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Heo S, Yang J, Park J, Hui RWH, Song BG, Song IH, Yoon YI, Cheung TT, Chung SW, Choi J, Lee D, Shim JH, Kim KM, Lim YS, Lee HC, Seto WK, Lee JH, Choi WM. Association Between Viral Replication Activity and Postoperative Recurrence of HBV-Related Hepatocellular Carcinoma. Aliment Pharmacol Ther 2025. [PMID: 40091291 DOI: 10.1111/apt.70085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 10/23/2024] [Accepted: 03/06/2025] [Indexed: 03/19/2025]
Abstract
BACKGROUND Baseline viral replication activity influences the risk of hepatocellular carcinoma (HCC) development in patients with chronic hepatitis B virus (HBV) infection. AIMS To evaluate the impact of baseline viral replication activity on recurrence in HBV-related HCC after curative resection. METHODS A multinational retrospective cohort of 2384 patients with very early or early-stage HBV-related HCC who consecutively underwent curative resection and received antiviral therapy (AVT) between 2010 and 2018 was analysed. Patients were categorised into ongoing-AVT (previously on AVT with viral suppression) and initiation-AVT (initiated AVT at the time of resection) groups. HCC recurrence was compared between these two groups based on baseline viral replication activity. RESULTS During a median follow-up of 4.9 years, 1188 (49.8%) patients developed recurrence. Multivariable analysis showed similar recurrence risk between the ongoing-AVT and initiation-AVT groups (HR, 1.09; 95% CI, 0.96-1.24). However, in cirrhotic patients, the initiation-AVT group had a higher recurrence risk than the ongoing-AVT group (HR, 1.22; 95% CI, 1.02-1.45) but not in non-cirrhotic patients (HR, 0.90; 95% CI, 0.73-1.09). Intriguingly, in the non-cirrhotic initiation-AVT group, a parabolic association was observed between baseline HBV DNA levels and the risk of recurrence, with those having 5-6 log10 IU/mL HBV DNA levels showing significantly higher recurrence risk compared to the ongoing-AVT group (HR, 1.78; 95% CI, 1.32-2.42). CONCLUSIONS The association between HBV replication activity and the risk of HCC recurrence varied depending on cirrhosis, providing important insights for optimising the timing of AVT and post-operative surveillance strategies.
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Affiliation(s)
- Subin Heo
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Jiwon Yang
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Jeayeon Park
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Rex Wan-Hin Hui
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Pokfulam, Hong Kong
| | - Byeong Geun Song
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - In-Hye Song
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Young-In Yoon
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Tan-To Cheung
- Department of Surgery, School of Clinical Medicine, The University of Hong Kong, Pokfulam, Hong Kong
| | - Sung Won Chung
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Jonggi Choi
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Danbi Lee
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Ju Hyun Shim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Kang Mo Kim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Young-Suk Lim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Han Chu Lee
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Wai-Kay Seto
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Pokfulam, Hong Kong
| | - Jeong-Hoon Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Won-Mook Choi
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
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Wu KC, Lee IC, Liu CA, Chiu NC, Hsu SJ, Lee PC, Wu CJ, Chi CT, Luo JC, Hou MC, Huang YH. Diabetes Mellitus Negatively Impacts Outcomes of HBV-Related Hepatocellular Carcinoma Following Thermal Ablation. J Hepatocell Carcinoma 2024; 11:2257-2267. [PMID: 39588492 PMCID: PMC11586263 DOI: 10.2147/jhc.s488061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 11/13/2024] [Indexed: 11/27/2024] Open
Abstract
Purpose Diabetes mellitus (DM) negatively impacts chronic hepatitis B patients, but its role in those with HBV-related hepatocellular carcinoma (HCC) undergoing ablation remains unclear. This study aims to evaluate the influence of DM on recurrence patterns and overall survival (OS) among patients with HBV-related HCC undergoing ablation. Patients and Methods We retrospectively enrolled 372 patients receiving thermal ablation for HBV-related HCC, including 96 (25.8%) patients with DM. Factors associated with local tumor progression (LTP), distant recurrence, and OS were analyzed. The prognostic value of DM in IMbrave050-defined high-risk population was validated. Results DM did not correlate with LTP, whereas patients with DM had significantly higher risk of distant recurrence (median time to recurrence 23.7 versus 46.2 months, p=0.032), poorer OS (median OS 75.6 versus 106 months, p=0.011), and poorer post-recurrence survival (70.7 versus 106 months, p=0.009). In multivariate analysis, DM (hazard ratio (HR)=1.466, p=0.012), FIB-4 score, multiple tumors, and AFP level were independent predictors of distant recurrence, while DM (HR=1.424, p=0.028), ALBI score, tumor size, AFP and creatinine levels were significantly associated with OS. A DM-based risk score effectively discriminated the risk of distant recurrence. The IMbrave050 criteria could stratify the risk of LTP but not distant recurrence. DM status further discriminated the risk of distant recurrence and mortality in the IMbrave050-defined high-risk population. Conclusion Patients with DM had an increased risk of distant recurrence and mortality after thermal ablation for HBV-related HCC, highlighting the importance of increasing awareness of DM and implementing rigorous post-ablation monitoring for diabetic HCC patients.
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Affiliation(s)
- Kuo-Cheng Wu
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Keelung Hospital, Ministry of Health and Welfare, Keelung, Taiwan
| | - I-Cheng Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chien-An Liu
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Nai-Chi Chiu
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Shao-Jung Hsu
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Pei-Chang Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chi-Jung Wu
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chen-Ta Chi
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Jiing-Chyuan Luo
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Ming-Chih Hou
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yi-Hsiang Huang
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Healthcare and Service Center, Taipei Veterans General Hospital, Taipei, Taiwan
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Cardoso MF, Machado MV. The Changing Face of Hepatitis Delta Virus Associated Hepatocellular Carcinoma. Cancers (Basel) 2024; 16:3723. [PMID: 39594679 PMCID: PMC11591730 DOI: 10.3390/cancers16223723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 09/22/2024] [Accepted: 11/01/2024] [Indexed: 11/28/2024] Open
Abstract
Hepatitis delta virus (HDV) infection requires the presence of hepatitis B virus (HBV), and chronic HBV-HDV coinfection is considered the most severe form of viral hepatitis. When compared with HBV mono-infection, HBV-HDV coinfection is associated with higher rates of liver cirrhosis and hepatocellular carcinoma (HCC). In this review, we aim to elucidate the complex relationship between HDV infection and the development of HCC. The exact mechanisms underlying the carcinogenic potential of HDV remain to be fully elucidated. Evidence suggests that HDV has both indirect and direct oncogenic effects. Indirect effects promote accelerated progression to liver cirrhosis, which results in a different tumor microenvironment. Direct oncogenic effects are suggested by a distinct molecular signature. The recent epidemiological data regarding HBV-HDV coinfection should make us reconsider the HCC screening strategy, with special focus in younger non-cirrhotic patients. Finally, treating HCC in patients with chronic HDV poses unique challenges due to the complex interplay between HBV and HDV and the severity of liver disease. An in-depth understanding of the epidemiology and pathophysiology of HDV infection and carcinogenesis is essential to improve disease management in this high-risk population.
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Affiliation(s)
- Mariana Ferreira Cardoso
- Gastroenterology Department, Hospital Prof. Doutor Fernando Fonseca, 2720-276 Amadora, Portugal;
- Clínica Universitária de Gastrenterologia, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal
| | - Mariana Verdelho Machado
- Clínica Universitária de Gastrenterologia, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal
- Gastroenterology Department, Hospital de Vila Franca de Xira, 2600-009 Vila Franca de Xira, Portugal
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Wu KC, Lee IC, Chi CT, Liu CA, Chiu NC, Hsu SJ, Lee PC, Wu CJ, Luo JC, Hou MC, Huang YH. Impact of HCV eradication on recurrence pattern and long-term outcomes in patients with HCV-related hepatocellular carcinoma undergoing radiofrequency ablation. Aliment Pharmacol Ther 2024; 60:940-952. [PMID: 39113355 DOI: 10.1111/apt.18199] [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: 04/29/2024] [Revised: 06/10/2024] [Accepted: 07/23/2024] [Indexed: 11/01/2024]
Abstract
BACKGROUND The benefits of HCV eradication on distinct recurrence patterns and long-term hepatic outcomes in patients with hepatocellular carcinoma (HCC) undergoing radiofrequency ablation (RFA) remain uncertain. This study aims to assess the impact of HCV eradication on HCC recurrence patterns and long-term hepatic outcomes after RFA and to identify predictors of recurrence in patients achieving sustained virological response (SVR). METHODS We retrospectively enrolled 274 patients receiving RFA for HCV-related HCC, including 73 and 88 patients treated with interferon-based (IFN) and direct-acting antivirals (DAA) therapy, respectively. We analysed factors associated with local tumour progression (LTP), distant recurrence, overall survival, and hepatic decompensation. RESULTS SVR was achieved in 49.3% of patients undergoing IFN therapy and 93.2% of patients undergoing DAA therapy. HCV eradication was not associated with LTP but significantly correlated with reduced risk of distant recurrence (by DAA: hazard ratio (HR) = 0.449, p = 0.006), overall survival (by IFN: HR = 0.242, p < 0.001; by DAA: HR = 0.274, p < 0.001) and hepatic decompensation (by IFN: HR = 0.313, p = 0.004; by DAA: HR = 0.281, p < 0.001). The benefits of achieving SVR in terms of overall survival and hepatic decompensation remained significant in subgroups of patients with and without recurrence. Patients with SVR showed a significant decline in FIB-4 score and a higher proportion of ALBI grade improvement. Among SVR patients, the IMbrave050 criteria predicted LTP but not distant recurrence, whereas the FIB-4 score after SVR, rather than the baseline FIB-4, predicted distant recurrence. CONCLUSIONS HCV eradication was associated with a significant reduction in distant recurrence, mortality and hepatic decompensation following RFA in patients with HCV-related HCC.
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Affiliation(s)
- Kuo-Cheng Wu
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Keelung Hospital, Ministry of Health and Welfare, Keelung, Taiwan
| | - I-Cheng Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chen-Ta Chi
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chien-An Liu
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Nai-Chi Chiu
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Shao-Jung Hsu
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Pei-Chang Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chi-Jung Wu
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Jiing-Chyuan Luo
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Ming-Chih Hou
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yi-Hsiang Huang
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Healthcare and Service Center, Taipei Veterans General Hospital, Taipei, Taiwan
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Kim MN, Kim BK, Cho H, Goh MJ, Roh YH, Yu SJ, Sinn DH, Park SY, Kim SU. Similar recurrence after curative treatment of HBV-related HCC, regardless of HBV replication activity. PLoS One 2024; 19:e0307712. [PMID: 39186715 PMCID: PMC11346930 DOI: 10.1371/journal.pone.0307712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Accepted: 07/09/2024] [Indexed: 08/28/2024] Open
Abstract
BACKGROUND AND AIMS Antiviral therapy (AVT) is required in patients with newly diagnosed hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), if HBV DNA is detectable. We compared the risk of recurrence according to HBV replication activity at the curative treatment of HBV-related HCC. METHODS Patients with HBV-related HCC who underwent surgical resection or radiofrequency ablation between 2013 and 2018 were enrolled in this retrospective cohort study. Patients were categorized into two groups according to HBV replication activity at the curative treatment of HBV-related HCC (group 1: patients who met the AVT indication for HBV-related HCC due to detectable HBV DNA but did not meet the AVT indication if without HCC; group 2: patients who met the AVT indication, regardless of HCC). RESULTS In the entire cohort (n = 911), HCC recurred in 303 (33.3%) patients during a median follow-up of 4.7 years. After multivariate adjustment, group 2 showed a statistically similar risk of HCC recurrence (adjusted hazard ratio [aHR] = 1.18, P = 0.332) compared to that of group 1. In addition, group 2 showed statistically similar risks of early (< 2 years; aHR = 1.31) and late (≥ 2 years; aHR = 0.83) recurrence than that of group 1 (all P>0.05). Propensity score matching and inverse probability of treatment weighting analysis also yielded similar risks of HCC recurrence between the two groups (all P>0.05, log-rank tests). CONCLUSIONS The risk of HCC recurrence in patients who received curative treatment for newly diagnosed HBV-related HCC was similar regardless of HBV replication activity, if AVT was properly initiated.
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Affiliation(s)
- Mi Na Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
| | - Heejin Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Myung Ji Goh
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yun Ho Roh
- Biostatistics Collaboration Unit, Department of Biomedical Systems Informatics, Yonsei 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
| | - Dong Hyun Sinn
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Soo Young Park
- Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
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Peng JX, Wang LZ, Wang QT, Li HL, Lin LJ, He JM. Tenofovir versus entecavir on the prognosis of hepatitis B virus-related hepatocellular carcinoma: a reconstructed individual patient data meta-analysis. Front Pharmacol 2024; 15:1393861. [PMID: 39239648 PMCID: PMC11374766 DOI: 10.3389/fphar.2024.1393861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Accepted: 07/16/2024] [Indexed: 09/07/2024] Open
Abstract
Background: Hepatitis B, often leading to Hepatocellular carcinoma (HCC), poses a major global health challenge. While Tenofovir (TDF) and Entecavir (ETV) are potent treatments, their comparative effectiveness in improving recurrence-free survival (RFS) and overall survival (OS) rates in HBV-related HCC is not well-established. Methods: We conducted an individual patient data meta-analysis using survival data from randomized trials and high-quality propensity score-matched studies to compare the impact of Tenofovir (TDF) and Entecavir (ETV) on RFS and OS in HBV-related HCC patients. Data from six databases and gray literature up to 30 August 2023, were analyzed, utilizing Kaplan-Meier curves, stratified Cox models, and shared frailty models for survival rate assessment and to address between-study heterogeneity. The study employed restricted mean survival time analysis to evaluate differences in RFS and OS between TDF-treated and ETV-treated patients. Additionally, landmark analyses compared early (<2 years) and late (≥2 years) tumor recurrence in these cohorts. Results: This study incorporated seven research articles, covering 4,602 patients with HBV-related HCC (2,082 on TDF and 2,520 on ETV). Within the overall cohort, TDF recipients demonstrated significantly higher RFS (p = 0.042) and OS (p < 0.001) than those on ETV. The stratified Cox model revealed significantly improved OS for the TDF group compared to the ETV group (hazard ratio, 0.756; 95% confidence interval, 0.639-0.896; p = 0.001), a result corroborated by the shared frailty model. Over a follow-up period of 1-8 years, no significant difference was noted in the mean time to death between the TDF and ETV groups. The rates of early recurrence did not significantly differ between the groups (p = 0.735). However, TDF treatment was significantly associated with a reduced risk of late recurrence compared to ETV (p < 0.001). In the HCC resection subgroup, the disparities in OS, early, and late recurrence rates between the two treatments paralleled those seen in the overall cohort. Conclusion: Compared to ETV, TDF may enhance OS and reduce late tumor recurrence risk in HBV-related HCC patients receiving curative treatment. However, there was no statistically significant distinction in the timing of tumor recurrence and mortality between patients administered TDF and those prescribed ETV. Systematic Review Registration: http://www.crd.york.ac.uk/prospero/.
