIVER RESEARCH 2020. [DOI: 10.1016/j.livres.2020.11.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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Jin YJ, Byun S, Han S, Chamberlin J, Kim D, Kim MJ, Lee Y. Differential alternative splicing regulation among hepatocellular carcinoma with different risk factors. BMC Med Genomics 2019; 12:175. [PMID: 31856847 PMCID: PMC6923823 DOI: 10.1186/s12920-019-0635-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Accepted: 11/25/2019] [Indexed: 12/11/2022] Open
Abstract
Background Hepatitis B virus (HBV), hepatitis C virus (HCV), and alcohol consumption are predominant causes of hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying how differently these causes are implicated in HCC development are not fully understood. Therefore, we investigated differential alternative splicing (AS) regulation among HCC patients with these risk factors. Methods We conducted a genome-wide survey of AS events associated with HCCs among HBV (n = 95), HCV (n = 47), or alcohol (n = 76) using RNA-sequencing data obtained from The Cancer Genome Atlas. Results In three group comparisons of HBV vs. HCV, HBV vs. alcohol, and HCV vs. alcohol for RNA seq (ΔPSI> 0.05, FDR < 0.05), 133, 93, and 29 differential AS events (143 genes) were identified, respectively. Of 143 AS genes, eight and one gene were alternatively spliced specific to HBV and HCV, respectively. Through functional analysis over the canonical pathways and gene ontologies, we identified significantly enriched pathways in 143 AS genes including immune system, mRNA splicing-major pathway, and nonsense-mediated decay, which may be important to carcinogenesis in HCC risk factors. Among eight genes with HBV-specific splicing events, HLA-A, HLA-C, and IP6K2 exhibited more differential expression of AS events (ΔPSI> 0.1). Intron retention of HLA-A was observed more frequently in HBV-associated HCC than HCV- or alcohol-associated HCC, and intron retention of HLA-C showed vice versa. Exon 3 (based on ENST00000432678) of IP6K2 was less skipped in HBV-associated in HCC compared to HCV- or alcohol-associated HCC. Conclusion AS may play an important role in regulating transcription differences implicated in HBV-, HCV-, and alcohol-related HCC development.
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Affiliation(s)
- Young-Joo Jin
- Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, UT, USA.,Division of Gastroenterology, Department of Internal Medicine, Inha University School of Medicine, Incheon, South Korea
| | - Seyoun Byun
- Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Seonggyun Han
- Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - John Chamberlin
- Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Dongwook Kim
- Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Min Jung Kim
- Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, UT, USA.,Pharmacy program, Massachusetts College of Pharmacy and Health Sciences, Worcester, MA, USA
| | - Younghee Lee
- Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, UT, USA. .,Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA.
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Yousef S, Alsaab HO, Sau S, Iyer AK. Development of asialoglycoprotein receptor directed nanoparticles for selective delivery of curcumin derivative to hepatocellular carcinoma. Heliyon 2018; 4:e01071. [PMID: 30603704 PMCID: PMC6305692 DOI: 10.1016/j.heliyon.2018.e01071] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Revised: 10/11/2018] [Accepted: 12/17/2018] [Indexed: 12/22/2022] Open
Abstract
Hepatocellular cellular carcinoma (HCC) is one of the most challenging liver cancer subtypes. Due to lack of cell surface biomarkers and highly metastatic nature, early detection and targeted therapy of HCC is an unmet need. Galactosamine (Gal) is among the few selective ligands used for targeting HCCs due to its high binding affinity to asialoglycoprotein receptors (ASGPRs) overexpressed in HCC. In the present work, we engineered nanoscale G4 polyamidoamine (PAMAM) dendrimers anchored to galactosamine and loaded with the potent anticancer curcumin derivative (CDF) as a platform for targeted drug delivery to HCC. In vivo targeting ability and bio-distribution of PAMAM-Gal were assessed via its labeling with the clinically used, highly contrast, near infrared (NIR) dye: S0456, with testing of the obtained conjugate in aggressive HCC xenograft model. Our results highlighted the targeted dendrimer PAMAM-Gal ability to achieve selective high cellular uptake via ASGPR mediated endocytosis and significantly enhance the delivery of CDF into the studied HCC cell lines. Cytotoxicity MTT assays in HCC cell lines, interestingly highlighted, the comparative high potency of CDF, where CDF was more potent as a chemotherapeutic anticancer small molecule than the currently in use Doxorubicin, Sorafenib and Cisplatin chemotherapeutic agents. In conclusion the proof-of-concept study using nanoscale PAMAM-Gal dendrimer has demonstrated its competency as an efficient delivery system for selective delivery of potent CDF for HCC anticancer therapy as well as HCC diagnosis via NIR imaging.
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Affiliation(s)
- Shaimaa Yousef
- Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA
| | - Hashem O. Alsaab
- Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA
| | - Samaresh Sau
- Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA
| | - Arun K. Iyer
- Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA
- Molecular Imaging Program, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, MI 48201, USA
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Islam MA, Al Mamun MA, Faruk M, Ul Islam MT, Rahman MM, Alam MN, Rahman AFMT, Reza HM, Alam MA. Astaxanthin Ameliorates Hepatic Damage and Oxidative Stress in Carbon Tetrachloride-administered Rats. Pharmacognosy Res 2017; 9:S84-S91. [PMID: 29333048 PMCID: PMC5757332 DOI: 10.4103/pr.pr_26_17] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Background Astaxanthin is of carotenoids group which possess strong antioxidant properties. The present study was conducted to evaluate the hepatoprotective effects of astaxanthin in carbon tetrachloride (CCl4)-treated rats. Materials and Methods Female Long-Evans rats were administered with CCl4 orally (1 ml/kg) twice a week for 2 weeks and were treated with astaxanthin (10 mg/kg) every day for 2 weeks. Blood plasma samples were isolated from each group and were analyzed for alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase activities. Oxidative stress parameters such as malondialdehyde (MDA), nitric oxide (NO), and advanced protein oxidation product (APOP) were measured. Several enzyme functions such as myeloperoxidase (MPO), superoxide dismutase (SOD), and catalase (CAT) activities in the plasma and liver tissues were also analyzed. Moreover, inflammation and tissue fibrosis were also confirmed by histological staining of liver tissues. Results This investigation revealed that CCl4 administration in rats increased plasma AST, ALT, and ALP activities which were normalized by astaxanthin treatment. Moreover, CCl4 administration increased as MDA, NO, and APOP level both in plasma and tissues compared to control rats. Astaxanthin also exhibited a significant reduction of those parameters in CCl4-administered rats. Astaxanthin treatment also restored the CAT and SOD activities and lowered MPO activity in CCl4-administered rats. Histological assessment also revealed that the astaxanthin prevented the inflammatory cells infiltration, decreased free iron deposition, and fibrosis in liver of CCl4-administered rats. Conclusion These results suggest that astaxanthin protects liver damage induced by CCl4 by inhibiting lipid peroxidation and stimulating the cellular antioxidant system. SUMMARY Carbon tetrachloride (CCl4) administration increased oxidative stress-mediated hepatic damage and inflammation in ratsAstaxanthin, a potent antioxidant, prevents oxidative stress and inflammatory cells infiltration in CCl4-administered ratsAstaxanthin also ameliorated the progression of hepatic fibrosis in CCl4-administered rats. Abbreviations Used: APOP: Advanced protein oxidation product; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; ALP: Alkaline phosphatase; CAT: Catalase; CCl4: Carbon tetrachloride; CVD: Cardiovascular disease; HSCs: Hepatic stellate cells; H2O2: Hydrogen peroxide; MDA: Malondialdehyde; MMP2: Matrix metalloproteinase2; MPO: Myeloperoxidase; NF-κB: Nuclear factor kappa B; NO: Nitric oxide; Nrf2: Nuclear factor erythroid 2-related factor 2; ·ONOO-: Peroxynitrate; ROS: Reactive oxygen species; SOD: superoxide dismutase; TCA: Trichloroacetic acid; TBA: Thiobarbituric acid; TGF-1: Transforming growth factor 1, TGF-β: Transforming growth factor-β; TIMP1: Tissue inhibitor of metalloproteinase 1; TNF-α: Tumor necrosis factor-alpha;·CCl3: Trichloromethyl free radical; CCl3O2-: Trichloroperoxyl radical.
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Affiliation(s)
- Md Ariful Islam
- Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh
| | - Md Abdullah Al Mamun
- Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh
| | - Md Faruk
- Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh
| | - Md Tauhid Ul Islam
- Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh
| | - Md Mizanur Rahman
- Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh
| | - Mohammad Nazmul Alam
- Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh
| | | | - Hasan Mahmud Reza
- Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh
| | - Md Ashraful Alam
- Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh
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Kwon JH, Ahn KS, Moon YH, Park JY, Wang HJ, Choi KY, Kim G, Joh JW, Lee KG, Kang KJ. AROS Is a Significant Biomarker for Tumor Aggressiveness in Non-cirrhotic Hepatocellular Carcinoma. J Korean Med Sci 2015; 30:1253-1259. [PMID: 26339164 PMCID: PMC4553671 DOI: 10.3346/jkms.2015.30.9.1253] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2014] [Accepted: 05/27/2015] [Indexed: 12/15/2022] Open
Abstract
Despite a low risk of liver failure and preserved liver function, non-cirrhotic hepatocellular carcinoma (HCC) has a poor prognosis. In the current study, we evaluated an active regulator of SIRT1 (AROS) as a prognostic biomarker in non-cirrhotic HCC. mRNA levels of AROS were measured in tumor and non-tumor tissues obtained from 283 non-cirrhotic HCC patients. AROS expression was exclusively up-regulated in recurrent tissues from the non-cirrhotic HCC patients (P = 0.015) and also in tumor tissues irrespective of tumor stage (P < 0.001) or BCLC stage (P < 0.001). High mRNA levels of AROS were statistically significantly associated with tumor stage (P < 0.001), BCLC stage (P = 0.007), alpha fetoprotein (AFP) level (P = 0.013), microvascular invasion (P = 0.001), tumor size (P = 0.036), and portal vein invasion (P = 0.005). Kaplan-Meir curve analysis demonstrated that HCC patients with higher AROS levels had shorter disease-free survival (DFS) in both the short-term (P < 0.001) and long-term (P = 0.005) compared to those with low AROS. Cox regression analysis demonstrated that AROS is a significant predictor for DFS along with large tumor size, tumor multiplicity, vascular invasion, and poor tumor differentiation, which are the known prognostic factors. In conclusion, AROS is a significant biomarker for tumor aggressiveness in non-cirrhotic hepatocellular carcinoma.
