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Song Z, Chen B, Wen H, Zhou Q, Lin S, Qian B, Huang Y, Yu X, Shen S. Negative serum alpha-fetoprotein at recurrence predicts good prognosis in recurrent hepatocellular carcinoma patients receiving repeated hepatectomy:a single-center retrospective cohort study. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2025; 51:110145. [PMID: 40393143 DOI: 10.1016/j.ejso.2025.110145] [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: 02/27/2025] [Revised: 05/03/2025] [Accepted: 05/08/2025] [Indexed: 05/22/2025]
Abstract
BACKGROUND The serum alpha-fetoprotein (AFP) serves as a crucial prognostic indicator in patients diagnosed with hepatocellular carcinoma (HCC). Examining the impact of baseline-AFP (b-AFP), recurrence -AFP (r-AFP), and changes in AFP levels on the prognosis of individuals with recurrent hepatocellular carcinoma (RHCC) who undergo repeated hepatectomy holds substantial clinical significance. METHOD A total of 400 RHCC patients who had undergone repeated hepatectomy in the Center of Hepato-Pancreato-Biliary Surgery at the First Affiliated Hospital of Sun Yat-Sen University between January 1, 2006, and December 31, 2019 were included in this study. The analysis focused on evaluating the impact of b-AFP, r-AFP, and changes in AFP levels on the prognosis of RHCC patients. RESULTS The recurrence rate among HCC patients who underwent hepatectomy was approximately 40.03 %. Among the 400 HCC patients who underwent twice hepatectomy, the 5-year mortality rate was 34.25 %, with an overall mortality rate of 38.75 %. Survival analysis indicated statistically significant disparities in overall survival (OS) and recurrence-free survival (RFS) between the b-AFP (-) group and the b-AFP (+) group, with the latter exhibiting shorter OS and RFS. The 3-year mortality rates for the two groups were 31.7 % and 42.5 %, respectively. The median overall survival (mOS) for the two groups were 107.4 months and 89.5 months, respectively. A statistically significant discrepancy in recurrence-death survival (RDS) was observed between the r-AFP (-) and r-AFP (+) groups (P < 0.0001), with patients in the r-AFP (+) category experiencing a shorter RDS. The median RDS for these two groups were 88.1 months and 31.7 months, respectively. Significant differences in both overall survival (OS) and RDS were observed among the AFP (+/+), AFP (±), AFP (-/+), and AFP (-/-) groups. The order of OS and RDS from lowest to highest was as follows: AFP (+/+) group < AFP (-/+) group < AFP (-/-) group < AFP (±) group. Irrespective of the b-AFP status, patients with positive r-AFP exhibited notably shorter OS and RFS compared to their r-AFP negative counterparts. The 3-year mortality rates for the four groups were 50.9 %, 26.1 %, 39.3 %, and 29.7 %, respectively. Median OS values were 42.4 months, not reached (NA), 77.1 months, and 107.4 months, respectively. Furthermore, an analysis of the cumulative 1-year, 3-year, and 5-year OS, RDS, and RFS rates for each group was conducted. CONCLUSION The b-AFP, r-AFP and AFP fluctuations serve as valuable prognostic indicators in individuals who have undergone hepatectomy for HCC on two occasions. These indicators can offer valuable insights for guiding the diagnosis and treatment strategies for HCC recurrence in such patients.
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Affiliation(s)
- Zimin Song
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510030, China
| | - Bin Chen
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510030, China
| | - Haoxiang Wen
- Department of Hepatobiliary Surgery, National Cancer Center/Cancer Hospital &Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, 518100, China
| | - Qian Zhou
- Department of Medical Statistics, Clinical Trials Unit, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhong Shan Er Road, 510080, Guangzhou, China
| | - Shuirong Lin
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510030, China
| | - Baifeng Qian
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510030, China
| | - Yihao Huang
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510030, China
| | - Xi Yu
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510030, China
| | - Shunli Shen
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510030, China.
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Sheng Y, Lin Y, Qiang Z, Shen X, He Y, Li L, Li S, Zhang G, Wang F. Protein kinase a suppresses antiproliferative effect of interferon-α in hepatocellular carcinoma by activation of protein tyrosine phosphatase SHP2. J Biol Chem 2025; 301:108195. [PMID: 39826687 PMCID: PMC11849638 DOI: 10.1016/j.jbc.2025.108195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 12/16/2024] [Accepted: 12/18/2024] [Indexed: 01/22/2025] Open
Abstract
Src homology-2-containing protein tyrosine phosphatase 2 (SHP2) plays a dual role in cancer initiation and progression. Identifying signals that modulate the function of SHP2 can improve current therapeutic approaches for IFN-α/β in HCC. We showed that cAMP-dependent PKA suppresses IFN-α/β-induced JAK/STAT signaling by increasing the phosphatase activity of SHP2, promoting the dissociation of SHP2 from the receptor for activated C-kinase 1 (RACK1) and binding to STAT1. Additionally, cAMP-degrading phosphodiesterase 4D (PDE4D) physically interacts with RACK1 to regulate PKA-mediated SHP2 activity and STAT1 phosphorylation. IFN-α activates PKA by inducing the expression of cyclooxygenase 2 (COX2) and the production of prostaglandin E2 (PGE2), which in turn stimulates the binding of SHP2 to IFNAR2 via RACK1. A COX inhibitor aspirin potently increases the antitumor effects of IFN-α in the suppression of HCC cell proliferation in vivo. Higher expression of COX2 and phosphorylated STAT3 is associated with poor development and prognosis in HCC patients by analyzing human HCC clinical samples. These observations suggest that a fundamental PKA/SHP2-dependent negative feedback loop acts on IFN signaling, and inhibition of this signaling by the selective COX2 inhibitors may enhance the clinical efficacy of type I IFNs in treating HCC.
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MESH Headings
- Humans
- Protein Tyrosine Phosphatase, Non-Receptor Type 11/metabolism
- Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/enzymology
- Liver Neoplasms/pathology
- Liver Neoplasms/metabolism
- Liver Neoplasms/drug therapy
- Liver Neoplasms/genetics
- Liver Neoplasms/enzymology
- Interferon-alpha/pharmacology
- Interferon-alpha/metabolism
- Receptors for Activated C Kinase
- Animals
- Cell Proliferation/drug effects
- Cyclic AMP-Dependent Protein Kinases/metabolism
- Cyclic AMP-Dependent Protein Kinases/genetics
- Mice
- Neoplasm Proteins/metabolism
- Neoplasm Proteins/genetics
- Signal Transduction/drug effects
- STAT1 Transcription Factor/metabolism
- STAT1 Transcription Factor/genetics
- Cyclooxygenase 2/metabolism
- Cyclooxygenase 2/genetics
- Receptor, Interferon alpha-beta/metabolism
- Receptor, Interferon alpha-beta/genetics
- GTP-Binding Proteins/metabolism
- GTP-Binding Proteins/genetics
- Cell Line, Tumor
- Phosphorylation/drug effects
- STAT3 Transcription Factor/metabolism
- STAT3 Transcription Factor/genetics
- Dinoprostone/metabolism
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Affiliation(s)
- Yuwen Sheng
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China
| | - Yuan Lin
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China
| | - Zhe Qiang
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China; Chongqing Academy of Chinese Materia Medica, Chongqing, China
| | - Xiaofei Shen
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China; Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yujiao He
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China; Anti-infective Agent Creation Engineering Research Centre of Sichuan Province, Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu, China
| | - Lingyu Li
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China; University of Chinese Academy of Sciences, Beijing, China
| | - Sheng Li
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China
| | - Guolin Zhang
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China
| | - Fei Wang
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China.
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Li L, Li ZZ, Pan LX, Su JY, Huang S, Ma L, Zhong JH. Adjuvant Therapy for Hepatocellular Carcinoma After Curative Treatment: Several Unanswered Questions. J Clin Transl Hepatol 2024; 12:525-533. [PMID: 38779519 PMCID: PMC11106350 DOI: 10.14218/jcth.2024.00030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 03/31/2024] [Accepted: 04/09/2024] [Indexed: 05/25/2024] Open
Abstract
Most patients with hepatocellular carcinoma (HCC) have a poor prognosis. Hepatectomy and local ablation are the main curative treatments for HCC. Nevertheless, the recurrence rate after hepatectomy or ablation is up to 70%, which seriously affects patient prognosis. Several adjuvant therapies have been explored to reduce postoperative recurrence. However, although a variety of adjuvant therapies have been shown to reduce the recurrence rate and improve overall survival, a standard consensus of national HCC guidelines for adjuvant treatment is lacking. Therefore, there are significant differences in the recommendations for adjuvant therapy for HCC between the Eastern and Western guidelines. A variety of adjuvant treatment methods, such as antiviral therapy, transarterial chemoembolization or traditional Chinese medicine, are recommended by the Chinese HCC guidelines. However, Western guidelines make few recommendations other than antiviral therapy. Adjuvant immune checkpoint inhibitors are recommended only in the recently updated American Association for the Study of Liver Diseases guidelines. This review summarized the existing adjuvant therapy options after curative hepatectomy or ablation and discusses several important dilemmas of adjuvant treatments.
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Affiliation(s)
- Le Li
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
- Guangxi Academy of Medical Sciences, Emergency Department, The People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, China
| | - Zhen-Zhen Li
- Pathology Department, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
| | - Li-Xin Pan
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
| | - Jia-Yong Su
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
| | - Shan Huang
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
| | - Liang Ma
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
| | - Jian-Hong Zhong
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, China
- Guangxi Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Nanning, Guangxi, China
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Hashimoto M, Kobayashi T, Ohira M, Okimoto S, Abe T, Inoue M, Onoe T, Honmyo N, Kuroda S, Ohdan H. Comparison of postoperative outcomes in cases achieving sustained virological response with direct-acting antiviral and interferon therapy. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2024; 31:318-328. [PMID: 38135908 DOI: 10.1002/jhbp.1406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 10/23/2023] [Accepted: 11/15/2023] [Indexed: 12/24/2023]
Abstract
BACKGROUND/PURPOSE The effect of direct-acting antiviral agents (DAAs) on hepatocellular carcinoma (HCC) recurrence after curative hepatectomy remains uncertain. This retrospective study aimed to evaluate the effect of sustained virological response (SVR) with DAAs or interferon (IFN) therapy on recurrence and overall survival (OS) after hepatectomy. METHODS We enrolled 593 patients who underwent curative resections between January 2010 and December 2017. Among them, 186 achieved SVR before hepatectomy: a total of 51 (27.4%) in the DAA-SVR group and 132 (72.6%) in the IFN-based SVR group. RESULTS SVR before hepatectomy was an independent predictor of OS, and the 5-year OS rate was significantly higher in the SVR group than that in the non-SVR group (82.2% vs. 63.9%). There were no significant differences in the recurrence rates or OS between DAA and IFN treatments in achieving SVR before hepatectomy, regardless of poor hepatic function in the DAA therapy group. CONCLUSIONS There was no significant difference in OS and recurrence-free survival (RFS) between the preoperative SVR achieved with DAA and IFN groups in this study, although liver function was significantly worse at the time of surgery in the DAA group compared to the IFN group.
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Affiliation(s)
- Masakazu Hashimoto
- Department of Gastroenterological Surgery, Hiroshima Prefectural Hospital, Hiroshima, Japan
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
- HiSCO: Hiroshima Surgical study group of Clinical Oncology, Hiroshima, Japan
| | - Tsuyoshi Kobayashi
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
- HiSCO: Hiroshima Surgical study group of Clinical Oncology, Hiroshima, Japan
| | - Masahiro Ohira
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
- HiSCO: Hiroshima Surgical study group of Clinical Oncology, Hiroshima, Japan
| | - Sho Okimoto
- Department of Surgery, Chugoku Rosai Hospital, Kure, Japan
- HiSCO: Hiroshima Surgical study group of Clinical Oncology, Hiroshima, Japan
| | - Tomoyuki Abe
- Department of Surgery, JA Onomichi General Hospital, Onomichi, Japan
- HiSCO: Hiroshima Surgical study group of Clinical Oncology, Hiroshima, Japan
| | - Masashi Inoue
- Department of Surgery, National Hospital Organization Higashihiroshima Medical Center, Higashihiroshima, Japan
- HiSCO: Hiroshima Surgical study group of Clinical Oncology, Hiroshima, Japan
| | - Takashi Onoe
- Department of Surgery, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure, Japan
- HiSCO: Hiroshima Surgical study group of Clinical Oncology, Hiroshima, Japan
| | - Naruhiko Honmyo
- Department of Surgery, Hiroshima City North Medical Center, Asa Citizens Hospital, Hiroshima, Japan
- HiSCO: Hiroshima Surgical study group of Clinical Oncology, Hiroshima, Japan
| | - Shintaro Kuroda
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
- HiSCO: Hiroshima Surgical study group of Clinical Oncology, Hiroshima, Japan
| | - Hideki Ohdan
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
- HiSCO: Hiroshima Surgical study group of Clinical Oncology, Hiroshima, Japan
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Zhu Y, Tan H, Wang J, Zhuang H, Zhao H, Lu X. Molecular insight into T cell exhaustion in hepatocellular carcinoma. Pharmacol Res 2024; 203:107161. [PMID: 38554789 DOI: 10.1016/j.phrs.2024.107161] [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: 12/21/2023] [Revised: 03/17/2024] [Accepted: 03/26/2024] [Indexed: 04/02/2024]
Abstract
Hepatocellular carcinoma is one of the leading causes of cancer-related mortality globally. The emergence of immunotherapy has been shown to be a promising therapeutic approach for hepatocellular carcinoma in recent years. It has been well known that T cell plays a key role in current immunotherapy. However, sustained exposure to antigenic stimulation within the tumor microenvironment may lead to T cell exhaustion, which may cause treatment ineffectiveness. Therefore, reversing T cell exhaustion has been an important issue for the clinical application of immunotherapy, and a comprehensive understanding of the intricacies surrounding T cell exhaustion and its underlying mechanisms is imperative for devising strategies to overcome the T cell exhaustion during treatment. In this review, we summarized the reported drivers of T cell exhaustion in hepatocellular carcinoma and delineate potential ways to reverse it. Additionally, we discussed the interplay among metabolic plasticity, epigenetic regulation, and transcriptional factors in exhausted T cells in hepatocellular carcinoma, and their implication for future clinical applications.
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Affiliation(s)
- Yonghua Zhu
- Department of General Surgery, Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Huabing Tan
- Department of Infectious Diseases, Hepatology Institute, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China; Shiyan Key Laboratory of Virology, Hubei University of Medicine, Shiyan, Hubei Province 442000, China
| | - Jincheng Wang
- Graduate School of Biomedical Science and Engineering, Hokkaido University, Japan
| | - Haiwen Zhuang
- Department of General Surgery, Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Huanbin Zhao
- Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
| | - Xiaojie Lu
- Department of General Surgery, Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
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Jia KW, Yao RQ, Fan YW, Zhang DJ, Zhou Y, Wang MJ, Zhang LY, Dong Y, Li ZX, Wang SY, Wang M, Li YH, Zhang LX, Lei T, Gui LC, Lu S, Yang YY, Wang SX, Yu YZ, Yao YM, Hou J. Interferon-α stimulates DExH-box helicase 58 to prevent hepatocyte ferroptosis. Mil Med Res 2024; 11:22. [PMID: 38622688 PMCID: PMC11017495 DOI: 10.1186/s40779-024-00524-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 03/19/2024] [Indexed: 04/17/2024] Open
Abstract
BACKGROUND Liver ischemia/reperfusion (I/R) injury is usually caused by hepatic inflow occlusion during liver surgery, and is frequently observed during war wounds and trauma. Hepatocyte ferroptosis plays a critical role in liver I/R injury, however, it remains unclear whether this process is controlled or regulated by members of the DEAD/DExH-box helicase (DDX/DHX) family. METHODS The expression of DDX/DHX family members during liver I/R injury was screened using transcriptome analysis. Hepatocyte-specific Dhx58 knockout mice were constructed, and a partial liver I/R operation was performed. Single-cell RNA sequencing (scRNA-seq) in the liver post I/R suggested enhanced ferroptosis by Dhx58hep-/-. The mRNAs and proteins associated with DExH-box helicase 58 (DHX58) were screened using RNA immunoprecipitation-sequencing (RIP-seq) and IP-mass spectrometry (IP-MS). RESULTS Excessive production of reactive oxygen species (ROS) decreased the expression of the IFN-stimulated gene Dhx58 in hepatocytes and promoted hepatic ferroptosis, while treatment using IFN-α increased DHX58 expression and prevented ferroptosis during liver I/R injury. Mechanistically, DHX58 with RNA-binding activity constitutively associates with the mRNA of glutathione peroxidase 4 (GPX4), a central ferroptosis suppressor, and recruits the m6A reader YT521-B homology domain containing 2 (YTHDC2) to promote the translation of Gpx4 mRNA in an m6A-dependent manner, thus enhancing GPX4 protein levels and preventing hepatic ferroptosis. CONCLUSIONS This study provides mechanistic evidence that IFN-α stimulates DHX58 to promote the translation of m6A-modified Gpx4 mRNA, suggesting the potential clinical application of IFN-α in the prevention of hepatic ferroptosis during liver I/R injury.
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Affiliation(s)
- Kai-Wei Jia
- National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai, 200433, China
| | - Ren-Qi Yao
- Department of General Surgery, the First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China
- Translational Medicine Research Center, Medical Innovation Research Division and Fourth Medical Center of the Chinese PLA General Hospital, Beijing, 100853, China
| | - Yi-Wen Fan
- National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai, 200433, China
| | - Ding-Ji Zhang
- National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai, 200433, China
| | - Ye Zhou
- National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai, 200433, China
| | - Min-Jun Wang
- National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai, 200433, China
| | - Li-Yuan Zhang
- National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai, 200433, China
| | - Yue Dong
- National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai, 200433, China
| | - Zhi-Xuan Li
- National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai, 200433, China
| | - Su-Yuan Wang
- National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai, 200433, China
| | - Mu Wang
- National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai, 200433, China
| | - Yun-Hui Li
- National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai, 200433, China
| | - Lu-Xin Zhang
- National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai, 200433, China
| | - Ting Lei
- National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai, 200433, China
| | - Liang-Chen Gui
- National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai, 200433, China
| | - Shan Lu
- National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai, 200433, China
| | - Ying-Yun Yang
- Center for Immunotherapy, Chinese Academy of Medical Sciences, Beijing, 100005, China
| | - Si-Xian Wang
- National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai, 200433, China
| | - Yi-Zhi Yu
- National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai, 200433, China
| | - Yong-Ming Yao
- Translational Medicine Research Center, Medical Innovation Research Division and Fourth Medical Center of the Chinese PLA General Hospital, Beijing, 100853, China.
| | - Jin Hou
- National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai, 200433, China.