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Affiliation(s)
- Jian-Xin Peng
- Department of Hepatobiliary Surgery, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - Ling-Zhi Wang
- Department of Anesthesia, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Qiu-Ting Wang
- Department of Hepatobiliary Surgery, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - Hui-Long Li
- Department of Hepatobiliary Surgery, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - Li-Jun Lin
- Department of Hepatobiliary Surgery, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - Jun-Ming He
- Department of Hepatobiliary Surgery, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
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Suddle A, Reeves H, Hubner R, Marshall A, Rowe I, Tiniakos D, Hubscher S, Callaway M, Sharma D, See TC, Hawkins M, Ford-Dunn S, Selemani S, Meyer T. British Society of Gastroenterology guidelines for the management of hepatocellular carcinoma in adults. Gut 2024; 73:1235-1268. [PMID: 38627031 PMCID: PMC11287576 DOI: 10.1136/gutjnl-2023-331695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 03/19/2024] [Indexed: 05/01/2024]
Abstract
Deaths from the majority of cancers are falling globally, but the incidence and mortality from hepatocellular carcinoma (HCC) is increasing in the United Kingdom and in other Western countries. HCC is a highly fatal cancer, often diagnosed late, with an incidence to mortality ratio that approaches 1. Despite there being a number of treatment options, including those associated with good medium to long-term survival, 5-year survival from HCC in the UK remains below 20%. Sex, ethnicity and deprivation are important demographics for the incidence of, and/or survival from, HCC. These clinical practice guidelines will provide evidence-based advice for the assessment and management of patients with HCC. The clinical and scientific data underpinning the recommendations we make are summarised in detail. Much of the content will have broad relevance, but the treatment algorithms are based on therapies that are available in the UK and have regulatory approval for use in the National Health Service.
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Affiliation(s)
- Abid Suddle
- King's College Hospital NHS Foundation Trust, London, UK
| | - Helen Reeves
- Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, UK
| | - Richard Hubner
- Department of Oncology, The Christie NHS Foundation Trust, Manchester, UK
| | | | - Ian Rowe
- University of Leeds, Leeds, UK
- St James's University Hospital, Leeds, UK
| | - Dina Tiniakos
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - Stefan Hubscher
- Department of Pathology, University of Birmingham, Birmingham, UK
| | - Mark Callaway
- Division of Diagnostics and Therapies, University Hospitals Bristol NHS Trust, Bristol, UK
| | | | - Teik Choon See
- Department of Radiology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Maria Hawkins
- Department of Medical Physics and Biomedical Engineering, University College London, London, UK
| | | | - Sarah Selemani
- King's College Hospital NHS Foundation Trust, London, UK
| | - Tim Meyer
- Department of Oncology, University College, London, UK
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Kaneko S, Asahina Y, Murakawa M, Azuma S, Inada K, Mochida T, Watakabe K, Shimizu T, Tsuchiya J, Miyoshi M, Kawai-Kitahata F, Nitta S, Takahashi M, Fujioka T, Kishino M, Anzai T, Kakinuma S, Nakagawa M, Okamoto R. Analysis of prognosis and background liver disease in non-advanced hepatocellular carcinoma in two decades. PLoS One 2024; 19:e0297882. [PMID: 38452155 PMCID: PMC10919582 DOI: 10.1371/journal.pone.0297882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 01/03/2024] [Indexed: 03/09/2024] Open
Abstract
BACKGROUND/AIM Antiviral hepatitis and systemic therapies for hepatocellular carcinoma (HCC) remarkably progressed in the recent 10 years. This study aimed to reveal the actual transition and changes in the prognosis and background liver disease in non-advanced HCC in the past 20 years. METHODS This retrospectively recruited 566 patients who were diagnosed with non-advanced HCC from February 2002 to February 2022. The prognosis was analyzed by subdividing according to the diagnosis date (period I: February 2002-April 2009 and period Ⅱ: May 2009-February 2022). RESULTS Patients in period II (n = 351) were significantly older, with lower albumin-bilirubin (ALBI) scores and alpha-fetoprotein (AFP) and more anti-viral therapy, systemic therapy, and hepatic arterial infusion chemotherapy as compared with those in period I (n = 215). The etiology ratio of the background liver disease revealed decreased hepatitis C virus from 70.6% to 49.0% and increased non-B, non-C from 17.7% to 39.9% from periods I to Ⅱ. The multivariate analysis revealed older age and higher ALBI score in Barcelona Clinic Liver Cancer (BCLC) 0/A stage, AFP of >20 ng/mL, and higher ALBI score in BCLC B stage as independent prognosis factors. Fine-Gray competing risk model analysis revealed that liver-related deaths significantly decreased in period II as compared to period I, especially for BCLC stage 0/A (HR: 0.656; 95%CI: 0.442-0.972, P = 0.036). CONCLUSION The characteristics of patients with non-advanced HCC have changed over time. Appropriate background liver management led to better liver-related prognoses in BCLC 0/A.
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Affiliation(s)
- Shun Kaneko
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yasuhiro Asahina
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Liver Disease Control, Tokyo Medical and Dental University, Tokyo, Japan
| | - Miyako Murakawa
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Seishin Azuma
- Department of Gastroenterology and Hepatology, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan
| | - Kento Inada
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tomohiro Mochida
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Keiya Watakabe
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Taro Shimizu
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Jun Tsuchiya
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Masato Miyoshi
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Fukiko Kawai-Kitahata
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Sayuri Nitta
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Marie Takahashi
- Department of Diagnostic Radiology and Nuclear Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tomoyuki Fujioka
- Department of Diagnostic Radiology and Nuclear Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Mitsuhiro Kishino
- Department of Diagnostic Radiology and Nuclear Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tatsuhiko Anzai
- Department of Biostatistics, M&D Data Science Center, Tokyo Medical and Dental University, Tokyo, Japan
| | - Sei Kakinuma
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Mina Nakagawa
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Ryuichi Okamoto
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
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9
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Lee TY, Hsu YC, Ho HJ, Lin JT, Chen YJ, Wu CY. Daily aspirin associated with a reduced risk of hepatocellular carcinoma in patients with non-alcoholic fatty liver disease: a population-based cohort study. EClinicalMedicine 2023; 61:102065. [PMID: 37434747 PMCID: PMC10331813 DOI: 10.1016/j.eclinm.2023.102065] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 06/09/2023] [Accepted: 06/12/2023] [Indexed: 07/13/2023] Open
Abstract
Background Emerging laboratory and animal studies suggest that aspirin may prevent non-alcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma (HCC), however clinical evidence remains lacking. Methods Using Taiwan's National Health Insurance Research Database, we screened 145,212 NAFLD patients from 1997 through 2011. After excluding any confounding conditions, 33,484 patients who continuously received a daily dose of aspirin for 90 days or more (treated group), along with 55,543 patients who had not received antiplatelet therapy (untreated group), were respectively recruited. Inverse probability of treatment weighting using the propensity score was applied to balance the baseline characteristics. Cumulative incidence of, and hazard ratio (HR) for HCC occurrence were analyzed after adjusting competing events. The high-risk patients, who were defined as age ≥ 55 years & elevated serum alanine aminotransferase, were further analyzed. Findings The 10-year cumulative incidence of HCC in the treated group was significantly lower than that in the untreated group (0.25% [95% CI, 0.19-0.32%] vs. 0.67% [95% CI, 0.54-0.81%]; P < 0.001). Aspirin therapy was significantly associated with a reduced HCC risk (adjusted HR [aHR] 0.48 [95% CI, 0.37-0.63]; P < 0.001). In the high-risk patients, the 10-year cumulative incidence of HCC in the treated group was significantly lower than that in the untreated group (3.59% [95% CI, 2.99-4.19%] vs. 6.54% [95% CI, 5.65-7.42%]; P < 0.001). Aspirin therapy remained associated with a reduced HCC risk (aHR 0.63 [95% CI, 0.53-0.76]; P < 0.001). Subgroup sensitivity analyses verified this significant association in nearly all subgroups. In the time-varying model amongst aspirin users, HCC risk was significantly lower through the use of aspirin for ≥ 3 years (aHR 0.64 [95% CI, 0.44-0.91]; P = 0.013), when compared with short-term use (< 1 year). Interpretation Daily aspirin therapy is significantly associated with a reduced HCC risk in NAFLD patients. Funding Ministry of Science and Technology, Ministry of Health and Welfare, and Taichung Veterans General Hospital, Taiwan.
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Affiliation(s)
- Teng-Yu Lee
- Division of Gastroenterology & Hepatology, Taichung Veterans General Hospital, Taichung, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Yao-Chun Hsu
- Division of Gastroenterology and Hepatology, E-Da Hospital, Kaohsiung, Taiwan
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan
- Division of Gastroenterology and Hepatology, Fu-Jen Catholic University Hospital, New Taipei, Taiwan
- Institute of Biomedical Informatics, Health Innovation Center, and Microbiota Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Hsiu J. Ho
- Institute of Biomedical Informatics, Health Innovation Center, and Microbiota Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Jaw-Town Lin
- Division of Gastroenterology and Hepatology, E-Da Hospital, Kaohsiung, Taiwan
| | - Yi-Ju Chen
- Institute of Biomedical Informatics, Health Innovation Center, and Microbiota Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Department of Dermatology, Taichung Veterans General Hospital, Taichung, Taiwan
- Department of Post Baccalaureate Medicine, National Chung Hsing University, Taichung, Taiwan
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chun-Ying Wu
- Institute of Biomedical Informatics, Health Innovation Center, and Microbiota Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Translational Medicine, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
- College of Public Health, China Medical University, Taichung, Taiwan
- National Institute of Cancer Research and Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan
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10
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Wang P, Wang X, Liu X, Yan F, Yan H, Zhou D, Yu L, Wang X, Yang Z. Primary non-response to antiviral therapy affects the prognosis of hepatitis B virus-related hepatocellular carcinoma. BMC Cancer 2023; 23:564. [PMID: 37340357 PMCID: PMC10280839 DOI: 10.1186/s12885-023-11059-y] [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: 12/02/2022] [Accepted: 06/12/2023] [Indexed: 06/22/2023] Open
Abstract
BACKGROUND AND AIM Although antiviral treatments have been shown to affect the recurrence and long-term survival of patients with hepatocellular carcinoma (HCC) who have high viral loads, the effect of different responses to antiviral therapy on the clinical outcomes remains unclear. This study aimed to assess the effect of primary non-response (no-PR) to antiviral therapy on the survival or prognosis of patients with HCC with a high load of hepatitis B virus (HBV) DNA. METHODS A total of 493 HBV-HCC patients hospitalized at Beijing Ditan Hospital of Capital Medical University were admitted to this retrospective study. Patients were divided into two groups based on viral response (no-PR and primary response). Kaplan-Meier (KM) curves were used to compare the overall survival of the two cohorts. Serum viral load comparison and subgroup analysis were performed. Additionally, risk factors were screened and the risk score chart was created. RESULTS This study consisted of 101 patients with no-PR and 392 patients with primary response. In the different categories based on hepatitis B e antigen and HBV DNA, no-PR group had a poor 1-year overall survival (OS). In addition, in the alanine aminotransferase < 50 IU/L and cirrhosis groups, primary nonresponse was related to poor overall survival and progression-free survival. Based on multivariate risk analysis, primary non-response (hazard ratio (HR) = 1.883, 95% CI 1.289-2.751, P = 0.001), tumor multiplicity (HR = 1.488, 95% CI 1.036-2.136, P = 0.031), portal vein tumor thrombus (HR = 2.732, 95% CI 1.859-4.015, P < 0.001), hemoglobin < 120 g/L (HR = 2.211, 95% CI 1.548-3.158, P < 0.001) and tumor size ≥ 5 cm (HR = 2.202, 95% CI 1.533-3.163, P < 0.001) were independent risk factors for 1-year OS. According to the scoring chart, patients were divided into three risk groups (high-, medium-, and low-risk groups) with mortality rates of 61.7%, 30.5%, and 14.1%, respectively. CONCLUSIONS The level of viral decline at 3 months post-antiviral treatment may predict the OS of patients with HBV-related HCC, and primary non-response may shorten the median survival time of patients with high HBV-DNA levels.
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Affiliation(s)
- Peng Wang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8 Jing Shun East Street, Beijing, 100015, P.R. China
| | - Xinhui Wang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8 Jing Shun East Street, Beijing, 100015, P.R. China
| | - Xiaoli Liu
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8 Jing Shun East Street, Beijing, 100015, P.R. China
| | - Fengna Yan
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8 Jing Shun East Street, Beijing, 100015, P.R. China
| | - Huiwen Yan
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8 Jing Shun East Street, Beijing, 100015, P.R. China
| | - Dongdong Zhou
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8 Jing Shun East Street, Beijing, 100015, P.R. China
| | - Lihua Yu
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8 Jing Shun East Street, Beijing, 100015, P.R. China
| | - Xianbo Wang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8 Jing Shun East Street, Beijing, 100015, P.R. China
| | - Zhiyun Yang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8 Jing Shun East Street, Beijing, 100015, P.R. China.
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11
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Nevola R, Delle Femine A, Rosato V, Kondili LA, Alfano M, Mastrocinque D, Imbriani S, Perillo P, Beccia D, Villani A, Ruocco R, Criscuolo L, La Montagna M, Russo A, Marrone A, Sasso FC, Marfella R, Rinaldi L, Esposito N, Barberis G, Claar E. Neoadjuvant and Adjuvant Systemic Therapies in Loco-Regional Treatments for Hepatocellular Carcinoma: Are We at the Dawn of a New Era? Cancers (Basel) 2023; 15:cancers15112950. [PMID: 37296912 DOI: 10.3390/cancers15112950] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 05/20/2023] [Accepted: 05/26/2023] [Indexed: 06/12/2023] Open
Abstract
Despite maximizing techniques and patient selection, liver resection and ablation for HCC are still associated with high rates of recurrence. To date, HCC is the only cancer with no proven adjuvant or neoadjuvant therapy used in association to potentially curative treatment. Perioperative combination treatments are urgently needed to reduce recurrence rates and improve overall survival. Immunotherapy has demonstrated encouraging results in the setting of adjuvant and neoadjuvant treatments for non-hepatic malignancies. Conclusive data are not yet available in the context of liver neoplasms. However, growing evidence suggests that immunotherapy, and in particular immune checkpoint inhibitors, could represent the cornerstone of an epochal change in the treatment of HCC, improving recurrence rates and overall survival through combination treatments. Furthermore, the identification of predictive biomarkers of treatment response could drive the management of HCC into the era of a precision medicine. The purpose of this review is to analyze the state of the art in the setting of adjuvant and neoadjuvant therapies for HCC in association with loco-regional treatments in patients not eligible for liver transplantation and to hypothesize future scenarios.
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Affiliation(s)
- Riccardo Nevola
- Liver Unit, Ospedale Evangelico Betania, 80147 Naples, Italy
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Augusto Delle Femine
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Valerio Rosato
- Liver Unit, Ospedale Evangelico Betania, 80147 Naples, Italy
| | | | - Maria Alfano
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | | | - Simona Imbriani
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | | | - Domenico Beccia
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Angela Villani
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Rachele Ruocco
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Livio Criscuolo
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Marco La Montagna
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Antonio Russo
- Department of Mental Health and Public Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Aldo Marrone
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Ferdinando Carlo Sasso
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Raffaele Marfella
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Luca Rinaldi
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | | | | | - Ernesto Claar
- Liver Unit, Ospedale Evangelico Betania, 80147 Naples, Italy
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12
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Chen S, Shen B, Wu Y, Shen L, Qi H, Cao F, Huang T, Tan H, Wen C, Fan W. The relationship between the efficacy of thermal ablation and inflammatory response and immune status in early hepatocellular carcinoma and the progress of postoperative adjuvant therapy. Int Immunopharmacol 2023; 119:110228. [PMID: 37121111 DOI: 10.1016/j.intimp.2023.110228] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Revised: 04/10/2023] [Accepted: 04/20/2023] [Indexed: 05/02/2023]
Abstract
Hepatocellular carcinoma (HCC) is a highly heterogeneous disease. Thermal ablation has the advantages of being equivalent to surgical resection, minimally invasive, low cost and significantly reducing hospital stay. Therefore, it is recommended as one of the first-line radical treatment for early HCC. However, with the deepening of research on early HCC, more and more studies have found that not all patients with early HCC can obtain similar efficacy after radical thermal ablation, which may be related to the heterogeneity of HCC. Previous studies have shown that inflammation and immunity play an extremely important role in the prognostic heterogeneity of patients with HCC. Therefore, the inflammatory response and immune status of patients may be closely related to the efficacy of early HCC after curative thermal ablation. This article elaborates the mechanism of high inflammatory response and poor immune status in the poor prognosis after radical thermal ablation of early HCC, and clarifies the population who may benefit from adjuvant therapy after radical thermal ablation in patients with early HCC, which provides a new idea for the precise adjuvant treatment after radical ablation of early HCC in the future.
