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Castro V, Calvo G, Oliveros JC, Pérez-Del-Pulgar S, Gastaminza P. Hepatitis C virus-induced differential transcriptional traits in host cells after persistent infection elimination by direct-acting antivirals in cell culture. J Med Virol 2024; 96:e29787. [PMID: 38988177 DOI: 10.1002/jmv.29787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 06/11/2024] [Accepted: 07/02/2024] [Indexed: 07/12/2024]
Abstract
Chronic hepatitis C virus infection (HCV) causes liver inflammation and fibrosis, leading to the development of severe liver disease, such as cirrhosis or hepatocellular carcinoma (HCC). Approval of direct-acting antiviral drug combinations has revolutionized chronic HCV therapy, with virus eradication in >98% of the treated patients. The efficacy of these treatments is such that it is formally possible for cured patients to carry formerly infected cells that display irreversible transcriptional alterations directly caused by chronic HCV Infection. Combining differential transcriptomes from two different persistent infection models, we observed a major reversion of infection-related transcripts after complete infection elimination. However, a small number of transcripts were abnormally expressed in formerly infected cells. Comparison of the results obtained in proliferating and growth-arrested cell culture models suggest that permanent transcriptional alterations may be established by several mechanisms. Interestingly, some of these alterations were also observed in the liver biopsies of virologically cured patients. Overall, our data suggest a direct and permanent impact of persistent HCV infection on the host cell transcriptome even after virus elimination, possibly contributing to the development of HCC.
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Affiliation(s)
- Victoria Castro
- Department of Cellular and Molecular Biology, Centro Nacional de Biotecnología-Consejo Superior de Investigaciones Científicas, Madrid, Spain
| | - Gema Calvo
- Department of Cellular and Molecular Biology, Centro Nacional de Biotecnología-Consejo Superior de Investigaciones Científicas, Madrid, Spain
| | - Juan Carlos Oliveros
- Bioinformatics for Genomics and Proteomics Unit, Centro Nacional de Biotecnología-Consejo Superior de Investigaciones Científicas, Madrid, Spain
| | | | - Pablo Gastaminza
- Department of Cellular and Molecular Biology, Centro Nacional de Biotecnología-Consejo Superior de Investigaciones Científicas, Madrid, Spain
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Tao XM, Zeng MH, Zhao YF, Han JX, Mi YQ, Xu L. Direct-acting antivirals failed to reduce the incidence of hepatocellular carcinoma occurrence in hepatitis C virus associated cirrhosis: A real-world study. World J Hepatol 2024; 16:41-53. [PMID: 38313240 PMCID: PMC10835484 DOI: 10.4254/wjh.v16.i1.41] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 12/18/2023] [Accepted: 01/09/2024] [Indexed: 01/23/2024] Open
Abstract
BACKGROUND Direct-acting antivirals (DAAs) revolutionized the treatment of chronic hepatitis C virus (HCV)-associated disease achieving high rates of sustained virological response (SVR). However, whether DAAs can reduce the occurrence of hepatocellular carcinoma (HCC) in patients with HCV-associated cirrhosis who are at high risk have not been concluded. AIM To investigate the effect of DAAs on the occurrence of HCC in patients with HCV-associated cirrhosis after achieving SVR. METHODS Of 427 inpatients with HCV-associated cirrhosis were enrolled in Tianjin Second People's Hospital from January 2014 to April 2020. 118 patients weren't received antiviral treatment with any reasons named non-antiviral treatment group, and 236 patients obtained from the 309 DAAs treatment patients according to the propensity score matching named DAAs treatment group. Demographic information and laboratory data were collected from baseline and the following up. Kaplan-Meier curve and Log-Rank test were used to compare the incidence and cumulative incidence of HCC between the two groups. Cox proportional risk regression was used to re-evaluate the risk factors for HCC. RESULTS HCC incidence was 4.68/100PY (95%CI, 3.09-6.81) in the DAAs treatment group, while it was 3.00/100PY (95%CI, 1.50-5.37) in the non-antiviral treatment group, and the relative risk was 1.82 (95%CI, 0.93-3.53, P > 0.05). The incidence of HCC at 12, 24, 36 and 48 months was 3.39%, 6.36%, 8.47% and 10.17% in the DAAs treatment group, and it was 0%, 0%, 3.39% and 9.32% in the non-antiviral treatment group, respectively. Age > 58 [hazard ratio (HR) = 1.089; 95%CI, 1.033-1.147; P = 0.002] and liver stiffness measurement > 27.85 kPa (HR = 1.043; 95%CI, 1.022-1.065; P = 0.000) were risk factors for HCC in all patients (n = 427), and DAAs treatment didn't show protective efficacy. CONCLUSION DAAs treatment seems failed to reduce the incidence of HCC occurrence in HCV-associated cirrhosis in 48 months, and even increased the incidence of HCC in 36 months.
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Affiliation(s)
- Xue-Mei Tao
- Clinical School of the Second People's Hospital, Tianjin Medical University, Tianjin 300192, China
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin 300192, China
| | - Ming-Hui Zeng
- Clinical School of the Second People's Hospital, Tianjin Medical University, Tianjin 300192, China
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin 300192, China
| | - You-Fei Zhao
- Clinical School of the Second People's Hospital, Tianjin Medical University, Tianjin 300192, China
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin 300192, China
| | - Jia-Xin Han
- Clinical School of the Second People's Hospital, Tianjin Medical University, Tianjin 300192, China
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin 300192, China
| | - Yu-Qiang Mi
- Clinical School of the Second People's Hospital, Tianjin Medical University, Tianjin 300192, China
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin 300192, China
| | - Liang Xu
- Clinical School of the Second People's Hospital, Tianjin Medical University, Tianjin 300192, China
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin 300192, China
- Department of Hepatology, Tianjin Research Institute of Liver Diseases, Tianjin 300192, China.
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Brown AJ, Won JJ, Wolfisberg R, Fahnøe U, Catanzaro N, West A, Moreira FR, Nogueira Batista M, Ferris MT, Linnertz CL, Leist SR, Nguyen C, De la Cruz G, Midkiff BR, Xia Y, Evangelista MD, Montgomery SA, Billerbeck E, Bukh J, Scheel TK, Rice CM, Sheahan TP. Host genetic variation guides hepacivirus clearance, chronicity, and liver fibrosis in mice. Hepatology 2024; 79:183-197. [PMID: 37540195 PMCID: PMC10718216 DOI: 10.1097/hep.0000000000000547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Accepted: 06/14/2023] [Indexed: 08/05/2023]
Abstract
BACKGROUND AIMS Human genetic variation is thought to guide the outcome of HCV infection, but model systems within which to dissect these host genetic mechanisms are limited. Norway rat hepacivirus, closely related to HCV, causes chronic liver infection in rats but causes acute self-limiting hepatitis in typical strains of laboratory mice, which resolves in 2 weeks. The Collaborative Cross (CC) is a robust mouse genetics resource comprised of a panel of recombinant inbred strains, which model the complexity of the human genome and provide a system within which to understand diseases driven by complex allelic variation. APPROACH RESULTS We infected a panel of CC strains with Norway rat hepacivirus and identified several that failed to clear the virus after 4 weeks. Strains displayed an array of virologic phenotypes ranging from delayed clearance (CC046) to chronicity (CC071, CC080) with viremia for at least 10 months. Body weight loss, hepatocyte infection frequency, viral evolution, T-cell recruitment to the liver, liver inflammation, and the capacity to develop liver fibrosis varied among infected CC strains. CONCLUSIONS These models recapitulate many aspects of HCV infection in humans and demonstrate that host genetic variation affects a multitude of viruses and host phenotypes. These models can be used to better understand the molecular mechanisms that drive hepacivirus clearance and chronicity, the virus and host interactions that promote chronic disease manifestations like liver fibrosis, therapeutic and vaccine performance, and how these factors are affected by host genetic variation.
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Affiliation(s)
- Ariane J. Brown
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - John J. Won
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Raphael Wolfisberg
- Department of Infectious Diseases, Copenhagen Hepatitis C Program (CO-HEP), Copenhagen University Hospital, Hvidovre and Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Ulrik Fahnøe
- Department of Infectious Diseases, Copenhagen Hepatitis C Program (CO-HEP), Copenhagen University Hospital, Hvidovre and Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Nicholas Catanzaro
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Ande West
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Fernando R. Moreira
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Mariana Nogueira Batista
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York, USA
| | - Martin T. Ferris
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Colton L. Linnertz
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Sarah R. Leist
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Cameron Nguyen
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Gabriela De la Cruz
- Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
| | - Bentley R. Midkiff
- Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
| | - Yongjuan Xia
- Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
| | - Mia D. Evangelista
- Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
| | - Stephanie A. Montgomery
- Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
- Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
| | - Eva Billerbeck
- Department of Medicine and Department of Microbiology and Immunology, Division of Hepatology, Albert Einstein College of Medicine, Bronx, New York, USA
| | - Jens Bukh
- Department of Infectious Diseases, Copenhagen Hepatitis C Program (CO-HEP), Copenhagen University Hospital, Hvidovre and Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Troels K.H. Scheel
- Department of Infectious Diseases, Copenhagen Hepatitis C Program (CO-HEP), Copenhagen University Hospital, Hvidovre and Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York, USA
| | - Charles M. Rice
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York, USA
| | - Timothy P. Sheahan
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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Yamagiwa Y, Tanaka K, Matsuo K, Wada K, Lin Y, Sugawara Y, Mizoue T, Sawada N, Takimoto H, Ito H, Kitamura T, Sakata R, Kimura T, Tanaka S, Inoue M. Response to antiviral therapy for chronic hepatitis C and risk of hepatocellular carcinoma occurrence in Japan: a systematic review and meta-analysis of observational studies. Sci Rep 2023; 13:3445. [PMID: 36859564 PMCID: PMC9977913 DOI: 10.1038/s41598-023-30467-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 02/23/2023] [Indexed: 03/03/2023] Open
Abstract
In Japan, hepatocellular carcinoma (HCC) is a leading cause of cancer mortality and hepatitis C virus infection is a major cause of HCC. We conducted a systematic review and meta-analysis of published studies evaluating patient response to antiviral therapy for chronic hepatitis C on the risk of HCC occurrence in Japan. Articles were searched using terms determined a priori through PubMed, screened by title and abstract, and selected by full-text assessment according to criteria determined a priori, including HCC occurrence in response to interferon (IFN)-based or IFN-free therapy, Japanese study, and 2 or more years of follow-up. We excluded studies on HCC recurrence. We calculated the pooled estimate of the crude incidence rate ratio with data from the selected studies using the person-years method with Poisson regression model and pooled estimate of the hazard ratio adjusted for potential confounders reported by the studies using a random effects model. A total of 26 studies were identified, all of which examined only IFN-based therapy as a result of the selection process. The pooled estimate (95% confidence interval [CI]) of 25 studies was 0.37 (0.33-0.43) for sustained virologic response (SVR) and 1.70 (1.61-1.80) for non-SVR for the HCC incidence rate per 100 person-years, and 0.22 (0.19-0.26) for the incidence rate ratio (SVR vs. non-SVR). The pooled estimate of the hazard ratio (95% CI) of HCC incidence adjusted for potential confounders of 8 studies was 0.25 (0.19-0.34). SVR to interferon therapy for chronic hepatitis C reduces the risk of HCC occurrence.
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Affiliation(s)
- Yoko Yamagiwa
- Division of Prevention, National Cancer Center Institute for Cancer Control, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
- Clinical Research Centers for Medicine, International University of Health and Welfare, Tokyo, Japan
| | - Keitaro Tanaka
- Department of Preventive Medicine, Faculty of Medicine, Saga University, Saga, Japan
| | - Keitaro Matsuo
- Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan
| | - Keiko Wada
- Department of Epidemiology and Preventive Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Yingsong Lin
- Department of Public Health, Aichi Medical University School of Medicine, Aichi, Japan
| | - Yumi Sugawara
- Division of Epidemiology, Department of Public Health and Forensic Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tetsuya Mizoue
- Department of Epidemiology and Prevention, Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo, Japan
| | - Norie Sawada
- Division of Cohort Research, National Cancer Center Institute for Cancer Control, Tokyo, Japan
| | - Hidemi Takimoto
- Department of Nutritional Epidemiology, National Institute of Health and Nutrition, National Institute of Biomedical Innovation, Health and Nutrition, Tokyo, Japan
| | - Hidemi Ito
- Division of Cancer Information and Control, Department of Preventive Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan
| | - Tetsuhisa Kitamura
- Department of Social Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Ritsu Sakata
- Department of Epidemiology, Radiation Effects Research Foundation, Hiroshima, Japan
| | - Takashi Kimura
- Department of Public Health, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Shiori Tanaka
- Division of Prevention, National Cancer Center Institute for Cancer Control, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Manami Inoue
- Division of Prevention, National Cancer Center Institute for Cancer Control, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
- Division of Cohort Research, National Cancer Center Institute for Cancer Control, Tokyo, Japan.
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5
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Nephew LD, Wang Y, Mohamed K, Nichols D, Rawl SM, Orman E, Desai AP, Patidar KR, Ghabril M, Chalasani N, Kasting ML. Removal of medicaid restrictions were associated with increased hepatitis C virus treatment rates, but disparities persist. J Viral Hepat 2022; 29:366-374. [PMID: 35254695 PMCID: PMC9314034 DOI: 10.1111/jvh.13661] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 01/07/2022] [Accepted: 01/30/2022] [Indexed: 12/21/2022]
Abstract
Despite the release of a growing number of direct-acting antivirals and evolving policy landscape, many of those diagnosed with hepatitis C virus (HCV) have not received treatment. Those from vulnerable populations are at particular risk of being unable to access treatment, threatening World Health Organization (WHO) HCV elimination goals. The aim of this study was to understand the association between direct-acting antivirals approvals, HCV-related policy changes and access to HCV virus treatment in Indiana, and to explore access to treatment by race, birth cohort and insurance type. We performed a retrospective cohort study of adults with HCV from 05/2011-03/2021, using statewide electronic health data. Nine policy and treatment changes were defined a priori. A Lowess curve evaluated treatment trends over time. Monthly screening and treatment rates were examined. Multivariable logistic regression explored predictors of treatment. The population (N = 10,336) was 13.4% Black, 51.8% was born after 1965 and 44.7% was Medicaid recipients. Inflections in the Lowess curve defined four periods: (1) Interferon + DAA, (2) early direct-acting antivirals, (3) Medicaid expansion/optimization and (4) Medicaid restrictions (fibrosis/prescriber) removed. The largest increase in monthly treatment rates was during period 4, when Medicaid prescriber and fibrosis restrictions were removed (2.4 persons per month [PPM] in period 1 to 72.3 PPM in period 4, p < 0.001; 78.0% change in slope). Multivariable logistic regression analysis showed being born after 1965 (vs. before 1945; OR 0.69; 95% 0.49-0.98) and having Medicaid (vs. private insurance; OR 0.47; 95% CI 0.42-0.53), but not race was associated with lower odds of being treated. In conclusion, DAAs had limited impact on HCV treatment rates until Medicaid restrictions were removed. Additional policies may be needed to address HCV treatment-related age and insurance disparities.