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Luo JX, Zhang Y, Hu XY, Xiang N. Interferon therapy improves survival in patients with hepatitis B virus-related hepatocellular carcinoma after curative surgery: a meta-analysis. Hepatol Int 2024; 18:63-72. [PMID: 38165580 DOI: 10.1007/s12072-023-10618-6] [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: 05/02/2023] [Accepted: 11/16/2023] [Indexed: 01/04/2024]
Abstract
BACKGROUND AND AIM A novel study found interferon enhanced antitumor activity of anti-PD-1-based immunotherapy and played a crucial role in improving efficacy on HCC, but the opposite results about the efficacy of interferon on HBV-related HCC were obtained from previous clinical studies and meta-analyses. Thus, this meta-analysis aimed to re-evaluate whether interferon could improve survival and reduce recurrence of patients with HBV-related HCC after curative surgery. METHODS MEDLINE/PubMed, Cochrane Library, EMBASE, Web of Science and CNKI were searched for eligible studies from inception to November 2022 and a meta-analysis was done. RESULTS 10 trials with a total of 2062 subjects were screened. Interferon significantly improved 1-, 2-, 3- and 5-year OS and 1-, 2- and 3-year DFS, and reduced 2-, 3- and 5-year recurrence rates of patients with HBV-related HCC after curative surgery. However, interferon did not improve 8-year OS and 5-year DFS, did not reduce 1-year recurrence rate. CONCLUSIONS Interferon may significantly reduce recurrence and improve DFS of patients with HBV-related HCC after curative surgery, and finally improve the OS. However, the efficacy advantage may gradually weaken as time goes on. The clinical application of interferon combined with NAs recommended in this meta-analysis is needed to be further studied.
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Affiliation(s)
- Jian-Xing Luo
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- Department of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Yang Zhang
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- Department of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Xiao-Yu Hu
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.
- Department of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.
| | - Ne Xiang
- Department of TCM, Caojiaxiang Community Health Service Center, Chengdu, Sichuan, China.
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Eguia E, Baker T, Baker M. Hepatocellular Carcinoma: Surgical Management and Evolving Therapies. Cancer Treat Res 2024; 192:185-206. [PMID: 39212922 DOI: 10.1007/978-3-031-61238-1_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer in men and the eighth most common cancer in women worldwide. It is also the second leading cause of cancer death worldwide, with 780,000 deaths in 2018. Seventy-two percent of HCC cases occur in Asia, 10% in Europe, 8% in Africa, 5% in North America, and 5% in Latin America (Singal et al. in J Hepatol 72(2):250-261, 2020 [1]).
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Affiliation(s)
- Emanuel Eguia
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Talia Baker
- Huntsman Cancer Center, University of Utah Eccles School of Medicine, Salt Lake City, UT, USA
| | - Marshall Baker
- Huntsman Cancer Center, University of Utah Eccles School of Medicine, Salt Lake City, UT, USA.
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Chen YJ, Huang JY, Baskaran R, Abomughaid MM, Hsieh CC, Lin WT. Long-Term Survival and Cancer Risk in the Hepatitis C Virus-Infected Patients After Antiviral Treatment: A Nationwide Cohort Study. J Cancer 2024; 15:113-125. [PMID: 38164272 PMCID: PMC10751673 DOI: 10.7150/jca.87259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Accepted: 10/31/2023] [Indexed: 01/03/2024] Open
Abstract
Background: Exposure to the Hepatitis C virus (HCV) has been identified as one of the most critical risk factors for Hepatocellular carcinoma (HCC). Interferons and direct-acting antivirals (DAAs) have been used to treat HCV infection with high rates (95%) of prolonged virological response, a suitable safety profile, and good compliance rates. Methods: We obtained information from Taiwan's Health and Welfare Data Science Center. (HWDSC). In this observational cohort research, patients with HCV who received a diagnosis in Taiwan between 2011 and 2018 were included. Results: 78,300 untreated HCV patients were paired for age, sex, and index date with 39,150 HCV patients who received interferon or DAAs treatment. Compared to the control group, the Interferon or DAAs treatment sample has fewer low-income individuals and more hospitalization requirements. The percentage of kidney illness was reduced in the therapy group compared to the control group, but the treatment group had a greater comorbidity rate of gastric ulcers. Interferon or DAA therapy for HCV-infected patients can substantially lower mortality. All cancer diagnoses after HCV infection with interferon treatment aHR 95% CI = 0.809 (0.774-0.846), Sofosbuvir-based DAA aHR 95% CI = 1.009 (0.737-1.381) and Sofosbuvir free DAA aHR 95% CI = 0.944 (0.584-1.526) showing cancer-protective effects in the INF-treated cohort but not DAA. Conclusion: Following antiviral therapy, women appear to have a more substantial preventive impact than men against pancreatic, colorectal, and lung cancer. Interferon or DAAs treatment effect was more significant in the cirrhotic group.
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Affiliation(s)
- Yi-Ju Chen
- Department of Surgery, Taichung Veterans General Hospital, Taichung 40704, Taiwan
- Department of Animal Science and Biotechnology, Tunghai University, Taichung 40704, Taiwan
| | - Jing-Yang Huang
- Center for health data science, Chung Shan Medical University Hospital, Taichung, Taiwan
- Institute of Medicine, College of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Rathinasamy Baskaran
- Department of Bioinformatics and Medical Engineering, Asia University, Taichung 413305, Taiwan
| | - Mosleh Mohammad Abomughaid
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Bisha, Bisha 61922, Saudi Arabia
| | - Chang-Chi Hsieh
- Department of Animal Science and Biotechnology, Tunghai University, Taichung 40704, Taiwan
| | - Wan-Teng Lin
- Department of Hospitality Management, College of Agriculture, Tunghai University, Taichung 407224, Taiwan
- R&D Division, Utopia Holiday Hotel Corporation, Taichung, Taiwan
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10
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Kim GD. Harmine Hydrochloride Induces G2/M Cell Cycle Arrest and Apoptosis in SK-Hep1 Hepatocellular Carcinoma Cells by Regulating Mitogen-Activated Protein Kinases and the PI3K/AKT Pathway. Prev Nutr Food Sci 2023; 28:436-443. [PMID: 38188092 PMCID: PMC10764232 DOI: 10.3746/pnf.2023.28.4.436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 11/08/2023] [Accepted: 11/10/2023] [Indexed: 01/09/2024] Open
Abstract
Liver cancer is a globally common form of cancer. Thus, novel drugs derived from natural products are needed to reduce the side effects of chemotherapy. The present study aimed to analyze the anticancer properties and effects of harmine hydrochloride (HMH), a water-soluble metabolite of harmine that can be easily absorbed into tissues, in treating liver cancer cells. HMH dose-dependently inhibited cell growth, migration, invasion, and colony formation in SK-Hep1 cells. It also induced G2/M arrest by reducing the expression of p-cdc2, cyclin B1, and Rb (G2/M phase regulatory proteins) in a dose-dependent manner. HMH treatment reduced the expression of caspase-9, caspase-3, PARP, and Bcl-2 and increased the expression of Bax (a proapoptotic protein). Moreover, it increased the production of reactive oxygen species and decreased the intracellular uptake of rhodamine 123 due to mitochondrial dysfunction because of oxidative stress. HMH treatment also upregulated the phosphorylation of JNK, p38, and FOXO3a in SK-Hep1 cells and downregulated the PI3K/AKT signaling pathway. Our findings suggest that HMH may activate the compounds responsible for anticancer effects in hepatocellular carcinoma cells.
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Affiliation(s)
- Gi Dae Kim
- Department of Food and Nutrition, Kyungnam University, Gyeongnam 51767, Korea
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11
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Lin KY, Lin ZW, Chen QJ, Luo LP, Zhang JX, Chen JH, Wang K, Tai S, Zhang ZB, Wang SF, Zhang JY, You WY, Wang B, You PH, Lin KC, Yang T, Zeng YY. Perioperative safety, oncologic outcome, and risk factors of salvage liver resection for initially unresectable hepatocellular carcinoma converted by transarterial chemoembolization plus tyrosine kinase inhibitor and anti-PD-1 antibody: a retrospective multicenter study of 83 patients. Hepatol Int 2023; 17:1477-1489. [PMID: 37382760 DOI: 10.1007/s12072-023-10561-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Accepted: 06/10/2023] [Indexed: 06/30/2023]
Abstract
BACKGROUND To assess the perioperative safety, oncological outcomes, and determinants influencing the oncological outcomes of salvage liver resection for initially unresectable hepatocellular carcinoma (HCC) rendered resectable through transarterial chemoembolization (TACE) combined with tyrosine kinase inhibitors (TKIs) and anti-PD-1 antibodies (α-PD-1). METHODS We retrospectively reviewed data from 83 consecutive patients across six tertiary hospitals who underwent salvage liver resection for initially unresectable HCC following conversion by TACE combined with TKIs and α-PD-1, emphasizing perioperative and oncological outcomes. Multivariate Cox regression analysis was employed to discern independent risk factors for postoperative recurrence-free survival (RFS). RESULTS The median operative duration was 200 min, with a median blood loss of 400 ml. Intraoperative blood transfusions were necessitated for 27 patients. The overall perioperative complication rate was 48.2%, with a major complication rate of 16.9%. One patient died during the perioperative period due to postoperative liver failure. During the median follow-up period of 15.1 months, 24 patients experienced recurrence, with early and intrahepatic recurrence being the most common. Seven patients died during follow-up. Median RFS was 25.4 months, with 1- and 2-year RFS rates of 68.2% and 61.8%, respectively. Median overall survival was not reached, with 1- and 2-year overall survival rates of 92.2% and 87.3%, respectively. Multivariate Cox regression analysis revealed that pathological complete response (pCR) and intraoperative blood transfusion served as independent prognostic determinants for postoperative RFS. CONCLUSIONS Our study provides preliminary evidence suggesting that salvage liver resection may be an effective and feasible treatment option for patients with unresectable HCC who achieve resectability after conversion therapy with TACE, TKIs, and α-PD-1. The perioperative safety of salvage liver resection for these patients was manageable and acceptable. However, further research, particularly prospective comparative studies, is needed to better evaluate the potential benefits of salvage liver resection in this patient population.
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Affiliation(s)
- Kong-Ying Lin
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Xihong Road 312, Fuzhou, 350025, China
- Department of Hepatopancreatobiliary Surgery, First Affiliated Hospital of Fujian Medical University, Fuzhou, 350000, China
| | - Zhi-Wen Lin
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Xihong Road 312, Fuzhou, 350025, China
- Department of Hepatopancreatobiliary Surgery, First Affiliated Hospital of Fujian Medical University, Fuzhou, 350000, China
| | - Qing-Jing Chen
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Xihong Road 312, Fuzhou, 350025, China
- Department of Hepatopancreatobiliary Surgery, First Affiliated Hospital of Fujian Medical University, Fuzhou, 350000, China
| | - Liu-Ping Luo
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Xihong Road 312, Fuzhou, 350025, China
| | - Jian-Xi Zhang
- Department of Hepatobiliary Surgery, Xiamen Hospital, Beijing University of Chinese Medicine, Xiamen, 361000, China
| | - Jin-Hong Chen
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, 200000, China
| | - Kui Wang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Navy Medical University (Second Military Medical University), Shanghai, 200000, China
| | - Sheng Tai
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Harbin, 150086, China
| | - Zhi-Bo Zhang
- Department of Hepatopancreatobiliary Surgery, First Affiliated Hospital of Fujian Medical University, Fuzhou, 350000, China
| | - Shi-Feng Wang
- Department of Hepatopancreatobiliary Surgery, Ganzhou Fifth People's Hospital of Gannan Medical University, Ganzhou, 341000, China
| | - Jin-Yu Zhang
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Xihong Road 312, Fuzhou, 350025, China
| | - Wu-Yi You
- Department of Radiation, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350000, China
| | - Bin Wang
- Department of Pathology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350000, China
| | - Peng-Hui You
- Biobank in Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350000, China
| | - Ke-Can Lin
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Xihong Road 312, Fuzhou, 350025, China.
| | - Tian Yang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Navy Medical University (Second Military Medical University), Shanghai, 200000, China.
| | - Yong-Yi Zeng
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Xihong Road 312, Fuzhou, 350025, China.
- Department of Hepatopancreatobiliary Surgery, First Affiliated Hospital of Fujian Medical University, Fuzhou, 350000, China.
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12
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Hund HC, Du L, Matsuoka L, Sze DY, Kennedy AS, Golzarian J, Gandhi RT, Collins ZS, Brown DB. Effect of Previous Transarterial Chemoembolization on Survival and Toxicity after Yttrium-90 Transarterial Radioembolization of Hepatocellular Carcinoma in the Radiation-Emitting SIR-Spheres in Nonresectable Liver Tumor Registry. J Vasc Interv Radiol 2023; 34:2147-2154.e2. [PMID: 37657500 DOI: 10.1016/j.jvir.2023.08.039] [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: 03/30/2023] [Revised: 07/28/2023] [Accepted: 08/23/2023] [Indexed: 09/03/2023] Open
Abstract
PURPOSE To determine overall survival (OS), best response, and toxicities in patients with hepatocellular carcinoma (HCC) previously treated with chemoembolization (TACE+) or yttrium-90 resin transarterial radioembolization (TARE) compared with those of TACE-naïve (T-N) participants. MATERIALS AND METHODS In this prospective, observational study, 262 adult participants with HCC were divided into TACE+ (n = 93, 35%) or T-N (n = 169, 65%) groups, included from 36 centers in the United States. Overall survival (OS) was assessed using Kaplan-Meier analysis from the date of TARE. Best response at 6 months was evaluated using modified Response Evaluation Criteria in Solid Tumors. Six-month toxicities were reported using Common Terminology Criteria for Adverse Events, version 5. RESULTS Median OS for patients in the TACE+ and T-N groups was 22.3 months (95% CI: 17.2 to not reachable) and 21.5 months (95% confidence interval [CI]: 14.9-29.9), respectively (P = .6). Imaging at 6 months ± 2 weeks was available in 156 of 262 (60%) participants. Partial or complete response was seen in 27 of 55 patients (49%) in the TACE+ group and 65 of 101 patients (64%) in the T-N group (P = .2). Six-month toxicities were available in 69 of 93 patients (74%) in the TACE+ group and 135 of 167 patients (81%) in the T-N group. Attributable Grade 3 or greater liver function toxicities were similar between the study groups (all P > .05). CONCLUSIONS OS and imaging response at 6 months in the TACE+ group was similar to that in the T-N group with similar toxicities. Radioembolization is an acceptable treatment option for patients with HCC previously treated with TACE.
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Affiliation(s)
- Hannah C Hund
- Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Liping Du
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Lea Matsuoka
- Transplant Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Daniel Y Sze
- Interventional Radiology, Stanford University, Palo Alto, California
| | - Andrew S Kennedy
- Radiation Oncology, Sarah Cannon Research Institute, Nashville, Tennessee
| | - Jafar Golzarian
- Interventional Radiology, University of Minnesota, Minneapolis, Minnesota
| | - Ripal T Gandhi
- Interventional Radiology, Miami Cardiac and Vascular Institute, Miami, Florida
| | | | - Daniel B Brown
- Interventional Radiology, Vanderbilt University Medical Center, Nashville, Tennessee.
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13
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Öcal O, Schütte K, Malfertheiner P, Berg T, Loewe C, Klümpen HJ, Zech CJ, van Delden O, Ümütlü MR, Deniz S, Khaled NB, De Toni EN, Hoang TPT, Seidensticker R, Aghdassi A, Pech M, Ricke J, Seidensticker M. Prognostic value of baseline MRI features in patients treated with thermal ablation for hepatocellular carcinoma. Eur J Radiol 2023; 168:111120. [PMID: 37806190 DOI: 10.1016/j.ejrad.2023.111120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 09/05/2023] [Accepted: 09/27/2023] [Indexed: 10/10/2023]
Abstract
PURPOSE To investigate prognostic value of baseline MRI features for time-to-recurrence (TTR) and local recurrence in patients with early hepatocellular carcinoma (HCC). METHOD Baseline and follow-up images of 88 patients treated with thermal ablation followed by adjuvant sorafenib or matching placebo due to HCC within the phase II prospective randomized trial (SORAMIC) were included. Baseline MRI images were evaluated in terms of atypical enhancement (lack of wash-in or wash-out), lesion diameter, tumor capsule, peritumoral enhancement on arterial phase, intratumoral fat, irregular margin, satellite lesions, and peritumoral hypointensity on hepatobiliary phase. Prognostic value of these features for TTR and local recurrence were assessed with univariable and multivariable Cox proportional hazard models. RESULTS Recurrence at any location was diagnosed during follow-up in 30 patients, and the median TTR was 16.4 (95% CI, 15 - NA) months. The presence of more than one lesion (p = 0.028) and peritumoral hypointensity on hepatobiliary phase images (p = 0.012) at baseline were significantly associated with shorter TTR in univariable analysis. AFP > 15 mg/dL (p = 0.084), and history of cirrhosis (p = 0.099) were marginally non-significant. Peritumoral hypointensity on hepatobiliary phase images was the only significant risk factor for recurrence in multivariable analysis (p = 0.003). Local recurrence (adjacent to thermal scar) was diagnosed in eleven (8.3%) out of 132 lesions that underwent thermal ablation. The only significant risk factor for local recurrence was a lesion diameter larger than 3 cm (22.2% vs. 4.5%, p = 0.007). CONCLUSIONS Peritumoral hypointensity on hepatobiliary phase can serve as imaging biomarker to identify increased recurrence risk in patients undergoing thermal ablation for early-stage HCC.
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Affiliation(s)
- Osman Öcal
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Kerstin Schütte
- Department of Internal Medicine and Gastroenterology, Niels-Stensen-Kliniken Marienhospital, Osnabrück, Germany
| | | | - Thomas Berg
- Klinik und Poliklinik für Gastroenterologie, Sektion Hepatologie, Universitätsklinikum Leipzig, Germany
| | - Christian Loewe
- Section of Cardiovascular and Interventional Radiology, Department of Bioimaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria
| | - Heinz Josef Klümpen
- Department of Medical Oncology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Christoph Johannes Zech
- Radiology and Nuclear Medicine, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Otto van Delden
- Department of Radiology and Nuclear Medicine, Academic University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | | | - Sinan Deniz
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Najib Ben Khaled
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | | | | | | | - Ali Aghdassi
- Department of Medicine A, University Medicine Greifswald, 17489 Greifswald, Germany
| | - Maciej Pech
- Departments of Radiology and Nuclear Medicine, University of Magdeburg, Magdeburg, Germany
| | - Jens Ricke
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Max Seidensticker
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany.