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Affiliation(s)
- Shuanggang Chen
- Department of Oncology, Yuebei People's Hospital, Shantou University Medical College, Shaoguan 512025, Guangdong, People's Republic of China; Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China.
| | - Binyan Shen
- Department of Nursing, Medical College of Shaoguan University, Shaoguan 512026, People's Republic of China
| | - Ying Wu
- Department of Interventional Therapy, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China
| | - Lujun Shen
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, People's Republic of China
| | - Han Qi
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, People's Republic of China
| | - Fei Cao
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, People's Republic of China
| | - Tao Huang
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, People's Republic of China
| | - Hongtong Tan
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, People's Republic of China
| | - Chunyong Wen
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, People's Republic of China
| | - Weijun Fan
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, People's Republic of China.
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13
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Liu J, Shen H, Huang S, Lin J, Yan Z, Qian G, Lu Z, Wan X, Zhang F, Wang K, Zhang Y, Li J. Antiviral therapy inhibited HBV-reactivation and improved long-term outcomes in patients who underwent radiofrequency ablation for HBV-related hepatocellular carcinoma. World J Surg Oncol 2023; 21:42. [PMID: 36765340 PMCID: PMC9921597 DOI: 10.1186/s12957-023-02921-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Accepted: 01/30/2023] [Indexed: 02/12/2023] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) reactivation impact negatively the prognosis of patients with HBV-related hepatocellular carcinoma (HCC). This study aimed to observe the effect of antiviral therapy (AVT) on viral reactivation and long-term outcomes after percutaneous radiofrequency ablation (PRFA) for HBV-related HCC. METHODS Data on 538 patients between 2009 and 2013 were reviewed. Propensity score matching (PSM) analysis was used to adjust for differences in baseline features between patients who received AVT (AVT group) and did not receive it (non-AVT group). Logistic regression was used to identify the independent factors for viral reactivation. The tumor recurrence and overall survival (OS) rates were analyzed using the Kaplan-Meier method. Recurrence patterns were also investigated. RESULTS HBV reactivation developed in 10.8% (58/538) of patients after PRFA. AVT was associated independently with decreased viral reactivation (odd ratio: 0.061, 95% confidence interval: 0.018-0.200). In 215 pairs of patients obtained after PSM, the AVT group had lower 1-, 3-, and 5-year recurrence rates (24%, 55%, and 67% vs 33%, 75%, and 85%, respectively) and higher 1-, 3-, and 5-year OS rates (100%, 67%, and 59% vs 100%, 52%, and 42%, respectively) than non-AVT group (P < 0.001 for both). Additionally, the relapses in distant hepatic segments and the late recurrence after 2 years of PRFA were significantly reduced in the AVT group (78/215 vs 111/215 vs., P = 0.001; 39/109 vs. 61/91, P = 0.012, respectively). CONCLUSIONS AVT reduced late and distal intrahepatic recurrence and improved OS in patients undergoing PRFA for HBV-related HCC by inhibiting viral reactivation.
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Affiliation(s)
- Jian Liu
- Department of Hepatic Surgery, The Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China ,Department of Biliary Surgery, The Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Hao Shen
- Department of Hepatic Surgery, The Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Shengyu Huang
- grid.412538.90000 0004 0527 0050Department of Hepatobiliary and Pancreatic Surgery, Tenth People’s Hospital of Tongji University, Shanghai, China
| | - Jianbo Lin
- grid.412538.90000 0004 0527 0050Department of Hepatobiliary and Pancreatic Surgery, Tenth People’s Hospital of Tongji University, Shanghai, China
| | - Zhenlin Yan
- Department of Hepatic Surgery, The Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Guojun Qian
- Department of Minimally Intervention Therapy, The Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Zhenghua Lu
- Department of Minimally Intervention Therapy, The Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Xuying Wan
- Department of Clinical Database, The Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Fabiao Zhang
- grid.268099.c0000 0001 0348 3990Taizhou Hospital of Zhejiang Province, Affiliated to Wenzhou Medical University, Taizhou, China
| | - Kui Wang
- Department of Hepatic Surgery, The Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Yongjie Zhang
- Department of Biliary Surgery, The Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China.
| | - Jun Li
- Department of Hepatobiliary and Pancreatic Surgery, Tenth People's Hospital of Tongji University, Shanghai, China.
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Kim MN, Kim BK, Roh YH, Choi NR, Yu SJ, Kim SU. Comparable Efficacy Between Ongoing Versus Initiation of Antiviral Therapy at Treatment for HBV-related Hepatocellular Carcinoma. Clin Gastroenterol Hepatol 2022; 20:1877-1880.e3. [PMID: 35181566 DOI: 10.1016/j.cgh.2022.02.014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Revised: 02/04/2022] [Accepted: 02/07/2022] [Indexed: 02/07/2023]
Abstract
Suppression of hepatitis B virus (HBV) replication with antiviral therapy (AVT) using nucleos(t)ide analogs reduces the risk of hepatocellular carcinoma (HCC) recurrence and prolongs survival after curative treatment.1-5 Studies of the association between timing of AVT initiation and prognosis of patients with HCC receiving curative treatment are scarce. In the present study, we compared the therapeutic benefit of AVT, commenced before vs after curative treatment of HBV-related HCC, on long-term prognosis.
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Affiliation(s)
- Mi Na Kim
- Division of Gastroenterology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Republic of Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea; Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea
| | - Yun Ho Roh
- Biostatistics Collaboration Unit, Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Na Ryung Choi
- 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.
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea; Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea.
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15
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Wang Y, Li X, Yu J, Cheng Z, Hou Q, Liang P. Prognostic Nutritional Index in Hepatocellular Carcinoma Patients With Hepatitis B Following US-Guided Percutaneous Microwave Ablation: A Retrospective Study With 1,047 Patients. Front Surg 2022; 9:878737. [PMID: 35846958 PMCID: PMC9276976 DOI: 10.3389/fsurg.2022.878737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 06/03/2022] [Indexed: 12/24/2022] Open
Abstract
ObjectiveSeveral studies have revealed that the prognostic nutritional index (PNI) was associated with survival in several cancers. However, the prognostic value of PNI in hepatocellular carcinoma (HCC) patients following ultrasound-guided percutaneous microwave ablation (US-PMWA) remains unknown, especially in patients with hepatitis B virus (HBV) infection. Therefore, the present study aimed to evaluate the potential prognostic value of PNI in these patients.MaterialsThe medical records of 1,047 HCC patients with HBV infection following US-PMWA were retrospectively reviewed. The association between preoperative PNI and overall survival (OS), as well as other clinical characteristics of HCC, were analyzed using the Kaplan–Meier plot, log-rank test, multi-parameter Cox proportional hazards model, restricted cubic spline (RCS), and time-dependent receiver operating characteristic (ROC) curve analyses.ResultsPatients with a preoperative PNI more than 45 were verified to have better OS than patients with a PNI less than 45. In the multi-parameter Cox proportional hazards models, the log-transformed PNI was verified as an independent prognostic factor for OS. The result of the RCS analysis revealed that there was a nearly linear relationship between PNI and OS. The area under the time-dependent ROC curve for PNI in predicting OS was 0.56, which is relatively stable.ConclusionPreoperative PNI represents a convenient, noninvasive, and independent prognostic indicator in HCC patients with HBV infection following US-PMWA.
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KASL clinical practice guidelines for management of chronic hepatitis B. Clin Mol Hepatol 2022; 28:276-331. [PMID: 35430783 PMCID: PMC9013624 DOI: 10.3350/cmh.2022.0084] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 04/01/2022] [Indexed: 01/10/2023] Open
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Hu Z, Zeng H, Hou J, Wang J, Xu L, Zhang Y, Chen M, Zhou Z. Tenofovir vs. Entecavir on Outcomes of Hepatitis B Virus-Related Hepatocellular Carcinoma after Radiofrequency Ablation. Viruses 2022; 14:v14040656. [PMID: 35458386 PMCID: PMC9024443 DOI: 10.3390/v14040656] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 03/10/2022] [Accepted: 03/19/2022] [Indexed: 01/01/2023] Open
Abstract
For patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) treated with curative radiofrequency ablation (RFA), the effect of entecavir (ETV) vs. tenofovir disoproxil fumarate (TDF) on recurrence-free survival (RFS) and overall survival (OS) remains unclear. We aimed to compare the outcomes of patients receiving ETV or TDF after RFA. This study consecutively collected patients who were treated with ETV (n = 202) or TDF (n = 102) for chronic hepatitis B (CHB) after curative RFA of HCC from December 2015 to January 2021 at Sun Yat-sen University Cancer Center. There were 130 patients in the ETV group and 77 patients in the TDF group after we performed 1-to-n propensity score matching. Kaplan−Meier and Cox regression analyses were performed to validate possible risk factors for RFS and OS. In addition, we estimated the curative effect of ETV and TDF for HBV-related hepatitis by recording the change in serum HBV DNA and ALBI grade after RFA. During the study period (median 34.1 (interquartile range: 19.6−47.4 months) months), 123 (40.5%) patients suffered HCC recurrence, and 15 (4.9%) died. In the full cohort, the probability of HCC recurrence (41.6% vs. 37.3%, p = 0.49) and overall survival (95% vs. 95.1%, p = 0.39) at 5 years were similar between the ETV and TDF groups. In the matched cohort, HCC recurrence (40.8% vs. 40.3%, p = 0.35) and overall survival (96.9% vs. 93.5%, p = 0.12) at 5 years were similar between the ETV and TDF groups. Furthermore, the early RFS (<2 years) did not differ significantly between the two groups in the full and matched cohorts (p = 0.26, p = 0.13). Compared with the ALBI grade before RFA, the ALBI grade of 80 patients (41%) remained stable or improved in the ETV group and 64 patients (64%) in the TDF group (p < 0.001). The mean time of serum HBV DNA reduction to 0 was 9.13 (95% CI: 5.92−12.33) and 2.75 (95% CI: 2.01−3.49) months in the ETV and TDF groups, respectively (p = 0.015). The RFS and OS of patients after curative RFA for HCC were not significantly different between the ETV and TDF groups. TDF therapy was associated with a better effect of protecting liver function and reducing the load of HBV. Further validation studies are needed.
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Affiliation(s)
- Zili Hu
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (Z.H.); (H.Z.); (J.H.); (J.W.); (L.X.); (Y.Z.)
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Huilan Zeng
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (Z.H.); (H.Z.); (J.H.); (J.W.); (L.X.); (Y.Z.)
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Jingyu Hou
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (Z.H.); (H.Z.); (J.H.); (J.W.); (L.X.); (Y.Z.)
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Juncheng Wang
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (Z.H.); (H.Z.); (J.H.); (J.W.); (L.X.); (Y.Z.)
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Li Xu
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (Z.H.); (H.Z.); (J.H.); (J.W.); (L.X.); (Y.Z.)
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Yaojun Zhang
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (Z.H.); (H.Z.); (J.H.); (J.W.); (L.X.); (Y.Z.)
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Minshan Chen
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (Z.H.); (H.Z.); (J.H.); (J.W.); (L.X.); (Y.Z.)
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
- Correspondence: (M.C.); (Z.Z.); Tel.: +86-20-87-343-117 (M.C.); +86-20-87-343-879 (Z.Z.)
| | - Zhongguo Zhou
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (Z.H.); (H.Z.); (J.H.); (J.W.); (L.X.); (Y.Z.)
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
- Correspondence: (M.C.); (Z.Z.); Tel.: +86-20-87-343-117 (M.C.); +86-20-87-343-879 (Z.Z.)
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Guan RY, Sun BY, Wang ZT, Zhou C, Yang ZF, Gan W, Huang JL, Liu G, Zhou J, Fan J, Yi Y, Qiu SJ. Antiviral therapy improves postoperative survival of patients with HBV-related hepatocellular carcinoma. Am J Surg 2022; 224:494-500. [DOI: 10.1016/j.amjsurg.2022.01.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 12/15/2021] [Accepted: 01/19/2022] [Indexed: 11/01/2022]
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Shen JY, Qi WL, Dai JL, Leng SS, Jiang KY, Zhang Y, Ran S, Li C, Wen TF. Tenofovir vs. entecavir on recurrence of hepatitis B virus-related hepatocellular carcinoma beyond Milan criteria after hepatectomy. Chin Med J (Engl) 2021; 135:301-308. [PMID: 34958539 PMCID: PMC8812695 DOI: 10.1097/cm9.0000000000001864] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Background: Hepatectomy for hepatocellular carcinoma (HCC) beyond the Milan criteria is shown to be beneficial. However, a high rate of post-operative HCC recurrence hinders the long-term survival of the patients. This study aimed to investigate and compare the impacts of tenofovir (TDF) and entecavir (ETV) on the recurrence of hepatitis B viral (HBV)-related HCC beyond the Milan criteria. Methods: Data pertaining to 1532 patients who underwent hepatectomy and received antiviral therapy between January 2014 and January 2019 were collected from five centers. Recurrence-free survival (RFS) analysis was performed using the Kaplan–Meier method. Cox proportional hazards regression analysis was performed to determine prognostic factors for HCC recurrence. Results: The analysis incorporates 595 HBV-related HCC patients. The overall 5-year RFS was 21.3%. Among them, 533 and 62 patients received ETV and TDF treatment, respectively. The 1-, 3-, and 5-year RFS rates were 46.3%, 27.4%, and 19.6%, respectively, in the ETV group compared with 65.1%, 41.8%, and 37.2%, respectively, in the TDF group (P < 0.001). Multivariate analysis showed that TDF treatment (hazard ratio [HR]: 0.604, P = 0.005), cirrhosis (HR: 1.557, P = 0.004), tumor size (HR: 1.037, P = 0.008), microvascular invasion (MVI) (HR: 1.403, P = 0.002), portal vein tumor thrombus (PVTT) (HR: 1.358, P = 0.012), capsular invasion (HR: 1.228, P = 0.040), and creatinine levels (CREA) (HR: 0.993, P = 0.031) were statistically significant prognostic factors associated with RFS. Conclusions: Patients with HCC beyond the Milan criteria exhibited a high rate of HCC recurrence after hepatectomy. Compared to the ETV therapy, TDF administration significantly lowered the risk of HCC recurrence.
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Cun J, Xu Y, Li W, Zhao X. Analysis of factors affecting the prognosis of transcatheter arterial chemoembolization for hepatitis B-related hepatocellular carcinoma. J Interv Med 2021; 4:66-70. [PMID: 34805950 PMCID: PMC8562176 DOI: 10.1016/j.jimed.2021.02.008] [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: 11/20/2020] [Revised: 02/22/2021] [Accepted: 02/23/2021] [Indexed: 11/19/2022] Open
Abstract
Objectives The purpose of this study was to investigate the prognostic factors for transcatheter arterial chemoembolization (TACE) for hepatitis B-related hepatocellular carcinoma (HCC). Materials and methods The variables that may affect overall survival (OS), such as age, gender, AFP, Child Pugh classification, body mass index, HBV-DNA, HbeAg, tumor number, tumor diameter, BCLC stage, embolization method, ablation therapy, and targeted therapy, were analyzed by single factor and many factor COX regression. In addition, predictive factors of OS were stratified and a Kaplan-Meier survival curve was drawn. Results Among the 136 patients, the median follow-up time was 14.5 months (range: 2-72 months). HCC patients with the tumor diameter <3 cm had the highest survival rate, followed by patients with a tumor diameter of 3-5 cm; the survival rate of patients with the tumor diameter (greater than 5 cm) was the lowest. Among the BCLC stages, stage A patients had the highest survival rate, followed by stage B and stage C patients, which had the lowest survival rate.The survival rate of Child Pugh grade A patients was higher than those with Child Pugh grade B. Compared with patients who did not undergo ablation treatment, the survival rate of patients with combined ablation treatment was relatively high. The survival rate of patients receiving drug-eluting beads transarterial chemoembolization (DEB-TACE) treatment was higher than those receiving conventional transarterial chemoembolization (cTACE) treatment. Additionally, repeated TACE treatment improved the OS rate of patients. These six factors were related to patient prognosis and the differences were statistically significant (P < 0.05). Conclusions Tumor diameter, BCLC stage, TACE repetition, and TACE combined with ablation were independent prognostic factors of OS.
