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Hong SK, Lee KW, Lee S, Hong SY, Suh S, Han ES, Choi Y, Yi NJ, Suh KS. Impact of tumor size on hepatectomy outcomes in hepatocellular carcinoma: a nationwide propensity score matching analysis. Ann Surg Treat Res 2022; 102:193-204. [PMID: 35475226 PMCID: PMC9010965 DOI: 10.4174/astr.2022.102.4.193] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 02/19/2022] [Accepted: 02/22/2022] [Indexed: 11/30/2022] Open
Abstract
Purpose The aim of this study was to compare surgical outcomes after liver resection for hepatocellular carcinoma (HCC) according to tumor size using a large, nationwide cancer registry-based cohort and propensity score matching. Methods From 2008 to 2015, a total of 12,139 patients were diagnosed with liver cancer and registered in the Korean Primary Liver Cancer Registry. Patients without distant metastasis who underwent hepatectomy as a primary treatment were selected. We performed 1:1 propensity score matching between the small (<5 cm), large (≥5 cm and <10 cm), and huge (≥10 cm) groups. Results Overall, 265 patients in the small and large groups were compared, and 64 patients each in the large and huge groups were compared. The overall and progression-free survival rates were significantly lower in the large group than in the small group (P < 0.001 and P < 0.001, respectively). Overall survival tended to be poorer in the huge group than in the large group (P = 0.051). The progression-free survival rate was significantly lower in the huge group than in the large group (P = 0.002). Conclusion Although primary liver resection can be considered even in patients with huge HCC, greater caution with careful screening for recurrence is needed.
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Affiliation(s)
- Suk Kyun Hong
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Kwang-Woong Lee
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Sola Lee
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Su young Hong
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Sanggyun Suh
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Eui Soo Han
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - YoungRok Choi
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Nam-Joon Yi
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Kyung-Suk Suh
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
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Tarao K, Nozaki A, Ikeda T, Sato A, Komatsu H, Komatsu T, Taguri M, Tanaka K. Real impact of liver cirrhosis on the development of hepatocellular carcinoma in various liver diseases-meta-analytic assessment. Cancer Med 2019; 8:1054-1065. [PMID: 30791221 PMCID: PMC6434205 DOI: 10.1002/cam4.1998] [Citation(s) in RCA: 102] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Revised: 12/27/2018] [Accepted: 01/06/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND It is well known that the incidence of developing hepatocelluler carcinoma (HCC) is increased in liver cirrhosis of different etiologies. However, comparison of HCC incidence in various liver diseases has not yet been estimated. We surveyed this comparison. METHODS The PubMed database was examined (1989-2017) for studies published in English language regarding the prospective follow-up results for the development of HCC in various liver diseases. A meta-analysis was performed for each liver disease. RESULTS The annual incidence (%) of HCC in the non-cirrhotic stage and cirrhotic stage, and the ratio of HCC incidence in the cirrhotic stage/non-cirrhotic stage were as follows. (a) hepatitis B virus liver disease: 0.37%→3.23% (8.73-fold), (b) hepatitis C virus liver diseases: 0.68%→4.81% (7.07-fold), (c) primary biliary cholangitis (0.26%→1.79%, 6.88-fold), (d) autoimmune hepatitis (0.19%→0.53%, 2.79-fold), and (e) NASH (0.03%→1.35%, 45.00-fold). Regarding primary hemochromatosis and alcoholic liver diseases, only follow-up studies in the cirrhotic stage were presented, 1.20% and 2.06%, respectively. CONCLUSIONS When the liver diseases advance to cirrhosis, the incidence of HCC is markedly increased. The development of HCC must be closely monitored by ultrasonography, magnetic resonance imaging, and computed tomography, irrespective of the different kinds of liver diseases.
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Affiliation(s)
- Kazuo Tarao
- Tarao’s Gastroenterological ClinicYokohamaJapan
| | - Akito Nozaki
- Gastroenterological Center, Medical CenterYokohama City UniversityYokohamaJapan
| | - Takaaki Ikeda
- Gastroenterology DepartmentYokosuka General Hospital UwamachiYokosukaJapan
| | - Akira Sato
- Division of Gastroenterology, Department of Internal MedicineSt. Marianna University, Yokohama City Seibu HospitalYokohamaJapan
| | - Hirokazu Komatsu
- Department of GastroenterologyYokohama Municipal Citizen’s HospitalYokohamaJapan
| | - Tatsuji Komatsu
- Department Clinical ResearchNational Hospital Organization, Yokohama Medical CenterYokohamaJapan
| | - Masataka Taguri
- Department of Data ScienceYokohama City UniversityYokohamaJapan
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Rey S, Quintavalle C, Burmeister K, Calabrese D, Schlageter M, Quagliata L, Cathomas G, Diebold J, Molinolo A, Heim MH, Terracciano LM, Matter MS. Liver damage and senescence increases in patients developing hepatocellular carcinoma. J Gastroenterol Hepatol 2017; 32:1480-1486. [PMID: 28052383 DOI: 10.1111/jgh.13717] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2016] [Revised: 12/10/2016] [Accepted: 12/29/2016] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIM Most patients with a hepatocellular carcinoma (HCC) have an underlying chronic liver inflammation, which causes a continuous damage leading to liver cirrhosis and eventually HCC. However, only a minority of cirrhotic patients develop HCC. To assess a possible differential impact of liver inflammation in patients developing HCC versus patients remaining tumor-free, we designed a longitudinal study and analysed liver tissue of the same patients (n = 33) at two points in time: once when no HCC was present and once several years later when an HCC was present. As a control group, we followed cirrhotic patients (n = 37) remaining tumor-free over a similar time frame. METHODS We analysed cell damage and senescence of hepatocytes by measuring γ-H2AX positivity, p16INK4 and p21WAF/Cip1 expression, nuclear size, and telomere length. RESULTS γ-H2AX positivity, p16INK4 and p21WAF/Cip1 expression, in the first liver biopsy was similar in patients developing HCC later on and cirrhotic patients remaining tumor free. In contrast, γ-H2AX positivity, p16INK4 and p21WAF/Cip1 expression, was significantly higher in the second non-tumoral liver biopsy of HCC patients than in the control patients. Consequently, the individual increase in γ-H2AX positivity, p16INK4 and p21WAF/Cip1 expression, from the first biopsy to the second biopsy was significantly higher in patients developing HCC than in patients remaining tumor free. In addition, changes in nuclear size and telomere length revealed a more pronounced cell aging in patients developing HCC than in patients remaining tumor free. CONCLUSIONS Hepatocytes from patients developing HCC go through more pronounced cell damage and senescence in contrast to cirrhotic patients remaining tumor free.
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Affiliation(s)
- Silvia Rey
- Institute of Pathology, University Hospital of Basel, Basel, Switzerland
| | | | | | - Diego Calabrese
- Department of Gastroenterology and Hepatology, University Hospital of Basel, Basel, Switzerland
| | - Manuel Schlageter
- Institute of Pathology, University Hospital of Basel, Basel, Switzerland
| | - Luca Quagliata
- Institute of Pathology, University Hospital of Basel, Basel, Switzerland
| | - Gieri Cathomas
- Institute of Pathology, Kantonsspital Baselland, Liestal, Switzerland
| | - Joachim Diebold
- Institute of Pathology, Luzerner Kantonsspital, Lucerne, Switzerland
| | | | - Markus H Heim
- Department of Gastroenterology and Hepatology, University Hospital of Basel, Basel, Switzerland
| | | | - Matthias S Matter
- Institute of Pathology, University Hospital of Basel, Basel, Switzerland
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4
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Miyaki E, Imamura M, Hiraga N, Murakami E, Kawaoka T, Tsuge M, Hiramatsu A, Kawakami Y, Aikata H, Hayes CN, Chayama K. Daclatasvir and asunaprevir treatment improves liver function parameters and reduces liver fibrosis markers in chronic hepatitis C patients. Hepatol Res 2016; 46:758-64. [PMID: 26574180 DOI: 10.1111/hepr.12621] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Revised: 11/04/2015] [Accepted: 11/05/2015] [Indexed: 12/22/2022]
Abstract
AIM Although interferon (IFN)-free antiviral therapy is expected to improve the treatment response for chronic hepatitis C, the effect on liver function and liver fibrosis is unknown. In this study, we analyzed the long-term follow up of liver function parameters and liver fibrosis markers in genotype 1b hepatitis C virus (HCV)-infected patients treated with daclatasvir and asunaprevir. METHODS Thirty patients were treated with daclatasvir and asunaprevir for 24 weeks, and 26 patients achieved sustained virological response (SVR). We measured liver function parameters, serum alanine aminotransferase (ALT) and albumin levels and liver fibrosis markers, hyaluronic acid, type IV collagen and Mac-2-binding protein (M2BPGi) before and after (median, 27 months; range, 17-47) completion of the treatment in SVR and non-SVR patients. We also measured serum α-fetoprotein (AFP) levels during the therapy and follow-up period. RESULTS Pretreatment serum ALT and albumin levels and liver fibrosis markers were similar between SVR and non-SVR patients. Twenty-seven months after treatment, serum ALT and albumin levels significantly improved only in SVR patients. Although there was no change in non-SVR patients, platelet count and serum liver fibrosis markers significantly improved in SVR patients. Serum AFP levels rapidly decreased during the treatment in both SVR and non-SVR patients, but the change was significant only in SVR patients. CONCLUSION Successful viral eradication by IFN-free daclatasvir and asunaprevir therapy could lead to improved liver function parameters and reduced liver fibrosis markers and AFP levels. This treatment has the potential to improve liver fibrosis and decrease the incidence of hepatocarcinogenesis.