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14
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Elderkin J, Al Hallak N, Azmi AS, Aoun H, Critchfield J, Tobon M, Beal EW. Hepatocellular Carcinoma: Surveillance, Diagnosis, Evaluation and Management. Cancers (Basel) 2023; 15:5118. [PMID: 37958294 PMCID: PMC10647678 DOI: 10.3390/cancers15215118] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 10/11/2023] [Accepted: 10/13/2023] [Indexed: 11/15/2023] Open
Abstract
Hepatocellular carcinoma (HCC) ranks fourth in cancer-related deaths worldwide. Semiannual surveillance of the disease for patients with cirrhosis or hepatitis B virus allows for early detection with more favorable outcomes. The current underuse of surveillance programs demonstrates the need for intervention at both the patient and provider level. Mail outreach along with navigation provision has proven to increase surveillance follow-up in patients, while provider-targeted electronic medical record reminders and compliance reports have increased provider awareness of HCC surveillance. Imaging is the primary mode of diagnosis in HCC with The Liver Imaging Reporting and Data System (LI-RADS) being a widely accepted comprehensive system that standardizes the reporting and data collection for HCC. The management of HCC is complex and requires multidisciplinary team evaluation of each patient based on their preference, the state of the disease, and the available medical and surgical interventions. Staging systems are useful in determining the appropriate intervention for HCC. Early-stage HCC is best managed by curative treatment modalities, such as liver resection, transplant, or ablation. For intermediate stages of the disease, transarterial local regional therapies can be applied. Advanced stages of the disease are treated with systemic therapies, for which there have been recent advances with new drug combinations. Previously sorafenib was the mainstay systemic treatment, but the recent introduction of atezolizumab plus bevacizumab proves to have a greater impact on overall survival. Although there is a current lack of improved outcomes in Phase III trials, neoadjuvant therapies are a potential avenue for HCC management in the future.
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Affiliation(s)
- Jessica Elderkin
- Wayne State University School of Medicine, Detroit, MI 48201, USA;
| | - Najeeb Al Hallak
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA; (N.A.H.); (A.S.A.)
| | - Asfar S. Azmi
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA; (N.A.H.); (A.S.A.)
| | - Hussein Aoun
- Department of Radiology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA; (H.A.); (J.C.)
| | - Jeffrey Critchfield
- Department of Radiology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA; (H.A.); (J.C.)
| | - Miguel Tobon
- Department of Surgery, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA;
| | - Eliza W. Beal
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA; (N.A.H.); (A.S.A.)
- Department of Surgery, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA;
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15
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Zhou J, Sun H, Wang Z, Cong W, Zeng M, Zhou W, Bie P, Liu L, Wen T, Kuang M, Han G, Yan Z, Wang M, Liu R, Lu L, Ren Z, Zeng Z, Liang P, Liang C, Chen M, Yan F, Wang W, Hou J, Ji Y, Yun J, Bai X, Cai D, Chen W, Chen Y, Cheng W, Cheng S, Dai C, Guo W, Guo Y, Hua B, Huang X, Jia W, Li Q, Li T, Li X, Li Y, Li Y, Liang J, Ling C, Liu T, Liu X, Lu S, Lv G, Mao Y, Meng Z, Peng T, Ren W, Shi H, Shi G, Shi M, Song T, Tao K, Wang J, Wang K, Wang L, Wang W, Wang X, Wang Z, Xiang B, Xing B, Xu J, Yang J, Yang J, Yang Y, Yang Y, Ye S, Yin Z, Zeng Y, Zhang B, Zhang B, Zhang L, Zhang S, Zhang T, Zhang Y, Zhao M, Zhao Y, Zheng H, Zhou L, Zhu J, Zhu K, Liu R, Shi Y, Xiao Y, Zhang L, Yang C, Wu Z, Dai Z, Chen M, Cai J, Wang W, Cai X, Li Q, Shen F, Qin S, Teng G, et alZhou J, Sun H, Wang Z, Cong W, Zeng M, Zhou W, Bie P, Liu L, Wen T, Kuang M, Han G, Yan Z, Wang M, Liu R, Lu L, Ren Z, Zeng Z, Liang P, Liang C, Chen M, Yan F, Wang W, Hou J, Ji Y, Yun J, Bai X, Cai D, Chen W, Chen Y, Cheng W, Cheng S, Dai C, Guo W, Guo Y, Hua B, Huang X, Jia W, Li Q, Li T, Li X, Li Y, Li Y, Liang J, Ling C, Liu T, Liu X, Lu S, Lv G, Mao Y, Meng Z, Peng T, Ren W, Shi H, Shi G, Shi M, Song T, Tao K, Wang J, Wang K, Wang L, Wang W, Wang X, Wang Z, Xiang B, Xing B, Xu J, Yang J, Yang J, Yang Y, Yang Y, Ye S, Yin Z, Zeng Y, Zhang B, Zhang B, Zhang L, Zhang S, Zhang T, Zhang Y, Zhao M, Zhao Y, Zheng H, Zhou L, Zhu J, Zhu K, Liu R, Shi Y, Xiao Y, Zhang L, Yang C, Wu Z, Dai Z, Chen M, Cai J, Wang W, Cai X, Li Q, Shen F, Qin S, Teng G, Dong J, Fan J. Guidelines for the Diagnosis and Treatment of Primary Liver Cancer (2022 Edition). Liver Cancer 2023; 12:405-444. [PMID: 37901768 PMCID: PMC10601883 DOI: 10.1159/000530495] [Show More Authors] [Citation(s) in RCA: 170] [Impact Index Per Article: 85.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 01/24/2023] [Indexed: 10/31/2023] Open
Abstract
Background Primary liver cancer, of which around 75-85% is hepatocellular carcinoma in China, is the fourth most common malignancy and the second leading cause of tumor-related death, thereby posing a significant threat to the life and health of the Chinese people. Summary Since the publication of Guidelines for Diagnosis and Treatment of Primary Liver Cancer in China in June 2017, which were updated by the National Health Commission in December 2019, additional high-quality evidence has emerged from researchers worldwide regarding the diagnosis, staging, and treatment of liver cancer, that requires the guidelines to be updated again. The new edition (2022 Edition) was written by more than 100 experts in the field of liver cancer in China, which not only reflects the real-world situation in China but also may reshape the nationwide diagnosis and treatment of liver cancer. Key Messages The new guideline aims to encourage the implementation of evidence-based practice and improve the national average 5-year survival rate for patients with liver cancer, as proposed in the "Health China 2030 Blueprint."
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Affiliation(s)
- Jian Zhou
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Huichuan Sun
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zheng Wang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wenming Cong
- Department of Pathology, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Mengsu Zeng
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Weiping Zhou
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Ping Bie
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Lianxin Liu
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Tianfu Wen
- Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Ming Kuang
- Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Guohong Han
- Department of Liver Diseases and Digestive Interventional Radiology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Zhiping Yan
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Maoqiang Wang
- Department of Interventional Radiology, Chinese PLA General Hospital, Beijing, China
| | - Ruibao Liu
- Department of Interventional Radiology, The Tumor Hospital of Harbin Medical University, Harbin, China
| | - Ligong Lu
- Department of Interventional Oncology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Zhenggang Ren
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhaochong Zeng
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ping Liang
- Department of Interventional Ultrasound, Chinese PLA General Hospital, Beijing, China
| | - Changhong Liang
- Department of Radiology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Min Chen
- Editorial Department of Chinese Journal of Digestive Surgery, Chongqing, China
| | - Fuhua Yan
- Department of Radiology, Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Wenping Wang
- Department of Ultrasound, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jinlin Hou
- Department of Infectious Diseases, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yuan Ji
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jingping Yun
- Department of Pathology, Tumor Prevention and Treatment Center, Sun Yat-sen University, Guangzhou, China
| | - Xueli Bai
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Dingfang Cai
- Department of Integrative Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Weixia Chen
- Department of Radiology, West China Hospital of Sichuan University, Chengdu, China
| | - Yongjun Chen
- Department of Hematology, Ruijin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wenwu Cheng
- Department of Integrated Therapy, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Shuqun Cheng
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Chaoliu Dai
- Department of Hepatobiliary and Spleenary Surgery, The Affiliated Shengjing Hospital, China Medical University, Shenyang, China
| | - Wengzhi Guo
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yabing Guo
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Baojin Hua
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaowu Huang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Weidong Jia
- Department of Hepatic Surgery, Affiliated Provincial Hospital, Anhui Medical University, Hefei, China
| | - Qiu Li
- Department of Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Tao Li
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Xun Li
- The First Hospital of Lanzhou University, Lanzhou, China
| | - Yaming Li
- Department of Nuclear Medicine, The First Hospital of China Medical University, Shenyang, China
| | - Yexiong Li
- Department of Radiation Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jun Liang
- Department of Oncology, Peking University International Hospital, Beijing, China
| | - Changquan Ling
- Changhai Hospital of Traditional Chinese Medicine, Second Military Medical University, Shanghai, China
| | - Tianshu Liu
- Department of Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiufeng Liu
- Department of Medical Oncology, PLA Cancer Center, Nanjing Bayi Hospital, Nanjing, China
| | - Shichun Lu
- Institute and Hospital of Hepatobiliary Surgery of Chinese PLA, Chinese PLA Medical School, Chinese PLA General Hospital, Beijing, China
| | - Guoyue Lv
- Department of General Surgery, The First Hospital of Jilin University, Jilin, China
| | - Yilei Mao
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC and Chinese Academy of Medical Sciences, Beijing, China
| | - Zhiqiang Meng
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Weixin Ren
- Department of Interventional Radiology the First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Hongcheng Shi
- Department of Nuclear Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Guoming Shi
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ming Shi
- Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Tianqiang Song
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Kaishan Tao
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Jianhua Wang
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Kui Wang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Lu Wang
- Department of Hepatic Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China
| | - Wentao Wang
- Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Xiaoying Wang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhiming Wang
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, China
| | - Bangde Xiang
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Baocai Xing
- Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital and Institute, Beijing, China
| | - Jianming Xu
- Department of Gastrointestinal Oncology, Affiliated Hospital Cancer Center, Academy of Military Medical Sciences, Beijing, China
| | - Jiamei Yang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Jianyong Yang
- Department of Interventional Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yefa Yang
- Department of Hepatic Surgery and Interventional Radiology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Yunke Yang
- Department of Integrative Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Shenglong Ye
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhenyu Yin
- Department of Hepatobiliary Surgery, Zhongshan Hospital of Xiamen University, Xiamen, China
| | - Yong Zeng
- Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Bixiang Zhang
- Department of Surgery, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Boheng Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Leida Zhang
- Department of Hepatobiliary Surgery Institute, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Shuijun Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, ZhengZhou, China
| | - Ti Zhang
- Department of Hepatic Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China
| | - Yanqiao Zhang
- Department of Gastrointestinal Medical Oncology, The Affiliated Tumor Hospital of Harbin Medical University, Harbin, China
| | - Ming Zhao
- Minimally Invasive Interventional Division, Liver Cancer Group, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Yongfu Zhao
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, ZhengZhou, China
| | - Honggang Zheng
- Department of Oncology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Ledu Zhou
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Jiye Zhu
- Department of Hepatobiliary Surgery, Peking University People’s Hospital, Beijing, China
| | - Kangshun Zhu
- Department of Minimally Invasive Interventional Radiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Rong Liu
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yinghong Shi
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yongsheng Xiao
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Lan Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Chun Yang
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhifeng Wu
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhi Dai
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Minshan Chen
- Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jianqiang Cai
- Department of Abdominal Surgical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Weilin Wang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiujun Cai
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Qiang Li
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Feng Shen
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Shukui Qin
- Department of Medical Oncology, PLA Cancer Center, Nanjing Bayi Hospital, Nanjing, China
| | - Gaojun Teng
- Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China
| | - Jiahong Dong
- Department of Hepatobiliary and Pancreas Surgery, Beijing Tsinghua Changgung Hospital (BTCH), School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Jia Fan
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
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Ye Y, Wang Y, Xu H, Yi F. Network meta-analysis of adjuvant treatments for patients with hepatocellular carcinoma after curative resection. BMC Gastroenterol 2023; 23:320. [PMID: 37730533 PMCID: PMC10510134 DOI: 10.1186/s12876-023-02955-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 09/10/2023] [Indexed: 09/22/2023] Open
Abstract
PURPOSE The prevention of recurrence for patients with hepatocellular carcinoma after curative resection is still a great challenge in clinical practice. There are numerous studies that trying to search for favorable strategies to decrease the recurrence and prolong life span for these patients, whereas no consensus is reached till now. Herein, we aim to compare the efficacy between different reported treatments by network meta-analysis(NMA). METHODS We searched Pubmed, Web of Science and Cochrane Library for abstracts and full-text articles published from database inception through February 2023. All of the random controlled trials(RCTs) were evaluated and collected as eligible studies. The primary outcome was the prevention of recurrence between different procedures. The second outcomes were one-year survival, three-year survival and five-year survival. RESULTS Thirty-two RCTs including 5783 patients were selected, and 12 treatments were classified. Most of the studies were high quality with low bias. Thirty-one studies including 5629 patients were recruited for recurrence analysis. The network meta-analysis showed benefits from transarterial chemoembolization(TACE) + portal vein chemotherapy(PVC)[OR, 2.84 (1.15,6.99)] and internal radiotherapy(IRT) [OR, 2.63 (1.41,4.91)] compared to non-adjuvant(NA) treatment when considering prevention of recurrence. Seventeen studies including 2047 patients were collected for one-year survival analysis. The network meta-analysis showed benefit from TACE[OR, 0.33 (0.14,0.75)] when considering one-year survival. Twenty-one studies including 2463 patients were collected for three-year survival analysis. The network meta-analysis showed TACE [OR, 0.51 (0.30,0.86)], IRT[OR, 0.41 (0.20,0.83)] and dendritic cell(DC) [OR, 0.09 (0.01,0.98)] were better than NA when considering three-year survival. Sixteen studies including 1915 patients were collected for five-year survival analysis. The network meta-analysis didn't show any benefit from different treatments when considering five-year survival. Other strategies including external radiotherapy(ERT), branched-chain amino acids(BCAA), hepatic artery infusion chemotherapy(HAIC), cytokine-induced killer(CIK), adoptive immunotherapy(AIT), Huaier, interferon(IFN), oral chemotherapy(OCT) and sorafenib(SOR) didn't show significant benefit regardless of prevention of recurrence or short-, long- time survival. CONCLUSION This NMA found that TACE + PVC and IRT were considered as the procedures to decrease HCC recurrence rate. TACE, IRT and DC were preferred when considering the extending of life span for post-operative patients with HCC. Large scale of RCTs are needed to verify it.
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Affiliation(s)
- Yanyan Ye
- Department of Ultrasound, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, P.R. of China
| | - Ying Wang
- Department of Oncology, Second Affiliated Hospital of Nanchang University, Nanchang, 330006, P.R. of China
- JiangXi Key Laboratory of Clinical and Translational Cancer Research, Nanchang, 330006, P.R. of China
| | - Haoqian Xu
- Department of Oncology, Second Affiliated Hospital of Nanchang University, Nanchang, 330006, P.R. of China
- JiangXi Key Laboratory of Clinical and Translational Cancer Research, Nanchang, 330006, P.R. of China
| | - Fengming Yi
- Department of Oncology, Second Affiliated Hospital of Nanchang University, Nanchang, 330006, P.R. of China.
- JiangXi Key Laboratory of Clinical and Translational Cancer Research, Nanchang, 330006, P.R. of China.
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Yuan L, Feng J, Zhang Y, Lu C, Xu L, Liang C, Liu Z, Mao F, Xiang Y, Wang W, Wang K, Cheng S. Transarterial chemoembolization plus immune checkpoint inhibitor as postoperative adjuvant therapy for hepatocellular carcinoma with portal vein tumor thrombus: A multicenter cohort study. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2023; 49:1226-1233. [PMID: 36739252 DOI: 10.1016/j.ejso.2023.01.020] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 01/09/2023] [Accepted: 01/16/2023] [Indexed: 01/20/2023]
Abstract
PURPOSE This study aimed to assess the efficacy and safety of postoperative adjuvant transarterial chemoembolization (PA-TACE) plus immune checkpoint inhibitor (ICI) for hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT). PATIENTS AND METHODS This study was conducted on three centers from June 2018 to December 2020. Patients were divided into the PA-TACE (n = 48) and PA-TACE plus ICI groups (n = 42). The recurrence-free survival (RFS) and overall survival (OS) curves were depicted by Kaplan-Meier method, and the differences between the two groups were compared using log-rank test. Univariate and multivariate Cox analyses were performed to identify independent risk factors for RFS and OS. Adverse events (AEs) were assessed according to the Common Terminology Criteria for AEs (CTCAE) version 5.0. RESULTS The median RFS of the PA-TACE plus ICI group was significantly longer than the PA-TACE group (12.76 months vs. 8.11 months; P = 0.038). The median OS of the PA-TACE plus ICI group was also significanfly better than the PA-TACE group (24.5 months vs. 19.1 months; P = 0.032). PA-TACE plus ICI treatment was an independent prognostic factor for RFS (HR: 0.54, 95% CI: 0.32-0.9, P = 0.019) and OS (HR: 0.47, 95% CI: 0.26-0.86, P = 0.014). Only one patient experienced grade ≥3 immune-related AEs in the PA-TACE plus ICI group. CONCLUSIONS PA-TACE plus ICI treatment had better efficacy in preventing recurrence and prolonging survival than PA-TACE alone for HCC patients with PVTT after R0 resection. This novel treatment modality may be an appropriate option for HCC with PVTT.
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Affiliation(s)
- Luyun Yuan
- Cancer Center, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200083, China
| | - Jinkai Feng
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200433, China
| | - Yuqing Zhang
- Cancer Center, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200083, China
| | - Chongde Lu
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200433, China
| | - Liu Xu
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jiaxing, The First Affiliated Hospital of Jiaxing University, Jiaxing, 314001, Zhejiang, China
| | - Chao Liang
- Department of Hepatobiliary Surgery, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200083, China
| | - Zonghan Liu
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200433, China
| | - Feifei Mao
- Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China
| | - Yanjun Xiang
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200433, China
| | - Weijun Wang
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200433, China
| | - Kang Wang
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200433, China
| | - Shuqun Cheng
- Cancer Center, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200083, China; Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jiaxing, The First Affiliated Hospital of Jiaxing University, Jiaxing, 314001, Zhejiang, China; Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200433, China.
