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Nabi P, Rammohan A, Rela M. Living Donor Liver Transplantation for Hepatocellular Carcinoma. J Clin Exp Hepatol 2024; 14:101933. [PMID: 39183736 PMCID: PMC11342762 DOI: 10.1016/j.jceh.2024.101933] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Accepted: 07/06/2024] [Indexed: 08/27/2024] Open
Abstract
Liver transplantation (LT) offers the best chance of cure for patients with hepatocellular carcinoma (HCC), as it addresses simultaneously the underlying disease and the tumour. The Milan criteria has been the standard for over 3 decades in selecting patients with HCC who will benefit from LT. While, early studies showed higher recurrence rates for HCC following living donor LT (LDLT), recent series, especially in the past decade have shown LDLT to have equal oncological outcomes as compared to deceased donor LT (DDLT) for HCC, even in patients beyond Milan criteria. Further, the intention to treat analysis data suggests that LDLT may actually provide a survival advantage. In the west, factors such as improved outcomes on par with DDLT, ability to time the LT etc., have led to a steadily increased number of LDLTs being performed for this indication. On the other hand, in the east, given its geo-socio-cultural idiosyncrasies, LDLT has always been the predominant form of LT for HCC, consequently resulting in an increased number of LDLTs being performed for this indication across the world. While LDLT in HCC has its distinctive advantages compared to DDLT, the double equipoise of balancing the donor risk with the recipient outcomes has to be considered while selecting patients for LDLT. There have been several advances including the application of downstaging therapies and the use of biological markers, which have further helped improve outcomes of LDLT for this indication. This review aims to provide an update on the current advances in the field of transplant oncology related to the practice of LDLT in HCC.
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Affiliation(s)
- Prithiviraj Nabi
- The Institute of Liver Disease & Transplantation, Dr. Rela Institute & Medical Centre, Bharath Institute of Higher Education & Research, Chennai, India
| | - Ashwin Rammohan
- The Institute of Liver Disease & Transplantation, Dr. Rela Institute & Medical Centre, Bharath Institute of Higher Education & Research, Chennai, India
| | - Mohamed Rela
- The Institute of Liver Disease & Transplantation, Dr. Rela Institute & Medical Centre, Bharath Institute of Higher Education & Research, Chennai, India
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Batı IB, Tüysüz U. Outcomes of liver transplantation for hepatocelluler carcinoma from living donor versus deceased donor within University of Southern California San Francisco criteria: a report from Turkey. Front Oncol 2024; 14:1419740. [PMID: 39281373 PMCID: PMC11393828 DOI: 10.3389/fonc.2024.1419740] [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: 04/18/2024] [Accepted: 07/22/2024] [Indexed: 09/18/2024] Open
Abstract
Background Hepatocellular cancer (HCC) is the most common primary liver cancer with increasing incidence. Liver transplantation (LT) has been accepted as main curative liver cancer treatment. The effectiveness of LDLT as opposed to Deceased Donor Liver Transplant (DDLT) for patients with HCC is still controversial. There is limited data comparing the long-term outcomes of patients undergoing LDLT or DDLT for HCCs that do not meet the Milan criteria. Methods We aimed to compare the perioperative and survival outcomes of LDLT with DDLT in HCC patients.Patients underwent LT between January 2012 and December 2020 were retrospectively analyzed. There were 137 patients who met the UCSF criteria. Of these, 75 patients received LDLT and 62 patients DDLT.The primary end points in the present study were oncologic outcomes such as the recurrence rate, disease-free survival (DFS) and overall survival (OS) of LDLT and DDLT in patients with HCC. Results PET-CT SUVmax value, the amount of erythrocyte solution (ES) as blood transfusion of red cells given and the tumor recurrence rate were significantly higher among the deceased patients recurrence, ES, PET-CT SUVmax value and tumor differentiation had significant effects on survival. In the multivariate reduced model, cox regression analysis showed significant effects of recurrence, ES, locoregional treatment response and PET-CT on survival.Albeit not significant, the one-year recurrence rate in the LDLT was similar to that in the DDLT, three- and five-year recurrence rates were higher in DDLT compared to LDLT. Conclusion There is less chance of cold ischemia time and better-quality grafts with minimal fatty changes, lower recurrence rates and similar survival rates can be achieved in LDLT compared to DDLT.
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Affiliation(s)
- Imam Bakır Batı
- Department of Liver Transplant Surgery, Faculty of Medicine, Acıbadem University, Istanbul, Türkiye
| | - Umut Tüysüz
- Department of Liver Transplant Surgery, Şişli Etfal Hamidiye Training and Research Hospital, Istanbul, Türkiye
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Kim DG, Hwang S, Lee KW, Kim JM, You YK, Choi D, Ryu JH, Kim BW, Kim DS, Cho JY, Nah YW, Ju MK, Kim TS, Lee JG, Kim MS, Parente A, Kim KH, Schlegel A, Choi SJN, Joo DJ. Small graft size and hepatocellular carcinoma outcomes in living donor liver transplantation: a retrospective multicentric cohort study. Int J Surg 2024; 110:4859-4866. [PMID: 38701521 PMCID: PMC11325899 DOI: 10.1097/js9.0000000000001532] [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: 02/22/2024] [Accepted: 04/15/2024] [Indexed: 05/05/2024]
Abstract
INTRODUCTION This study examined associations between the graft-to-recipient weight ratio (GRWR) for adult-to-adult living donor liver transplantation (LDLT) and hepatocellular carcinoma (HCC) outcomes. MATERIALS AND METHODS Data from patients in the Korean Organ Transplantation Registry who underwent LDLT for HCC from 2014 to 2021 were retrospectively reviewed. Patients were categorized using the cutoff GRWR for HCC recurrence determined by an adjusted cubic spline (GRWR <0.7% vs. GRWR ≥0.7%). Recurrence-free survival (RFS) and HCC recurrence were analyzed in the entire and a 1:5 propensity-matched cohort. RESULTS The eligible cohort consisted of 2005 LDLT recipients [GRWR <0.7 ( n =59) vs. GRWR ≥0.7 ( n =1946)]. In the entire cohort, 5-year RFS was significantly lower in the GRWR <0.7 than in the GRWR ≥0.7 group (66.7% vs. 76.7%, P =0.019), although HCC recurrence was not different between groups (77.1% vs. 80.7%, P =0.234). This trend was similar in the matched cohort ( P =0.014 for RFS and P =0.096 for HCC recurrence). In multivariable analyses, GRWR <0.7 was an independent risk factor for RFS [adjusted hazard ratio (aHR) 1.89, P =0.012], but the result was marginal for HCC recurrence (aHR 1.61, P =0.066). In the pretransplant tumor burden subgroup analysis, GRWR <0.7 was a significant risk factor for both RFS and HCC recurrence only for tumors exceeding the Milan criteria (aHR 3.10, P <0.001 for RFS; aHR 2.92, P =0.003 for HCC recurrence) or with MoRAL scores in the fourth quartile (aHR 3.33, P <0.001 for RFS; aHR 2.61, P =0.019 for HCC recurrence). CONCLUSIONS A GRWR <0.7 potentially leads to lower RFS and higher HCC recurrence after LDLT when the pretransplant tumor burden is high.
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Affiliation(s)
- Deok-Gie Kim
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine
| | - Shin Hwang
- Department of Surgery, College of Medicine University of Ulsan, Asan Medical Center
| | - Kwang-Woong Lee
- Department of Surgery, Seoul National University College of Medicine
| | - Jong Man Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine
| | - Young Kyoung You
- Department of Surgery, College of Medicine, The Catholic University of Korea
| | - Donglak Choi
- Department of Surgery, Catholic University of Daegu
| | - Je Ho Ryu
- Department of Surgery, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Pusan
| | - Bong-Wan Kim
- Department of Hepato-Biliary-Pancreatic Surgery, Ajou University School of Medicine, Suwon
| | - Dong-Sik Kim
- Division of HBP Surgery and Liver Transplantation, Department of Surgery, University College of Medicine
| | - Jai Young Cho
- Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam
| | - Yang Won Nah
- Department of Surgery, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan
| | - Man ki Ju
- Departmentof Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul
| | - Tae-Seok Kim
- Department of Surgery, Dongsan Medical Center, Keimyung University School of Medicine, Daegu
| | - Jae Geun Lee
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine
| | - Myoung Soo Kim
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine
| | - Alessandro Parente
- Department of Surgery, College of Medicine University of Ulsan, Asan Medical Center
| | - Ki-Hun Kim
- Department of Surgery, College of Medicine University of Ulsan, Asan Medical Center
| | - Andrea Schlegel
- Transplantation Center, Department of Surgery, Digestive Disease Institute, Cleveland Clinic, Ohio, USA
| | - Soo Jin Na Choi
- Department of Surgery, Chonnam National University Medical School, Chonnam National University Hospital, Gwangju, South Korea
| | - Dong Jin Joo
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine
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Zhu M, Li Y, Liu D, Gong Z. Partial Hepatectomy Promotes the Development of KRASG12V-Induced Hepatocellular Carcinoma in Zebrafish. Cancers (Basel) 2024; 16:1793. [PMID: 38791872 PMCID: PMC11119731 DOI: 10.3390/cancers16101793] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 04/30/2024] [Accepted: 05/04/2024] [Indexed: 05/26/2024] Open
Abstract
The purpose of this study was to investigate the effects of PH on the development of oncogenic krasG12V-induced HCC in zebrafish. The inducible HCC model in Tg(fabp10a:rtTA2s-M2; TRE2:EGFP-krasG12V) zebrafish was used. PH or sham surgery was performed before the induction of oncogenic krasG12V expression in the livers of transgenic zebrafish. Histological analysis was carried out to determine the progression of HCC and other HCC-associated features including hepatocyte proliferation, extracellular matrix production, and local oxidative stress. The similarity between the process of PH-induced liver regeneration and that of krasG12V-induced HCC development was further compared by RNA-Seq analysis. The results show that PH promotes the development of krasG12V-induced HCC in zebrafish possibly through enhancing neutrophil-mediated oxidative stress and promoting the upregulation of s100a1, and the downregulation of ribosome biogenesis.
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Affiliation(s)
- Mingkai Zhu
- Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore; (M.Z.); (Y.L.)
- School of Life Science, Southern University of Science and Technology, Shenzhen 518055, China
| | - Yan Li
- Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore; (M.Z.); (Y.L.)
| | - Dong Liu
- School of Life Science, Southern University of Science and Technology, Shenzhen 518055, China
| | - Zhiyuan Gong
- Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore; (M.Z.); (Y.L.)
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YAN X, Shi JH, Xue JF, Guo WZ, Li B, Zhang SJ. PD-1/PD-L1 inhibition promotes hepatic regeneration in small-for-size liver following extended hepatectomy. Cytokine 2022; 159:156017. [DOI: 10.1016/j.cyto.2022.156017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 08/12/2022] [Accepted: 08/22/2022] [Indexed: 11/09/2022]
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Cheng N, Shi JH, Jin Y, Shi YB, Liu XD, Zhang HP, Cao SL, Yang H, Guo WZ, Zhang SJ. Pharmacological Activating Transcription Factor 6 Activation Is Beneficial for Liver Retrieval With ex vivo Normothermic Mechanical Perfusion From Cardiac Dead Donor Rats. Front Surg 2021; 8:665260. [PMID: 34222317 PMCID: PMC8249577 DOI: 10.3389/fsurg.2021.665260] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Accepted: 05/24/2021] [Indexed: 01/17/2023] Open
Abstract
Background: Normothermic machine perfusion (NMP) could be beneficial for organ retrieval from donors after cardiac death (DCD). Activating transcription factor 6 (ATF6) was recently shown to mitigate liver ischemia/reperfusion injury and confer protection. The aims of this study were to assess the implication of ATF6 in liver retrieval from DCD rat livers with NMP and explore the effect of pharmacologic ATF-6 activation on liver retrieval. Methods: The livers from DCD rats were exposed to 30 min of warm ischemia and 8 h cold preservation followed by 2 h NMP with or without an ATF6 activator in the perfusate. Perfusates and livers were harvested to detect ATF6 expression, liver function, and inflammation. Results: DCD livers with NMP were associated with ATF6 overexpression and activation based on IHC and WB (P < 0.05). The ATF6 activator downregulated perfusate aminotransferases, decreased the Suzuki score, downregulated CD68 and MPO based on IHC, induced the expression of cytochrome c in mitochondria and inhibited the expression of cytochrome c in cytoplasm based on WB, reduced TNFα and IL-6 levels based on ELISA, decreased levels of MDA, GSSG and ATP, and increased SOD activity and GSH levels in the perfused livers (P < 0.05). Conclusion: ATF6 is important for liver retrieval, and an exogenous ATF6 activator accelerates liver retrieval from DCD rats in an ex vivo NMP model.