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Affiliation(s)
| | - Keun Soo Ahn
- Department of Surgery, Keimyung University School of Medicine, Dongsan Medical Center, Daegu, Korea
| | | | | | - Hee Jung Wang
- Department of Surgery, Ajou University School of Medicine, Suwon, Korea
| | - Kwan Yong Choi
- Department of Life Science, Pohang University of Science and Technology, Pohang, Korea
| | - Gundo Kim
- Department of Microbiology, Pukyong National University, Busan, Korea
| | - Jae Won Joh
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kyeong Geun Lee
- Department of Surgery, Hanyang University School of Medicine, Seoul, Korea
| | - Koo Jeong Kang
- Department of Surgery, Keimyung University School of Medicine, Dongsan Medical Center, Daegu, Korea
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Karidis NP, Delladetsima I, Theocharis S. Hepatocyte Turnover in Chronic HCV-Induced Liver Injury and Cirrhosis. Gastroenterol Res Pract 2015; 2015:654105. [PMID: 25892989 PMCID: PMC4393903 DOI: 10.1155/2015/654105] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2014] [Accepted: 03/16/2015] [Indexed: 12/29/2022] Open
Abstract
Chronic hepatitis C virus (HCV) infection may eventually lead to progressive liver fibrosis and cirrhosis through a complex, multistep process involving hepatocyte death and regeneration. Despite common pathogenetic pathways present in all forms of liver cirrhosis irrespective of etiology, hepatocyte turnover and related molecular events in HCV-induced cirrhosis are increasingly being distinguished from even "similar" causes, such as hepatitis B virus- (HBV-) related cirrhosis. New insights in HCV-induced hepatocellular injury, differential gene expression, and regenerative pathways have recently revealed a different pattern of progression to irreversible parenchymal liver damage. A shift to the significant role of the host immune response rather than the direct effect of HCV on hepatocytes and the imbalance between antiapoptotic and proapoptotic signals have been investigated in several studies but need to be further elucidated. The present review aims to comprehensively summarize the current evidence on HCV-induced hepatocellular turnover with a view to outline the significant trends of ongoing research.
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Affiliation(s)
- Nikolaos P. Karidis
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, 11527 Athens, Greece
| | - Ioanna Delladetsima
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, 11527 Athens, Greece
| | - Stamatios Theocharis
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, 11527 Athens, Greece
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Abstract
Abundant evidence supports the belief of a causal relationship between cirrhosis and hepatocellular carcinoma, but one that differs between high- and low-incidence regions of the tumor. In high-incidence regions, the cirrhosis is of the macronodular variety, is typically asymptomatic, and is caused predominantly by chronic hepatitis B virus infection, whereas in low-incidence regions, the cirrhosis, although usually macronodular, may be micronodular, is commonly symptomatic and of long-standing, and is caused by chronic hepatitis C virus infection, alcohol abuse over many years, the metabolic syndrome, or hereditary hemochromatosis. In a minority of patients, hepatocellular carcinoma develops in the absence of cirrhosis, supporting a direct hepatocarcinogenic effect of some of the causal agents. Cirrhosis is the major risk factor for tumor formation in patients with chronic hepatitis C virus infection. This virus does not integrate into cellular DNA, and malignant transformation results from increased liver cell turnover induced by recurring injury and regeneration of cells in the context of persisting inflammation, oxidative DNA damage, fibrosis, cirrhosis, and changes induced by the virus at a DNA level that have yet to be fully defined. Hepatitis B virus causes malignant transformation by both direct and indirect routes. The direct route results, in part, from integration of the viral DNA into host cellular DNA; transcriptional activation of host growth regulatory genes by hepatitis B virus-encoded proteins; and effects on apoptosis, cell signaling, and DNA repair. The direct route may share some similarities with that of hepatitis C virus infection. The metabolic syndrome may cause malignant transformation by production of oxidative stress and the induction of a variety of mutations, including some in the p53 gene.
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Affiliation(s)
- Michael C Kew
- Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa,
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Hou YL, Tsai YH, Lin YH, Chao JCJ. Ginseng extract and ginsenoside Rb1 attenuate carbon tetrachloride-induced liver fibrosis in rats. Altern Ther Health Med 2014; 14:415. [PMID: 25344394 PMCID: PMC4216840 DOI: 10.1186/1472-6882-14-415] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Accepted: 10/16/2014] [Indexed: 02/06/2023]
Abstract
Background Ginsenosides, the major bioactive compounds in ginseng root, have been found to have antioxidant, immunomodulatory and anti-inflammatory activities. This study investigated the effects of ginsenosides on carbon tetrachloride (CCl4)-induced hepatitis and liver fibrosis in rats. Methods Male Sprague–Dawley rats were randomly divided into four groups: control, CCl4, CCl4 + 0.5 g/kg Panax ginseng extract and CCl4 + 0.05 g/kg ginsenoside Rb1 groups. The treated groups were orally given Panax ginseng extract or ginsenoside Rb1 two weeks before the induction of liver injury for successive 9 weeks. Liver injury was induced by intraperitoneally injected with 400 ml/l CCl4 at a dose of 0.75 ml/kg body weight weekly for 7 weeks. The control group was intraperitoneally injected with olive oil. Results The pathological results showed that ginsenoside Rb1 decreased hepatic fat deposition (2.65 ± 0.82 vs 3.50 ± 0.75, p <0.05) and Panax ginseng extract lowered hepatic reticular fiber accumulation (1.05 ± 0.44 vs 1.60 ± 0.39, p <0.01) increased by CCl4. Plasma alanine aminotransferase and aspartate aminotransferase activities were increased by CCl4 (p <0.01), and aspartate aminotransferase activity was decreased by Panax ginseng extract at week 9 (p <0.05). Exposure to CCl4 for 7 weeks, the levels of plasma and hepatic triglycerides (p <0.01), hepatic cholesterol (p <0.01), interleukin-1β (p <0.01), prostaglandin E2 (p <0.05), soluble intercellular adhesion molecule-1 (p <0.05), hydroxyproline (p <0.05), matrix metalloproteinase-2 (p <0.05) and tissue inhibitor of metalloproteinase-1 (TIMP-1) (p <0.01) were elevated, however, hepatic interleukin-10 level was lowered (p <0.05). Both Panax ginseng extract and ginsenoside Rb1 decreased plasma and hepatic triglyceride, hepatic prostaglandin E2, hydroxyproline and TIMP-1 levels, and Panax ginseng extract further inhibited interleukin-1β concentrations (p <0.05). Conclusions Panax ginseng extract and ginsenoside Rb1 attenuate plasma aminotransferase activities and liver inflammation to inhibit CCl4-induced liver fibrosis through down-regulation of hepatic prostaglandin E2 and TIMP-1.
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Kudo A, Tanaka S, Ban D, Matsumura S, Irie T, Ochiai T, Nakamura N, Arii S, Tanabe M. Alcohol consumption and recurrence of non-B or non-C hepatocellular carcinoma after hepatectomy: a propensity score analysis. J Gastroenterol 2014; 49:1352-1361. [PMID: 24136219 DOI: 10.1007/s00535-013-0899-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2013] [Accepted: 10/04/2013] [Indexed: 02/04/2023]
Abstract
BACKGROUND The aim of this study was to identify factors related to the recurrence of non-B or non-C (NBNC) hepatocellular carcinoma (HCC). STUDY DESIGN Between April 2000 and March 2012, out of 621 consecutive HCC patients at our institution, 543 who underwent initial hepatectomy and had no extrahepatic metastases were enrolled in the study. Multivariate analysis were performed to identify risk factors for poor disease-free survival (DFS). RESULTS The 5-year DFS rate of NBNC (34 %) was better than that of hepatitis virus B (30 %, P = 0.011) and hepatitis virus C (21 %, P < 0.0001), significantly. Multivariate analysis revealed NBNC [hazard ratio (HR), 0.5; 95 % CI, 0.4-0.8; P < 0.0001)] to be an independent factor for DFS rate. We constructed a propensity score matching model with the 543 patients, and the 5-year DFS rates with and without severe alcohol liver disease (ALD) were 31.6 and 47.5 %, respectively (P = 0.013). In the 163 NBNC patients, severe ALD, mild ALD, and no ALD were seen in 35, 56, and 72 patients, respectively. Multivariate analysis revealed a vascular invasion into the hepatic vein (HR, 3.3; 95 % CI, 1.7-6.3; P < 0.0001) and severe ALD (HR, 2.0; 95 % CI, 1.1-3.6; P = 0.020) to be independent risk factors for poor DFS. By propensity score matching between mild and severe ALD, the 5-year DFS rates with severe and mild ALD were 26 and 50 %, respectively (P = 0.035). CONCLUSIONS The prognoses of NBNC patients were better than those of patients with viral infections. Among the NBNC patients, preoperative excessive alcohol intake decreased DFS rate of HCC occurrence after surgery.