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18
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Seidensticker M, Öcal O, Schütte K, Malfertheiner P, Berg T, Loewe C, Klümpen HJ, van Delden O, Ümütlü MR, Ben Khaled N, de Toni EN, Seidensticker R, Aghdassi A, Tran A, Bronowicki JP, Peynircioglu B, Sangro B, Pech M, Ricke J. Impact of adjuvant sorafenib treatment after local ablation for HCC in the phase II SORAMIC trial. JHEP Rep 2023; 5:100699. [PMID: 36968218 PMCID: PMC10031000 DOI: 10.1016/j.jhepr.2023.100699] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 12/22/2022] [Accepted: 01/17/2023] [Indexed: 03/29/2023] Open
Abstract
Background & Aims The aim of the study was to evaluate the efficacy and safety of adjuvant sorafenib treatment compared with placebo in patients with hepatocellular carcinoma who underwent local ablation. Methods The SORAMIC trial is a randomised controlled trial with diagnostic, local ablation, and palliative sub-study arms. After initial imaging within the diagnostic study, patients were assigned to local ablation or palliative arms. In the local ablation cohort, patients were randomised 1:1 to local ablation + sorafenib vs. local ablation + placebo. The primary endpoint was time-to-recurrence (TTR). Secondary endpoints were local control rate and safety in terms of adverse events and quality-of-life. Results The recruitment was terminated prematurely after 104 patients owing to slow recruitment. One patient was excluded because of a technical failure. Fifty-four patients were randomised to local ablation + sorafenib and 49 to local ablation + placebo. Eighty-eight patients who underwent standardised follow-up imaging comprised the per-protocol population. The median TTR was 15.2 months in the sorafenib arm and 16.4 months in the placebo arm (hazard ratio 1.1; 95% CI 0.53-2.2; p = 0.82). Out of 136 lesions ablated within the trial, there was no difference in local recurrence rate between sorafenib (6/69, 8.6%) and placebo groups (5/67, 5.9%; p = 0.792).Overall (92.5% vs. 71.4%, p = 0.008) and drug-related (81.4% vs. 55.1%, p = 0.003) adverse events were more common in the sorafenib arm compared with the placebo arm. Dose reduction because of adverse events were common in the sorafenib arm (79.6% vs. 30.6%, p <0.001). Conclusions Adjuvant sorafenib did not improve in TTR or local control rate after local ablation in patients with hepatocellular carcinoma within the limitations of an early terminated trial. Impact and implications Local ablation is the standard of care treatment in patients with early stages of hepatocellular carcinoma, along with surgical therapies. However, there is a risk of disease recurrence during follow-up. Sorafenib, an oral medication, is a routinely used treatment for patients with advanced hepatocellular carcinoma. This study found that sorafenib treatment after local ablation in people with early hepatocellular carcinoma did not significantly improve the disease-free period compared with placebo. Clinical trial number EudraCT 2009-012576-27, NCT01126645.
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Key Words
- Adjuvant
- BCLC, Barcelona Clinic Liver Cancer
- CONSORT, Consolidated Standards of Reporting Trials
- CT, computed tomography
- ECOG PS, Eastern Cooperative Oncology Group Performance Status
- HCC, hepatocellular carcinoma
- HR, hazard ratio
- Hepatocellular carcinoma
- ITT, intention-to-treat
- Local ablation
- MRI, magnetic resonance imaging
- MWA, microwave ablation
- PP, per protocol
- RFA, radiofrequency ablation
- RFS, relapse-free survival
- SIRT, selective internal radiation therapy
- SORAMIC, SORAfenib in combination with local MICro-therapy guided by gadolinium-EOB-DTPA-enhanced MRI
- Sorafenib
- TTR, time-to-recurrence
- Time-to-recurrence
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Affiliation(s)
- Max Seidensticker
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Osman Öcal
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Kerstin Schütte
- Department of Internal Medicine and Gastroenterology, Niels-Stensen-Kliniken Marienhospital, Osnabrück, Germany
| | | | - Thomas Berg
- Klinik und Poliklinik für Gastroenterologie, Sektion Hepatologie, Universitätsklinikum Leipzig, Germany
| | - Christian Loewe
- Section of Cardiovascular and Interventional Radiology, Department of Bioimaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria
| | - Heinz Josef Klümpen
- Department of Medical Oncology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Otto van Delden
- Department of Radiology and Nuclear Medicine, Academic University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | | | - Najib Ben Khaled
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | | | | | - Ali Aghdassi
- Department of Medicine A, University Medicine Greifswald, 17489 Greifswald, Germany
| | - Albert Tran
- Pôle Appareil Digestif, Hôpital l'Archet 2, CHU Nice, Route Saint-Antoine de Ginestière - BP 3079, Nice, France
| | - Jean-Pierre Bronowicki
- Department of Hepatology, INSERM U1254, Hôpital de Brabois, CHU de Nancy, University of Lorraine, Nancy, France
| | - Bora Peynircioglu
- Department of Radiology, Hacettepe University Hospital, Ankara, Turkey
| | - Bruno Sangro
- Liver Unit, Clínica Universidad de Navarra and CIBEREHD, Pamplona, Spain
| | - Maciej Pech
- Department of Radiology and Nuclear Medicine, University of Magdeburg, Magdeburg, Germany
| | - Jens Ricke
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
- Corresponding author. Address: Department of Radiology, University Hospital, Ludwig Maximilian University of Munich, Marchioninistrasse 15, 81377 Munich, Germany. Tel: +49-4400-72750..
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Yang YQ, Wen ZY, Liu XY, Ma ZH, Liu YE, Cao XY, Hou L, Xie H. Current status and prospect of treatments for recurrent hepatocellular carcinoma. World J Hepatol 2023; 15:129-150. [PMID: 36926237 PMCID: PMC10011906 DOI: 10.4254/wjh.v15.i2.129] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Revised: 11/13/2022] [Accepted: 01/23/2023] [Indexed: 02/24/2023] Open
Abstract
Owing to its heterogeneous and highly aggressive nature, hepatocellular carcinoma (HCC) has a high recurrence rate, which is a non-negligible problem despite the increasing number of available treatment options. Recent clinical trials have attempted to reduce the recurrence and develop innovative treatment options for patients with recurrent HCC. In the event of liver remnant recurrence, the currently available treatment options include repeat hepatectomy, salvage liver transplantation, tumor ablation, transcatheter arterial chemoembolization, stereotactic body radiotherapy, systemic therapies, and combination therapy. In this review, we summarize the strategies to reduce the recurrence of high-risk tumors and aggressive therapies for recurrent HCC. Additionally, we discuss methods to prevent HCC recurrence and prognostic models constructed based on predictors of recurrence to develop an appropriate surveillance program.
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Affiliation(s)
- Yu-Qing Yang
- Department of Epidemiology and Biostatistics, Jilin University, Changchun 130021, Jilin Province, China
| | - Zhen-Yu Wen
- Department of Occupational and Environmental Health, Jilin University, Changchun 130021, Jilin Province, China
| | - Xiao-Yan Liu
- Senior Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Zhen-Hu Ma
- Senior Department of Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Yan-E Liu
- Department of Epidemiology and Biostatistics, Jilin University, Changchun 130021, Jilin Province, China
| | - Xue-Ying Cao
- Senior Department of Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Li Hou
- Senior Department of Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Hui Xie
- Senior Department of Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
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Magalhães D, Dos Santos J, Frutuoso A, Mesquita A. Human Epidermal Growth Factor Receptor 2 (HER2) Expression by Immunohistochemistry and Its Clinical Significance in Hepatocellular Carcinoma: A Single-Center Analysis. Cureus 2023; 15:e34724. [PMID: 36909127 PMCID: PMC9997104 DOI: 10.7759/cureus.34724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/07/2023] [Indexed: 02/10/2023] Open
Abstract
BACKGROUND Human epidermal growth factor receptor 2 (HER2) is a member of the tyrosine kinase receptor family. It has been identified as an oncogene and is associated with poor outcomes in multiple tumor types. In hepatocellular carcinoma (HCC), there are contradictory data regarding the HER2 expression and its role in tumor development and progression. Some studies have identified HER2 expression as an early event during tumorigenesis, which decreases with progression and metastasis. Additional data provided evidence that treatment with anti-HER2 therapy resulted in local response and reduction in the metastasis rate in HCC mice models. METHODS Patients with histological diagnoses of HCC between 2010 and 2020 were included. HER2 staining was performed by immunohistochemistry (IHC), and scoring was done in accordance with the gastric cancer guidelines as 0, 1+, 2+, and 3+. Clinicopathological features were accessed by medical records. This study aims to evaluate HER2 expression by IHC in HCC and to correlate this expression with some clinicopathological features such as Barcelona Clinic Liver Cancer (BCLC) staging, number of hepatic lesions, alpha-fetoprotein level, underlying liver disease, presence of liver cirrhosis, Child-Pugh score, and tumor recurrence. RESULTS A total of 57 specimens from 54 patients were included. Of the patients, 85% were men, and the median age at diagnosis was 71 years (interquartile range: 59-75 years). Regarding stage, 61% were at stage 0-A of BCLC. Of the patients, 57% had a solitary HCC nodule. Concerning treatment, surgery was performed in 50% of the patients. HER2 expression was identified in seven patients: five in the membrane and two in the cytoplasm. Concerning the membrane staining, HER2 expression was scored as 1+/2+ in 7.4% (n = 4 patients). Of the patients with HER2 expression, four had a BCLC stage of 0-A and a single HCC nodule; alpha-fetoprotein was <400 ng/mL in all cases. There was no correlation to clinicopathological features. In one patient with HER2 2+ expression at diagnosis, this expression was not identified at tumor progression. Median disease-free survival in HER2 with IHC scores 1+/2+ and cytoplasmatic was 38 months versus 22 months in HER2 with a score of 0 (p = 0.604). CONCLUSIONS HER2 expression is a rare event in HCC. It was not possible to identify any relation to clinicopathological features. However, when we relate our data to previous trials, HER2 appears to be an early event in the course of HCC.
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Affiliation(s)
| | | | | | - Alexandra Mesquita
- Oncology, Hospital Pedro Hispano, Matosinhos, PRT.,Faculty of Medicine, University of Porto, Porto, PRT
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Chen W, Hu S, Liu Z, Sun Y, Wu J, Shen S, Peng Z. Adjuvant anti-PD-1 antibody for hepatocellular carcinoma with high recurrence risks after hepatectomy. Hepatol Int 2023; 17:406-416. [PMID: 36645648 DOI: 10.1007/s12072-022-10478-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 12/27/2022] [Indexed: 01/17/2023]
Abstract
BACKGROUND AND PURPOSE The clinical role of postoperative adjuvant therapy in hepatocellular carcinoma (HCC) is still unclear. The purpose of our study was to explore the clinical value of postoperative adjuvant anti-programed cell death 1 antibody (PA-PD-1) on the prognosis of HCC patients with high relapse risks after surgery. PATIENTS AND METHODS Data of consecutive HCC patients with high recurrence risks treated with liver resection at our center during January 2019 and March 2021 were prospectively collected. Baseline differences were balanced between HCC patients with (PA-PD-1 group) or without PA-PD-1 (non-PD-1 group) after hepatectomy by propensity-score matching (PSM). Between these two groups, we compared overall survival (OS) and recurrence-free survival (RFS). Independent prognostic risk factors for OS and RFS were confirmed by Cox regression analysis, and subgroup analysis was also performed. RESULTS 47 pairs of patients with or without PD-1 treatment after hepatectomy were matched. After PSM, the 1-year and 2-year RFS was 58.4% and 44.1% in the PA-PD-1 group, and 34.0% and 21.3% in the non-PD-1 group (p = 0.008). The OS at 1 year and 2 years was 91.2% and 91.2% in the PA-PD-1 group, compared with 85.1% and 61.7% in the non-PD-1 group (p = 0.024). Multivariable analyses demonstrated that PA-PD-1 was an independent protective predictor associated with RFS and OS. Through subgroup analysis, we concluded that HCC patients with portal venous tumor thrombus (PVTT) or tumor size ≥ 5 cm significantly benefited from PA-PD-1 therapy in RFS and OS. CONCLUSIONS Adjuvant anti-PD-1 antibody can effectively improve the survival outcomes of HCC patients with high relapse risks after hepatectomy in this prospective observational study. This finding should be confirmed by results of the ongoing phase 3 randomized controlled trials.
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Affiliation(s)
- Wei Chen
- Center of Hepato-Pancreato- Biliary Surgery, The First Affiliated Hospital of Sun Yat-Sen University, NO.58 Zhongshan Road 2, Guangzhou, 510080, Guangdong, People's Republic of China.,Department of Pancreaticobiliary Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China
| | - Shuifang Hu
- Department of Radiation Oncology, The First Affiliated Hospital of Sun Yat-Sen University, NO.58 Zhongshan Road 2, Guangzhou, 510080, Guangdong, People's Republic of China
| | - Zelong Liu
- Department of Radiation Oncology, The First Affiliated Hospital of Sun Yat-Sen University, NO.58 Zhongshan Road 2, Guangzhou, 510080, Guangdong, People's Republic of China
| | - Yukun Sun
- Department of Radiation Oncology, The First Affiliated Hospital of Sun Yat-Sen University, NO.58 Zhongshan Road 2, Guangzhou, 510080, Guangdong, People's Republic of China
| | - Jian Wu
- Center of Hepato-Pancreato- Biliary Surgery, The First Affiliated Hospital of Sun Yat-Sen University, NO.58 Zhongshan Road 2, Guangzhou, 510080, Guangdong, People's Republic of China.
| | - Shunli Shen
- Department of Liver Surgery, The First Affiliated Hospital of Sun Yat-Sen University, NO.58 Zhongshan Road 2, Guangzhou, 510080, Guangdong, People's Republic of China.
| | - Zhenwei Peng
- Department of Radiation Oncology, The First Affiliated Hospital of Sun Yat-Sen University, NO.58 Zhongshan Road 2, Guangzhou, 510080, Guangdong, People's Republic of China. .,Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China. .,Cancer Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China. .,Clinical Trials Unit, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China.
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Guo B, Chen Q, Liu Z, Chen X, Zhu P. Adjuvant therapy following curative treatments for hepatocellular carcinoma: current dilemmas and prospects. Front Oncol 2023; 13:1098958. [PMID: 37139151 PMCID: PMC10149944 DOI: 10.3389/fonc.2023.1098958] [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: 11/15/2022] [Accepted: 04/04/2023] [Indexed: 05/05/2023] Open
Abstract
Curative surgical treatments, mainly liver resection, are still one of the optimal options for patients with early-, mid-, and even progression-stage hepatocellular carcinoma (HCC). However, the recurrence rate within 5 years after surgery is as high as 70%, especially in patients with high risk factors for recurrence, most of whom experience early recurrence within 2 years. Effective adjuvant therapy may improve prognosis, previous studies found that adjuvant transarterial chemoembolization, antiviral, and traditional Chinese medicine et al. were helpful in preventing HCC recurrence. Nevertheless, due to controversial results or lack of high-level evidence, there is no standardized postoperative management protocol worldwide at present. Continued exploration of effective postoperative adjuvant treatments to improve surgical prognosis is necessary.
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Affiliation(s)
- Bin Guo
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Qian Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hepatobiliary Surgery Department, The First Affiliated Hospital of Shihezi University, Shihezi, Xinjiang, China
| | - Zhicheng Liu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiaoping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Peng Zhu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- *Correspondence: Peng Zhu,
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23
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Nevarez NM, Chang GY, Yopp AC. An Overview of Clinical Trials in the Treatment of Resectable Hepatocellular Carcinoma. Surg Oncol Clin N Am 2023; 32:101-117. [PMID: 36410911 DOI: 10.1016/j.soc.2022.07.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide. Partial hepatectomy, one of a few curative therapeutic modalities, is plagued by high recurrence rate of up to 70% at 5 years. Throughout the past 3 decades, many clinical trials have attempted to improve HCC recurrence rate following partial hepatectomy using adjuvant and neoadjuvant treatment modalities such as antiviral therapy, brachytherapy, systemic chemotherapy, immunotherapy, transarterial chemoembolization and radioembolization, and radiotherapy. The goal of this review is to discuss the clinical trials pertaining to resectable HCC including surgical technique considerations, adjuvant, and neoadjuvant treatment modalities.
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Affiliation(s)
- Nicole M Nevarez
- Department of Surgery, Division of Surgical Oncology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
| | - Gloria Y Chang
- Department of Surgery, Division of Surgical Oncology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
| | - Adam C Yopp
- Department of Surgery, Division of Surgical Oncology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
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Zhu Y, Qin LX. Strategies for improving the efficacy of immunotherapy in hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int 2022; 21:420-429. [PMID: 35977874 DOI: 10.1016/j.hbpd.2022.08.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 08/02/2022] [Indexed: 02/05/2023]
Abstract
Primary liver cancer, mainly hepatocellular carcinoma (HCC), is the sixth most diagnosed cancer and third leading cause of cancer-related death globally. Recently, immunotherapies such as immune checkpoint inhibitors (ICIs) have made great progress in the systemic treatment of HCC. However, anti-PD-1 therapy with pembrolizumab or nivolumab as a single agent did not meet their predefined end points of overall survival in the KEYNOTE-240 and CheckMate 459 trials. It is urgent to understand the immunological rationale and explore novel ways to improve the efficacy of immunotherapy. The combination of ICIs with other therapies, such as tyrosine kinase inhibitors (TKIs), monoclonal antibodies, or local therapy, has been demonstrated to improve overall response rate and survival. In addition, modulating tumor microenvironment is a potential way to overcome the primary and secondary resistance to immunotherapies. In this review, we summarized the latest findings in the immune microenvironment, the mechanisms of their synergistic effects when combined with anti-VEGF agents or TKIs, as well as other kinds of immune treatment.
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Affiliation(s)
- Ying Zhu
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai 200040, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Lun-Xiu Qin
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai 200040, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
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Zeng ZM, Mo N, Zeng J, Ma FC, Jiang YF, Huang HS, Liao XW, Zhu GZ, Ma J, Peng T. Advances in postoperative adjuvant therapy for primary liver cancer. World J Gastrointest Oncol 2022; 14:1604-1621. [PMID: 36187393 PMCID: PMC9516643 DOI: 10.4251/wjgo.v14.i9.1604] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 05/13/2022] [Accepted: 07/26/2022] [Indexed: 02/05/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly heterogeneous, invasive, and conventional chemotherapy-insensitive tumor with unique biological characteristics. The main methods for the radical treatment of HCC are surgical resection or liver transplantation. However, recurrence rates are as high as 50% and 70% at 3 and 5 years after liver resection, respectively, and even in Milan-eligible recipients, the recurrence rate is approximately 20% at 5 years after liver transplantation. Therefore, reducing the postoperative recurrence rate is key to improving the overall outcome of liver cancer. This review discusses the risk factors for recurrence in patients with HCC radical surgical resection and adjuvant treatment options that may reduce the risk of recurrence and improve overall survival, including local adjuvant therapy (e.g., transcatheter arterial chemoembolization), adjuvant systemic therapy (e.g., molecular targeted agents and immunotherapy), and other adjuvant therapies (e.g., antiviral and herbal therapy). Finally, potential research directions that may change the paradigm of adjuvant therapy for HCC are analyzed.