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Affiliation(s)
- Nuo Cheng
- Department of Hepatobiliary and Pancreatic Surgery, Zhengzhou Key Laboratory for HPB Diseases and Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Ji-Hua Shi
- Department of Hepatobiliary and Pancreatic Surgery, Zhengzhou Key Laboratory for HPB Diseases and Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Yang Jin
- Department of Hepatobiliary and Pancreatic Surgery, Zhengzhou Key Laboratory for HPB Diseases and Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Yuan-Bin Shi
- Department of Hepatobiliary and Pancreatic Surgery, Zhengzhou Key Laboratory for HPB Diseases and Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Xu-Dong Liu
- Department of Hepatobiliary and Pancreatic Surgery, Zhengzhou Key Laboratory for HPB Diseases and Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Hua-Peng Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Zhengzhou Key Laboratory for HPB Diseases and Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Sheng-Li Cao
- Department of Hepatobiliary and Pancreatic Surgery, Zhengzhou Key Laboratory for HPB Diseases and Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Han Yang
- Department of Hepatobiliary and Pancreatic Surgery, Zhengzhou Key Laboratory for HPB Diseases and Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Wen-Zhi Guo
- Department of Hepatobiliary and Pancreatic Surgery, Zhengzhou Key Laboratory for HPB Diseases and Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Shui-Jun Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Zhengzhou Key Laboratory for HPB Diseases and Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
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Doğan SM, Kutlutürk K. Living Donor Versus Deceased Donor Liver Transplantation for HCC. J Gastrointest Cancer 2021; 51:1104-1106. [PMID: 32833221 DOI: 10.1007/s12029-020-00481-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
INTRODUCTION Liver transplantation is the definitive treatment modality of the patients having an end-stage liver disease with hepatocellular carcinoma. DISCUSSION The number of living donor liver transplantations has been increased because of the deceased donor organ shortage, especially in Asian countries. CONCLUSION Reports of different clinics about the postoperative course and tumor recurrence rates comparing living donor versus deceased donor liver transplantations, besides patient selection criteria, are reviewed along with our clinic's experiences.
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Affiliation(s)
- Sait Murat Doğan
- Department of Surgery and Liver Transplantation Institute, İnönü University Faculty of Medicine, Elazığ yolu 10.km, 44280, Malatya, Turkey.
| | - Koray Kutlutürk
- Department of Surgery and Liver Transplantation Institute, İnönü University Faculty of Medicine, Elazığ yolu 10.km, 44280, Malatya, Turkey
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Kim JM, Chung YJ, Kim S, Rhu J, Choi GS, Joh JW. Impact of Graft Weight Change During Perfusion on Hepatocellular Carcinoma Recurrence After Living Donor Liver Transplantation. Front Oncol 2021; 10:609844. [PMID: 33718110 PMCID: PMC7945034 DOI: 10.3389/fonc.2020.609844] [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: 09/24/2020] [Accepted: 12/04/2020] [Indexed: 11/28/2022] Open
Abstract
BACKGROUNDS Inadequate liver volume and weight is a major source of morbidity and mortality after adult living donor liver transplantation (LDLT). The purpose of our study was to investigate HCC recurrence, graft failure, and patient survival according to change in right liver graft weight after histidine-tryptophan-ketoglutarate (HTK) solution perfusion in LDLT. METHODS Two hundred twenty-eight patients underwent LDLT between 2013 and 2017. We calculated the change in graft weight by subtracting pre-perfusion graft weight from post-perfusion graft weight. Patients with increased graft weight were defined as the positive group, and patients with decreased graft weight were defined as the negative group. RESULTS After excluding patients who did not meet study criteria, 148 patients underwent right or extended right hepatectomy. The negative group included 89 patients (60.1%), and the positive group included 59 patients (39.9%). Median graft weight change was -28 g (range; -132-0 g) in the negative group and 21 g (range; 1-63 g) in the positive group (P<0.001). Median hospitalization time was longer for the positive group than the negative group (27 days vs. 23 days; P=0.048). There were no statistical differences in tumor characteristics, postoperative complications, early allograft dysfunction, or acute rejection between the two groups. Disease-free survival, death-censored graft survival, and patient survival were lower in the positive group than the negative group. Additionally, the positive group showed strong association with HCC recurrence, death-censored graft survival, and patient survival in multivariate analysis. CONCLUSION This study suggests that positive graft weight change during HTK solution perfusion indicates poor prognosis in LDLT.
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Lee S, Song GW, Kim KW, Kwon JH, Lee SG. Living Donor Liver Transplantation Versus Deceased Donor Liver Transplantation for Hepatocellular Carcinoma Within or Beyond the Milan Criteria: Comparable Long-Term Outcomes. Transplant Proc 2020; 53:92-97. [PMID: 33288309 DOI: 10.1016/j.transproceed.2020.10.012] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Revised: 09/27/2020] [Accepted: 10/20/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND The long-term outcomes after living donor liver transplantation (LDLT) vs deceased donor liver transplantation (DDLT) for hepatocellular carcinoma (HCC) remain controversial. We compared the long-term outcomes between LDLT and DDLT in patients with HCCs within or beyond the Milan criteria. METHODS This retrospective study included 896 patients who underwent liver transplantation (829 LDLTs and 67 DDLTs) for HCC from June 2005 to May 2015. Recurrence-free survival (RFS) and overall survival (OS) were estimated using the Kaplan-Meier method with log-rank test. RESULTS RFS at 1, 3, 5, and 10 years after LDLT was 89.6%, 84.6%, 82.4%, and 79.6%, respectively, and, after DDLT, was 92.4%, 86.2%, 82.4%, and 82.4%, respectively, and OS at 1, 3, 5, and 10 years after LDLT was 96.1%, 88.1%, 85.6%, and 82.7%, respectively, and, after DDLT, was 97.0%, 83.6%, 82.1%, and 77.3%, respectively, with no significant differences in RFS (P = .838) or OS (P = .293) between groups. No statistically significant differences after LDLT or DDLT were identified in RFS (89.8% vs 98.1%, respectively, at 5 years; P = .053) or OS (90.4% vs 90.6% , respectively, at 5 years; P = .583) for HCCs meeting the Milan criteria as well as for those beyond the Milan criteria (RFS, 37.8% vs 28.6%, respectively, at 5 years; P = .560 and OS, 57.3% vs 50.0%, respectively, at 5 years; P = .743). CONCLUSIONS Patients who underwent LDLT for HCCs showed comparable long-term outcomes to patients who underwent DDLT. Patients with HCCs within the Milan criteria demonstrated acceptable long-term outcomes after both LDLT and DDLT.
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Affiliation(s)
- Sunyoung Lee
- Department of Radiology and Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Gi-Won Song
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
| | - Kyoung Won Kim
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
| | - Jae Hyun Kwon
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Sung-Gyu Lee
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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Weidle UH, Schmid D, Birzele F, Brinkmann U. MicroRNAs Involved in Metastasis of Hepatocellular Carcinoma: Target Candidates, Functionality and Efficacy in Animal Models and Prognostic Relevance. Cancer Genomics Proteomics 2020; 17:1-21. [PMID: 31882547 PMCID: PMC6937123 DOI: 10.21873/cgp.20163] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 10/31/2019] [Accepted: 11/04/2019] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is responsible for the second-leading cancer-related death toll worldwide. Although sorafenib and levantinib as frontline therapy and regorafenib, cabazantinib and ramicurimab have now been approved for second-line therapy, the therapeutic benefit is in the range of only a few months with respect to prolongation of survival. Aggressiveness of HCC is mediated by metastasis. Intrahepatic metastases and distant metastasis to the lungs, lymph nodes, bones, omentum, adrenal gland and brain have been observed. Therefore, the identification of metastasis-related new targets and treatment modalities is of paramount importance. In this review, we focus on metastasis-related microRNAs (miRs) as therapeutic targets for HCC. We describe miRs which mediate or repress HCC metastasis in mouse xenograft models. We discuss 18 metastasis-promoting miRs and 35 metastasis-inhibiting miRs according to the criteria as outlined. Six of the metastasis-promoting miRs (miR-29a, -219-5p, -331-3p, 425-5p, -487a and -1247-3p) are associated with unfavourable clinical prognosis. Another set of six down-regulated miRs (miR-101, -129-3p, -137, -149, -503, and -630) correlate with a worse clinical prognosis. We discuss the corresponding metastasis-related targets as well as their potential as therapeutic modalities for treatment of HCC-related metastasis. A subset of up-regulated miRs -29a, -219-5p and -425-5p and down-regulated miRs -129-3p and -630 were evaluated in orthotopic metastasis-related models which are suitable to mimic HCC-related metastasis. Those miRNAs may represent prioritized targets emerging from our survey.
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Affiliation(s)
- Ulrich H Weidle
- Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany
| | - Daniela Schmid
- Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany
| | - Fabian Birzele
- Pharmaceutical Sciences, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, Basel, Switzerland
| | - Ulrich Brinkmann
- Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany
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Nakano T, Chen IH, Wang CC, Chen PJ, Tseng HP, Huang KT, Hu TH, Li LC, Goto S, Cheng YF, Lin CC, Chen CL. Circulating exosomal miR-92b: Its role for cancer immunoediting and clinical value for prediction of posttransplant hepatocellular carcinoma recurrence. Am J Transplant 2019; 19:3250-3262. [PMID: 31162867 DOI: 10.1111/ajt.15490] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Revised: 05/08/2019] [Accepted: 05/11/2019] [Indexed: 01/25/2023]
Abstract
A recurrence of hepatocellular carcinoma (HCC) after living donor liver transplantation (LDLT) is one of the major concerns reflecting the higher mortality of HCC. This study aimed to explore the impact of circulating exosomes on HCC development and recurrence. One-shot transfusion of hepatoma serum to naïve rats induced liver cancer development with gradual elevation of alpha-fetoprotein (AFP), but exosome-free hepatoma serum failed to induce AFP elevation. The microarray analysis revealed miR-92b as one of the highly expressing microribonucleic acids in hepatoma serum exosomes. Overexpression of miR-92b enhanced the migration ability of liver cancer cell lines with active release of exosomal miR-92b. The hepatoma-derived exosomal miR-92b transferred to natural killer (NK) cells, resulting in the downregulation of CD69 and NK cell-mediated cytotoxicity. Furthermore, higher expression of miR-92b in serum exosomes was confirmed in HCC patients before LDLT, and its value at 1 month after LDLT was maintained at a higher level in the patients with posttransplant HCC recurrence. In summary, we demonstrated the impact of circulating exosomes on liver cancer development, partly through the suppression of CD69 on NK cells by hepatoma-derived exosomal miR-92b. The value of circulating exosomal miR-92b may predict the risk of posttransplant HCC recurrence.
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Affiliation(s)
- Toshiaki Nakano
- Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Liver Transplantation Center and Division of General Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - I-Hsuan Chen
- Liver Transplantation Center and Division of General Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Chih-Chi Wang
- Liver Transplantation Center and Division of General Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Po-Jung Chen
- Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Hui-Peng Tseng
- Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Kuang-Tzu Huang
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Tsung-Hui Hu
- Liver Transplantation Center and Division of Hepato-Gastroenterology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Lung-Chih Li
- Liver Transplantation Center and Division of Nephrology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Shigeru Goto
- Liver Transplantation Center and Division of General Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.,Nobeoka Medical Check Center, Fukuoka Institution of Occupational Health, Nobeoka, Miyazaki, Japan.,Faculty of Nursing, Department of Nursing, Josai International University, Togane, Chiba, Japan
| | - Yu-Fan Cheng
- Liver Transplantation Center and Department of Diagnostic Radiology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Chih-Che Lin
- Liver Transplantation Center and Division of General Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Chao-Long Chen
- Liver Transplantation Center and Division of General Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
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12
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Yi PS, Shu Y, Bi WX, Zheng XB, Feng WJ, He LY, Li JS. Emerging role of zinc finger protein A20 as a suppressor of hepatocellular carcinoma. J Cell Physiol 2019; 234:21479-21484. [PMID: 31134613 DOI: 10.1002/jcp.28877] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 05/04/2019] [Accepted: 05/07/2019] [Indexed: 12/15/2022]
Abstract
Hepatocellular carcinoma (HCC), the third leading cause of cancer-associated mortality worldwide, is a major public health problem. Zinc finger protein A20 (A20), an acute phase response gene, is a potent inhibitor of NF-κB signaling. A20 serves a critical role in liver protection, including limiting inflammation following hepatic injury, stimulating hepatocyte growth, and preventing hepatic ischemia-reperfusion injury. A20 is also involved in different processes, including tumorigenesis, progression, and metastasis through multiple mechanisms. Accumulated studies have reported the clinical implications and biological relevance of A20 in the development and progression of HCC. The underlying mechanisms of A20 in HCC include inhibition of epithelial-mesenchymal transition, protein tyrosine kinase 2 activation and Rac family GTPase 1 activity. Combining liver protection with tumor inhibition is a unique advantage of A20, which has the potential to be a novel treatment for promoting liver regeneration following liver resection in patients with HCC with liver cirrhosis. This review discusses the hepato-protective effect of A20 on hepatocytes and its potential role in cancer development, particularly its suppressor effect on HCC.