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Affiliation(s)
- Lauren D. Nephew
- Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of MedicineIndianapolisIndianaUSA,Indiana University Simon Comprehensive Cancer CenterIndianapolisIndianaUSA
| | - Yumin Wang
- Department of BiostatisticsIndiana University Fairbanks School of Public Health and School of MedicineIndianapolisIndianaUSA
| | - Kawthar Mohamed
- Department of MedicineIndiana University School of MedicineIndianapolisIndianaUSA
| | - Deborah Nichols
- Indiana Department of HealthDivision of HIV/STD and Viral HepatitisIndianapolisIndianaUSA
| | - Susan M. Rawl
- Indiana University Simon Comprehensive Cancer CenterIndianapolisIndianaUSA,Indiana University School of NursingIndianapolisIndianaUSA
| | - Eric Orman
- Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of MedicineIndianapolisIndianaUSA
| | - Archita P. Desai
- Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of MedicineIndianapolisIndianaUSA
| | - Kavish R. Patidar
- Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of MedicineIndianapolisIndianaUSA
| | - Marwan Ghabril
- Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of MedicineIndianapolisIndianaUSA
| | - Naga Chalasani
- Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of MedicineIndianapolisIndianaUSA
| | - Monica L. Kasting
- Indiana University Simon Comprehensive Cancer CenterIndianapolisIndianaUSA,Department of Public HealthPurdue UniversityWest LafayetteIndianaUSA
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Kilany S, Ata L, Gomaa A, Sabry A, Nada A, Tharwa ES, Badra G, Abogabal A, Elwaraky M, Moaz E, Ezzat S, Elsharawy A, Waked I. Decreased Incidence of Hepatocellular Carcinoma after Directly Acting Antiviral Therapy in Patients with Hepatitis C-Related Advanced Fibrosis and Cirrhosis. J Hepatocell Carcinoma 2021; 8:925-935. [PMID: 34408991 PMCID: PMC8367200 DOI: 10.2147/jhc.s295330] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 05/06/2021] [Indexed: 01/03/2023] Open
Abstract
Background and Aim Existing data are controversial regarding the incidence of hepatitis C (HCV)-related hepatocellular carcinoma (HCC) following directly acting antiviral (DAA) therapy. This prospective study aimed to assess incidence, and risk factorss of HCC following DAA therapy in patients with HCV-related advanced fibrosis (F3) and cirrhosis (F4). Methods Incidence of HCC was calculated in 1,630 patients with HCV-related F3 and F4 treated with DAA prospectively followed for up to 43 months in a single tertiary referral center and compared to historical controls. Risk factors of incident HCC were also determined. Results The crude outcome rate was 2.15/100 person-years, significantly lower than a similar historical cohort (5.57/100 person-years). Risk of developing HCC was higher with the presence of cirrhosis (F4 vs F3, AHR 3.59) and treatment failure (vs achieving SVR, AHR 3.37). Presence of decompensated cirrhosis, platelet count <100×103/mL, and high AFP were independent risk factors of developing HCC. Conclusion Incidence of HCC was significantly lower in patients with HCV-related advanced fibrosis and cirrhosis treated with DAAs than in a historical cohort of untreated patients. Decompensated cirrhosis, baseline AFP ≥10 ng/mL, diabetes, and nonresponse to DAA were independent risk factors of incident HCC.
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Affiliation(s)
- Shimaa Kilany
- Hepatology and Gastroenterology Department, National Liver Institute, Menoufia University, Menoufia, Egypt
| | - Lmyaa Ata
- Hepatology and Gastroenterology Department, National Liver Institute, Menoufia University, Menoufia, Egypt
| | - Asmaa Gomaa
- Hepatology and Gastroenterology Department, National Liver Institute, Menoufia University, Menoufia, Egypt
| | - Aliaa Sabry
- Hepatology and Gastroenterology Department, National Liver Institute, Menoufia University, Menoufia, Egypt
| | - Ali Nada
- Hepatology and Gastroenterology Department, National Liver Institute, Menoufia University, Menoufia, Egypt
| | - El-Sayed Tharwa
- Hepatology and Gastroenterology Department, National Liver Institute, Menoufia University, Menoufia, Egypt
| | - Gamal Badra
- Hepatology and Gastroenterology Department, National Liver Institute, Menoufia University, Menoufia, Egypt
| | - Ashraf Abogabal
- Hepatology and Gastroenterology Department, National Liver Institute, Menoufia University, Menoufia, Egypt
| | - Mohamed Elwaraky
- Radiology Department, National Liver Institute, Menoufia University, Menoufia, Egypt
| | - Enas Moaz
- Epidemiology Department, National Liver Institute, Menoufia University, Menoufia, Egypt
| | - Sameera Ezzat
- Epidemiology Department, National Liver Institute, Menoufia University, Menoufia, Egypt
| | - Ahmed Elsharawy
- Clinical Pathology Department, National Liver Institute, Menoufia University, Menoufia, Egypt
| | - Imam Waked
- Hepatology and Gastroenterology Department, National Liver Institute, Menoufia University, Menoufia, Egypt
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Lee RT, Yang P, Alahmadi A, McQuade J, Yuan E, Difeo A, Narla G, Kaseb A. Mistletoe Extract Viscum Fraxini-2 for Treatment of Advanced Hepatocellular Carcinoma: A Case Series. Case Rep Oncol 2021; 14:224-231. [PMID: 33776708 PMCID: PMC7983630 DOI: 10.1159/000511566] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 09/10/2020] [Indexed: 01/10/2023] Open
Abstract
Background Hepatocellular carcinoma (HCC) is the fourth leading cause of death from cancer worldwide, and for advanced HCC the prognosis is poor. Preliminary studies indicate mistletoe extracts may have anticancer activity for HCC. Methods A prospective observational case series of advanced HCC patients that chose to take a mistletoe extract called viscum fraxini-2 (VF-2) alone for treatment. Time on treatment, imaging, and laboratory values were collected for descriptive analyses. Results A total of 12 patients with advanced HCC enrolled onto the protocol, and 10 patients had data available for evaluation. The majority were male (10/12) with a median age of 64 (SD 11). Most patients had received sorafenib therapy (9/12) and had varying Child-Pugh classes (A-4, B-6, C-2). Treatment with VF-2 ranged from 1 to 36 weeks with a mean of 12.3 weeks (SD 12). Six patients received 8 weeks of treatment, and 3 patients received 12 or more weeks of treatment. For patients that received at least 4 weeks of treatment, the average AFP value stabilized during the first 4 weeks of treatment. Two patients experienced an AFP decrease of >30%, approximately 37 and 40% decreases at the nadir. One patient had stable disease of 9 months. Major side effects were fever, fatigue, rash, and local injection site reaction of swelling, redness, and tenderness. Conclusion This case series of advanced HCC indicates that mistletoe extract VF-2 may have potential biological activity against HCC for selected patients. Research is needed to identify the active compound and predictive markers of response.
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Affiliation(s)
- Richard T Lee
- Department of Medicine, University Hospitals Cleveland Medical Center & Case Western Reserve University, Cleveland, Ohio, USA
| | - Peiying Yang
- Department of Palliative, Rehabilitation, and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Asrar Alahmadi
- Department of Medicine, University Hospitals Cleveland Medical Center & Case Western Reserve University, Cleveland, Ohio, USA
| | - Jennifer McQuade
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Eric Yuan
- Department of Medicine, University Hospitals Cleveland Medical Center & Case Western Reserve University, Cleveland, Ohio, USA
| | - Analisa Difeo
- Departments of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan, USA
| | - Goutham Narla
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Ahmed Kaseb
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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Change in γ-glutamyl transpeptidase activity as a useful tool in identifying a group of patients with elevated risk of hepatocellular carcinoma development after DAA treatment of chronic hepatitis C. Clin Exp Hepatol 2021; 7:93-100. [PMID: 34027121 PMCID: PMC8122098 DOI: 10.5114/ceh.2021.104466] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 12/16/2020] [Indexed: 12/30/2022] Open
Abstract
Aim of the study Hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) incidence will be diminishing due to use of direct acting antiviral agents (DAA), but there is still constant risk for HCC development. Elevated serum g-glutamyl transpeptidase (GGT) activity is associated with increased risk of liver cancer. In our study we tried to determine whether change in GGT activity may be useful in identifying patients with elevated risk of HCC development after DAA treatment. Material and methods The study population consisted of 111 patients with chronic hepatitis C (CHC) treated with DAA. Laboratory tests [alanine aminotransferase (ALT), GGT, a-fetoprotein (AFP)] and liver stiffness measurement (using FibroScan) were performed at the beginning and at the end of therapy. Results Pre-treatment ALT activity, GGT activity and AFP concentration in patients with CHC were directly associated with the stage of liver fibrosis. Elimination of HCV after DAA treatment caused significant reduction in serum GGT activity and was not associated with pre-treatment liver fibrosis. AFP concentration was significantly lower after treatment. It was observed regardless of pre-treatment AFP concentration, but the largest reduction was demonstrated in the group of patients with advanced fibrosis. In multivariate analysis there was no significant difference in GGT activity after treatment only in patients with pre-treatment normal AFP concentration and advanced liver fibrosis. Conclusions Patients who after achieving a sustained virological response (SVR) did not lower both AFP concentration and GGT activity may have higher risk of HCC development. Special monitoring may be required in patients with advanced liver fibrosis and normal AFP concentration before treatment.
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Sepulveda-Crespo D, Resino S, Martinez I. Strategies Targeting the Innate Immune Response for the Treatment of Hepatitis C Virus-Associated Liver Fibrosis. Drugs 2021; 81:419-443. [PMID: 33400242 DOI: 10.1007/s40265-020-01458-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Direct-acting antivirals eliminate hepatitis C virus (HCV) in more than 95% of treated individuals and may abolish liver injury, arrest fibrogenesis, and reverse fibrosis and cirrhosis. However, liver regeneration is usually a slow process that is less effective in the late stages of fibrosis. What is more, fibrogenesis may prevail in patients with advanced cirrhosis, where it can progress to liver failure and hepatocellular carcinoma. Therefore, the development of antifibrotic drugs that halt and reverse fibrosis progression is urgently needed. Fibrosis occurs due to the repair process of damaged hepatic tissue, which eventually leads to scarring. The innate immune response against HCV is essential in the initiation and progression of liver fibrosis. HCV-infected hepatocytes and liver macrophages secrete proinflammatory cytokines and chemokines that promote the activation and differentiation of hepatic stellate cells (HSCs) to myofibroblasts that produce extracellular matrix (ECM) components. Prolonged ECM production by myofibroblasts due to chronic inflammation is essential to the development of fibrosis. While no antifibrotic therapy is approved to date, several drugs are being tested in phase 2 and phase 3 trials with promising results. This review discusses current state-of-the-art knowledge on treatments targeting the innate immune system to revert chronic hepatitis C-associated liver fibrosis. Agents that cause liver damage may vary (alcohol, virus infection, etc.), but fibrosis progression shows common patterns among them, including chronic inflammation and immune dysregulation, hepatocyte injury, HSC activation, and excessive ECM deposition. Therefore, mechanisms underlying these processes are promising targets for general antifibrotic therapies.
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Affiliation(s)
- Daniel Sepulveda-Crespo
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda-Pozuelo, Km 2.2, 28220, Majadahonda, Madrid, Spain
| | - Salvador Resino
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda-Pozuelo, Km 2.2, 28220, Majadahonda, Madrid, Spain.
| | - Isidoro Martinez
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda-Pozuelo, Km 2.2, 28220, Majadahonda, Madrid, Spain.
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10
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Janjua NZ, Wong S, Darvishian M, Butt ZA, Yu A, Binka M, Alvarez M, Woods R, Yoshida EM, Ramji A, Feld J, Krajden M. The impact of SVR from direct-acting antiviral- and interferon-based treatments for HCV on hepatocellular carcinoma risk. J Viral Hepat 2020; 27:781-793. [PMID: 32187430 DOI: 10.1111/jvh.13295] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2019] [Revised: 02/02/2020] [Accepted: 02/17/2020] [Indexed: 12/12/2022]
Abstract
We evaluated the effect of sustained virologic response (SVR) from direct-acting antiviral (DAA)- and interferon-based treatments on hepatocellular carcinoma (HCC) risk in a large population-based cohort in Canada. We used data from the BC Hepatitis Testers Cohort, which includes ~1.3 million individuals tested for HCV since 1990, linked with healthcare administrative and registry datasets. Patients were followed from the end of HCV treatment to HCC, death or 31 December 2016. We assessed HCC risk among those who did and did not achieve SVR by treatment type using proportional hazard models. Of 12 776 eligible individuals, 3905 received DAAs while 8871 received interferon-based treatments, followed for a median of 1.0 [range: 0.6-2.7] and 7.9 [range: 4.4-17.1] years, respectively. A total of 3613 and 6575 achieved SVR with DAAs- and interferon-based treatments, respectively. Among DAAs-treated patients, HCC incidence rate was 6.9 (95%CI: 4.7-10.1)/1000 person yr (PY) in SVR group (HCC cases: 26) and 38.2 (95%CI: 20.6-71.0) in the no-SVR group (HCC cases: 10, P < .001). Among interferon-treated individuals, HCC incidence rate was 1.8 (95%CI: 1.5-2.2) in the SVR (HCC cases: 99) and 13.9 (95%CI: 12.3-15.8) in the no-SVR group (HCC cases: 239, P < .001). Compared with no-SVR from interferon, SVR from DAA- and interferon-based treatments resulted in significant reduction in HCC risk (adjusted subdistribution hazard ratio (adjSHR) DAA = 0.30, 95%CI: 0.19-0.48 and adjSHR interferon = 0.2, 95%CI: 0.16-0.26). Among those with SVR, treatment with DAAs compared to interferon was not associated with HCC risk (adjSHR = 0.93, 95%CI: 0.51-1.71). In conclusion, similar to interferon era, DAA-related SVR is associated with 70% reduction in HCC risk.