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Affiliation(s)
- Atsushi Kudo
- Department of Hepatobiliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan,
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Li F, Ma N, Zhao R, Wu G, Zhang Y, Qiao Y, Han D, Xu Y, Xiang Y, Yan B, Jin J, Lv G, Wang L, Xu C, Gao X, Luo S. Overexpression of miR-483-5p/3p cooperate to inhibit mouse liver fibrosis by suppressing the TGF-β stimulated HSCs in transgenic mice. J Cell Mol Med 2014; 18:966-74. [PMID: 24801603 PMCID: PMC4508137 DOI: 10.1111/jcmm.12293] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2013] [Accepted: 03/10/2014] [Indexed: 01/04/2023] Open
Abstract
The transition from liver fibrosis to hepatocellular carcinoma (HCC) has been suggested to be a continuous and developmental pathological process. MicroRNAs (miRNAs) are recently discovered molecules that regulate the expression of genes involved in liver disease. Many reports demonstrate that miR-483-5p and miR-483-3p, which originate from miR-483, are up-regulated in HCC, and their oncogenic targets have been identified. However, recent studies have suggested that miR-483-5p/3p is partially down-regulated in HCC samples and is down-regulated in rat liver fibrosis. Therefore, the aberrant expression and function of miR-483 in liver fibrosis remains elusive. In this study, we demonstrate that overexpression of miR-483 in vivo inhibits mouse liver fibrosis induced by CCl4. We demonstrate that miR-483-5p/3p acts together to target two pro-fibrosis factors, platelet-derived growth factor-β and tissue inhibitor of metalloproteinase 2, which suppress the activation of hepatic stellate cells (HSC) LX-2. Our work identifies the pathway that regulates liver fibrosis by inhibiting the activation of HSCs.
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Affiliation(s)
- Fuyuan Li
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China
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Kew MC. Hepatitis B Virus: Epidemiology and Clinical Features of Related Cancer. VIRUSES AND HUMAN CANCER 2014:133-165. [DOI: 10.1007/978-1-4939-0870-7_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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14
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Hung CH, Chen CH, Lee CM, Hu TH, Lu SN, Wang JH, Huang CM. Role of viral genotypes and hepatitis B viral mutants in the risk of hepatocellular carcinoma associated with hepatitis B and C dual infection. Intervirology 2013; 56:316-24. [PMID: 23838434 DOI: 10.1159/000350738] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2012] [Accepted: 03/07/2013] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND/AIMS The independent and interactive effects of hepatitis B virus (HBV) and hepatitis C virus (HCV) factors on the development of hepatocellular carcinoma (HCC) in chronic HBV/HCV dually-infected patients remain unclear. METHODS In a cross-sectional and case-controlled study, the HBV and HCV loads and genotypes and the sequences of pre-S and precore/core promoter regions were determined in 146 HCC patients and 167 chronic carriers with HBV/HCV dual infection. RESULTS Age (odds ratio (OR) 1.1), male sex (OR 2.3), pre-S deletion (OR 5.0), A1762T/G1764A mutant (OR 2.5), HCV genotype-1 (OR 2.4) and platelet count <15 × 10(4)/μl (OR 1.9) were independently associated with HCC by stepwise logistic regression analysis. Patients with combined HBV mutations (pre-S deletion and A1762T/G1764A mutant) and HCV genotype-1 had a 39-fold increased risk of developing HCC compared to those with A1762T/G1764A and pre-S wild-type strains and HCV genotype non-1. In the nested case-control study, patients with HCC had a higher HBV DNA level (p < 0.001), a higher frequency of pre-S deletion (p < 0.001) and A1762T/G1764A mutant (p = 0.005), a lower HCV RNA level (p = 0.012) and a higher prevalence of HCV genotype-1 (p = 0.002) than those without. CONCLUSIONS Pre-S deletion, A1762T/G1764A mutation and HCV genotype-1 are important in hepatocarcinogenesis in chronic HBV/HCV dual infection.
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Affiliation(s)
- C-H Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan, ROC.
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15
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Hepatocellular carcinoma and other malignancies in autoimmune hepatitis. Dig Dis Sci 2013; 58:1459-76. [PMID: 23306849 DOI: 10.1007/s10620-012-2525-5] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2012] [Accepted: 12/03/2012] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma and extrahepatic malignancies can complicate the course of autoimmune hepatitis, and these occurrences may increase in frequency as the survival of patients with cirrhosis is extended and the prospect of new nonstandard immune-modifying intervention is realized. The frequency of hepatocellular carcinoma in patients with autoimmune hepatitis and cirrhosis is 1-9 %, and annual occurrence in patients with cirrhosis is 1.1-1.9 %. The standardized incidence ratio for hepatocellular carcinoma in autoimmune hepatitis is 23.3 (95 % confidence interval (CI) 7.5-54.3) in Sweden, and the standardized mortality ratio for hepatobiliary cancer is 42.3 (95 % CI 20.3-77.9) in New Zealand. The principal risk factor is long-standing cirrhosis, and patients at risk are characterized mainly by cirrhosis for ≥ 10 years, manifestations of portal hypertension, persistent liver inflammation, and immunosuppressive therapy for ≥ 3 years. Multiple molecular disturbances, including the accumulation of senescent hepatocytes because of telomere shortening, step-wise accumulation of chromosomal injuries, and aberrations in transcription factors and genes, may contribute to the risk. Extraheptic malignancies of diverse cell types occur in 5 % in an unpredictable fashion. The standardized incidence ratio is 2.7 (95 % CI 1.8-3.9) in New Zealand, and non-melanoma skin cancers are most common. Outcomes are related to the nature and stage of the tumor at diagnosis. Surveillance recommendations have not been promulgated, but hepatic ultrasonography every six months in patients with cirrhosis is a consideration. Routine health screening measures for other malignancies should be applied diligently.
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Shrager B, Jibara G, Schwartz M, Roayaie S. Resection of Hepatocellular Carcinoma Without Cirrhosis. Ann Surg 2012; 255:1135-43. [DOI: 10.1097/sla.0b013e31823e70a3] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Wörns MA, Bosslet T, Victor A, Koch S, Hoppe-Lotichius M, Heise M, Hansen T, Pitton MB, Niederle IM, Schuchmann M, Weinmann A, Düber C, Galle PR, Otto G. Prognostic factors and outcomes of patients with hepatocellular carcinoma in non-cirrhotic liver. Scand J Gastroenterol 2012; 47:718-28. [PMID: 22472070 DOI: 10.3109/00365521.2012.677952] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVES To report the outcome of patients with hepatocellular carcinoma (HCC) in non-cirrhotic liver depending on the mode of primary treatment and to define clinicopathological factors influencing patients' prognosis. METHODS A retrospective analysis of an unselected cohort of 105 patients was performed. Overall survival (OS) was estimated by the Kaplan-Meier method and potentially prognostic factors were analyzed in Cox regression models. RESULTS OS of the whole cohort at 1, 3, and 5 years was 66%, 47%, and 29%, respectively. Tobacco consumption, ECOG >0, macroscopic vascular invasion, continuous tumor diameter, and treatment other than resection were predictors of decreased OS in the whole cohort. Resection was performed in 64% of patients with 1-, 3-, and 5-year OS rates of 84%, 69%, and 42%, respectively. Siderosis and BCLC stage were associated with decreased OS after resection. Recurrence occurred in 57% of patients with 1-, 3-, and 5-year disease-free survival (DFS) rates of 63%, 39%, and 31%, respectively. Viral hepatitis and macroscopic vascular invasion were associated with decreased DFS. One-, 3-, and 5-year OS rates in patients with non-surgical approaches (transarterial chemoembolization, systemic therapy, best supportive care) were 38%, 11%, and 7%, respectively. Tobacco consumption and Okuda stage were associated with decreased OS in these patients. CONCLUSIONS OS and DFS of patients with HCC in non-cirrhotic liver depend most notably on tumor-related, demographic, and etiological factors. Features of the non-neoplastic liver tissue play only a minor role. Liver resection leads to a significantly better prognosis than non-surgical treatment approaches.
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Affiliation(s)
- Marcus A Wörns
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
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Kew MC. Hepatocellular carcinoma in developing countries: Prevention, diagnosis and treatment. World J Hepatol 2012; 4:99-104. [PMID: 22489262 PMCID: PMC3321496 DOI: 10.4254/wjh.v4.i3.99] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2011] [Revised: 03/08/2012] [Accepted: 03/17/2012] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) occurs commonly and with increasing frequency in developing countries, where it also carries an especially grave prognosis. The major risk factor for HCC in these regions is chronic hepatitis B virus (HBV) infection, although dietary exposure to aflatoxin B1 also plays an important etiological role. Prevention of HCC in developing regions is unlikely in the foreseeable future. Although an effective vaccine against HBV is available, the percentage of babies born in developing countries that receive the full course of immunization remains low. Moreover, the usually long interval between infection with HBV and the development of HCC means that 30 to 50 years will elapse before the full effect of the vaccine will be realized. Practical measures to prevent aflatoxin B1 exposure are not in place. Serum α-fetoprotein levels are a useful pointer to the diagnosis of HCC in low-income countries, but definitive diagnosis is hampered both by the lack of the sophisticated imaging equipment now available in developed countries and by obstacles to obtaining histological proof. In the majority of patients in low-income regions, the tumor is inoperable by the time the patient presents. Hepatic resection is seldom possible in sub-Saharan Africa, although the tumor is successfully resected in a larger number of patients in China. Liver transplantation for HCC is rarely performed in either region. Sophisticated new radiotherapy techniques are not available in developing countries. The beneficial effects of the multikinase inhibitor, sorafenib, are encouraging, although financial considerations may restrict its use in low-income countries.
