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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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Finotti M, Romano M, Grossi U, Dalla Bona E, Pelizzo P, Piccino M, Scopelliti M, Zanatta P, Zanus G. Innovations in Liver Preservation Techniques for Transplants from Donors after Circulatory Death: A Special Focus on Transplant Oncology. J Clin Med 2024; 13:5371. [PMID: 39336858 PMCID: PMC11432009 DOI: 10.3390/jcm13185371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 09/02/2024] [Accepted: 09/03/2024] [Indexed: 09/30/2024] Open
Abstract
Liver transplantation is the preferred treatment for end-stage liver disease. Emerging evidence suggests a potential role for liver transplantation in treating liver tumors such as colorectal liver metastases and cholangiocarcinoma. However, due to a limited donor pool, the use of marginal grafts from donation after circulatory death (DCD) donors is increasing to meet demand. Machine perfusion is crucial in this context for improving graft acceptance rates and reducing ischemia-reperfusion injury. Few studies have evaluated the role of machine perfusion in the context of transplant oncology. Perfusion machines can be utilized in situ (normothermic regional perfusion-NRP) or ex situ (hypothermic and normothermic machine perfusion), either in combination or as a complement to conventional in situ cold flush and static cold storage. The objective of this analysis is to provide an up-to-date overview of perfusion machines and their function in donation after circulatory death with particular attention to their current and likely potential effects on transplant oncology. A literature review comparing standard cold storage to machine perfusion methods showed that, so far, there is no evidence that these devices can reduce the tumor recurrence rate. However, some evidence suggests that these innovative perfusion techniques can improve graft function, reduce ischemia-reperfusion injury, and, based on this mechanism, may lead to future improvements in cancer recurrence.
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Affiliation(s)
- Michele Finotti
- Hepatobiliary and General Surgery Unit, Regional Hospital Treviso, Dipartimento di Scienze Chirurgiche Oncologiche e Gastroenterologiche (DISCOG), University of Padua, 35128 Padua, Italy
- Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX 75246, USA
| | - Maurizio Romano
- Hepatobiliary and General Surgery Unit, Regional Hospital Treviso, Dipartimento di Scienze Chirurgiche Oncologiche e Gastroenterologiche (DISCOG), University of Padua, 35128 Padua, Italy
| | - Ugo Grossi
- Hepatobiliary and General Surgery Unit, Regional Hospital Treviso, Dipartimento di Scienze Chirurgiche Oncologiche e Gastroenterologiche (DISCOG), University of Padua, 35128 Padua, Italy
| | - Enrico Dalla Bona
- Hepatobiliary and General Surgery Unit, Regional Hospital Treviso, Dipartimento di Scienze Chirurgiche Oncologiche e Gastroenterologiche (DISCOG), University of Padua, 35128 Padua, Italy
| | - Patrizia Pelizzo
- Hepatobiliary and General Surgery Unit, Regional Hospital Treviso, Dipartimento di Scienze Chirurgiche Oncologiche e Gastroenterologiche (DISCOG), University of Padua, 35128 Padua, Italy
| | - Marco Piccino
- Hepatobiliary and General Surgery Unit, Regional Hospital Treviso, Dipartimento di Scienze Chirurgiche Oncologiche e Gastroenterologiche (DISCOG), University of Padua, 35128 Padua, Italy
| | - Michele Scopelliti
- Hepatobiliary and General Surgery Unit, Regional Hospital Treviso, Dipartimento di Scienze Chirurgiche Oncologiche e Gastroenterologiche (DISCOG), University of Padua, 35128 Padua, Italy
| | - Paolo Zanatta
- Department of Anesthesiology and Critical Care, Treviso Regional Hospital AULSS 2 Marca Trevigiana, 31100 Treviso, Italy
| | - Giacomo Zanus
- Hepatobiliary and General Surgery Unit, Regional Hospital Treviso, Dipartimento di Scienze Chirurgiche Oncologiche e Gastroenterologiche (DISCOG), University of Padua, 35128 Padua, Italy
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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] [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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Ng KTP, Liu J, Yeung OWH, Pang L, Shiu HC, Liu H, Yang XX, Chan ACY, Wong TCL, Lo CM, Man K. Post-transplant inflammatory cytokine signature adds value for predicting tumor recurrence after liver transplantation for hepatocellular carcinoma. Hepatol Int 2023; 17:1596-1609. [PMID: 37542605 DOI: 10.1007/s12072-023-10566-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 06/23/2023] [Indexed: 08/07/2023]
Abstract
BACKGROUND Cytokines are key regulators of post-transplant inflammation responses which reconstitute post-transplant hepatic and systemic environments to influence the likelihood of tumor relapse. This study investigated the prognostic value of post-transplant cytokines on tumor recurrence after liver transplantation (LT) for hepatocellular carcinoma (HCC). METHODS A retrospective analysis was conducted in prospectively collected 150 adult HCC patients who received liver transplantation from 1997 to 2015. The post-transplant 41 inflammatory cytokines were quantified by multiplexing analysis and determined their prognostic value for predicting post-LT tumor recurrence by receiver operative characteristic analysis. A prediction model for post-LT tumor recurrence was generated by the logistic regression and internally validated Bootstrapping and compared with external prediction models. RESULTS Post-transplant circulating CCL11, IFNα2, and IL17A cytokines were identified to be significant predictors of post-LT tumor recurrence and survival. A prediction score composed of the post-transplant 3-cytokine (P3C) signature, UCSF criteria, and pre-LT AFP was established. The P3C-UCSF-AFP score significantly predicted post-LT tumor recurrence and poor survival both in deceased donor liver transplantation (DDLT) and living donor liver transplantation (LDLT). The P3C-UCSF-AFP score was validated to significantly predict post-LT 2-year and 5-year tumor recurrence, outperforming the RETREAT score, French AFP model, up-to-seven, UCSF criteria, and Milan criteria. Importantly, the P3C-UCSF-AFP score could cost-effectively stratify high-risk recipients subjected to a refinement of post-recurrence survival. CONCLUSION The integrated P3C-UCSF-AFP score not only compensated for the pre-LT unpredictability and predicted post-LT tumor recurrence accurately, but also guided the clinical refinements of post-LT surveillance and therapeutic strategies in transplant oncology.
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Affiliation(s)
- Kevin Tak-Pan Ng
- Department of Surgery, School of Clinical Medicine, Faculty of Medicine, HKU-SZH & LKS, The University of Hong Kong, Hong Kong SAR, China
| | - Jiang Liu
- Department of Surgery, School of Clinical Medicine, Faculty of Medicine, HKU-SZH & LKS, The University of Hong Kong, Hong Kong SAR, China
- Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Oscar Wai-Ho Yeung
- Department of Surgery, School of Clinical Medicine, Faculty of Medicine, HKU-SZH & LKS, The University of Hong Kong, Hong Kong SAR, China
| | - Li Pang
- Department of Surgery, School of Clinical Medicine, Faculty of Medicine, HKU-SZH & LKS, The University of Hong Kong, Hong Kong SAR, China
| | - Hoi Chung Shiu
- Department of Surgery, School of Clinical Medicine, Faculty of Medicine, HKU-SZH & LKS, The University of Hong Kong, Hong Kong SAR, China
| | - Hui Liu
- Department of Surgery, School of Clinical Medicine, Faculty of Medicine, HKU-SZH & LKS, The University of Hong Kong, Hong Kong SAR, China
| | - Xin Xiang Yang
- Department of Surgery, School of Clinical Medicine, Faculty of Medicine, HKU-SZH & LKS, The University of Hong Kong, Hong Kong SAR, China
| | - Albert Chi-Yan Chan
- Department of Surgery, School of Clinical Medicine, Faculty of Medicine, HKU-SZH & LKS, The University of Hong Kong, Hong Kong SAR, China
| | - Tiffany Cho-Lam Wong
- Department of Surgery, School of Clinical Medicine, Faculty of Medicine, HKU-SZH & LKS, The University of Hong Kong, Hong Kong SAR, China
| | - Chung Mau Lo
- Department of Surgery, School of Clinical Medicine, Faculty of Medicine, HKU-SZH & LKS, The University of Hong Kong, Hong Kong SAR, China.
| | - Kwan Man
- Department of Surgery, School of Clinical Medicine, Faculty of Medicine, HKU-SZH & LKS, The University of Hong Kong, Hong Kong SAR, China.