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Affiliation(s)
- Naveed Z Janjua
- British Columbia Centre for Disease Control, Vancouver, BC, Canada.,School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada
| | - Stanley Wong
- British Columbia Centre for Disease Control, Vancouver, BC, Canada
| | - Maryam Darvishian
- British Columbia Centre for Disease Control, Vancouver, BC, Canada.,School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada.,BC Cancer, Vancouver, BC, Canada
| | - Zahid A Butt
- British Columbia Centre for Disease Control, Vancouver, BC, Canada.,School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada
| | - Amanda Yu
- British Columbia Centre for Disease Control, Vancouver, BC, Canada
| | - Mawuena Binka
- British Columbia Centre for Disease Control, Vancouver, BC, Canada
| | - Maria Alvarez
- British Columbia Centre for Disease Control, Vancouver, BC, Canada
| | | | - Eric M Yoshida
- Division of Gastroenterology, University of British Columbia, Vancouver, BC, Canada
| | - Alnoor Ramji
- Division of Gastroenterology, University of British Columbia, Vancouver, BC, Canada
| | - Jordan Feld
- Toronto Centre for Liver Disease, Sandra Rotman Centre for Global Health, Toronto General Hospital, University of Toronto, Toronto, ON, Canada
| | - Mel Krajden
- British Columbia Centre for Disease Control, Vancouver, BC, Canada.,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
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11
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Luo Y, Zhang Y, Wang D, Shen D, Che YQ. Eradication of Hepatitis C Virus (HCV) Improves Survival of Hepatocellular Carcinoma Patients with Active HCV Infection - A Real-World Cohort Study. Cancer Manag Res 2020; 12:5323-5330. [PMID: 32753950 PMCID: PMC7345970 DOI: 10.2147/cmar.s254580] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 06/15/2020] [Indexed: 12/12/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) caused by hepatitis C virus (HCV) infection has become less and less due to the use of direct-acting antiviral agents (DAAs). Although it may be common to assume that eradication of the virus should improve the survival of HCC patients, large-scale randomized clinical data to support the correlation between viral load and prognosis are still lacking in China. The aim of the study was to evaluate the efficacy of antiviral therapy for HCC patients with active HCV infection. Patients and Methods We retrospectively enrolled 80 HCC patients with active HCV infection. Active HCV infection was defined as positive for HCV antibody with detectable HCV RNA by polymerase chain reaction. Results Forty-four patients (55.0%) received interferon combined with ribavirin treatment and 23 patients achieved sustained virological response (SVR). The 1-year survival rate in patients who achieved SVR was the highest, followed by those with non-SVR after antiviral treatment, and those without antiviral therapy (1-year survival rate were 91.3%, 88.4%, and 73.1%, respectively, P = 0.012). In the univariate analysis, alcohol intake and alpha-fetoprotein >20 ng/mL were associated with lower overall survival (OS) (P = 0.025 and P = 0.044, respectively), while SVR after antiviral treatment was associated with longer OS (P = 0.016). In the multivariate analysis, only SVR after antiviral treatment was significantly associated with OS (P = 0.014). Conclusion Our results ensured that the elimination of HCV substantially improved OS in HCC patients with active HCV infection, and the prognosis of those patients without antiviral therapy was poor.
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Affiliation(s)
- Yang Luo
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, People's Republic of China
| | - Yue Zhang
- Department of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, People's Republic of China
| | - Di Wang
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, People's Republic of China
| | - Di Shen
- Department of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, People's Republic of China
| | - Yi-Qun Che
- Department of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, People's Republic of China
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12
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Origin and role of hepatic myofibroblasts in hepatocellular carcinoma. Oncotarget 2020; 11:1186-1201. [PMID: 32284794 PMCID: PMC7138168 DOI: 10.18632/oncotarget.27532] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Accepted: 03/03/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is the second leading cause of cancer-related death worldwide. Fibrosis and cirrhosis are important risk factors for the development of HCC. Hepatic myofibroblasts are the cells responsible for extracellular matrix deposition, which is the hallmark of liver fibrosis. It is believed that myofibroblasts are predominantly derived from hepatic stellate cells (HSCs), also known as Ito cells. Nevertheless, depending on the nature of insult to the liver, it is thought that myofibroblasts may also originate from a variety of other cell types such as the portal fibroblasts (PFs), fibrocytes, hepatocytes, hepatic progenitor cells (HPCs), and mesothelial cells. Liver myofibroblasts are believed to transform into cancer-associated fibroblasts (CAFs) while HCC is developing. There is substantial evidence suggesting that activated HSCs (aHSCs)/cancer-associated fibroblasts (CAFs) may play an important role in HCC initiation and progression. In this paper, we aim to review current literature on cellular origins of myofibroblasts with a focus on hepatitis B virus (HBV)- and hepatitis C virus (HCV)-induced hepatic fibrosis. We also address the role of aHSCs/CAFs in HCC progression through the regulation of immune cells as well as mechanisms of evolvement of drug resistance.
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13
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Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is the second leading cause of cancer-related death worldwide. Fibrosis and cirrhosis are important risk factors for the development of HCC. Hepatic myofibroblasts are the cells responsible for extracellular matrix deposition, which is the hallmark of liver fibrosis. It is believed that myofibroblasts are predominantly derived from hepatic stellate cells (HSCs), also known as Ito cells. Nevertheless, depending on the nature of insult to the liver, it is thought that myofibroblasts may also originate from a variety of other cell types such as the portal fibroblasts (PFs), fibrocytes, hepatocytes, hepatic progenitor cells (HPCs), and mesothelial cells. Liver myofibroblasts are believed to transform into cancer-associated fibroblasts (CAFs) while HCC is developing. There is substantial evidence suggesting that activated HSCs (aHSCs)/cancer-associated fibroblasts (CAFs) may play an important role in HCC initiation and progression. In this paper, we aim to review current literature on cellular origins of myofibroblasts with a focus on hepatitis B virus (HBV)- and hepatitis C virus (HCV)-induced hepatic fibrosis. We also address the role of aHSCs/CAFs in HCC progression through the regulation of immune cells as well as mechanisms of evolvement of drug resistance.
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14
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Chun HS, Kim BK, Park JY, Kim DY, Ahn SH, Han KH, Lee CH, Lee YB, Cho EJ, Yu SJ, Kim YJ, Yoon JH, Lee JH, Kim SU. Design and validation of risk prediction model for hepatocellular carcinoma development after sustained virological response in patients with chronic hepatitis C. Eur J Gastroenterol Hepatol 2020; 32:378-385. [PMID: 32011388 DOI: 10.1097/meg.0000000000001512] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
OBJECTIVES Hepatocellular carcinoma can develop after hepatitis C virus eradication. We developed a new hepatocellular carcinoma risk score (HCC-SVR score) based on independent predictors for chronic hepatitis C after sustained virological response. METHODS Between 2003 and 2016, a total of 1193 patients with chronic hepatitis C who achieved sustained virological response through antiviral therapy were included (669 for training cohort and 524 for validation cohort). The HCC-SVR score was developed using multivariate Cox proportional hazards regression modelling. RESULTS Hepatocellular carcinoma (n = 19) occurred more frequently in older, male patients and was associated with liver cirrhosis; hypertension; diabetes; lower platelet count; higher alpha-fetoprotein, aspartate, and alanine aminotransferase; lower total cholesterol; and higher fibrosis-4 index (FIB-4) (all P < 0.05). FIB-4 (hazard ratio = 1.080), male gender (hazard ratio = 8.189), and higher alpha-fetoprotein (hazard ratio = 1.060) independently predicted hepatocellular carcinoma (all P < 0.05). HCC-SVR score successfully predicted hepatocellular carcinoma development risk [area under receiver operating characteristic curve (AUC) = 0.771, 0.857, and 0.911 at 2, 4, and 6 years, respectively]. The cumulative incidence rate of hepatocellular carcinoma differed significantly among groups stratified by HCC-SVR risk score (0-2 points, low; 3-7 points, intermediate; 8-9 points, high risk) (all P < 0.05 by log-rank test). HCC-SVR score was maintained in a validation cohort (n = 524) (AUC = 0.728 at 2 years, 0.737 at 4 years, and 0.809 at 6 years). CONCLUSION The HCC-SVR score enables risk stratification for hepatocellular carcinoma development at sustained virological response in patients with chronic hepatitis C.
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Affiliation(s)
- Ho Soo Chun
- Department of Internal Medicine, Yonsei University College of Medicine
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine
- Yonsei Liver Center, Severance Hospital
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine
- Yonsei Liver Center, Severance Hospital
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine
- Yonsei Liver Center, Severance Hospital
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine
- Yonsei Liver Center, Severance Hospital
| | - Kwang-Hyub Han
- Department of Internal Medicine, Yonsei University College of Medicine
- Yonsei Liver Center, Severance Hospital
| | - Cheol-Hyung Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Yun Bin Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Eun Ju Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Su Jong Yu
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Yoon Jun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jung-Hwan Yoon
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jeong-Hoon Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine
- Yonsei Liver Center, Severance Hospital
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15
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Cullaro G, Rubin JB, Mehta N, Lai JC. Differential Impact of Age Among Liver Transplant Candidates With and Without Hepatocellular Carcinoma. Liver Transpl 2020; 26:349-358. [PMID: 31610089 PMCID: PMC7036008 DOI: 10.1002/lt.25662] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Accepted: 10/07/2019] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma (HCC) is the fastest-rising cause of cancer-related mortality in the United States and is a leading indication for liver transplantation (LT). Changes have been noted in the age of the population with chronic liver disease, but how this change affects patients with HCC is unknown. This study aims to characterize trends and transplant-associated outcomes among patients ≥65 years old listed for LT with HCC. Using the United Network for Organ Sharing database, we analyzed all patients ≥18 years old listed for LT during 2003-2017 in the United States in 2 groups (<65 or ≥65 years). Time trends between HCC and non-HCC patients were compared and stratified by disease etiology. Competing-risks and Cox proportional hazards regressions associated HCC and age with wait-list and post-LT survival. There were 161,724 LT candidates included: 14% were ≥65 years old at listing and 25% had HCC. The proportion of patients ≥65 years old rose significantly faster among those with HCC, as compared with those without HCC (Δ = 0.80; P < 0.001). Age ≥65 years was significantly associated with both wait-list mortality (adjusted subhazard ratio, 1.51; 95% confidence interval [CI], 1.40-1.64) and post-LT mortality (adjusted hazard ratio, 1.50; 95% CI, 1.41-1.60) in the multivariate analysis. There were significant interactions between age and HCC on both wait-list (P < 0.001) and post-LT mortality (P = 0.04), suggesting that older age does not impact patients with HCC as much as patients without HCC. The proportion of older adults with HCC listed for LT has nearly tripled from 2003 to 2017, and the rapidly growing population of older adults with HCC may provide an opportunity to expand LT access without compromising outcomes.
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Affiliation(s)
- Giuseppe Cullaro
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California-San Francisco, San Francisco, CA
| | - Jessica B. Rubin
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California-San Francisco, San Francisco, CA
| | - Neil Mehta
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California-San Francisco, San Francisco, CA
| | - Jennifer C. Lai
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California-San Francisco, San Francisco, CA
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Abou-Alfa GK, Jarnagin W, El Dika I, D'Angelica M, Lowery M, Brown K, Ludwig E, Kemeny N, Covey A, Crane CH, Harding J, Shia J, O'Reilly EM. Liver and Bile Duct Cancer. ABELOFF'S CLINICAL ONCOLOGY 2020:1314-1341.e11. [DOI: 10.1016/b978-0-323-47674-4.00077-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Abstract
Introduction: Liver cirrhosis is the most deleterious consequence of chronic liver diseases of different etiologies. Progression of liver diseases to cirrhosis, irrespective of etiology, involves chronic parenchymal injury, persistent activation of inflammatory response, sustained activation of fibrogenesis and wound-healing response. Despite intensive research on antifibrotic drugs, novel therapeutics specifically for liver have not been yet licensed. This review will examine compounds currently under development and key challenges in specific settings as for example that of NAFLD associated fibrosis.Areas covered: Results of the main phase II and III trial, including those with negative results, are presented and discussed. The endpoints selected and their limitations highlighted in order to suggest potential options to move forward.Expert opinion: Strategies based on single-molecule targets, associated so far with some disappointing results, may be unlikely to succeed in the context of such complex pathogenesis. Blocking at the same time different pathways that drive fibrosis progression may be required to provide significant benefit.
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Affiliation(s)
- Rosanna Santoro
- Liver Unit, IRCCS "Ospedale Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy
| | - Alessandra Mangia
- Liver Unit, IRCCS "Ospedale Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy
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18
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Kasting ML, Giuliano AR, Reich RR, Duong LM, Rathwell J, Roetzheim RG, Vadaparampil ST. Electronic medical record-verified hepatitis C virus screening in a large health system. Cancer Med 2019; 8:4555-4564. [PMID: 31225703 PMCID: PMC6712519 DOI: 10.1002/cam4.2247] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Revised: 04/10/2019] [Accepted: 05/03/2019] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Baby boomers are at increased risk for hepatitis C virus (HCV) infection and related cancer; therefore, one-time HCV screening is recommended. METHODS To assess prevalence of, and factors associated with providers ordering HCV screening, we examined a retrospective cohort of electronic medical records for patient visits from 01 August 2015 until 31 July 2017 in a large health system. HCV screening ordered was examined by patient age, gender, race/ethnicity, provider specialty, and number of clinical visits, stratified by birth cohort: born ≤1945, 1945-1965 (baby boomers), 1966-1985, and ≥1985. Multivariable regression identified factors independently associated with HCV screening ordered among average risk baby boomers. RESULTS A total of 65 114 patients ages ≥18 years were evaluated. Among baby boomers HCV screening test order increased threefold between the two study years (4.0%-12.9%). Odds of screening test ordered were significantly higher for non-Hispanic Blacks (multivariable adjusted odds ratio [aOR]=1.36; 95% CI = 1.19-1.55), males (aOR = 1.44; 95% CI = 1.33-1.57), and having a clinic visit with a primary care provider alone or with specialty care (aOR = 3.25-4.16). Medicare (aOR = 0.89; 95% CI = 0.80-0.99), Medicaid (aOR 0.89; 95% CI 0.80-0.99), and an unknown provider type (aOR = 0.16; 95% CI = 0.08-0.33), were associated with lower odds of screening tests ordered. CONCLUSIONS While the proportion of baby boomers with an HCV screening test ordered increased during the study, the rate of screening remains far below national goals. Data from this study indicate that providers are not ordering HCV screening universally for all of their baby boomer patients. Continued efforts to increase HCV screening are needed to reduce the incidence of HCV-related morbidity and mortality.