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Affiliation(s)
- Eisuke Miyaki
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Nobuhiko Hiraga
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Eisuke Murakami
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Masataka Tsuge
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Akira Hiramatsu
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Yoshiiku Kawakami
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - C Nelson Hayes
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Liver Research Project Center, Hiroshima University, Hiroshima, Japan
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Abstract
Hepatocellular carcinoma (HCC) is the seventh most common malignancy worldwide. HCC meets all the criteria established by the World Health Organization for performing surveillance on those at-risk for developing cancer. Although there are consensus guidelines in the United States, Europe, and Asia for HCC surveillance, it is unclear if these guidelines are regularly implemented in routine practice to optimize real-life clinical outcomes. We reviewed the current literature on the adherence to current HCC practice guidelines by the American Association for the Study of Liver Diseases (2009), the European Association for the Study of the Liver (2012), and the Asia Pacific Association for the Study of the Liver (2010) for screening/surveillance and outcomes of optimal versus poor adherence. We performed PubMed search for relevant articles regarding HCC surveillance and screening worldwide. Currently, HCC screening is underutilized to a large extent. In most studies, the adherence to HCC screening and surveillance is suboptimal. Various patient, provider, and health care system factors may have all contributed to such nonadherence. Strategies to improve HCC screening and surveillance are urgently needed for early HCC detection and improved survival of HCC patients. Further research is needed to elucidate the various medical and/or cultural knowledge, belief, and practice patterns that can lead to barriers to HCC screening and surveillance at both patient and provider levels. These data will help focus and target advocacy and educational efforts to improve HCC surveillance at all levels: patients, providers, and health care system/government.
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6
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Rino Y, Yukawa N, Yamamoto N. Does herbal medicine reduce the risk of hepatocellular carcinoma? World J Gastroenterol 2015; 21:10598-10603. [PMID: 26457019 PMCID: PMC4588081 DOI: 10.3748/wjg.v21.i37.10598] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2015] [Revised: 06/15/2015] [Accepted: 08/25/2015] [Indexed: 02/06/2023] Open
Abstract
Many herbal medicines are effective anti-inflammatory agents and may therefore suppress the development of hepatocellular carcinoma (HCC). Recently, treatment with a single-tablet regimen containing ledipasvir and sofosbuvir resulted in high rates of sustained virologic response among patients with hepatitis C virus genotype 1 infection who did not respond to prior interferon-based treatment. Patients with chronic hepatitis C are expected to receive this treatment worldwide. However, many patients have hepatitis-like fatty liver and nonalcoholic steatohepatitis. A strategy to prevent the development of HCC in this subgroup of patients is urgently required. Whether herbal medicines can suppress the development of HCC remains to be established. However, herbal medicines are effective anti-inflammatory agents and may inhibit the development of HCC. Clinical trials exploring the effectiveness of herbal medicines in the prevention and treatment of HCC are therefore warranted. The current lack of knowledge and of educational programs is a barrier to increasing the use of potentially effective herbal medicines and performing prospective clinical trials.
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7
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Yamasaki K, Tateyama M, Abiru S, Komori A, Nagaoka S, Saeki A, Hashimoto S, Sasaki R, Bekki S, Kugiyama Y, Miyazoe Y, Kuno A, Korenaga M, Togayachi A, Ocho M, Mizokami M, Narimatsu H, Yatsuhashi H. Elevated serum levels of Wisteria floribunda agglutinin-positive human Mac-2 binding protein predict the development of hepatocellular carcinoma in hepatitis C patients. Hepatology 2014; 60:1563-70. [PMID: 25042054 PMCID: PMC4278450 DOI: 10.1002/hep.27305] [Citation(s) in RCA: 199] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2014] [Revised: 06/18/2014] [Accepted: 07/08/2014] [Indexed: 12/11/2022]
Abstract
UNLABELLED The Wisteria floribunda agglutinin-positive human Mac-2-binding protein (WFA+-M2BP) was recently shown to be a liver fibrosis glycobiomarker with a unique fibrosis-related glycoalteration. We evaluated the ability of WFA+-M2BP to predict the development of hepatocellular carcinoma (HCC) in patients who were infected with the hepatitis C virus (HCV). A total of 707 patients who had been admitted to our hospital with chronic HCV infection without other potential risk factors were evaluated to determine the ability of WFA+-M2BP to predict the development of HCC; factors evaluated included age, sex, viral load, genotypes, fibrosis stage, aspartate and alanine aminotransferase levels, bilirubin, albumin, platelet count, alpha-fetoprotein (AFP), WFA+-M2BP, and the response to interferon (IFN) therapy. Serum WFA+-M2BP levels were significantly increased according to the progression of liver fibrosis stage (P<0.001). In each distinctive stage of fibrosis (F0-F1, F2, F3, and F4), the risk of development of HCC was increased according to the elevation of WFA+-M2BP. Multivariate analysis identified age>57 years, F4, AFP>20 ng/mL, WFA+-M2BP ≥4, and WFA+-M2BP 1-4 as well as the response to IFN (no therapy vs. sustained virological response) as independent risk factors for the development of HCC. The time-dependent areas under the receiver operating characteristic curve demonstrated that the WFA+-M2BP assay predicted the development of HCC with higher diagnostic accuracy than AFP. CONCLUSION WFA+-M2BP can be applied as a useful surrogate marker for the risk of HCC development, in addition to liver biopsy.
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Affiliation(s)
- Kazumi Yamasaki
- Clinical Research Center, National Hospital Organization, Nagasaki Medical CenterŌmura, Japan
| | - Masakuni Tateyama
- Department of Gastroenterology and Hepatology, Kumamoto University of Medicine KumamotoJapan
| | - Seigo Abiru
- Clinical Research Center, National Hospital Organization, Nagasaki Medical CenterŌmura, Japan
| | - Atsumasa Komori
- Clinical Research Center, National Hospital Organization, Nagasaki Medical CenterŌmura, Japan
| | - Shinya Nagaoka
- Clinical Research Center, National Hospital Organization, Nagasaki Medical CenterŌmura, Japan
| | - Akira Saeki
- Clinical Research Center, National Hospital Organization, Nagasaki Medical CenterŌmura, Japan
| | - Satoru Hashimoto
- Clinical Research Center, National Hospital Organization, Nagasaki Medical CenterŌmura, Japan
| | - Ryu Sasaki
- Clinical Research Center, National Hospital Organization, Nagasaki Medical CenterŌmura, Japan
| | - Shigemune Bekki
- Clinical Research Center, National Hospital Organization, Nagasaki Medical CenterŌmura, Japan
| | - Yuki Kugiyama
- Clinical Research Center, National Hospital Organization, Nagasaki Medical CenterŌmura, Japan
| | - Yuri Miyazoe
- Clinical Research Center, National Hospital Organization, Nagasaki Medical CenterŌmura, Japan
| | - Atsushi Kuno
- Research Center for Medical Glycoscience, National Institute of Advanced Industrial Science and TechnologyTsukuba, Japan
| | - Masaaki Korenaga
- The Research Center for Hepatitis and Immunology, National Center for Global Health and MedicineIchikawa, Japan
| | - Akira Togayachi
- Research Center for Medical Glycoscience, National Institute of Advanced Industrial Science and TechnologyTsukuba, Japan
| | - Makoto Ocho
- Research Center for Medical Glycoscience, National Institute of Advanced Industrial Science and TechnologyTsukuba, Japan
| | - Masashi Mizokami
- The Research Center for Hepatitis and Immunology, National Center for Global Health and MedicineIchikawa, Japan
| | - Hisashi Narimatsu
- Research Center for Medical Glycoscience, National Institute of Advanced Industrial Science and TechnologyTsukuba, Japan
| | - Hiroshi Yatsuhashi
- Clinical Research Center, National Hospital Organization, Nagasaki Medical CenterŌmura, Japan,Address reprint requests to: Hiroshi Yatsuhashi, M.D., Ph.D., Clinical Research Center, National Hospital Organization, Nagasaki Medical Center, 2-1001-1 Kubara, Ōmura, Nagasaki 856-8562, Japan. E-mail: ; fax: +81 957 54 0292
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Méndez-Sánchez N, Ridruejo E, Alves de Mattos A, Chávez-Tapia NC, Zapata R, Paraná R, Mastai R, Strauss E, Guevara-Casallas LG, Daruich J, Gadano A, Parise ER, Uribe M, Aguilar-Olivos NE, Dagher L, Ferraz-Neto BH, Valdés-Sánchez M, Sánchez-Avila JF. Latin American Association for the Study of the Liver (LAASL) clinical practice guidelines: management of hepatocellular carcinoma. Ann Hepatol 2014. [PMID: 24998696 DOI: 10.1016/s1665-2681(19)30919-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third most common cause of cancer death, and accounts for 5.6% of all cancers. Nearly 82% of the approximately 550,000 liver cancer deaths each year occur in Asia. In some regions, cancer-related death from HCC is second only to lung cancer. The incidence and mortality of HCC are increasing in America countries as a result of an ageing cohort infected with chronic hepatitis C, and are expected to continue to rise as a consequence of the obesity epidemic. Clinical care and survival for patients with HCC has advanced considerably during the last two decades, thanks to improvements in patient stratification, an enhanced understanding of the pathophysiology of the disease, and because of developments in diagnostic procedures and the introduction of novel therapies and strategies in prevention. Nevertheless, HCC remains the third most common cause of cancer-related deaths worldwide. These LAASL recommendations on treatment of hepatocellular carcinoma are intended to assist physicians and other healthcare providers, as well as patients and other interested individuals, in the clinical decision-making process by describing the optimal management of patients with liver cancer.