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Maspero M, Yilmaz S, Cazzaniga B, Raj R, Ali K, Mazzaferro V, Schlegel A. The role of ischaemia-reperfusion injury and liver regeneration in hepatic tumour recurrence. JHEP Rep 2023; 5:100846. [PMID: 37771368 PMCID: PMC10523008 DOI: 10.1016/j.jhepr.2023.100846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 06/20/2023] [Accepted: 07/01/2023] [Indexed: 09/30/2023] Open
Abstract
The risk of cancer recurrence after liver surgery mainly depends on tumour biology, but preclinical and clinical evidence suggests that the degree of perioperative liver injury plays a role in creating a favourable microenvironment for tumour cell engraftment or proliferation of dormant micro-metastases. Understanding the contribution of perioperative liver injury to tumour recurrence is imperative, as these pathways are potentially actionable. In this review, we examine the key mechanisms of perioperative liver injury, which comprise mechanical handling and surgical stress, ischaemia-reperfusion injury, and parenchymal loss leading to liver regeneration. We explore how these processes can trigger downstream cascades leading to the activation of the immune system and the pro-inflammatory response, cellular proliferation, angiogenesis, anti-apoptotic signals, and release of circulating tumour cells. Finally, we discuss the novel therapies under investigation to decrease ischaemia-reperfusion injury and increase regeneration after liver surgery, including pharmaceutical agents, inflow modulation, and machine perfusion.
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Affiliation(s)
- Marianna Maspero
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
- General Surgery and Liver Transplantation Unit, IRCCS Istituto Tumori, Milan, Italy
| | - Sumeyye Yilmaz
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Beatrice Cazzaniga
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Roma Raj
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Khaled Ali
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Vincenzo Mazzaferro
- General Surgery and Liver Transplantation Unit, IRCCS Istituto Tumori, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Italy
| | - Andrea Schlegel
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
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Rigo F, De Stefano N, Patrono D, De Donato V, Campi L, Turturica D, Doria T, Sciannameo V, Berchialla P, Tandoi F, Romagnoli R. Impact of Hypothermic Oxygenated Machine Perfusion on Hepatocellular Carcinoma Recurrence after Liver Transplantation. J Pers Med 2023; 13:jpm13050703. [PMID: 37240873 DOI: 10.3390/jpm13050703] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 04/16/2023] [Accepted: 04/21/2023] [Indexed: 05/28/2023] Open
Abstract
BACKGROUND Machine perfusion may be able to mitigate ischemia-reperfusion injury (IRI), which increases hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT). This study aimed to investigate the impact of dual-hypothermic oxygenated machine perfusion (D-HOPE) on HCC recurrence in LT. METHODS A single-center retrospective study was conducted from 2016 to 2020. Pre- and postoperative data of HCC patients undergoing LT were analyzed. Recipients of a D-HOPE-treated graft were compared to those of livers preserved using static cold storage (SCS). The primary endpoint was recurrence-free survival (RFS). RESULTS Of 326 patients, 246 received an SCS-preserved liver and 80 received a D-HOPE-treated graft (donation after brain death (DBD), n = 66; donation after circulatory death (DCD), n = 14). Donors of D-HOPE-treated grafts were older and had higher BMI. All DCD donors were treated by normothermic regional perfusion and D-HOPE. The groups were comparable in terms of HCC features and estimated 5-year RFS according to the Metroticket 2.0 model. D-HOPE did not reduce HCC recurrence (D-HOPE 10%; SCS 8.9%; p = 0.95), which was confirmed using Bayesian model averaging and inverse probability of treatment weighting-adjusted RFS analysis. Postoperative outcomes were comparable between groups, except for lower AST and ALT peak in the D-HOPE group. CONCLUSIONS In this single-center study, D-HOPE did not reduce HCC recurrence but allowed utilizing livers from extended criteria donors with comparable outcomes, improving access to LT for patients suffering from HCC.
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Affiliation(s)
- Federica Rigo
- General Surgery 2U-Liver Transplant Unit, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, 10126 Turin, Italy
| | - Nicola De Stefano
- General Surgery 2U-Liver Transplant Unit, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, 10126 Turin, Italy
| | - Damiano Patrono
- General Surgery 2U-Liver Transplant Unit, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, 10126 Turin, Italy
| | - Victor De Donato
- General Surgery 2U-Liver Transplant Unit, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, 10126 Turin, Italy
| | - Ludovico Campi
- General Surgery 2U-Liver Transplant Unit, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, 10126 Turin, Italy
| | - Diana Turturica
- General Surgery 2U-Liver Transplant Unit, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, 10126 Turin, Italy
| | - Teresa Doria
- General Surgery 2U-Liver Transplant Unit, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, 10126 Turin, Italy
| | - Veronica Sciannameo
- Centre for Biostatistics, Epidemiology and Public Health (C-BEPH), Department of Clinical and Biological Sciences, University of Torino, 10126 Turin, Italy
| | - Paola Berchialla
- Centre for Biostatistics, Epidemiology and Public Health (C-BEPH), Department of Clinical and Biological Sciences, University of Torino, 10126 Turin, Italy
| | - Francesco Tandoi
- General Surgery 2U-Liver Transplant Unit, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, 10126 Turin, Italy
- HPB and Liver Transplant Unit, Azienda Ospedaliero Universitaria Consorziale Policlinico, 70124 Bari, Italy
| | - Renato Romagnoli
- General Surgery 2U-Liver Transplant Unit, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, 10126 Turin, Italy
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8
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Parente A, Cho HD, Kim KH, Schlegel A. Association between Hepatocellular Carcinoma Recurrence and Graft Size in Living Donor Liver Transplantation: A Systematic Review. Int J Mol Sci 2023; 24:6224. [PMID: 37047199 PMCID: PMC10093934 DOI: 10.3390/ijms24076224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 03/21/2023] [Accepted: 03/22/2023] [Indexed: 03/29/2023] Open
Abstract
The aim of this work was to assess the association between graft-to-recipient weight ratio (GRWR) in adult-to-adult living donor liver transplantation (LDLT) and hepatocellular carcinoma (HCC) recurrence. A search of the MEDLINE and EMBASE databases was performed until December 2022 for studies comparing different GRWRs in the prognosis of HCC recipients in LDLT. Data were pooled to evaluate 1- and 3-year survival rates. We identified three studies, including a total of 782 patients (168 GRWR < 0.8 vs. 614 GRWR ≥ 0.8%). The pooled overall survival was 85% and 77% at one year and 90% and 83% at three years for GRWR < 0.8 and GRWR ≥ 0.8, respectively. The largest series found that, in patients within Milan criteria, the GRWR was not associated with lower oncological outcomes. However, patients with HCC outside the Milan criteria with a GRWR < 0.8% had lower survival and higher tumor recurrence rates. The GRWR < 0.8% appears to be associated with lower survival rates in HCC recipients, particularly for candidates with tumors outside established HCC criteria. Although the data are scarce, the results of this study suggest that considering the individual GRWR not only as risk factor for small-for-size-syndrome but also as contributor to HCC recurrence in patients undergoing LDLT would be beneficial. Novel perfusion technologies and pharmacological interventions may contribute to improving outcomes.