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Affiliation(s)
| | - Yonghui Xu
- Corresponding author. Department of Radiology, The Second Affiliated Hospital, Kunming Medical University.
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21
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Jin M, Chen Y, Hu S, Zhu M, Wang Y, Chen M, Peng Z. Association of Virological Response to Antiviral Therapy With Survival in Intermediate-Stage Hepatitis B Virus-Related Hepatocellular Carcinoma After Chemoembolization. Front Oncol 2021; 11:751777. [PMID: 34745980 PMCID: PMC8569860 DOI: 10.3389/fonc.2021.751777] [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: 08/02/2021] [Accepted: 10/11/2021] [Indexed: 11/30/2022] Open
Abstract
Introduction Role of response to antiviral therapies on survival of patients with intermediate-stage hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) undergoing transarterial chemoembolization (TACE) remains unknown. We aimed to determine whether virological response (VR) or prolonged maintained virological response (MVR) to nucelos(t)ide analogues (NA) therapy could result in improved survival in HBV-HCC patients receiving TACE. Methods Between January 2012 and October 2018, data of patients with intermediate HBV-HCC who underwent TACE and started NA therapy within one week prior to TACE treatment at our institution were reviewed. Overall survival (OS) was compared using the Kaplan-Meier method with log-rank test between different VR status groups. Univariable and multivariable Cox regression analyses were used to determine the association between achievement of VR or MVR and OS. VR was defined as an undetectable HBV DNA level (<100 IU/ml) on two consecutive measurements during NA treatment. MVR was defined as a persistently undetectable HBV DNA level after achieving a VR. Results A total of 1265 patients undergoing TACE with a median follow-up time of 18 months (range, 2-78 months) were included in the analysis. Of 1265 NA-treated patients [1123 (88.8%) male, median (range) age, 56 (18-75) years], 744 patients (58.8%) achieved VR and the remaining patients (41.2%) did not. Patients with achievement of VR showed a significantly longer OS than those without VR (median OS: 21 vs 16 months; HR, 0.707; 95% CI, 0.622-0.804; P<0.001). Among patients with VR, MVR was present in 542 patients (72.8%), while the other 202 patients (27.2%) in the non-MVR group. The OS for the MVR group was significantly higher than the non-MVR group (median OS: 23.2 vs 18 months; HR, 0.736; 95% CI, 0.612-0.885; P=0.001). Additionally, patients with MVR status more than two years showed a better OS than those with just one-year (HR, 0.719; 95% CI, 0.650-0.797; P<0.001) or one-to-two-year MVR (HR, 0.612; 95% CI, 0.471-0.795; P=0.024). On multivariable analyses, splenomegaly and up-to-seven criteria were independent prognostic factors of OS in both VR and MVR cohorts. Conclusions In patients with intermediate-stage HBV-HCC, both VR to antiviral therapy and prolonged response are associated with prolonged OS after TACE, especially for those within up-to-seven criteria.
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Affiliation(s)
- Meng Jin
- Department of Radiation Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yong Chen
- Department of Radiation Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Shuifang Hu
- Department of Radiation Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Meiyan Zhu
- Department of Radiation Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yan Wang
- Department of Radiation Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Minshan Chen
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Zhenwei Peng
- Department of Radiation Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Clinical Trials Unit, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Cancer Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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Watanabe T, Inoue T, Tanaka Y. Hepatitis B Core-Related Antigen and New Therapies for Hepatitis B. Microorganisms 2021; 9:microorganisms9102083. [PMID: 34683404 PMCID: PMC8537336 DOI: 10.3390/microorganisms9102083] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 09/29/2021] [Accepted: 09/30/2021] [Indexed: 02/06/2023] Open
Abstract
The hepatitis B core-related antigen (HBcrAg) is an unprecedented novel HBV biomarker that plays an essential role in reflecting covalently closed circular DNA (cccDNA) in chronic hepatitis B (CHB) because its levels correlate with intrahepatic cccDNA and serum HBV DNA. In this review, we describe the clinical application of serum HBcrAg in CHB patients, with a particular focus on new therapies targeting intrahepatic HBV replication. (1) HBcrAg can be detected in clinical cases where serum HBV DNA is undetectable during anti-HBV therapy. (2) A highly sensitive HBcrAg assay (iTACT-HBcrAg) may be useful for monitoring HBV reactivation, as an alternative to HBV DNA. (3) Decreased HBcrAg levels have been significantly associated with promising outcomes in CHB patients, reducing the risk of progression or recurrence of hepatocellular carcinoma. Additionally, we focus on and discuss several drugs in development that target HBV replication, and monitoring HBcrAg may be useful for determining the therapeutic efficacies of such novel drugs. In conclusion, HBcrAg, especially when measured by the recently developed iTACT-HBcrAg assay, may be the most appropriate surrogate marker, over other HBV biomarkers, to predict disease progression and treatment response in CHB patients.
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Affiliation(s)
- Takehisa Watanabe
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan;
| | - Takako Inoue
- Department of Clinical Laboratory Medicine, Nagoya City University Hospital, Nagoya 467-8602, Japan;
| | - Yasuhito Tanaka
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan;
- Correspondence:
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Bai XM, Yang W. Radiofrequency ablation of hepatocellular carcinoma: Prognostic factors and recent advances. Shijie Huaren Xiaohua Zazhi 2021; 29:677-683. [DOI: 10.11569/wcjd.v29.i13.677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
With the improvement of technology and diagnostic level, radiofrequency ablation (RFA) has made rapid progress in the treatment of primary hepatocellular carcinoma (HCC) in the past two decades. Especially, the overall survival after the treatment of small HCCs by RFA can be comparable to that achieved by hepatic resection. The 10-year survival rates of RFA for HCC were 27.3%-46.1%, and for solitary HCC less than 3 cm, the 10-year survival rate is about 74.0%. RFA combined with other therapies can expand the indications of RFA treatment and benefit the survival of patients with HCC. The prognostic model of RFA for HCC provides a powerful tool for individualized clinical diagnosis and treatment.
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Affiliation(s)
- Xiu-Mei Bai
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Ultrasound, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Wei Yang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Ultrasound, Peking University Cancer Hospital and Institute, Beijing 100142, China
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Abd El Aziz MA, Sacco R, Facciorusso A. Nucleos(t)ide analogues and Hepatitis B virus-related hepatocellular carcinoma: A literature review. Antivir Chem Chemother 2021; 28:2040206620921331. [PMID: 32418480 PMCID: PMC7232045 DOI: 10.1177/2040206620921331] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Hepatitis B virus is mainly considered to cause hepatocellular carcinoma which is
the fourth leading cause of cancer-related mortality worldwide. Treatment of
Hepatitis B virus with nucleos(t)ide analogues can decrease the progression of
the disease and subsequently decreases the incidence of hepatocellular
carcinoma. In this review, we have discussed the different classes of
nucleos(t)ide analogues used in the treatment of Hepatitis B virus and their
relationship with the development of hepatocellular carcinoma. Furthermore, we
discussed the effect of treatment of Hepatitis B virus with Nucleoside analogues
(NAs) before, during and after surgery, chemoembolization, radiofrequency
ablation, and chemotherapy for the treatment of hepatocellular carcinoma.
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Affiliation(s)
| | - Rodolfo Sacco
- Department of Medical Sciences, Section of Gastroenterology, University of Foggia, Foggia Italy
| | - Antonio Facciorusso
- Department of Medical Sciences, Section of Gastroenterology, University of Foggia, Foggia Italy
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25
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Jang JW, Yoo SH, Nam HC, Jang BH, Sung Sung PS, Lee W, Kwon JH, Nam SW, Bae SH, Yoon SK, Choi JY. Association of Prophylactic Anti-Hepatitis B Virus Therapy With Improved Long-term Survival in Patients With Hepatocellular Carcinoma Undergoing Transarterial Therapy. Clin Infect Dis 2021; 71:546-555. [PMID: 31504352 DOI: 10.1093/cid/ciz860] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 08/30/2019] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND The effect of prophylactic antiviral therapy (AVT) on survival of patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remains unknown. This study aimed to determine whether prophylactic AVT could improve long-term survival in patients undergoing transarterial chemotherapy (TAC). METHODS Between 2002 and 2016, 2860 newly diagnosed HBV-related patients with HCC treated with TAC were screened to analyze 2 groups based on prophylactic use of antivirals. Treatment effects were analyzed using propensity score (PS) matching (1:1) separately for the entire cohort and each subgroup. The primary endpoint was overall survival. RESULTS A total of 1547 patients met the inclusion criteria and 1084 were PS matched for the 2 groups. Median follow-up duration was 16.55 months. In the entire unmatched cohort, patients receiving prophylactic AVT survived significantly longer than those who did not. Among AVT-untreated patients, baseline high viremia and HBV reactivation during treatment were significantly associated with shorter survival. Regarding types of antivirals, survival was significantly longer for patients receiving high-potency antivirals than those receiving low-potency antivirals. Survival differed with antiviral response. In the PS-matched cohort, the prophylactic AVT group survived significantly longer than the nonprophylactic group, irrespective of viral status or tumor stage. Prophylactic AVT remained an independent factor for survival. The association of prophylactic AVT with decreased risk of mortality persisted in patient subgroups after adjusting for baseline risk factors. Sensitivity analyses also confirmed estimated treatment effects. CONCLUSIONS Prophylactic AVT is associated with significantly improved long-term survival among patients undergoing TAC. High-potency antivirals are indicated for this approach.Hepatitis B virus-associated morbidity is a well-known complication during transarterial chemotherapy (TAC). Our large-scale study demonstrated that prophylactic therapy with high-potency antivirals provides a significantly better survival in TAC-treated patients, irrespective of baseline viremia status or tumor stage.
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Affiliation(s)
- Jeong Won Jang
- Department of Internal Medicine, College of Medicine, World Health Organization Collaborating Center on Viral Hepatitis, The Catholic University of Korea, Seoul
| | - Sun Hong Yoo
- Department of Internal Medicine, College of Medicine, World Health Organization Collaborating Center on Viral Hepatitis, The Catholic University of Korea, Seoul
| | - Hee Chul Nam
- Department of Internal Medicine, College of Medicine, World Health Organization Collaborating Center on Viral Hepatitis, The Catholic University of Korea, Seoul
| | - Bo Hyun Jang
- Department of Internal Medicine, College of Medicine, World Health Organization Collaborating Center on Viral Hepatitis, The Catholic University of Korea, Seoul
| | - Pil Soo Sung Sung
- Department of Internal Medicine, College of Medicine, World Health Organization Collaborating Center on Viral Hepatitis, The Catholic University of Korea, Seoul
| | - Won Lee
- Department of Internal Medicine, College of Medicine, World Health Organization Collaborating Center on Viral Hepatitis, The Catholic University of Korea, Seoul
| | - Jung Hyun Kwon
- Department of Internal Medicine, College of Medicine, World Health Organization Collaborating Center on Viral Hepatitis, The Catholic University of Korea, Seoul
| | - Soon Woo Nam
- Department of Internal Medicine, College of Medicine, World Health Organization Collaborating Center on Viral Hepatitis, The Catholic University of Korea, Seoul
| | - Si Hyun Bae
- Department of Internal Medicine, College of Medicine, World Health Organization Collaborating Center on Viral Hepatitis, The Catholic University of Korea, Seoul
| | - Seung Kew Yoon
- Department of Internal Medicine, College of Medicine, World Health Organization Collaborating Center on Viral Hepatitis, The Catholic University of Korea, Seoul
| | - Jong Young Choi
- Department of Internal Medicine, College of Medicine, World Health Organization Collaborating Center on Viral Hepatitis, The Catholic University of Korea, Seoul
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Tertiary Prevention of HCC in Chronic Hepatitis B or C Infected Patients. Cancers (Basel) 2021; 13:cancers13071729. [PMID: 33917345 PMCID: PMC8038691 DOI: 10.3390/cancers13071729] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 03/29/2021] [Accepted: 03/29/2021] [Indexed: 01/27/2023] Open
Abstract
Simple Summary Hepatocellular carcinoma (HCC) recurrence is the major obstacle concerning patients’ survival. Tertiary prevention by antiviral therapies could reduce HCC recurrence rate in both chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infected patients. In chronic hepatitis B (CHB) patients, nucleos(t)ide analogues (Nuc) provide a more effective HCC tertiary prevention effect than an interferon (IFN)-based regimen. In chronic hepatitis C (CHC) patients, the tertiary prevention effect by direct acting antiviral agents (DAAs) was reported non-inferior to that by IFN-based therapy. Chronic hepatitis C patients left untreated had the worst survival benefit as well as shorted recurrence-free interval than those treated by either type of antiviral regimen. Although the risk of HCC recurrence could only be decreased but not diminished by antiviral therapies due to host and microenvironmental factors beyond virus infection, antiviral therapy helps to preserve and improve liver function which makes multi-modality anticancer treatment feasible to improve survival. Abstract Hepatocellular carcinoma (HCC) ranks as a leading cause of common cancer and cancer-related death. The major etiology of HCC is due to chronic hepatitis virus including HBV and HCV infections. Scheduled HCC surveillance in high risk populations improves the early detection rate and the feasibility of curative treatment. However, high HCC recurrence rate still accounts for the poor prognosis of HCC patients. In this article, we critically review the pathogenesis of viral hepatitis-related hepatocellular carcinoma and the evidence of tertiary prevention efficacy by current available antiviral treatment, and discuss the knowledge gap in viral hepatitis-related HCC tertiary prevention.
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Lee TY, Hsu YC, Tseng HC, Lin JT, Wu MS, Wu CY. Association of Daily Aspirin Therapy With Hepatocellular Carcinoma Risk in Patients With Chronic Hepatitis C Virus Infection. Clin Gastroenterol Hepatol 2020; 18:2784-2792.e7. [PMID: 32360983 DOI: 10.1016/j.cgh.2020.04.036] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Revised: 03/30/2020] [Accepted: 04/10/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Aspirin therapy has been associated with reduced risk of colon cancer, but there is only limited evidence for its effects on risk of hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). We aimed to investigate the association of daily aspirin therapy with HCV-related HCC risk. METHODS In this cohort study, based on Taiwan's National Health Insurance Research Database, we screened 237,963 patients with chronic HCV infection for the period of 1997 through 2011. We excluded patients with confounding conditions and 2478 patients who continuously received daily aspirin therapy for 90 days or more (treated group) were randomly matched 1:2 with 4956 patients who had never received antiplatelet therapy (untreated group) by means of propensity scores. Cumulative incidence of, and hazard ratio (HR) for, HCC development were analyzed after we adjusted for patient mortality as a competing risk event. RESULTS The cumulative incidence of HCC in the treated group was significantly lower than that in the untreated group over 5 years (4.67%; 95% CI, 3.74%-5.59% vs 7.32%; 95% CI, 6.33%-8.30%; P<.001). In the multivariable regression analysis, aspirin therapy was independently associated with a reduced HCC risk (HR, 0.78, 95% CI, 0.64-0.95; P = .011), after adjustment for age per year, male sex, cirrhosis, liver decompensation, hyperlipidemia, statin use, and interferon therapy. Sensitivity subgroup analyses also verified this association (all HRs<1.0). In addition, older age (HR, 1.03 per year; 95% CI, 1.02-1.04), male sex (HR, 1.46; 95% CI, 1.21-1.77), and cirrhosis (HR, 3.13; 95% CI, 2.55-3.84) were independently associated with an increased HCC risk. CONCLUSIONS In a nationwide cohort study in Taiwan, we found aspirin therapy to be significantly associated with a reduced risk of HCV-related HCC.