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Affiliation(s)
| | - Ezequiel Ridruejo
- Hepatology Section, Department of Medicine. Centro de Educación Médica e Investigaciones Clínicas Norberto Quirno "CEMIC". Ciudad Autónoma de Buenos Aires, Argentina; Hepatology and Liver Transplant Unit. Hospital Universitario Austral, Pilar, Argentina
| | | | | | - Rodrigo Zapata
- Hepatology and Liver Transplantation Unit. University of Chile School of Medicine, German Clinic. Santiago, Chile
| | - Raymundo Paraná
- Associate Professor of School of Medicine - Federal University of Bahia Head of the Gastro-Hepatologist Unit of the University Bahia University Hospital
| | - Ricardo Mastai
- Transplantation Unit. German Hospital.Buenos Aires, Argentina
| | - Edna Strauss
- Clinical hepatologist of Hospital do Coraçao - São Paulo - Brazil. Professor of the Post Graduate Course in the Department of Pathology at the School of Medicine, University of São Paulo
| | | | - Jorge Daruich
- Hepatology Department, Clinical Hospital San Martín. University of Buenos Aires Buenos Aires, Argentina
| | - Adrian Gadano
- Section of Hepatology, Italian Hospital of Buenos Aires. Buenos Aires, Argentina
| | - Edison Roberto Parise
- Professor Associado da Disciplina de Gastroenterologia da Universidade Federal de São Paulo, Presidente Eleito da Sociedade Brasileira de Hepatologia
| | - Misael Uribe
- Digestive Diseases and Obesity Clinic, Medica Sur Clinic Foundation. México City, Mexico
| | - Nancy E Aguilar-Olivos
- Digestive Diseases and Obesity Clinic, Medica Sur Clinic Foundation. México City, Mexico
| | - Lucy Dagher
- Consultant Hepatologist. Metropolitan Policlinic- Caracas- Venezuela
| | - Ben-Hur Ferraz-Neto
- Director of Liver Institute - Beneficencia Portuguesa de São Paulo. Chief of Liver Transplantation Team
| | - Martha Valdés-Sánchez
- Department of Pediatric Oncology National Medical Center "Siglo XXI". Mexico City, Mexico
| | - Juan F Sánchez-Avila
- Hepatology and Liver Transplantation Department National Institute of Nutrition and Medical Sciences "Salvador Zubirán" Mexico City, Mexico
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9
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Raoul JL, Bruix J, Greten TF, Sherman M, Mazzaferro V, Hilgard P, Scherubl H, Scheulen ME, Germanidis G, Dominguez S, Ricci S, Nadel A, Moscovici M, Voliotis D, Llovet JM. Relationship between baseline hepatic status and outcome, and effect of sorafenib on liver function: SHARP trial subanalyses. J Hepatol 2012; 56:1080-1088. [PMID: 22245896 DOI: 10.1016/j.jhep.2011.12.009] [Citation(s) in RCA: 96] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2011] [Revised: 12/06/2011] [Accepted: 12/12/2011] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Hepatic markers are utilized in many classification systems of patients with hepatocellular carcinoma and, by measuring organ damage and tumor stage, can influence treatment. Moreover, elevated serum concentrations of aminotransferases and alpha-fetoprotein are indicators of poor prognosis in patients with hepatocellular carcinoma. We examined the effects of sorafenib on hepatic markers by performing exploratory subset analyses of the Sorafenib HCC Assessment Randomized Protocol (SHARP) trial in patients categorized by baseline concentrations of alanine aminotransferase/aspartate aminotransferase, alpha-fetoprotein, and bilirubin; and by evaluating the effects of sorafenib on bilirubin concentrations during treatment. METHODS Patients (n=602) were grouped by baseline concentrations of alanine aminotransferase/aspartate aminotransferase (not significantly elevated, mildly elevated, or moderately elevated), alpha-fetoprotein (normal or elevated), and bilirubin (normal or elevated). Bilirubin was measured at baseline and on day 1 of each cycle. RESULTS Patients with elevated baseline concentrations of alanine aminotransferase/aspartate aminotransferase, alpha-fetoprotein, or bilirubin had shorter overall survival (OS) than those with normal baseline concentrations, irrespective of treatment group. No notable differences in safety profiles were observed between patients with normal vs. elevated alanine aminotransferase/aspartate aminotransferase, alpha-fetoprotein, or bilirubin. Median changes from baseline in bilirubin concentration at the last cycle of treatment were +0.17 and +0.19 mg/dl in the sorafenib and placebo groups, respectively. CONCLUSIONS These subset analyses suggest that sorafenib is safe and effective for hepatocellular carcinoma, irrespective of baseline alanine aminotransferase/aspartate aminotransferase, alpha-fetoprotein, or bilirubin concentration and that hepatic function remains stable over the course of sorafenib therapy.
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Affiliation(s)
- Jean-Luc Raoul
- Institut Paoli-Calmettes, Marseille, France; Institut National de la Santé et de la Recherche Médicale (INSERM) U991, Rennes, France.
| | - Jordi Bruix
- Barcelona Clínic Liver Cancer (BCLC) Group, Liver Unit, CIBERehd, Institut d'Investigacions Biomèdiques, August Pi i Sunyer (IDIBAPS), Hospital Clínic Barcelona, Barcelona, Spain
| | - Tim F Greten
- Medizinische Hochschule Hannover, Abteilung fur Gastroenterologie, Hepatologie und Endokrinologie, Hannover, Germany
| | | | - Vincenzo Mazzaferro
- National Cancer Institute, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Foundation, Milan, Italy
| | | | - Hans Scherubl
- Medizinische Klinik "Charite", Campus Benjamin Franklin, Berlin, Germany
| | - Max E Scheulen
- Innere Klinik (Tumorforschung), West German Cancer Center, Universitätsklinikum Essen, Essen, Germany
| | - Georgios Germanidis
- AHEPA University Hospital, First Department of Medicine, Thessaloniki, Greece
| | - Sophie Dominguez
- Centre Oscar Lambret, Departement de Cancerologie Digestive et Urologique, Lille, France
| | | | - Andrea Nadel
- Bayer HealthCare Pharmaceuticals, Montville, NJ, USA
| | | | | | - Josep M Llovet
- Barcelona Clínic Liver Cancer (BCLC) Group, Liver Unit, CIBERehd, Institut d'Investigacions Biomèdiques, August Pi i Sunyer (IDIBAPS), Hospital Clínic Barcelona, Barcelona, Spain; Mount Sinai Liver Cancer Program, Mount Sinai School of Medicine, New York, NY, USA; Institució Catalana de Recerca I Estudis Avançats, Catalonia, Spain
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10
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Tumor-related factors do not influence the prognosis of solitary hepatocellular carcinoma after partial hepatectomy. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2011; 18:689-99. [PMID: 21445633 DOI: 10.1007/s00534-011-0379-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND/PURPOSE Although many factors related to the tumor or the hepatic functional reserve may affect the outcome of partial hepatectomy for hepatocellular carcinoma (HCC), these factors have not yet been intensively investigated in patients with solitary HCC. The purpose of this study is to determine the clinicopathological factors influencing the long-term outcomes of partial hepatectomy for solitary HCC. METHODS Data on 266 consecutive patients with a solitary HCC who underwent curative hepatectomy between 1997 and 2006 were analyzed with regard to prognosis. RESULTS Overall survival rates at 3, 5, and 10 years were 89.5, 79.6, and 56.1%, respectively. The significant independent predictors for overall survival included hepatitis C virus infection, liver cirrhosis, and prolonged prothrombin activity. Disease-free survival rates at 3, 5, and 10 years were 51.7, 41.1, and 20.4%, respectively. The significant independent predictors for disease-free survival included elevated levels of aspartate amino transferase, decreased platelet counts, presence of liver cirrhosis, and prolonged prothrombin activity. Tumor-related factors such as tumor size and microscopic vascular invasion were not significant predictors of overall or disease-free survival. CONCLUSIONS The long-term outcomes of patients with a solitary HCC who underwent partial hepatectomy mainly depended on the background liver status but not on tumor-related factors; this suggests that partial hepatectomy is a remarkably effective antitumor therapy. If the hepatic functional reserve is within the permissible range, partial hepatectomy should be considered as the treatment of choice for patients with a solitary HCC.
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Zhong JH, Li LQ, Wu LC. Lamivudine with or without adefovir dipivoxil for postoperative hepatocellular carcinoma. Cochrane Database Syst Rev 2011:CD008713. [PMID: 22161435 DOI: 10.1002/14651858.cd008713.pub2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a significant cause of death, especially in Asia and sub-Saharan Africa. Removal of the cancer through surgery or other techniques is considered the first-line therapy in early HCC, but relapse of HCC is the main postoperative problem. The main risk factor for HCC is hepatitis B virus (HBV) infection. Lamivudine and adefovir dipivoxil are effective and tolerable for chronic hepatitis B by suppressing the viral load and to reduce fibrosis in the liver. OBJECTIVES To assess the benefits and harms of postoperative administration of lamivudine with or without adefovir dipivoxil in participants with surgically treated HCC and chronic HBV infection or HBV carrier state. SEARCH METHODS A systematic search was performed in The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded (SCI Exp) in October 2011. Further trials have been sought through scanning reference lists of relevant articles. SELECTION CRITERIA Randomised clinical trials comparing the administration of lamivudine with and without adefovir dipivoxil for participants with ablation treated HCC (surgical or through other techniques) and chronic HBV infection or HBV carrier state, regardless of publication status, language, blinding, and publication status, were to be included in this review. We planned to extract data on harms from quasi-randomised studies or cohort studies when retrieved with the search results. DATA COLLECTION AND ANALYSIS Two authors independently selected studies for inclusion, and extracted and analysed the data. The type and number of adverse events were reported descriptively. MAIN RESULTS No randomised trials could be included into this systematic review. Thus, we were unable to follow our pre-published protocol and perform meta-analyses.Through our searches for randomised clinical trials, four cohort trials with 230 participants were retrieved. We read them in order to find data on harm, ie, adverse events. Breakthrough hepatitis was a serious adverse event attributable to lamivudine. No other adverse events seemed to be caused by the administration of lamivudine or adefovir dipivoxil were reported in the four cohort studies. AUTHORS' CONCLUSIONS No evidence from randomised trials on the beneficial or harmful effects of lamivudine with or without adefovir dipivoxil for postoperative HCC was found. Randomised clinical trials with large number of participants and long follow-up period should be carried out to direct clinical practice.