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Affiliation(s)
- Zhi-Ming Zeng
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Ning Mo
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Jie Zeng
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Fu-Chao Ma
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Yan-Feng Jiang
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Hua-Sheng Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Xi-Wen Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Guang-Zhi Zhu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Jie Ma
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
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26
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Zhu Y, Chen M, Xu D, Li TE, Zhang Z, Li JH, Wang XY, Yang X, Lu L, Jia HL, Dong QZ, Qin LX. The combination of PD-1 blockade with interferon-α has a synergistic effect on hepatocellular carcinoma. Cell Mol Immunol 2022; 19:726-737. [PMID: 35459855 PMCID: PMC9151669 DOI: 10.1038/s41423-022-00848-3] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Accepted: 02/18/2022] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND The efficacy of immune checkpoint inhibitors (ICIs), such as programmed cell death protein-1 (PD-1) or its ligand 1 (PD-L1) antibody, in hepatocellular carcinoma (HCC) is limited, and it is recommended that they be combined with other therapies. We evaluated the combination of pegylated interferon-α (Peg-IFNα) with PD-1 blockade in HCC mouse models. METHODS We analyzed the effects of Peg-IFNα on tumor-infiltrating immune cells and PD-1 expression in the HCC immune microenvironment and examined the underlying mechanism of its unique effect on the PD-1 pathway. The in vivo efficacy of anti-PD-1 and Peg-IFNα was evaluated in both subcutaneous and orthotopic mouse models of HCC. RESULTS The combination of Peg-IFNα with PD-1 blockade dramatically enhanced T-cell infiltration, improved the efficacy of PD-1 antibody and prolonged mouse survival compared with PD-1 antibody monotherapy. Mechanistically, Peg-IFNα could recruit cytotoxic CD8+ T cells to infiltrate the HCC microenvironment by inducing tumor cells to secrete the chemokine CCL4. Nevertheless, the HCC microenvironment quickly overcame the immune responses by upregulating PD-1 expression in CD8+ T cells via the IFNα-IFNAR1-JAK1-STAT3 signaling pathway. The combination of PD-1 blockade with Peg-IFNα could restore the cytotoxic capacity of CD8+ T cells and exerted a significant synergistic effect on HCC. CONCLUSION These results indicate that in addition to initiating the antitumor immune response itself, Peg-IFNα can also generate a microenvironment favoring PD-1 blockade. Thus, the combination of Peg-IFNα and PD-1 blockade can be a promising strategy for HCC.
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Affiliation(s)
- Ying Zhu
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Mo Chen
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Da Xu
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Tian-En Li
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Ze Zhang
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Jian-Hua Li
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Xiang-Yu Wang
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Xin Yang
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Lu Lu
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Hu-Liang Jia
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Qiong-Zhu Dong
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China.
- Institutes of Biomedical Sciences, Fudan University, 131 Dong An Road, Shanghai, 200032, China.
| | - Lun-Xiu Qin
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China.
- Institutes of Biomedical Sciences, Fudan University, 131 Dong An Road, Shanghai, 200032, China.
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Lin K, Wei F, Huang Q, Lai Z, Zhang J, Chen Q, Jiang Y, Kong J, Tang S, Lin J, Chen Y, Chen J, Zeng Y. Postoperative Adjuvant Transarterial Chemoembolization Plus Tyrosine Kinase Inhibitor for Hepatocellular Carcinoma: a Multicentre Retrospective Study. J Hepatocell Carcinoma 2022; 9:127-140. [PMID: 35300207 PMCID: PMC8922443 DOI: 10.2147/jhc.s352480] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Accepted: 02/16/2022] [Indexed: 01/27/2023] Open
Abstract
PURPOSE This study aimed to assess the efficacy and safety of adjuvant transarterial chemoembolization (TACE) plus tyrosine kinase inhibitor (TKI) treatment in patients with hepatocellular carcinoma (HCC) with a high risk of early recurrence after curative resection. PATIENTS AND METHODS Patients from multiple centres were divided into postoperative adjuvant TACE with (n=57) or without (n=142) TKI administration groups. The disease-free survival (DFS) curve was depicted by the Kaplan-Meier method, and the difference between the two groups was tested using the log rank test. Univariate and multivariate Cox analyses were performed to identify independent risk factors for DFS. Additionally, three propensity score analyses were performed to minimise the potential confounding factors to facilitate a more reliable conclusion. Adverse events (AEs) were assessed according to the Common Terminology Criteria for Adverse Events, version 4.0. RESULTS The 1-and 2-year DFS rates of the TACE plus TKI treatment group were 45.5% and 34.9%, respectively, which were significantly better than those of the TACE alone group (26.8% and 18.3%, respectively). Multivariate analysis identified adjuvant TACE plus TKI treatment as an independent prognostic factor for DFS (hazard ratio: 0.611, 95% confidence interval: 0.408-0.915, P=0.017). Further analysis based on the various propensity score methods yielded similar results. Subgroup analysis showed that patients with tumour diameter ≥5 cm, tumour number <3, absence of hepatic vein tumour thrombus and bile duct tumour thrombus, ruptured tumours, and stage IIIB could benefit more from TACE plus TKI treatment (all P<0.05). Some patients (33.33%) experienced grade ≥3 AEs in the TACE plus TKI group. CONCLUSION TACE plus TKI treatment can reduce the incidence of early recurrence with tolerable adverse events in HCC patients at high risk of recurrence after hepatectomy and may be an appropriate option in postoperative anti-recurrence treatment.
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Affiliation(s)
- Kongying Lin
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People’s Republic of China
| | - Fuqun Wei
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People’s Republic of China
- Department of Interventional Radiology, First Affiliated Hospital of Fujian Medical University, Fuzhou, 350025, People’s Republic of China
| | - Qizhen Huang
- Department of Radiation Oncology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People’s Republic of China
| | - Zisen Lai
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People’s Republic of China
| | - Jinyu Zhang
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People’s Republic of China
| | - Qingjing Chen
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People’s Republic of China
| | - Yabin Jiang
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People’s Republic of China
| | - Jie Kong
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People’s Republic of China
- Department of Hepatobiliary, Heze Municipal Hospital, Heze, Shandong, 274000, People’s Republic of China
| | - Shichuan Tang
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People’s Republic of China
| | - Jianhuai Lin
- Biobank in Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People’s Republic of China
| | - Yufeng Chen
- Department of Hepatopancreatobiliary Surgery, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, 363000, People’s Republic of China
| | - Jinhong Chen
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, 200000, People’s Republic of China
| | - Yongyi Zeng
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People’s Republic of China
- Department of Hepatopancreatobiliary Surgery, First Affiliated Hospital of Fujian Medical University, Fuzhou, 350025, People’s Republic of China
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Wang Z, Yu XL, Zhang J, Cheng ZG, Han ZY, Liu FY, Dou JP, Kong Y, Dong XJ, Zhao QX, Yu J, Liang P, Tang WZ. Huaier granule prevents the recurrence of early-stage hepatocellular carcinoma after thermal ablation: A cohort study. JOURNAL OF ETHNOPHARMACOLOGY 2021; 281:114539. [PMID: 34428522 DOI: 10.1016/j.jep.2021.114539] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Revised: 08/03/2021] [Accepted: 08/17/2021] [Indexed: 06/13/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Clinical trials have demonstrated that Trametes robinophila Murr (Huaier granule) can inhibit recurrence and metastasis after hepatocellular carcinoma (HCC) resection, but its efficacy as an adjuvant therapy after thermal ablation of early HCC is unknown. AIM OF THE STUDY To analyze the prognostic value and side effects of Huaier granules in HCC patients undergoing thermal ablation. MATERIALS AND METHODS Clinical information from 340 eligible subjects with early-stage HCC who were admitted to our department from September 1, 2008 to January 1, 2019 was extracted from the electronic medical record database. They were divided into the thermal ablation + TCM group and the thermal ablation group. Differences in their overall survival (OS), progression-free survival (PFS), extrahepatic metastatic rate (EMR), and therapeutic side effects (TSEs) between the two groups were compared. Beneficiaries of the integrated treatment and adequate treatment length were predicted. RESULTS The median follow-up was 32.5 months (range 2-122 months). The 1-year, 3-year and 5-year OS rates in the integrated treatment group and the control group were 93.2% vs. 92.6%, 54.5% vs. 51.4%, 23.5% vs. 19.7% (p = 0.110, HR 0.76(0.54-1.07)). The 1-year, 3-year and 5-year PFS rates were 78.8% vs. 69.4%, 50.6% vs. 40.6%, 35.3% vs. 26.5%, respectively (p = 0.020, HR 0.67(0.48-0.94)). The median OS (35 vs. 31 months) and PFS (24 vs. 12.5 months) were longer in the integrated treatment group. The EMR in the integrated treatment group was significantly lower than that in the control group (p = 0.018, HR 0.49 (0.27-0.89)). Patients with any two of the following three factors might be predicted to be beneficiaries of the integrated treatment, including younger than 65 years (p =0.039, HR 0.70 (0.50-0.98)), single tumor (p = 0.035, HR 0.70 (0.50-0.98), and tumor size ≤3 cm (p = 0.029, HR 0.69 (0.50-0.96). Patients with continuous oral administration of TCM following ablation had a lower probability of recurrence and metastasis within 2 years (p = 0.015, HR 0.67 (0.49-0.93)). Although the integrated treatment group reported a higher incidence of nausea and emesis, there were no significant differences between the two groups. CONCLUSION TCM following ablation may prolong PFS and suppress recurrence in patients with HCC, with continuous oral administration for more than 2 years maybe experience a greater benefit. The TSEs of the treatment are mild and can be tolerated.
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Affiliation(s)
- Zhen Wang
- Department of Gastrointestinal Surgery, Affiliated Tumor Hospital, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, PR China; Department of Interventional Ultrasound, Chinese PLA General Hospital, Beijing, 100853, China
| | - Xiao-Ling Yu
- Department of Interventional Ultrasound, Chinese PLA General Hospital, Beijing, 100853, China
| | - Jing Zhang
- Department of Interventional Ultrasound, Chinese PLA General Hospital, Beijing, 100853, China
| | - Zhi-Gang Cheng
- Department of Interventional Ultrasound, Chinese PLA General Hospital, Beijing, 100853, China
| | - Zhi-Yu Han
- Department of Interventional Ultrasound, Chinese PLA General Hospital, Beijing, 100853, China
| | - Fang-Yi Liu
- Department of Interventional Ultrasound, Chinese PLA General Hospital, Beijing, 100853, China
| | - Jian-Ping Dou
- Department of Interventional Ultrasound, Chinese PLA General Hospital, Beijing, 100853, China
| | - Yi Kong
- Department of Clinical Laboratory Medicine, Chinese PLA General Hospital & Postgraduate Medical School, Beijing, 100853, China; Department of Clinical Laboratory Medicine, Jining First People's Hospital, Jining, Shandong Province, 272000, PR China
| | - Xue-Juan Dong
- Department of Interventional Ultrasound, Chinese PLA General Hospital, Beijing, 100853, China
| | - Qin-Xian Zhao
- Department of Interventional Ultrasound, Chinese PLA General Hospital, Beijing, 100853, China
| | - Jie Yu
- Department of Interventional Ultrasound, Chinese PLA General Hospital, Beijing, 100853, China.
| | - Ping Liang
- Department of Interventional Ultrasound, Chinese PLA General Hospital, Beijing, 100853, China.
| | - Wei-Zhong Tang
- Department of Gastrointestinal Surgery, Affiliated Tumor Hospital, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, PR China; Guangxi Clinical Research Center for Colorectal Cancer, Nanning, Guangxi Zhuang Autonomous Region, 530021, PR China.
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Liu Y, Wang Y, Guo X, He Y, Zhou J, Lv Q, Huang X, Li X. Comparative Effectiveness of Adjuvant Treatment for Resected Hepatocellular Carcinoma: A Systematic Review and Network Meta-Analysis. Front Oncol 2021; 11:709278. [PMID: 34540675 PMCID: PMC8445365 DOI: 10.3389/fonc.2021.709278] [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: 05/13/2021] [Accepted: 08/09/2021] [Indexed: 12/24/2022] Open
Abstract
Background It is controversial whether adjuvant treatment could be recommended for hepatocellular carcinoma (HCC) after curative hepatectomy. Thus, we performed a network meta-analysis (NMA) to assess adjuvant treatment’s benefit and determine the optimal adjuvant regimen. Methods We systematically searched PubMed, Embase, and Cochrane Library for randomized controlled trials comparing adjuvant therapy versus no active treatment after curative hepatectomy among patients with HCC. Pooled data on recurrence and overall survival (OS) were analyzed within pairwise meta-analysis and NMA. Results Twenty-three eligible trials (3,940 patients) reporting eight treatments were included. The direct meta-analysis showed that adjuvant therapy prevented the recurrence (OR = 0.65; 95% CI: 0.55, 0.77; P = 0.177; I2 = 21.7%) and contributed to OS (HR = 0.63; 95% CI: 0.54, 0.73; P = 0.087; I2 = 31.1%) in comparison to the observation. In the NMA, internal radiotherapy (IRT; OR = 0.55; 95% CI: 0.39, 0.77; SUCRA = 87.7%) followed by hepatic artery infusion chemotherapy (HAIC; OR = 0.6; 95% CI: 0.36, 0.97; SUCRA = 77.8%), and HAIC (HR = 0.44; 95% CI: 0.21, 0.87; SUCRA = 82.6%) followed by IRT (HR 0.54; 95% CI:0.36, 0.81; SUCRA = 69.7%) were ranked superior to other treatments in terms of preventing recurrence and providing survival benefit, respectively. Conclusions The addition of adjuvant therapy lowers the risk of recurrence and provide survival benefit after surgical resection for HCC. HAIC and IRT are likely to be the two most effective adjuvant regimens. Systematic Review Registration https://inplasy.com/inplasy-2020-11-0039/.
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Affiliation(s)
- Ying Liu
- Department of Pharmacy, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yuzhu Wang
- Department of Pharmacy, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xinkun Guo
- Deparment of Hepatic Oncology, Zhongshan Hospital, Fudan University, Xiamen, China
| | - Yifeng He
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Qianzhou Lv
- Department of Pharmacy, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiaowu Huang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Xiaoyu Li
- Department of Pharmacy, Zhongshan Hospital, Fudan University, Shanghai, China
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30
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Ding WB, Wang MC, Yu J, Huang G, Sun DP, Liu L, Zhang JN, Yang Y, Liu H, Zhou WP, Yang F, Yuan SX. HBV/Pregenomic RNA Increases the Stemness and Promotes the Development of HBV-Related HCC Through Reciprocal Regulation With Insulin-Like Growth Factor 2 mRNA-Binding Protein 3. Hepatology 2021; 74:1480-1495. [PMID: 33825218 DOI: 10.1002/hep.31850] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 02/22/2021] [Accepted: 03/14/2021] [Indexed: 01/04/2023]
Abstract
BACKGROUND AND AIMS HBV-pgRNA (pregenomic RNA) has been proposed for predicting the response of nucleos(t)ide analogue (NA) treatment, guiding discontinuation of NA therapy and monitoring the emergence of viral mutations. However, the contributions of HBV-pgRNA to HCC remain open for study. APPROACH AND RESULTS Double-center cohorts of serum samples with undetectable serum HBV-DNA (below the lower limit of detection) were obtained from long-term NA-treated (≥48 weeks) HBV-related HCC patients. The correlation between serum pgRNA concentration and the prognosis of HCC were analyzed. The role pgRNA played in HCC development was assessed both in vitro and in vivo. Our findings revealed that for patients who underwent long-term NA therapy with undetectable serum HBV-DNA, patients with high serum pgRNA expression had a poorer overall survival rate and higher cumulative recurrence rate after hepatectomy. Experiments demonstrated that pgRNA promotes proliferation, stemness, and tumorigenicity of HCC cells. Mechanistically, we found that pgRNA could up-regulate the expression of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), a well-proven oncoprotein, at the posttranscriptional level. Furthermore, interferon (IFN)-α-2a could degrade the stability of pgRNA through increasing its N6-methyladenosine (m6A) RNA modification. Collectively, our findings uncover that serum pgRNA could serve as a potential biomarker for predicting the prognosis and recurrence of HCC in patients who received long-term NA therapy with undetectable serum HBV-DNA; and the pgRNA-IGF2BP3 axis plays an important role in the development of HBV-related HCC. Moreover, IFN-α-2a could reduce the stability of pgRNA by increasing its m6A RNA modification level, thereby suppressing the development of HBV-related HCC. CONCLUSIONS In conclusion, our studies reveal a significance and mechanism of HBV-pgRNA in increasing stemness features and offer a potential prognostic marker and a therapeutic target for HBV-related HCC.
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Affiliation(s)
- Wen-Bin Ding
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.,Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education, Shanghai, China.,Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai, China
| | - Meng-Chao Wang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.,Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education, Shanghai, China.,Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai, China
| | - Jian Yu
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.,Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education, Shanghai, China.,Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai, China
| | - Gang Huang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.,Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education, Shanghai, China.,Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai, China
| | - Da-Peng Sun
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.,Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education, Shanghai, China.,Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai, China
| | - Lei Liu
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.,Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education, Shanghai, China.,Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai, China
| | - Jia-Ning Zhang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.,Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education, Shanghai, China.,Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai, China
| | - Yuan Yang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.,Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education, Shanghai, China.,Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai, China
| | - Hui Liu
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.,Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education, Shanghai, China.,Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai, China
| | - Wei-Ping Zhou
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.,Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education, Shanghai, China.,Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai, China
| | - Fu Yang
- The Department of Medical Genetics, Second Military Medical University, Shanghai, China
| | - Sheng-Xian Yuan
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.,Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education, Shanghai, China.,Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai, China
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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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Zhang W, Zhang B, Chen XP. Adjuvant treatment strategy after curative resection for hepatocellular carcinoma. Front Med 2021; 15:155-169. [PMID: 33754281 DOI: 10.1007/s11684-021-0848-3] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 02/20/2021] [Indexed: 01/27/2023]
Abstract
Hepatic resection represents the first-line treatment for patients with resectable hepatocellular carcinoma (HCC). However, the 5-year recurrence rates of HCC after surgery have been reported to range from 50% to 70%. In this review, we evaluated the available evidence for the efficiency of adjuvant treatments to prevent HCC recurrence after curative liver resection. Antiviral therapy has potential advantages in terms of reducing the recurrence rate and improving the overall survival (OS) and/or disease-free survival of patients with hepatitis-related HCC. Postoperative adjuvant transarterial chemoembolization can significantly reduce the intrahepatic recurrence rate and improve OS, especially for patients with a high risk of recurrence. The efficacy of molecular targeted drugs as an adjuvant therapy deserves further study. Adjuvant adoptive immunotherapy can significantly improve the clinical prognosis in the early stage. Randomized controlled trial (RCT) studies evaluating adjuvant immune checkpoint inhibitors are ongoing, and the results are highly expected. Adjuvant hepatic artery infusion chemotherapy might be beneficial in patients with vascular invasion. Huaier granule, a traditional Chinese medicine, has been proved to be effective in prolonging the recurrence-free survival and reducing extrahepatic recurrence. The efficiency of other adjuvant treatments needs to be further confirmed by large RCT studies.