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Affiliation(s)
- Teng-Yu Lee
- Division of Gastroenterology and Hepatology, Taichung Veterans General Hospital, Taichung; Department of Medicine, Chung Shan Medical University, Taichung
| | - Yao-Chun Hsu
- Division of Gastroenterology and Hepatology, Fu-Jen Catholic University Hospital, New Taipei; School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei; Division of Gastroenterology and Hepatology, E-Da Hospital, Kaohsiung; Graduate Institute of Clinical Medicine, China Medical University, Taichung
| | - Hsiao-Ching Tseng
- Division of Gastroenterology and Hepatology, Taichung Veterans General Hospital, Taichung
| | - Jaw-Town Lin
- Digestive Medicine Center, China Medical University Hospital, Taichung
| | - Ming-Shiang Wu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei
| | - Chun-Ying Wu
- Division of Translational Medicine and Excellence Cancer Research Center, Department of Medical Research, Taipei Veterans General Hospital, Taipei; Institute of Biomedical Informatics and Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei; College of Public Health, China Medical University, Taichung; National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan.
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Qi W, Zhang Q, Xu Y, Wang X, Yu F, Zhang Y, Zhao P, Guo H, Zhou C, Wang Z, Sun Y, Liu L, Xuan W, Wang J. Peg-interferon and nucleos(t)ide analogue combination at inception of antiviral therapy improves both anti-HBV efficacy and long-term survival among HBV DNA-positive hepatocellular carcinoma patients after hepatectomy/ablation. J Viral Hepat 2020; 27:387-396. [PMID: 31755220 DOI: 10.1111/jvh.13236] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Revised: 09/30/2019] [Accepted: 10/11/2019] [Indexed: 01/27/2023]
Abstract
Antiviral therapy has been shown to improve the prognosis of hepatitis B virus (HBV) DNA-positive hepatocellular carcinoma (HCC) after radical treatment, but antiviral treatments require further optimization. This study aimed to evaluate the efficacies of different antiviral strategies with HCC patients after hepatectomy/ablation. This prospective, randomized, controlled and multi-centre trial enrolled HBV DNA-positive primary HCC patients after hepatectomy/ablation between January 2007 and January 2009. Patients were divided into four groups: early combination (entecavir plus Peg-interferon [IFN]α-2a co-administration during year 1); late combination (addition of Peg-IFNα-2a for 48 weeks after 1 year of entecavir); nucleos(t)ide analogue[NA] monotherapy; and non-antiviral treatment. Primary endpoints included recurrence-free survival and overall survival. A total of 447 patients were enrolled. The 2-year and 8-year recurrence-free survival and 8-year overall survival rates were significantly higher in the early combination group than in the other two antiviral groups (P < .05). After 48-week treatment, more patients achieved an HBsAg reduction >1500 IU/mL and the mean HBsAg level was significantly lower in the early combination group compared with the late combination and NA monotherapy groups (P < .05). Multivariate analysis showed that early combination therapy and a reduction in HBsAg by >1500 IU/mL after 48 weeks of therapy correlated with reduced mortality and disease recurrence. Early introduction of combination antiviral treatment may represent a more effective therapeutic strategy for patients with HBV DNA-positive HCC after hepatectomy/ablation. A reduction in HBsAg by >1500 IU/mL after 48-week treatment is associated with reduced mortality and disease recurrence of HBV DNA-positive HCC patients after hepatectomy/ablation.
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Affiliation(s)
- Wenqian Qi
- Digestive Department, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Qian Zhang
- Digestive Department, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Yan Xu
- Digestive Department, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Xu Wang
- Digestive Department, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Fan Yu
- Digestive Department, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Yonggui Zhang
- Digestive Department, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Ping Zhao
- Digestive Department, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Honghua Guo
- Digestive Department, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Changyu Zhou
- Digestive Department, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Zhe Wang
- Digestive Department, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Yu Sun
- Invasive Technology Department, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Lin Liu
- Invasive Technology Department, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Wei Xuan
- Hepatobiliary Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Jiangbin Wang
- Digestive Department, China-Japan Union Hospital of Jilin University, Changchun, China
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Predictors for the progression of hepatic cirrhosis to hepatocellular carcinoma under long-term antiviral therapy. Eur J Gastroenterol Hepatol 2020; 32:447-453. [PMID: 32012142 DOI: 10.1097/meg.0000000000001631] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Patients diagnosed with hepatitis B virus (HBV)-related hepatic cirrhosis have the potential for progression to hepatocellular carcinoma (HCC) even while undergoing long-term nucleos(t)ide analog (NA) therapy. This study investigated the predictors for the progression of hepatic cirrhosis to HCC under long-term NA therapy. METHODS This retrospective study enrolled 898 patients diagnosed with HBV-related hepatic cirrhosis. They received NA therapy between January 2012 and January 2015. The values for the liver stiffness measurement (LSM), laboratory tests, and disease history were collected. The diagnostic specificity of the serum, was assessed with a receiver operating characteristic curve. RESULTS The overall 2- and 3-year cumulative incidence of HCC was 6.8% and 15.15%, respectively. The LSM values were higher in the patients who had progressed to HCC. The serum PIVKA-II levels were more efficient than the serum AFP levels for the diagnosis of early HCC as the larger area under curve (0.866 vs. 0.687). The multivariate logistic regression analysis showed that HCC occurrence was significantly associated with the baseline LSM value (odds ratio = 1.035). At the end of the study, the death rate for the patients with larger LSM values was higher than that for those with lower LSM values (67.88% vs. 39.90%). CONCLUSION Patients with HBV-related cirrhosis have the potential for progression to HCC even under long-term NA therapy. The LSM value and the serum PIVKA-II level are significant predictors of HCC occurrence.
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Sheu MJ, Liang FW, Li ST, Li CY, Lu TH. Validity of ICD-10-CM Codes Used to Identify Patients with Chronic Hepatitis B and C Virus Infection in Administrative Claims Data from the Taiwan National Health Insurance Outpatient Claims Dataset. Clin Epidemiol 2020; 12:185-192. [PMID: 32110110 PMCID: PMC7039074 DOI: 10.2147/clep.s236823] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Accepted: 02/02/2020] [Indexed: 12/20/2022] Open
Abstract
PURPOSE To validate the use of International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes to identify patients with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection in the Taiwan National Health Insurance (NHI) Outpatient Claims Dataset. METHODS We conducted a retrospective study using results of HBV surface antigen (HBsAg), HBV e antigen (HBeAg), and anti-HCV antibody tests in the NHI Lab & Exam Dataset from January 1 to March 31, 2018, as the reference standard to confirm HBV and HCV infection cases. We calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) to assess the performance of HBV infection-specific ICD-10-CM codes (B180, B181, and B191) and HCV infection-specific ICD-10-CM codes (B182 and B192) recorded in the NHI Outpatient Claims Dataset to identify patients with HBV or HCV infection. RESULTS In total, 196,635 and 120,628 patients had analyzable results for HBsAg/HBeAg tests and anti-HCV tests, respectively. Moreover, 44,574 and 14,443 were confirmed to have HBV and HCV infection, respectively. The sensitivity, specificity, PPV, and NPV were, respectively, 46%, 83%, 45%, and 84% for HBV infection-specific ICD-10-CM codes and 47%, 99%, 81%, and 93% for HCV infection-specific ICD-10-CM codes. The sensitivity demonstrated great variation by region, clinical setting, and physician specialty. CONCLUSION The HBV and HCV infection-specific ICD-10-CM codes recorded by physicians in Taiwan NHI outpatient claims data in 2018 had moderate sensitivity and high specificity for both HBV and HCV infection. The PPV was high for HCV ICD-10-CM codes, yet moderate for HBV ICD-10-CM codes.
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Affiliation(s)
- Ming-Jen Sheu
- Division of Gastroenterology and Hepatology, Chi Mei Medical Center, Tainan, Taiwan
- Department of Medicinal Chemistry, Chia Nan University of Pharmacy and Science, Tainan, Taiwan
| | - Fu-Weng Liang
- Department of Public Health, College of Health Science, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Sheng-Tun Li
- Department of Industrial and Information Management, College of Management, National Cheng Kung University, Tainan, Taiwan
| | - Chung-Yi Li
- Department of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Healthcare Administration, College of Medical and Health Science, Asia University, Taichung, Taiwan
- Department of Public Health, College of Public Health, China Medical University, Taichung, Taiwan
| | - Tsung-Hsueh Lu
- Department of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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Liver stiffness measured by acoustic radiation force impulse elastography predicted prognoses of hepatocellular carcinoma after radiofrequency ablation. Sci Rep 2020; 10:2006. [PMID: 32029840 PMCID: PMC7005159 DOI: 10.1038/s41598-020-58988-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Accepted: 01/23/2020] [Indexed: 02/08/2023] Open
Abstract
The prognostic factors of patients who undergo radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) is not fully elucidated. We aimed to investigate the role of liver stiffness (LS) and spleen stiffness (SS) measured by acoustic radiation force impulse (ARFI) elastography in determining the prognoses of patients with HCC after RFA. We prospectively enrolled 173 patients with HCC who underwent ARFI elastography for measurement of LS and SS on the same day of RFA. Overall survival (OS), recurrence-free survival (RFS) after adjusting for competing mortality, and presence of hepatic decompensation were investigated. Patients with LS > 1.5 m/s had significantly shorter OS and RFS than their counterparts. Anti-viral treatment (hazard ratio [HR]: 0.396, p = 0.015) and LS > 1.5 m/s (HR 4.105, p = 0.028) correlated with OS by a multivariate analysis. Besides, serum alpha fetoprotein >10 ng/mL and LS > 1.5 m/s independently predicted poorer RFS. On the other hand, anti-viral treatment (HR: 0.315, p = 0.010), creatinine > 1.5 mg/dL (HR: 9.447, p = 0.006), and SS > 2.7 m/s (HR: 2.869, p = 0.044) predicted a higher risk of hepatic decompensation. In conclusion, LS but not SS measured by ARFI elastography predicted tumor recurrence and OS in RFA-treated HCC; whereas, SS predicted development of hepatic decompensation in these patients.
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Novel Biomarkers of Hepatitis B and Hepatocellular Carcinoma: Clinical Significance of HBcrAg and M2BPGi. Int J Mol Sci 2020; 21:ijms21030949. [PMID: 32023902 PMCID: PMC7037346 DOI: 10.3390/ijms21030949] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 01/19/2020] [Accepted: 01/29/2020] [Indexed: 12/12/2022] Open
Abstract
The hepatitis B virus (HBV) cannot be removed completely from infected hepatocytes, owing to the presence of intrahepatic covalently closed circular DNA (cccDNA). As chronic hepatitis B (CHB) can progress to cirrhosis and hepatocellular carcinoma (HCC), predicting HCC development in high-risk patients with high viral replicative activity or advanced fibrosis is important. Novel serological biomarkers reflect intrahepatic viral replicative activity or the progression of liver fibrosis, indicating non-invasive alternatives to liver biopsy: (1) Hepatitis B core-related antigen (HBcrAg) correlates with serum HBV DNA and intrahepatic cccDNA. In CHB patients, a decrease in HBcrAg is associated with favorable outcomes. HBcrAg can predict HCC occurrence or recurrence. (2) Measurement of the Mac-2 binding protein glycosylation isomer (M2BPGi) has been introduced for the evaluation of liver fibrosis. An increase in M2BPGi in CHB patients is related to the progression of liver fibrosis and high potential (risk) of HCC development. Here, we describe the clinical applications of HBcrAg and M2BPGi in CHB patients. Additionally, because new potential therapeutic agents that eliminate intrahepatic cccDNA are being developed, monitoring of HBcrAg or M2BPGi might be suitable for evaluating therapeutic effects and the clinical outcomes. In conclusion, these would be appropriate surrogate markers for predicting disease progression.
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Novel Biomarkers of Hepatitis B and Hepatocellular Carcinoma: Clinical Significance of HBcrAg and M2BPGi. Int J Mol Sci 2020. [DOI: 10.3390/ijms21030949
expr 921756688 + 899694353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2023] Open
Abstract
The hepatitis B virus (HBV) cannot be removed completely from infected hepatocytes, owing to the presence of intrahepatic covalently closed circular DNA (cccDNA). As chronic hepatitis B (CHB) can progress to cirrhosis and hepatocellular carcinoma (HCC), predicting HCC development in high-risk patients with high viral replicative activity or advanced fibrosis is important. Novel serological biomarkers reflect intrahepatic viral replicative activity or the progression of liver fibrosis, indicating non-invasive alternatives to liver biopsy: (1) Hepatitis B core-related antigen (HBcrAg) correlates with serum HBV DNA and intrahepatic cccDNA. In CHB patients, a decrease in HBcrAg is associated with favorable outcomes. HBcrAg can predict HCC occurrence or recurrence. (2) Measurement of the Mac-2 binding protein glycosylation isomer (M2BPGi) has been introduced for the evaluation of liver fibrosis. An increase in M2BPGi in CHB patients is related to the progression of liver fibrosis and high potential (risk) of HCC development. Here, we describe the clinical applications of HBcrAg and M2BPGi in CHB patients. Additionally, because new potential therapeutic agents that eliminate intrahepatic cccDNA are being developed, monitoring of HBcrAg or M2BPGi might be suitable for evaluating therapeutic effects and the clinical outcomes. In conclusion, these would be appropriate surrogate markers for predicting disease progression.
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Zhou HQ, Liu MS, Deng TB, Xie PB, Wang W, Shao T, Wu Y, Zhang P. The TGF-β/Smad Pathway Inhibitor SB431542 Enhances The Antitumor Effect Of Radiofrequency Ablation On Bladder Cancer Cells. Onco Targets Ther 2019; 12:7809-7821. [PMID: 31576139 PMCID: PMC6765330 DOI: 10.2147/ott.s212596] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Accepted: 09/09/2019] [Indexed: 12/12/2022] Open
Abstract
Background Despite progress achieved in bladder cancer (BC) treatment, the prognosis of patients with advanced BC (ie, metastasized from the bladder to other organs) is poor. Although mortality in cases of low-grade BC is rare, the treatment, such as a radical cystectomy, often has a serious impact on the quality of life. Thus, research is needed to identify more effective treatment strategies and this work is aiming to examine the potential application of combination of radiofrequency ablation (RFA) and SB435142, a inhibitor of transforming growth factor β (TGFβ)/Smad pathway. Methods BC cells were transplanted into nude mice (thymusdeficiency Bal B/c) to form subcutaneous tumors. The mice with subcutaneous tumors were then treated with RFA and oral administration of SB431542, an inhibitor of TGFβ/Smad signaling pathway. The antitumor effect of RFA was measured by tumor proliferation curves and micro-positron emission computed tomography (micro-PET). The effect of SB431542 on epithelial-mesenchymal transition (EMT) related regulators in subcutaneous tumor tissues formed by BC cells were examined by quantitative real-time polymerase chain reaction (qPCR) experiments. Results The SB431542 treatment enhanced the antitumor effect of RFA on subcutaneous growth of BCs. SB431542 also decreased EMT-related regulators in subcutaneous tumor tissues formed by BC cells in nude mice. Conclusion SB431542 enhances the effect of RFA on BC.