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Affiliation(s)
- Michael C Kew
- Michael C Kew, Department of Medicine, University of Cape Town and Groote Schuur Hospital, Cape Town, Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa
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Kondo M, Moriishi K, Wada H, Noda T, Marubashi S, Wakasa K, Matsuura Y, Doki Y, Mori M, Nagano H. Upregulation of nuclear PA28γ expression in cirrhosis and hepatocellular carcinoma. Exp Ther Med 2011; 3:379-385. [PMID: 22969899 DOI: 10.3892/etm.2011.415] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2011] [Accepted: 12/02/2011] [Indexed: 11/06/2022] Open
Abstract
We previously reported that proteasome activator 28γ (PA28γ) is an oncogenic protein in hepatitis C virus (HCV) core protein transgenic mice. The aim of this study was to determine the role of PA28γ expression at the protein level in the development and progression of human hepatocarcinogenesis and hepatocellular carcinoma (HCC). Samples from tissues representing a wide spectrum of liver disease were analyzed, including histologically normal livers (n=5), HCV-related chronic hepatitis (CH) (n=15) and cirrhosis (n=31). The level of nuclear PA28γ increased with the progression of liver disease from CH to cirrhosis. The majority of cirrhotic livers (68%; 21/31) displayed high nuclear PA28γ expression. However, in half of the HCCs (50%; 18/36), little or no nuclear PA28γ expression was observed, while the remaining 50% (18/36) of the cases displayed high levels of nuclear PA28γ expression. A clinicopathological survey demonstrated a significant correlation between nuclear PA28γ expression and capsular invasion in HCC (P=0.026); a striking difference was found between nuclear PA28γ expression in non-tumor tissues and shorter disease-free survival (P<0.01). Moreover, nuclear PA28γ expression in non-tumor tissues correlated with the expression of molecules related to the genesis of hepatic steatosis and HCC, such as sterol regulatory element binding protein-1c mRNA. The findings suggest the involvement of nuclear PA28γ expression in the progression and relapse of HCC, and suggest that nuclear PA28γ is a potentially suitable target for the prevention and/or treatment of HCC.
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Affiliation(s)
- Motoi Kondo
- Evidence Based Medical Research Center, Osaka
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De Mitri MS, Cassini R, Bernardi M. Hepatitis B virus-related hepatocarcinogenesis: Molecular oncogenic potential of clear or occult infections. Eur J Cancer 2010; 46:2178-86. [DOI: 10.1016/j.ejca.2010.03.034] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2009] [Accepted: 03/25/2010] [Indexed: 12/20/2022]
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Hung CH, Wang JH, Hu TH, Chen CH, Chang KC, Yen YH, Kuo YH, Tsai MC, Lu SN, Lee CM. Insulin resistance is associated with hepatocellular carcinoma in chronic hepatitis C infection. World J Gastroenterol 2010; 16:2265-71. [PMID: 20458764 PMCID: PMC2868220 DOI: 10.3748/wjg.v16.i18.2265] [Citation(s) in RCA: 87] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To elucidate the role of insulin resistance (IR) and serum adiponectin level in hepatocellular carcinoma (HCC) associated with chronic hepatitis C.
METHODS: Clinical and biochemical characteristics were collected from 165 consecutive patients with newly diagnosed HCC. Homeostasis model assessment of IR (HOMA-IR) and serum adiponectin level were investigated in 188 patients with different stages of hepatitis C virus (HCV) infection.
RESULTS: Among HCC patients, type 2 diabetics (DM) was more prevalent in HCV subjects (35.6%, n = 59) compared to hepatitis B virus (HBV; 12.7%, n = 63) or non-HBV, non-HCV cases (7.1%, n = 28). In patients with chronic hepatitis C, HCC subjects had higher blood sugar (P < 0.001), insulin level (P = 0.003) and HOMA-IR (P = 0.018) than those with chronic hepatitis and advanced fibrosis. Age, male sex and body mass index were significantly associated with serum adiponectin level, whereas HOMA-IR was not. Based on stepwise logistic regression analysis, age (OR: 1.124, P < 0.001), serum insulin level (OR: 1.585, P < 0.001), HOMA-IR (OR: 0.495, P = 0.001), DM (OR: 11.601, P = 0.002) and male sex (OR: 3.877, P = 0.016) were independently associated with HCC. This result was similar even if the diabetic subjects were excluded for analysis.
CONCLUSION: Insulin resistance measured by HOMA-IR, regardless of the presence of diabetes, is significantly associated with HCC development in patients with chronic HCV infection.
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Hepatocellular carcinoma in non-cirrhotic liver: a reappraisal. Dig Liver Dis 2010; 42:341-7. [PMID: 19828388 DOI: 10.1016/j.dld.2009.09.002] [Citation(s) in RCA: 141] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2009] [Revised: 09/06/2009] [Accepted: 09/11/2009] [Indexed: 12/11/2022]
Abstract
Although not frequently, hepatocellular carcinoma (HCC) can ensue in a non-cirrhotic liver. As compared to cirrhotic HCC, this kind of tumour has some peculiarities, such as: (a) a lower male preponderance and a bimodal age distribution; (b) a lower prevalence of the three main risk factors (hepatitis B and C virus infections and alcohol abuse), with an increased prevalence of other etiologic factors, such as exposure to genotoxic substances and sex hormones, inherited diseases, genetic mutations; (c) a more advanced tumour stage at the time of diagnosis, as it is usually detected due to the occurrence of cancer-related symptoms, outside any scheduled surveillance program; (d) a much higher amenability to hepatic resection, due to the low risk of liver failure even after extended parenchymal mutilation; (e) overall and disease-free survivals after resection of non-advanced tumours (meeting the Milano criteria) comparable to that obtained with liver transplantation in cirrhotic patients carrying an early tumour; (f) overall survival strictly dependent on tumour burden (and its recurrence) and barely influenced by liver function.
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Abstract
BACKGROUND Hepatocellular carcinoma (HCC) occurring in "noncirrhotic" hepatitis C virus (HCV)-infected patients has been reported; but the exact prevalence or incidence has not been described before. METHODS We conducted a systematic review of literature: Ovid was used to search the literature from January 1, 1990, to September 1, 2008. Articles containing "HCC" keywords (hepatocellular carcinoma, hepatoma, liver cancer) were combined with the word "cirrhosis" or "fibrosis" and with "absence" keywords [noncirrhotic, absence, without]. Two hundred articles were selected and screened according to predesigned exclusion and inclusion criteria. RESULTS Nineteen articles met the inclusion criteria. The estimated prevalence of noncirrhotic HCC ranged from 6.7% to 50.1%. The pooled prevalence estimates for HCV in noncirrhotic HCC ranged from 0% and 68.4% according to the geographic location. Reports from Japan had the highest estimated pooled prevalence of HCV (55.01%) followed by Italy (29.95%). CONCLUSION HCV can occur in patients with HCC without cirrhosis, but the true incidence and prevalence are very difficult to ascertain. Further studies are needed to define this group of patients.
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24
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Hepatic iron overload and hepatocellular carcinoma. Cancer Lett 2008; 286:38-43. [PMID: 19081672 DOI: 10.1016/j.canlet.2008.11.001] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2008] [Accepted: 11/04/2008] [Indexed: 01/09/2023]
Abstract
The liver is the main storage site for iron in the body. Excess accumulation of iron in the liver has been well-documented in two human diseases, hereditary hemochromatosis and dietary iron overload in the African. Hepatic iron overload in these conditions often results in fibrosis and cirrhosis and may be complicated by the development of hepatocellular carcinoma. Malignant transformation usually occurs in the presence of cirrhosis, suggesting that free iron-induced chronic necroinflammatory hepatic disease plays a role in the hepatocarcinogenesis. However, the supervention of hepatocellular carcinoma in the absence of cirrhosis raises the possibility that ionic iron may also be directly hepatocarcinogenic. Support for this possibility is provided by a recently described animal model of dietary iron overload in which iron-free preneoplastic nodules and hepatocellular carcinoma developed in the absence of fibrosis or cirrhosis. The mechanisms by which iron induces malignant transformation have yet to be fully characterized but the most important appears to be the generation of oxidative stress. Free iron generates reactive oxygen intermediates that disrupt the redox balance of the cells and cause chronic oxidative stress. Oxidative stress leads to lipid peroxidation of unsaturated fatty acids in membranes of cells and organelles. Cytotoxic by-products of lipid peroxidation, such as malondialdehyde and 4-hydroxy-2'-nonenal, are produced and these impair cellular function and protein synthesis and damage DNA. Deoxyguanosine residues in DNA are also hydroxylated by reactive oxygen intermediates to form 8-hydroxy-2'-deoxyguanosine, a major promutagenic adduct that causes G:C to T:A transversions and DNA unwinding and strand breaks. Free iron also induces immunologic abnormalities that may decrease immune surveillance for malignant transformation.
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Lubrano J, Huet E, Tsilividis B, François A, Goria O, Riachi G, Scotté M. Long-term outcome of liver resection for hepatocellular carcinoma in noncirrhotic nonfibrotic liver with no viral hepatitis or alcohol abuse. World J Surg 2008; 32:104-9. [PMID: 18026787 DOI: 10.1007/s00268-007-9291-0] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) occurs primarily in cirrhotic liver, with less than 10% occurring in normal liver parenchyma. Limited studies have described the outcome of liver resection in strictly normal liver parenchyma with no cirrhosis, fibrosis, underlying viral hepatitis, alcohol abuse, or dysmetabolic syndrome. MATERIALS AND METHODS Between January 1986 and 2005, a total of 321 patients were referred to our institution for HCC. Of these patients, 20 (6.2%) underwent surgery for HCC arising in noncirrhotic nonfibrotic liver parenchyma; they comprise our study group. Pathology examinations were reviewed based on the Chevallier fibrosis score and the Metavir viral score. Pre-, per-, and postoperative data were collected to assess their influence on tumor recurrence and survival. RESULTS The median age was 57 years (35-80 years), and 71% patients were male. Alpha-fetoprotein serum levels were normal in 9 patients. A preoperative diagnosis was made in 14 cases. Morbidity and morality rates were 10% and 5%, respectively. The 1-, 3-, and 5-year survival rates were 85%, 70%, and 64%, respectively; and disease-free survivals at 1, 3, and 5 years were 84%, 66%, and 58%, respectively. Eight patients had a recurrence with a median delay of 15 months (2-70 months). Univariate analysis showed that survival was influenced by preoperative cytolysis, R0 resection, recurrence, and recurrence within 1 year. A multivariate analysis revealed that recurrence and recurrence within 1 year significantly decreased survival. The 1-, 3-, and 5-year survival rates of patients with recurrence were 75%, 37%, and 25%, respectively. CONCLUSION These results for HCC in patients with normal liver parenchyma justify liver resection and underline the differences in outcome of patients with HCC in a cirrhotic liver.