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Affiliation(s)
- Jian Hong Zhong
- Department of Hepato-Biliary Diseases, Tumor Hospital, Guangxi Medical University, Nanning, Guangxi, China, 530021
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Yang T, Zhang J, Lu JH, Yang LQ, Yang GS, Wu MC, Yu WF. A new staging system for resectable hepatocellular carcinoma: comparison with six existing staging systems in a large Chinese cohort. J Cancer Res Clin Oncol 2011; 137:739-50. [PMID: 20607551 DOI: 10.1007/s00432-010-0935-3] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2010] [Accepted: 06/21/2010] [Indexed: 12/23/2022]
Abstract
PURPOSE Surgical resection remains the gold standard for hepatocellular carcinoma (HCC). Although various staging systems have been developed in recent years, the best tool for staging of HCC remains controversial. The aims of this study were to establish a new staging for patients with HCC undergoing surgical resection and to identify whether this staging is superior to other staging systems in predicting survival of resectable HCC. METHODS The subjects of this retrospective study were 958 consecutive HCC patients who underwent surgical resection between 2000 and 2006. Predictors of survival were identified using the Kaplan-Meier method and the Cox model. The disease state was staged by our proposed Eastern staging system by integrating independent risk predictors, as well as six existing staging systems. The accuracy of prediction of 1-, 3-, and 5-year mortality for each system was evaluated by the area under the receiver operating characteristic curve (AUC). RESULTS Macroscopic vascular invasion, multiple tumors, performance status 1-2, microscopic vascular invasion, extrahepatic spread, tumor size > 5 cm, albumin < 35 g/L, aspartate aminotransferase > 40 U/L, total bilirubin > 17 μmol/L, and presence of cirrhosis were identified as independent risk factors of survival after resection by multivariate analysis. The comparison of the results of the different staging systems showed that our Eastern staging had the best homogeneity (likelihood ratio χ(2) test 543.51, P < 0.001), monotonicity of gradients (linear trend χ(2) test 414.97, P < 0.001), and discriminatory ability (the highest AUCs for 1-, 3-, and 5-year mortality). CONCLUSIONS Compared with other existing staging systems, our proposed Eastern staging system shows a superior predictive ability in a Chinese cohort of patients with resectable HCC, and it can give important prognostic information after surgery.
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Affiliation(s)
- Tian Yang
- Department of 2nd Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, No. 225, Changhai Road, Yangpu District, Shanghai, China
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Tateyama M, Yatsuhashi H, Taura N, Motoyoshi Y, Nagaoka S, Yanagi K, Abiru S, Yano K, Komori A, Migita K, Nakamura M, Nagahama H, Sasaki Y, Miyakawa Y, Ishibashi H. Alpha-fetoprotein above normal levels as a risk factor for the development of hepatocellular carcinoma in patients infected with hepatitis C virus. J Gastroenterol 2011; 46:92-100. [PMID: 20711614 DOI: 10.1007/s00535-010-0293-6] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2009] [Accepted: 07/06/2010] [Indexed: 02/07/2023]
Abstract
BACKGROUND Noninvasive risk factors are required for predicting the development of hepatocellular carcinoma (HCC) not only in patients with cirrhosis but also in those with chronic hepatitis who are infected with hepatitis C virus (HCV). METHODS A total of 707 patients with chronic HCV infection without other risks were evaluated for the predictive value of noninvasive risk factors for HCC, including age, sex, viral load, genotype, fibrosis stage, aspartate and alanine aminotransferase levels, bilirubin, albumin, platelet count, and alpha-fetoprotein (AFP) at entry to the study, as well as interferon (IFN) therapy they received. RESULTS The ten-year cumulative incidence rates of HCC for patients with fibrosis stages F0/F1, F2, F3, and F4 were 2.5, 12.8, 19.3, and 55.9%, respectively. Multivariate analysis identified age ≥57 years [hazard ratio (HR) 2.026, P = 0.004], fibrosis stage F4 (HR 3.957, P < 0.001), and AFP 6-20 ng/mL (HR 1.942, P = 0.030) and ≥20 ng/mL (HR 3.884, P < 0.001), as well as the response to IFN [relative risk (RR) 0.099, P < 0.001], as independent risk factors for the development of HCC. The ten-year cumulative incidence rates of HCC in the patients with AFP levels of <6, 6-20, and ≥20 ng/mL at entry were 6.0, 24.6, and 47.3%, respectively. CONCLUSIONS Not only high (>20 ng/mL), but also even slightly elevated (6-20 ng/mL) AFP levels, could serve as a risk factor for HCC to complement the fibrosis stage. In contrast, AFP levels <6 ng/mL indicate a low risk of HCC development in patients infected with HCV, irrespective of the fibrosis stage.
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Affiliation(s)
- Masakuni Tateyama
- Clinical Research Center, National Nagasaki Medical Center, Nagasaki, 856-8562, Japan
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Xu Z, Zhang M, Lv X, Xiang D, Zhang X, Chen L. The inhibitory effect of celecoxib on mouse hepatoma H22 cell line on the arachidonic acid metabolic pathway. Biochem Cell Biol 2010; 2011:390676. [PMID: 22084728 PMCID: PMC3195877 DOI: 10.5402/2011/390676] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2011] [Accepted: 05/18/2011] [Indexed: 12/23/2022] Open
Abstract
Nowadays, patients with chronic hepatitis C in all countries are generally treated with interferon (IFN), and more than 50% of patients become HCV-RNA negative following PEG-IFN plus ribavirin therapy, but unfortunately, the IFN therapy is not effective in about 70% of patients with HCV-associated LC. In Japan, HCC actually develops in about 7% of those patients every year. A strategy for preventing HCC development other than IFN therapy is, therefore, urgently needed for those patients.
We reported that the recurrence rate and the development of HCC was more rapid in the high serum ALT level (>80 IU) patients with HCV-associated LC. Sho-saiko-to, Juzen-taiho-to, and stronger-neo minophagen C are herbal medicines used in Japan to treat chronic viral liver diseases, and they work by reducing inflammatory processes and controlling ALT levels. Aggressive reduction therapy for ALT levels in HCV-LC patients could significantly prevent HCC development.
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Affiliation(s)
- Zhigang Xu
- Department of Pharmacology, Norman Bethune College of Medicine, Jilin University, Changchun, Jilin, China
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Tomimaru Y, Nagano H, Eguchi H, Kobayashi S, Marubashi S, Wada H, Tanemura M, Umeshita K, Hiramatsu N, Takehara T, Doki Y, Mori M. Effects of preceding interferon therapy on outcome after surgery for hepatitis C virus-related hepatocellular carcinoma. J Surg Oncol 2010; 102:308-14. [DOI: 10.1002/jso.21633] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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Kumada T, Toyoda H, Kiriyama S, Sone Y, Tanikawa M, Hisanaga Y, Kanamori A, Atsumi H, Takagi M, Nakano S, Arakawa T, Fujimori M. Incidence of hepatocellular carcinoma in hepatitis C carriers with normal alanine aminotransferase levels. J Hepatol 2009; 50:729-35. [PMID: 19232448 DOI: 10.1016/j.jhep.2008.11.019] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2008] [Revised: 11/03/2008] [Accepted: 11/08/2008] [Indexed: 12/18/2022]
Abstract
BACKGROUND/AIMS This study sought to identify the independent risk factors involved in the development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C virus (HCV) infection who have normal alanine aminotransferase (ALT) levels. METHODS A total of 519 patients with average ALT integration values less than or equal to 40 IU/L over 10 years were included. Baseline ultrasound was done in all patients and 68 patients underwent liver biopsy at the start of this study. Factors associated with the cumulative incidence of HCC were determined. RESULTS HCC occurred in 48 of 519 patients (9.2%). The following factors were significantly associated with the incidence of HCC: age>65 years (adjusted hazard ratio: 2.006 [95% confidence interval: 1.078-3.733]), ALT>20 IU/L (6.242 [1.499-25.987]), platelet count<15.0x10(4)/m(3) (2.675 [1.407-5.085]), total bilirubin>1.2mg/dL (2.798 [1.257-6.228]), ALP>338 IU/L (2.486 [1.327-4.657]), and total albumin<3.5g/dl (2.707 [1.177-6.223]). The 5- and 10-year cumulative incidences of HCC were 4.4% and 26.5% in patients with ALT>20 IU/L and platelet count<15.0x10(4)/m(3), respectively. CONCLUSIONS High ALT level and low platelet count are closely associated with the development of hepatocarcinogenesis. Therefore, individuals within this group are candidates for antiviral therapy.