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Affiliation(s)
- Wei Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Bixiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Xiao-Ping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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33
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Mai RY, Zeng J, Meng WD, Lu HZ, Liang R, Lin Y, Wu GB, Li LQ, Ma L, Ye JZ, Bai T. Artificial neural network model to predict post-hepatectomy early recurrence of hepatocellular carcinoma without macroscopic vascular invasion. BMC Cancer 2021; 21:283. [PMID: 33726693 PMCID: PMC7962237 DOI: 10.1186/s12885-021-07969-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Accepted: 02/24/2021] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND The accurate prediction of post-hepatectomy early recurrence (PHER) of hepatocellular carcinoma (HCC) is vital in determining postoperative adjuvant treatment and monitoring. This study aimed to develop and validate an artificial neural network (ANN) model to predict PHER in HCC patients without macroscopic vascular invasion. METHODS Nine hundred and three patients who underwent curative liver resection for HCC participated in this study. They were randomly divided into derivation (n = 679) and validation (n = 224) cohorts. The ANN model was developed in the derivation cohort and subsequently verified in the validation cohort. RESULTS PHER morbidity in the derivation and validation cohorts was 34.8 and 39.2%, respectively. A multivariable analysis revealed that hepatitis B virus deoxyribonucleic acid load, γ-glutamyl transpeptidase level, α-fetoprotein level, tumor size, tumor differentiation, microvascular invasion, satellite nodules, and blood loss were significantly associated with PHER. These factors were incorporated into an ANN model, which displayed greater discriminatory abilities than a Cox's proportional hazards model, preexisting recurrence models, and commonly used staging systems for predicting PHER. The recurrence-free survival curves were significantly different between patients that had been stratified into two risk groups. CONCLUSION When compared to other models and staging systems, the ANN model has a significant advantage in predicting PHER for HCC patients without macroscopic vascular invasion.
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Affiliation(s)
- Rong-Yun Mai
- Department of Hepatobilliary & Pancreatic Surgery, Guangxi Medical University Cancer Hospital, 71 He Di Road, Nanning, China
- Department of Experimental Research, Guangxi Medical University Cancer Hospital, Nanning, 530021, China
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning, 530021, China
| | - Jie Zeng
- Department of Experimental Research, Guangxi Medical University Cancer Hospital, Nanning, 530021, China
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning, 530021, China
| | - Wei-da Meng
- Department of Hepatobilliary & Pancreatic Surgery, Guangxi Medical University Cancer Hospital, 71 He Di Road, Nanning, China
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning, 530021, China
| | - Hua-Ze Lu
- Department of Hepatobilliary & Pancreatic Surgery, Guangxi Medical University Cancer Hospital, 71 He Di Road, Nanning, China
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning, 530021, China
| | - Rong Liang
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning, 530021, China
- Department of First Chemotherapy, Guangxi Medical University Cancer Hospital, Nanning, 530021, China
| | - Yan Lin
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning, 530021, China
- Department of First Chemotherapy, Guangxi Medical University Cancer Hospital, Nanning, 530021, China
| | - Guo-Bin Wu
- Department of Hepatobilliary & Pancreatic Surgery, Guangxi Medical University Cancer Hospital, 71 He Di Road, Nanning, China
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning, 530021, China
| | - Le-Qun Li
- Department of Hepatobilliary & Pancreatic Surgery, Guangxi Medical University Cancer Hospital, 71 He Di Road, Nanning, China
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning, 530021, China
| | - Liang Ma
- Department of Hepatobilliary & Pancreatic Surgery, Guangxi Medical University Cancer Hospital, 71 He Di Road, Nanning, China
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning, 530021, China
| | - Jia-Zhou Ye
- Department of Hepatobilliary & Pancreatic Surgery, Guangxi Medical University Cancer Hospital, 71 He Di Road, Nanning, China.
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning, 530021, China.
| | - Tao Bai
- Department of Hepatobilliary & Pancreatic Surgery, Guangxi Medical University Cancer Hospital, 71 He Di Road, Nanning, China.
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning, 530021, China.
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34
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Zhang Z, Zhu Y, Xu D, Li TE, Li JH, Xiao ZT, Chen M, Yang X, Jia HL, Dong QZ, Qin LX. IFN-α facilitates the effect of sorafenib via shifting the M2-like polarization of TAM in hepatocellular carcinoma. Am J Transl Res 2021; 13:301-313. [PMID: 33527025 PMCID: PMC7847501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 11/20/2020] [Indexed: 06/12/2023]
Abstract
Tumor-associated macrophages (TAMs) and how they are activated play critical roles in tumor progression and metastasis, and in hepatocellular carcinoma (HCC), they are associated with sorafenib resistance. Reprogramming of TAMs into M1-like macrophages has been proposed as an approach to stimulate tumor regression. Here we studied the collective effects of interferon-alpha (IFN-α) and sorafenib on HCC. We found that IFN-α delayed tumor growth and inhibited pulmonary metastasis in an orthotopic HCC implantation model. Via in vitro studies, we found that IFN-α treatment could reprogram M2-like RAW264.7 and THP-1 macrophage cells toward M1-like cells. In addition, we also found that IFN-α combined with a low dose of sorafenib has a synergistic inhibitory effect on HCC tumor growth and pulmonary metastasis without obvious toxicity in an in vivo mice model. Moreover, IFN-α increased sorafenib's therapeutic efficacy by shifting TAM polarization to an M1-like phenotype, increasing and activating intratumoral CD8+ T cells in HCCs. In conclusion, a combination of IFN-α and sorafenib have synergistic inhibitory effects on HCC growth and metastasis resulting from a shift in TAM polarization rather than their depletion. Our study supports the future clinical use of a combination of IFN-α and sorafenib for the treatment of advanced HCC.
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Affiliation(s)
- Ze Zhang
- Department of General Surgery, Huashan Hospital of Fudan UniversityShanghai 200040, China
| | - Ying Zhu
- Department of General Surgery, Huashan Hospital of Fudan UniversityShanghai 200040, China
| | - Da Xu
- Department of General Surgery, Huashan Hospital of Fudan UniversityShanghai 200040, China
| | - Tian-En Li
- Department of General Surgery, Huashan Hospital of Fudan UniversityShanghai 200040, China
| | - Jian-Hua Li
- Department of General Surgery, Huashan Hospital of Fudan UniversityShanghai 200040, China
| | - Zi-Tian Xiao
- Department of General Surgery, Huashan Hospital of Fudan UniversityShanghai 200040, China
| | - Mo Chen
- Department of General Surgery, Huashan Hospital of Fudan UniversityShanghai 200040, China
| | - Xin Yang
- Department of General Surgery, Huashan Hospital of Fudan UniversityShanghai 200040, China
| | - Hu-Liang Jia
- Department of General Surgery, Huashan Hospital of Fudan UniversityShanghai 200040, China
- Cancer Metastasis Institute, Huashan Hospital of Fudan UniversityShanghai 200040, China
| | - Qiong-Zhu Dong
- Department of General Surgery, Huashan Hospital of Fudan UniversityShanghai 200040, China
- Cancer Metastasis Institute, Huashan Hospital of Fudan UniversityShanghai 200040, China
- Institutes of Biomedical Sciences, Fudan UniversityShanghai 200040, China
| | - Lun-Xiu Qin
- Department of General Surgery, Huashan Hospital of Fudan UniversityShanghai 200040, China
- Cancer Metastasis Institute, Huashan Hospital of Fudan UniversityShanghai 200040, China
- Institutes of Biomedical Sciences, Fudan UniversityShanghai 200040, China
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35
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Zhou J, Sun H, Wang Z, Cong W, Wang J, Zeng M, Zhou W, Bie P, Liu L, Wen T, Han G, Wang M, Liu R, Lu L, Ren Z, Chen M, Zeng Z, Liang P, Liang C, Chen M, Yan F, Wang W, Ji Y, Yun J, Cai D, Chen Y, Cheng W, Cheng S, Dai C, Guo W, Hua B, Huang X, Jia W, Li Y, Li Y, Liang J, Liu T, Lv G, Mao Y, Peng T, Ren W, Shi H, Shi G, Tao K, Wang W, Wang X, Wang Z, Xiang B, Xing B, Xu J, Yang J, Yang J, Yang Y, Yang Y, Ye S, Yin Z, Zhang B, Zhang B, Zhang L, Zhang S, Zhang T, Zhao Y, Zheng H, Zhu J, Zhu K, Liu R, Shi Y, Xiao Y, Dai Z, Teng G, Cai J, Wang W, Cai X, Li Q, Shen F, Qin S, Dong J, Fan J. Guidelines for the Diagnosis and Treatment of Hepatocellular Carcinoma (2019 Edition). Liver Cancer 2020; 9:682-720. [PMID: 33442540 PMCID: PMC7768108 DOI: 10.1159/000509424] [Citation(s) in RCA: 556] [Impact Index Per Article: 111.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 06/12/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Primary liver cancer, around 90% are hepatocellular carcinoma in China, is the fourth most common malignancy and the second leading cause of tumor-related death, thereby posing a significant threat to the life and health of the Chinese people. SUMMARY Since the publication of Guidelines for Diagnosis and Treatment of Primary Liver Cancer (2017 Edition) in 2018, additional high-quality evidence has emerged with relevance to the diagnosis, staging, and treatment of liver cancer in and outside China that requires the guidelines to be updated. The new edition (2019 Edition) was written by more than 70 experts in the field of liver cancer in China. They reflect the real-world situation in China regarding diagnosing and treating liver cancer in recent years. KEY MESSAGES Most importantly, the new guidelines were endorsed and promulgated by the Bureau of Medical Administration of the National Health Commission of the People's Republic of China in December 2019.
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Affiliation(s)
- Jian Zhou
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Huichuan Sun
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zheng Wang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wenming Cong
- Department of Pathology, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Jianhua Wang
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Mengsu Zeng
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Weiping Zhou
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Ping Bie
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Lianxin Liu
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Tianfu Wen
- Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Guohong Han
- Department of Liver Diseases and Digestive Interventional Radiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Maoqiang Wang
- Department of Interventional Radiology, Chinese PLA General Hospital, Beijing, China
| | - Ruibao Liu
- Department of Interventional Radiology, The Tumor Hospital of Harbin Medical University, Harbin, China
| | - Ligong Lu
- Department of Interventional Oncology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Zhengang Ren
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Minshan Chen
- Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Zhaochong Zeng
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ping Liang
- Department of Interventional Ultrasound, Chinese PLA General Hospital, Beijing, China
| | - Changhong Liang
- Department of Radiology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Min Chen
- Editorial Department of Chinese Journal of Digestive Surgery, Chongqing, China
| | - Fuhua Yan
- Department of Radiology, Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Wenping Wang
- Department of Ultrasound, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yuan Ji
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jingping Yun
- Department of Pathology, Tumor Prevention and Treatment Center, Sun Yat-sen University, Guangzhou, China
| | - Dingfang Cai
- Department of Integrative Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yongjun Chen
- Department of Hematology, Ruijin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wenwu Cheng
- Department of Integrated Therapy, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Shuqun Cheng
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Chaoliu Dai
- Department of Hepatobiliary and Spleenary Surgery, The Affiliated Shengjing Hospital, China Medical University, Shenyang, China
| | - Wenzhi Guo
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Baojin Hua
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaowu Huang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Weidong Jia
- Department of Hepatic Surgery, Affiliated Provincial Hospital, Anhui Medical University, Hefei, China
| | - Yaming Li
- Department of Nuclear Medicine, The First Hospital of China Medical University, Shenyang, China
| | - Yexiong Li
- Department of Radiation Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jun Liang
- Department of Oncology, Peking University International Hospital, Beijing, China
| | - Tianshu Liu
- Department of Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Guoyue Lv
- Department of General Surgery, The First Hospital of Jilin University, Jilin, China
| | - Yilei Mao
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC and Chinese Academy of Medical Sciences, Beijing, China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Weixin Ren
- Department of Interventional Radiology The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Hongcheng Shi
- Department of Nuclear Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Guoming Shi
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Kaishan Tao
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Wentao Wang
- Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Xiaoying Wang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhiming Wang
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, China
| | - Bangde Xiang
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Baocai Xing
- Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital and Institute, Beijing, China
| | - Jianming Xu
- Department of Gastrointestinal Oncology, Affiliated Hospital Cancer Center, Academy of Military Medical Sciences, Beijing, China
| | - Jiamei Yang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Jianyong Yang
- Department of Interventional Oncology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yefa Yang
- Department of Hepatic Surgery & Interventional Radiology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Yunke Yang
- Department of Integrative Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Shenglong Ye
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhengyu Yin
- Department of Hepatobiliary Surgery, Zhongshan Hospital of Xiamen University, Hubing South Road, Xiamen, China
| | - Bixiang Zhang
- Department of Surgery, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Boheng Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Leida Zhang
- Department of Hepatobiliary Surgery Institute, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Shuijun Zhang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, ZhengZhou, China
| | - Ti Zhang
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Yongfu Zhao
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, ZhengZhou, China
| | - Honggang Zheng
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jiye Zhu
- Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing, China
| | - Kangshun Zhu
- Department of Minimally Invasive Interventional Radiology, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Rong Liu
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yinghong Shi
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yongsheng Xiao
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhi Dai
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Gaojun Teng
- Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China
| | - Jianqiang Cai
- Department of Abdominal Surgical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Weilin Wang
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiujun Cai
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China
| | - Qiang Li
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Feng Shen
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Shukui Qin
- Department of Medical Oncology, PLA Cancer Center, Nanjing Bayi Hospital, Nanjing, China
| | - Jiahong Dong
- Department of Hepatobiliary and Pancreas Surgery, Beijing Tsinghua Changgung Hospital (BTCH), School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Jia Fan
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
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Four gene intrahepatic metastasis-risk signature predicts hepatocellular carcinoma malignant potential and early recurrence from intrahepatic metastasis. Surgery 2020; 169:903-910. [PMID: 33160638 DOI: 10.1016/j.surg.2020.09.032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Revised: 09/16/2020] [Accepted: 09/30/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND Hepatocellular carcinoma has a high recurrence rate even after curative surgery, and hepatocellular carcinoma risk-predictive biomarkers will enable identification of patients who most need close monitoring and cancer-preventive intervention. Hepatocellular carcinoma has 2 different recurrence patterns-a multicentric recurrence and an intrahepatic metastasis. We have reported that the molecular gene signature from the gene expression of adjacent liver can be used to predict multicentric recurrence of hepatocellular carcinoma, but the signature to predict recurrence from intrahepatic metastasis has not been established. We aimed to identify the recurrence from intrahepatic metastasis gene signature from the gene expression of tumor to predict recurrence from intrahepatic metastasis. METHODS The intrahepatic metastasis-risk signature was created based on the exhaustive analysis using a microarray transcriptome database of hepatocellular carcinoma. The intrahepatic metastasis-risk signature was measured in a cohort of 80 hepatocellular carcinoma patients, and the correlation with hepatocellular carcinoma recurrence and overall survival and each gene signature were analyzed and validated. RESULTS The gene signature assay classified the patients into high- (n = 20), intermediate- (n = 40), and low-risk (n = 20) groups. The high-risk prediction was independently associated with higher early hepatocellular carcinoma recurrence (hazard ratio = 3.7, P = .03) in multivariable modeling adjusted by tumor size, tumor number, and microvascular invasion. Gene set enrichment analysis demonstrates that the gene sets associated with "cell cycle" or "histone modulation" are highly enriched in the high intrahepatic metastasis gene signature group CONCLUSION: The intrahepatic metastasis gene signature predicts early recurrence and is associated with malignant potential related to the promoted cell cycle.
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Zhu XD, Li KS, Sun HC. Adjuvant therapies after curative treatments for hepatocellular carcinoma: Current status and prospects. Genes Dis 2020; 7:359-369. [PMID: 32884990 PMCID: PMC7452398 DOI: 10.1016/j.gendis.2020.02.002] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2019] [Accepted: 02/20/2020] [Indexed: 02/07/2023] Open
Abstract
Tumor recurrence rate after surgery or ablation of hepatocellular carcinoma (HCC) is as high as 70%. However, there are no widely accepted adjuvant therapies; therefore, no treatment has been recommended by guidelines from the American Association for the Study of Liver Disease or the European Association for the Study of the Liver. All the registered trials failed to find any treatment to prolong recurrence-free survival, which is the primary outcome in most studies, including sorafenib. Some investigator-initiated studies revealed that anti-hepatitis B virus agents, interferon-α, transcatheter chemoembolization, chemokine-induced killer cells, and other treatments prolonged patient recurrence-free survival or overall survival after curative therapies. In this review, we summarize the current status of adjuvant treatments for HCC and explain the challenges associated with designing a clinical trial for adjuvant therapy. Promising new treatments being used as adjuvant therapy, especially anti-PD-1 antibodies, are also discussed.
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Key Words
- Adjuvant therapy
- Anti-PD-1 antibody
- CIK, chemokine-induced killer cells
- CR, complete response
- Clinical trial
- HCC, hepatocellular carcinoma
- Hepatocellular carcinoma
- ICI, immune checkpoint inhibitor
- Molecular targeted therapy
- ORR, objective response rate
- OS, overall survival
- PD-1, program death-1
- PD-L1, program death-1 ligand
- PR, partial response
- RCT, randomized clinical trial
- RECIST, Response Evaluation Criteria in Solid Tumors
- RFS, recurrence-free survival
- Recurrence-free survival
- TACE, transcatheter chemoembolization
- TKI, tyrosine kinase inhibitor
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Affiliation(s)
- Xiao-Dong Zhu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Kang-Shuai Li
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Hui-Chuan Sun
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, 200032, China
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Xie DY, Ren ZG, Zhou J, Fan J, Gao Q. 2019 Chinese clinical guidelines for the management of hepatocellular carcinoma: updates and insights. Hepatobiliary Surg Nutr 2020; 9:452-463. [PMID: 32832496 DOI: 10.21037/hbsn-20-480] [Citation(s) in RCA: 324] [Impact Index Per Article: 64.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Importance Approximately half of newly-diagnosed hepatocellular carcinoma (HCC) cases in the world occur in China, with hepatitis B virus (HBV) infection being the predominant risk factor. Recently, the guidelines for the management of Chinese HCC patients were updated. Objective The past decade has witnessed a great improvement in the management of hepatocellular carcinoma (HCC). This study reviews the recommendations in the 2019 Chinese guidelines and makes comparison with the practices from the Western world. Evidence Review The updated recommendations on the surveillance, diagnosis, and treatment algorithm of HCC in the 2019 Chinese guidelines were summarized, and comparisons among the updated Chinese guidelines, the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD) guidelines were made. Findings Besides imaging and pathological diagnoses, novel biomarkers like the seven-micro-RNA panel are advocated for early diagnoses and therapeutic efficacy evaluation in the updated Chinese guidelines. The China liver cancer (CNLC) staging system, proposed in the 2017 guidelines, continues to be the standard model for patient classification, with subsequent modifications and updates being made in treatment allocations. Compared to the Barcelona Clinic Liver Cancer (BCLC) system, the CNLC staging system employs resection, transplantation, and transarterial chemoembolization (TACE) for more progressed HCC. TACE in combination with other regional therapies like ablation or with systemic therapies like sorafenib are also encouraged in select patients in China. The systemic treatments for HCC have evolved considerably since lenvatinib, regorafenib, carbozantinib, ramucirumab and immune checkpoint inhibitors (ICIs)were first prescribed as first-line or second-line agents. Conclusions and Relevances Novel biomarkers, imaging and operative techniques are recommended in the updated Chinese guideline. More aggressive treatment modalities are suggested for more progressed HBV-related HCC in China.