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Affiliation(s)
- Monica L. Kasting
- Department of Health and KinesiologyPurdue UniversityWest LafayetteIndiana
| | - Anna R. Giuliano
- Department of Cancer EpidemiologyMoffitt Cancer CenterTampaFlorida
- Center for Immunization and Infection Research in CancerMoffitt Cancer CenterTampaFlorida
| | - Richard R. Reich
- Department of Biostatistics and BioinformaticsMoffitt Cancer CenterTampaFlorida
| | - Linh M. Duong
- Department of Health Outcomes and BehaviorMoffitt Cancer CenterTampaFlorida
- Department of Epidemiology and BiostatisticsUniversity of South FloridaTampaFlorida
| | - Julie Rathwell
- Department of Cancer EpidemiologyMoffitt Cancer CenterTampaFlorida
- Center for Immunization and Infection Research in CancerMoffitt Cancer CenterTampaFlorida
| | - Richard G. Roetzheim
- Department of Health Outcomes and BehaviorMoffitt Cancer CenterTampaFlorida
- Department of Family MedicineUniversity of South FloridaTampaFlorida
| | - Susan T. Vadaparampil
- Center for Immunization and Infection Research in CancerMoffitt Cancer CenterTampaFlorida
- Department of Health Outcomes and BehaviorMoffitt Cancer CenterTampaFlorida
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19
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Tamaki N, Higuchi M, Kurosaki M, Kirino S, Osawa L, Watakabe K, Wang W, Okada M, Shimizu T, Takaura K, Takada H, Kaneko S, Yasui Y, Tsuchiya K, Nakanishi H, Itakura J, Takahashi Y, Enomoto N, Izumi N. Risk assessment of hepatocellular carcinoma development by magnetic resonance elastography in chronic hepatitis C patients who achieved sustained virological responses by direct-acting antivirals. J Viral Hepat 2019; 26:893-899. [PMID: 30974045 DOI: 10.1111/jvh.13103] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 03/05/2019] [Accepted: 03/11/2019] [Indexed: 01/02/2023]
Abstract
Prediction of hepatocellular carcinoma (HCC) development after sustained virological response (SVR) is clinically important, and the usefulness of noninvasive markers for prediction HCC have been reported. The aim of this study was to compare the prediction accuracy for HCC development by noninvasive markers. A total of 346 patients with chronic hepatitis C without history of HCC who achieved SVR through direct-acting antivirals were included. Magnetic resonance elastography (MRE) and serum fibrosis markers were measured 12 weeks after the end of treatment, and the subsequent HCC development was examined. The mean observation period was 26.4 ± 7.9 months, and 24 patients developed HCC. Area under the receiver operating characteristic curve of liver stiffness by MRE, Wisteria floribunda agglutinin-positive mac-2 binding protein and FIB-4 for predicting HCC within 3 years was 0.743, 0.697 and 0.647, respectively. The 1/2/3-year rates of HCC development in patients with liver stiffness ≥3.75 KPa were 6.6%, 11.9% and 14.5%, whereas they were 1.4%, 2.5% and 2.5% in patients with liver stiffness <3.75 KPa (P < 0.001). Multivariate analysis revealed that liver stiffness ≥3.75 was an independent predictive factor for HCC development (hazard ratio, 3.51; 95% confidence interval, 1.24-9.99). In subgroup analysis, there were 132 patients who were <73 years old and had liver stiffness <3.75 KPa, and no HCC development was observed in these patients. Diagnostic accuracy for predicting HCC development was higher in MRE than serum fibrosis markers and measurement of liver stiffness by MRE could identify patients with high and low risk of HCC development after SVR.
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Affiliation(s)
- Nobuharu Tamaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan.,First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Japan
| | - Mayu Higuchi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Sakura Kirino
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Leona Osawa
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Keiya Watakabe
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Wan Wang
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Mao Okada
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Takao Shimizu
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Kenta Takaura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Hitomi Takada
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan.,First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Japan
| | - Shun Kaneko
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Yutaka Yasui
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Kaoru Tsuchiya
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Hiroyuki Nakanishi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Jun Itakura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Yuka Takahashi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Nobuyuki Enomoto
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
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20
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Morimoto N, Miura K, Watanabe S, Tsukui M, Takaoka Y, Nomoto H, Murayama K, Hirosawa T, Goka R, Kunitomo N, Nakamura H, Sugimoto H, Isoda N, Yamamoto H. Usefulness of Gd-EOB-DTPA-enhanced MRI for evaluating the potential for early development of hepatocellular carcinoma after HCV eradication by direct-acting antiviral treatment. J Rural Med 2019; 14:78-86. [PMID: 31191770 PMCID: PMC6545425 DOI: 10.2185/jrm.2993] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Accepted: 12/07/2018] [Indexed: 12/27/2022] Open
Abstract
Objective: The development of hepatocellular carcinoma (HCC) is not uncommon in patients who achieve eradication of the hepatitis C virus through direct-acting antiviral (DAA) treatment. The aim of this study was to identify the patients at high risk for novel HCC development after a sustained virologic response (SVR) by DAA treatment. Patients and Methods: A total of 518 patients with no history of HCC treatment and who achieved SVR by DAA treatment were evaluated retrospectively. The correlations between HCC development and the patients' characteristics were evaluated. For patients who underwent gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) or dynamic contrast-enhanced computed tomography, the relationship between the imaging findings and subsequent HCC development was also assessed. Results: HCC developed newly in 22 patients, and the 1-year and 3-year cumulative HCC rates were 2.0% and 8.5%, respectively. In multivariate analysis, a FIB-4 index >4.0 and a post-treatment α-fetoprotein >4.0 ng/ml were significant risk factors for HCC. In 26 of 118 patients who underwent an MRI before DAA treatment, a non-hypervascular hypo-intense nodule was seen in the hepatobiliary phase, and in 6 of 182 patients who underwent a CT, a non-hypervascular hypo-enhanced nodule was seen in the delayed phase. The sensitivity and specificity of the MRI-positive findings for the subsequent development of HCC were 0.92 and 0.87, respectively, and those of the CT were 0.40 and 0.99, respectively. In multivariate analysis of patients who underwent an MRI, a non-hypervascular hypo-intense nodule was the only factor that was significantly related to HCC development (HR 32.4, p = 0.001). Conclusion: Gd-EOB-DTPA-enhanced MRI was found to be reliable for risk evaluation of subsequent HCC development in patients after SVR by DAA treatment. Patients with a non-hypervascular hypo-intense nodule need more careful observation for incident HCC.
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Affiliation(s)
- Naoki Morimoto
- Department of Medicine, Division of Gastroenterology, Jichi Medical University, Japan
| | - Kouichi Miura
- Department of Medicine, Division of Gastroenterology, Jichi Medical University, Japan
| | - Shunji Watanabe
- Department of Medicine, Division of Gastroenterology, Jichi Medical University, Japan
| | - Mamiko Tsukui
- Department of Medicine, Division of Gastroenterology, Jichi Medical University, Japan
| | - Yoshinari Takaoka
- Department of Medicine, Division of Gastroenterology, Jichi Medical University, Japan
| | - Hiroaki Nomoto
- Department of Medicine, Division of Gastroenterology, Jichi Medical University, Japan
| | - Kozue Murayama
- Department of Medicine, Division of Gastroenterology, Jichi Medical University, Japan
| | - Takuya Hirosawa
- Department of Medicine, Division of Gastroenterology, Jichi Medical University, Japan
| | - Rie Goka
- Department of Medicine, Division of Gastroenterology, Jichi Medical University, Japan
| | - Naoki Kunitomo
- Department of Radiology, Jichi Medical University, Japan
| | | | | | - Norio Isoda
- Department of Medicine, Division of Gastroenterology, Jichi Medical University, Japan
| | - Hironori Yamamoto
- Department of Medicine, Division of Gastroenterology, Jichi Medical University, Japan
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21
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Flynn MJ, Sayed AA, Sharma R, Siddique A, Pinato DJ. Challenges and Opportunities in the Clinical Development of Immune Checkpoint Inhibitors for Hepatocellular Carcinoma. Hepatology 2019; 69:2258-2270. [PMID: 30382576 DOI: 10.1002/hep.30337] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 10/19/2018] [Indexed: 12/14/2022]
Abstract
After a decade of stagnation in drug development, therapeutic reversal of immune-exhaustion with immune checkpoint inhibitors (ICPIs) has been shown to be effective in advanced hepatocellular carcinoma (HCC). The clinical development of novel ICPIs continues at a rapid pace, with more than 50 clinical trials of immunotherapeutic agents registered as of May 2018 for this indication. The development of ICPI is particularly challenging in patients with HCC, a population with unique features which impact on safety and efficacy of immune-modulating therapies. In this review, we discuss the biological foundations supporting the development of ICPIs across the advancing stages of HCC, focusing on the rational positioning of ICPIs across the various Barcelona-Clinic Liver Cancer (BCLC) stages of the disease. Translational studies should guide adequate prioritization of those therapeutic agents and combination strategies which are most likely to achieve patient benefit based on solid mechanistic and clinical justifications.
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Affiliation(s)
- Michael J Flynn
- Department of Medicine, The Royal Marsden NHS Foundation Trust, London, United Kingdom
| | - Anwar A Sayed
- Centre for Haematology, Imperial College London, London, United Kingdom
- Department of Medical Microbiology and Immunology, Taibah University, Medina, Saudi Arabia
| | - Rohini Sharma
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, United Kingdom
| | - Abdul Siddique
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, United Kingdom
| | - David J Pinato
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, United Kingdom
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22
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Darvishian M, Janjua NZ, Chong M, Cook D, Samji H, Butt ZA, Yu A, Alvarez M, Yoshida E, Ramji A, Wong J, Woods R, Tyndall M, Krajden M. Estimating the impact of early hepatitis C virus clearance on hepatocellular carcinoma risk. J Viral Hepat 2018; 25:1481-1492. [PMID: 30047609 DOI: 10.1111/jvh.12977] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Revised: 06/04/2018] [Accepted: 07/03/2018] [Indexed: 12/15/2022]
Abstract
Although achieving sustained virological response (SVR) through antiviral therapy could reduce the risk of hepatocellular carcinoma (HCC) attributable to hepatitis C virus (HCV) infection, the impact of early viral clearance on HCC is not well defined. In this study, we compared the risk of HCC among individuals who spontaneously cleared HCV (SC), the referent population, with the risk in untreated chronic HCV (UCHC), those achieved SVR, and those who failed interferon-based treatment (TF). The BC Hepatitis Testers Cohort (BC-HTC) includes individuals tested for HCV between 1990-2013, integrated with medical visits, hospitalizations, cancers, prescription drugs and mortality data. This analysis included all HCV-positive patients with at least one valid HCV RNA by PCR on or after HCV diagnosis. Of 46 666 HCV-infected individuals, there were 12 527 (26.8%) SC; 24 794 (53.1%) UCHC; 5355 (11.5%) SVR and 3990 (8.5%) TF. HCC incidence was lowest (0.3/1000 person-years (PY)) in the SC group and highest in the TF group (7.7/1000 PY). In a multivariable model, compared to SC, TF had the highest HCC risk (hazard ratio (HR):14.52, 95% confidence interval (CI): 9.83-21.47), followed by UCHC (HR: 5.85; 95% CI: 4.07-8.41). Earlier treatment-based viral clearance similar to SC could decrease HCC incidence by 69.4% (95% CI: 57.5-78.0), 30% (95% CI: 10.8-45.1) and 77.5% (95% CI: 69.4-83.5) among UCHC, SVR and TF patients, respectively. In conclusion, using SC as a real-world comparator group, it showed that substantial reduction in HCC risk could be achieved with earlier treatment initiation. These analyses should be replicated in patients who have been treated with direct acting antiviral therapies.
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Affiliation(s)
- Maryam Darvishian
- British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada.,School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada
| | - Naveed Z Janjua
- British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada.,School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada
| | - Mei Chong
- British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada
| | - Darrel Cook
- British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada
| | - Hasina Samji
- British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada.,School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada
| | - Zahid A Butt
- British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada.,School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada
| | - Amanda Yu
- British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada
| | - Maria Alvarez
- British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada
| | - Eric Yoshida
- Division of Gastroenterology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Alnoor Ramji
- Division of Gastroenterology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.,GI Research Institute, Vancouver, British Columbia, Canada
| | - Jason Wong
- British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada.,School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada
| | - Ryan Woods
- British Columbia Cancer Agency, Vancouver, British Columbia, Canada
| | - Mark Tyndall
- British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada.,School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada
| | - Mel Krajden
- British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada.,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
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23
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O’Rourke JM, Sagar VM, Shah T, Shetty S. Carcinogenesis on the background of liver fibrosis: Implications for the management of hepatocellular cancer. World J Gastroenterol 2018; 24:4436-4447. [PMID: 30357021 PMCID: PMC6196335 DOI: 10.3748/wjg.v24.i39.4436] [Citation(s) in RCA: 112] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 09/03/2018] [Accepted: 10/05/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is now the second leading cause of cancer-related deaths globally and many patients have incurable disease. HCC predominantly occurs in the setting of liver cirrhosis and is a paradigm for inflammation-induced cancer. The causes of chronic liver disease promote the development of transformed or premalignant hepatocytes and predisposes to the development of HCC. For HCC to grow and progress it is now clear that it requires an immunosuppressive niche within the fibrogenic microenvironment of cirrhosis. The rationale for targeting this immunosuppression is supported by responses seen in recent trials with checkpoint inhibitors. With the impact of immunotherapy, HCC progression may be delayed and long term durable responses may be seen. This makes the management of the underlying liver cirrhosis in HCC even more crucial as studies demonstrate that measures of liver function are a major prognostic factor in HCC. In this review, we discuss the development of cancer in the setting of liver inflammation and fibrosis, reviewing the microenvironment that leads to this tumourigenic climate and the implications this has for patient management.
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Affiliation(s)
- Joanne Marie O’Rourke
- Centre for Liver Research, Institute of Biomedical Research, Birmingham B15 2TT, United Kingdom
- NIHR Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, United Kingdom
| | - Vandana Mridhu Sagar
- Centre for Liver Research, Institute of Biomedical Research, Birmingham B15 2TT, United Kingdom
- NIHR Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, United Kingdom
| | - Tahir Shah
- NIHR Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, United Kingdom
| | - Shishir Shetty
- Centre for Liver Research, Institute of Biomedical Research, Birmingham B15 2TT, United Kingdom
- NIHR Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, United Kingdom
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24
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Federico A, Dallio M, Caprio GG, de Sio I, Cotticelli G, Esposito P, Loguercio C. A Real-Life Study of New Antiviral Therapies in a High Prevalence Geographical Area for Hepatitis C Virus Infection. HEPATITIS MONTHLY 2018; In Press. [DOI: 10.5812/hepatmon.74224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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25
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Shirasaki T, Honda M, Yamashita T, Nio K, Shimakami T, Shimizu R, Nakasyo S, Murai K, Shirasaki N, Okada H, Sakai Y, Sato T, Suzuki T, Yoshioka K, Kaneko S. The osteopontin-CD44 axis in hepatic cancer stem cells regulates IFN signaling and HCV replication. Sci Rep 2018; 8:13143. [PMID: 30177680 PMCID: PMC6120883 DOI: 10.1038/s41598-018-31421-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Accepted: 08/15/2018] [Indexed: 12/17/2022] Open
Abstract
Osteopontin (OPN) is involved in cell proliferation, migration, inflammation, and tumor progression in various tissues. OPN induces stemness by interacting with CD44, but the functional relevance of OPN-mediated interferon (IFN) signaling and hepatitis C virus (HCV) replication in stem cell populations remains unclear. In this study, we investigated the effect of OPN on HCV replication and IFN signaling in cancer stem cells (CSCs) positive for epithelial cell adhesion molecule (EpCAM) and CD44. We show that the EpCAM+/CD44+ CSCs show marked HCV replication when compared to EpCAM−/CD44− cells. In addition, OPN significantly enhances this HCV replication in EpCAM+/CD44+ CSCs and markedly suppresses IFN-stimulated gene expression. The GSK-3β inhibitor BIO increases the EpCAM+/CD44+ CSC population and OPN expression and impairs IFN signaling via STAT1 degradation. Taken together, our data suggest that OPN enhances HCV replication in the EpCAM+/CD44+ CSCs, while it also negatively regulates the IFN signaling pathway via inhibition of STAT1 phosphorylation and degradation. Therefore, OPN may represent a novel therapeutic target for treating HCV-related hepatocellular carcinoma.