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Affiliation(s)
- Takashi Kumada
- Department of Gastroenterology, Ogaki Municipal Hospital, 4-86, Minaminokawa-cho, Ogaki, Gifu 503-8052, Japan.
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Serum aminotransferase level and the risk of hepatocellular carcinoma: a population-based cohort study in Japan. Eur J Cancer Prev 2009; 18:26-32. [PMID: 19077561 DOI: 10.1097/cej.0b013e3282fa9edd] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Aminotransferase level is presumed to be a marker of hepatic inflammation, but uncertainty remains whether elevated aminotransferase levels are associated with an increased risk of hepatocellular carcinoma (HCC). We evaluated the incidence of HCC by aminotransferase level in 19 812 middle-aged and older individuals with and without hepatitis virus infection from a large-scale population-based cohort study (JPHC Study cohort II) in Japan. Hepatitis virus infection was identified at baseline in 1236 participants, namely 737 (3.7%) with hepatitis C virus, 479 (2.4%) with hepatitis B virus, and 20 (0.1%) with both. By the end of follow-up, a total of 109 newly arising HCC cases were diagnosed (71 men, 38 women), of which 87 (79.8%) had evidence of viral etiology. Alanine aminotransferase (ALT) was concentration-dependently associated with an increased risk of HCC in both virus-positive and virus-negative participants. Compared with virus-negative participants with ALT levels of less than 30 IU/l, a significant increase in the risk of HCC was observed in virus-negative participants with an ALT level greater than 30 IU/l, and in virus-positive participants with an ALT less than 30 IU/l, 30-69 IU/l, and > or =70 IU/l [Hazard ratio (95% confidence interval): 9.4 (3.9-22.3), 15.2 (6.1-37.6), 180.5 (89.4-364.2), 454.2 (221.5-931.2), respectively; P for trend <0.001]. In conclusion, our findings suggest that elevated ALT levels are strongly associated with the incidence of HCC regardless of hepatitis virus positivity. This finding indicates that ALT level is a good independent determinant of the need for intervention. Clinical application of these findings may help decrease HCC-associated mortality in hepatitis virus-endemic regions.
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Sakai Y, Honda M, Fujinaga H, Tatsumi I, Mizukoshi E, Nakamoto Y, Kaneko S. Common transcriptional signature of tumor-infiltrating mononuclear inflammatory cells and peripheral blood mononuclear cells in hepatocellular carcinoma patients. Cancer Res 2009; 68:10267-79. [PMID: 19074895 DOI: 10.1158/0008-5472.can-08-0911] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Hepatocellular carcinoma (HCC) is frequently associated with infiltrating mononuclear inflammatory cells. We performed laser capture microdissection of HCC-infiltrating and noncancerous liver-infiltrating mononuclear inflammatory cells in patients with chronic hepatitis C (CH-C) and examined gene expression profiles. HCC-infiltrating mononuclear inflammatory cells had an expression profile distinct from noncancerous liver-infiltrating mononuclear inflammatory cells; they differed with regard to genes involved in biological processes, such as antigen presentation, ubiquitin-proteasomal proteolysis, and responses to hypoxia and oxidative stress. Immunohistochemical analysis and gene expression databases suggested that the up-regulated genes involved macrophages and Th1 and Th2 CD4 cells. We next examined the gene expression profile of peripheral blood mononuclear cells (PBMC) obtained from CH-C patients with or without HCC. The expression profiles of PBMCs from patients with HCC differed significantly from those of patients without HCC (P < 0.0005). Many of the up-regulated genes in HCC-infiltrating mononuclear inflammatory cells were also differentially expressed by PBMCs of HCC patients. Analysis of the commonly up-regulated or down-regulated genes in HCC-infiltrating mononuclear inflammatory cells and PBMCs of HCC patients showed networks of nucleophosmin, SMAD3, and proliferating cell nuclear antigen that are involved with redox status, the cell cycle, and the proteasome system, along with immunologic genes, suggesting regulation of anticancer immunity. Thus, exploring the gene expression profile of PBMCs may be a surrogate approach for the assessment of local HCC-infiltrating mononuclear inflammatory cells.
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Affiliation(s)
- Yoshio Sakai
- Department of Gastroenterology, Kanazawa University, School of Medicine, Kanazawa, Japan
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Nojiri S, Nakao H, Sugauchi F, Miyaki T, Senda K, Sasaki M, Kataoka H, Kamiya T, Nakazawa T, Ohara H, Orito E, Joh T. Effect of ursodeoxycholic acid on serum liver enzymes and bile acid metabolism in chronic active hepatitis C virus infection. Hepatol Res 2009; 39:21-30. [PMID: 18721155 DOI: 10.1111/j.1872-034x.2008.00406.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
AIM Many reports have revealed ursodeoxycholic acid (UDCA) to be effective against chronic hepatitis C virus (HCV). However, some cases resist this therapy and the mechanism of action remains unclear. In this study, UDCA was administered to patients with chronic HCV and the correlation between the bile acids of the biliary bile and serum and the drug efficacy was investigated. METHODS Fifteen patients were given 600 mg/day of UDCA for more than 24 weeks. The serum bile acid concentrations and biliary and serum bile acid were collected before and after 24 weeks of UDCA treatment, and composition determined by high-performance liquid chromatography. RESULTS The treatment was effective in nine cases (ALT decreased to less than twice the normal values 80 IU/L) and ineffective in six cases. There was no significant difference in the serum bile acid concentrations before and after UDCA treatment between the values of both cases. After UDCA treatment, the serum percentage of UDCA (effective, 62.5 +/- 2.0; ineffective, 53.5 +/- 2.5, (P = 0.02)) and the percentage of chenodeoxycholic acid (CDCA) showed no remarkable changes. In the biliary bile the percentage of CDCA (effective, 30.9 +/- 2.0; ineffective, 20.0 +/- 3.0, (P = 0.007)) and the percentage of UDCA showed no remarkable changes. CONCLUSION In the effective cases, the percentage of UDCA in the serum and the percentage of CDCA in biliary bile were significantly higher than in the ineffective cases. This indicates that, when effective, CDCA decreases in hepatocytes and this reduction contributes to hepatoprotection.
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Affiliation(s)
- Shunsuke Nojiri
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
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Elevated perioperative transaminase level predicts intrahepatic recurrence in hepatitis B-related hepatocellular carcinoma after curative hepatectomy. Asian J Surg 2008; 31:41-9. [PMID: 18490213 DOI: 10.1016/s1015-9584(08)60056-1] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVE We aimed to evaluate the role of elevated perioperative alanine aminotransferase (ALT) as a surrogate marker of hepatitis activity in determining the risk of recurrence and survival in hepatitis B-related hepatocellular carcinoma (HCC) after curative hepatectomy. METHODS A retrospective review of the hepatectomy database was performed and 142 patients were found who had hepatitis B-related HCC from January 2001 to March 2006. Their ALT levels preoperatively and 1 month, 3 months, and 6 months postoperatively were recorded. The risk factors for recurrence and prognostic factors of survival were analysed. RESULTS An elevated perioperative ALT level (p = 0.021), multiple tumour nodules in the resected specimen (p < 0.001), and a tumour size greater than 5 cm (p = 0.001) were significant independent risk factors for tumour recurrence. The latter two factors were also independent prognostic factors for overall survival and disease-free survival. An elevated ALT level was an independent prognostic factor for disease-free survival (p = 0.025). CONCLUSION An elevated perioperative ALT level, which reflects increased hepatitis activity, is an independent risk factor for intrahepatic recurrence of hepatitis B-related HCC. It is also associated with a poorer disease-free survival rate.
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Chuma M, Hige S, Nakanishi M, Ogawa K, Natsuizaka M, Yamamoto Y, Asaka M. 8-Hydroxy-2'-deoxy-guanosine is a risk factor for development of hepatocellular carcinoma in patients with chronic hepatitis C virus infection. J Gastroenterol Hepatol 2008; 23:1431-6. [PMID: 18854000 DOI: 10.1111/j.1440-1746.2008.05502.x] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIM Increased production of reactive oxygen species, which cause oxidative DNA damage, is considered to be related to hepatocarcinogenesis. 8-Hydroxy-2'-deoxy-guanosine (8-OHdG) is a useful marker of DNA damage induced by oxidative stress. The aim of this study was to determine whether expression of 8-OHdG is a risk factor for the development of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV) infection. METHODS The expression of 8-OHdG in liver biopsy specimens was assessed immunohistochemically. In total, 104 patients with chronic HCV infection who were diagnosed on liver biopsy between January 1987 and December 2002 were studied retrospectively. Univariate and multivariate analyses using age, gender, habitual drinking, tobacco exposure, diabetes mellitus, serum alanine aminotransferase level, HCV genotype, hepatic fibrosis, inflammation, steatosis, and 8-OHdG expression in liver biopsy specimens were conducted to identify factors related to the development of HCC. RESULTS On multivariate analysis, 8-OHdG and fibrosis were independent and significant risk factors for HCC development (relative risk, 2.48; P = 0.023; relative risk, 5.35; P = 0.001, respectively). Furthermore, the cumulative incidence rate of HCC in 39 patients with high 8-OHdG expression levels was significantly greater than that in 65 patients with low 8-OHdG expression levels (P = 0.043). In addition, liver 8-OHdG expression was correlated with hepatic inflammation. CONCLUSIONS 8-OHdG is a risk factor for the development of HCC in patients with chronic HCV infection. Patients with chronic HCV who express 8-OHdG should be monitored carefully for the development of HCC.
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Affiliation(s)
- Makoto Chuma
- Department of Gastroentelology and Hematology, Hokkaido University Hospital, Kitaku, Sapporo, Japan.