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Affiliation(s)
- Hong-Qing Zhou
- Second Ward of Urology, Qujing Affiliated Hospital of Kunming Medical University , Qujing City 655000, Yunnan Province, People's Republic of China
| | - Ming-Sheng Liu
- Second Ward of Urology, Qujing Affiliated Hospital of Kunming Medical University , Qujing City 655000, Yunnan Province, People's Republic of China
| | - Ti-Bin Deng
- Second Ward of Urology, Qujing Affiliated Hospital of Kunming Medical University , Qujing City 655000, Yunnan Province, People's Republic of China
| | - Ping-Bo Xie
- Second Ward of Urology, Qujing Affiliated Hospital of Kunming Medical University , Qujing City 655000, Yunnan Province, People's Republic of China
| | - Wei Wang
- Second Ward of Urology, Qujing Affiliated Hospital of Kunming Medical University , Qujing City 655000, Yunnan Province, People's Republic of China
| | - Tao Shao
- Second Ward of Urology, Qujing Affiliated Hospital of Kunming Medical University , Qujing City 655000, Yunnan Province, People's Republic of China
| | - Yao Wu
- Second Ward of Urology, Qujing Affiliated Hospital of Kunming Medical University , Qujing City 655000, Yunnan Province, People's Republic of China
| | - Peng Zhang
- Department of Urology, State Key Laboratory of Kidney Diseases, Chinese People's Liberation Army (PLA) General Hospital/Chinese PLA Medical Academy, Beijing 100853, People's Republic of China
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Cheung KS, Leung WK, Seto WK. Application of Big Data analysis in gastrointestinal research. World J Gastroenterol 2019; 25:2990-3008. [PMID: 31293336 PMCID: PMC6603810 DOI: 10.3748/wjg.v25.i24.2990] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 04/14/2019] [Accepted: 04/29/2019] [Indexed: 02/06/2023] Open
Abstract
Big Data, which are characterized by certain unique traits like volume, velocity and value, have revolutionized the research of multiple fields including medicine. Big Data in health care are defined as large datasets that are collected routinely or automatically, and stored electronically. With the rapidly expanding volume of health data collection, it is envisioned that the Big Data approach can improve not only individual health, but also the performance of health care systems. The application of Big Data analysis in the field of gastroenterology and hepatology research has also opened new research approaches. While it retains most of the advantages and avoids some of the disadvantages of traditional observational studies (case-control and prospective cohort studies), it allows for phenomapping of disease heterogeneity, enhancement of drug safety, as well as development of precision medicine, prediction models and personalized treatment. Unlike randomized controlled trials, it reflects the real-world situation and studies patients who are often under-represented in randomized controlled trials. However, residual and/or unmeasured confounding remains a major concern, which requires meticulous study design and various statistical adjustment methods. Other potential drawbacks include data validity, missing data, incomplete data capture due to the unavailability of diagnosis codes for certain clinical situations, and individual privacy. With continuous technological advances, some of the current limitations with Big Data may be further minimized. This review will illustrate the use of Big Data research on gastrointestinal and liver diseases using recently published examples.
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Affiliation(s)
- Ka-Shing Cheung
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
- Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518053, Guangdong Province, China
| | - Wai K Leung
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
| | - Wai-Kay Seto
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
- Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518053, Guangdong Province, China
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Inoue T, Tanaka Y. The Role of Hepatitis B Core-Related Antigen. Genes (Basel) 2019; 10:genes10050357. [PMID: 31075974 PMCID: PMC6562807 DOI: 10.3390/genes10050357] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 05/02/2019] [Accepted: 05/06/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) cannot be completely eliminated from infected hepatocytes due to the existence of intrahepatic covalently closed circular DNA (cccDNA). Serological biomarkers reflect intrahepatic viral replicative activity as non-invasive alternatives to liver biopsy. Hepatitis B core-related antigen (HBcrAg) is a novel biomarker that has an important role in chronic hepatitis B (CHB), because it correlates with serum HBV DNA and intrahepatic cccDNA. In clinical cases with undetectable serum HBV DNA or loss of HBsAg, HBcrAg still can be detected and the decrease in HBcrAg levels is significantly associated with promising outcomes for CHB patients. HBcrAg can predict spontaneous or treatment-induced hepatitis B envelope antigen (HBeAg) seroconversion, persistent responses before and after cessation of nucleos(t)ide analogues, potential HBV reactivation, HBV reinfection after liver transplantation, and risk of hepatocellular carcinoma progression or recurrence. In this review, the clinical applications of HBcrAg in CHB patients based on its virological features are described. Furthermore, new potential therapeutic anti-HBV agents that affect intrahepatic cccDNA are under development, and the monitoring of HBcrAg might be useful to judge therapeutic effects. In conclusion, HBcrAg might be a suitable surrogate marker beyond other HBV markers to predict the disease progression and treatment responses of CHB patients.
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Affiliation(s)
- Takako Inoue
- Department of Clinical Laboratory Medicine, Nagoya City University Hospital, Nagoya 467-8602, Japan.
| | - Yasuhito Tanaka
- Department of Clinical Laboratory Medicine, Nagoya City University Hospital, Nagoya 467-8602, Japan.
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
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Lee TY, Hsu YC, Tseng HC, Yu SH, Lin JT, Wu MS, Wu CY. Association of Daily Aspirin Therapy With Risk of Hepatocellular Carcinoma in Patients With Chronic Hepatitis B. JAMA Intern Med 2019; 179:633-640. [PMID: 30882847 PMCID: PMC6503573 DOI: 10.1001/jamainternmed.2018.8342] [Citation(s) in RCA: 119] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
IMPORTANCE Antiviral therapy cannot erase hepatocellular carcinoma (HCC) risk in patients with chronic hepatitis B, and it is not indicated for most hepatitis B virus (HBV) carriers. Another effective way of reducing HCC risk needs to be developed. Aspirin may prevent cancer development, but clinical evidence in patients with HBV-related HCC remains limited. OBJECTIVE To investigate the association of daily aspirin therapy with HBV-related HCC risk. DESIGN, SETTING, AND PARTICIPANTS In this Taiwan nationwide cohort study, we screened 204 507 patients with chronic hepatitis B for the period January 1, 1997, to December 31, 2012. After excluding patients with confounding conditions, 2123 patients who continuously received daily aspirin for 90 or more days (treated group) were randomly matched 1:4 with 8492 patients who had never received antiplatelet therapy (untreated group) by means of propensity scores, consisting of the follow-up index date, baseline characteristics, and potentially chemopreventive drug use during follow-up. Data were analyzed from August 1 to November 30, 2018. EXPOSURES Daily aspirin therapy during the study period. MAIN OUTCOMES AND MEASURES Both cumulative incidence of and hazard ratios (HRs) for HCC development were analyzed after adjusting patient mortality as a competing risk event. RESULTS Of the 10 615 patients included in the analysis, 7690 (72.4%) were men; mean (SD) age was 58.8 (11.8) years. The cumulative incidence of HCC in the treated group was significantly lower than that in the untreated group in 5 years (5.20%; 95% CI, 4.11%-6.29% vs 7.87%; 95% CI, 7.15%-8.60%; P < .001). In the multivariable regression analysis, aspirin therapy was independently associated with a reduced HCC risk (HR, 0.71; 95% CI, 0.58-0.86; P < .001). Sensitivity subgroup analyses also verified this association (all HRs <1.0). In addition, older age (HR, 1.01 per year; 95% CI, 1.00-1.02), male sex (HR, 1.75; 95% CI, 1.43-2.14), and cirrhosis (HR, 2.89; 95% CI, 2.45-3.40) were independently associated with an increased HCC risk, but nucleos(t)ide analogue (HR, 0.54; 95% CI, 0.41-0.71) or statin (HR, 0.62; 95% CI, 0.42-0.90) use was correlated with a decreased HCC risk. CONCLUSIONS AND RELEVANCE Daily aspirin therapy may be associated with a reduced risk of HBV-related HCC.
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Affiliation(s)
- Teng-Yu Lee
- Division of Gastroenterology & Hepatology, Taichung Veterans General Hospital, Taichung, Taiwan.,Department of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Yao-Chun Hsu
- Division of Gastroenterology and Hepatology, Fu-Jen Catholic University Hospital, New Taipei, Taiwan.,School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei, Taiwan.,Division of Gastroenterology and Hepatology, E-Da Hospital, Kaohsiung, Taiwan.,Graduate Institute of Clinical Medicine, China Medical University, Taichung, Taiwan
| | - Hsiao-Ching Tseng
- Division of Translational Medicine and Excellence Cancer Research Center, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Shi-Hang Yu
- Division of Gastroenterology & Hepatology, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Jaw-Town Lin
- School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei, Taiwan.,Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan
| | - Ming-Shiang Wu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Chun-Ying Wu
- Division of Translational Medicine and Excellence Cancer Research Center, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.,Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,College of Public Health and Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.,National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan
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Efficacy of Nucleoside Analogs for Chronic Hepatitis B Virus-Related Hepatocellular Carcinoma After Curative Treatment: A Meta-Analysis. Dig Dis Sci 2018; 63:3207-3219. [PMID: 30140982 DOI: 10.1007/s10620-018-5252-8] [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: 04/24/2018] [Accepted: 08/14/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIM The efficacy of nucleoside analogs (NAs) for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after curative treatment remains unclear. The present study aimed to evaluate the efficacy of these agents by conducting a comprehensive meta-analysis of available studies. METHODS We searched several databases including Pubmed, Embase, Cochrane Library, Clinical Trials, and Web of Science, according to PRISMA guidelines. We considered all randomized controlled trials and cohort studies that met the inclusion criteria. Statistical analyses were conducted using Review Manager 5.3 and Stata 14.0. RESULTS Twenty-one studies with 8752 participants were included in the final analysis. The pooled data showed that patients treated with NAs had significantly lower 1- and 3-year HCC recurrence rates (relative risk [RR] 0.76, 95% confidence interval [CI] 0.65-0.90; P = 0.001 and RR 0.79, 95% CI 0.71-0.88; P < 0.001, respectively), but there was no difference in 5-year recurrence rates (RR 0.87, 95% CI 0.74-1.03; P = 0.10). Regarding overall survival (OS), patients treated with NAs had significantly higher 1-, 3-, and 5-year OS rates (RR 1.05, 95% CI 1.02-1.08; P = 0.003; RR 1.25, 95% CI 1.16-1.34; P < 0.001; and RR 1.28, 95% CI 1.18-1.39; P < 0.001, respectively). CONCLUSION NA therapy has the potential to reduce the risk of early recurrence and improve OS in patients with HBV-related HCC after curative treatment, compared with placebo or no treatment. Further research including more homogeneous studies with large sample sizes is required to improve the reliability of these conclusions.
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Li Z, Lei Z, Xia Y, Li J, Wang K, Zhang H, Wan X, Yang T, Zhou W, Wu M, Pawlik TM, Lau WY, Shen F. Association of Preoperative Antiviral Treatment With Incidences of Microvascular Invasion and Early Tumor Recurrence in Hepatitis B Virus-Related Hepatocellular Carcinoma. JAMA Surg 2018; 153:e182721. [PMID: 30073257 DOI: 10.1001/jamasurg.2018.2721] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Importance A reduced incidence of microvascular invasion (MVI) in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) may be associated with a decreased risk of early tumor recurrence and better survival after partial hepatectomy. Objective To examine the association of preoperative antiviral treatment (AVT) with the incidences of MVI and posthepatectomy early tumor recurrence in HBV-related HCC. Design, Setting, and Participants Data on a cohort of 2362 patients who underwent R0 resection for HBV-related HCC between January 2008 and April 2010 at the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China, were reviewed. The median (interquartile range) postoperative follow-up was 44.8 (22.8-59.3) months. Data were analyzed from June 2016 to October 2017. Interventions Preoperative AVT and partial hepatectomy. Main Outcomes and Measures Overall survival and time to recurrence after surgery were calculated and compared using the Kaplan-Meier method, log-rank test, and Cox regression analysis. Independent risk factors of MVI presence were assessed by logistic regression analysis. Results Among 2362 included patients, 1999 (84.6%) were men, and the median (interquartile range) age was 50.6 (43.1-57.3) years. A total of 2036 patients (86.2%) did not receive any preoperative AVT, while 326 (13.8%) received ongoing AVT more than 90 days before surgery. In the non-AVT group, compared with a preoperative HBV DNA level of less than 2000 IU/mL, a preoperative HBV DNA level of 2000 IU/mL or greater was associated with an increased risk of MVI (odds ratio [OR], 1.399; 95% CI, 1.151-1.701). Compared with the non-AVT group, patients receiving AVT had a lower incidence of MVI (38.7% [126 of 326] vs 48.6% [989 of 2036]; P = .001) and reduced risk of MVI (OR, 0.758; 95% CI, 0.575-0.998). A complete response to AVT was an independent protective factor of MVI (OR, 0.690; 95% CI, 0.500-0.952). Accordingly, preoperative AVT was associated with decreased 6-month, 1-year, and 2-year recurrences vs non-AVT (14.2%, 24.6%, and 38.5%, respectively, vs 23.4%, 37.1%, and 52.3%; P < .001); AVT was protective of early tumor recurrence (hazard ratio, 0.732; 95% CI, 0.605-0.886). In addition, patients in the non-AVT group were more likely to have multiple intrahepatic recurrences (49.1% [549 of 1119] vs 36.2% [54 of 149]; P = .003) and recurrences involving multiple hepatic segments compared with patients receiving AVT. Conclusions and Relevance A high preoperative HBV DNA level was an independent risk factor of MVI. Antiviral treatment administered more than 90 days before surgery was associated with reduced incidences of MVI and early tumor recurrence after partial hepatectomy for HBV-related HCC.
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Affiliation(s)
- Zheng Li
- Department of Hepatic Surgery, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Zhengqing Lei
- Department of Hepatic Surgery, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Yong Xia
- Department of Hepatic Surgery, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Jun Li
- Department of Hepatic Surgery, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Kui Wang
- Department of Hepatic Surgery, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Han Zhang
- Department of Hepatic Surgery, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Xuying Wan
- Department of Hepatic Surgery, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Tian Yang
- Department of Hepatic Surgery, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Weiping Zhou
- Department of Hepatic Surgery, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Mengchao Wu
- Department of Hepatic Surgery, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Timothy M Pawlik
- Department of Surgery, Wexner Medical Center, Ohio State University, Columbus
| | - Wan Yee Lau
- Faculty of Medicine, the Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Feng Shen
- Department of Hepatic Surgery, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
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Comparison of acoustic radiation force impulse elastography and transient elastography for prediction of hepatocellular carcinoma recurrence after radiofrequency ablation. Eur J Gastroenterol Hepatol 2018; 30:1230-1236. [PMID: 29794814 DOI: 10.1097/meg.0000000000001170] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND To compare the clinical value of acoustic radiation force impulse (ARFI) elastography and transient elastography (TE) for hepatocellular carcinoma (HCC) recurrence prediction after radiofrequency ablation (RFA) and to investigate other predictors of HCC recurrence. PATIENTS AND METHODS Between 2011 and 2016, 130 patients with HCC who underwent ARFI elastography and TE within 6 months before curative RFA were prospectively enrolled. Independent predictors of HCC recurrence were analyzed separately using ARFI elastography and TE. ARFI elastography and TE accuracy to predict HCC recurrence was determined by receiver operating characteristic curve analysis. RESULTS Of all included patients (91 men; mean age, 63.5 years; range: 43-84 years), 51 (42.5%) experienced HCC recurrence during the follow-up period (median, 21.9 months). In multivariable analysis using ARFI velocity, serum albumin and ARFI velocity [hazard ratios: 2.873; 95% confidence interval (CI): 1.806-4.571; P<0.001] were independent predictors of recurrence, and in multivariable analysis using TE value, serum albumin and TE value (hazard ratios: 1.028; 95% CI: 1.013-1.043; P<0.001) were independent predictors of recurrence. The area under the receiver operating characteristic curve of ARFI elastography (0.821; 95% CI: 0.747-0.895) was not statistically different from that of TE (0.793; 95% CI: 0.712-0.874) for predicting HCC recurrence (P=0.827). The optimal ARFI velocity and TE cutoff values were 1.6 m/s and 14 kPa, respectively. CONCLUSION ARFI elastography and TE yield comparable predictors of HCC recurrence after RFA.