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Affiliation(s)
- Jean Lubrano
- Department of General and Digestive Surgery, Rouen University Hospital, Charles Nicolle 1, rue de Germont, 76031, Rouen, France
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Abstract
Hepatocellular carcinoma (HCC) is frequently diagnosed at advanced stages and has a high mortality rate. With improved survival of patients with cirrhotic liver disease and increased prevalence of chronic hepatitis C viral infections, a rise in the number of HCC cases is being reported worldwide. Early diagnosis and treatment can significantly improve the prognosis of patients with HCC. Although surgical resection is an important potentially curative therapy for liver tumors, in appropriately selected patients, liver transplantation has been shown to achieve excellent survival rates for a solid tumor. Locally ablative and locoregional therapies in the form of percutaneous ethanol injection, radiofrequency ablation, transcatheter arterial chemoembolization and transcatheter arterial radioembolization (TheraSphere) are viable options in patients with unresectable HCC. Unfortunately, the role of systemic therapy has been very limited in the treatment of these patients. Novel treatment options based on an improved understanding of the molecular pathogenesis of HCC are being explored. These targeted molecular therapies are aimed at growth factors and their receptors, intracellular signal transduction and cell cycle control. A substantial improvement in outcomes of intermediate and advanced stage HCC is expected with the advent of these targeted therapies, used in combination with surgical or locoregional therapies. Recent positive results from a large Phase III study of the receptor tyrosine kinase inhibitor, sorafenib, hold great promise in the treatment of HCC.
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Affiliation(s)
- Dalbir S Sandhu
- Miles and Shirley Fiterman Center for Digestive Diseases, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
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27
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Hung CH, Chen CH, Lee CM, Wu CM, Hu TH, Wang JH, Yen YH, Lu SN. Association of amino acid variations in the NS5A and E2-PePHD region of hepatitis C virus 1b with hepatocellular carcinoma. J Viral Hepat 2008; 15:58-65. [PMID: 18088246 DOI: 10.1111/j.1365-2893.2007.00892.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
NS5A and E2 proteins of the hepatitis C virus (HCV) have the potential to repress protein kinase R (PKR) that exerts a tumour suppressor function. We investigated the relationship between amino acid variations in the NS5A-PKR-binding domain and E2-PKR-eIF2alpha phosphorylation homology domain (PePHD) region and the development of hepatocellular carcinoma (HCC) in chronic HCV-1b patients. In a cross-sectional, hospital-based setting, we compared the amino acid sequences of NS5A-PKR-binding domain and E2-PePHD in the sera of 104 chronic hepatitis, 44 cirrhosis and 96 HCC patients. The nucleotide sequences were inferred by direct sequencing of the amplified HCV products and deduced amino acid were compared with the sequence of HCV-J. By univariate analysis, old age, lower viral load, fewer amino acid substitutions in the NS5A-PKR-binding domain (codons 2209-2274) and the interferon sensitivity-determining region (ISDR; codons 2209-2248), and wild-type amino acid at codon 2209 and codon 2240 was significantly correlated with HCC, whereas substitutions in the E2-PePHD was not. Patients with a mutated-type (> or = 4) NS5A-ISDR had a lower prevalence of HCC than those with intermediate or wild type (P < 0.05). Based on stepwise logistic regression analysis, age [odds ratio (OR): 1.132, P < 0.001], viral load (OR: 0.305, P < 0.001) and mutated-type ISDR (OR: 0.137, P = 0.001) were independently associated with HCC. In conclusion, NS5A-ISDR variations may play an important role in the development of HCV-related HCC.
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Affiliation(s)
- C-H Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan
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Milich DR, Jones J, Hughes J, Maruyama T. Hepatitis B virus infection, the immune response and hepatocellular carcinoma. CIBA FOUNDATION SYMPOSIUM 2007; 187:113-29; discussion 129-31. [PMID: 7796667 DOI: 10.1002/9780470514672.ch8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
More than 250 million people worldwide are chronically infected with the hepatitis B virus (HBV) and have a 200-fold increased risk of developing hepatocellular carcinoma (HCC). This is one of the most common cancers in the world with a geographical distribution highest in areas where HBV is endemic. A number of molecular mechanisms have been proposed to explain this correlation including an acutely transforming viral oncogene; chromosomal aberrations due to HBV integration (i.e. deletions, translocations, duplications); activation of cellular proto-oncogenes; inactivation of cellular anti-oncogenes; and transactivation of cellular genes by HBV gene products. HCC usually develops only after 20-30 years of persistent HBV infection accompanied by hepatocyte necrosis, inflammation and regenerative hyperplasia. Because HBV is not directly cytopathic, liver injury must be immune mediated. Factors that predispose HBV-infected individuals to develop HCC are chronicity, an immune response and liver injury rather than a direct genetic event. Hepatic injury and continuous hepatocyte regeneration may allow an accumulation of multiple mutational events sufficient for the emergence of HCC. Pathways which lead to chronicity, the immune response during HBV infection, mechanisms of pathogenesis and methods to prevent HBV infection are all relevant to the development of HCC. Recent studies characterizing the humoral and cellular immune responses in patients chronically infected with HBV and transgenic mouse models of HBV-specific immune tolerance and pathogenesis are providing new insights into the complex association between HBV infection and HCC.
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Affiliation(s)
- D R Milich
- Department of Molecular Biology, Scripps Research Institute, La Jolla, CA 92037, USA
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Sebastiani G, Walker AP. HFE gene in primary and secondary hepatic iron overload. World J Gastroenterol 2007; 13:4673-89. [PMID: 17729389 PMCID: PMC4611189 DOI: 10.3748/wjg.v13.i35.4673] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2007] [Revised: 05/01/2007] [Accepted: 05/09/2007] [Indexed: 02/06/2023] Open
Abstract
Distinct from hereditary haemochromatosis, hepatic iron overload is a common finding in several chronic liver diseases. Many studies have investigated the prevalence, distribution and possible contributory role of excess hepatic iron in non-haemochromatotic chronic liver diseases. Indeed, some authors have proposed iron removal in liver diseases other than hereditary haemochromatosis. However, the pathogenesis of secondary iron overload remains unclear. The High Fe (HFE) gene has been implicated, but the reported data are controversial. In this article, we summarise current concepts regarding the cellular role of the HFE protein in iron homeostasis. We review the current status of the literature regarding the prevalence, hepatic distribution and possible therapeutic implications of iron overload in chronic hepatitis C, hepatitis B, alcoholic and non-alcoholic fatty liver diseases and porphyria cutanea tarda. We discuss the evidence regarding the role of HFE gene mutations in these liver diseases. Finally, we summarize the common and specific features of iron overload in liver diseases other than haemochromatosis.
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Affiliation(s)
- Giada Sebastiani
- Venetian Institute of Molecular Medicine (VIMM), Padova and Digestive Diseases, Hepatology and Clinical Nutrition Department, Umberto I Hospital, Venice, Italy.
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30
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Abstract
Dietary iron overload occurs commonly in parts of sub-Saharan Africa. It results from the consumption of large volumes of traditional beer that is home-brewed in iron pots or drums and consequently has a high iron content. The liver becomes iron overloaded and may develop portal fibrosis or, less often, cirrhosis. A genetic predisposition to the condition has been suggested, but no putative gene has yet been identified. Although originally believed not to cause hepatocellular carcinoma, recent case-control studies have shown African Blacks with dietary iron overload to be at increased risk for the tumour and a causal association has been confirmed in an animal model. The mechanisms of iron-induced malignant transformation are yet to be fully characterised, but the close association between cirrhosis and hepatocellular carcinoma in patients with hereditary haemochromatosis and the lesser association in those with dietary iron overload, suggests that chronic necroinflammatory hepatic disease contributes to the malignant transformation. Increased hepatic iron may, however, also be directly carcinogenic. Probable mechanisms include the generation of reactive oxygen intermediates and the resultant chronic oxidative stress that damages hepatocytes and proteins, causes lipid peroxidation, and induces strand breaks, DNA unwinding, and mutations in tumour-suppressor genes and critical DNA repair genes.
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Affiliation(s)
- Michael C Kew
- MRC/CANSA/University Molecular Hepatology Research Unit, Department of Medicine, Baragwanath Hospital, University of the Witwatersrand, Johannesburg, South Africa.