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Ibrahim S, Roychowdhury A, Hean TK. Risk factors for intrahepatic recurrence after hepatectomy for hepatocellular carcinoma. Am J Surg 2007; 194:17-22. [PMID: 17560903 DOI: 10.1016/j.amjsurg.2006.06.051] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2006] [Revised: 06/28/2006] [Accepted: 06/28/2006] [Indexed: 12/22/2022]
Abstract
BACKGROUND Long-term survival after hepatectomy for hepatocellular carcinoma is still poor because of tumor recurrence especially in the liver remnant. The risk factors for intrahepatic recurrence after liver resection are studied in our cohort of patients. METHODS A retrospective analysis from a prospective database was performed on 76 consecutive successful hepatectomies for hepatocellular carcinoma. RESULTS Twenty-two patients had intrahepatic recurrence. The following were not found to be risk factors for recurrence: age, sex, race, number of segments resected, and mean operating time. By using multivariate analysis, serum aspartate transaminase level, more than 1 hepatocellular carcinoma nodule, and presence of tumor thrombi were found to be significant risk factors. CONCLUSION Patients who with these risk factors should undergo close follow-up to detect recurrence early; treatment with reresection, chemoembolization, or radiofrequency ablation can be considered.
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Affiliation(s)
- Salleh Ibrahim
- Department of General Surgery, Changi General Hospital, 2 Simei Street 3, Changi, Singapore 507027.
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Shan YS, Hsieh YH, Lin PW. Telomerase Activity in Tumor and Remnant Liver as Predictor of Recurrence and Survival in Hepatocellular Carcinoma after Resection. World J Surg 2007; 31:1121-8. [PMID: 17429564 DOI: 10.1007/s00268-006-0783-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIM Results after curative liver resection in hepatocellular carcinoma are unsatisfactory with regard to high postoperative intrahepatic recurrence and liver failure. This study evaluates telomerase activity in liver with and without tumor as a predictor of recurrence and survival. MATERIALS AND METHODS Liver tissue with and without tumor from 53 hepatocellular carcinoma patients receiving curative resection during the period of 1998-2000 was used for detecting telomerase activity by PCR-ELISA. Clinicopathological data were compared to identify predictors of recurrence and survival. RESULTS Telomerase activity was detected in 98% of liver tissue with tumor and 70% liver tissue without. Telomerase activity in cancerous liver correlated significantly with HCV infection (P = 0.012) and cirrhotic change in liver parenchyma (P = 0.006). Telomerase activity in non-cancerous liver correlated with high serum AFP level (P = 0.002). The telomerase activity of liver tissue with and without tumor is significant higher in patients with recurrence than in those without recurrence, 413.7 +/- 100.5 versus 110.8 +/- 32.7, P = 0.006, and 34.7 +/- 14.2 versus 4.2 +/- 1.4, P = 0.039. Recurrence could be predicted by abnormally high tumor telomerase activity (P = 0.026) or by advanced TNM stage (P = 0.001). TNM stage or high serum ALT level could predict multinodular intrahepatic recurrence (P = 0.028 and P = 0.030). High serum AFP combined with high telomerase activity in liver without tumor had a significant ability to predict poor survival (OR: 11.19, CI: 1.95-64.12, P = 0.007). CONCLUSION Tumor telomerase is an independent predictor of recurrence. Simultaneous high remnant liver telomerase and high serum AFP is a strong negative predictor of survival.
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Affiliation(s)
- Yan-Shen Shan
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 70428, Tainan, Taiwan ROC
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García-García JA, Romero-Gómez M, Girón-González JA, Rivera-Irigoin R, Torre-Cisneros J, Montero JL, González-Serrano M, Andrade RJ, Aguilar-Guisado M, Grilo I, Martín-Vivaldi J, Salmerón J, Caballero-Granado FJ, Macías J, Vergara-López S, Pineda JA. Incidence of and factors associated with hepatocellular carcinoma among hepatitis C virus and human immunodeficiency virus coinfected patients with decompensated cirrhosis. AIDS Res Hum Retroviruses 2006; 22:1236-41. [PMID: 17209765 DOI: 10.1089/aid.2006.22.1236] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
We compared the incidence of and factors associated with hepatocellular carcinoma (HCC) among hepatitis C virus (HCV)-monoinfected subjects and human immunodeficiency virus (HIV)/HCV-coinfected individuals, both with decompensated cirrhosis. In a retrospective study, a cohort of 180 individuals with HIV coinfection and 1037 HCV-monoinfected patients with decompensated HCV-related cirrhosis from eight centres in Spain were analyzed. HCC was found in 234 (23%) HCV-monoinfected subjects and in four (2%) HIV-coinfected subjects (p<0.001). At the time of the first hepatic decompensation, 188 (17%) and 4 (2%) (p<0.001) patients in the former and in the latter group, respectively, showed HCC. Fifty-four (11%) patients without HCC at baseline developed such a disease during follow-up. There were no incident cases among the HIV-coinfected population. The density of incidence (95% IC) of HCC in HIV/HCV-coinfected and HCV-monoinfected patients was 0 (0-1.70) and 3.31 (2.70-4.64) cases per 100 person-years (p<0.001), respectively. Lack of HIV infection [adjusted odds risk (AOR) (95% IC)=16.7 (3.9-71.1)] and high alanine aminotransferase levels [AOR (95% IC)=2.5 (1.1-5)] were the only two independent predictors of the emergence of HCC. In the group of patients in whom the date of HCV infection could be estimated, the time elapsed until HCC diagnosis was shorter among HIV-coinfected subjects. The incidence of HCC in patients with HCV-related cirrhosis after the first hepatic decompensation is lower in HIV-coinfected patients. This is probably due to the fact that HIV infection shortens the survival of HCV-coinfected patients with end-stage liver disease to such an extent that HCC not had a chance to emerge.
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Affiliation(s)
- José A García-García
- Unidad de Enfermedades Infecciosas, Servicio de Medicina Interna, Hospital Universitario de Valme, Sevilla, Spain
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Lei HJ, Chau GY, Lui WY, Tsay SH, King KL, Loong CC, Wu CW. Prognostic value and clinical relevance of the 6th Edition 2002 American Joint Committee on Cancer staging system in patients with resectable hepatocellular carcinoma. J Am Coll Surg 2006; 203:426-35. [PMID: 17000385 DOI: 10.1016/j.jamcollsurg.2006.06.030] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2006] [Revised: 06/27/2006] [Accepted: 06/28/2006] [Indexed: 12/20/2022]
Abstract
BACKGROUND A simplified American Joint Committee on Cancer (AJCC) TNM staging system for hepatocellular carcinoma (HCC) (the 6th edition) was proposed in 2002. In this study, we validated the prognostic value of the staging system in a patient cohort undergoing hepatic resection with longterm followup. STUDY DESIGN From a prospective database, the study cohort consisted of 440 patients who underwent curative hepatic resection for HCC between July 1991 and January 1999. Median followup time was 66 months. Multivariate analysis was performed to identify the independent prognostic factors related to postoperative survival. Patients were staged according to both the 5th edition (TNM-5) and 6th edition (TNM-6) AJCC TNM staging criteria. RESULTS The independent prognostic factors included major vascular invasion, microvascular invasion, surgical margin < 1 cm, indocyanine green retention rate at 15 minutes > 10%, multiple tumors, tumor rupture, male, and serum aspartate aminotransferase > 90 U/L. The breakdown by TNM-5 staging: I, 27 (6.1%); II, 108 (24.5%); III, 218 (49.5%); and IVA, 87 (19.8%) and by TNM-6 staging: I, 120 (27.3%); II, 170 (38.6%); and III, 150 (34.1%). When stratified according to the TNM-5 system, difference in survival was notable between stages II and IIIA (p < 0.001), between stages IIIA and IVA (p < 0.001), but not between stages I and II (p > 0.05). When stratified according to the TNM-6 system, difference in survival was considerable between stages I and II (p < 0.01), stages II and III (p < 0.001), and stages I and III (p < 0.001). CONCLUSIONS Overall, the TNM-6 staging system appears to provide a reliable prognostic classification of HCC patients and is simpler to use than the TNM-5 staging system.
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Affiliation(s)
- Hao-Jan Lei
- Departments of Surgery and Pathology, Taipei Veterans General Hospital, and College of Medicine, National Yang-Ming University, Shih-pai, Taipei, Taiwan, Republic of China
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Suruki R, Hayashi K, Kusumoto K, Uto H, Ido A, Tsubouchi H, Stuver SO. Alanine aminotransferase level as a predictor of hepatitis C virus-associated hepatocellular carcinoma incidence in a community-based population in Japan. Int J Cancer 2006; 119:192-5. [PMID: 16432841 DOI: 10.1002/ijc.21796] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
We evaluated the utility of alanine aminotransferase (ALT) measurements in predicting the incidence of hepatocellular carcinoma (HCC) in a cohort of 667 adults with chronic hepatitis C virus (HCV) infection from a community-based population in Japan, between 1994 and 2003. Cox proportional hazards regression analysis was used to describe the relationship between prediagnostic levels of ALT and the rate of HCC, after adjusting for age and gender; hazard ratios (HRs) and 95% confidence intervals (CIs) were obtained. Over an average of 8 years of follow-up, 52 HCC cases were identified. A significant association between a 20 IU/L difference in higher ALT level and subsequent HCC incidence was observed (HR = 1.2; 95% CI: 1.1, 1.3). An abnormal ALT level (> or =35 IU/L) increased the HCC rate by 4-fold compared to a normal ALT level (HR = 4.1; 95% CI: 2.1, 8.0). Among 551 subjects with at least 4 repeated measurements of ALT, those with persistently abnormal ALT levels (n = 118) had a strong, significantly increased HCC rate compared to those with persistently normal ALT levels (n = 296) (HR = 23.2; 95% CI: 3.0, 178.5). This study demonstrates that elevated ALT levels, measured on an average of 8 years before HCC diagnosis, predict an increased rate of HCV-associated HCC in a community-based population and that utilizing serial measurements to identify persistent ALT abnormality may be useful in determining HCC risk.