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Affiliation(s)
- Takayoshi Shirasaki
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.,Department of Advanced Medical Technology, Kanazawa University Graduate School of Health Medicine, Kanazawa, Japan
| | - Masao Honda
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan. .,Department of Advanced Medical Technology, Kanazawa University Graduate School of Health Medicine, Kanazawa, Japan.
| | - Taro Yamashita
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.,Department of General Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Kouki Nio
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Tetsuro Shimakami
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Ryougo Shimizu
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.,Department of Advanced Medical Technology, Kanazawa University Graduate School of Health Medicine, Kanazawa, Japan
| | - Saki Nakasyo
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.,Department of Advanced Medical Technology, Kanazawa University Graduate School of Health Medicine, Kanazawa, Japan
| | - Kazuhisa Murai
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.,Department of Advanced Medical Technology, Kanazawa University Graduate School of Health Medicine, Kanazawa, Japan
| | - Natsumi Shirasaki
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Hikari Okada
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Yoshio Sakai
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Tokiharu Sato
- Division of Molecular Cell Signaling, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Tetsuro Suzuki
- Department of Virology and Parasitology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Katsuji Yoshioka
- Division of Molecular Cell Signaling, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Shuichi Kaneko
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
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26
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Zhou H, Wang SC, Ma JM, Yu LQ, Jing JS. Sperm-Associated Antigen 5 Expression Is Increased in Hepatocellular Carcinoma and Indicates Poor Prognosis. Med Sci Monit 2018; 24:6021-6028. [PMID: 30157168 PMCID: PMC6126414 DOI: 10.12659/msm.911434] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Background Sperm-associated antigen 5 (SPAG5), a gene that encodes a mitotic spindle-associated protein, is closely related to tumor development and is involved in cell migration and proliferation. The objective of this research was to explore the clinical significance of SPAG5 expression in hepatocellular carcinoma (HCC) and the relationship between SPAG5 expression and HCC prognosis. Material/Methods Twenty pairs of fresh-frozen HCC samples and samples from 95 HCC patients in a tissue microarray were subjected to quantitative real-time reverse-transcription (qRT)-PCR and immunohistochemistry (IHC), respectively, to investigate the relationship between the expression of SPAG5 and the clinicopathological features of HCC patients. Results PCR data showed that the messenger RNA (mRNA) expression level of SPAG5 in HCC tissue specimens was higher than that in adjacent non-tumor tissue specimens (p<0.05). IHC analyses demonstrated that SPAG5 expression was significantly correlated with tumor grade (p=0.003), tumor number (p=0.009), vascular invasion (p=0.001), and TNM stage (p=0.001). Survival analysis and Kaplan-Meier curves showed that SPAG5 expression is an independent prognostic indicator for disease-free survival (p=0.017) and overall survival (p=0.016) in HCC patients. Conclusions Our results indicate that SPAG5 expression may be considered as an oncogenic biomarker and a novel predictor for HCC prognosis.
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Affiliation(s)
- Hua Zhou
- Department of Infectious Diseases, Jurong People's Hospital Affiliated to Jiangsu University, Zhenjiang, Jiangsu, China (mainland)
| | - Shun-Cai Wang
- Department of Infectious Diseases, Jurong People's Hospital Affiliated to Jiangsu University, Zhenjiang, Jiangsu, China (mainland)
| | - Jiu-Ming Ma
- Department of Infectious Diseases, Jurong People's Hospital Affiliated to Jiangsu University, Zhenjiang, Jiangsu, China (mainland)
| | - La-Qing Yu
- Department of Infectious Diseases, Jurong People's Hospital Affiliated to Jiangsu University, Zhenjiang, Jiangsu, China (mainland)
| | - Ji-Sheng Jing
- Department of Infectious Diseases, Jurong People's Hospital Affiliated to Jiangsu University, Zhenjiang, Jiangsu, China (mainland)
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27
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Jing J, Wang S, Ma J, Yu L, Zhou H. Elevated CTSL2 expression is associated with an adverse prognosis in hepatocellular carcinoma. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2018; 11:4035-4043. [PMID: 31949793 PMCID: PMC6962798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Accepted: 06/29/2018] [Indexed: 06/10/2023]
Abstract
OBJECTIVE Cathepsin V, also known as CTSL2, plays an important role in tumor development and progression. This study was designed to investigate the clinical significance of CTSL2 expression in hepatocellular carcinoma (HCC) and the relationship between CTSL2 expression and prognosis. METHODS Quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) were performed to determine the levels of CTSL2 mRNA and protein, respectively, in tumor tissue and matched non-tumor (NT) tissue. Moreover, the relationship between CTSL2 expression and hepatocellular carcinoma's clinicopathological features and survival was evaluated in HCC tissue. RESULTS The levels of CTSL2 mRNA and protein were increased in HCC tissue. Moreover, for HCC patients, a high level of CTSL2 protein was significantly correlated with tumor number (P = 0.008), pathological grade (P = 0.001), vascular invasion (P = 0.001), T (P = 0.001), and TNM stage (P = 0.006). A Kaplan-Meier analysis showed that elevated CTSL2 expression was correlated with shorter disease-free survival (DFS) (P < 0.001) and overall survival (OS) (P < 0.001). Furthermore, a multivariate analysis showed that CTSL2 expression was an independent prognostic factor for DFS (P = 0.032) and OS (P = 0.025). CONCLUSION This study showed that abnormal CTSL2 expression may contribute to HCC progression and that elevated CTSL2 expression is associated with an adverse prognosis in HCC.
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Affiliation(s)
- Jisheng Jing
- Department of Infectious Diseases, Jurong People's Hospital Affliated to Jiangsu University Zhenjiang, Jiangsu, China
| | - Shuncai Wang
- Department of Infectious Diseases, Jurong People's Hospital Affliated to Jiangsu University Zhenjiang, Jiangsu, China
| | - Jiuming Ma
- Department of Infectious Diseases, Jurong People's Hospital Affliated to Jiangsu University Zhenjiang, Jiangsu, China
| | - Laqing Yu
- Department of Infectious Diseases, Jurong People's Hospital Affliated to Jiangsu University Zhenjiang, Jiangsu, China
| | - Hua Zhou
- Department of Infectious Diseases, Jurong People's Hospital Affliated to Jiangsu University Zhenjiang, Jiangsu, China
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28
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Li DK, Ren Y, Fierer DS, Rutledge S, Shaikh OS, Lo Re V, Simon T, Abou-Samra AB, Chung RT, Butt AA. The short-term incidence of hepatocellular carcinoma is not increased after hepatitis C treatment with direct-acting antivirals: An ERCHIVES study. Hepatology 2018; 67:2244-2253. [PMID: 29205416 DOI: 10.1002/hep.29707] [Citation(s) in RCA: 124] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Revised: 11/12/2017] [Accepted: 11/20/2017] [Indexed: 12/12/2022]
Abstract
UNLABELLED Recent studies have reported higher rates of hepatocellular carcinoma (HCC) in individuals treated with direct-acting antivirals (DAAs). However, making definitive conclusions has been challenging because of the heterogeneous populations and methodologies of these reports. We investigated whether DAA use is associated with higher rates of incident HCC compared to treatment with interferon (IFN)-based regimens. We performed a retrospective, population-based cohort study using the Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES) database. In a cohort of 17,836 persons, sustained virological response (SVR) was achieved by 66.6% and 96.2% of the IFN and DAA groups, respectively. Among all treated persons, risk of HCC was not higher in the DAA group compared to the IFN group (hazard ratio, 1.07; 95% confidence interval, 0.55, 2.08). Among persons with cirrhosis who achieved SVR, neither the HCC incidence rate nor HCC-free survival were significantly different in the DAA group compared to the IFN group (21.2 vs. 22.8 per 1,000 person-years; P = 0.78 and log-rank P = 0.17, respectively). Untreated persons with cirrhosis had a significantly higher HCC incidence rate (45.3 per 1,000 person-years) compared to those treated with either IFN or DAAs (P = 0.03). Both groups of treated persons had significantly lower probability of HCC development compared to untreated persons (log-rank, P = 0.0004). CONCLUSION DAA treatment is not associated with a higher risk of HCC in persons with cirrhosis with chronic HCV infection in the short term. Previously reported higher rates of HCC associated with DAA treatment may be explained by both the presence of relatively fewer baseline HCC risk factors in persons treated with IFN as well as selection bias, given that DAA regimens were used to treat persons at higher risk for developing HCC. (Hepatology 2018;67:2244-2253).
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Affiliation(s)
- Darrick K Li
- Department of Medicine, Massachusetts General Hospital, Boston, MA.,Liver Center, Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Yanjie Ren
- VA Pittsburgh Healthcare System, Pittsburgh, PA
| | - Daniel S Fierer
- Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY
| | | | | | - Vincent Lo Re
- Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Tracey Simon
- Department of Medicine, Massachusetts General Hospital, Boston, MA.,Liver Center, Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Abdul-Badi Abou-Samra
- Hamad Medical Corporation, Doha, Qatar.,Weill Cornell Medical College, Doha, Qatar and New York, NY
| | - Raymond T Chung
- Department of Medicine, Massachusetts General Hospital, Boston, MA.,Liver Center, Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Adeel A Butt
- VA Pittsburgh Healthcare System, Pittsburgh, PA.,Hamad Medical Corporation, Doha, Qatar.,Weill Cornell Medical College, Doha, Qatar and New York, NY
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29
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Yen YH, Lin MT, Kuo FY, Chang KC, Tsai MC, Tseng PL, Wu CK, Lin JT, Hu TH, Lu SN, Wang JH, Hung CH, Chen CH. The association between steatosis and diabetes with hepatocellular carcinoma in non-genotype 3 chronic hepatitis C patients. Liver Int 2018; 38:1064-1073. [PMID: 29164767 DOI: 10.1111/liv.13633] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Accepted: 11/13/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Diabetes mellitus (DM) has been found to be strongly associated with an increased risk of hepatocellular carcinoma (HCC) among chronic hepatitis C (CHC) patients. Several studies have also found an association between metabolic steatosis and the risk of HCC in CHC patients, whether this latter association has been accounted for by the known relationship between DM and HCC is still unknown. METHODS A cohort consisting of 976 non-genotype 3 patients histologically proven to have CHC and treated with interferon and ribavirin was studied. Cumulative incidence and HCC risk were analysed using the Kaplan-Meier method and Cox proportional hazard analysis. RESULTS Hepatocellular carcinoma developed in 140 subjects over a median follow-up period of 97.3 months, while 699 patients achieved sustained virological response (SVR). According to multivariate analyses, age ≥ 60 years, advanced fibrosis and genotype 1 were identified as independent factors significantly associated with HCC development in SVR patients. Furthermore, using the absence of steatosis and absence of DM as references, the presence of steatosis without DM (HR = 2.09, 95% CI = 1.12-3.9, P = .021), the presence of DM without steatosis (HR = 2.78, 95% CI = 1.3-5.92, P = .008) and the combined presence of steatosis and DM (HR = 3.25, 95% CI = 1.44-7.33, P = .004) were identified as independent factors significantly associated with HCC development in the SVR patients. In contrast, steatosis alone, DM alone and the combined presence of steatosis and DM were not associated with HCC development in non-SVR patients. CONCLUSIONS Steatosis and DM may be associated with HCC development in non-genotype 3 CHC patients with SVR.
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Affiliation(s)
- Yi-Hao Yen
- Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Ming-Tsung Lin
- Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Fang-Ying Kuo
- Department of Pathology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Kuo-Chin Chang
- Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Ming-Chao Tsai
- Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Po-Lin Tseng
- Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Cheng-Kun Wu
- Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Jung-Ting Lin
- Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Tsung-Hui Hu
- Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Sheng-Nan Lu
- Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Jing-Houng Wang
- Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chao-Hung Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung University College of Medicine, Kaohsiung, Taiwan
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Schuppan D, Ashfaq-Khan M, Yang AT, Kim YO. Liver fibrosis: Direct antifibrotic agents and targeted therapies. Matrix Biol 2018; 68-69:435-451. [PMID: 29656147 DOI: 10.1016/j.matbio.2018.04.006] [Citation(s) in RCA: 322] [Impact Index Per Article: 46.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2018] [Revised: 04/10/2018] [Accepted: 04/11/2018] [Indexed: 12/11/2022]
Abstract
Liver fibrosis and in particular cirrhosis are the major causes of morbidity and mortality of patients with chronic liver disease. Their prevention or reversal have become major endpoints in clinical trials with novel liver specific drugs. Remarkable progress has been made with therapies that efficiently address the cause of the underlying liver disease, as in chronic hepatitis B and C. Highly effective antiviral therapy can prevent progression or even induce reversal in the majority of patients, but such treatment remains elusive for the majority of liver patients with advanced alcoholic or nonalcoholic steatohepatitis, genetic or autoimmune liver diseases. Moreover, drugs that would speed up fibrosis reversal are needed for patients with cirrhosis, since even with effective causal therapy reversal is slow or the disease may further progress. Therefore, highly efficient and specific antifibrotic agents are needed that can address advanced fibrosis, i.e., the detrimental downstream result of all chronic liver diseases. This review discusses targeted antifibrotic therapies that address molecules and mechanisms that are central to fibrogenesis or fibrolysis, including strategies that allow targeting of activated hepatic stellate cells and myofibroblasts and other fibrogenic effector cells. Focus is on collagen synthesis, integrins and cells and mechanisms specific including specific downregulation of TGFbeta signaling, major extracellular matrix (ECM) components, ECM-crosslinking, and ECM-receptors such as integrins and discoidin domain receptors, ECM-crosslinking and methods for targeted delivery of small interfering RNA, antisense oligonucleotides and small molecules to increase potency and reduce side effects. With an increased understanding of the biology of the ECM and liver fibrosis and an improved preclinical validation, the translation of these approaches to the clinic is currently ongoing. Application to patients with liver fibrosis and a personalized treatment is tightly linked to the development of noninvasive biomarkers of fibrosis, fibrogenesis and fibrolysis.