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Affiliation(s)
- Alessandro Parente
- HPB and Transplant Unit, Department of Surgical Science, University of Rome Tor Vergata, 00133 Rome, Italy
- Division of Hepatobiliary and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
| | - Hwui-Dong Cho
- Division of Hepatobiliary and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
| | - Ki-Hun Kim
- Division of Hepatobiliary and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
| | - Andrea Schlegel
- Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Centre of Preclinical Research, 20122 Milan, Italy
- Department of Surgery and Transplantation, Swiss HPB Centre, University Hospital Zurich, 8091 Zurich, Switzerland
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Pang L, Yeung OWH, Ng KTP, Liu H, Zhu J, Liu J, Yang X, Ding T, Qiu W, Wang Y, Chiu TLS, Chen Z, Lo CM, Man K. Postoperative Plasmacytoid Dendritic Cells Secrete IFNα to Promote Recruitment of Myeloid-Derived Suppressor Cells and Drive Hepatocellular Carcinoma Recurrence. Cancer Res 2022; 82:4206-4218. [PMID: 36112065 DOI: 10.1158/0008-5472.can-22-1199] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 08/01/2022] [Accepted: 09/12/2022] [Indexed: 12/14/2022]
Abstract
Patients with hepatocellular carcinoma (HCC) confront a high incidence of tumor recurrence after curative surgical resection. Hepatic ischemia-reperfusion injury (IRI) is the major consequence of surgical stress during hepatectomy. Although it has been suggested that hepatic IRI-induced immunosuppression could contribute to tumor relapse after surgery, the underlying mechanisms have not been fully defined. Here, using a multiplex cytokine array, we found that levels of postoperative IFNα serve as an independent risk factor for tumor recurrence in 100 patients with HCC with curative hepatectomy. Plasmacytoid dendritic cells (pDC), the major source of IFNα, were activated after surgery and correlated with poor disease-free survival. Functionally, IFNα was responsible for mobilization of myeloid-derived suppressor cells (MDSC) following hepatic IRI. Conditioned medium from IFNα-treated hepatocytes mediated the migration of MDSCs in vitro. Mechanistically, IFNα upregulated IRF1 to promote hepatocyte expression of CX3CL1, which subsequently recruited CX3CR1+ monocytic MDSCs. Knockdown of Irf1 or Cx3cl1 in hepatocytes significantly inhibited the accumulation of monocytic MDSCs in vivo. Therapeutically, elimination of pDCs, IFNα, or CX3CR1 could restore the tumor-killing activity of CD8+ T cells, hence limiting tumor growth and lung metastasis following hepatic IRI. Taken together, these data suggest that IFNα-producing pDCs drive CX3CR1+ MDSC recruitment via hepatocyte IRF1/CX3CL1 signaling and lead to tumor recurrence after hepatectomy in HCC. Targeting pDCs and the IFNα/CX3CL1/CX3CR1 axis could inhibit surgical stress-induced HCC recurrence by attenuating postoperative immunosuppression. SIGNIFICANCE IFNα secreted by plasmacytoid dendritic cells drives postoperative immunosuppression and early recurrence of hepatocellular carcinoma, providing new biomarkers and therapeutic targets to improve patient outcomes after surgical resection.
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Affiliation(s)
- Li Pang
- Department of Surgery, School of Clinical Medicine, HKU-SZH & LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Oscar W H Yeung
- Department of Surgery, School of Clinical Medicine, HKU-SZH & LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Kevin T P Ng
- Department of Surgery, School of Clinical Medicine, HKU-SZH & LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Hui Liu
- Department of Surgery, School of Clinical Medicine, HKU-SZH & LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Jiye Zhu
- Department of Surgery, School of Clinical Medicine, HKU-SZH & LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Jiang Liu
- Department of Surgery, School of Clinical Medicine, HKU-SZH & LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.,Hepato-pancreato-biliary Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Xinxiang Yang
- Department of Surgery, School of Clinical Medicine, HKU-SZH & LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Tao Ding
- Department of Surgery, School of Clinical Medicine, HKU-SZH & LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Wenqi Qiu
- Department of Surgery, School of Clinical Medicine, HKU-SZH & LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Yuewen Wang
- Department of Surgery, School of Clinical Medicine, HKU-SZH & LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - T L Shirley Chiu
- Department of Surgery, School of Clinical Medicine, HKU-SZH & LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Zhiwei Chen
- Department of Microbiology, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Chung-Mau Lo
- Department of Surgery, School of Clinical Medicine, HKU-SZH & LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Kwan Man
- Department of Surgery, School of Clinical Medicine, HKU-SZH & LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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10
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SOCS5 knockdown suppresses metastasis of hepatocellular carcinoma by ameliorating HIF-1α-dependent mitochondrial damage. Cell Death Dis 2022; 13:918. [PMID: 36319626 PMCID: PMC9626553 DOI: 10.1038/s41419-022-05361-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 10/14/2022] [Accepted: 10/20/2022] [Indexed: 11/17/2022]
Abstract
The Pringle maneuver (PM) is widely used during hepatocellular carcinoma (HCC) resection. However, it inevitably leads to ischemia and hypoxia, which promotes tumor metastasis. In this study, immunohistochemical staining of specimens from 130 HCC patients revealed that long-time PM significantly affected the prognosis of patients with high expression of suppressor of cytokine signaling 5 (SOCS5), but did not affect the prognosis of patients with low expression of SOCS5. The TCGA database showed that patients with high expression of SOCS5 had higher hypoxia scores, and it was proved that SOCS5 could promote the expression of hypoxia-inducible factor 1 subunit alpha (HIF-1α) protein by clinical tissue samples, cell experiments, lung metastases, and subcutaneous tumorigenesis experiments. Then, we used CoCl2 to construct a hypoxia model, and confirmed that SOCS5 knockdown resisted hypoxia-induced mitochondrial damage by inhibiting the expression of HIF-1α, thereby inhibiting the invasion and migration of HCC cells by immunofluorescence, electron microscopy, migration, invasion, and other experiments. We performed rescue experiments using LY294002 and rapamycin and confirmed that the knockdown of SOCS5-inhibited HCC cell invasion and migration by inhibiting the PI3K/Akt/mTOR/HIF-1α signaling axis. More importantly, we obtained consistent conclusions from clinical, cellular, and animal studies that the hypoxia-induced invasion and migration ability of SOCS5-inhibited HCC were weaker than that of normal HCC. In conclusion, we identified a novel role for SOCS5 in regulating HIF-1α-dependent mitochondrial damage and metastasis through the PI3K/Akt/mTOR pathway. The development of a SOCS5-specific inhibitor, an indirect inhibitor of HIF-1α, might be effective at controlling PM-induced tumor micrometastases during HCC resection.
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11
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Ince V, Sahin TT, Akbulut S, Yilmaz S. Liver transplantation for hepatocellular carcinoma: Historical evolution of transplantation criteria. World J Clin Cases 2022; 10:10413-10427. [PMID: 36312504 PMCID: PMC9602233 DOI: 10.12998/wjcc.v10.i29.10413] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 07/27/2022] [Accepted: 08/25/2022] [Indexed: 02/05/2023] Open
Abstract
Liver transplantation (LT) for hepatocellular carcinoma is still a hot topic, and the main factor that is associated with the success of treatment is to determine the patients who will benefit from LT. Milan criteria have been defined 25 years ago and still is being used for patient selection for LT. However, in living donor LT, the Milan criteria is being extended. Current criteria for patient selection do not only consider morphologic characteristics such as tumor size and number of tumor nodules but also biologic markers that show tumor aggressiveness is also being considered. In the present review article, we have summarized all the criteria and scoring systems regarding LT for hepatocellular carcinoma. All criteria have 5-year overall survival rates that were comparable to the Milan Criteria and ranged between 60%-85%. On the other hand, it was seen that the recurrence rates had increased as the Milan criteria were exceeded; the 5-year recurrence rates ranged between 4.9% to 39.9%. Treatment of hepatocellular carcinoma needs a multidisciplinary approach. Ideal selection criteria are yet to be discovered. The same is true for treatment modalities. The goal will be achieved by a harmonic interplay between basic science researchers and clinicians.