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Affiliation(s)
- Robert Suruki
- Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.
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Hung CH, Lee CM, Lu SN, Wang JH, Hu TH, Tung HD, Chen CH, Chen WJ, Changchien CS. Long-term effect of interferon alpha-2b plus ribavirin therapy on incidence of hepatocellular carcinoma in patients with hepatitis C virus-related cirrhosis. J Viral Hepat 2006; 13:409-14. [PMID: 16842444 DOI: 10.1111/j.1365-2893.2005.00707.x] [Citation(s) in RCA: 86] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
We assessed the efficacy of interferon (IFN) alpha-2b plus ribavirin therapy in patients with hepatitis C virus (HCV)-related cirrhosis, and elucidated the risk factors for the development of hepatocellular carcinoma (HCC) to determine whether these therapies might reduce the incidence of HCC. One hundred and thirty-two HCV-cirrhotic patients receiving IFN alpha-2b (3 or 5 MU thrice weekly) and oral ribavirin (1,000-1,200 mg/day) for 24 or 48 weeks were analysed. Cumulative incidence of HCC was estimated by the Kaplan-Meier method. The prognostic relevance of clinical variables and HCC occurrence was evaluated by univariate analysis with the log-rank test and by multivariate Cox's regression analysis. A total of 116 patients completed the treatment and 73 (55%) achieved a sustained virological response (SVR). Stepwise logistic regression analysis showed that nongenotype 1b (P < 0.001) and low viral load (P = 0.018) were independent variables of SVR. During a median follow-up period of 37 (12-63) months, HCC developed in 11 patients with non-SVR and five with SVR (P = 0.0178), whereas there was no difference between those with transient biochemical response and nonresponse (P = 0.5970). The Kaplan-Meier method also showed that old age (>or=60 years) (P = 0.0034) and genotype 1b (P = 0.0104) were associated with HCC occurrence. Using Cox's regression analysis, non-SVR (odds ratio = 3.521, P = 0.036), male (odds ratio = 6.269, P = 0.011) and old age (odds ratio = 3.076, P = 0.049) were independent significant risk factors contributing to HCC development. Our results suggest that achieving SVR by IFN alpha-2b plus ribavirin therapy may decrease the incidence of HCC in patients with HCV-related cirrhosis.
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Affiliation(s)
- C-H Hung
- Department of Internal Medicine, Division of Hepatogastroenterology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
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Nakamuta M, Morizono S, Kohjima M, Kotoh K, Enjoji M. Baseline characterization of patients aged 70 years and above with hepatocellular carcinoma. World J Gastroenterol 2006; 11:7512-4. [PMID: 16437725 PMCID: PMC4725168 DOI: 10.3748/wjg.v11.i47.7512] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To characterize the baseline profiles of patients aged 70 years and above with hepatocellular carcinoma (HCC). METHODS A series of 127 consecutive patients with HCC were enrolled between 2000 and 2004, and none of them had been diagnosed as having HCC previously. Baseline profiles, including parameters of hepatic function such as serum transaminase and prothrombin time [PT (% activity)] were compared between patients aged > or = 70 and < 70 years. RESULTS Patients > or = 70 years old showed significantly lower levels of aspartate aminotransferase (P = 0.04) and alanine aminotransferase (P = 0.01), and significantly higher PTs (P = 0.04) and platelet counts (P = 0.02). Concomitantly, among > or = 70-year-old patients, HCC was more common in non-cirrhotics, whereas among patients < 70 years old, HCC was more common in cirrhotics. There was no significant difference between the groups in the number or size of tumors. CONCLUSION Older HCC patients showed less inflammation and better preservation of hepatic function, indicating that not only cirrhotic patients but also non-cirrhotic patients should be considered as a high-risk group among the elderly.
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Affiliation(s)
- Makoto Nakamuta
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-5282, Japan.
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Toyoda H, Kumada T, Kiriyama S, Sone Y, Tanikawa M, Hisanaga Y, Yamaguchi A, Isogai M, Kaneoka Y, Washizu J. Prognostic significance of simultaneous measurement of three tumor markers in patients with hepatocellular carcinoma. Clin Gastroenterol Hepatol 2006; 4:111-7. [PMID: 16431313 DOI: 10.1016/s1542-3565(05)00855-4] [Citation(s) in RCA: 83] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS We conducted a prospective study to evaluate the significance of simultaneous measurement of 3 currently used tumor markers in the evaluation of tumor progression and prognosis of patients with hepatocellular carcinoma (HCC). METHODS Three tumor markers for HCC, alpha-fetoprotein (AFP), Lens culinaris agglutinin A-reactive fraction of AFP (AFP-L3), and des-gamma-carboxy prothrombin (DCP), were measured in the same serum samples obtained from 685 patients at the time of initial diagnosis of HCC. Positivity for AFP >20 ng/dL, AFP-L3 >10% of total AFP, and/or DCP >40 mAU/mL was determined. In addition, tumor markers were measured after treatment of HCC. RESULTS Of the 685 patients, 337 (55.8%) were positive for AFP, 206 (34.1%) were positive for AFP-L3, and 371 (54.2%) were positive for DCP. In a comparison of patients positive for only 1 tumor marker, patients positive for AFP-L3 alone had a greater number of tumors, whereas patients positive for DCP alone had larger tumors and a higher prevalence of portal vein invasion. When patients were compared according to the number of tumor markers present, the number of markers present clearly reflected the extent of HCC and patient outcomes. The number of markers present significantly decreased after treatment. CONCLUSIONS Tumor markers AFP-L3 and DCP appear to represent different features of tumor progression in patients with HCC. The number of tumor markers present could be useful for the evaluation of tumor progression, prediction of patient outcome, and treatment efficacy.
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Affiliation(s)
- Hidenori Toyoda
- Department of Gastroenterology, Ogaki Municipal Hospital, Gifu, Japan.
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Hung CH, Lee CM, Wang JH, Tung HD, Chen CH, Lu SN. Antiviral therapy after non-surgical tumor ablation in patients with hepatocellular carcinoma associated with hepatitis C virus. J Gastroenterol Hepatol 2005; 20:1553-9. [PMID: 16174073 DOI: 10.1111/j.1440-1746.2005.03925.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Antiviral therapy for chronic hepatitis C virus (HCV) infection has led to a reduction in the incidence of hepatocellular carcinoma (HCC). The purpose of the present paper was to assess whether antiviral therapy might suppress tumor recurrence and influence overall survival in patients with HCV-related HCC who had complete ablation of nodules by non-surgical treatments. METHODS Twenty patients with three or fewer nodules of HCV-related HCC who were treated with percutaneous tumor ablation and/or transcatheter arterial embolization received combined interferon (IFN; 3 or 5 million units of IFN alpha-2b thrice weekly) plus ribavirin (1000-1200 mg per day) therapy for 24-48 weeks after complete ablation of lesions. During the same period, an additional 40 age- and sex-matched control patients with similar characteristics of tumors (sizes, numbers and treatment modalities) and severity of liver disease were recruited from the HCC database. Both recurrence-free survival and actuarial survival were evaluated. RESULTS Of the 20 patients, 16 completed therapy and 10 showed a sustained response with normalization of alanine aminotransferase and negative HCV-RNA at 6 months after therapy completion. Due to severe side-effects experienced by Child B patients, who mostly discontinued antiviral therapy, clinical outcome was analyzed in the Child A treated (n = 16) and control (n = 33) patients. There was no significant difference in the incidence of local recurrence in sustained responders compared with non-responders or control patients (P = 0.174, 0.1284, respectively); but the second recurrence-free interval in the sustained responders was significantly longer than that of non-responders and the control group (P = 0.0141, 0.0243, respectively). Survival in sustained responders was better than in non-responders and control patients (P = 0.0691, 0.0554, respectively). CONCLUSIONS These results indicate that successful antiviral therapy after non-surgical tumor ablation for HCV-related HCC may lower tumor recurrence rate and prolong survival.
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Affiliation(s)
- Chao-Hung Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
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El-Zayadi AR, Attia M, Badran HM, El-Tawil A, Zalata K, Barakat E, Selim O, El-Nakeeb A, Saied A. Non-interferon-based therapy: an option for amelioration of necro-inflammation in hepatitis C patients who cannot afford interferon therapy. Liver Int 2005; 25:746-51. [PMID: 15998425 DOI: 10.1111/j.1478-3231.2005.01110.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Interferon (IFN) therapy is not affordable by the majority of Egyptian patients. Our aim was to tailor an effective and inexpensive regimen that ameliorates hepatic necro-inflammatory activity among chronic hepatitis C (CHC) patients. METHODS One hundred and seventy naïve CHC patients with elevated alanine aminotransferase (ALT) (>1.5-fold) and detectable hepatitis C virus (HCV)-RNA by polymerase chain reaction, who cannot afford IFN-based therapy were randomly allocated either to non-interferon-based therapy (N-IFN-BT) (group I) or silymarin therapy (group II). Group I comprised 87 patients (biopsy proved chronic hepatitis in 62 patients) who were administered a daily combination of ribavirin (600-800 mg) plus amantadine (200 mg) and ursodeoxycholic acid (UDCA) (500 mg) for 24 weeks. Group II comprised 83 patients who were administered Silymarin 450 mg/day for 24 weeks. RESULTS Statistical evaluation was conducted on 82 patients from group I and 72 from group II because of the withdrawal of five and 11 patients from Groups I and II, respectively. Age, sex, social status and biochemical parameters were comparable in both groups. Normalization of ALT at the end of treatment was achieved in 58.5% and 15.3% (P<0.001), whereas end of treatment virologic response (ETVR) was achieved in 2.4% and 0% of Groups I and II, respectively. Twenty-four weeks after cessation of therapy, sustained biochemical response (SBR) was achieved in 28% and 2.8% (P<0.001), while sustained virologic response (SVR) was maintained in 2.4% and 0% of the patients in Groups I and II, respectively. In Group I, histopathological examination revealed a decreased activity index by an average score of 1.5 points among 38/62 of the rebiopsied patients. CONCLUSION Twenty-four weeks N-IFN-BT achieved a fourfold-higher ETBR and a tenfold-higher SBR compared with silymarin therapy, which reflects an improvement of necroinflammatory activity as proven by repeat histopathology.