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Affiliation(s)
- Peng Sheng Yi
- Department of Hepato-biliary-pancrease and Center of Severe Acute Pancreatitis of Northeast Sichuan, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, P. R. China
| | - Yan Shu
- Department of Hepato-biliary-pancrease and Center of Severe Acute Pancreatitis of Northeast Sichuan, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, P. R. China
| | - Wang Xiu Bi
- Department of Hepato-biliary-pancrease and Center of Severe Acute Pancreatitis of Northeast Sichuan, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, P. R. China
| | - Xiao Bo Zheng
- Department of Liver Surgery and Transplantation, Affiliated Hospital of Sichuan University, P. R. China
| | - Wan Jing Feng
- Department of Liver Surgery and Transplantation, Affiliated Hospital of Sichuan University, P. R. China
| | - Lin Ye He
- Department of Liver Surgery and Transplantation, Affiliated Hospital of Sichuan University, P. R. China
| | - Jian Shui Li
- Department of Hepato-biliary-pancrease and Center of Severe Acute Pancreatitis of Northeast Sichuan, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, P. R. China
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13
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Long-term Outcomes and Risk Factors After Adult Living Donor Liver Transplantation. Transplantation 2019; 102:e382-e391. [PMID: 29912047 DOI: 10.1097/tp.0000000000002324] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Although risk factors for the long-term mortality of liver transplantation are well described, there is a lack of detailed study regarding these factors for adult living donor liver transplantation (LDLT). METHODS We retrospectively analyzed 528 adult LDLT recipients in our hospital. The risk factors were analyzed for overall deaths more than 5 years post-LDLT. RESULTS Over the 20-year follow-up, 137 patients died. Patient survival at 1, 3, 5, and 10 years post-LDLT was 87.8%, 81.8%, 79.4%, and 72.8%, respectively. The independent risk factors for more than 5 years post-LDLT overall death were hepatocellular carcinoma recurrence (hazard ratio [HR], 38.9; P < 0.001), lymphoid de novo malignancy (HR, 47.2; P = 0.001), primary sclerosing cholangitis as primary diagnosis (HR, 11.5; P < 0.001), chronic rejection (HR, 6.93; P = 0.006), acute rejection (HR, 2.96; P = 0.017), and bile duct stenosis (HR, 2.30; P = 0.045). CONCLUSIONS Not only malignancies and rejection but also bile duct stenosis and primary sclerosing cholangitis had significant impacts on late period post-LDLT mortality.
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Ouyang G, Liu J, Wang P, Ren Y, Yi P, Zhou Q, Chen J, Xiang B, Zhang Y, Zhang Z, Li L. Multiple factors affect the regeneration of liver. ACTA ACUST UNITED AC 2019; 64:791-798. [PMID: 30672999 DOI: 10.1590/1806-9282.64.09.791] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Accepted: 01/20/2018] [Indexed: 11/21/2022]
Abstract
OBJECTIVE To study factors affecting the liver regeneration after hepatectomy. METHODS With 3D reconstitution technology, liver regeneration ability of 117 patients was analysed, and relative factors were studied. RESULTS There was no statistically difference between the volume of simulated liver resection and the actual liver resection. All livers had different degrees of regeneration after surgery. Age, gender and blood indicators had no impact on liver regeneration, while surgery time, intraoperative blood loss, blood flow blocking time and different ways of liver resection had a significant impact on liver regeneration; In addition, the patients' own pathological status, including, hepatitis and liver fibrosis all had a significant impact on liver regeneration. CONCLUSION 3D reconstitution model is a good model to calculate liver volume. Age, gender, blood indicators and biochemistry indicators have no impact on liver regeneration, but surgery indicators and patients' own pathological status have influence on liver regeneration.
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Affiliation(s)
- Gaoxiong Ouyang
- . Department of Hepatobiliary Surgery, Affiliated Cancer Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Jianyong Liu
- . Department of Hepatobiliary Surgery, Affiliated Cancer Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Peng Wang
- . Department of Radiology, Affiliated Cancer Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Yuan Ren
- . Department of Hepatobiliary Surgery, Affiliated Cancer Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Ping Yi
- . Department of Hepatobiliary Surgery, Affiliated Cancer Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Quan Zhou
- . Department of Hepatobiliary Surgery, Affiliated Cancer Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Jun Chen
- . Department of Pathology, Affiliated Cancer Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Bangde Xiang
- . Department of Hepatobiliary Surgery, Affiliated Cancer Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Yumei Zhang
- . Department of Hepatobiliary Surgery, Affiliated Cancer Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Zhiming Zhang
- . Department of Hepatobiliary Surgery, Affiliated Cancer Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Lequn Li
- . Department of Hepatobiliary Surgery, Affiliated Cancer Hospital of Guangxi Medical University, Nanning, Guangxi, China
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15
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Zhu B, Wang J, Li H, Chen X, Zeng Y. Living or deceased organ donors in liver transplantation for hepatocellular carcinoma: a systematic review and meta-analysis. HPB (Oxford) 2019; 21:133-147. [PMID: 30503300 DOI: 10.1016/j.hpb.2018.11.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 10/18/2018] [Accepted: 11/02/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND The outcomes of living donor liver transplantation (LDLT) versus deceased donor liver transplantation (DDLT) for HCC patients were not well defined and it was necessary to reassess. METHODS A comprehensive literature search was conducted in PubMed, Embase, Cochrane Library, Google Scholar and WanFang database for eligible studies. Perioperative and survival outcomes of HCC patients underwent LDLT were pooled and compared to those underwent DDLT. RESULTS Twenty-nine studies with 5376 HCC patients were included. For HCC patients underwent LDLT and DDLT, there were comparable rates of overall survival (OS) (1-year, RR = 1.04, 95%CI = 1.00-1.09, P = 0.03; 3-year, RR = 1.03, 95%CI = 0.96-1.11, P = 0.39; 5-year, RR = 1.04, 95%CI = 0.95-1.13, P = 0.43), disease free survival (DFS) (1-year, RR = 1.00, 95%CI = 0.95-1.05, P = 0.99; 3-year, RR = 1.00, 95%CI = 0.94-1.08, P = 0.89; 5-year, RR = 1.01, 95%CI = 0.93-1.09, P = 0.85), recurrence (1-year, RR = 1.41, 95%CI = 0.72-2.77, P = 0.32; 3-year, RR = 0.89, 95%CI = 0.57-1.39, P = 0.60; and 5-year, RR = 0.85, 95%CI = 0.56-1.31, P = 0.47), perioperative mortality within 3 months (RR = 0.89, 95%CI = 0.50-1.59, p = 0.70) and postoperative complication (RR = 0.99, 95%CI = 0.70-1.39, P = 0.94). LDLT was associated with better 5-year intention-to-treat patient survival (ITT-OS) than DDLT (RR = 1.11, 95% CI = 1.01-1.22, P = 0.04). CONCLUSION This meta-analysis suggested that LDLT was not inferior to DDLT in consideration of comparable perioperative and survival outcomes. However, in terms of 5-year ITT-OS, LDLT was a possibly better choice for HCC patients.
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Affiliation(s)
- Bo Zhu
- Department of Liver Surgery & Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, 610041, China; Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jinju Wang
- Department of Liver Surgery & Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, 610041, China; Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Hui Li
- Department of Liver Surgery & Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, 610041, China; Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xing Chen
- Department of Liver Surgery & Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, 610041, China; Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yong Zeng
- Department of Liver Surgery & Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, 610041, China; Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China.
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Liu YT, Tseng TC, Soong RS, Peng CY, Cheng YH, Huang SF, Chuang TH, Kao JH, Huang LR. A novel spontaneous hepatocellular carcinoma mouse model for studying T-cell exhaustion in the tumor microenvironment. J Immunother Cancer 2018; 6:144. [PMID: 30526672 PMCID: PMC6286542 DOI: 10.1186/s40425-018-0462-3] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 11/23/2018] [Indexed: 12/15/2022] Open
Abstract
Immunotherapy has ushered in a new era of cancer therapy, and this is also applicable to therapy of hepatocellular carcinoma (HCC). In this context, effective development of therapeutic strategies requires an HCC mouse model with known tumor-associated antigens (TAAs) and an HCC growth reporter. We created such a model using hydrodynamic injection and a transposon system to introduce AKT and NRAS and open reading frames (ORFs) encoding surrogate tumor antigens and luciferase into chromosomes of hepatocytes to induce nodular and diffuse tumors in the liver. TAA-specific CD8+ T cells were detected during HCC progression; however, these showed exhausted-like phenotypes and were unable to control tumor growth. Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAM) from the tumor microenvironment were found to contribute to the suppression of the CD8+ T-cell response. The transposon-based Akt/N-Ras-induced HCC mouse model we developed enables researchers to monitor tumor growth non-invasively and to quantify and characterize endogenous or adoptively transferred TAA-specific CD8+ T-cell responses. These features make it a suitable preclinical model for exploration and evaluation of immune checkpoint inhibitors and cell-based immunotherapies for HCC treatment.
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Affiliation(s)
- Yu-Tzu Liu
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, No.35, Keyan Road, Zhunan Town, Miaoli County, 350, Taiwan
| | - Tai-Chung Tseng
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University, National Taiwan University Hospital, Taipei, Taiwan
| | - Ruey-Shyang Soong
- Department of General Surgery, Chang Gung Memorial Hospital, Keelung, Taiwan.,College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chun-Yi Peng
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, No.35, Keyan Road, Zhunan Town, Miaoli County, 350, Taiwan
| | - Yu-Hsing Cheng
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, No.35, Keyan Road, Zhunan Town, Miaoli County, 350, Taiwan
| | - Shiu-Feng Huang
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, No.35, Keyan Road, Zhunan Town, Miaoli County, 350, Taiwan
| | - Tsung-Hsien Chuang
- Immunology Research Center, National Health Research Institutes, Miaoli, Taiwan
| | - Jia-Horng Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University, National Taiwan University Hospital, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan.,Department of Medical Research, National Taiwan University, National Taiwan University Hospital, Taipei, Taiwan
| | - Li-Rung Huang
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, No.35, Keyan Road, Zhunan Town, Miaoli County, 350, Taiwan. .,Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan.
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17
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Chen J, Wu Y, Zhang L, Fang X, Hu X. Evidence for calpains in cancer metastasis. J Cell Physiol 2018; 234:8233-8240. [PMID: 30370545 DOI: 10.1002/jcp.27649] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 10/02/2018] [Indexed: 02/06/2023]
Abstract
Metastatic dissemination represents the final stage of tumor progression as well as the principal cause of cancer-associated deaths. Calpains are a conserved family of calcium-dependent cysteine proteinases with ubiquitous or tissue-specific expression. Accumulating evidence indicates a central role for calpains in tumor migration and invasion via participating in several key processes, including focal adhesion dynamics, cytoskeletal remodeling, epithelial-to-mesenchymal transition, and apoptosis. Activated after the increased intracellular calcium concentration ( [ Ca 2 + ] i ) induced by membrane channels and extracellular or intracellular stimuli, calpains induce the limited cleavage or functional modulation of various substrates that serve as metastatic mediators. This review covers established literature to summarize the mechanisms and underlying signaling pathways of calpains in cancer metastasis, making calpains attractive targets for aggressive tumor therapies.
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Affiliation(s)
- Jiaxin Chen
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Sir Run Shaw Hospital, Zhejiang University, Hangzhou, China
| | - Yizheng Wu
- Department of Orthopaedic Surgery and Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Sir Run Shaw Hospital, Zhejiang University, Hangzhou, China
| | - Lumin Zhang
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Sir Run Shaw Hospital, Zhejiang University, Hangzhou, China
| | - Xiao Fang
- Department of Anesthesiology and Key Laboratory of Biotherapy of Zhejiang Province, Sir Run Shaw Hospital, Zhejiang University, Hangzhou, China
| | - Xiaotong Hu
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Sir Run Shaw Hospital, Zhejiang University, Hangzhou, China
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18
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Jo HS, Kim DS, Jung SW, Yu YD, Choi SB, Kim WB, Han HJ, Song TJ. Clinical significance of post-hepatectomy hepatic failure in patients with liver metastases from colorectal cancer. Ann Hepatobiliary Pancreat Surg 2018; 22:93-100. [PMID: 29896569 PMCID: PMC5981151 DOI: 10.14701/ahbps.2018.22.2.93] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Revised: 02/04/2018] [Accepted: 02/06/2018] [Indexed: 12/17/2022] Open
Abstract
Backgrounds/Aims This study attempted to identify risk factors for development of post-hepatectomy hepatic failure (PHF) and its effect on long-term survival of patients with liver metastases from colorectal cancer. Methods We carried out a retrospective study of 143 patients who had been diagnosed with liver metastases from colorectal cancer and who had undergone hepatectomy between 2003 and 2010. We allocated these patients to PHF and non-PHF groups, using the definition of the International Study Group of Liver Surgery, and compared the clinical factors of the two groups, using Cox regression and Kaplan-Meier analysis to evaluate the differences in overall survival (OS) and recurrence-free survival (RFS) between these groups. Results The PHF group comprised 19 patients (13.3%); all had Grade A PHF. Independent risk factors for development of PHF were metachronous liver metastases and major hepatectomy. The differences between the PHF and non-PHF groups in OS or RFS were not statistically significant; however, the PHF group tended to have a worse prognosis. Multivariate analysis revealed significant associations between OS and the factors of poor differentiation of the primary colorectal cancer, major hepatectomy, and positive resection margin. Conclusions Major hepatectomy is an important risk factor for PHF in patients with liver metastases from colorectal cancer. The pathological characteristics of the primary tumor are more important as predictors than is Grade A PHF.