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Affiliation(s)
- Volkan Ince
- Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya 44280, Turkey
| | - Tevfik Tolga Sahin
- Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya 44280, Turkey
| | - Sami Akbulut
- Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya 44280, Turkey
- Biostatistics and Medical Informatics, Inonu University Faculty of Medicine, Malatya 44280, Turkey
| | - Sezai Yilmaz
- Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya 44280, Turkey
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12
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Liu H, Man K. New Insights in Mechanisms and Therapeutics for Short- and Long-Term Impacts of Hepatic Ischemia Reperfusion Injury Post Liver Transplantation. Int J Mol Sci 2021; 22:ijms22158210. [PMID: 34360975 PMCID: PMC8348697 DOI: 10.3390/ijms22158210] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Revised: 07/26/2021] [Accepted: 07/28/2021] [Indexed: 02/07/2023] Open
Abstract
Liver transplantation has been identified as the most effective treatment for patients with end-stage liver diseases. However, hepatic ischemia reperfusion injury (IRI) is associated with poor graft function and poses a risk of adverse clinical outcomes post transplantation. Cell death, including apoptosis, necrosis, ferroptosis and pyroptosis, is induced during the acute phase of liver IRI. The release of danger-associated molecular patterns (DAPMs) and mitochondrial dysfunction resulting from the disturbance of metabolic homeostasis initiates graft inflammation. The inflammation in the short term exacerbates hepatic damage, leading to graft dysfunction and a higher incidence of acute rejection. The subsequent changes in the graft immune environment due to hepatic IRI may result in chronic rejection, cancer recurrence and fibrogenesis in the long term. In this review, we mainly focus on new mechanisms of inflammation initiated by immune activation related to metabolic alteration in the short term during liver IRI. The latest mechanisms of cancer recurrence and fibrogenesis due to the long-term impact of inflammation in hepatic IRI is also discussed. Furthermore, the development of therapeutic strategies, including ischemia preconditioning, pharmacological inhibitors and machine perfusion, for both attenuating acute inflammatory injury and preventing late-phase disease recurrence, will be summarized in the context of clinical, translational and basic research.
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13
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Masior Ł, Grąt M. Methods of Attenuating Ischemia-Reperfusion Injury in Liver Transplantation for Hepatocellular Carcinoma. Int J Mol Sci 2021; 22:8229. [PMID: 34360995 PMCID: PMC8347959 DOI: 10.3390/ijms22158229] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 07/18/2021] [Accepted: 07/29/2021] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most frequent indications for liver transplantation. However, the transplantation is ultimately associated with the occurrence of ischemia-reperfusion injury (IRI). It affects not only the function of the graft but also significantly worsens the oncological results. Various methods have been used so far to manage IRI. These include the non-invasive approach (pharmacotherapy) and more advanced options encompassing various types of liver conditioning and machine perfusion. Strategies aimed at shortening ischemic times and better organ allocation pathways are still under development as well. This article presents the mechanisms responsible for IRI, its impact on treatment outcomes, and strategies to mitigate it. An extensive review of the relevant literature using MEDLINE (PubMed) and Scopus databases until September 2020 was conducted. Only full-text articles written in English were included. The following search terms were used: "ischemia reperfusion injury", "liver transplantation", "hepatocellular carcinoma", "preconditioning", "machine perfusion".
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Affiliation(s)
- Łukasz Masior
- Department of General, Vascular and Oncological Surgery, Medical University of Warsaw, Stępińska Street 19/25, 00-739 Warsaw, Poland
| | - Michał Grąt
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Banacha Street 1A, 02-097 Warsaw, Poland;
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14
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Glutathione S-transferase A2 promotes hepatocellular carcinoma recurrence after liver transplantation through modulating reactive oxygen species metabolism. Cell Death Discov 2021; 7:188. [PMID: 34290233 PMCID: PMC8295304 DOI: 10.1038/s41420-021-00569-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Revised: 06/10/2021] [Accepted: 06/20/2021] [Indexed: 02/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) recurrence after liver transplantation remains a significant clinical problem. Ischemia-reperfusion injury (IRI) occurred inevitably at the early phase after liver transplantation (LT) spawns a significant risk of HCC recurrence. However, their linkage and IRI-derived risk factors for HCC recurrence remain exclusive. Understanding the mechanism of post-transplantation hepatic injury could provide new strategies to prevent the later event of HCC recurrence. We demonstrated that glutathione S-transferase A2 (GSTA2) expression was significantly associated with early phase hepatic and systemic injury and ROS level after liver transplantation. Early phase circulating GSTA2 (EPCGSTA2) protein was a significant predictor of HCC recurrence and survival. Heterogeneous single nucleotide polymorphism at G335C of GSTA2 was significantly associated with poor survival of HCC recipients. Enhancement of GSTA2 could protect HCC cells against H2O2-induced cell death by compensating for the elevated ROS stress. We also demonstrated that GSTA2 played crucial roles in regulating the ROS-associated JNK and AKT signaling pathways and ROS metabolism in HCCs in responding to a dynamic ROS environment. Functionally, endogenous or exogenous upregulation of GSTA2 could promote HCC growth and invasion through activating the epithelial–mesenchymal-transition process. Targeted inhibition of GSTA2 could suppress HCC growth and metastasis. In conclusion, GSTA2 could be a novel prognostic and therapeutic target to combat HCC recurrence after liver transplantation.
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15
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Monocytic MDSC mobilization promotes tumor recurrence after liver transplantation via CXCL10/TLR4/MMP14 signaling. Cell Death Dis 2021; 12:489. [PMID: 33990548 PMCID: PMC8121858 DOI: 10.1038/s41419-021-03788-4] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Revised: 05/03/2021] [Accepted: 05/03/2021] [Indexed: 12/24/2022]
Abstract
Tumor recurrence is the major obstacle for pushing the envelope of liver transplantation for hepatocellular carcinoma (HCC) patients. The inflammatory cascades activated by acute liver graft injury promote tumor recurrence. We aimed to explore the role and mechanism of myeloid-derived suppressor cell (MDSC) mobilization induced by liver graft injury on tumor recurrence. By analyzing 331 HCC patients who received liver transplantation, the patients with graft weight ratio (GWR, the weight of liver graft divided by the estimated standard liver weight of recipient) <60% had higher tumor recurrence than GWR ≥60% ones. MDSCs and CXCL10/TLR4 levels were significantly increased in patients with GWR <60% or tumor recurrence. These findings were further validated in our rat orthotopic liver transplantation model. In CXCL10−/− and TLR4−/− mice of hepatic ischemia/reperfusion injury plus major hepatectomy (IRH) model, monocytic MDSCs, instead of granulocytic MDSCs, were significantly decreased. Importantly, CXCL10 deficiency reduced the accumulation of TLR4+ monocytic MDSCs, and CXCL10 increased MDSC mobilization in the presence of TLR4. Moreover, MMP14 was identified as the key molecule bridging CXCL10/TLR4 signaling and MDSC mobilization. Knockout or inhibition of CXCL10/TLR4 signaling significantly reduced the tumor growth with decreased monocytic MDSCs and MMP14 in the mouse tumor recurrent model. Our data indicated that monocytic MDSCs were mobilized and recruited to liver graft during acute phase injury, and to promote HCC recurrence after transplantation. Targeting MDSC mobilization via CXCL10/TLR4/MMP14 signaling may represent the therapeutic potential in decreasing post-transplant liver tumor recurrence.