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Schwartz M, Roayaie S, Konstadoulakis M. Strategies for the management of hepatocellular carcinoma. ACTA ACUST UNITED AC 2007; 4:424-32. [PMID: 17597707 DOI: 10.1038/ncponc0844] [Citation(s) in RCA: 204] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2005] [Accepted: 03/19/2007] [Indexed: 12/11/2022]
Abstract
Hepatocellular carcinoma (HCC) generally develops as a consequence of underlying liver disease, most commonly viral hepatitis. The development of HCC follows an orderly progression from cirrhosis to dysplastic nodules to early cancer development, which can be reliably cured if discovered before the development of vascular invasion (typically occurring at a tumor diameter of approximately 2 cm). The identifiable population at risk makes screening a realistic possibility, and liver imaging is recommended every 6 months for patients with cirrhosis. For patients with preserved liver function and no portal hypertension who develop HCC that is confined to one region of the liver, resection is the preferred treatment. If resection is not possible because of poor liver function, and the HCC is within the Milan criteria (1 nodule > or =5 cm, 2-3 nodules > or =3 cm), liver transplantation is the treatment of choice. To prevent tumor progression while waiting, nonsurgical treatments including percutaneous ethanol injection, radiofrequency ablation, and transarterial chemoembolization are employed, but drop-out from the waiting list remains a problem. Living donor transplantation is an alternative that can eliminate drop-out and enable liver transplantation for patients with HCC whose disease does not fall within the Milan criteria. There is a need for more effective adjuvant therapies after resection and liver transplantation; newer antiangiogenic agents offer hope for improved outcomes in the future.
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Affiliation(s)
- Myron Schwartz
- Mount Sinai School of Medicine, New York, NY 10029, USA.
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Hollinger FB, Lau DTY. Hepatitis B: the pathway to recovery through treatment. Gastroenterol Clin North Am 2006; 35:895-931. [PMID: 17129820 DOI: 10.1016/j.gtc.2006.10.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2023]
Affiliation(s)
- F Blaine Hollinger
- Department of Medicine, Eugene B. Casey Hepatitis Research Center and Diagnostic Laboratory, Baylor College of Medicine, One Baylor Plaza, BCM-385, Houston, TX 77030-3498, USA.
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Sotiropoulos GC, Molmenti EP, Lang H, Beckebaum S, Kaiser GM, Brokalaki EI, Frilling A, Malagó M, Neuhauser M, Broelsch CE. Surgery for Hepatocellular Carcinoma Arising in Hereditary Hemochromatosis. Eur Surg Res 2006; 38:371-6. [PMID: 16837807 DOI: 10.1159/000094532] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2006] [Accepted: 05/25/2006] [Indexed: 12/29/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a well-known complication of hereditary hemochromatosis. The benefit of surgical therapy in this clinical entity is not well documented. The purpose of this study was to evaluate the outcome of such patients both in our own experience as well as in the published literature. METHODS 320 patients with a diagnosis of HCC were evaluated at our institution to undergo either surgical resection (n = 262) or liver transplantation (n = 58) during the 4- year period from January 2001 to December 2004. We identified 5 patients with HCC arising in the setting of hemochromatosis. A literature search was performed to estimate resectability rates as well as outcomes after liver transplantation for HCC arising in hemochromatosis. RESULTS HCC was multifocal in 4 instances and solitary in 1 case. The liver was cirrhotic in all but 1 case. Three patients underwent an exploratory laparotomy, 1 an exploratory laparoscopy, and 1 underwent transplantation. HCC was unresectable in all cases. The patient with a solitary tumor and cirrhosis underwent 5 sessions of transarterial chemoembolization and is alive 37 months after surgical exploration. The 3 patients with multifocal tumors who underwent exploratory laparotomies died within 6 months after the intervention. The fifth patient who underwent a deceased donor split liver transplantation for multifocal tumor is alive without recurrence 3 years after transplantation. These results are similar to those in the literature that concur with the low resectability rate and the favorable outcome after liver transplantation. CONCLUSION Resectability rates of HCCs arising in hemochromatosis are extremely low, given that tumors are usually multifocal and the livers cirrhotic in the majority of the instances. Early detection of hemochromatosis as well as intensive tumor screening of cirrhotic patients with hemochromatosis could possibly optimize the role of surgery or accelerate the decision to proceed with liver transplantation.
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Affiliation(s)
- Georgios C Sotiropoulos
- Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany.
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Abstract
Hepatitis B is a major public health problem in the world today. Since 1985, the number of reported cases has declined as a direct result of universal immunization of neonates, vaccination of at-risk populations, lifestyle or behavioral changes in high-risk groups, refinements in the screening of blood donors, and the use of virally inactivated or genetically engineered products in patients with bleeding disorders. New and potent antiviral agents being developed and evaluated provide hope and optimism for those who are chronically infected with hepatitis B virus. Prevention remains the most effective strategy in the global management of hepatitis B virus. Universal immunization programs prevent hepatitis B virus transmission and circumvent acute and chronic infection.
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Affiliation(s)
- F Blaine Hollinger
- Department of Medicine, Eugene B. Casey Hepatitis Research Center and Diagnostic Laboratory, Baylor College of Medicine, One Baylor Plaza, BCM-385, Houston, TX 77030-3498, USA.
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Deutsch M, Vasiliou K, Papatheodoridis GV. Hepatocellular carcinoma presenting with pleuritic pain. Eur J Intern Med 2006; 17:222. [PMID: 16618464 DOI: 10.1016/j.ejim.2005.11.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2005] [Revised: 11/10/2005] [Accepted: 11/14/2005] [Indexed: 10/24/2022]
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Kobayashi M, Ikeda K, Hosaka T, Sezaki H, Someya T, Akuta N, Suzuki F, Suzuki Y, Saitoh S, Arase Y, Miyakawa Y, Kumada H. Natural history of compensated cirrhosis in the Child-Pugh class a compared between 490 patients with hepatitis C and 167 with B virus infections. J Med Virol 2006; 78:459-65. [PMID: 16482557 DOI: 10.1002/jmv.20562] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Natural histories of compensated cirrhosis in the Child-Pugh class A were compared between the 490 patients infected with hepatitis C virus (HCV) and 167 patients with hepatitis B virus (HBV) who were followed for more than 1 year up to 20 years without antiviral treatment. Patients with HCV were older (median age: 59 vs. 45 years), less predominantly male (59.0% vs. 76.0%), transfused more frequently (49.2% vs. 9.0%), and had higher aminotransferase as well as lower albumin levels and fewer platelets (P < 0.001 for all). Death was commoner (55.1% vs. 35.9%, P < 0.001) and hepatocellular carcinoma developed more often (53.9% vs. 28.7%, P < 0.001) in patients with HCV than HBV. In multivariate analysis, low albumin levels (hazard ratio: 1.65), alpha-fetoprotein (1.55), alcohol consumption (1.49), age >55 years (1.47), and retention of indocyanine green (1.39) were independent risk factors for the survival in patients with HCV, while male gender (4.43), age >45 years (2.24), retention of indocyanine green (2.14), hepatitis B e antigen (2.11), and low platelet counts (1.91) were in those with HBV. Chances for survival was significantly different (P < 0.001) among patients with HCV having low (number of factors: 0-1), medium (2-3), and high risks (4-5), as well as in those with HBV having low (0-1), medium (2-4), and high risks (5-6). In conclusion, survival and development of hepatocellular carcinoma, and factors for survival, are considerably different between patients with compensated cirrhosis infected with HCV and HBV, which would need to be taken into consideration in their management and planning treatment strategies.
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Yao F, Guo JM, Xu CF, Lou YL, Xiao BX, Zhou WH, Chen J, Hu YR, Liu Z, Hong GF. Detecting AFP mRNA in peripheral blood of the patients with hepatocellular carcinoma, liver cirrhosis and hepatitis. Clin Chim Acta 2005; 361:119-27. [PMID: 15993394 DOI: 10.1016/j.cccn.2005.05.005] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2005] [Revised: 05/03/2005] [Accepted: 05/05/2005] [Indexed: 12/27/2022]
Abstract
BACKGROUND The low frequency of disseminated carcinoma cells in the blood now makes immunomagnetic bead sorting and reverse transcriptase-polymerase chain reaction (RT-PCR) technique more popular. METHODS Three milliliters of peripheral blood were collected from 91 patients and 18 normal donors. The circulating carcinoma cells were enriched with CD45 and Ber-EP4 immunomagnetic beads. The alpha-fetoprotein (AFP) mRNA was amplified with nested RT-PCR. RESULTS The total positive detection rate was 72.1%, 43.8%, 25.0%, 100%, and 66.7% in patients with hepatocellular carcinoma (HCC) untreated, liver cirrhosis (LC), hepatitis, metastasis liver cancer, and postsurgery of hepatocellular carcinoma, respectively. There was a significant difference among the patients with HCC, LC and hepatitis (HCC vs. LC, P<0.05; HCC vs. hepatitis, P<0.01) and between Class A and B of the HCC patients (P<0.05). Meanwhile, AFP mRNA was markedly expressed in HCC patients compared to the patients with no HCC (LC and hepatitis). The levels of aspartate transaminase (AST) and gamma-glutamyltranspeptidase (GGT) were significantly different in AFP mRNA-positive patients with autoimmune chronic active hepatitis B (CAHB) or LC in contrast to the corresponding negative patients. CONCLUSION Combining negative and positive immunomagnetic bead sorting and RT-PCR technique can effectively detect circulating tumor cells. AFP mRNA is a more reliable marker of metastasis compared to serum AFP.
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Affiliation(s)
- Feng Yao
- Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai, China
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Abstract
AIM: To examine the serum from black African patients with acute hepatitis B to ascertain if integrants of viral DNA can be detected in fragments of cellular DNA leaking from damaged hepatocytes into the circulation.
METHODS: DNA was extracted from the sera of five patients with uncomplicated acute hepatitis B and one with fulminant disease. Two subgenomic PCRs designed to amplify the complete genome of HBV were used and the resulting amplicons were cloned and sequenced.