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Affiliation(s)
- Hye-Sung Jo
- Division of Hepatobiliary, Pancreas Surgery and Liver Transplantation, Department of Surgery, Korea University College of Medicine, Seoul, Korea
| | - Dong-Sik Kim
- Division of Hepatobiliary, Pancreas Surgery and Liver Transplantation, Department of Surgery, Korea University College of Medicine, Seoul, Korea
| | - Sung-Won Jung
- Division of Hepatobiliary, Pancreas Surgery and Liver Transplantation, Department of Surgery, Korea University College of Medicine, Seoul, Korea
| | - Young-Dong Yu
- Division of Hepatobiliary, Pancreas Surgery and Liver Transplantation, Department of Surgery, Korea University College of Medicine, Seoul, Korea
| | - Sae-Byeol Choi
- Division of Hepatobiliary, Pancreas Surgery and Liver Transplantation, Department of Surgery, Korea University College of Medicine, Seoul, Korea
| | - Wan-Bae Kim
- Division of Hepatobiliary, Pancreas Surgery and Liver Transplantation, Department of Surgery, Korea University College of Medicine, Seoul, Korea
| | - Hyung-Joon Han
- Division of Hepatobiliary, Pancreas Surgery and Liver Transplantation, Department of Surgery, Korea University College of Medicine, Seoul, Korea
| | - Tae-Jin Song
- Division of Hepatobiliary, Pancreas Surgery and Liver Transplantation, Department of Surgery, Korea University College of Medicine, Seoul, Korea
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Abstract
Hepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide. In select patients, surgical treatment in the form of either resection or transplantation offers a curative option. The aims of this review are to (1) review the current American Association for the Study of Liver Diseases/European Association for the Study of the Liver guidelines on the surgical management of HCC and (2) review the proposed changes to these guidelines and analyze the strength of evidence underlying these proposals. Three authors identified the most relevant publications in the literature on liver resection and transplantation for HCC and analyzed the strength of evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) classification. In the United States, the liver allocation system provides priority for liver transplantation to patients with HCC within the Milan criteria. Current evidence suggests that liver transplantation may also be indicated in certain patient groups beyond Milan criteria, such as pediatric patients with large tumor burden or adult patients who are successfully downstaged. Patients with no underlying liver disease may also benefit from liver transplantation if the HCC is unresectable. In patients with no or minimal (compensated) liver disease and solitary HCC ≥2 cm, liver resection is warranted. If liver transplantation is not available or contraindicated, liver resection can be offered to patients with multinodular HCC, provided that the underlying liver disease is not decompensated. Many patients may benefit from surgical strategies adapted to local resources and policies (hepatitis B prevalence, organ availability, etc). Although current low-quality evidence shows better overall survival with aggressive surgical strategies, this approach is limited to select patients. Larger and well-designed prospective studies are needed to better define the benefits and limits of such approach.
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Affiliation(s)
- Daniel Zamora-Valdes
- 1 Divisions of Transplantation Surgery, William J. von Liebig Transplant Center, Mayo Clinic, Rochester, MN, USA
| | - Timucin Taner
- 1 Divisions of Transplantation Surgery, William J. von Liebig Transplant Center, Mayo Clinic, Rochester, MN, USA
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20
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Padickakudy R, Pereyra D, Offensperger F, Jonas P, Oehlberger L, Schwarz C, Haegele S, Assinger A, Brostjan C, Gruenberger T, Starlinger P. Bivalent role of intra-platelet serotonin in liver regeneration and tumor recurrence in humans. J Hepatol 2017; 67:1243-1252. [PMID: 28842294 DOI: 10.1016/j.jhep.2017.08.009] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Revised: 07/16/2017] [Accepted: 08/11/2017] [Indexed: 12/29/2022]
Abstract
BACKGROUND & AIMS Besides its critical role during liver regeneration, serotonin (5-HT) has been found to act as a mitogenic factor in several neoplastic entities. Accordingly, we aimed to evaluate whether intra-platelet 5-HT (IP5-HT) was associated with oncological outcome after liver resection and concomitantly evaluate its ability to serve as a therapeutic target to promote liver regeneration. METHODS A total of 96 patients undergoing liver resection for malignant liver tumors were prospectively included. Optimized plasma and serum preparation were performed and IP5-HT levels were determined. Patients were followed up for postoperative liver dysfunction (LD), morbidity, disease free and overall survival (OS). RESULTS We found increased preoperative IP5-HT levels in patients with disease recurrence at 6 and 12months (p=0.046, p=0.020, respectively). In clear contrast, patients suffering from postoperative morbidity, severe morbidity or LD had significantly reduced IP5-HT levels (p=0.011, p=0.035, p=0.003, respectively). Patients with high IP5-HT levels (>134ng/ml) suffered from an increased incidence of postoperative disease recurrence at 6 and 12months (p=0.045, p=0.006, respectively) but exhibited a reduction in morbidity, severe morbidity, and LD (p=0.006, p=0.008, p=0.005, respectively). We confirmed these results in our two largest subgroups, demonstrating that they were independent of tumor type. This bivalent effect of IP5-HT was also reflected in patients receiving selective serotonin reuptake inhibitor treatment, who displayed a reduction in disease recurrence accompanied by an increase in postoperative morbidity. Yet, both early disease recurrence and morbidity worsened OS. CONCLUSION Herein, we present first clinical evidence for IP5-HT being associated with early disease recurrence after liver resection in humans. Thus, pharmacological intervention at the level of platelets and platelet-derived 5-HT to promote liver regeneration should be considered with caution. A careful definition of indications and timing is needed to promote liver regeneration without inducing deleterious effects. LAY SUMMARY Preoperative intra-platelet serotonin (IP5-HT) levels seem to substantially affect patient outcomes after liver resection for liver tumors. While there is a narrow window of IP5-HT levels where liver regeneration and tumor progression is balanced, excessively high IP5-HT levels (>134ng/ml IP5-HT) lead to an increased incidence of early tumor recurrence and excessively low IP5-HT levels (<73ng/ml IP5-HT) lead to a higher rate of morbidity. Ultimately, overall survival is negatively affected by both postoperative early disease recurrence and morbidity. ClinicalTrials.gov-Identifier: NCT01700231.
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Affiliation(s)
- Robin Padickakudy
- Department of Surgery, Medical University of Vienna, General Hospital, Vienna, Austria
| | - David Pereyra
- Department of Surgery, Medical University of Vienna, General Hospital, Vienna, Austria
| | - Florian Offensperger
- Department of Surgery, Medical University of Vienna, General Hospital, Vienna, Austria
| | - Philipp Jonas
- Department of Surgery I, Rudolfstiftung Hospital, Vienna, Austria
| | - Lukas Oehlberger
- Department of Surgery I, Rudolfstiftung Hospital, Vienna, Austria
| | - Christian Schwarz
- Department of Surgery, Medical University of Vienna, General Hospital, Vienna, Austria
| | - Stefanie Haegele
- Department of Surgery, Medical University of Vienna, General Hospital, Vienna, Austria
| | - Alice Assinger
- Department of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Christine Brostjan
- Department of Surgery, Medical University of Vienna, General Hospital, Vienna, Austria
| | | | - Patrick Starlinger
- Department of Surgery, Medical University of Vienna, General Hospital, Vienna, Austria.
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21
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Shi JH, Hammarström C, Grzyb K, Line PD. Experimental evaluation of liver regeneration patterns and liver function following ALPPS. BJS Open 2017; 1:84-96. [PMID: 29951610 PMCID: PMC5989993 DOI: 10.1002/bjs5.18] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Accepted: 08/04/2017] [Indexed: 12/23/2022] Open
Abstract
Background The underlying mechanism of liver regeneration after Associating Liver Partition and Portal vein ligation (PVL) for Staged hepatectomy (ALPPS) is still unclear. The aim of this study was to evaluate the relationship between future liver remnant (FLR) volume, liver regeneration characteristics and restoration of function in an experimental model of ALPPS. Methods An ALPPS model in rats was developed with selective PVL, parenchymal transection and partial hepatectomy (step 1), followed by resection of the liver (step 2). Three different ALPPS groups with FLR sizes of 30, 20 and 10 per cent of total liver volume were compared with sham‐operated controls and animals undergoing resection of left lateral lobe and 90 per cent PVL with respect to morbidity, mortality, liver regeneration and function. Results Three of 15 animals that had ALPPS with 10 per cent FLR (ALPPS10) died after step 1. Ascites developed in two of five rats that had ALPPS with 20 per cent FLR and in three of four animals in the ALPPS10 group after step 2. Although the relative increments in FLR size and growth rates were highest in the ALPPS groups, small FLR size was associated with a sustained increase in levels of serum aminotransferases and bilirubin, a lower albumin concentration, severe sinusoidal injury, increased expression of proliferation markers and increased activation of hepatic progenitor cells after step 2. Conclusion There is discordance between FLR volume increase and functional restoration after the ALPPS procedure.
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Affiliation(s)
- J H Shi
- Department of Hepatobiliary and Pancreatic Surgery The First Affiliated Hospital of Zhengzhou University, Zhengzhou University Zhengzhou China.,Department of Transplantation Medicine Oslo University Hospital, Rikshospitalet Oslo Norway.,Institute of Surgical Research Oslo University Hospital, Rikshospitalet Oslo Norway
| | - C Hammarström
- Department of Pathology Oslo University Hospital, Rikshospitalet Oslo Norway
| | - K Grzyb
- Department of Pathology Oslo University Hospital, Rikshospitalet Oslo Norway
| | - P D Line
- Department of Transplantation Medicine Oslo University Hospital, Rikshospitalet Oslo Norway.,Institute of Surgical Research Oslo University Hospital, Rikshospitalet Oslo Norway.,Faculty of Medicine Institute of Clinical Medicine, University of Oslo Oslo Norway
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Wang S, Yang FJ, Wang X, Zhou Y, Dai B, Han B, Ma HC, Ding YT, Shi XL. PARP-1 promotes tumor recurrence after warm ischemic liver graft transplantation via neutrophil recruitment and polarization. Oncotarget 2017; 8:88918-88933. [PMID: 29179487 PMCID: PMC5687657 DOI: 10.18632/oncotarget.21493] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Accepted: 08/26/2017] [Indexed: 12/21/2022] Open
Abstract
Poly (ADP-ribose) polymerase 1 (PARP-1) is a crucial contributor to exacerbate ischemia and reperfusion (IR) injury and cancer process. However, there is little research into whether PARP-1 affects the hepatocellular carcinoma (HCC) recurrence after liver transplantation. In this study, we investigated the influence of PARP-1 on hepatic neutrophil mobilizing and phenotype shifting which may lead to HCC recurrence after liver transplantation. We found that rats received the grafts with warm ischemic injury had higher risk of HCC recurrence, which was markedly prevented by pharmacological inhibition of PARP-1 after liver transplantation. In mouse models, the up-regulation of PARP-1 was closely related to the greater tumor burden and increased hepatic susceptibility to recurrence after IR injury. The reason was that high hepatic PARP-1 led to increased liver CXCL1 levels, which in turn promoted recruitment of neutrophils. Both blocking CXCL1/CXCR2 signaling pathway and depleting neutrophils decreased tumor burden. Moreover, these infiltrating neutrophils were programmed to a proangiogenic phenotype under the influence of PARP-1 in vivo after hepatic IR injury. In conclusion, IR-induced PARP-1 up-regulation increased the hepatic recruitment of neutrophils through regulation of CXCL1/CXCR2 signaling and polarized hepatic neutrophils to proangiogenic phenotype, which further promoted HCC recurrence after transplantation.