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Loglio A, Iavarone M, Grossi G, Viganò M, Rumi MG, Facchetti F, Lunghi G, Sangiovanni A, Colombo M, Lampertico P. Clinical features and outcomes of hepatocellular carcinoma in Caucasian cirrhotic patients on long-term analogue therapy for hepatitis B. Aliment Pharmacol Ther 2018; 48:431-439. [PMID: 29920698 DOI: 10.1111/apt.14848] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Revised: 03/02/2018] [Accepted: 05/23/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Long-term oral nucleos(t)ide analogue (NUC) therapy in hepatitis B virus (HBV)-related compensated cirrhotics prevents clinical decompensation but not hepatocellular carcinoma (HCC) development. AIMS To define the clinical features and outcomes of HCC in long-term NUC-treated HBV patients. METHODS All HCCs developing between 2005 and 2016 in NUC-treated HBV patients under surveillance were studied, excluding those that occurred within the first 6 months of therapy. Clinical features of HCC, alpha faetoprotein (AFP) patterns and patients' outcome were studied. RESULTS Seventy-six HCC patients were included. Median age was 67 (40-83) years, 84% males, 96% Caucasian, 95% HBeAg-negative, 96% with undetectable HBV DNA, 83% with normal ALT levels, and 92% with compensated cirrhosis. Median serum AFP levels were 4 (1-3615) ng/mL (>7 ng/mL in 36%). HCC was monofocal in 78%, had a median diameter of 20 (6-57) mm and was in its early stage in 92% which allowed potentially curative treatments in 78% (39% ablation, 28% surgical resection, 11% liver transplantation). Overall, a complete response was obtained in 61 (80%) patients: in 40 after a first-line treatment, in 3 after the second-line treatment, in 2 after the third-line treatment, while 16 underwent liver transplantation (8 as second line). During 45 (7-144) months after HCC diagnosis, 19 patients died, 84% from HCC progression. The median time to recurrence was 20.2 (3-53) months, and the cumulative 5-year liver-related survival was 74%. CONCLUSIONS HCCs developing in patients under long-term NUC treatment were single, small tumours, amenable to curative therapies able to confer excellent 5-year survival rates.
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Affiliation(s)
- A Loglio
- CRC "A.M. e A. Migliavacca" Center for the Study of Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - M Iavarone
- CRC "A.M. e A. Migliavacca" Center for the Study of Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - G Grossi
- CRC "A.M. e A. Migliavacca" Center for the Study of Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - M Viganò
- Hepatology Division, Ospedale San Giuseppe, Università degli Studi di Milano, Milan, Italy
| | - M G Rumi
- Hepatology Division, Ospedale San Giuseppe, Università degli Studi di Milano, Milan, Italy
| | - F Facchetti
- CRC "A.M. e A. Migliavacca" Center for the Study of Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - G Lunghi
- Virology Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - A Sangiovanni
- CRC "A.M. e A. Migliavacca" Center for the Study of Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - M Colombo
- Center for Translational Hepatology Research, Clinical and Research Center, Humanitas Hospital, Rozzano, Italy
| | - P Lampertico
- CRC "A.M. e A. Migliavacca" Center for the Study of Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
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Chen VL, Yeh ML, Le AK, Jun M, Saeed WK, Yang JD, Huang CF, Lee HY, Tsai PC, Lee MH, Giama N, Kim NG, Nguyen PP, Dang H, Ali HA, Zhang N, Huang JF, Dai CY, Chuang WL, Roberts LR, Jun DW, Lim YS, Yu ML, Nguyen MH. Anti-viral therapy is associated with improved survival but is underutilised in patients with hepatitis B virus-related hepatocellular carcinoma: real-world east and west experience. Aliment Pharmacol Ther 2018; 48:44-54. [PMID: 29797518 DOI: 10.1111/apt.14801] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Revised: 03/02/2018] [Accepted: 04/23/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND Hepatitis B virus (HBV) is the leading cause of hepatocellular carcinoma (HCC) worldwide. It remains incompletely understood in the real world how anti-viral therapy affects survival after HCC diagnosis. METHODS This was an international multicentre cohort study of 2518 HBV-related HCC cases diagnosed between 2000 and 2015. Cox proportional hazards models were utilised to estimate hazard ratios (HR) with 95% (CI) for anti-viral therapy and cirrhosis on patients' risk of death. RESULTS Approximately, 48% of patients received anti-viral therapy at any time, but only 17% were on therapy at HCC diagnosis (38% at US centres, 11% at Asian centres). Anti-viral therapy would have been indicated for >60% of the patients not on anti-viral therapy based on American criteria. Patients with cirrhosis had lower 5-year survival (34% vs 46%; P < 0.001) while patients receiving anti-viral therapy had increased 5-year survival compared to untreated patients (42% vs 25% with cirrhosis and 58% vs 36% without cirrhosis; P < 0.001 for both). Similar findings were seen for other patient subgroups by cancer stages and cancer treatment types. Anti-viral therapy was associated with a decrease in risk of death, whether started before or after HCC diagnosis (adjusted HR 0.62 and 0.79, respectively; P < 0.001). CONCLUSIONS Anti-viral therapy improved overall survival in patients with HBV-related HCC across cancer stages and treatment types but was underutilised at both US and Asia centres. Expanded use of anti-viral therapy in HBV-related HCC and better linkage-to-care for HBV patients are needed.
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Affiliation(s)
- V L Chen
- Division of Gastroenterology, University of Michigan Health System, Ann Arbor, MI, USA.,Department of Medicine, Stanford University Medical Center, Stanford, CA, USA
| | - M-L Yeh
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - A K Le
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford, CA, USA
| | - M Jun
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - W K Saeed
- Division of Gastroenterology, Hanyang University Medical Center, Seoul, Korea
| | - J D Yang
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - C-F Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - H Y Lee
- Division of Gastroenterology, Hanyang University Medical Center, Seoul, Korea
| | - P-C Tsai
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - M-H Lee
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
| | - N Giama
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - N G Kim
- Stanford University School of Medicine, Stanford, CA, USA
| | - P P Nguyen
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford, CA, USA
| | - H Dang
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford, CA, USA
| | - H A Ali
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - N Zhang
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - J-F Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - C-Y Dai
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - W-L Chuang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - L R Roberts
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - D W Jun
- Division of Gastroenterology, Hanyang University Medical Center, Seoul, Korea
| | - Y-S Lim
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - M-L Yu
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - M H Nguyen
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford, CA, USA
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Lin CL, Kao JH. Review article: the prevention of hepatitis B-related hepatocellular carcinoma. Aliment Pharmacol Ther 2018; 48:5-14. [PMID: 29722445 DOI: 10.1111/apt.14683] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Revised: 02/08/2018] [Accepted: 04/03/2018] [Indexed: 12/14/2022]
Abstract
BACKGROUND Ample evidence indicates an aetiological association of persistent hepatitis B virus (HBV) infection with hepatocellular carcinoma (HCC). Several viral, host and external risk factors for the development of HBV-related HCC have been documented. AIMS To summarise and discuss the risk stratification and the preventive strategies of HBV-related HCC. METHODS Recent published studies identified from PubMed were comprehensively reviewed. The key words included chronic hepatitis B, HBV, hepatocellular carcinoma, prevention and antiviral therapy. RESULTS The incidence of HCC is extremely high in HBV hyperendemic areas. For HBV patients left untreated, significant risk factors for HCC include male gender, aging, advanced hepatic fibrosis, persistent serum transaminase elevation, specific HBV entry receptor (NTCP) genotype, PM2.5 exposure, HBeAg positivity, HBV genotype C/D/F, high proportion of core promoter mutation, pre-S deletion, high serum levels of HBV DNA and HBsAg as well as co-infection with HCV, HDV and HIV. Primary prevention of HBV-related HCC can be achieved through universal HBV vaccination and anti-viral prophylaxis for high viraemic mothers. The goal of secondary prevention has been reached by effective anti-viral therapy to reduce the risk of HCC development in chronic hepatitis B patients. However, whether HCC is prevented or delayed deserves further examination. Finally, several studies confirmed the tertiary preventive effect of anti-viral therapy in reducing risk of HCC recurrence after curative therapies. CONCLUSIONS Through the strategies of three-level prevention, the global burden of HBV-related HCC should decline over time and even be eliminated in conjunction with HBV cure.
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Affiliation(s)
- C-L Lin
- Department of Gastroenterology, Taipei City Hospital, Taipei, Taiwan.,Department of Psychology, National Chengchi University, Taipei, Taiwan
| | - J-H Kao
- Graduate Institute of Clinical Medicine, National Taiwan University, College of Medicine, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University, National Taiwan University Hospital, Taipei, Taiwan.,Department of Medical Research, National Taiwan University, National Taiwan University Hospital, Taipei, Taiwan
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Cho H, Ahn H, Lee DH, Lee JH, Jung YJ, Chang Y, Nam JY, Cho YY, Lee DH, Cho EJ, Yu SJ, Lee JM, Kim YJ, Yoon JH. Entecavir and tenofovir reduce hepatitis B virus-related hepatocellular carcinoma recurrence more effectively than other antivirals. J Viral Hepat 2018; 25:707-717. [PMID: 29316069 DOI: 10.1111/jvh.12855] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Accepted: 11/13/2017] [Indexed: 12/15/2022]
Abstract
Nucleos(t)ide analogues (NAs) have been shown to decrease the risk of hepatocellular carcinoma (HCC) recurrence. This study evaluated whether high-potency NAs (entecavir and tenofovir disoproxil fumarate [TDF]) reduce the risk of tumour recurrence more potently than low-potency NAs after curative treatment of hepatitis B virus (HBV)-related HCC. This study included 607 consecutive HBV-related HCC patients treated with surgical resection or radiofrequency ablation. The patients were categorized into three groups according to antiviral treatment: group A (no antiviral; n = 261), group B (low-potency NA; n = 90) and group C (high-potency NA; n = 256). The primary end-point was recurrence-free survival (RFS). During the duration of follow-up, the median RFS was 29.4, 25.1, and 88.2 months in groups A, B and C, respectively (P < .001, log-rank test). The multivariate Cox analysis indicated that group C had a significantly longer RFS than both group A (adjusted hazard ratio [HR] = 0.39, P < .001) and group B (adjusted HR = 0.47, P < .001). When baseline characteristics were balanced using inverse probability weighting, group C still had a significantly longer RFS than group A (adjusted HR = 0.46, P < .001) and group B (adjusted HR = 0.59, P = .007). Group C had significantly lower risk of viral breakthrough than group B (HR = 0.19, P < .001). Viral breakthrough was an independent risk factor for shorter RFS among groups B and C (adjusted HR = 2.03, P = .007, time-dependent Cox analysis). Antiviral agents with high genetic barrier to resistance (entecavir and TDF) reduced the risk of HCC recurrence compared with other antivirals and no antiviral treatment, especially in patients with high baseline viral load.
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Affiliation(s)
- H Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - H Ahn
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - D H Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea.,Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea
| | - J-H Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Y J Jung
- Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea
| | - Y Chang
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - J Y Nam
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Y Y Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - D H Lee
- Department of Radiology, Seoul National University College of Medicine, Seoul, Korea
| | - E J Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - S J Yu
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - J M Lee
- Department of Radiology, Seoul National University College of Medicine, Seoul, Korea
| | - Y J Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - J-H Yoon
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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Lee TY, Hsu YC, Yu SH, Lin JT, Wu MS, Wu CY. Effect of Nucleos(t)ide Analogue Therapy on Risk of Intrahepatic Cholangiocarcinoma in Patients With Chronic Hepatitis B. Clin Gastroenterol Hepatol 2018; 16:947-954.e4. [PMID: 28951229 DOI: 10.1016/j.cgh.2017.09.031] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Revised: 08/30/2017] [Accepted: 09/08/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Chronic infection with hepatitis B virus (HBV) increases risk of intrahepatic cholangiocarcinoma (ICC), but it is not clear whether antiviral therapy reduces risk. We investigated the association between nucleos(t)ide analogue therapy and ICC risk. METHODS We performed a nationwide long-term cohort study using Taiwan's National Health Insurance Research Database to obtain data on 185,843 patients with chronic HBV infection from October 1, 2003 through December 31, 2012. We excluded patients with confounding disorders such as infection with hepatitis C virus, HIV, or other hepatitis-associated viruses; liver flukes; biliary stone diseases; cholangitis; congenital biliary anomalies; biliary tract surgeries; or cancer. We identified 10,062 patients who received nucleos(t)ide analogue therapy (the treated group), and used propensity scores to match them (1:1) with patients who received hepatoprotectants (the untreated group). Cumulative incidences of and hazard ratios (HRs) for ICC development were analyzed. RESULTS The cumulative incidence of ICC was significantly lower in the treated group after 3 years of therapy (1.28%; 95% CI, 0.56-2.01) than in the untreated group (3.14%; 95% CI, 2.02-4.27) and after 5 years of therapy (1.53%; 95% CI, 0.73-2.33 vs 4.32% in untreated group; 95% CI, 2.96-5.6869). In multivariable regression analysis, nucleos(t)ide analogue therapy was independently associated with a reduced risk of ICC (HR, 0.44; 95% CI, 0.25-0.78; P = .005). Older age (HR 1.05 per year; 95% CI, 1.03-1.07) and cirrhosis (HR, 2.80; 95% CI, 1.52-5.1415) were independently associated with an increased risk of ICC. Sensitivity analyses verified the association between nucleos(t)ide analogue therapy and a reduced ICC risk. CONCLUSION A nationwide long-term cohort study in Taiwan showed that nucleos(t)ide analogue therapy for chronic HBV infection is significantly associated with a reduced ICC risk.
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Affiliation(s)
- Teng-Yu Lee
- Division of Gastroenterology and Hepatology, Taichung Veterans General Hospital, Taichung; Department of Medicine, Chung Shan Medical University, Taichung
| | - Yao-Chun Hsu
- Big Data Research Center, School of Medicine, Fu-Jen Catholic University, New Taipei; Division of Gastroenterology, Fu-Jen Catholic University Hospital, New Taipei; Graduate Institute of Clinical Medicine, China Medical University, Taichung; Division of Gastroenterology and Hepatology, E-Da Hospital, Kaohsiung
| | - Shi-Hang Yu
- Division of Gastroenterology and Hepatology, Taichung Veterans General Hospital, Taichung
| | - Jaw-Town Lin
- School of Medicine, Fu Jen Catholic University, New Taipei City; Institute of Population Health Sciences, National Health Research Institutes, Miaoli
| | - Ming-Shiang Wu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei
| | - Chun-Ying Wu
- Division of Gastroenterology and Hepatology, Taichung Veterans General Hospital, Taichung; Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei; College of Public Health and Graduate Institute of Clinical Medical Science, China Medical University, Taichung; Department of Life Sciences and Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung; National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan; Division of Translational Medicine, Department of Medical Research, Taipei Veterans General Hospital, Beitou District, Taipei, Taiwan.