RESULTS: HBV and chromosomal DNA were amplified from the sera of all the patients. In one patient with uncomplicated disease, HBV DNA was integrated into host chromosome 7 q11.23 in the WBSCR1 gene. The viral DNA comprised 200 nucleotides covering the S and X genes in opposite orientation, with a 1 169 nucleotide deletion. The right virus/host junction was situated at nucleotide 1 774 in the cohesive overlap region of the viral genome, at a preferred topoisomerase I cleavage motif. The chromosomal DNA was not rearranged. The patient made a full recovery and seroconverted to anti-HBs- and anti-HBe-positivity. Neither HBV nor chromosomal DNA could be amplified from his serum at that time.
CONCLUSION: Integration of viral DNA into chromosomal DNA may occur rarely during acute hepatitis B and, with clonal propagation of the integrant, might play a role in hepatocarcinogenesis.
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Affiliation(s)
- Gerald C Kimbi
- Department of Medicine, University of the Witwatersrand Medical School, 7 York Road, Parktown 2193, Johannesburg, South Africa
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39
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Kim S, Park YM. Specific gene expression patterns in liver cirrhosis. Biochem Biophys Res Commun 2005; 334:681-8. [PMID: 16009336 DOI: 10.1016/j.bbrc.2005.06.143] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2005] [Accepted: 06/20/2005] [Indexed: 11/20/2022]
Abstract
Liver cirrhosis (LC) is a complex disease that can develop into hepatocellular carcinoma (HCC). In an effort to investigate genetic differences between LC and HCC, we used cDNA microarray analysis to characterize the gene expression profiles in LC and HCC tissues. Consistent differences were observed among the expression patterns in LC, HCC, and normal liver tissues. Interestingly, the expression patterns of LC without tumor association (LCT) were also readily distinguished from those of LC tissues near hepatic tumor tissues (near-tumor tissue, NTT). Moreover, 25 cirrhosis-specific genes could be used to divide the NTT samples into two groups: inflammatory active cirrhosis (NTTa) and inflammatory inactive cirrhosis (NTTi). We found that NTTa samples showed gene expression patterns similar to those of the LCT and HCC groups, whereas the expression patterns of the NTTi group were significantly different from those of the LCT, NTTa, and HCC groups. Finally, we selected two of the 25 LC-specific genes and showed that these markers could be used to successfully discriminate among the different LC subtypes. Collectively, these novel results allow the identification of new genetic subgroups of LC and provide new candidate genes for use as early markers for active cirrhosis and HCC.
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Affiliation(s)
- Soyoun Kim
- Department of Chemistry, Dongguk University, Seoul, Republic of Korea.
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40
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Buendia MA, Paterlini‐Bréchot P, Tiollais P, Bréchot C. Hepatocellular Carcinoma: Molecular Aspects in Hepatitis B. VIRAL HEPATITIS 2005:269-294. [DOI: 10.1002/9780470987131.ch17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Lang H, Sotiropoulos GC, Dömland M, Frühauf NR, Paul A, Hüsing J, Malagó M, Broelsch CE. Liver resection for hepatocellular carcinoma in non-cirrhotic liver without underlying viral hepatitis. Br J Surg 2005; 92:198-202. [PMID: 15609381 DOI: 10.1002/bjs.4763] [Citation(s) in RCA: 88] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) arising in normal liver parenchyma is rare and the outcome after hepatectomy is not well documented. METHODS Between June 1998 and September 2003, 33 patients without viral hepatitis underwent resection for HCC in a non-cirrhotic, non-fibrotic liver. Data were analysed with regard to operative details, pathological findings including completeness of resection, and outcome as measured by tumour recurrence and survival. RESULTS Twenty-three major hepatectomies and ten segmentectomies or bisegmentectomies were performed. After potentially curative resection, 19 of 29 patients were alive at a median follow-up of 25 months, with calculated 1- and 3-year survival rates of 87 and 50 per cent respectively. Survival was significantly better after resection of tumours without vascular invasion (3-year survival rate 89 versus 18 per cent; P = 0.024). Disseminated recurrence developed in nine of 29 patients, leading to death within 28 months of operation in all but one of the nine. CONCLUSION These data justify hepatic resection for HCC arising in non-cirrhotic, non-fibrotic liver without underlying viral hepatitis. Liver transplantation is rarely indicated because the outcome is good after resection of tumours without vascular infiltration, whereas vascular invasion is invariably associated with diffuse extrahepatic recurrence.
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Affiliation(s)
- H Lang
- Klinik für Allgemein- und Transplantationschirurgie, University Hospital Essen, Germany.
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42
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Harrison SA, Bacon BR. Relation of hemochromatosis with hepatocellular carcinoma: epidemiology, natural history, pathophysiology, screening, treatment, and prevention. Med Clin North Am 2005; 89:391-409. [PMID: 15656932 DOI: 10.1016/j.mcna.2004.08.005] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
HH is a common inherited disorder of iron metabolism affecting about 1 out of 250 individuals of Northern European decent. Many of these patients do not have evident phenotypic expression and do not develop significant iron loading. Some patients, however, develop progressive iron overload and cirrhosis. These individuals are at risk of developing HCC. Cirrhotics with hemochromatosis should undergo regular screening for HCC. If HCC is identified early, treatment with either resection or liver transplantation is optimal. Palliative measures, including ablative therapy and chemoembolization, can be used. With increasing clinical recognition,hemochromatosis should be diagnosed earlier and progression to cirrhosis and HCC should be minimized.
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Affiliation(s)
- Stephen A Harrison
- Department of Medicine, Brooke Army Medical Center, Fort Sam Houston, TX, USA
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Huang LR, Coughtrie MWH, Hsu HC. Down-regulation of dehydroepiandrosterone sulfotransferase gene in human hepatocellular carcinoma. Mol Cell Endocrinol 2005; 231:87-94. [PMID: 15713538 DOI: 10.1016/j.mce.2004.10.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2004] [Revised: 10/01/2004] [Accepted: 10/12/2004] [Indexed: 11/27/2022]
Abstract
Differential display (DD) PCR cloning of differentially expressed genes in hepatocellular carcinoma (HCC) and adjacent unaffected tissue demonstrated preferential down-regulation of a vital sex steroid precursor (dehydroepiandrosterone sulfotransferase; DHEA-ST; SULT2A1) in HCC. SULT2A1 mRNA and/or protein expression in HCC were markedly reduced in 61 of 120 (50.8%) primary unicentric HCCs. The down-regulation was more frequent in grade III versus grade I HCC (68.1% versus 32.1%, P = 0.0025), and in stage 3 versus stage 1 HCC (62.7% versus 29.2%, P = 0.007). The lowered expression in tumor cells of SULT2A1 in HCC tissues involved in metabolism and/or inactivation of sex steroids is consistent with a regulatory role of the SULT2A1 gene product in the development and/or tumor cell differentiation and progression of human HCC. This suggestion is partly supported by our observations that the down-regulated SULT2A1 gene expression correlated with a higher grade and stage of HCC.
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Affiliation(s)
- Lan-Ru Huang
- Chungtai Institute of Health Sciences and Technology, Department of Medical Technology, No. 11, Pu-tzu Lane, Pei-tun Distr., Taichung 406, Taiwan.
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Sze KMF, Ching YP, Jin DY, Ng IOL. Association of MAD2 expression with mitotic checkpoint competence in hepatoma cells. J Biomed Sci 2004; 11:920-7. [PMID: 15591789 DOI: 10.1007/bf02254377] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2004] [Accepted: 05/15/2004] [Indexed: 10/25/2022] Open
Abstract
Chromosomal instability (CIN) refers to high rates of chromosomal gains and losses and is a major cause of genomic instability of cells. It is thought that CIN caused by loss of mitotic checkpoint contributes to carcinogenesis. In this study, we evaluated the competence of mitotic checkpoint in hepatoma cells and investigated the cause of mitotic checkpoint defects. We found that 6 (54.5%) of the 11 hepatoma cell lines were defective in mitotic checkpoint control as monitored by mitotic indices and flow-cytometric analysis after treatment with microtubule toxins. Interestingly, all 6 hepatoma cell lines with defective mitotic checkpoint showed significant underexpression of mitotic arrest deficient 2 (MAD2), a key mitotic checkpoint protein. The level of MAD2 underexpression was significantly associated with defective mitotic checkpoint response (p < 0.001). In addition, no mutations were found in the coding sequences of MAD2 in all 11 hepatoma cell lines. Our findings suggest that MAD2 deficiency may cause a mitotic checkpoint defect in hepatoma cells.
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Affiliation(s)
- Karen Man-Fong Sze
- Department of Pathology, University of Hong Kong, Faculty of Medicine, Hong Kong, China
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Ohata K, Hamasaki K, Toriyama K, Ishikawa H, Nakao K, Eguchi K. High viral load is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis B virus infection. J Gastroenterol Hepatol 2004; 19:670-5. [PMID: 15151623 DOI: 10.1111/j.1440-1746.2004.03360.x] [Citation(s) in RCA: 81] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIMS Hepatitis B virus (HBV) is considered a major risk factor for the progression to liver cirrhosis and hepatocellular carcinoma (HCC). The serum level of HBV-DNA is correlated with progression of the disease. The aim of the present study was to determine the relationship between the level of HBV-DNA and hepatocarcinogenesis in patients with chronic HBV infection. METHODS The authors studied 73 patients who were diagnosed with chronic HBV infection at Nagasaki University Hospital (Nagasaki, Japan) between January 1980 and December 1999. The significance of age, sex, habitual drinking, serum alanine aminotransferase level, HBV viral load, interferon treatment, hepatic fibrosis and hepatic inflammation on the development of HCC were examined using univariate and multivariate analyses. RESULTS The cumulative incidence rates of HCC were 14%, 29% and 48% at 5, 10 and 15 years after liver biopsy, respectively. Multivariate analysis identified high viral load, together with age and severe fibrosis, as independent and significant risk factors (P = 0.045, 0.047 and 0.013, respectively) for HCC. CONCLUSIONS The present findings indicate that high viral load is a risk factor for HCC in patients with chronic HBV infection. Patients with a high HBV viral load should be carefully monitored for HCC.