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Affiliation(s)
- Shuai Wang
- Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China.,Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Fa-Ji Yang
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Xun Wang
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Yuan Zhou
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Bo Dai
- Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China
| | - Bing Han
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Hu-Cheng Ma
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Yi-Tao Ding
- Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China.,Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Xiao-Lei Shi
- Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China.,Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
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Pinheiro RS, Waisberg DR, Nacif LS, Rocha-Santos V, Arantes RM, Ducatti L, Martino RB, Lai Q, Andraus W, D’Albuquerque LAC. Living donor liver transplantation for hepatocellular cancer: an (almost) exclusive Eastern procedure? Transl Gastroenterol Hepatol 2017; 2:68. [PMID: 28905009 PMCID: PMC5590014 DOI: 10.21037/tgh.2017.08.02] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Accepted: 07/21/2017] [Indexed: 01/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most prevalent cancer and it is linked with chronic liver disease. Liver transplantation (LT) is the best curative treatment modality, since it can cure simultaneously the underlying liver disease and HCC. Milan criteria (MC) are the benchmark for selecting patients with HCC for LT, achieving up to 91% 1-year survival post transplantation. However, when considering intention-to-treat (ITT) rates are substantially lower, mainly due dropout. Additionally, Milan criteria (MC) are too restrictive and more inclusive criteria have been reported with good outcomes. Mainly, in Eastern countries, deceased donors are scarce, therefore Asian centers have developed living-donor liver transplantation (LDLT) to a state-of-art status. There are many eastern centers reporting huge numbers of LDLT with outstanding results. Regarding HCC patients, they have reported many criteria including more advanced tumors achieving reasonable outcomes. Western countries have well-established deceased-donor liver transplantation (DDLT) programs. However, organ shortage and restrictive criteria for listing patients with HCC endorses LDLT as a good option to offer curative treatment to more HCC patients. However, there are some controversial reports claiming higher rates of HCC recurrence after LDLT than DDLT. An extensive review included 30 studies with cohorts of HCC patients who underwent LDLT in both East and West countries. We reported also the results of our Institution, in Brazil, where it was performed the first LDLT. This review also addresses the eligibility criteria for transplanting patients with HCC developed in Western and Eastern countries.
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Affiliation(s)
- Rafael S. Pinheiro
- Digestive Organs Transplant Unit, Department of Gastroenterology, University of Sao Paulo School of Medicine, Sao Paulo, Brazil
| | - Daniel R. Waisberg
- Digestive Organs Transplant Unit, Department of Gastroenterology, University of Sao Paulo School of Medicine, Sao Paulo, Brazil
| | - Lucas S. Nacif
- Digestive Organs Transplant Unit, Department of Gastroenterology, University of Sao Paulo School of Medicine, Sao Paulo, Brazil
| | - Vinicius Rocha-Santos
- Digestive Organs Transplant Unit, Department of Gastroenterology, University of Sao Paulo School of Medicine, Sao Paulo, Brazil
| | - Rubens M. Arantes
- Digestive Organs Transplant Unit, Department of Gastroenterology, University of Sao Paulo School of Medicine, Sao Paulo, Brazil
| | - Liliana Ducatti
- Digestive Organs Transplant Unit, Department of Gastroenterology, University of Sao Paulo School of Medicine, Sao Paulo, Brazil
| | - Rodrigo B. Martino
- Digestive Organs Transplant Unit, Department of Gastroenterology, University of Sao Paulo School of Medicine, Sao Paulo, Brazil
| | - Quirino Lai
- Transplant Unit, Department of Surgery, University of L’Aquila, San Salvatore Hospital, L’Aquila, Italy
| | - Wellington Andraus
- Digestive Organs Transplant Unit, Department of Gastroenterology, University of Sao Paulo School of Medicine, Sao Paulo, Brazil
| | - Luiz A. C. D’Albuquerque
- Digestive Organs Transplant Unit, Department of Gastroenterology, University of Sao Paulo School of Medicine, Sao Paulo, Brazil
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24
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Liver transplantation for hepatocellular carcinoma: outcomes and novel surgical approaches. Nat Rev Gastroenterol Hepatol 2017; 14:203-217. [PMID: 28053342 DOI: 10.1038/nrgastro.2016.193] [Citation(s) in RCA: 322] [Impact Index Per Article: 40.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Liver transplantation for hepatocellular carcinoma (HCC) is the best treatment option for patients with early-stage tumours and accounts for ∼20-40% of all liver transplantations performed at most centres worldwide. The Milan criteria are the most common criteria to select patients with HCC for transplantation but they can be seen as too restrictive. Several proposals have been made for a moderate expansion of the criteria, which result in good outcomes but with an increase in the risk of tumour recurrence. In this Review, we provide a comprehensive overview of the outcomes after liver transplantation for HCC, focusing on tumour recurrence in terms of surveillance, prevention and treatment. Additionally, novel surgical techniques have been developed to increase the available pool of organs for liver transplantation (such as living donor liver transplantation, donation after circulatory death and split livers), but the effect of these techniques on patients with HCC is still under debate. Thus, we will describe these techniques and expose the benefits and disadvantages of each surgical approach. Finally, we will comment on the limitations of the current priority policies for liver transplantation and the need to further refine them to better serve the population.
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25
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Zheng X, Chen X, Xu L, Zhang M, Feng L, Yi P, Tang J, Xu M. miR-203 inhibits augmented proliferation and metastasis of hepatocellular carcinoma residual in the promoted regenerating liver. Cancer Sci 2017; 108:338-346. [PMID: 28100026 PMCID: PMC5378262 DOI: 10.1111/cas.13167] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Revised: 12/16/2016] [Accepted: 01/02/2017] [Indexed: 02/05/2023] Open
Abstract
Liver resection is still the most commonly used therapeutic treatment for hepatocellular carcinoma (HCC), and liver regeneration promotes HCC growth in the regenerating liver. The high recurrence/metastasis of HCC is the main cause of death for HCC patients after liver resection. However, how the augmented growth and metastasis of residual HCC induced by the promoted liver regeneration following liver resection can be abolished remains unclear. In this study, a rat model with liver cirrhosis and diffused HCC was established by administration of diethylnitrosamine. Recombinant miR-203 adenovirus was administered to induce hepatic miR-203 overexpression and 30% partial hepatectomy (PH) followed. The effect of miR-203 on the proliferation, invasion and metastasis of the residual HCC in the remnant cirrhotic liver with promoted regeneration was investigated. We found that the basic spontaneous regeneration of the non-tumorous liver by 30% PH promoted proliferation, invasion and lung metastasis of the hepatic residual HCC. miR-203 overexpression further promoted the regeneration of the non-tumorous liver by upregulating Ki67 expression and enhancing IL-6/SOCS3/STAT3 pro-proliferative signals. Importantly, miR-203 overexpression markedly inhibited the proliferation, invasion and metastasis of hepatic residual HCC through suppressing expression of Ki67, CAPNS1 and lung metastasis. Moreover, it was found that miR-203 overexpression reversed the epithelial-mesenchymal transition induced by hepatectomy through targeting IL-1β, Snail1 and Twist1. In conclusion, our results suggested that miR-203 overexpression inhibited the augmented proliferation and lung metastasis of the residual HCC induced by the promoted liver regeneration following PH partly by regulating epithelial-mesenchymal transition.
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Affiliation(s)
- Xiao‐Bo Zheng
- Department of Liver SurgeryWest China HospitalSichuan UniversityChengduChina
| | - Xiao‐Bo Chen
- Department of Liver SurgeryWest China HospitalSichuan UniversityChengduChina
- Department of Hepatobiliary SurgeryThe Affiliated Hospital of Kunming University of Science and Technology (the First People's Hospital of Yunnan Province)KunmingChina
| | - Liang‐Liang Xu
- Department of Liver SurgeryWest China HospitalSichuan UniversityChengduChina
| | - Ming Zhang
- Department of Liver SurgeryWest China HospitalSichuan UniversityChengduChina
| | - Lei Feng
- Department of Liver SurgeryWest China HospitalSichuan UniversityChengduChina
| | - Peng‐Sheng Yi
- Department of Liver SurgeryWest China HospitalSichuan UniversityChengduChina
| | - Jian‐Wei Tang
- Department of Liver SurgeryWest China HospitalSichuan UniversityChengduChina
| | - Ming‐Qing Xu
- Department of Liver SurgeryWest China HospitalSichuan UniversityChengduChina
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26
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Yang PC, Akamatsu N, Hasegawa K, Kokudo N. Twenty years of Milan criteria: how far do we go. Hepatobiliary Surg Nutr 2016; 5:488-491. [PMID: 28124004 PMCID: PMC5218914 DOI: 10.21037/hbsn.2016.12.01] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Accepted: 09/29/2016] [Indexed: 12/12/2022]
Affiliation(s)
- Po-Chih Yang
- Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, National Taiwan University Hospital Hsinchu Branch, Hsinchu, Taiwan
| | - Nobuhisa Akamatsu
- Artificial Organ and Transplantation Surgery Division, Department of Surgery, University of Tokyo, Tokyo, Japan
| | - Kiyoshi Hasegawa
- Artificial Organ and Transplantation Surgery Division, Department of Surgery, University of Tokyo, Tokyo, Japan
| | - Norihiro Kokudo
- Artificial Organ and Transplantation Surgery Division, Department of Surgery, University of Tokyo, Tokyo, Japan
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27
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Chen XB, Zheng XB, Cai ZX, Lin XJ, Xu MQ. MicroRNA-203 promotes liver regeneration after partial hepatectomy in cirrhotic rats. J Surg Res 2016; 211:53-63. [PMID: 28501131 DOI: 10.1016/j.jss.2016.11.043] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Revised: 11/06/2016] [Accepted: 11/23/2016] [Indexed: 02/05/2023]
Abstract
BACKGROUND Liver resection or partial hepatectomy (PH) is still the most commonly used therapeutic option for hepatocellular carcinoma (HCC) at present. However, the impaired regenerative ability induced by the accompanied liver cirrhosis is an important risk factor of posthepatectomy liver failure, and posthepatectomy liver failure is a feared complication that accounts for up to 75% of mortality after extensive liver resection. MicroRNA(miR)-203 is a tumor suppressor of HCC and may act as a positive intermediary in A20-enhanced interleukin (IL-6)/signal transducer and activator of transcription 3 (STAT3) pro-proliferative signals, which may promote liver regeneration after PH. However, its direct pro-proliferative effect on cirrhotic liver after hepatectomy is unknown. MATERIALS AND METHODS Liver cirrhosis was induced by intraperitoneal injection of 50% CCl4-olive oil solution in adult male Wistar rat. Rats with liver cirrhosis received portal vein injection of physiological saline, miR-203 lentivirus, or control empty lentivirus, and then 70% PH was performed under ether anesthesia 7 d later. Liver samples were harvested at 0, 24, 36, and 72 h after 70% PH. Hepatic expressions of cyclin D1 and Ki67 were checked to evaluate the liver regenerative ability. Hepatic expressions of IL-6, suppressor of cytokine signaling 3 (SOCS3), and phospho-STAT3 were also tested to clarify the mechanisms of miR-203 in liver regeneration. RESULTS The regeneration of miR-203 overexpression cirrhotic liver after 70% PH was enhanced and peaked at 24 and 36 h after 70% PH. The cyclin D1-positive liver cells/high-power field (HPF) in miR-203 overexpression liver markedly increased at 24 and 36 h after 70% PH compared with 0-h samples. When comparing with the control groups, cyclin D1-positive liver cells/HPF in miR-203 overexpression liver were also significantly increased at 24 and 36 h after 70% PH. A similar result of the Ki67-positive liver cells/HPF was achieved at 36 h after 70% PH. The hepatic expression of IL-6 showed a rising tendency after 70% PH, and the levels of IL-6 are significantly higher in miR-203 overexpression livers. Hepatic expression of SOCS3 was negatively expressed with hepatic miR-203 expression level, and the reduced expression of SOCS3 facilitated the phosphorylation of STAT3. CONCLUSIONS By targeting SOCS3 and then enhancing proliferating IL-6/STAT3 signaling pathway, hepatic overexpression of miR-203 can facilitate the initiation of liver regeneration and enhance the potency of liver regeneration after 70% PH in cirrhotic rat. Together with the tumor suppressive effect on HCC, miR-203 would be an ideal candidate for promoting liver regeneration in HCC patients undergoing liver resection without the risk of tumorigenesis or cancer recurrence.
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Affiliation(s)
- Xiao-Bo Chen
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Xiao-Bo Zheng
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Zhen-Xing Cai
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Xian-Jian Lin
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Ming-Qing Xu
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
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28
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Akamatsu N, Kokudo N. Liver transplantation for hepatocellular carcinoma from living-donor vs. deceased donor. Hepatobiliary Surg Nutr 2016; 5:422-428. [PMID: 27826557 PMCID: PMC5075829 DOI: 10.21037/hbsn.2016.08.03] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2016] [Accepted: 06/20/2016] [Indexed: 12/15/2022]
Abstract
With the increasing prevalence of living-donor liver transplantation (LDLT), the possible increased recurrence rate of hepatocellular carcinoma (HCC) in LDLT recipients in comparison with deceased-donor liver transplantation (DDLT) recipients has become a matter of debate. The aim of this review is to encompass current opinions and clinical reports regarding differences in the outcome, especially the recurrence of HCC, between LDLT and DDLT. In reviewing literatures, some studies reported increased recurrence rates among LDLT recipients, a majority of authors, including large database studies, reported comparable recurrence-free survival and recurrence rates between LDLT and DDLT. The postulated reasons for the increased recurrence in LDLT were the effect of graft regeneration on tumor progression, fast-tracking of patients into liver transplantation, and the more aggressive tumor characteristics in LDLT, however, many Asian LDLT centers have reported the comparable outcomes with those of DDLT in Western countries, even with the expanded criteria for HCC. In the absence of a prospective study regarding the use of LDLT versus DDLT for HCC patients, there is no evidence to support the higher HCC recurrence after LDLT than DDLT, and LDLT remains a reasonable treatment option for HCC patients with cirrhosis, especially in Asian countries where the number of deceased donor is scarce.