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16
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Sapisochin G, Hibi T, Toso C, Man K, Berenguer M, Heimbach J, Greten TF, Pugh TJ, Dawson LA, Mazzaferro V. Transplant Oncology in Primary and Metastatic Liver Tumors: Principles, Evidence, and Opportunities. Ann Surg 2021; 273:483-493. [PMID: 33065633 DOI: 10.1097/sla.0000000000004071] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Transplant oncology defines any application of transplant medicine and surgery aimed at improving cancer patients' survival and/or quality of life. In practice, liver transplantation for selected hepato-biliary cancers is the only solid organ transplant with demonstrated efficacy in curing cancer. Four are the proposed future contributions of transplant oncology in hepato-biliary cancer (4-e). (1) evolutionary approach to cancer care that includes liver transplantation; (2) elucidation of self and non-self recognition systems, by linking tumor and transplant immunology; (3) exploration of innovative endpoints both in clinical and experimental settings taking advantage from the access to the entire liver explant; (4) extension of surgical limitation in the multidisciplinary approach to hepato-biliary oncology. The aim of this review is to define the principles of transplant oncology that may be applied to hepato-biliary cancer treatment and research, attempting to balance current evidences with future opportunities.
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Affiliation(s)
- Gonzalo Sapisochin
- Multi-Organ Transplant and HPB Surgical Oncology, Division of General Surgery, University Health Network, Department of Surgery, University of Toronto, Toronto, Ontario, Canada
| | - Taizo Hibi
- Department of Pediatric Surgery and Transplantation, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
| | - Christian Toso
- Division of Abdominal Surgery and Hepato-pancreato-biliary Center, Department of Surgery, Geneva University Hospitals, Geneva, Switzerland
| | - Kwan Man
- Department of Surgery, HKU-SZH and LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Marina Berenguer
- Hepatology and Liver Transplantation Unit, Ciberehd, IISLaFe and Facultad de Medicina, La Fe University Hospital, Valencia, Spain
| | - Julie Heimbach
- Department of Surgery Liver Transplant Program, Mayo Clinic, Rochester, Minnesota
| | - Tim F Greten
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research and NCI-CCR Liver Cancer Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Trevor J Pugh
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
- Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Laura A Dawson
- Radiation Medicine Program, Princess Margaret Cancer Centre, Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada
| | - Vincenzo Mazzaferro
- HPB Surgery and Liver Transplantation, Department of Oncology, University of Milan, Milan, Italy and Istituto Nazionale Tumori, Fondazione IRCCS, Milan, Italy
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17
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Ho KM, Cheng KC, Chan FKM, Yeung YP. Laparoscopic hepatectomy versus open hepatectomy for hepatocellular carcinoma: A propensity case-matched analysis of the long-term survival. Ann Hepatobiliary Pancreat Surg 2021; 25:1-7. [PMID: 33649248 PMCID: PMC7952667 DOI: 10.14701/ahbps.2021.25.1.1] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2020] [Revised: 07/12/2020] [Accepted: 07/13/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUNDS/AIMS Despite the widespread popularity of laparoscopic surgery, laparoscopic liver resection (LLR) remains in evolution. This study aimed to compare the long-term outcomes for patients undergoing laparoscopic versus open hepatectomy for hepatocellular carcinoma (HCC) ≤7 cm. METHODS Patients diagnosed with HCC treated by hepatectomy from October 2000 to May 2019 were included. Excluding tumors larger than 7 cm, 1:2 propensity score matching was performed between laparoscopic and open hepatectomies. The perioperative outcomes, 5-year overall survival (OS) and disease-free survival (DFS) of the two groups were compared. RESULTS Forty-five patients who underwent LLR were matched to 90 open hepatectomy (OH) during the same period. LLR group had shorter median hospital stay (5 days vs. 9 days, p=0.00) but required longer operative time (326.0 minutes vs. 272.5 minutes, p=0.018) than the OH group. The 5-year overall survival was better in the LLR group (84.9% vs. 61.1%; p=0.036), though there was no significant difference in the 5-year disease free survival (20.0% vs. 22.2%, p=0.613). The rate of R0 resection was comparable between the 2 groups with a slightly better margin distance in the LLR (5 mm vs. 3 mm, p=0.043). CONCLUSIONS Laparoscopic liver resection is safe and feasible for cirrhotic patients with HCC size up to 7 cm. It has better short-term outcomes and comparable perioperative blood loss and complication rates. The resection margin is not jeopardized and the 5-year overall and disease-free survivals are comparable with the open group.
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Affiliation(s)
- Kit-Man Ho
- Department of Surgery, Kwong Wah Hospital, Hong Kong, China
| | - Kai-Chi Cheng
- Department of Surgery, Kwong Wah Hospital, Hong Kong, China
| | | | - Yuk-Pang Yeung
- Department of Surgery, Kwong Wah Hospital, Hong Kong, China
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18
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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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19
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Lin N, Li J, Ke Q, Xin F, Zeng Y, Wang L, Liu J. Does the intermittent Pringle maneuver affect the recurrence following surgical resection for hepatocellular carcinoma? A systematic review. PLoS One 2020; 15:e0229870. [PMID: 32160231 PMCID: PMC7065790 DOI: 10.1371/journal.pone.0229870] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2019] [Accepted: 02/15/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND AND AIM To evaluate the effect of intermittent pringle maneuver (IPM) on the long-term prognosis and recurrence of hepatocellular carcinoma (HCC). METHODS Eligible studies were identified by PubMed and other databases from Jan 1st 1990 to Mar 31st 2019. Hazard ratios (HR) with 95% confidence interval (CI) were calculated to evaluate the effects of IPM on the long-term prognosis and recurrence of patients with HCC. RESULTS Six studies were enrolled in this meta-analysis. Results showed that there were no differences between IPM group and non-IPM group in the pooled HRs for the overall survival (OS) and disease-free survival (DFS) (HR 1.04, 95%CI 0.84~1.28, P = 0.74; HR 0.93, 95%CI 0.81~1.07, P = 0.29; respectively). However, subgroup analysis showed that the pooled Odd ratios (OR) for the 1-year OS and DFS rates of the IPM group when compared with the non-IPM group were 0.65 (95% CI 0.45~0.94, P = 0.02), 0.38 (95% CI 0.20~0.72, P = 0.003), respectively. In addition, there were no significant differences in the proportions of liver cirrhosis, HBsAg (+), Child-Pugh A class, multiple tumor, vascular invasion, and major hepatectomy between groups of IPM and non-IPM. CONCLUSION Since IPM would increase the risk of early-recurrence, it should be used cautiously in the procedure of hepatectomy for resectable HCC. However, the current conclusion needs further validation. TRIAL REGISTRY NUMBER CRD 42019124923.