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Affiliation(s)
- Kazuyuki Ohata
- First Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan.
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Loguercio C, Cuomo A, Tuccillo C, Gazzerro P, Cioffi M, Molinari AM, Del Vecchio Blanco C. Liver p53 expression in patients with HCV-related chronic hepatitis. J Viral Hepat 2003; 10:266-70. [PMID: 12823592 DOI: 10.1046/j.1365-2893.2003.00432.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
Mutated p53 acts as a dominant oncogene and alterations in the p53 gene are described in a large number of patients with hepatocellular carcinoma (HCC). It has been demonstrated that hepatitis C virus (HCV)-core protein regulates transcriptionally cellular genes, as well as cell growth and apoptosis. This study was undertaken to evaluate whether p53 may be expressed also in a precocious stage of HCV-related liver damage. We studied p53 expression by immunoluminometric assay on liver samples from 40 patients (M/F 18/ 22, median age 44 years, range 13-64 years) with biopsy-proven HCV-related chronic hepatitis. We considered the following factors: degree of liver damage, liver iron content and HCV-RNA titre. We also evaluated as possible co-factors alcohol and food intake in the last 3 years. p53 was over-expressed in seven of 40 (17.5%) patients. Liver histology documented the presence of unexpected cirrhosis in two patients among the p53 positive subjects. The p53 positive group had a daily ethanol intake significantly higher in respect to that of the p53 negative group (P < 0.05). Alimentary history documented that patients with a p53 over-expression had a lower intake of total calories, monounsaturated fatty acids, vitamin C and riboflavin. Data indicate that p53 over-expression can occur even in initial stages of HCV-related liver disease.
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Affiliation(s)
- C Loguercio
- Department of Gastroenterology and Institute of Pathology and Oncology, Second University of Naples, Naples, Italy
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Poon TCW, Mok TSK, Chan ATC, Chan CML, Leong V, Tsui SHT, Leung TWT, Wong HTM, Ho SKW, Johnson PJ. Quantification and Utility of Monosialylated α-Fetoprotein in the Diagnosis of Hepatocellular Carcinoma with Nondiagnostic Serum Total α-Fetoprotein. Clin Chem 2002. [DOI: 10.1093/clinchem/48.7.1021] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
AbstractBackground: At concentrations <500 μg/L, serum α-fetoprotein (AFP) has low specificity in the diagnosis of hepatocellular carcinoma (HCC), but monosialylated AFP (msAFP) is more specific for HCC. We describe two strategies for quantitative analysis of msAFP and explore their diagnostic accuracy in cases of HCC with nondiagnostic serum total AFP concentrations.Methods: We first used isoelectric focusing, Western blot, and densitometry (IEF-Western blot assay). We then developed a second assay, a novel glycosylation immunosorbent assay (GISA), based on the specificity of sialyltransferase and immunosorbent technology. Both assays were used to measure msAFP and msAFP percentage relative to total AFP in sera with nondiagnostic AFP concentrations from 36 patients with newly diagnosed HCC and from 18 patients with liver cirrhosis.Results: The msAFP percentages and concentrations were significantly higher in the HCC patient group regardless of the quantification methods. The msAFP concentrations and msAFP percentages obtained by the two assays were highly correlated (r = 0.70 and 0.49, respectively). For discrimination of HCC with nondiagnostic serum total AFP from liver cirrhosis, the areas under the ROC curves were 0.81 (95% confidence interval, 0.70–0.92) for msAFP by IEF-Western blot assay, 0.73 (0.58–0.87) for msAFP by GISA, 0.89 (0.80–0.97) for msAFP percentage by IEF-Western blot assay, and 0.74 (0.59–0.89) for msAFP percentage by GISA.Conclusions: Both the serum concentration and percentage of msAFP are potential diagnostic markers for HCC with nondiagnostic AFP. GISA can quantify a specific glycoform of a serologic marker.
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Affiliation(s)
- Terence CW Poon
- Department of Clinical Oncology, the Sir Y.K. Pao Centre for Cancer, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Tony SK Mok
- Department of Clinical Oncology, the Sir Y.K. Pao Centre for Cancer, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Anthony TC Chan
- Department of Clinical Oncology, the Sir Y.K. Pao Centre for Cancer, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Charles ML Chan
- Department of Clinical Oncology, the Sir Y.K. Pao Centre for Cancer, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Veronica Leong
- Department of Clinical Oncology, the Sir Y.K. Pao Centre for Cancer, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Steven HT Tsui
- Department of Clinical Oncology, the Sir Y.K. Pao Centre for Cancer, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Thomas WT Leung
- Department of Clinical Oncology, the Sir Y.K. Pao Centre for Cancer, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Herman TM Wong
- Department of Clinical Oncology, the Sir Y.K. Pao Centre for Cancer, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Stephen KW Ho
- Department of Clinical Oncology, the Sir Y.K. Pao Centre for Cancer, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Philip J Johnson
- Department of Clinical Oncology, the Sir Y.K. Pao Centre for Cancer, The Chinese University of Hong Kong, Shatin, Hong Kong
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De Mitri MS, Morsica G, Cassini R, Bagaglio S, Zoli M, Alberti A, Bernardi M. Prevalence of wild-type in NS5A-PKR protein kinase binding domain in HCV-related hepatocellular carcinoma. J Hepatol 2002; 36:116-22. [PMID: 11804673 DOI: 10.1016/s0168-8278(01)00235-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND/AIMS Experimental studies have demonstrated that the wild-type PKR-NS5A strain of hepatitis C virus (HCV) may have oncogenic potential through the binding and functional repression of PKR protein kinase. To assess whether the NS5A-PKR-binding domain may be involved in HCV-related liver carcinogenesis, its sequence was analyzed in the sera of 85 patients with hepatocellular carcinoma (HCC) and in 51 patients with chronic active hepatitis (CAH). In 13 HCC cases sequence analysis was also performed in tumor and nontumor liver tissues. METHODS The nucleotide sequences of the PKR-binding domain were inferred by direct sequencing of the amplified HCV products and deduced amino acids were compared with the sequence of HCV-J. RESULTS A wild-type or single mutated strain which retains PKR-binding activity was found in 88% of HCC and 69% of CAH cases (P=0.0096). All but three HCC cases showed no divergences in amino acid changes between serum and liver tissues. The wild-type strains were equally distributed between the HCC with or without cirrhosis. CONCLUSIONS The prevalance of the wild-type NS5A-PKR strain is significantly higher in HCC than in CAH. These data suggest that inhibition of PKR activity by HCV might represent a potential mechanism of HCV-related carcinogenesis.
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Affiliation(s)
- Maria Stella De Mitri
- Department of Internal Medicine, Cardioangiology, Hepatology, University of Bologna, Bologna, Italy.
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Kew MC. Hepatitis B virus in the etiology of hepatocellular carcinoma. VIRUSES AND LIVER CANCER 2002. [DOI: 10.1016/s0168-7069(02)06063-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Podnos YD, Henry G, Ortiz JA, Ji P, Cooke J, Cao S, Imagawa DK. Laparoscopic Ultrasound with Radiofrequency Ablation in Cirrhotic Patients with Hepatocellular Carcinoma: Technique and Technical Considerations. Am Surg 2001. [DOI: 10.1177/000313480106701214] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
The optimal treatment for hepatocellular carcinoma (HCC) is surgical resection. However, only a small percentage of patients are operative candidates. CT-guided percutaneous radiofrequency ablation (RFA) has been shown to be efficacious in treatment of unresectable HCC. CT-guided RFA, however, may fail to detect small intrahepatic metastases and tumor thrombi, which thus minimizes possible gains from the procedure. Recent advances in laparoscopic ultrasound have greatly improved the accuracy in detecting intrahepatic HCC metastases many of which were missed by CT. Combining intraoperative laparoscopic ultrasound with laparoscopic RFA greatly utilizes advances in both fields and is technically feasible. Our objective is to introduce a novel operative combination of laparoscopic ultrasound with laparoscopic RFA in treatment of HCC. Childs class B patients with unresectable HCC were considered for this study. Twelve patients underwent laparoscopic ultrasound and RFA of 17 lesions. Tumors ranged from 0.27 to 7 cm in diameter. Laparoscopic ultrasound identified tumor not detected preoperatively in one patient (8.3%). A single pneumothorax was the only complication. A single patient (8.3%) had recurrent disease and accounted for the only mortality in the study. We conclude that the use of both laparoscopic ultrasound and RFA is an excellent use of existing technology. The procedure combines improved tumor localization with the means to treat patients with unresectable disease. Because RFA is a relatively recent development long-term results are not yet available. Randomized prospective studies comparing RFA with other modalities will determine the ultimate utility of this procedure.
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Affiliation(s)
- Yale D. Podnos
- Department of Surgery, Division of Transplantation, University of California, Irvine Medical Center, Orange, California
| | - Ginard Henry
- Department of Surgery, Division of Transplantation, University of California, Irvine Medical Center, Orange, California
| | - Jorge A. Ortiz
- Department of Surgery, Division of Transplantation, University of California, Irvine Medical Center, Orange, California
| | - Ping Ji
- Department of Surgery, Division of Transplantation, University of California, Irvine Medical Center, Orange, California
| | - Jonathon Cooke
- Department of Surgery, Division of Transplantation, University of California, Irvine Medical Center, Orange, California
| | - Sean Cao
- Department of Surgery, Division of Transplantation, University of California, Irvine Medical Center, Orange, California
| | - David K. Imagawa
- Department of Surgery, Division of Transplantation, University of California, Irvine Medical Center, Orange, California
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