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Affiliation(s)
- Nobuhisa Akamatsu
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Norihiro Kokudo
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
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29
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Hu Z, Qian Z, Wu J, Zhou J, Zhang M, Zhou L, Zheng S. Clinical outcomes and risk factors of hepatocellular carcinoma treated by liver transplantation: A multi-centre comparison of living donor and deceased donor transplantation. Clin Res Hepatol Gastroenterol 2016; 40:315-326. [PMID: 26382281 DOI: 10.1016/j.clinre.2015.08.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2015] [Revised: 08/01/2015] [Accepted: 08/05/2015] [Indexed: 02/08/2023]
Abstract
BACKGROUND The different outcomes of deceased donor liver transplantation (DDLT) and living donor liver transplantation (LDLT) for hepatocellular carcinoma (HCC) are currently being debated. We aimed to retrospectively compare the outcomes following LDLT and DDLT and to analyse the factors influencing this. METHODS We compared the overall survival (OS) and disease-free survival (DFS) rates of HCC patients after LDLT (n=389) and DDLT (n=6471) from 81 centres over a 10-year period. OS and DFS rates were calculated with the Kaplan-Meier method. And univariate and multivariate Cox proportional hazards regressions were performed on the entire cohort to identify predictors. RESULTS Of 6860 patients, the 1-, 3-, and 5-year OS rates were 86.79%, 70.16%, and 66.31% after LDLT, respectively, and 74.2%, 54.21%, and 46.97% after DDLT, respectively (P<0.001). The 1-, 3-, and 5-year DFS rates were 78.46%, 63.68%, and 61.63% after LDLT, respectively, and 65.65%, 48.61%, and 41.87% after DDLT, respectively (P<0.001). The multivariate Cox regression model determined that the DFS and OS of HCC patients post-liver transplantation (LT) were strongly associated with tumour morphology and biology, but not graft type. CONCLUSIONS With regards to OS and DFS, there were no disadvantages to LDLT as compared with DDLT; tumour morphology and biology may affect the prognosis of LT.
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Affiliation(s)
- Zhenhua Hu
- Zhejiang University, School of Medicine, First Affiliated Hospital, Department of Hepatobiliary and Pancreatic Surgery, Hangzhou, China; Zhejiang University, School of Medicine, First Affiliated Hospital, Ministry of Public Health, Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China; Zhejiang University, College of Medicine, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, 310003 Hangzhou, China
| | - Ze Qian
- Zhejiang University, School of Medicine, First Affiliated Hospital, Department of Hepatobiliary and Pancreatic Surgery, Hangzhou, China; Zhejiang University, School of Medicine, First Affiliated Hospital, Ministry of Public Health, Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China; Zhejiang University, College of Medicine, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, 310003 Hangzhou, China
| | - Jian Wu
- Zhejiang University, School of Medicine, First Affiliated Hospital, Department of Hepatobiliary and Pancreatic Surgery, Hangzhou, China; Zhejiang University, School of Medicine, First Affiliated Hospital, Ministry of Public Health, Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China; Zhejiang University, College of Medicine, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, 310003 Hangzhou, China
| | - Jie Zhou
- Zhejiang University, School of Medicine, First Affiliated Hospital, Department of Hepatobiliary and Pancreatic Surgery, Hangzhou, China; Zhejiang University, School of Medicine, First Affiliated Hospital, Ministry of Public Health, Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China; Zhejiang University, College of Medicine, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, 310003 Hangzhou, China
| | - Min Zhang
- Zhejiang University, School of Medicine, First Affiliated Hospital, Department of Hepatobiliary and Pancreatic Surgery, Hangzhou, China; Zhejiang University, School of Medicine, First Affiliated Hospital, Ministry of Public Health, Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China; Zhejiang University, College of Medicine, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, 310003 Hangzhou, China
| | - Lin Zhou
- Zhejiang University, School of Medicine, First Affiliated Hospital, Department of Hepatobiliary and Pancreatic Surgery, Hangzhou, China; Zhejiang University, School of Medicine, First Affiliated Hospital, Ministry of Public Health, Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China; Zhejiang University, College of Medicine, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, 310003 Hangzhou, China
| | - Shusen Zheng
- Zhejiang University, School of Medicine, First Affiliated Hospital, Department of Hepatobiliary and Pancreatic Surgery, Hangzhou, China; Zhejiang University, School of Medicine, First Affiliated Hospital, Ministry of Public Health, Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China; Zhejiang University, College of Medicine, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, 310003 Hangzhou, China.
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30
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Ogawa K, Takada Y. Living vs. deceased-donor liver transplantation for patients with hepatocellular carcinoma. Transl Gastroenterol Hepatol 2016; 1:35. [PMID: 28138602 DOI: 10.21037/tgh.2016.04.03] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Accepted: 04/07/2016] [Indexed: 12/12/2022] Open
Abstract
With the scarcity of deceased donor liver grafts, living donor liver transplantation (LDLT) is gaining popularity as an alternative to deceased donor liver transplantation (DDLT) for patients with hepatocellular carcinoma (HCC). However, as the evidence of cases of LDLT accumulates, several authors have reported higher HCC recurrence rates after LDLT. The suggested reasons for the higher recurrence rates following LDLT are related to the small-for-size graft in LDLT, surgical procedures that are specific to LDLT, and the fast-track to LDLT. Fast-tracking to LDLT may not allow sufficient time for evaluation of the biological aggressiveness of tumors, which may result in high recurrence rates due to inclusion of patients with more inherently aggressive tumors. Actually, some studies that reported higher recurrence rates with LDLT included a larger number of cases of HCC with microvascular invasion or poorly differentiated HCC. In order to exclude biologically aggressive HCC preoperatively, selection criteria incorporating tumor markers, such as alpha-fetoprotein (AFP) and des-gamma-carboxyprothrombin (DCP), as well as morphological tumor number and size have been proposed. With more reliable selection criteria incorporating biological markers to eliminate biologically aggressive HCC, LDLT can be a viable treatment option for patients with HCC, providing similar recurrence rates as those achieved with DDLT.
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Affiliation(s)
- Kohei Ogawa
- Department of HBP and Breast Surgery, Ehime University, Ehime, Japan
| | - Yasutsugu Takada
- Department of HBP and Breast Surgery, Ehime University, Ehime, Japan
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Park GC, Song GW, Moon DB, Lee SG. A review of current status of living donor liver transplantation. Hepatobiliary Surg Nutr 2016; 5:107-17. [PMID: 27115004 DOI: 10.3978/j.issn.2304-3881.2015.08.04] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Living donor liver transplantation (LDLT) has become an inevitable procedure in Asia due to its shortage of deceased donor under the influence of the religion and native cultures. Through a broad variety of experience, LDLT has been evolved and extended its indication. Although there have been many surgical and ethical efforts to prevent donor risk, concerns of donor's safety still are remaining questions due to its strict selection criteria. Therefore, dual grafts LDLT or ABO incompatible (ABO-I) LDLT may be effective means in its application and safety aspect. Many Asian LDLT centers have pointed out the useful extended criteria of LDLT for hepatocellular carcinoma (HCC), but the applicability of extended criteria should be validated and standardized by worldwide prospective studies based on the Milan criteria. Recent struggling efforts have been reported to surmount extensive portal vein thrombosis and Budd-Chiari syndrome which were previously contraindicated to LDLT. There is no doubt that LDLT is a surely complicated therapy to be performed successfully and requires devoted efforts by surgeons and co-workers. Nonetheless, comprehensive increasing understandings of partial graft LT and improvements of surgical techniques with challenges to obstacles in LDLT will make its prosperity with satisfactory outcomes.
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Affiliation(s)
- Gil-Chun Park
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Gi-Won Song
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Deok-Bog Moon
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Sung-Gyu Lee
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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32
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Gu XQ, Zheng WP, Teng DH, Sun JS, Zheng H. Impact of non-oncological factors on tumor recurrence after liver transplantation in hepatocellular carcinoma patients. World J Gastroenterol 2016; 22:2749-2759. [PMID: 26973413 PMCID: PMC4777997 DOI: 10.3748/wjg.v22.i9.2749] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Revised: 12/13/2015] [Accepted: 12/30/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary neoplasm of the liver and is one of the leading causes of cancer-related death worldwide. Liver transplantation (LT) has become one of the best curative therapeutic options for patients with HCC, although tumor recurrence after LT is a major and unaddressed cause of mortality. Furthermore, the factors that are associated with recurrence are not fully understood, and most previous studies have focused on the biological properties of HCC, such as the number and size of the HCC nodules, the degree of differentiation, the presence of hepatic vascular invasion, elevated serum levels of alpha-fetoprotein, and the tumor stage outside of the Milan criteria. Thus, little attention has been given to factors that are not directly related to HCC (i.e., "non-oncological factors"), which have emerged as predictors of tumor recurrence. This review was performed to assess the effects of non-oncological factors on tumor recurrence after LT. The identification of these factors may provide new research directions and clinical strategies for the prophylaxis and surveillance of tumor recurrence after LT, which can help reduce recurrence and improve patient survival.
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Lauterio A, Di Sandro S, Giacomoni A, De Carlis L. The role of adult living donor liver transplantation and recent advances. Expert Rev Gastroenterol Hepatol 2015; 9:431-445. [PMID: 25307897 DOI: 10.1586/17474124.2015.967762] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Twenty years since the first cases were described, adult living donor liver transplantation (ALDLT) is now considered a valid option to expand the donor pool in view of the ongoing shortage of organs and the high waiting list mortality rate. Despite the rapid evolution and acceptance of this complex process of donation and transplantation in clinical practice, the indications, outcome, ethical considerations and quality and safety aspects continue to evolve based on new data from large cohort studies. This article reviews the surgical and clinical advances in the field of liver transplantation, focusing on technical refinements and discussing the issues that may lead to a further expansion of this complex surgical procedure and the role of ALDLT.
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Affiliation(s)
- Andrea Lauterio
- Transplant Center, Department of Surgery and Abdominal Transplantation, Niguarda Cà Granda Hospital, Milan, Italy
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Kim JH, Sohn BH, Lee HS, Kim SB, Yoo JE, Park YY, Jeong W, Lee SS, Park ES, Kaseb A, Kim BH, Kim WB, Yeon JE, Byun KS, Chu IS, Kim SS, Wang XW, Thorgeirsson SS, Luk JM, Kang KJ, Heo J, Park YN, Lee JS. Genomic predictors for recurrence patterns of hepatocellular carcinoma: model derivation and validation. PLoS Med 2014; 11:e1001770. [PMID: 25536056 PMCID: PMC4275163 DOI: 10.1371/journal.pmed.1001770] [Citation(s) in RCA: 82] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2014] [Accepted: 11/07/2014] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Typically observed at 2 y after surgical resection, late recurrence is a major challenge in the management of hepatocellular carcinoma (HCC). We aimed to develop a genomic predictor that can identify patients at high risk for late recurrence and assess its clinical implications. METHODS AND FINDINGS Systematic analysis of gene expression data from human liver undergoing hepatic injury and regeneration revealed a 233-gene signature that was significantly associated with late recurrence of HCC. Using this signature, we developed a prognostic predictor that can identify patients at high risk of late recurrence, and tested and validated the robustness of the predictor in patients (n = 396) who underwent surgery between 1990 and 2011 at four centers (210 recurrences during a median of 3.7 y of follow-up). In multivariate analysis, this signature was the strongest risk factor for late recurrence (hazard ratio, 2.2; 95% confidence interval, 1.3-3.7; p = 0.002). In contrast, our previously developed tumor-derived 65-gene risk score was significantly associated with early recurrence (p = 0.005) but not with late recurrence (p = 0.7). In multivariate analysis, the 65-gene risk score was the strongest risk factor for very early recurrence (<1 y after surgical resection) (hazard ratio, 1.7; 95% confidence interval, 1.1-2.6; p = 0.01). The potential significance of STAT3 activation in late recurrence was predicted by gene network analysis and validated later. We also developed and validated 4- and 20-gene predictors from the full 233-gene predictor. The main limitation of the study is that most of the patients in our study were hepatitis B virus-positive. Further investigations are needed to test our prediction models in patients with different etiologies of HCC, such as hepatitis C virus. CONCLUSIONS Two independently developed predictors reflected well the differences between early and late recurrence of HCC at the molecular level and provided new biomarkers for risk stratification. Please see later in the article for the Editors' Summary.