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Tarao K, Fujiyama S, Ohkawa S, Miyakawa K, Tamai S, Hirokawa S, Masaki T, Tanaka K. Ursodiol Use Is Possibly Associated with Lower Incidence of Hepatocellular Carcinoma in Hepatitis C Virus–Associated Liver Cirrhosis. Cancer Epidemiol Biomarkers Prev 2005. [DOI: 10.1158/1055-9965.164.14.1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Abstract
In a previous study of patients with hepatitis C virus (HCV)–associated liver cirrhosis (HCV-LC), we showed that increased liver inflammation, as assessed by higher serum alanine aminotransferase (ALT), was associated with increased risk for the development of hepatocellular carcinoma (HCC). This suggested that suppression of inflammation might inhibit HCC development in HCV-LC. Several agents have been suggested to possess chemopreventive potential against the development of HCC in chronic HCV-associated liver disease, including herbal medicines, such as Stronger-Neo-Minophagen C (glycyrrhizin) and Sho-saiko-to (TJ-9). Ursodiol [ursodeoxycholic acid (UDCA)], a bile acid widely used to treat cholestatic liver diseases, also possesses anti-inflammatory properties in liver disease. We hypothesized that suppression of liver inflammation, as assessed by decreases in serum ALT, might inhibit HCC occurrence in patients with HCV-LC. In this study, the preventive effect of UDCA on HCC was examined in patients with early-stage HCV-LC. One hundred two patients with HCV-LC (Child stage A) were treated with anti-inflammatory drugs, Stronger-Neo-Minophagen C,Sho-saiko-to, or UDCA, with the goal of lowering the average serum ALT level to <80 IU. Iftheaverage ALT level did not remain <80 IU after treatment with one agent, multiagent therapy was initiated. The patients were followed up for >5 years and were retrospectively subdivided into two groups: 56 UDCA users (group A) and 46 UDCA nonusers (group B). The mean ± SD dosage of UDCA administered in group A was 473.7 ± 183.0 mg/d. The average duration of UDCA administration in group A was 37.3 ± 15.9 months over the 5-year study period. The cumulative incidence of HCC was recorded. The 5-year incidence of HCC in group A was 17.9% (10 of 56) and was significantly lower than that in group B (39.1%, 18 of 46; P = 0.025). The risk for HCC incidence, calculated by a logistic regression model, showed that the administration of UDCA significantly decreased hepatocarcinogenesis (P = 0.036). The herbal medicines used were comparable in dosage and treatment duration in the UDCA and non-UDCA groups. In conclusion, UDCA might prevent HCC development in HCV-LC. Interestingly, because the serum ALT trends over time were nearly the same in both groups, the chemopreventive effectiveness of UDCA was not accompanied by greater reductions in ALT compared with the UDCA nonusers.
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Affiliation(s)
- Kazuo Tarao
- 1Department of Gastroenterology, Kanagawa Cancer Center Hospital
| | | | - Shinichi Ohkawa
- 1Department of Gastroenterology, Kanagawa Cancer Center Hospital
| | - Kaoru Miyakawa
- 1Department of Gastroenterology, Kanagawa Cancer Center Hospital
| | - Setsuo Tamai
- 1Department of Gastroenterology, Kanagawa Cancer Center Hospital
| | - Satoru Hirokawa
- 1Department of Gastroenterology, Kanagawa Cancer Center Hospital
| | - Takahiro Masaki
- 1Department of Gastroenterology, Kanagawa Cancer Center Hospital
| | - Katsuaki Tanaka
- 2School of Medicine, Yokohama City University, Yokohama, Japan and
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Abstract
Emerging data indicate that the mortality rate of hepatocellular carcinoma (HCC) associated with cirrhosis is rising in some developed countries, whereas mortality from non-HCC complications of cirrhosis is decreasing or is stable. Cohort studies indicate that HCC is currently the major cause of liver-related death in patients with compensated cirrhosis. Hepatitis C virus (HCV) infection is associated with the highest HCC incidence in persons with cirrhosis, occurring twice as commonly in Japan than in the West (5-year cumulative incidence, 30% and 17%, respectively), followed by hereditary hemochromatosis (5-year cumulative incidence, 21%). In hepatitis B virus (HBV)-related cirrhosis, the 5-year cumulative HCC risk is 15% in high endemic areas and 10% in the West. In the absence of HCV and HBV infection, the HCC incidence is lower in alcoholic cirrhotics (5-year cumulative risk, 8%) and subjects with advanced biliary cirrhosis (5-year cumulative risk, 4%). There are limited data on HCC risk in cirrhosis of other causes. Older age, male sex, severity of compensated cirrhosis at presentation, and sustained activity of liver disease are important predictors of HCC, independent of etiology of cirrhosis. In viral-related cirrhosis, HBV/HCV and HBV/HDV coinfections increase the HCC risk (2- to 6-fold relative to each infection alone) as does alcohol abuse (2- to 4-fold relative to alcohol abstinence). Sustained reduction of HBV replication lowers the risk of HCC in HBV-related cirrhosis. Further studies are needed to investigate other viral factors (eg, HBV genotype/mutant, occult HBV, HIV coinfection) and preventable or treatable comorbidities (eg, obesity, diabetes) in the HCC risk in cirrhosis.
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Tsutsumi T, Suzuki T, Moriya K, Shintani Y, Fujie H, Miyoshi H, Matsuura Y, Koike K, Miyamura T. Hepatitis C virus core protein activates ERK and p38 MAPK in cooperation with ethanol in transgenic mice. Hepatology 2003. [PMID: 14512869 DOI: 10.1002/hep.1840380408] [Citation(s) in RCA: 57] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
In human chronic hepatitis C, alcohol intake is a synergistic factor for the acceleration of hepatocarcinogenesis. Recently, we showed a significant increase of reactive oxygen species (ROS) in hepatitis C virus (HCV) core-transgenic mice fed ethanol-containing diets. Because previous studies indicated that ROS is closely associated with mitogen-activated protein kinases (MAPK), we examined activities of c-Jun N-terminal kinase, p38 MAPK, and extracellular signal-regulated kinase (ERK) in the liver of core-transgenic and nontransgenic mice with short-term ethanol feeding. Activity of ERK and p38 MAPK was increased in core-transgenic mice compared with nontransgenic mice, whereas neither ERK nor p38 MAPK was activated in core-transgenic mice with normal diets. In addition, activity of cyclic-AMP and serum responsive element, downstream pathways of p38 MAPK and ERK, was also increased. Comparison of gene expression profiles by cDNA microarray and real-time PCR revealed that galectin-1, which is associated with cell transformation, was significantly increased in ethanol-fed core-transgenic mice. On the other hand, glutathione S-transferase (GST), which plays a key role in protecting cells from oxidative stress, was decreased. In conclusion, these results suggest that HCV core protein cooperates with ethanol for the activation of some MAPK pathways, and leads to the modulation of several genes, contributing to the pathogenesis of liver disease of HCV-infected patients with high ethanol consumption.
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Affiliation(s)
- Takeya Tsutsumi
- Department of Virology II, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan
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Kaplan DE, Reddy KR. Rising incidence of hepatocellular carcinoma: the role of hepatitis B and C; the impact on transplantation and outcomes. Clin Liver Dis 2003; 7:683-714. [PMID: 14509534 DOI: 10.1016/s1089-3261(03)00060-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma caused by hepatitis B and hepatitis C are global scourges but are likely to peak in incidence in the next 2 decades and then decline. Universal vaccination has been effective in stemming the incidence of chronic hepatitis B and early-onset HCC in regions of high endemicity where implemented, but preventive measures in HCV are not yet available. After the attrition of older affected generations, the incidence of HCC will likely decline rapidly. While no vaccine is currently available for hepatitis C, cases are projected to peak and decline because of a marked reduction in transmission as a result of behavioral modification and safeguarding of blood supplies. Until these epidemiologic projections come to pass, management of hepatocellular carcinoma will continue to become a progressively more frequently encountered clinical challenge. Therapy for chronic hepatitis may ameliorate but will not eliminate the development of tumors. The demand for orthotopic liver transplantation will continue to climb, and palliative therapies for non-resectable cases will require studies aimed at optimization of benefit. LDLT may remain an option for high-risk patients affording tumor-free survival for some otherwise terminal patients.
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Affiliation(s)
- David E Kaplan
- Division of Gastroenterology and Hepatology, University of Pennsylvania School of Medicine, 3 Raydin, 3400 Spruce Street, Philadelphia, PA 19104, USA
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