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Affiliation(s)
- Detlef Schuppan
- Institute of Translational Immunology and Research Center for Immunotherapy, University of Mainz Medical Center, Mainz, Germany; Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA.
| | - Muhammad Ashfaq-Khan
- Institute of Translational Immunology and Research Center for Immunotherapy, University of Mainz Medical Center, Mainz, Germany
| | - Ai Ting Yang
- Institute of Translational Immunology and Research Center for Immunotherapy, University of Mainz Medical Center, Mainz, Germany
| | - Yong Ook Kim
- Institute of Translational Immunology and Research Center for Immunotherapy, University of Mainz Medical Center, Mainz, Germany
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Kasting ML, Giuliano AR, Reich RR, Roetzheim RG, Nelson DR, Shenkman E, Vadaparampil ST. Hepatitis C Virus Screening Trends: Serial Cross-Sectional Analysis of the National Health Interview Survey Population, 2013-2015. Cancer Epidemiol Biomarkers Prev 2018; 27:503-513. [PMID: 29588306 PMCID: PMC5884715 DOI: 10.1158/1055-9965.epi-17-0855] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Revised: 11/20/2017] [Accepted: 01/31/2018] [Indexed: 12/18/2022] Open
Abstract
Background: Rates of hepatitis C virus (HCV) infection are markedly higher for baby boomers compared with other birth cohorts, and they are now recommended for universal one-time screening. This study examines HCV screening rates and predictors for four birth cohorts [born <1945, born 1945-1965 (baby boomers), born 1966-1985, and born >1985] of a nationally representative sample over time.Methods: We used data from the 2013-2015 National Health Interview Surveys, an annual weighted survey of the U.S. civilian noninstitutionalized population. We assessed HCV screening prevalence stratified birth cohort with bivariate and multivariable logistic regression analyses.Results: There were 15,100 participants born <1945, 28,725 baby boomers, 28,089 born 1966-1985, and 13,296 born >1985 in the final analytic sample. Screening was 11.5%-12.8% for baby boomers. The second youngest birth cohort was similar to baby boomers (13.7%-14.9%), whereas the older birth cohort was screened less. After excluding participants who typically have higher rates of HCV screening than the general population, we developed a multivariable model of the general population. In the final model for baby boomers the odds of HCV screening increased significantly with each subsequent year (OR=1.20; 95% CI=1.05-1.38 and OR=1.31; 95% CI=1.13-1.52). HCV screening was also significantly associated with age, gender, and race/ethnicity in baby boomers.Conclusions: While HCV screening is increasing over time, these increases are minimal and there is substantial room for improvement.Impact: Future research should develop interventions to increase HCV screening with special focus on groups demonstrating significantly lower screening rates, such as Hispanics and females. Cancer Epidemiol Biomarkers Prev; 27(4); 503-13. ©2018 AACR.
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Affiliation(s)
- Monica L Kasting
- Department of Health Outcomes and Behavior, H. Lee Moffitt Cancer Center, Tampa, Florida
- Center for Infection Research in Cancer, H. Lee Moffitt Cancer Center, Tampa, Florida
| | - Anna R Giuliano
- Center for Infection Research in Cancer, H. Lee Moffitt Cancer Center, Tampa, Florida
- Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center, Tampa, Florida
| | - Richard R Reich
- Shared Resources, H. Lee Moffitt Cancer Center, Tampa, Florida
| | - Richard G Roetzheim
- Department of Health Outcomes and Behavior, H. Lee Moffitt Cancer Center, Tampa, Florida
- Department of Family Medicine, University of South Florida, Tampa, Florida
| | - David R Nelson
- Department of Medicine, University of Florida, Gainesville, Florida
| | - Elizabeth Shenkman
- Department of Health Outcomes and Policy, University of Florida Health, Gainesville, Florida
- Cancer Population Sciences, University of Florida Health, Gainesville, Florida
| | - Susan T Vadaparampil
- Department of Health Outcomes and Behavior, H. Lee Moffitt Cancer Center, Tampa, Florida.
- Center for Infection Research in Cancer, H. Lee Moffitt Cancer Center, Tampa, Florida
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Ramadori G, Bosio P, Moriconi F, Malik IA. Case report: 8 years after liver transplantation: de novo hepatocellular carcinoma 8 months after HCV clearance through IFN-free antiviral therapy. BMC Cancer 2018; 18:257. [PMID: 29510685 PMCID: PMC5840818 DOI: 10.1186/s12885-018-4175-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Accepted: 03/01/2018] [Indexed: 12/14/2022] Open
Abstract
Background After orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC), recurrent HCC mostly develops within 2 years. All cases of de novo HCC described so far occurred later than 2 years after OLT. Prevention of post-transplantation HCC has usually been tried to achieve by curing or controlling recurrent liver disease. This has been rationale for treatment with interferon (IFN)/ribavirin of HCV-recurrence in patients after OLT, transplanted for advanced HCV-induced liver disease and/or HCC. The availability of new and more efficient drugs has improved chances also for previously difficult-to-treat HCV-positive patients. Case presentation A 75 year-old male patient who had undergone OLT for decompensated HCV-cirrhosis in 2009, and bilio-digestive surgery in 2011 under tracrolimus (0.5 mg/day) and prednisone (5 mg/day) immunosuppressive therapy, started to receive antiviral treatment for recurrent HCV-infection of graft with 200 mg/day ribavirin in combination with ledipasvir and sofosbuvir by the end of October 2015. Because of multiple side effects (anemia, asthenia, infections, and reduction of kidney functions - palliated by treatment with erythropoietin), treatment was stopped after 16 weeks. At the third control, a minimal increase in alpha-fetoprotein (AFP) serum level to 10 μg/L was measured 8 months after therapy, whereas both liver sonography and serum transaminases were normal. The patient’s general condition; however, remained poor, and a magnetic resonance imaging (MRI) of abdomen was performed 2 months later. A nodule of 3 cm in diameter with a pseudocapsule was found centrally in the liver. The patient had to be hospitalized for recurrent infections of the lung, overt ascites and peritonitis. Rapid tumor growth (10 cm) was detected during last stay in hospital (April 2017), concomitant with a rise of AFP-serum levels to 91 μg/L. The family decided to take the patient home, and best supportive care was provided by a general practitioner, local nurses and the patient’s dedicated wife until his death. Conclusion Before treating OLT patients with HCV graft reinfection one should not only consider possible advantages of newly effective antiviral-therapies, but also life expectancy and possible side effects (difficult to manage at an outpatient service basis), including severe disadvantages such as the development of HCC.
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Affiliation(s)
- Giuliano Ramadori
- Department of Gastroenterology and Endocrinology, University Medical Center Goettingen, Robert-Koch-Street 40, D-37075, Goettingen, Germany.
| | - Patrizia Bosio
- General Practitioner, National health care system, Palazzago, BG, Italy
| | | | - Ihtzaz A Malik
- Institute of Anatomy and Cell Biology, University Medical Center, Kreuzbering 36, 37075, Goettingen, Germany
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Ban D, Ogura T, Akahoshi K, Tanabe M. Current topics in the surgical treatments for hepatocellular carcinoma. Ann Gastroenterol Surg 2018; 2:137-146. [PMID: 29863117 PMCID: PMC5881293 DOI: 10.1002/ags3.12065] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Accepted: 01/29/2018] [Indexed: 01/27/2023] Open
Abstract
Treatment strategy for hepatocellular carcinoma (HCC) requires optimal selection of therapies based on various factors related to tumor condition and liver functional reserve. Although several evidence-based guidelines have been proposed for the treatment of HCC, the criteria and range of indications differ among these guidelines according to the circumstances of each country. In European nations and the USA, patients with the Barcelona Clinic Liver Cancer stage 0-A are subjects for surgical resection, whereas in Asian countries, even those with the intermediate stage are regarded as surgical candidates. Furthermore, since the recent introduction and rapidly widely spreading use of laparoscopic liver resection, this technique has become an important treatment option for surgical resection. In this review article, we overview the current topics of treatment of HCC with a special focus on surgical therapy.
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Affiliation(s)
- Daisuke Ban
- Department of Hepatobiliary and Pancreatic Surgery Graduate School of Medicine Tokyo Medical and Dental University Tokyo Japan
| | - Toshiro Ogura
- Department of Hepatobiliary and Pancreatic Surgery Graduate School of Medicine Tokyo Medical and Dental University Tokyo Japan
| | - Keiichi Akahoshi
- Department of Hepatobiliary and Pancreatic Surgery Graduate School of Medicine Tokyo Medical and Dental University Tokyo Japan
| | - Minoru Tanabe
- Department of Hepatobiliary and Pancreatic Surgery Graduate School of Medicine Tokyo Medical and Dental University Tokyo Japan
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Hepatocellular Carcinoma Screening in Patients Treated for Hepatitis C. Am J Med 2018; 131:e79. [PMID: 29362113 DOI: 10.1016/j.amjmed.2017.09.036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Accepted: 09/27/2017] [Indexed: 11/23/2022]
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Funaki M, Kitabayashi J, Shimakami T, Nagata N, Sakai Y, Takegoshi K, Okada H, Murai K, Shirasaki T, Oyama T, Yamashita T, Ota T, Takuwa Y, Honda M, Kaneko S. Peretinoin, an acyclic retinoid, inhibits hepatocarcinogenesis by suppressing sphingosine kinase 1 expression in vitro and in vivo. Sci Rep 2017; 7:16978. [PMID: 29208982 PMCID: PMC5717167 DOI: 10.1038/s41598-017-17285-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Accepted: 11/22/2017] [Indexed: 02/07/2023] Open
Abstract
Sphingosine-1-phospate is a potent bioactive lipid metabolite that regulates cancer progression. Because sphingosine kinase 1 and sphingosine kinase 2 (SPHK 1/2) are both essential for sphingosine-1-phospate production, they could be a therapeutic target in various cancers. Peretinoin, an acyclic retinoid, inhibits post-therapeutic recurrence of hepatocellular carcinoma via unclear mechanisms. In this study, we assessed effects of peretinoin on SPHK expression and liver cancer development in vitro and in vivo. We examined effects of peretinoin on expression, enzymatic and promoter activity of SPHK1 in a human hepatoma cell line, Huh-7. We also investigated effects of SPHK1 on hepatocarcinogenesis induced by diethylnitrosamine using SPHK1 knockout mice. Peretinoin treatment of Huh-7 cells reduced mRNA levels, protein expression and enzymatic activity of SPHK1. Peretinoin reduced SPHK1 promoter activity; this effect of peretinoin was blocked by overexpression of Sp1, a transcription factor. Deletion of all Sp1 binding sites within the SPHK1 promoter region abolished SPHK1 promoter activity, suggesting that peretinoin reduced mRNA levels of SPHK1 via Sp1. Additionally, diethylnitrosamine-induced hepatoma was fewer and less frequent in SPHK1 knockout compared to wild-type mice. Our data showed crucial roles of SPHK1 in hepatocarcinogenesis and suggests that peretinoin prevents hepatocarcinogenesis by suppressing mRNA levels of SPHK1.
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Affiliation(s)
- Masaya Funaki
- Department of Gastroenterology, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Juria Kitabayashi
- Department of Gastroenterology, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Tetsuro Shimakami
- Department of Gastroenterology, Kanazawa University, Kanazawa, Ishikawa, Japan.
| | - Naoto Nagata
- Advanced Preventive Medical Sciences Research Center, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Yuriko Sakai
- Advanced Preventive Medical Sciences Research Center, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Kai Takegoshi
- Department of Gastroenterology, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Hikari Okada
- Department of Gastroenterology, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Kazuhisa Murai
- Department of Gastroenterology, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Takayoshi Shirasaki
- Department of Gastroenterology, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Takeru Oyama
- Department of Molecular and Cellular Pathology, Graduate School of Medical Science, Kanazawa University, Ishikawa, Japan
| | - Taro Yamashita
- Department of Gastroenterology, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Tsuguhito Ota
- Advanced Preventive Medical Sciences Research Center, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Yoh Takuwa
- Department of Physiology, Kanazawa University School of Medicine, Kanazawa, Ishikawa, Japan
| | - Masao Honda
- Department of Gastroenterology, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Shuichi Kaneko
- Department of Gastroenterology, Kanazawa University, Kanazawa, Ishikawa, Japan
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Kawaguchi T, Ide T, Koga H, Kondo R, Miyajima I, Arinaga-Hino T, Kuwahara R, Amano K, Niizeki T, Nakano M, Kuromatsu R, Torimura T. Rapidly growing hepatocellular carcinoma after direct-acting antiviral treatment of chronic hepatitis C. Clin J Gastroenterol 2017; 11:69-74. [PMID: 29082453 DOI: 10.1007/s12328-017-0789-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Accepted: 10/12/2017] [Indexed: 12/29/2022]
Abstract
We report on a 62-year-old man with chronic hepatitis C who developed rapidly growing hepatocellular carcinoma (HCC) after achieving sustained virological response at post-treatment week 24 (SVR 24) by direct-acting antiviral (DAA) treatment. In 2008, he failed interferon therapy at 56 years of age. He received daclatasvir plus asunaprevir for 24 weeks after confirmation of no liver tumor by abdominal ultrasonography. He had no advanced liver fibrosis. Three months after initiation of DAA treatment, a liver tumor measuring 6 mm in diameter was detected by ultrasonography and confirmed with magnetic resonance imaging. After achieving SVR 24, the tumor increased in size to 16 mm. Two months later, a tumor biopsy was performed, and histology revealed moderately to poorly differentiated HCC. The patient's alpha-fetoprotein (AFP) level was within the normal range, but the Lens culinaris agglutinin-reactive fraction of AFP level was elevated. The diameter of the tumor increased to 32 mm at 2 months after diagnosis. Lymph node metastasis in porta hepatis was found by positron emission tomography at 4 months after diagnosis. The patient received hepatic arterial infusion chemotherapy and radiation therapy, but died later. Careful monitoring is required during and after DAA treatment because HCC can grow fast even in patients with normal AFP and no advanced liver fibrosis.
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Affiliation(s)
- Toshihiro Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67, Asahi-machi, Kurume, Fukuoka, 830-0011, Japan.
| | - Tatsuya Ide
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67, Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
| | - Hironori Koga
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67, Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
| | - Reiichiro Kondo
- Department of Pathology, Kurume University School of Medicine, 67, Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
| | - Ichiro Miyajima
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67, Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
| | - Teruko Arinaga-Hino
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67, Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
| | - Reiichiro Kuwahara
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67, Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
| | - Keisuke Amano
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67, Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
| | - Takashi Niizeki
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67, Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
| | - Masahito Nakano
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67, Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
| | - Ryoko Kuromatsu
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67, Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
| | - Takuji Torimura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67, Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
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Affiliation(s)
- Hyun Woong Lee
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
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38
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Bruno S, Di Marco V, Iavarone M, Roffi L, Boccaccio V, Crosignani A, Cabibbo G, Rossi S, Calvaruso V, Aghemo A, Giacomelli L, Craxì A, Colombo M, Maisonneuve P. Improved survival of patients with hepatocellular carcinoma and compensated hepatitis C virus-related cirrhosis who attained sustained virological response. Liver Int 2017; 37:1526-1534. [PMID: 28418617 DOI: 10.1111/liv.13452] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Accepted: 04/10/2017] [Indexed: 02/13/2023]
Abstract
BACKGROUND Few studies examined the outcome of patients with hepatitis C virus (HCV)-related cirrhosis who developed hepatocellular carcinoma (HCC). The relative weight as determinant of death for cancer vs end-stage liver disease (ESLD) and the benefit of HCV eradication remain undefined. This multicentre, retrospective analysis evaluates overall survival (OS), rate of decompensation and tumour recurrence in compensated HCC patients treated with interferon (IFN) according to HCV status since HCC diagnosis. METHODS Two groups of patients with HCV-related cirrhosis and HCC were followed since HCC diagnosis: (i) compensated cirrhotics with prior sustained virological response (SVR) on IFN-based regimens (N=19); (ii) compensated cirrhotics without SVR (viraemic) (N=156). RESULTS Over a median follow-up of 3.0 years since the onset of HCC, OS was longer for HCC patients with SVR than for viraemic patients (log-rank P=.004). The 5-year OS rate was 65.9% in patients with SVR vs 31.9% in viraemic patients. Similar trends were reported for hepatic decompensation (log-rank P=.01) and tumour recurrence (log-rank P=.01). These findings were confirmed at multivariable and propensity score analysis. At propensity analysis, 0/19 compensated patients with SVR died for ESLD vs 7/19 (37%) viraemic patients (P=.004). HCC mortality was similar in the two groups. CONCLUSIONS Hepatocellular carcinoma patients with prior SVR and compensated cirrhosis at the time of tumour diagnosis have prolonged OS than viraemic patients. Given the lack of cirrhosis progression, no SVR patient ultimately died for ESLD while this condition appears the main cause of death among viraemic patients.