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Mak LY, Cruz-Ramón V, Chinchilla-López P, Torres HA, LoConte NK, Rice JP, Foxhall LE, Sturgis EM, Merrill JK, Bailey HH, Méndez-Sánchez N, Yuen MF, Hwang JP. Global Epidemiology, Prevention, and Management of Hepatocellular Carcinoma. Am Soc Clin Oncol Educ Book 2018; 38:262-279. [PMID: 30231359 DOI: 10.1200/edbk_200939] [Citation(s) in RCA: 145] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
The incidence rate of hepatocellular carcinoma (HCC) is rising. It is one of the most common cancers worldwide and accounts for substantial morbidity and mortality. Chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, and nonalcoholic fatty liver disease (NAFLD) are the most important etiologies of HCC, and effective screening and management strategies are crucial to reduce the HCC risk. For HBV, which accounts for the majority of HCC cases, most infections were acquired via perinatal and early horizontal transmission. Universal vaccination of newborns has led to a decline in HCC incidence compared with the pre-vaccination era. Effective antiviral therapies with nucleos(t)ide analogues or pegylated interferon reduced the incidence of HCC. For HCV, the emergence of effective direct-acting antiviral (DAA) agents has substantially improved cure rates; therefore all patients with HCV should be considered for DAA treatment. The most important obstacle in eliminating HCV is access to therapy. For NAFLD, the global incidence is increasing rapidly, thus its impact on HCC incidence may be explosive. Progression to HCC in NAFLD happens particularly in those with nonalcoholic steatohepatitis (NASH) and exacerbated by metabolic syndrome, or PNPLA3 gene polymorphism. Lifestyle changes are imperative while drug therapy has yet to demonstrate substantive protective effects on HCC prevention. For management of HCC, early diagnosis via imaging surveillance among persons with HCC risk factors remains the most important strategy to identify early-stage disease appropriate for resection or transplantation.
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MESH Headings
- Carcinoma, Hepatocellular/diagnosis
- Carcinoma, Hepatocellular/epidemiology
- Carcinoma, Hepatocellular/prevention & control
- Carcinoma, Hepatocellular/therapy
- Disease Management
- Global Health
- Hepatitis B, Chronic/complications
- Hepatitis B, Chronic/diagnosis
- Hepatitis B, Chronic/therapy
- Hepatitis B, Chronic/virology
- Hepatitis C, Chronic/complications
- Hepatitis C, Chronic/diagnosis
- Hepatitis C, Chronic/therapy
- Hepatitis C, Chronic/virology
- Humans
- Incidence
- Liver Neoplasms/diagnosis
- Liver Neoplasms/epidemiology
- Liver Neoplasms/prevention & control
- Liver Neoplasms/therapy
- Non-alcoholic Fatty Liver Disease/complications
- Non-alcoholic Fatty Liver Disease/diagnosis
- Non-alcoholic Fatty Liver Disease/therapy
- Population Surveillance
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Affiliation(s)
- Lung-Yi Mak
- From the Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China; Liver Research Unit, Medica Sur Clinic and Foundation, Mexico City, Mexico; The University of Texas MD Anderson Cancer Center, Houston, TX; University of Wisconsin Carbone Cancer Center, Madison, WI; University of Wisconsin School of Medicine, Madison, WI; American Society of Clinical Oncology, Alexandria, VA
| | - Vania Cruz-Ramón
- From the Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China; Liver Research Unit, Medica Sur Clinic and Foundation, Mexico City, Mexico; The University of Texas MD Anderson Cancer Center, Houston, TX; University of Wisconsin Carbone Cancer Center, Madison, WI; University of Wisconsin School of Medicine, Madison, WI; American Society of Clinical Oncology, Alexandria, VA
| | - Paulina Chinchilla-López
- From the Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China; Liver Research Unit, Medica Sur Clinic and Foundation, Mexico City, Mexico; The University of Texas MD Anderson Cancer Center, Houston, TX; University of Wisconsin Carbone Cancer Center, Madison, WI; University of Wisconsin School of Medicine, Madison, WI; American Society of Clinical Oncology, Alexandria, VA
| | - Harrys A Torres
- From the Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China; Liver Research Unit, Medica Sur Clinic and Foundation, Mexico City, Mexico; The University of Texas MD Anderson Cancer Center, Houston, TX; University of Wisconsin Carbone Cancer Center, Madison, WI; University of Wisconsin School of Medicine, Madison, WI; American Society of Clinical Oncology, Alexandria, VA
| | - Noelle K LoConte
- From the Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China; Liver Research Unit, Medica Sur Clinic and Foundation, Mexico City, Mexico; The University of Texas MD Anderson Cancer Center, Houston, TX; University of Wisconsin Carbone Cancer Center, Madison, WI; University of Wisconsin School of Medicine, Madison, WI; American Society of Clinical Oncology, Alexandria, VA
| | - John P Rice
- From the Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China; Liver Research Unit, Medica Sur Clinic and Foundation, Mexico City, Mexico; The University of Texas MD Anderson Cancer Center, Houston, TX; University of Wisconsin Carbone Cancer Center, Madison, WI; University of Wisconsin School of Medicine, Madison, WI; American Society of Clinical Oncology, Alexandria, VA
| | - Lewis E Foxhall
- From the Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China; Liver Research Unit, Medica Sur Clinic and Foundation, Mexico City, Mexico; The University of Texas MD Anderson Cancer Center, Houston, TX; University of Wisconsin Carbone Cancer Center, Madison, WI; University of Wisconsin School of Medicine, Madison, WI; American Society of Clinical Oncology, Alexandria, VA
| | - Erich M Sturgis
- From the Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China; Liver Research Unit, Medica Sur Clinic and Foundation, Mexico City, Mexico; The University of Texas MD Anderson Cancer Center, Houston, TX; University of Wisconsin Carbone Cancer Center, Madison, WI; University of Wisconsin School of Medicine, Madison, WI; American Society of Clinical Oncology, Alexandria, VA
| | - Janette K Merrill
- From the Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China; Liver Research Unit, Medica Sur Clinic and Foundation, Mexico City, Mexico; The University of Texas MD Anderson Cancer Center, Houston, TX; University of Wisconsin Carbone Cancer Center, Madison, WI; University of Wisconsin School of Medicine, Madison, WI; American Society of Clinical Oncology, Alexandria, VA
| | - Howard H Bailey
- From the Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China; Liver Research Unit, Medica Sur Clinic and Foundation, Mexico City, Mexico; The University of Texas MD Anderson Cancer Center, Houston, TX; University of Wisconsin Carbone Cancer Center, Madison, WI; University of Wisconsin School of Medicine, Madison, WI; American Society of Clinical Oncology, Alexandria, VA
| | - Nahum Méndez-Sánchez
- From the Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China; Liver Research Unit, Medica Sur Clinic and Foundation, Mexico City, Mexico; The University of Texas MD Anderson Cancer Center, Houston, TX; University of Wisconsin Carbone Cancer Center, Madison, WI; University of Wisconsin School of Medicine, Madison, WI; American Society of Clinical Oncology, Alexandria, VA
| | - Man-Fung Yuen
- From the Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China; Liver Research Unit, Medica Sur Clinic and Foundation, Mexico City, Mexico; The University of Texas MD Anderson Cancer Center, Houston, TX; University of Wisconsin Carbone Cancer Center, Madison, WI; University of Wisconsin School of Medicine, Madison, WI; American Society of Clinical Oncology, Alexandria, VA
| | - Jessica P Hwang
- From the Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China; Liver Research Unit, Medica Sur Clinic and Foundation, Mexico City, Mexico; The University of Texas MD Anderson Cancer Center, Houston, TX; University of Wisconsin Carbone Cancer Center, Madison, WI; University of Wisconsin School of Medicine, Madison, WI; American Society of Clinical Oncology, Alexandria, VA
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48
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Hsu YC, Ho HJ, Lee TY, Huang YT, Wu MS, Lin JT, Wu CY, El-Serag HB. Temporal trend and risk determinants of hepatocellular carcinoma in chronic hepatitis B patients on entecavir or tenofovir. J Viral Hepat 2018; 25:543-551. [PMID: 29193536 DOI: 10.1111/jvh.12832] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Accepted: 10/05/2017] [Indexed: 12/21/2022]
Abstract
This study aimed to elucidate the temporal change and determinants for the risk of HCC in patients with chronic hepatitis B continuously receiving NUC. Through analysis of the national healthcare database in Taiwan, we screened a total of 65 426 infected patients receiving entecavir or tenofovir for at least 3 months and excluded those with lamivudine, adefovir or telbivudine exposure, malignancy, end-stage renal failure or a diagnosis of HCC within 3 months of starting treatment. Eligible patients (N = 27 820) were followed until HCC occurrence, completion of the allowed 3-year regimen or 31 December 2013. During a median follow-up of 25.1 (12.1-35.6) months, 802 patients developed HCC, with 1-, 2- and 3-year cumulative incidence of 1.82% (95% CI, 1.66-1.99%), 3.05% (95% CI, 2.82-3.28%) and 4.06% (95% CI, 3.77-4.36%), respectively. HCC annual incidence decreased with an adjusted IRR of 0.73 (95% CI, 0.66-0.80) per yearly interval and was associated with cirrhosis (IRR, 10.07; 95% CI, 6.00-16.90 in age <40 years; 4.69; 95% CI, 3.94-5.59 in age ≧40 years), age (IRR, 3.38; 95% CI, 2.10-5.47 for 40-50 years; 6.92; 95% CI, 4.27-11.21 for 50-60 years; 12.50; 95% CI, 7.71-20.25 for ≧60 years; <40 years as reference), male sex (IRR, 1.71; 95% CI, 1.44-2.04), HCV coinfection (IRR, 1.27; 95% CI, 1.02-1.58) and diabetes (IRR, 1.24; 95% CI, 1.05-1.45). In conclusion, the risk of HCC in patients with chronic hepatitis B receiving entecavir or tenofovir declines over time and is determined by cirrhosis, age, male sex, HCV coinfection and diabetes.
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Affiliation(s)
- Yao-Chun Hsu
- School of Medicine and Big Data Research Center, Fu-Jen Catholic University, New Taipei, Taiwan.,Department of Internal Medicine, Fu-Jen Catholic University Hospital, New Taipei, Taiwan.,Department of Internal Medicine, E-Da Hospital, Kaohsiung, Taiwan.,Graduate Institute of Clinical Medicine, China Medical University, Taichung, Taiwan
| | - Hsiu-J Ho
- Division of Translational Research, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Teng-Yu Lee
- Division of Translational Research, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Yen-Tsung Huang
- Institute of Statistical Science, Academia Sinica, Taipei, Taiwan.,Departments of Epidemiology and Biostatistics, Brown University, Providence, RI, USA
| | - Ming-Shiang Wu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Jaw-Town Lin
- School of Medicine and Big Data Research Center, Fu-Jen Catholic University, New Taipei, Taiwan.,Department of Internal Medicine, Fu-Jen Catholic University Hospital, New Taipei, Taiwan.,Department of Internal Medicine, E-Da Hospital, Kaohsiung, Taiwan
| | - Chun-Ying Wu
- Graduate Institute of Clinical Medicine, China Medical University, Taichung, Taiwan.,Division of Translational Research, Taipei Veterans General Hospital, Taipei, Taiwan.,School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Hashem B El-Serag
- Section of Gastroenterology and Hepatology, Department of Medicine, Michael E DeBakey VA Medical Center, Baylor College of Medicine, Houston, TX, USA
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49
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Sohn W, Kang TW, Choi SK, Jung SH, Lee MW, Lim HK, Cho JY, Shim SG, Sinn DH, Gwak GY, Choi MS, Lee JH, Koh KC, Paik SW, Rhim H, Paik YH. Effect of oral antiviral treatment on long-term outcomes of radiofrequency ablation therapy for hepatitis B virus-related hepatocellular carcinoma. Oncotarget 2018; 7:47794-47807. [PMID: 27329596 PMCID: PMC5216979 DOI: 10.18632/oncotarget.10026] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Accepted: 05/28/2016] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES This study aimed to investigate the effect of oral antiviral treatment on the prognosis of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after radiofrequency (RF) ablation. METHODS Between January 2003 and December 2010, 228 patients without a history of antiviral treatment were treated with RF ablation for a single HBV-related HCC. We divided the patients into two groups, patients who received (n=125) or did not receive antiviral treatment (n=103), based on whether oral antiviral treatment was administered after RF ablation. The median duration of antiviral treatment was 60.1 months. HCC recurrence and overall survival were compared in the two groups in the full cohort and the propensity score-matched cohort. RESULTS In the matched cohort, the probability of HCC recurrence at 5 years was 43.8% for the non-antiviral treatment group and 14.7% for the antiviral treatment group (p<0.001). The probability of overall survival at 5 years was 77.2% for the non-antiviral treatment group and 93.5% for the antiviral treatment group (p=0.002). Multivariable analysis showed that risk factors for HCC recurrence included large tumor size (hazard ratio (HR)=1.30, p=0.022), HBV DNA serum level (HR=1.11, p=0.005), and serum AFP level ≥20 ng/mL (HR=1.66, p=0.005). Overall survival was associated with larger tumor size (HR=1.86, p=0.001) and Child-Pugh Class B (HR=2.13, p=0.019). Oral antiviral treatment after RF ablation was significantly associated with a lower risk of tumor recurrence and death (HR=0.33, p<0.001, and HR=0.44, p=0.004). CONCLUSION Use of oral antiviral treatment after curative RF ablation was associated with favorable outcomes in terms of tumor recurrence and overall survival in patients with HBV-related HCC.
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Affiliation(s)
- Won Sohn
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Department of Hepatology, Bundang Jesaeng Hospital, Sungnam, Korea
| | - Tae Wook Kang
- Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sun-Kyu Choi
- Department of Biostatistics and Clinical Epidemiology, Samsung Medical Center, Seoul, Korea
| | - Sin-Ho Jung
- Department of Biostatistics and Clinical Epidemiology, Samsung Medical Center, Seoul, Korea
| | - Min Woo Lee
- Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hyo Keun Lim
- Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Department of Health Science and Technology, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul, Korea
| | - Ju-Yeon Cho
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Department of Medicine, Chosun University Hospital, Gwang-Ju, Korea
| | - Sang Goon Shim
- Department of Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea
| | - Dong Hyun Sinn
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Geum-Youn Gwak
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Moon Seok Choi
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Joon Hyeok Lee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kwang Cheol Koh
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Seung Woon Paik
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hyunchul Rhim
- Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yong-Han Paik
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Department of Health Science and Technology, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul, Korea
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50
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Oxidative stress, a trigger of hepatitis C and B virus-induced liver carcinogenesis. Oncotarget 2018; 8:3895-3932. [PMID: 27965466 PMCID: PMC5354803 DOI: 10.18632/oncotarget.13904] [Citation(s) in RCA: 120] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Accepted: 12/05/2016] [Indexed: 12/11/2022] Open
Abstract
Virally induced liver cancer usually evolves over long periods of time in the context of a strongly oxidative microenvironment, characterized by chronic liver inflammation and regeneration processes. They ultimately lead to oncogenic mutations in many cellular signaling cascades that drive cell growth and proliferation. Oxidative stress, induced by hepatitis viruses, therefore is one of the factors that drives the neoplastic transformation process in the liver. This review summarizes current knowledge on oxidative stress and oxidative stress responses induced by human hepatitis B and C viruses. It focuses on the molecular mechanisms by which these viruses activate cellular enzymes/systems that generate or scavenge reactive oxygen species (ROS) and control cellular redox homeostasis. The impact of an altered cellular redox homeostasis on the initiation and establishment of chronic viral infection, as well as on the course and outcome of liver fibrosis and hepatocarcinogenesis will be discussed The review neither discusses reactive nitrogen species, although their metabolism is interferes with that of ROS, nor antioxidants as potential therapeutic remedies against viral infections, both subjects meriting an independent review.
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