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Affiliation(s)
- Ji Hoon Kim
- Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
- Kleberg Center for Molecular Markers, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Bo Hwa Sohn
- Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
- Kleberg Center for Molecular Markers, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Hyun-Sung Lee
- Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
- Kleberg Center for Molecular Markers, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Sang-Bae Kim
- Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
- Kleberg Center for Molecular Markers, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Jeong Eun Yoo
- Department of Pathology and Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Yun-Yong Park
- ASAN Institute for Life Sciences, Asan Medical Center, Department of Medicine, University of Ulsan College of Medicine, Seoul, Korea
| | - Woojin Jeong
- Department of Life Sciences, Division of Life and Pharmaceutical Sciences, Center for Cell Signaling and Drug Discovery Research, Ewha Womans University, Seoul, Korea
| | - Sung Sook Lee
- Department of Hematology-Oncology, Inje University Haeundae Paik Hospital, Busan, Korea
| | - Eun Sung Park
- Institute for Medical Convergence, Yonsei University College of Medicine, Seoul, Korea
| | - Ahmed Kaseb
- Department of GI Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Baek Hui Kim
- Department of Pathology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Wan Bae Kim
- Department of Surgery, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Jong Eun Yeon
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Kwan Soo Byun
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - In-Sun Chu
- Korean Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea
| | - Sung Soo Kim
- Department of Biochemistry and Molecular Biology, Medical Research Center and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul, Korea
| | - Xin Wei Wang
- Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Snorri S. Thorgeirsson
- Laboratory of Experimental Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - John M. Luk
- Department of Pharmacology, National University of Singapore, Singapore
| | - Koo Jeong Kang
- Department of Surgery, Keimyung University School of Medicine, Daegu, Korea
| | - Jeonghoon Heo
- Departments of Molecular Biology and Immunology, Kosin University College of Medicine, Busan, Korea
| | - Young Nyun Park
- Department of Pathology and Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Ju-Seog Lee
- Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
- Kleberg Center for Molecular Markers, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
- Department of Biochemistry and Molecular Biology, Medical Research Center and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul, Korea
- * E-mail:
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Shi JH, Line PD. Effect of liver regeneration on malignant hepatic tumors. World J Gastroenterol 2014; 20:16167-16177. [PMID: 25473170 PMCID: PMC4239504 DOI: 10.3748/wjg.v20.i43.16167] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2014] [Revised: 05/05/2014] [Accepted: 06/21/2014] [Indexed: 02/06/2023] Open
Abstract
Liver regeneration after major surgery may activate occult micrometastases and facilitate tumor growth, leading to liver tumor recurrence. Molecular changes during liver regeneration can provide a microenvironment that stimulates intrahepatic tumor propagation through alterations in cellular signaling pathways, where activation and proliferation of mature hepatocytes, hepatic progenitor cells, non-parenchymal liver cells might favor both liver regeneration and tumor growth. This review highlights recent advances of tumor growth and development in the regenerating liver, possible mechanisms and clinical implications.
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Akamatsu N, Sugawara Y, Kokudo N. Living-donor vs deceased-donor liver transplantation for patients with hepatocellular carcinoma. World J Hepatol 2014; 6:626-631. [PMID: 25276278 PMCID: PMC4179141 DOI: 10.4254/wjh.v6.i9.626] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2014] [Revised: 07/29/2014] [Accepted: 08/27/2014] [Indexed: 02/06/2023] Open
Abstract
With the increasing prevalence of living-donor liver transplantation (LDLT) for patients with hepatocellular carcinoma (HCC), some authors have reported a potential increase in the HCC recurrence rates among LDLT recipients compared to deceased-donor liver transplantation (DDLT) recipients. The aim of this review is to encompass current opinions and clinical reports regarding differences in the outcome, especially the recurrence of HCC, between LDLT and DDLT. While some studies report impaired recurrence - free survival and increased recurrence rates among LDLT recipients, others, including large database studies, report comparable recurrence - free survival and recurrence rates between LDLT and DDLT. Studies supporting the increased recurrence in LDLT have linked graft regeneration to tumor progression, but we found no association between graft regeneration/initial graft volume and tumor recurrence among our 125 consecutive LDLTs for HCC cases. In the absence of a prospective study regarding the use of LDLT vs DDLT for HCC patients, there is no evidence to support the higher HCC recurrence after LDLT than DDLT, and LDLT remains a reasonable treatment option for HCC patients with cirrhosis.
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Affiliation(s)
- Nobuhisa Akamatsu
- Nobuhisa Akamatsu, Yasuhiko Sugawara, Norihiro Kokudo, Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan
| | - Yasuhiko Sugawara
- Nobuhisa Akamatsu, Yasuhiko Sugawara, Norihiro Kokudo, Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan
| | - Norihiro Kokudo
- Nobuhisa Akamatsu, Yasuhiko Sugawara, Norihiro Kokudo, Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan
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Xiao GQ, Song JL, Shen S, Yang JY, Yan LN. Living donor liver transplantation does not increase tumor recurrence of hepatocellular carcinoma compared to deceased donor transplantation. World J Gastroenterol 2014; 20:10953-10959. [PMID: 25152599 PMCID: PMC4138476 DOI: 10.3748/wjg.v20.i31.10953] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2013] [Revised: 03/15/2014] [Accepted: 05/26/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To compare the recurrence-free survival (RFS) and overall survival (OS) of hepatitis B virus (HBV)-positive hepatocellular carcinoma (HCC) after living donor liver transplantation (LDLT) and deceased donor liver transplantation (DDLT).
METHODS: We retrospectively collected clinical data from 408 liver cancer patients from February 1999 to September 2012. We used the chi-squared test or Fisher’s exact test to analyze the characteristics of LDLT and DDLT. Kaplan-Meier analysis was used to compare the RFS and OS in HCC.
RESULTS: Three hundred sixty HBV-positive patients (276 DDLT and 84 LDLT) were included in this study. The mean follow-up time was 27.1 mo (range 1.1-130.8 mo). One hundred eighty-five (51.2%) patients died during follow-up. The 1-, 3-, and 5-year RFS rates for LDLT were 85.2%, 55.7%, and 52.9%, respectively; for DDLT, the RFS rates were 73.2%, 49.1%, and 45.3% (P = 0.115). The OS rates were similar between the LDLT and DDLT recipients, with 1-, 3-, and 5-year survival rates of 81.8%, 49.5%, and 43.0% vs 69.5%, 43.0%, and 38.3%, respectively (P = 0.30). The outcomes of HCC according to the Milan criteria after LDLT and DDLT were not significantly different (for LDLT: 1-, 3-, and 5-year RFS: 94.7%, 78.7%, and 78.7% vs 89.2%, 77.5%, and 74.5%, P = 0.50; for DDLT: 86.1%, 68.8%, and 68.8% vs 80.5%, 62.2%, and 59.8% P = 0.53).
CONCLUSION: The outcomes of LDLT for HCC are not worse compared to the outcomes of DDLT. LDLT does not increase tumor recurrence of HCC compared to DDLT.
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Wan P, Zhang JJ, Li QG, Xu N, Zhang M, Chen XS, Han LZ, Xia Q. Living-donor or deceased-donor liver transplantation for hepatic carcinoma: A case-matched comparison. World J Gastroenterol 2014; 20:4393-4400. [PMID: 24764678 PMCID: PMC3989976 DOI: 10.3748/wjg.v20.i15.4393] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2013] [Revised: 12/20/2013] [Accepted: 02/20/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To compare the surgical outcomes between living-donor and deceased-donor liver transplantation in patients with hepatic carcinoma.
METHODS: From January 2007 to December 2010, 257 patients with pathologically confirmed hepatic carcinoma met the eligibility criteria of the study. Forty patients who underwent living-donor liver transplantation (LDLT) constituted the LDLT group, and deceased-donor liver transplantation (DDLT) was performed in 217 patients. Patients in the LDLT group were randomly matched (1:2) to patients who underwent DDLT using a multivariate case-matched method, so 40 patients in the LDLT group and 80 patients in the DDLT group were enrolled into the study. We compared the two groups in terms of clinicopathological characteristics, postoperative complications, long-term cumulative survival and relapse-free survival outcomes. The modified Clavien-Dindo classification system of surgical complications was used to evaluate the severity of perioperative complications. Furthermore, we determined the difference in the overall biliary complication rates in the perioperative and follow-up periods between the LDLT and DDLT groups.
RESULTS: The clinicopathological characteristics of the enrolled patients were comparable between the two groups. The duration of operation was significantly longer (553 min vs 445 min, P < 0.001) in the LDLT group than in the DDLT group. Estimated blood loss (1188 mL vs 1035 mL, P = 0.055) and the proportion of patients with intraoperative transfusion (60.0% vs 43.8%, P = 0.093) were slightly but not significantly greater in the LDLT group. In contrast to DDLT, LDLT was associated with a lower rate of perioperative grade II complications (45.0% vs 65.0%, P = 0.036) but a higher risk of overall biliary complications (27.5% vs 7.5%, P = 0.003). Nonetheless, 21 patients (52.5%) in the LDLT group and 46 patients (57.5%) in the DDLT group experienced perioperative complications, and overall perioperative complication rates were similar between the two groups (P = 0.603). No significant difference was observed in 5-year overall survival (74.1% vs 66.6%, P = 0.372) or relapse-free survival (72.9% vs 70.9%, P = 0.749) between the LDLT and DDLT groups.
CONCLUSION: Although biliary complications were more common in the LDLT group, this group did not show any inferiority in long-term overall survival or relapse-free survival compared with DDLT.
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Living-donor liver transplantation associated with higher incidence of hepatocellular carcinoma recurrence than deceased-donor liver transplantation. Transplantation 2014; 97:71-7. [PMID: 24056623 DOI: 10.1097/tp.0b013e3182a68953] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Living-donor liver transplantation (LDLT) is becoming an important tool in hepatocellular carcinoma (HCC) treatment. However, the oncologic outcome between LDLT and deceased-donor LT (DDLT) for HCC remains controversial. This study aims to compare the HCC recurrence rates after LDLT versus DDLT. METHODS Two hundred sixteen patients (166 LDLTs and 50 DDLTs) who underwent LT for HCC within University of California-San Francisco criteria were retrospectively reviewed. LDLT patients were divided into two groups: small living-donor graft (LDG; graft-to-recipient body weight ratio <1.0, n=59) and nonsmall LDG (graft-to-recipient body weight ratio ≥1.0, n=107). Patients were further stratified into low- and high-risk settings by the number of risk factors for recurrence. RESULTS The recurrence-free survival was lower in LDLT compared with DDLT (88.6% and 80.7% vs. 96.0% and 94.0% at 1 and 5 years; P=0.045). There was no significant difference between two groups regarding the majority of clinical and tumor characteristics, with the exception of a higher proportion of microvascular invasion presence in LDLT. After the adjustment for microvascular invasion, LDLT was identified as an independent risk factor for recurrence. Moreover, recurrence-free survival between small and nonsmall LDG was not statistically significant. In low-risk setting (≤1 risk factor), LDLT showed comparable outcome with DDLT. However, the risk of recurrence was higher in LDLT than DDLT in high-risk patients. CONCLUSION In conclusion, LDLT showed poorer outcome than DDLT. This should be considered to select optimal strategy for HCC.