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Affiliation(s)
- Savino Bruno
- Humanitas University and IRCCS Istituto Clinico Humanitas, Rozzano, Italy
| | - Vito Di Marco
- Gastroenterology and Hepatology Unit, Di.Bi.M.I.S., University of Palermo, Palermo, Italy
| | - Massimo Iavarone
- Gastroenterology and Hepatology Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Luigi Roffi
- Department of Medicine, ASST Nord Milano, Milan, Italy
| | - Vincenzo Boccaccio
- Humanitas University and IRCCS Istituto Clinico Humanitas, Rozzano, Italy
| | - Andrea Crosignani
- Department of Internal Medicine, A.O. Santi Paolo e Carlo, Milan, Italy
| | - Giuseppe Cabibbo
- Gastroenterology and Hepatology Unit, Di.Bi.M.I.S., University of Palermo, Palermo, Italy
| | - Sonia Rossi
- Humanitas University and IRCCS Istituto Clinico Humanitas, Rozzano, Italy
| | - Vincenza Calvaruso
- Gastroenterology and Hepatology Unit, Di.Bi.M.I.S., University of Palermo, Palermo, Italy
| | - Alessio Aghemo
- Gastroenterology and Hepatology Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Luca Giacomelli
- Department of Surgery and Integrated Diagnostics, University of Genoa, Genoa, Italy
| | - Antonio Craxì
- Gastroenterology and Hepatology Unit, Di.Bi.M.I.S., University of Palermo, Palermo, Italy
| | - Massimo Colombo
- Gastroenterology and Hepatology Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Patrick Maisonneuve
- Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy
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Janjua NZ, Chong M, Kuo M, Woods R, Wong J, Yoshida EM, Sherman M, Butt ZA, Samji H, Cook D, Yu A, Alvarez M, Tyndall M, Krajden M. Long-term effect of sustained virological response on hepatocellular carcinoma in patients with hepatitis C in Canada. J Hepatol 2017; 66:504-513. [PMID: 27818234 DOI: 10.1016/j.jhep.2016.10.028] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Revised: 10/19/2016] [Accepted: 10/22/2016] [Indexed: 01/10/2023]
Abstract
BACKGROUND & AIMS Evidence is limited on hepatocellular carcinoma (HCC) risk after sustained virological response (SVR) to interferon-based treatment of hepatitis C virus (HCV) infection. We evaluated the effect of SVR on the risk of HCC and estimated its incidence in post-SVR HCV patients from a large population-based Canadian cohort. METHODS The British Columbia Hepatitis Testers Cohort includes individuals tested for HCV between 1990-2013 linked with data on their medical visits, hospitalizations, cancers, prescription drugs and mortality. Patients receiving interferon-based HCV treatments were followed from the end of treatment to HCC diagnosis, death or December 31, 2012. We examined HCC risk among those who did and did not achieve SVR using multivariable proportional hazard models with the Fine and Gray modification for competing risks. RESULTS Of 8147 individuals who received HCV treatment and were eligible for analysis, 4663 (57%) achieved SVR and 3484 (43%) did not. Each group was followed for a median of 5.6years (range: 0.5-12.9) for an HCC incidence rate of 1.1/1000 person-years (PY) among the SVR and 7.2/1000 PY among the no SVR group. The HCC incidence rate was higher among those with cirrhosis (SVR: 6.4, no SVR: 21.0/1000 PY). In the multivariable model, SVR was associated with a lower HCC risk (subdistribution hazard ratio [SHR]=0.20, 95% CI: 0.13-0.3), while cirrhosis (SHR=2.61, 95% CI: 1.68-4.04), age ⩾50years, being male and genotype 3 infection were associated with a higher HCC risk. Among those who achieved SVR, cirrhosis, age ⩾50years and being male were associated with a higher HCC risk. CONCLUSION SVR after interferon-based treatment substantially reduces but does not eliminate HCC risk, which is markedly higher among those with cirrhosis and age ⩾50years at treatment initiation. Treatment of patients at an advanced fibrosis stage with new highly effective drugs will warrant continued surveillance for HCC post-SVR. LAY SUMMARY We assessed the effect of successful hepatitis C treatment with older interferon-based treatment on the occurrence of liver cancer (hepatocellular carcinoma) and found that successful treatment prevents liver cancer. However, more people with cirrhosis and older age continued to develop liver cancer after successful treatment. Thus, treatment with new drugs among those with cirrhosis will require continued monitoring for liver cancer.
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Affiliation(s)
- Naveed Z Janjua
- British Columbia Centre for Disease Control, Vancouver, BC, Canada; School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada.
| | - Mei Chong
- British Columbia Centre for Disease Control, Vancouver, BC, Canada
| | - Margot Kuo
- British Columbia Centre for Disease Control, Vancouver, BC, Canada
| | - Ryan Woods
- British Columbia Cancer Agency, Vancouver, BC, Canada
| | - Jason Wong
- British Columbia Centre for Disease Control, Vancouver, BC, Canada; School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada
| | - Eric M Yoshida
- Division of Gastroenterology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Morris Sherman
- Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Zahid A Butt
- British Columbia Centre for Disease Control, Vancouver, BC, Canada; School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada
| | - Hasina Samji
- British Columbia Centre for Disease Control, Vancouver, BC, Canada; School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada
| | - Darrel Cook
- British Columbia Centre for Disease Control, Vancouver, BC, Canada
| | - Amanda Yu
- British Columbia Centre for Disease Control, Vancouver, BC, Canada
| | - Maria Alvarez
- British Columbia Centre for Disease Control, Vancouver, BC, Canada
| | - Mark Tyndall
- British Columbia Centre for Disease Control, Vancouver, BC, Canada; School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada
| | - Mel Krajden
- British Columbia Centre for Disease Control, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
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Tada T, Kumada T, Toyoda H, Kiriyama S, Tanikawa M, Hisanaga Y, Kanamori A, Kitabatake S, Yama T, Tanaka J. Viral eradication reduces all-cause mortality, including non-liver-related disease, in patients with progressive hepatitis C virus-related fibrosis. J Gastroenterol Hepatol 2017; 32:687-694. [PMID: 27577675 DOI: 10.1111/jgh.13589] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/24/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIM Eradication of hepatitis C virus (HCV) with interferon (IFN)-based therapy has been reported to reduce all-cause mortality in patients with chronic HCV infection. However, the impact of HCV eradication on non-liver-related mortality and causes of death has not been sufficiently investigated in patients with progressive HCV-related fibrosis. METHODS We enrolled 784 chronic HCV patients with progressive liver fibrosis (aspartate aminotransferase to platelet ratio index >1). Cause of death, incidence of hepatocellular carcinoma, and all-cause mortality including non-liver-related mortality were analyzed. RESULTS Of these 784 patients, 170 achieved sustained virological response (SVR) (eradication of HCV) with IFN-based therapy (IFN-SVR), and 614 did not receive IFN-based therapy (non-IFN patients, chronic HCV infection). The median follow-up duration was 10.3 years. Two hundred seventy-three patients died during follow-up (liver-related death, n = 171; non-liver-related death, n = 102). The mortality rate from non-liver-related disease was 63.6% (7/11) in IFN-SVR patients and 36.3% (95/262) in non-IFN patients, respectively. In multivariate analysis, the eradication of HCV associated with not only hepatocellular carcinoma incidence (hazard ratio (HR), 0.162; 95% confidence interval (CI), 0.092-0.284), and all-cause mortality (HR, 0.094; 95% CI, 0.047-0.187), but non-liver-related mortality (HR, 0.286; 95% CI, 0.127-0.644) as well. CONCLUSIONS Eradication of HCV reduced both liver-related and non-liver-related mortality in patients with progressive HCV-related fibrosis.
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Affiliation(s)
- Toshifumi Tada
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Takashi Kumada
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Seiki Kiriyama
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Makoto Tanikawa
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Yasuhiro Hisanaga
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Akira Kanamori
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Shusuke Kitabatake
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Tsuyoki Yama
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Junko Tanaka
- Department of Epidemiology, Infectious Disease Control, and Prevention, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima, Japan
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Thomas SM, Moke D, Lopez R, Hanna R, Kabbany MN, Alkhouri N. Liver Transplantation for Hepatocellular Carcinoma in Young Adults: A United Network for Organ Sharing Study. J Adolesc Young Adult Oncol 2016; 6:286-293. [PMID: 27996360 DOI: 10.1089/jayao.2016.0048] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
PURPOSE Orthotopic liver transplantation (OLT) is curative for hepatocellular carcinoma (HCC). HCC is typically a disease of older adults (OAs); therefore, characteristics and outcomes of OLT for young adults (YAs) (ages 18-40) are not described. The objective of this study was to assess the characteristics and outcomes of YAs with HCC receiving OLT and compare these to OAs (ages >40 years). METHODS YAs with HCC who had OLT from the United Network for Organ Sharing (UNOS) database were included in this study. As a comparison group, OAs with HCC were matched 4:1 to the YA group. Descriptive statistics of demographics, comorbidities, and outcomes were generated. Kaplan-Meier product limit estimates were used to assess patient and graft survival. Conditional logistic regression and Cox proportional hazards frailty models were used to compare the groups. RESULTS A total of 464 YAs received OLT for HCC. The most common underlying liver diseases were hepatitis C virus (21.3%), hepatitis B virus (HBV, 15.5%), and autoimmune/cholestatic disease (12.3%). An increased number of YAs received OLT for HCC after implementation of model for end-stage liver disease scoring. One thousand two hundred eighty OAs served as the comparison group. Post-transplant 5-year survival was 73.1% in YAs with a retransplantation rate of 7.8%. In OAs, survival and retransplantation rates were lower (68.6% p = 0.093; 4.3% p = 0.001). CONCLUSION Four hundred sixty-four YAs with HCC received OLT in the UNOS database. Compared to the older population, survival and retransplantation rates were higher. HBV, which is vaccine preventable, is a frequent contributor to HCC in YAs.
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Affiliation(s)
- Stefanie M Thomas
- 1 Children's Center for Cancer and Blood Disease , Children's Hospital Los Angeles, Los Angeles, California
- 2 Division of Hematology, Oncology and Blood and Marrow Transplantation, Department of Pediatrics, Keck School of Medicine, University of Southern California , Los Angeles, California
| | - Diana Moke
- 1 Children's Center for Cancer and Blood Disease , Children's Hospital Los Angeles, Los Angeles, California
| | - Rocio Lopez
- 3 Department of Quantitative Health Sciences, Cleveland Clinic , Cleveland, Ohio
| | - Rabi Hanna
- 4 Department of Pediatric Hematology, Oncology and Blood and Marrow Transplantation, Cleveland Clinic Children's , Cleveland, Ohio
| | - Mohammad Nasser Kabbany
- 5 Department of Pediatric Gastroenterology and Hepatology, Cleveland Clinic , Cleveland, Ohio
| | - Naim Alkhouri
- 5 Department of Pediatric Gastroenterology and Hepatology, Cleveland Clinic , Cleveland, Ohio
- 6 Digestive Disease Institute , Cleveland Clinic, Cleveland, Ohio
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Plasma Level of Interleukin-35 as an Independent Prognostic Indicator in Hepatocellular Carcinoma. Dig Dis Sci 2016; 61:3513-3521. [PMID: 27699510 DOI: 10.1007/s10620-016-4270-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2016] [Accepted: 07/26/2016] [Indexed: 01/18/2023]
Abstract
BACKGROUND Hepatocellular carcinoma is a major type of liver cancer with poor prognosis. AIM The aim of the study was to determine the prognostic significance of plasma interleukin-35 level in hepatocellular carcinoma. METHODS A total of 153 hepatocellular carcinoma patients and 153 healthy controls were enrolled. Blood samples were obtained at admission. Plasma interleukin-35 level was analyzed by enzyme-linked immunosorbent assay. Distribution of T cell subset and expression of Fas/FasL protein were detected by flow cytometry. The patients were followed up for 2 years. Poor prognosis was defined as death of hepatocellular carcinoma. RESULTS The plasma levels of interleukin-35 were significantly higher in the patients than the controls (25.1 ± 13.1, 9.3 ± 6.3 pg/mL, P < 0.001). After adjusted for multiple confounding factors, the multivariate logistic regression analyses reported that high level of interleukin-35 (≥25.0 pg/mL) was associated with the poor prognosis in the patients (OR 6.63, 95 % CI 3.27-13.47). Compared with the patients with low level of interleukin-35 (<25.0 pg/mL), the patients with high level of interleukin-35 showed higher frequencies of CD4+CD25+FoxP3+ and CD3+Foxp3+ regulatory T cells (P < 0.001 and P < 0.001) and also showed higher apoptosis levels of CD8+ T cells (P < 0.001). CONCLUSION Circulating interleukin-35 concentration might be an independent prognostic indicator in hepatocellular carcinoma. Such prognostic significance could be partly involved in the activation of regulatory T cell and the apoptosis of CD8+ T cell.
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Wang JH, Yen YH, Yao CC, Hung CH, Chen CH, Hu TH, Lee CM, Lu SN. Liver stiffness-based score in hepatoma risk assessment for chronic hepatitis C patients after successful antiviral therapy. Liver Int 2016; 36:1793-1799. [PMID: 27254286 DOI: 10.1111/liv.13179] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Accepted: 05/31/2016] [Indexed: 12/24/2022]
Abstract
BACKGROUND & AIMS Patients with chronic hepatitis C (CHC) after successful antiviral therapy remain at risk of hepatocellular carcinoma (HCC). This study was to determine whether liver stiffness measurement (LSM) was useful in HCC risk assessment and to develop a risk-score system for clinical use. METHODS This retrospective study enrolled patients with CHC achieving sustained virological response (SVR) after interferon-based therapy with LSM at/after SVR determination. The demographics, clinical characteristics and HCC development were obtained from medical chart reviews. The diagnosis of HCC was based on recommended criteria. RESULTS A total of 376 (M/F: 185/191, mean age: 54.1 years) patients, including 278 with pretreatment liver biopsy specimens, with a median follow-up period of 7.6 years were enrolled. Twenty-one patients developed HCC. The 5- and 10-year cumulative HCC incidences were 1.4% and 7.8%, respectively. Multivariate analysis showed advanced fibrosis/cirrhosis, diabetes and LSM were associated with HCC developments with odds ratio (OR) of 12.38, 2.80 and 1.01, respectively. For LSM in HCC prediction, the performance and cut-off were 0.783 and 12 kilopascal (kPa), respectively. For 278 patients with pretreatment biopsy, a risk-score system (score 0-4) combining advanced fibrosis/cirrhosis, diabetes and LSM >12 kPa was developed. With the low-risk group as a reference, patients in intermediate- (OR: 12.57) and high-risk (OR: 197.33) groups carried higher risk of HCC development. CONCLUSIONS For patients with CHC achieving SVR, liver stiffness value at/after SVR determination was associated with HCC development independently. Patients with pretreatment advanced fibrosis/cirrhosis, diabetes and LSM >12 kPa after SVR were at high risk of HCC development.