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Affiliation(s)
- Nanping Lin
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, China
- The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Jingrong Li
- Department of Laboratory, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
| | - Qiao Ke
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, China
- The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Fuli Xin
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, China
- The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Yongyi Zeng
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, China
- The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Lei Wang
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, China
- Department of Radiation Oncology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Jingfeng Liu
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, China
- The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
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20
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Report of the 24th Annual Congress of the International Liver Transplantation Society. Transplantation 2019; 103:465-469. [DOI: 10.1097/tp.0000000000002549] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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21
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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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22
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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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Lee NP, Wu H, Ng KT, Luo R, Lam TW, Lo CM, Man K. Transcriptome Analysis of Acute Phase Liver Graft Injury in Liver Transplantation. Biomedicines 2018; 6:biomedicines6020041. [PMID: 29642405 PMCID: PMC6027418 DOI: 10.3390/biomedicines6020041] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 04/04/2018] [Accepted: 04/05/2018] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Liver transplantation remains the treatment of choice for a selected group of hepatocellular carcinoma (HCC) patients. However, the long-term benefit is greatly hampered by post-transplant HCC recurrence. Our previous studies have identified liver graft injury as an acute phase event leading to post-transplant tumor recurrence. METHODS To re-examine this acute phase event at the molecular level and in an unbiased way, RNA sequencing (RNA-Seq) was performed on liver graft biopsies obtained from the transplant recipients two hours after portal vein reperfusion with an aim to capture frequently altered pathways that account for post-transplant tumor recurrence. Liver grafts from recurrent recipients (n = 6) were sequenced and compared with those from recipients without recurrence (n = 5). RESULTS RNA expression profiles comparison pointed to several frequently altered pathways, among which pathways related to cell adhesion molecules were the most involved. Subsequent validation using quantitative polymerase chain reaction confirmed the differential involvement of two cell adhesion molecules HFE (hemochromatosis) and CD274 and their related molecules in the acute phase event. CONCLUSION This whole transcriptome strategy unravels the molecular landscape of liver graft gene expression alterations, which can identify key pathways and genes that are involved in acute phase liver graft injury that may lead to post-transplant tumor recurrence.
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Affiliation(s)
- Nikki P. Lee
- Department of Surgery, The University of Hong Kong, Hong Kong, China; (K.T.P.N.); (C.-M.L.); (K.M.)
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou 310003, China
- Correspondence: ; Tel: +852-3917-9652; Fax: +852-3917-9634
| | - Haiyang Wu
- Department of Computer Science, The University of Hong Kong, Hong Kong, China; (H.W.); (R.L.); (T.-W.L.)
| | - Kevin T.P. Ng
- Department of Surgery, The University of Hong Kong, Hong Kong, China; (K.T.P.N.); (C.-M.L.); (K.M.)
| | - Ruibang Luo
- Department of Computer Science, The University of Hong Kong, Hong Kong, China; (H.W.); (R.L.); (T.-W.L.)
| | - Tak-Wah Lam
- Department of Computer Science, The University of Hong Kong, Hong Kong, China; (H.W.); (R.L.); (T.-W.L.)
| | - Chung-Mau Lo
- Department of Surgery, The University of Hong Kong, Hong Kong, China; (K.T.P.N.); (C.-M.L.); (K.M.)
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou 310003, China
| | - Kwan Man
- Department of Surgery, The University of Hong Kong, Hong Kong, China; (K.T.P.N.); (C.-M.L.); (K.M.)
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou 310003, China
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24
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Famularo S, Giani A, Di Sandro S, Sandini M, Giacomoni A, Pinotti E, Lauterio A, Gianotti L, De Carlis L, Romano F. Does the Pringle maneuver affect survival and recurrence following surgical resection for hepatocellular carcinoma? A western series of 441 patients. J Surg Oncol 2018; 117:198-206. [PMID: 29082526 DOI: 10.1002/jso.24819] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Accepted: 07/31/2017] [Indexed: 12/17/2022]
Abstract
BACKGROUND The impact of the Pringle maneuver (PM) on long-term outcome after curative resection for hepatocellular carcinoma (HCC) is controversial, with eastern series reporting conflicting results. We aim to evaluate the impact of the PM in a western cohort. METHODS We retrospectively analyzed patients with HCC who underwent liver resection between January 2001 and August 2015. Patients were divided in two groups based the use of the PM during resection. Primary outcomes were overall survival (OS) and disease-free survival (DFS). RESULTS A total of 441 patients were analyzed. Of these, 176 patients (39.9%) underwent PM. Median OS was 46.4 months (95%CI: 34.1-58.7) for the PM group and 56.5 months (95%CI: 37.1-75.9) for the no-PM group (P = 0.188), with a median DFS of 26.7 months (95%CI: 15.7-37.7) and 24.9 months (95%CI: 18.1-31.7), respectively (P = 0.883). CONCLUSIONS These results suggest that PM does not increase the risk of tumor recurrence or decrease long-term survival.
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Affiliation(s)
- Simone Famularo
- School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
- Department of Surgery, San Gerardo Hospital, Monza, Italy
| | - Alessandro Giani
- School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
- Department of Surgery, San Gerardo Hospital, Monza, Italy
| | - Stefano Di Sandro
- Department of General Surgery and Transplantation, Niguarda Ca' Granda Hospital, Milan, Italy
| | - Marta Sandini
- School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
- Department of Surgery, San Gerardo Hospital, Monza, Italy
| | - Alessandro Giacomoni
- Department of General Surgery and Transplantation, Niguarda Ca' Granda Hospital, Milan, Italy
| | - Enrico Pinotti
- School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
- Department of Surgery, San Gerardo Hospital, Monza, Italy
| | - Andrea Lauterio
- Department of General Surgery and Transplantation, Niguarda Ca' Granda Hospital, Milan, Italy
| | - Luca Gianotti
- School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
- Department of Surgery, San Gerardo Hospital, Monza, Italy
| | - Luciano De Carlis
- School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
- Department of General Surgery and Transplantation, Niguarda Ca' Granda Hospital, Milan, Italy
| | - Fabrizio Romano
- School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
- Department of Surgery, San Gerardo Hospital, Monza, Italy
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25
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Qi X, Ng KTP, Lian Q, Li CX, Geng W, Ling CC, Yeung WH, Ma YY, Liu XB, Liu H, Liu J, Yang XX, Lo CM, Man K. Glutathione Peroxidase 3 Delivered by hiPSC-MSCs Ameliorated Hepatic IR Injury via Inhibition of Hepatic Senescence. Theranostics 2018; 8:212-222. [PMID: 29290803 PMCID: PMC5743470 DOI: 10.7150/thno.21656] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Accepted: 07/24/2017] [Indexed: 12/18/2022] Open
Abstract
Background and Aims: Down-regulation of GPx3 accelerated hepatic senescence, which further caused overwhelming inflammation and severe liver graft injury. MSCs derived from human induced pluripotent stem cells (hiPSC-MSCs) have been developed as more efficient delivery vehicle with the property of injury tropism. Here, we aimed to explore the suppressive role of GPx3 in hepatic IR injury using novel delivery system of hiPSC-MSCs. Methods: The mice IR injury model with partial hepatectomy was established. The engineered hiPSC-MSCs delivering GPx3 was constructed. All the mice were segregated into three groups. hiPSC-MSC-GPx3, hiPSC-MSC-pCDH (vector control) or PBS were injected via portal vein after reperfusion. Liver injury was evaluated by histological and serological test. Hepatic apoptosis was detected by Tunel staining and remnant liver regeneration was assessed by Ki67 staining. The role of hepatic senescence in liver graft injury was evaluated in rat orthotopic liver transplantation model. The suppressive effect of GPx3 on hepatic senescence was examined in mice IR injury model and confirmed in vitro. Hepatic senescence was detected by SA-β-Gal and P16/ink4a staining. Results: GPx3 can be successfully delivered by hiPSC-MSCs into liver tissues. Histological examination showed that hiPSC-MSC-GPx3 treatment significantly ameliorated hepatic IR injury post-operation. Significantly lower LDH (891.43±98.45 mU/mL, P<0.05) and AST (305.77±36.22 IU/L, P<0.01) were observed in hiPSC-MSC-GPx3 group compared with control groups. Less apoptotic hepatocytes were observed and the remnant liver regeneration was more active in hiPSC-MSC-GPx3 group. In rat orthotopic liver transplantation model, more senescent hepatocytes were observed in small-for-size liver graft, in which GPx3 expression was significantly compromised. In mice IR injury model, hiPSC-MSC-GPx3 significantly suppressed hepatic senescence. In addition, rGPx3 inhibited cellular senescence of liver cells in a dose dependent manner. Four candidate genes (CD44, Nox4, IFNG, SERPERINB2) were identified to be responsible for suppressive effect of GPx3 on hepatic senescence. Conclusion: Engineered hiPSC-MSCs delivering GPx3 ameliorated hepatic IR injury via inhibition of hepatic senescence.