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40
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Shi JH, Scholz H, Huitfeldt HS, Line PD. The effect of hepatic progenitor cells on experimental hepatocellular carcinoma in the regenerating liver. Scand J Gastroenterol 2014; 49:99-108. [PMID: 24188385 DOI: 10.3109/00365521.2013.854406] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Liver regeneration following hepatectomy can stimulate the growth of hepatocellular carcinoma (HCC), and major hepatectomy can be associated with activation of hepatic progenitor cells (HPCs). The aim of this study was to evaluate how HPCs influence the malignant potential of tumor cells in vitro and HCC tumor growth after surgery in a rodent model. MATERIAL AND METHODS Hepatoma cells (JM1) were cultured with conditioned medium (CM) from syngeneic HPCs (WB-F344). Growth rate, resistance to Adriamycin, and expression patterns for invasiveness and stemness were compared with naïve JM1. Microscopic HCC tumors from naïve JM1 or JM1 cultured with CM were inoculated in Fischer 344 rats undergoing 70% hepatectomy with or without simultaneous infusion of WB-F344. Tumor growth and invasiveness-related factors were compared. Buffalo rats were induced with Morris hepatoma cells. Liver tissue from both in vivo models was examined with regard to activation of cells with progenitor-like phenotype. RESULTS Co-culture with CM resulted in an increased resistance to Adriamycin and enhanced expressions of α-FP, MMP9, ABCG2, CD133, and SOX2, as well as the activation of ERK, AKT, WNT, and TGF-β1 pathways. Tumor size and metastases were significantly higher in groups with co-cultured cells or HPCs infusion. After 70% hepatectomy and tumor implantation, cells positive for α-FP, CK19, and CD133 were found, thus suggesting a progenitor-like phenotype in the setting of epithelial-mesenchymal transition. CONCLUSION HPCs have a marked effect on HCC cells in vitro and appear to stimulate the growth and malignant potential of experimental HCC tumors.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily G, Member 2
- ATP-Binding Cassette Transporters/genetics
- Animals
- Antibiotics, Antineoplastic/therapeutic use
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/secondary
- Cell Line, Tumor
- Cell Proliferation
- Coculture Techniques
- Cytokine Receptor Common beta Subunit/metabolism
- Doxorubicin/therapeutic use
- Drug Resistance, Neoplasm
- Epithelial-Mesenchymal Transition
- Gene Expression
- Hepatectomy
- Humans
- Liver/physiology
- Liver/surgery
- Liver Neoplasms, Experimental/metabolism
- Liver Neoplasms, Experimental/pathology
- Liver Regeneration
- MAP Kinase Signaling System
- Matrix Metalloproteinase 9/metabolism
- Proto-Oncogene Proteins c-akt/metabolism
- RNA, Messenger/metabolism
- Rats
- Rats, Inbred BUF
- Rats, Inbred F344
- SOXB1 Transcription Factors/genetics
- Stem Cells/metabolism
- Transforming Growth Factor beta1/metabolism
- Tumor Burden
- Wnt Signaling Pathway
- alpha-Fetoproteins/metabolism
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Affiliation(s)
- Ji-Hua Shi
- Department of Transplantation Medicine, Oslo University Hospital , Oslo , Norway
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Shi JH, Liu SZ, Wierød L, Scholz H, Anmarkrud JA, Huitfeldt HS, Zhang SJ, Line PD. RAF-targeted therapy for hepatocellular carcinoma in the regenerating liver. J Surg Oncol 2013; 107:393-401. [PMID: 22927239 DOI: 10.1002/jso.23224] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2012] [Accepted: 06/25/2012] [Indexed: 01/19/2023]
Abstract
BACKGROUND Post-operative liver regeneration may contribute to tumor recurrence. There is a theoretical need for an adjuvant therapy that can suppress tumor growth without adversely affecting post-operative liver regeneration. OBJECTIVE To evaluate the effect of RAF inhibitor Sorafenib on cell viability and proliferation of hepatoma cells and hepatocytes in vitro and in an in vivo rat model. METHODS Cell viability, DNA synthesis, and RAF/MAPK kinase activity in the primary hepatocyte and hepatoma cell lines were investigated after Sorafenib exposure. Sequence analysis of the B-RAF gene in hepatic cells was determined. Tumor markers were compared within the rats after 70% hepatectomy with or without daily oral gavages of Sorafenib. Liver regeneration was assessed by liver function tests and proliferation markers. RESULTS Primary hepatocytes showed higher cell viability, proliferation rate, and stronger RAF/MAPK kinase activity compared with hepatoma cell lines. The in vivo tumor volumes, size, and metastases were significantly decreased (P < 0.05) whereas no significant change in liver regeneration related to Sorafenib exposure was found (P > 0.05). B-RAF V600E mutation was not detected neither in the hepatic cells nor untransformed hepatocytes. CONCLUSIONS The RAF targeted inhibitor can reduce tumor growth without retarding liver regeneration in this experiment.
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Affiliation(s)
- Ji-Hua Shi
- Department of Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway
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42
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Grouls C, Hatting M, Rix A, Pochon S, Lederle W, Tardy I, Kuhl CK, Trautwein C, Kiessling F, Palmowski M. Liver dysplasia: US molecular imaging with targeted contrast agent enables early assessment. Radiology 2013; 267:487-95. [PMID: 23360735 DOI: 10.1148/radiol.13120220] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
PURPOSE To investigate the ability of vascular endothelial growth factor receptor type 2 (VEGFR2)-targeted ultrasonographic (US) microbubbles for the assessment of liver dysplasia in transgenic mice. MATERIALS AND METHODS Animal experiments were approved by the governmental review committee. Nuclear factor-κB essential modulator knock-out mice with liver dysplasia and wild-type mice underwent liver imaging by using a clinical US system. Two types of contrast agents were investigated: nontargeted, commercially available, second-generation microbubbles (SonoVue) and clinically translatable PEGylated VEGFR2-targeted microbubbles (BR55). Microbubble kinetics was investigated over the course of 4 minutes. Targeted contrast material-enhanced US signal was quantified 5 minutes after injection. Competitive in vivo binding experiments with BR55 were performed in knock-out mice. Immunohistochemical and hematoxylin-eosin staining of liver sections was performed to validate the in vivo US results. Groups were compared by using the Mann-Whitney test. RESULTS Peak enhancement after injection of SonoVue and BR55 did not differ in healthy and dysplastic livers (SonoVue, P = .46; BR55, P = .43). Accordingly, immunohistochemical findings revealed comparable vessel densities in both groups. The specificity of BR55 to VEGFR2 was proved by in vivo competition (P = .0262). While the SonoVue signal decreased similarly in healthy and dysplastic livers during the 4 minutes, there was an accumulation of BR55 in dysplastic livers compared with healthy ones. Furthermore, targeted contrast-enhanced US signal indicated a significantly higher site-specific binding of BR55 in dysplastic than healthy livers (P = .005). Quantitative immunohistologic findings confirmed significantly higher VEGFR2 levels in dysplastic livers (P = .02). CONCLUSION BR55 enables the distinction of early stages of liver dysplasia from normal liver.
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Affiliation(s)
- Christoph Grouls
- Department of Experimental Molecular Imaging, Internal Medicine III, and Nuclear Medicine, RWTH-Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany
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Grant RC, Sandhu L, Dixon PR, Greig PD, Grant DR, McGilvray ID. Living vs. deceased donor liver transplantation for hepatocellular carcinoma: a systematic review and meta-analysis. Clin Transplant 2013; 27:140-7. [PMID: 23157398 DOI: 10.1111/ctr.12031] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/06/2012] [Indexed: 12/12/2022]
Abstract
Experimental studies suggest that the regenerating liver provides a "fertile field" for the growth of hepatocellular carcinoma (HCC). However, clinical studies report conflicting results comparing living donor liver transplantation (LDLT) and deceased donor liver transplantation (DDLT) for HCC. Thus, disease-free survival (DFS) and overall survival (OS) were compared after LDLT and DDLT for HCC in a systematic review and meta-analysis. Twelve studies satisfied eligibility criteria for DFS, including 633 LDLT and 1232 DDLT. Twelve studies satisfied eligibility criteria for OS, including 637 LDLT and 1050 DDLT. Altogether, there were 16 unique studies; 1, 2, and 13 of these were rated as high, medium, and low quality, respectively. Studies were heterogeneous, non-randomized, and mostly retrospective. The combined hazard ratio was 1.59 (95% confidence interval [CI]: 1.02-2.49; I(2) = 50.07%) for DFS after LDLT vs. DDLT for HCC, and 0.97 (95% CI: 0.73-1.27; I(2) = 5.68%) for OS. This analysis provides evidence of lower DFS after LDLT compared with DDLT for HCC. Improved study design and reporting is required in future research to ascribe the observed difference in DFS to study bias or biological risk specifically associated with LDLT.
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Affiliation(s)
- Robert C Grant
- Department of Surgery, University of Toronto, Toronto, ON, Canada
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Kulik LM, Fisher RA, Rodrigo D, Brown RS, Freise CE, Shaked A, Everhart J, Everson GT, Hong JC, Hayashi PH, Berg CL, Lok ASF, the A2ALL Study Group. Outcomes of living and deceased donor liver transplant recipients with hepatocellular carcinoma: results of the A2ALL cohort. Am J Transplant 2012; 12:2997-3007. [PMID: 22994906 PMCID: PMC3523685 DOI: 10.1111/j.1600-6143.2012.04272.x] [Citation(s) in RCA: 121] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Hepatocellular carcinoma (HCC) represents an increasing fraction of liver transplant indications; the role of living donor liver transplant (LDLT) remains unclear. In the Adult-to-Adult Living Donor Liver Transplantation Cohort Study, patients with HCC and an LDLT or deceased donor liver transplant (DDLT) for which at least one potential living donor had been evaluated were compared for recurrence and posttransplant mortality rates. Mortality from date of evaluation of each recipient's first potential living donor was also analyzed. Unadjusted 5-year HCC recurrence was significantly higher after LDLT (38%) than DDLT (11%), (p = 0.0004). After adjustment for tumor characteristics, HCC recurrence remained significantly different between LDLT and DDLT recipients (hazard ratio (HR) = 2.35; p = 0.04) for the overall cohort but not for recipients transplanted following the introduction of MELD prioritization. Five-year posttransplant survival was similar in LDLT and DDLT recipients from time of transplant (HR = 1.32; p = 0.27) and from date of LDLT evaluation (HR = 0.73; p = 0.36). We conclude that the higher recurrence observed after LDLT is likely due to differences in tumor characteristics, pretransplant HCC management and waiting time.
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Affiliation(s)
- L. M. Kulik
- Department of Medicine and Surgery, Northwestern University, Chicago IL
| | - R. A. Fisher
- Department of Surgery, Medical College of Virginia Hospitals, Virginia Commonwealth University, Richmond, VA
| | - D.R. Rodrigo
- Department of Surgery, University of Michigan, Ann Arbor, MI
| | - R. S. Brown
- Department of Medicine and Surgery, Columbia University College of Physicians and Surgeons, New York, NY
| | - C. E. Freise
- Department of Surgery, University of California, San Francisco, San Francisco, CA
| | - A. Shaked
- Department of Surgery, University of Pennsylvania, Philadelphia, PA
| | - J.E. Everhart
- Department of Medicine, University of Colorado, Denver, Aurora, CO
| | - G. T. Everson
- National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD
| | - J. C. Hong
- Department of Surgery, University of California, Los Angeles, CA
| | - P. H. Hayashi
- Department of Medicine, University of North Carolina, Chapel Hill, NC
| | - C. L. Berg
- Department of Medicine, University of Virginia, Charlottesville, VA
| | - A. S. F. Lok
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI
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Coban Z, Barton MC. Integrative genomics: liver regeneration and hepatocellular carcinoma. J Cell Biochem 2012; 113:2179-84. [PMID: 22345090 DOI: 10.1002/jcb.24104] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Numerous genome wide profiles of gene expression changes in human hepatocellular carcinoma (HCC), compared to normal liver tissue, have been reported. Hierarchical clustering of these data reveal distinct patterns, which underscore conservation between human disease and mouse models of HCC, as well as suggest specific classification of subtypes within the heterogeneous disease of HCC. Global profiling of gene expression in mouse liver, challenged by partial hepatectomy to regenerate, reveals alterations in gene expression that occur in response to acute injury, inflammation, and re-entry into cell cycle. When we integrated datasets of gene expression changes in mouse models of HCC and those that are altered at specific times of liver regeneration, we saw shared, conserved alterations in gene expression within specific biological pathways, both up-regulated, for example, cell cycle, cell death, and cellular development, or down-regulated, for example, vitamin and mineral metabolism, lipid metabolism, and molecular transport. Additional molecular mechanisms shared by liver regeneration and HCC, as yet undiscovered, may have important implications in tumor development and recurrence. These comparisons may offer a way to judge how liver resection, in the treatment of HCC, introduces challenges to care of the disease. Further, uncovering the pathways conserved in inflammatory response, hypertrophy, proliferation, and architectural remodeling of the liver, which are shared in liver regeneration and HCC, versus those specific to tumor development and progression in HCC, may reveal new biomarkers or potential therapeutic targets in HCC.
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Affiliation(s)
- Zeynep Coban
- Graduate School for Biomedical Sciences, Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
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Zheng Y, Yin L, Chen H, Yang S, Pan C, Lu S, Miao M, Jiao B. miR-376a suppresses proliferation and induces apoptosis in hepatocellular carcinoma. FEBS Lett 2012; 586:2396-403. [PMID: 22684007 DOI: 10.1016/j.febslet.2012.05.054] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2012] [Revised: 05/26/2012] [Accepted: 05/29/2012] [Indexed: 12/20/2022]
Abstract
MicroRNAs are known to be involved in the pathogenesis of hepatocellular carcinoma (HCC). This study aims to explore the potential biological function of miR-376a, which was found to be inhibited after partial hepatectomy, in HCC. We discovered that miR-376a was frequently down-regulated in HCC cell lines and HCC tissues, while higher relative level of miR-376a was significantly associated with high serum AFP level. Over-expression of miR-376a not only inhibited proliferation but induced apoptosis in Huh7 cells. Additionally, p85α (PIK3R1) was identified as a direct and functional target of miR-376a in Huh7 cells. Moreover, we confirmed that p85α and miR-376a were inversely correlated in HCC. These findings suggest that down-regulation of miR-376a may contribute to the development of HCC by targeting p85α.
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Affiliation(s)
- Yongxia Zheng
- Department of Biochemistry and Molecular Biology, Second Military Medical University, Shanghai, China
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The long-term outcomes of patients with hepatocellular carcinoma after living donor liver transplantation: a comparison of right and left lobe grafts. Surg Today 2012; 42:559-64. [DOI: 10.1007/s00595-011-0086-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2011] [Accepted: 05/16/2011] [Indexed: 02/07/2023]
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