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Affiliation(s)
- Di-Yang Xie
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Zheng-Gang Ren
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Jian Zhou
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China.,Institute of Biomedical Sciences, Fudan University, Shanghai, China
| | - Jia Fan
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China.,Institute of Biomedical Sciences, Fudan University, Shanghai, China
| | - Qiang Gao
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
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39
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Ou Q, Yu Y, Li A, Chen J, Yu T, Xu X, Xie X, Chen Y, Lin D, Zeng Q, Zhang Y, Tang X, Yao H, Luo B. Association of survival and genomic mutation signature with immunotherapy in patients with hepatocellular carcinoma. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:230. [PMID: 32309377 PMCID: PMC7154492 DOI: 10.21037/atm.2020.01.32] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Accepted: 12/20/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND Current guidelines lack recommendations for the use of immunotherapy and immune-related biomarkers for hepatocellular carcinoma (HCC). We aim to provide reliable evidence of the association of survival with HCC immunotherapy and to demonstrate that genomic mutation signature could be an effective biomarker to predict immunotherapy efficacy of HCC patients. METHODS We conducted a meta-analysis of 17 randomized trials with 2055 patients and an individual patient-level analysis of 31 patients. Trial data were identified in PubMed, EMBASE and Cochrane Central library, and individual patient data were obtained from the cBioPortal database. Overall survival (OS) and progression-free survival (PFS) were assessed with the hazard ratio (HR) and 95% CI. This study is registered with PROSPERO, number CRD42018083991. RESULTS The meta-analysis showed that compared to conventional therapy, immunotherapy resulted in prolonged OS (HR =0.65, P<0.0001, high quality) and PFS (HR =0.81, P<0.0001, high quality); the benefits were observed for cellular immunotherapy, tumor vaccine, and cytokine immunotherapy. Findings were robust to subgroup and trial sequential analyses. In the individual patient-level analysis of patients treated with immune checkpoint inhibitor, mutations in TERT, CTNNB1, BRD4, or MLL, and co-mutations in TP53 and TERT or BRD4 were associated with significantly worse survival. These oncogenes were used to develop a novel integrated mutation risk score, which exhibited better utility in predicting survival than the tumor mutation burden (TMB). Patients with low- versus high- mutation risk score had longer OS (HR =0.18, P=0.02) and PFS (HR =0.33, P=0.018). A nomogram comprising the mutation risk score and essential clinical factors further improved the predictive accuracy (AUC =0.840 for both 1- and 2-year OS). CONCLUSIONS Immunotherapy showed longer OS and PFS than conventional therapy among HCC patients, especially patients with a low mutation risk score. The nomogram based on genomic and clinical characteristics is effective in predicting survival of HCC patients undergoing immune checkpoint inhibitor.
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Affiliation(s)
- Qiyun Ou
- Department of Ultrasound in Medicine, Department of Oncology and Phase I Clinical Trial Centre, Breast Tumor Centre, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Yunfang Yu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Oncology and Phase I Clinical Trial Centre, Breast Tumor Centre, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Anlin Li
- Guangdong Medical University, Zhanjiang 524000, China
| | - Jie Chen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Oncology and Phase I Clinical Trial Centre, Breast Tumor Centre, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Tingting Yu
- Meizhou Academy of Medical Science, Meizhou Hospital Affiliated of Sun Yat-sen University, Meizhou 514031, China
| | - Xiaolin Xu
- Department of Ultrasound in Medicine, Department of Oncology and Phase I Clinical Trial Centre, Breast Tumor Centre, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Xinxin Xie
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Oncology and Phase I Clinical Trial Centre, Breast Tumor Centre, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Yongjian Chen
- Department of Medical Oncology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Dagui Lin
- Department of Colorectal Surgery, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China
| | - Qiaohong Zeng
- Meizhou Academy of Medical Science, Meizhou Hospital Affiliated of Sun Yat-sen University, Meizhou 514031, China
| | - Yuxin Zhang
- The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China
| | - Xudong Tang
- Guangdong Medical University, Zhanjiang 524000, China
| | - Herui Yao
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Oncology and Phase I Clinical Trial Centre, Breast Tumor Centre, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Baoming Luo
- Department of Ultrasound in Medicine, Department of Oncology and Phase I Clinical Trial Centre, Breast Tumor Centre, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
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40
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Feng AL, Zhu JK, Yang Y, Wang YD, Liu FY, Zhu M, Liu CZ. Repeated postoperative adjuvant TACE after curative hepatectomy improves outcomes of patients with HCC. MINIM INVASIV THER 2019; 30:163-168. [PMID: 31880482 DOI: 10.1080/13645706.2019.1707689] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS To gain a clear picture of the influence of postoperative adjuvant transcatheter arterial chemoembolization (TACE) on recurrence after curative resection for HCC. MATERIAL AND METHODS According to the inclusion criteria and the exclusion criteria, the clinical data of 118 patients with HCC at Qilu Hospital, Shan Dong University between January 2011 and August 2013, who were treated by curative hepatectomy and postoperative TACE (two groups of patients received TACE once or twice, respectively) or by curative hepatectomy alone were retrospectively studied. RESULTS The three-year survival (RFS) rate was 51.7% for the whole study population. The three-year relapse-free RFS rates were 73.0% and 55.0% for the patients who received two and one postoperative adjuvant TACE treatments, groups respectively, and 29.3% for the hepatectomy alone group. The three-year RFS of the patients who received postoperative adjuvant TACE once was significantly higher than that of the patients who received hepatectomy alone (p = .024). And the outcome of patients with two adjuvant TACE treatments was better than that of patients who received one treatment (p = .033). CONCLUSIONS Repeated postoperative adjuvant TACE seems to be a promising treatment for HCC that might delay tumor recurrence and improve the RFS rates of patients after curative hepatectomy.
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Affiliation(s)
- A Lei Feng
- Department of Oncology, Shandong Provincial Hospital affiliated to Shandong University, Shangdong, PR China
| | - Jian Kang Zhu
- Department of General Surgery, Qilu Hospital of Shan Dong University, Jinan, PR China.,Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, PR China
| | - Yupeng Yang
- Department of General Surgery, Zhangqiu District Hospital of traditional Chinese Medicine, Jinan, PR China
| | - Ya Dong Wang
- Department of General Surgery, Qilu Hospital of Shan Dong University, Jinan, PR China
| | - Feng Yue Liu
- Department of General Surgery, Qilu Hospital of Shan Dong University, Jinan, PR China
| | - Min Zhu
- Department of General Surgery, Qilu Hospital of Shan Dong University, Jinan, PR China
| | - Chong Zhong Liu
- Department of General Surgery, Qilu Hospital of Shan Dong University, Jinan, PR China
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Lu SD, Li L, Liang XM, Chen W, Chen FL, Fan LL, Ahir BK, Zhang WG, Zhong JH. Updates and advancements in the management of hepatocellular carcinoma patients after hepatectomy. Expert Rev Gastroenterol Hepatol 2019; 13:1077-1088. [PMID: 31648568 DOI: 10.1080/17474124.2019.1684898] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Accepted: 10/21/2019] [Indexed: 02/07/2023]
Abstract
Introduction: The 5-year recurrence rate of hepatocellular carcinoma (HCC) after hepatic resection or local ablation is up to 70%. Adjuvant therapies to prevent HCC recurrence have been reported but are not currently recommended by EASL or AASLD guidelines. This review examined evidence from randomized controlled trials, meta-analyses and systematic reviews on the safety and efficacy of adjuvant therapies and chemotherapies in HCC patients after resection or local ablation.Areas covered: PubMed was searched through 15 June 2019. Available evidence was assessed based on the GRADE system.Expert commentary: Transarterial chemoembolization is the best adjuvant therapy for HCC patients at high risk of recurrence, antiviral therapy with nucleoside analogs is effective for preventing recurrence of HBV-related HCC, and interferon-α is effective for preventing recurrence of HCV-related HCC. Further studies are needed to clarify the efficacy of adjuvant immune checkpoint inhibitors. Adjuvant sorafenib appears to offer negligible clinical benefit and high risk of adverse effects.
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Affiliation(s)
- Shi-Dong Lu
- Department of Hepatobiliary Surgery, the Third Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Lin Li
- Department of Hepatobiliary Surgery, the Third Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xin-Min Liang
- Grade 2016, Basic medical college of Guangxi Medical University, Nanning, China
| | - Wu Chen
- Grade 2016, Basic medical college of Guangxi Medical University, Nanning, China
| | - Fu-Li Chen
- Grade 2016, Basic medical college of Guangxi Medical University, Nanning, China
| | - Lang-Lin Fan
- Grade 2016, Basic medical college of Guangxi Medical University, Nanning, China
| | - Bhavesh K Ahir
- Section of Hematology and Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Wan-Guang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jian-Hong Zhong
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
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Liu TH, Shao YY, Lu LC, Shen YC, Hsu C, Lin ZZ, Hsu CH, Cheng AL. Considerations of heterogeneity in clinical trials for hepatocellular carcinoma. Expert Rev Gastroenterol Hepatol 2019; 13:615-621. [PMID: 31132887 DOI: 10.1080/17474124.2019.1621165] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Introduction: Clinical trials in hepatocellular carcinoma (HCC) exhibit a high degree of heterogeneity. These heterogeneities may lead to unexpected results among clinical trials. Area covered: In this review, we address the heterogeneity noted in early phase HCC trials, trials involving transarterial chemoembolization, and advanced HCC trials. Furthermore, we discuss possible methods to attenuate the detrimental effects of heterogeneity when conducting clinical trials. Expert opinion: Clinical trials in HCC exhibit an inherently high degree of heterogeneity because of various reasons: tumor heterogeneity, different cirrhotic backgrounds, various etiologies of cirrhosis, and geographical differences in practice and expertise. Such heterogeneity may cause imbalance among the enrolled patient population, premature withdrawal from the clinical trial, and variable response to the treatment. In addition, methodological heterogeneity also exists in designing trial protocol and response evaluation. All these factors may eventually lead to conflicting results among clinical trials. Accounting for these heterogeneities is important to foster the success of future trials. In recent years, significant progress with molecular targeted agents and immune checkpoint inhibitors was made in advanced HCC. These new agents are also being tested in clinical trials involving earlier stage HCC and will also face the challenge of these issues.
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Affiliation(s)
- Tsung-Hao Liu
- a Department of Internal Medicine , National Taiwan University Hospital Hsin-Chu Branch , Hsinchu , Taiwan.,b Department of Oncology , National Taiwan University Hospital , Taipei , Taiwan.,d Graduate Institute of Oncology , National Taiwan University College of Medicine , Taipei , Taiwan
| | - Yu-Yun Shao
- b Department of Oncology , National Taiwan University Hospital , Taipei , Taiwan.,d Graduate Institute of Oncology , National Taiwan University College of Medicine , Taipei , Taiwan.,e Department of Medical Oncology , National Taiwan University Cancer Center , Taipei , Taiwan
| | - Li-Chun Lu
- b Department of Oncology , National Taiwan University Hospital , Taipei , Taiwan.,d Graduate Institute of Oncology , National Taiwan University College of Medicine , Taipei , Taiwan.,e Department of Medical Oncology , National Taiwan University Cancer Center , Taipei , Taiwan
| | - Ying-Chun Shen
- b Department of Oncology , National Taiwan University Hospital , Taipei , Taiwan.,d Graduate Institute of Oncology , National Taiwan University College of Medicine , Taipei , Taiwan
| | - Chiun Hsu
- b Department of Oncology , National Taiwan University Hospital , Taipei , Taiwan.,d Graduate Institute of Oncology , National Taiwan University College of Medicine , Taipei , Taiwan
| | - Zhong-Zhe Lin
- b Department of Oncology , National Taiwan University Hospital , Taipei , Taiwan.,d Graduate Institute of Oncology , National Taiwan University College of Medicine , Taipei , Taiwan.,e Department of Medical Oncology , National Taiwan University Cancer Center , Taipei , Taiwan
| | - Chih-Hung Hsu
- b Department of Oncology , National Taiwan University Hospital , Taipei , Taiwan.,d Graduate Institute of Oncology , National Taiwan University College of Medicine , Taipei , Taiwan.,e Department of Medical Oncology , National Taiwan University Cancer Center , Taipei , Taiwan
| | - Ann-Lii Cheng
- b Department of Oncology , National Taiwan University Hospital , Taipei , Taiwan.,c Department of Internal Medicine , National Taiwan University Hospital , Taipei , Taiwan.,d Graduate Institute of Oncology , National Taiwan University College of Medicine , Taipei , Taiwan.,e Department of Medical Oncology , National Taiwan University Cancer Center , Taipei , Taiwan
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Ng KK, Cheung TT, Pang HH, Wong TC, Dai JW, Ma KW, She WH, Kotewall CN, Lo CM. A simplified prediction model for early intrahepatic recurrence after hepatectomy for patients with unilobar hepatocellular carcinoma without macroscopic vascular invasion: An implication for adjuvant therapy and postoperative surveillance. Surg Oncol 2019; 30:6-12. [PMID: 31500787 DOI: 10.1016/j.suronc.2019.05.017] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 05/03/2019] [Accepted: 05/18/2019] [Indexed: 01/27/2023]
Abstract
BACKGROUND An accurate prediction model of early recurrence of hepatocellular carcinoma (HCC) after hepatectomy is important to ascertain the postoperative adjuvant treatment and surveillance. METHODS This is a retrospective cohort study including 1125 patients with HCC underwent curative hepatic resection. They were randomly divided into training (n = 562) and validation (n = 563) sets. Early intrahepatic recurrence within 18 months from surgery is the primary outcome. In the training set, a prediction scoring model (Recurrent Liver Cancer Score RLCS) was developed, which was legitimised in the validation set. RESULTS RLCS was developed based on four clinicopathologic risk factors (serum alpha fetoprotein, tumor size, multiple tumors or satellite nodules, and microvascular invasion). Low-risk and high-risk groups had statistically significant differences in early recurrence rates (18% vs. 43.8%). The 5-year recurrence-free survival rates of low risk and high risk groups were 52.9% and 27.8%, respectively. This model showed good calibration and discriminatory ability in the validation set (c-index of 0.647). CONCLUSION RLCS is a user-friendly prediction scoring model which can accurately predict the occurrence of early intrahepatic recurrence of HCC. It establishes the basis of postoperative adjuvant treatment and surveillance in future studies.
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Affiliation(s)
- Kelvin K Ng
- Department of Surgery, The University of Hong Kong, Hong Kong.
| | - Tan-To Cheung
- Department of Surgery, The University of Hong Kong, Hong Kong; State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong
| | - Herbert H Pang
- School of Public Health, The University of Hong Kong, Hong Kong
| | - Tiffany C Wong
- Department of Surgery, The University of Hong Kong, Hong Kong; State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong
| | - Jeff W Dai
- Department of Surgery, The University of Hong Kong, Hong Kong
| | - Ka-Wing Ma
- Department of Surgery, The University of Hong Kong, Hong Kong
| | - Wong-Hoi She
- Department of Surgery, The University of Hong Kong, Hong Kong
| | | | - Chung-Mau Lo
- Department of Surgery, The University of Hong Kong, Hong Kong; State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong
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Abstract
Cancer immunotherapy has shown impressive clinical results in the last decade, improving both solid and hematologic cancer patients' overall survival. Nevertheless, most of the molecular aspects underlying the response to this approach are still under investigation. miRNAs in particular have been described as regulators of a plethora of different immunologic processes and thus have the potential to be key in the future developments of immunotherapy. In this review, we summarize and discuss the emerging role of miRNAs in the diagnosis and therapeutics of the four principal cancer immunotherapy approaches: immune checkpoint blockade, adoptive cell therapy, cancer vaccines, and cytokine therapy. In particular, this review is focused on potential roles for miRNAs to be adjuvants in soluble factor- and cell-based therapies, with the aim of helping to increase specificity and decrease toxicity, and on the potential for rationally identified miRNA-based diagnostic approaches to aid in precision clinical immunooncology.
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Nagaoki Y, Imamura M, Nishida Y, Daijo K, Teraoka Y, Honda F, Nakamura Y, Morio K, Fujino H, Nakahara T, Kawaoka T, Tsuge M, Hiramatsu A, Kawakami Y, Miki D, Hiyama Y, Ochi H, Chayama K, Aikata H. The impact of interferon-free direct-acting antivirals on clinical outcome after curative treatment for hepatitis C virus-associated hepatocellular carcinoma: Comparison with interferon-based therapy. J Med Virol 2019; 91:650-658. [PMID: 30381831 DOI: 10.1002/jmv.25352] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 10/23/2018] [Indexed: 01/04/2025]
Abstract
BACKGROUND AND AIM To examine the effect on recurrence and survival of treatment by interferon (IFN)-free direct-acting antivirals (DAA) for patients with hepatitis C virus (HCV)-associated hepatocellular carcinoma (HCC) who underwent primary curative treatment. METHODS This was a retrospective cohort study of 250 patients with HCV who had received curative treatment for primary HCC. As anti-HCV treatment after HCC treatment, 38 patients received IFN-free DAA therapy (DAA patients) and 94 received IFN-based therapy (IFN patients). The recurrence of HCC and overall survival of the patient groups were compared in a case-control study. RESULTS The cumulative HCC recurrence rates at 1, 3, and 5 years were 5%, 39%, and 39% for DAA patients and 0%, 46%, and 62% for IFN patients, respectively (P = 0.370). Multivariate analysis of the HCC recurrence identified treatment responses (sustained virological response [SVR]: hazard ratio [HR] 2.237; P = 0.003) as an independent predictive factor. The cumulative overall survival rates at 3 and 5 years were 96%, 96% for DAA patients and 93%, 73% for IFN patients, respectively ( P = 0.163). Multivariate analysis identified treatment responses (SVR: HR 8.742; P < 0.001) as independent predictors of overall survival. Propensity score matching analysis showed no significant difference in HCC development rates and overall survival rates in the two groups. CONCLUSIONS We found that SVR obtained after curative treatment for primary HCC suppressed recurrence and improved overall survival. And, IFN-free DAA therapy after curative treatment for primary HCC could predict improving overall survival and suppressed HCC recurrence.