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26
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Lee EC, Kim SH, Shim JR, Park SJ. Small-for-size grafts increase recurrence of hepatocellular carcinoma in liver transplantation beyond milan criteria. Liver Transpl 2018; 24:35-43. [PMID: 28885774 DOI: 10.1002/lt.24868] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Revised: 07/30/2017] [Accepted: 08/27/2017] [Indexed: 12/13/2022]
Abstract
Living donor liver transplantation (LDLT) has been reported to have high rates of hepatocellular carcinoma (HCC) recurrence compared with deceased donor liver transplantation (DDLT). This has been assumed to be due to the frequent use of small-for-size grafts (SFSGs) in LDLT rather than DDLT, but the relationship between graft size and prognosis remains controversial. This study aimed to clarify the effect of SFSGs on the oncologic outcomes of patients with HCC who underwent LDLT. Between January 2005 and December 2015, 597 consecutive patients underwent LDLT. Among these patients, those with HCC who underwent LDLT were randomly matched at a 1:3 ratio (graft-to-recipient body weight ratio [GRWR] < 0.8%:GRWR > 0.8%) according to propensity score. HCC recurrence and patient survival were analyzed using the Kaplan-Meier method and log-rank test. In addition, stratified subgroup analysis based on the Milan criteria was performed. SFSG was defined as a GRWR < 0.8%. Using propensity score matching, 82 patients with GRWR < 0.8% and 246 patients with GRWR ≥ 0.8% were selected. For patients with HCC within the Milan criteria, no significant difference of HCC recurrence (P = 0.82) and patient survival (P = 0.95) was found based on GRWR. However, for patients with HCC beyond the Milan criteria, 1-, 3-, and 5-year recurrence-free survival rates were 52.4%, 49.3%, and 49.3%, respectively, for patients with GRWR < 0.8%, and 76.5%, 68.3%, and 64.3%, respectively, for patients with GRWR ≥ 0.8% (P = 0.049). The former group exhibited poor patient survival rates (P = 0.047). In conclusion, for patients with HCC within the Milan criteria, no significant difference in oncologic outcomes was found based on liver graft size. However, among the patients with HCC beyond the Milan criteria, SFSG recipients showed poor oncologic outcomes. Because extended criteria are frequently used in LDLT for HCC, a recipient's prognosis can be improved if a liver graft of appropriate size is carefully selected during donor selection. Liver Transplantation 24 35-43 2018 AASLD.
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Affiliation(s)
- Eung Chang Lee
- Center for Liver Cancer, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea
| | - Seong Hoon Kim
- Center for Liver Cancer, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea
| | - Jae Ryong Shim
- Center for Liver Cancer, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea
| | - Sang-Jae Park
- Center for Liver Cancer, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea
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27
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Li CX, Lo CM, Lian Q, Ng KTP, Liu XB, Ma YY, Qi X, Yeung OWH, Tergaonkar V, Yang XX, Liu H, Liu J, Shao Y, Man K. Repressor and activator protein accelerates hepatic ischemia reperfusion injury by promoting neutrophil inflammatory response. Oncotarget 2017; 7:27711-23. [PMID: 27050284 PMCID: PMC5053682 DOI: 10.18632/oncotarget.8509] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Accepted: 03/22/2016] [Indexed: 12/27/2022] Open
Abstract
Repressor and activator protein (Rap1) directly regulates nuclear factor-κB (NF-κB) dependent signaling, which contributes to hepatic IRI. We here intended to investigate the effect of Rap1 in hepatic ischemia reperfusion injury (IRI) and to explore the underlying mechanisms. The association of Rap1 expression with hepatic inflammatory response were investigated in both human and rat liver transplantation. The effect of Rap1 in hepatic IRI was studied in Rap1 knockout mice IRI model in vivo and primary cells in vitro. Our results showed that over expression of Rap1 was associated with severe liver graft inflammatory response, especially in living donor liver transplantation. The results were also validated in rat liver transplantation model. In mice hepatic IRI model, the knockout of Rap1 reduced hepatic damage and hepatic inflammatory response. In primary cells, the knockout of Rap1 suppressed neutrophils migration activity and adhesion in response to liver sinusoidal endothelial cells through down-regulating neutrophils F-Actin expression and CXCL2/CXCR2 pathway. In addition, the knockout of Rap1 also decreased production of pro-inflammatory cytokines/chemokines in primary neutrophils and neutrophils-induced hepatocyte damage. In conclusion, Rap1 may induce hepatic IRI through promoting neutrophils inflammatory response. Rap1 may be the potential therapeutic target of attenuating hepatic IRI.
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Affiliation(s)
- Chang Xian Li
- Department of Surgery, The University of Hong Kong, Hong Kong, China.,Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China
| | - Chung Mau Lo
- Department of Surgery, The University of Hong Kong, Hong Kong, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The University of Hong Kong, Hong Kong, China.,Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China
| | - Qizhou Lian
- Department of Medicine, The University of Hong Kong, Hong Kong, China
| | - Kevin Tak-Pan Ng
- Department of Surgery, The University of Hong Kong, Hong Kong, China.,Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China
| | - Xiao Bing Liu
- Department of Surgery, The University of Hong Kong, Hong Kong, China.,Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China
| | - Yuen Yuen Ma
- Department of Surgery, The University of Hong Kong, Hong Kong, China.,Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China
| | - Xiang Qi
- Department of Surgery, The University of Hong Kong, Hong Kong, China.,Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China
| | - Oscar Wai Ho Yeung
- Department of Surgery, The University of Hong Kong, Hong Kong, China.,Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China
| | - Vinay Tergaonkar
- Institute of Molecular and Cellular Biology, Biopolis, Singapore
| | - Xin Xiang Yang
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Hui Liu
- Department of Surgery, The University of Hong Kong, Hong Kong, China.,Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China
| | - Jiang Liu
- Department of Surgery, The University of Hong Kong, Hong Kong, China.,Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China
| | - Yan Shao
- Department of Surgery, The University of Hong Kong, Hong Kong, China.,Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China
| | - Kwan Man
- Department of Surgery, The University of Hong Kong, Hong Kong, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The University of Hong Kong, Hong Kong, China.,Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China
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Ng KTP, Lo CM, Wong N, Li CX, Qi X, Liu XB, Geng W, Yeung OWH, Ma YY, Chan SC, Man K. Early-phase circulating miRNAs predict tumor recurrence and survival of hepatocellular carcinoma patients after liver transplantation. Oncotarget 2017; 7:19824-39. [PMID: 26918346 PMCID: PMC4991421 DOI: 10.18632/oncotarget.7627] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Accepted: 02/16/2016] [Indexed: 12/13/2022] Open
Abstract
Post-liver transplantation tumor recurrence is a major challenge for hepatocellular carcinoma (HCC) recipients. We aimed to identify early-phase circulating microRNAs after liver transplantation for predicting tumor recurrence and survival of HCC recipients. Circulating microRNA profiles at early-phase (2-hour after portal vein reperfusion) after liver transplantation were compared between HCC recipients with (n=4) and without tumor recurrence (n=8) by microarray analyses. Candidate microRNAs were validated in 62 HCC recipients by quantitative RT-PCR. The prognostic values of microRNAs for tumor recurrence and survival were examined. Simulated in vitro ischemia-reperfusion injury models were employed to characterize the possible mechanism of up-regulation of circulating microRNAs. Our results showed that up-regulation of circulating miR-148a, miR-1246 or miR-1290 at early-phase was significantly associated with HCC recurrence after liver transplantation. Among them, miR-148a (p=0.030) and miR-1246 (p=0.009) were significant predictors of HCC recurrence. MiR-1246 was an independent predictor of overall (p=0.023) and disease-free survival (p=0.020) of HCC recipients. The level of early-phase circulating miR-1246 was positively correlated with serum AST and ALT levels in HCC recipients after liver transplantation. The expression of hepatic miR-1246 was positively correlated with TNFα mRNA. In vitro experiments indicated that injury-induced activation and differentiation of macrophages significantly elevated the expression and secretion of miR-1246. In conclusion, early-phase circulating miR-1246 is an indicator of hepatic injury and a novel prognostic biomarker for tumor recurrence and survival of HCC recipients after liver transplantation.