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Affiliation(s)
- Jing-Houng Wang
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Yi-Hao Yen
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chih-Chien Yao
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chao-Hung Hung
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chien-Hung Chen
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Tsung-Hui Hu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chuan-Mo Lee
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Sheng-Nan Lu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
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Cho J, Lee SS, Choi YS, Jeon Y, Chung JW, Baeg JY, Si WK, Jang ES, Kim JW, Jeong SH. Occult hepatitis B virus infection is not associated with disease progression of chronic hepatitis C virus infection. World J Gastroenterol 2016; 22:9427-9436. [PMID: 27895431 PMCID: PMC5107707 DOI: 10.3748/wjg.v22.i42.9427] [Citation(s) in RCA: 7] [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: 06/30/2016] [Revised: 08/18/2016] [Accepted: 09/06/2016] [Indexed: 02/07/2023] Open
Abstract
AIM To clarify the prevalence of occult hepatitis B virus (HBV) infection (OBI) and the association between OBI and liver disease progression, defined as development of liver cirrhosis or hepatocellular carcinoma (HCC), worsening of Child-Pugh class, or mortality in cases of chronic hepatitis C virus (HCV) infection.
METHODS This prospective cohort study enrolled 174 patients with chronic HCV infection (chronic hepatitis, n = 83; cirrhosis, n = 47; HCC, n = 44), and evaluated disease progression during a mean follow-up of 38.7 mo. OBI was defined as HBV DNA positivity in 2 or more different viral genomic regions by nested polymerase chain reaction using 4 sets of primers in the S, C, P and X open reading frame of the HBV genome.
RESULTS The overall OBI prevalence in chronic HCV patients at enrollment was 18.4%, with 16.9%, 25.5% and 13.6% in the chronic hepatitis C, liver cirrhosis and HCC groups, respectively (P = 0.845). During follow-up, 52 patients showed disease progression, which was independently associated with aspartate aminotransferase > 40 IU/L, Child-Pugh score and sustained virologic response (SVR), but not with OBI positivity. In 136 patients who were not in the SVR state during the study period, OBI positivity was associated with neither disease progression, nor HCC development.
CONCLUSION The prevalence of OBI in chronic HCV patients was 18.4%, and OBI was not associated with disease progression in South Koreans.
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Gentile I, Maraolo AE, Niola M, Graziano V, Borgia G, Paternoster M. Limiting the access to direct-acting antivirals against HCV: an ethical dilemma. Expert Rev Gastroenterol Hepatol 2016; 10:1227-1234. [PMID: 27607920 DOI: 10.1080/17474124.2016.1234375] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatitis C virus (HCV) infection affects about 200 million people worldwide and represents a leading cause of liver-related mortality. Eradication of HCV infection, achieved mainly through direct-acting antivirals (DAA), results in a decrease of mortality and an improvement of quality of life. These drugs have a maximal efficacy and an optimal tolerability. However, their high cost precludes a universal access even in wealthy countries. Areas covered: This article deals with the policies adopted for the use of the new anti-HCV drugs, especially in Europe and most of all in Italy, supposedly the developed country with the highest HCV prevalence. The literature search was performed using Pubmed and Web of Science. Moreover, national regulatory institutional websites were consulted. Expert commentary: The current policy of limitation to the access of the DAA presents a series of ethical issues that makes it non-applicable. A 'treat-all' strategy should resolve all ethical dilemmas, by virtue of the wide benefits of anti-HCV treatment not only for the advanced stage of infection, but also for the initial stages. A reduction in price of the drugs is the actual condition to achieve such a change.
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Affiliation(s)
- Ivan Gentile
- a Department of Clinical Medicine and Surgery , University of Naples Federico II , Naples , Italy
| | - Alberto E Maraolo
- a Department of Clinical Medicine and Surgery , University of Naples Federico II , Naples , Italy
| | - Massimo Niola
- b Department of Advanced Biomedical Sciences , University of Naples Federico II , Naples , Italy
| | - Vincenzo Graziano
- b Department of Advanced Biomedical Sciences , University of Naples Federico II , Naples , Italy
| | - Guglielmo Borgia
- a Department of Clinical Medicine and Surgery , University of Naples Federico II , Naples , Italy
| | - Mariano Paternoster
- b Department of Advanced Biomedical Sciences , University of Naples Federico II , Naples , Italy
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Bandiera S, Billie Bian C, Hoshida Y, Baumert TF, Zeisel MB. Chronic hepatitis C virus infection and pathogenesis of hepatocellular carcinoma. Curr Opin Virol 2016; 20:99-105. [PMID: 27741441 DOI: 10.1016/j.coviro.2016.09.010] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2016] [Revised: 09/20/2016] [Accepted: 09/23/2016] [Indexed: 02/07/2023]
Abstract
Hepatitis C virus (HCV) infection is one of the major causes of advanced liver disease and hepatocellular carcinoma (HCC) worldwide. While the knowledge about the molecular virology of HCV infection has markedly advanced, the molecular mechanisms of disease progression leading to fibrosis, cirrhosis and HCC are still unclear. Accumulating experimental and clinical studies indicate that HCV may drive hepatocarcinogenesis directly via its proteins or transcripts, and/or indirectly through induction of chronic liver inflammation. Despite the possibility to eradicate HCV infection through direct-acting antiviral treatment, the risk of HCC persists although specific biomarkers to estimate this risk are still missing. Thus, a better understanding of HCV-induced HCC and more physiological liver disease models are required to prevent cancer development.
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Affiliation(s)
- Simonetta Bandiera
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France; Université de Strasbourg, Strasbourg, France
| | - C Billie Bian
- Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Yujin Hoshida
- Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Thomas F Baumert
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France; Université de Strasbourg, Strasbourg, France; Institut Hospitalo-Universitaire, Pôle hépato-digestif, Nouvel Hôpital Civil, Strasbourg, France.
| | - Mirjam B Zeisel
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France; Université de Strasbourg, Strasbourg, France.
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Obed A, Bashir A, Jarrad A. Rapid Virological Response After Early Treatment with a Combined Therapy of Ledipasvir and Sofosbuvir in HCV Genotype 4 After Living Donor Liver Transplantation in a HCC Downstaged Patient: Case Report and Review of the Literature. AMERICAN JOURNAL OF CASE REPORTS 2016; 17:672-5. [PMID: 27647003 PMCID: PMC5031172 DOI: 10.12659/ajcr.898594] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Patient: Male, 54 Final Diagnosis: HCC with portal vein Symptoms: Liver failure Medication: — Clinical Procedure: Hepatitis c treatment • hcc tratment Specialty: Transplantology
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Affiliation(s)
- Aiman Obed
- Department of Hepatobiliary and Transplant Surgery, Jordan Hospital, Amman, Jordan
| | - Abdalla Bashir
- Department of General and Transplant SurgerySurgery, Jordan Hospital, Amman, Jordan
| | - Anwar Jarrad
- Department of Gastroenterology and Hepatology, Jordan Hospital, Amman, Jordan
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Hasegawa K, Takata R, Nishikawa H, Enomoto H, Ishii A, Iwata Y, Miyamoto Y, Ishii N, Yuri Y, Nakano C, Nishimura T, Yoh K, Aizawa N, Sakai Y, Ikeda N, Takashima T, Iijima H, Nishiguchi S. Impact of Wisteria floribunda Agglutinin-Positive Mac-2-Binding Protein in Patients with Hepatitis C Virus-Related Compensated Liver Cirrhosis. Int J Mol Sci 2016; 17:1500. [PMID: 27626413 PMCID: PMC5037777 DOI: 10.3390/ijms17091500] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Revised: 08/30/2016] [Accepted: 08/31/2016] [Indexed: 02/06/2023] Open
Abstract
We aimed to examine the effect of Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA⁺-M2BP) level on survival comparing with other laboratory liver fibrosis markers in hepatitis C virus (HCV)-related compensated liver cirrhosis (LC) (n = 165). For assessing prognostic performance of continuous fibrosis markers, we adapted time-dependent receiver operating characteristics (ROC) curves for clinical outcome. In time-dependent ROC analysis, annual area under the ROCs (AUROCs) were plotted. We also calculated the total sum of AUROCs in all time-points (TAAT score) in each fibrosis marker. WFA⁺-M2BP value ranged from 0.66 cutoff index (COI) to 19.95 COI (median value, 5.29 COI). Using ROC analysis for survival, the optimal cutoff point for WFA⁺-M2BP was 6.15 COI (AUROC = 0.79348, sensitivity = 80.0%, specificity = 74.78%). The cumulative five-year survival rate in patients with WFA⁺-M2BP ≥ 6.15 COI (n = 69) was 43.99%, while that in patients with WFA⁺-M2BP < 6.15 COI (n = 96) was 88.40% (p < 0.0001). In the multivariate analysis, absence of hepatocellular carcinoma (p = 0.0008), WFA⁺-M2BP < 6.15 COI (p = 0.0132), achievement of sustained virological response (p < 0.0001) and des-γ-carboxy prothrombin < 41 mAU/mL (p = 0.0018) were significant favorable predictors linked to survival. In time-dependent ROC analysis in all cases, WFA⁺-M2BP had the highest TAAT score among liver fibrosis markers. In conclusion, WFA⁺-M2BP can be a useful predictor in HCV-related compensated LC.
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Affiliation(s)
- Kunihiro Hasegawa
- Division of Hepatobiliary and Pancreatic disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo 663-8501, Japan.
| | - Ryo Takata
- Division of Hepatobiliary and Pancreatic disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo 663-8501, Japan.
| | - Hiroki Nishikawa
- Division of Hepatobiliary and Pancreatic disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo 663-8501, Japan.
| | - Hirayuki Enomoto
- Division of Hepatobiliary and Pancreatic disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo 663-8501, Japan.
| | - Akio Ishii
- Division of Hepatobiliary and Pancreatic disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo 663-8501, Japan.
| | - Yoshinori Iwata
- Division of Hepatobiliary and Pancreatic disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo 663-8501, Japan.
| | - Yuho Miyamoto
- Division of Hepatobiliary and Pancreatic disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo 663-8501, Japan.
| | - Noriko Ishii
- Division of Hepatobiliary and Pancreatic disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo 663-8501, Japan.
| | - Yukihisa Yuri
- Division of Hepatobiliary and Pancreatic disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo 663-8501, Japan.
| | - Chikage Nakano
- Division of Hepatobiliary and Pancreatic disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo 663-8501, Japan.
| | - Takashi Nishimura
- Division of Hepatobiliary and Pancreatic disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo 663-8501, Japan.
| | - Kazunori Yoh
- Division of Hepatobiliary and Pancreatic disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo 663-8501, Japan.
| | - Nobuhiro Aizawa
- Division of Hepatobiliary and Pancreatic disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo 663-8501, Japan.
| | - Yoshiyuki Sakai
- Division of Hepatobiliary and Pancreatic disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo 663-8501, Japan.
| | - Naoto Ikeda
- Division of Hepatobiliary and Pancreatic disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo 663-8501, Japan.
| | - Tomoyuki Takashima
- Division of Hepatobiliary and Pancreatic disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo 663-8501, Japan.
| | - Hiroko Iijima
- Division of Hepatobiliary and Pancreatic disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo 663-8501, Japan.
| | - Shuhei Nishiguchi
- Division of Hepatobiliary and Pancreatic disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo 663-8501, Japan.
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Kobayashi M, Suzuki F, Fujiyama S, Kawamura Y, Sezaki H, Hosaka T, Akuta N, Suzuki Y, Saitoh S, Arase Y, Ikeda K, Kumada H. Sustained virologic response by direct antiviral agents reduces the incidence of hepatocellular carcinoma in patients with HCV infection. J Med Virol 2016; 89:476-483. [DOI: 10.1002/jmv.24663] [Citation(s) in RCA: 92] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/12/2016] [Indexed: 01/01/2023]
Affiliation(s)
| | | | | | | | - Hitomi Sezaki
- Department of Hepatology; Toranomon Hospital; Tokyo Japan
| | - Tetsuya Hosaka
- Department of Hepatology; Toranomon Hospital; Tokyo Japan
| | - Norio Akuta
- Department of Hepatology; Toranomon Hospital; Tokyo Japan
| | | | - Satoshi Saitoh
- Department of Hepatology; Toranomon Hospital; Tokyo Japan
| | - Yasuji Arase
- Department of Hepatology; Toranomon Hospital; Tokyo Japan
| | - Kenji Ikeda
- Department of Hepatology; Toranomon Hospital; Tokyo Japan
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Kubo N, Araki K, Kuwano H, Shirabe K. Cancer-associated fibroblasts in hepatocellular carcinoma. World J Gastroenterol 2016; 22:6841-6850. [PMID: 27570421 PMCID: PMC4974583 DOI: 10.3748/wjg.v22.i30.6841] [Citation(s) in RCA: 133] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Revised: 06/09/2016] [Accepted: 07/06/2016] [Indexed: 02/06/2023] Open
Abstract
The hepatic stellate cells in the liver are stimulated sustainably by chronic injury of the hepatocytes, activating myofibroblasts, which produce abundant collagen. Myofibroblasts are the major source of extracellular proteins during fibrogenesis, and may directly, or secreted products, contribute to carcinogenesis and tumor progression. Cancer-associated fibroblasts (CAFs) are one of the components of the tumor microenvironment that promote the proliferation and invasion of cancer cells by secreting various growth factors and cytokines. CAFs crosstalk with cancer cells stimulates tumor progression by creating a favorable microenvironment for progression, invasion, and metastasis through the epithelial-mesenchymal transition. Basic studies on CAFs have advanced, and the role of CAFs in tumors has been elucidated. In particular, for hepatocellular carcinoma, carcinogenesis from cirrhosis is a known fact, and participation of CAFs in carcinogenesis is supported. In this review, we discuss the current literature on the role of CAFs and CAF-related signaling in carcinogenesis, crosstalk with cancer cells, immunosuppressive effects, angiogenesis, therapeutic targets, and resistance to chemotherapy. The role of CAFs is important in cancer initiation and progression. CAFtargeted therapy may be effective for suppression not only of fibrosis but also cancer progression.
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