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Affiliation(s)
- Yuko Nagaoki
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Yuno Nishida
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kana Daijo
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yuji Teraoka
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Fumi Honda
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yuki Nakamura
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kei Morio
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hatsue Fujino
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Masataka Tsuge
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
- Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan
| | - Akira Hiramatsu
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Yoshiiku Kawakami
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Daiki Miki
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
- Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, Hiroshima, Japan
| | - Yuichi Hiyama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University
| | - Hidenori Ochi
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
- Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
- Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, Hiroshima, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
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Zhang N, Wang LR, Li DD, Ma DN, Wang CH, He XG, Gao DM, Wang L, Tang ZY. Interferon-α Combined With Herbal Compound "Songyou Yin" Effectively Inhibits the Increased Invasiveness and Metastasis by Insufficient Radiofrequency Ablation of Hepatocellular Carcinoma in an Animal Model. Integr Cancer Ther 2018; 17:1260-1269. [PMID: 30234394 PMCID: PMC6247542 DOI: 10.1177/1534735418801525] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Objective: We had previously proved that insufficient radiofrequency
ablation (RFA) could enhance invasiveness and metastasis of hepatocellular
carcinoma (HCC) through epithelial-mesenchymal transition (EMT), which is
mediated by activating β-catenin signaling. Thus, the aim of the present study
was to demonstrate whether the combined treatment of interferon-α (IFN-α) and
“Songyou Yin” (SYY) minimizes the pro-metastatic effects of insufficient RFA, as
well as to explore its underlying mechanism. Methods: Insufficient
RFA was performed in an orthotopic nude mice model of HCCLM3 with high
metastatic potential. The effects of IFN-α, SYY, and combined IFN-α and SYY were
observed in the animal model. Tumor sizes, lung metastasis, and survival time
were assessed. Immunochemistry staining, real-time polymerase chain reaction,
and Western blot were used to examine gene expression related to metastasis and
angiogenesis in residual cancer after insufficient RFA. Results:
For up to 8 weeks of treatment, the combined therapy significantly decreased the
residual cancer sizes, minimized the lung metastasis rate, and prolonged the
survival time of nude mice, which might be due to suppression of the EMT via
β-catenin signal blockade, in addition to attenuating angiogenesis in residual
cancer after insufficient RFA. Conclusion: IFN-α combined with SYY
significantly weakened the enhanced metastatic potential of residual cancer
after insufficient RFA by attenuating EMT, which is mediated through inhibiting
activation of β-catenin. In addition, decreasing angiogenesis of residual cancer
might also play a certain role.
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Affiliation(s)
- Ning Zhang
- 1 Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China.,2 Zhongshan Hospital, Liver Cancer Institute, Fudan University, Shanghai, People's Republic of China
| | - Long-Rong Wang
- 1 Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China
| | - Dou-Dou Li
- 1 Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China
| | - De-Ning Ma
- 3 Zhejiang Cancer Hospital, Hangzhou, Zhejiang, People's Republic of China
| | - Cheng-Hao Wang
- 1 Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China.,2 Zhongshan Hospital, Liver Cancer Institute, Fudan University, Shanghai, People's Republic of China
| | - Xi-Gan He
- 1 Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China
| | - Dong-Mei Gao
- 2 Zhongshan Hospital, Liver Cancer Institute, Fudan University, Shanghai, People's Republic of China
| | - Lu Wang
- 1 Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China
| | - Zhao-You Tang
- 2 Zhongshan Hospital, Liver Cancer Institute, Fudan University, Shanghai, People's Republic of China
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47
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Zhou J, Sun HC, Wang Z, Cong WM, Wang JH, Zeng MS, Yang JM, Bie P, Liu LX, Wen TF, Han GH, Wang MQ, Liu RB, Lu LG, Ren ZG, Chen MS, Zeng ZC, Liang P, Liang CH, Chen M, Yan FH, Wang WP, Ji Y, Cheng WW, Dai CL, Jia WD, Li YM, Li YX, Liang J, Liu TS, Lv GY, Mao YL, Ren WX, Shi HC, Wang WT, Wang XY, Xing BC, Xu JM, Yang JY, Yang YF, Ye SL, Yin ZY, Zhang BH, Zhang SJ, Zhou WP, Zhu JY, Liu R, Shi YH, Xiao YS, Dai Z, Teng GJ, Cai JQ, Wang WL, Dong JH, Li Q, Shen F, Qin SK, Fan J. Guidelines for Diagnosis and Treatment of Primary Liver Cancer in China (2017 Edition). Liver Cancer 2018; 7:235-260. [PMID: 30319983 PMCID: PMC6167671 DOI: 10.1159/000488035] [Citation(s) in RCA: 441] [Impact Index Per Article: 63.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Accepted: 02/24/2018] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) (about 85-90% of primary liver cancer) is particularly prevalent in China because of the high prevalence of chronic hepatitis B infection. HCC is the fourth most common malignancy and the third leading cause of tumor-related deaths in China. It poses a significant threat to the life and health of Chinese people. SUMMARY This guideline presents official recommendations of the National Health and Family Planning Commission of the People's Republic of China on the surveillance, diagnosis, staging, and treatment of HCC occurring in China. The guideline was written by more than 50 experts in the field of HCC in China (including liver surgeons, medical oncologists, hepatologists, interventional radiologists, and diagnostic radiologists) on the basis of recent evidence and expert opinions, balance of benefits and harms, cost-benefit strategies, and other clinical considerations. KEY MESSAGES The guideline presents the Chinese staging system, and recommendations regarding patients with HCC in China to ensure optimum patient outcomes.
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Affiliation(s)
- Jian Zhou
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, China
| | - Hui-Chuan Sun
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, China
| | - Zheng Wang
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, China
| | - Wen-Ming Cong
- Department of Pathology, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Jian-Hua Wang
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Meng-Su Zeng
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jia-Mei Yang
- Department of Hepatic Surgery, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Ping Bie
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Lian-Xin Liu
- Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Tian-Fu Wen
- Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Guo-Hong Han
- Department of Liver Diseases and Digestive Interventional Radiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Mao-Qiang Wang
- Department of Interventional Radiology, Chinese PLA General Hospital, Beijing, China
| | - Rui-Bao Liu
- Department of Interventional Radiology, the Tumor Hospital of Harbin Medical University, Harbin, China
| | - Li-Gong Lu
- Department of Interventional Oncology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Zheng-Gang Ren
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, China
| | - Min-Shan Chen
- Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Zhao-Chong Zeng
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ping Liang
- Department of Interventional Ultrasound, Chinese PLA General Hospital, Beijing, China
| | - Chang-Hong Liang
- Department of Radiology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Min Chen
- Editorial Department of Chinese Journal of Digestive Surgery, Chongqing, China
| | - Fu-Hua Yan
- Department of Radiology, Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Wen-Ping Wang
- Department of Ultrasound, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yuan Ji
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wen-Wu Cheng
- Department of integrated treatment, Tumor Hospital of Fudan University, Shanghai, China
| | - Chao-Liu Dai
- Department of Hepatobiliary and Spleenary Surgery, the Affiliated Shengjing Hospital, China Medical University, Shenyang, China
| | - Wei-Dong Jia
- Department of Hepatic Surgery, Affiliated Provincial Hospital, Anhui Medical University, Hefei, China
| | - Ya-Ming Li
- Department of Nuclear Medicine, the First Hospital of China Medical University, Shenyang, China
| | - Ye-Xiong Li
- Department of Radiation Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jun Liang
- Department of Oncology, Peking University International Hospital, Beijing, China
| | - Tian-Shu Liu
- Department of Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Guo-Yue Lv
- Department of General Surgery, the First Hospital of Jilin University, Jilin, China
| | - Yi-Lei Mao
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC and Chinese Academy of Medical Sciences, Beijing, China
| | - Wei-Xin Ren
- Department of Interventional Radiology, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Hong-Cheng Shi
- Department of Nuclear Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wen-Tao Wang
- Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Xiao-Ying Wang
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, China
| | - Bao-Cai Xing
- Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital and Institute, Beijing, China
| | - Jian-Ming Xu
- Department of Gastrointestinal Oncology, Affiliated Hospital Cancer Center, Academy of Military Medical Sciences, Beijing, China
| | - Jian-Yong Yang
- Department of Interventional Oncology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ye-Fa Yang
- Department of Hepatic Surgery and Interventional Radiology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Sheng-Long Ye
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, China
| | - Zheng-Yu Yin
- Department of Hepatobiliary Surgery, Zhongshan Hospital of Xiamen University, Xiamen, China
| | - Bo-Heng Zhang
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, China
| | - Shui-Jun Zhang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Wei-Ping Zhou
- Department of Hepatic Surgery, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Ji-Ye Zhu
- Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing, China
| | - Rong Liu
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ying-Hong Shi
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, China
| | - Yong-Sheng Xiao
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, China
| | - Zhi Dai
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, China
| | - Gao-Jun Teng
- Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China
| | - Jian-Qiang Cai
- Department of Abdominal Surgical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wei-Lin Wang
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jia-Hong Dong
- Department of Hepatobiliary and Pancreas Surgery, Beijing Tsinghua Changgung Hospital (BTCH), School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Qiang Li
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Feng Shen
- Department of Hepatic Surgery, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Shu-Kui Qin
- Department of Medical Oncology, PLA Cancer Center, Nanjing Bayi Hospital, Nanjing, China,**Dr. Shu-Kui Qin, Department of Medical Oncology, PLA Cancer Center, Nanjing Bayi Hospital, Nanjing 210002 (China), E-Mail
| | - Jia Fan
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, China,*Dr. Jia Fan, Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032 (China), E-Mail
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Wen T, Jin C, Facciorusso A, Donadon M, Han HS, Mao Y, Dai C, Cheng S, Zhang B, Peng B, Du S, Jia C, Xu F, Shi J, Sun J, Zhu P, Nara S, Millis JM. Multidisciplinary management of recurrent and metastatic hepatocellular carcinoma after resection: an international expert consensus. Hepatobiliary Surg Nutr 2018; 7:353-371. [PMID: 30498711 DOI: 10.21037/hbsn.2018.08.01] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Hepatocellular carcinoma (HCC) is the sixth-most common cancer and the third leading cause of cancer-related death in the world. However, 40-70% patients eventually suffer from postoperative recurrence within 5 years. HCC recurrence after surgery severely affects prognosis of the patients. Nevertheless, there is an opportunity to improve patients' prognosis if doctors and researchers can recognize the importance of a standardized perioperative management and study it in clinical and pre-clinical settings. Hence, based on our own experience and published studies from other researchers, we develop this consensus regarding multidisciplinary management of locally recurrent and metastatic hepatocellular carcinoma after resection. This consensus consists of the entire course of recurrent hepatocellular carcinoma (RHCC) management, including prediction of recurrence, prevention, diagnosis, treatment and surveillance of RHCC. Consensus recommendations are presented with grades of evidences (Ia, Ib, IIa, IIb, III and IV), and strength of recommendations (A, B, C, D and E). We also develop a decision-making path for RHCC treatment, which can intuitively demonstrate the management for RHCC. It is hoped that we may make some effort to standardize the management of RHCC and ultimately understand how to improve outcomes.
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Affiliation(s)
- Tianfu Wen
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Chen Jin
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Antonio Facciorusso
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Matteo Donadon
- Department of Hepatobiliary & General Surgery, Humanitas University, Humanitas Clinical and Research Center, Milan, Italy
| | - Ho-Seong Han
- Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Yilei Mao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Chaoliu Dai
- Department of Hepatobiliary and Splenic Surgery, Shengjing Hospital, China Medical University, Shenyang 110000, China
| | - Shuqun Cheng
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200433, China
| | - Bixiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Baogang Peng
- Department of Liver Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
| | - Shunda Du
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Changjun Jia
- Department of Hepatobiliary and Splenic Surgery, Shengjing Hospital, China Medical University, Shenyang 110000, China
| | - Feng Xu
- Department of Hepatobiliary and Splenic Surgery, Shengjing Hospital, China Medical University, Shenyang 110000, China
| | - Jie Shi
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200433, China
| | - Juxian Sun
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200433, China
| | - Peng Zhu
- Hepatic Surgery Center, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Satoshi Nara
- Hepatobiliary and Pancreatic Surgery Division, National Cancer Center Hospital, Tokyo, Japan
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49
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Lee WY, Bachtiar M, Choo CCS, Lee CG. Comprehensive review of Hepatitis B Virus-associated hepatocellular carcinoma research through text mining and big data analytics. Biol Rev Camb Philos Soc 2018; 94:353-367. [PMID: 30105774 DOI: 10.1111/brv.12457] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 07/19/2018] [Accepted: 07/24/2018] [Indexed: 02/06/2023]
Abstract
PubMed was text mined to glean insights into the role of Hepatitis B virus (HBV) in hepatocellular carcinoma (HCC) from the massive number of publications (9249) available to date. Reports from ∼70 countries identified >1300 human genes associated with either the Core, Surface or X gene in HBV-associated HCC. One hundred and forty-three of these host genes, which can potentially yield 1180 biomolecular interactions, each were reported in at least three different publications to be associated with the same HBV. These 143 genes function in 137 pathways, involved mainly in the cell cycle, apoptosis, inflammation and signalling. Fourteen of these molecules, primarily transcriptional regulators or kinases, play roles in several pathways pertinent to the hallmarks of cancers. 'Chronic' was the most frequent word used across the 9249 abstracts. A key event in chronic HBV infection is the integration of HBV into the host genome. The advent of cost-effective, next-generation sequencing technology facilitated the employment of big-data analytics comprehensively to characterize HBV-host integration within HCC patients. A total of 5331 integration events were reported across seven publications, with most of these integrations observed between the Core/X gene and the introns of genes. Nearly one-quarter of the intergenic integrations are within repeats, especially long interspersed nuclear elements (LINE) repeats. Integrations within 13 genes were each reported by at least three different studies. The human gene with the most HBV integrations observed is the TERT gene where a total of 224 integrations, primarily at its promoter and within the tumour tissue, were reported by six of seven publications. This unique review, which employs state-of-the-art text-mining and data-analytics tools, represents the most complete, systematic and comprehensive review of nearly all the publications associated with HBV-associated HCC research. It provides important resources to either focus future research or develop therapeutic strategies to target key molecules reported to play important roles in key pathways of HCC, through the systematic analyses of the commonly reported molecules associated with the various HBV genes in HCC, including information about the interactions amongst these commonly reported molecules, the pathways in which they reside as well as detailed information regarding the viral and host genes associated with HBV integration in HCC patients. Hence this review, which highlights pathways and key human genes associated with HBV in HCC, may facilitate the deeper elucidation of the role of HBV in hepato-carcinogenesis, potentially leading to timely intervention against this deadly disease.
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Affiliation(s)
- Wai Yeow Lee
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119077, Singapore.,NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, 119077, Singapore
| | - Maulana Bachtiar
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119077, Singapore.,Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore
| | - Cheryl C S Choo
- NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, 119077, Singapore.,Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore
| | - Caroline G Lee
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119077, Singapore.,NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, 119077, Singapore.,Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore.,Duke-National University of Singapore Graduate Medical School, Singapore, 169547, Singapore
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50
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Wu J, Yin Z, Cao L, Xu X, Yan T, Liu C, Li D. Adjuvant pegylated interferon therapy improves the survival outcomes in patients with hepatitis-related hepatocellular carcinoma after curative treatment: A meta-analysis. Medicine (Baltimore) 2018; 97:e11295. [PMID: 29995763 PMCID: PMC6076097 DOI: 10.1097/md.0000000000011295] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2017] [Accepted: 05/28/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most common cancers and the second leading cause of cancer-related deaths in men worldwide. Surgical resection of HCC remains the mainstay treatment procedure. As a result of hepatitis viral infection, the postoperative survival outcome in patients with HCC is not satisfactory. Recently, studies have reported that due to its treatment effect on hepatitis infection, pegylated interferon (Peg-IFN)-based therapy could improve the survival outcome after the treatment of hepatitis-related HCC. However, the postoperative effect of this regimen on the survival outcomes in patients with hepatitis-related HCC remains debatable. The present study conducted a meta-analysis to evaluate the effects of adjuvant Peg-IFN-based therapy on the survival outcomes in patients with hepatitis-related HCC after the curative treatment. METHODS A systematic search was conducted to identify studies on the survival outcomes in patients with hepatitis-related HCC after a curative treatment with adjuvant Peg-IFN. PubMed, EmBase, and Cochrane Library databases were searched until September 20, 2017. The retrieved studies were independently assessed by 2 reviewers, to identify the potentially eligible studies and extract data of interest. STATA software (Version 10.0, STATA Corporation, College Station, Texas) software was used for all statistical analyses. RESULTS The pooled results showed that adjuvant Peg-IFN-based therapy improved the 3- and 5-year recurrence-free survival (RFS) rates of patients with hepatitis-related HCC (3-year RFS, HR = 0.80; 95% CI: 0.64-0.99, P = .04; P = .81 for heterogeneity; 5-year RFS, HR = 0.82; 95% CI: 0.67-0.99, P = .04; P = .84 for heterogeneity). For the 5-year overall survival (OS) outcomes of Peg-IFN therapy for hepatitis-related HCC after the curative treatment, the pooled results showed a significant difference between the 2 groups (HR = 0.67; 95% CI: 0.47-0.97, P = .03; P = .99 for heterogeneity). CONCLUSIONS Adjuvant Peg-IFN-based therapy could improve the RFS and OS outcomes in patients after curative treatment of hepatitis-related HCC, with no severe adverse effects.
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Affiliation(s)
- Jiansong Wu
- Department of Infection Disease, General Hospital of the PLA Rocket Force
| | - Zhiwei Yin
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Disease
| | - Liuxia Cao
- Department of Infection Disease, General Hospital of the PLA Rocket Force
| | - Xiaodan Xu
- Department of Infection Disease, General Hospital of the PLA Rocket Force
| | - Tao Yan
- Department of Hepatobiliary Surgery, General Hospital of the PLA Rocket Force
| | - Changting Liu
- Nanlou Respiratory Diseases Department, Chinese PLA General Hospital, Beijing, China
| | - Diangeng Li
- Nanlou Respiratory Diseases Department, Chinese PLA General Hospital, Beijing, China
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