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Affiliation(s)
- Kevin Tak-Pan Ng
- Department of Surgery, The University of Hong Kong, Hong Kong.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Chung Mau Lo
- Department of Surgery, The University of Hong Kong, Hong Kong.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Nathalie Wong
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong
| | - Chang Xian Li
- Department of Surgery, The University of Hong Kong, Hong Kong.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Xiang Qi
- Department of Surgery, The University of Hong Kong, Hong Kong.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Xiao Bing Liu
- Department of Surgery, The University of Hong Kong, Hong Kong.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Wei Geng
- Department of Surgery, The University of Hong Kong, Hong Kong.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Oscar Wai-Ho Yeung
- Department of Surgery, The University of Hong Kong, Hong Kong.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Yuen Yuen Ma
- Department of Surgery, The University of Hong Kong, Hong Kong.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - See Ching Chan
- Department of Surgery, The University of Hong Kong, Hong Kong
| | - Kwan Man
- Department of Surgery, The University of Hong Kong, Hong Kong.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
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Orci LA, Oldani G, Lacotte S, Slits F, Friedli I, Wirth W, Toso C, Vallée JP, Crowe LA. Dynamic Volume Assessment of Hepatocellular Carcinoma in Rat Livers Using a Clinical 3T MRI and Novel Segmentation. J INVEST SURG 2017; 31:44-53. [PMID: 28107094 DOI: 10.1080/08941939.2016.1276987] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
PURPOSE In vivo liver cancer research commonly uses rodent models. One of the limitations of such models is the lack of accurate and reproducible endpoints for a dynamic assessment of growing tumor nodules. The aim of this study was to validate a noninvasive, true volume segmentation method using two rat hepatocellular carcinoma (HCC) models, correlating magnetic resonance imaging (MRI) with histological volume measurement, and with blood levels of α-fetoprotein. MATERIALS AND METHODS We used 3T clinical MRI to quantify tumor volume with follow-up over time. Using two distinct rat HCC models, calculated MRI tumor volumes were correlated with volumes from histological sections, or with blood levels of α-fetoprotein. Eleven rats, comprising six Buffalo rats (n = 9 scans) and five Fischer rats (n = 14 tumors), were injected in the portal vein with 2.5 × 105 and 2.0 × 106 syngeneic HCC cells, respectively. Longitudinal (T1) relaxation time- and transverse (T2) relaxation time-weighted MR images were acquired. RESULTS The three-dimensional (3D) T1-weighted gradient echo had 0.35-mm isotropic resolution allowing accurate semi-automatic volume segmentation. 2D T2-weighted imaging provided high tumor contrast. Segmentation of combined 3D gradient echo T1-weighted images and 2D turbo spin echo T2-weighted images provided excellent correlation with histology (y = 0.866x + 0.034, R² = 0.997 p < .0001) and with α-fetoprotein (y = 0.736x + 1.077, R² = 0.976, p < .0001). There was robust inter- and intra-observer reproducibility (intra-class correlation coefficient > 0.998, p < .0001). CONCLUSIONS We have developed a novel, noninvasive contrast imaging protocol which enables semi-automatic 3D volume quantification to analyze nonspherical tumor nodules and to follow up the growth of tumor nodules over time.
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Affiliation(s)
- Lorenzo A Orci
- a Divisions of Abdominal and Transplantation Surgery, Hepato-Pancreato-Biliary Centre, Department of Surgery , University Hospitals of Geneva and Faculty of Medicine, University of Geneva , Geneva , Switzerland
| | - Graziano Oldani
- a Divisions of Abdominal and Transplantation Surgery, Hepato-Pancreato-Biliary Centre, Department of Surgery , University Hospitals of Geneva and Faculty of Medicine, University of Geneva , Geneva , Switzerland
| | - Stephanie Lacotte
- a Divisions of Abdominal and Transplantation Surgery, Hepato-Pancreato-Biliary Centre, Department of Surgery , University Hospitals of Geneva and Faculty of Medicine, University of Geneva , Geneva , Switzerland
| | - Florence Slits
- a Divisions of Abdominal and Transplantation Surgery, Hepato-Pancreato-Biliary Centre, Department of Surgery , University Hospitals of Geneva and Faculty of Medicine, University of Geneva , Geneva , Switzerland
| | - Iris Friedli
- b Division of Radiology , University Hospitals of Geneva and Faculty of Medicine, University of Geneva , Geneva , Switzerland
| | - Wolfgang Wirth
- c Institute of Anatomy, Paracelsus Medical University , Salzburg , Austria
| | - Christian Toso
- a Divisions of Abdominal and Transplantation Surgery, Hepato-Pancreato-Biliary Centre, Department of Surgery , University Hospitals of Geneva and Faculty of Medicine, University of Geneva , Geneva , Switzerland
| | - Jean-Paul Vallée
- b Division of Radiology , University Hospitals of Geneva and Faculty of Medicine, University of Geneva , Geneva , Switzerland
| | - Lindsey A Crowe
- b Division of Radiology , University Hospitals of Geneva and Faculty of Medicine, University of Geneva , Geneva , Switzerland
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Li CX, Ling CC, Shao Y, Xu A, Li XC, Ng KTP, Liu XB, Ma YY, Qi X, Liu H, Liu J, Yeung OWH, Yang XX, Liu QS, Lam YF, Zhai Y, Lo CM, Man K. CXCL10/CXCR3 signaling mobilized-regulatory T cells promote liver tumor recurrence after transplantation. J Hepatol 2016; 65:944-952. [PMID: 27245433 DOI: 10.1016/j.jhep.2016.05.032] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2015] [Revised: 05/02/2016] [Accepted: 05/20/2016] [Indexed: 01/19/2023]
Abstract
BACKGROUND & AIMS Liver graft injury and tumor recurrence are the major challenges of liver transplantation for the patients with hepatocellular carcinoma (HCC). Here, we aimed to explore the role and mechanism of liver graft injury mobilizing regulatory T cells (Tregs), which lead to late phase tumor recurrence after liver transplantation. METHODS The correlation among tumor recurrence, liver graft injury and Tregs mobilization were studied in 257 liver transplant recipients with HCC and orthotopic rat liver transplantation models. The direct roles of CXCL10/CXCR3 signaling on Tregs mobilization and tumor recurrence were investigated in CXCL10-/- and CXCR3-/- mice models with hepatic IR injury. RESULTS Clinically, patients received the graft with graft weight ratio (GWR) <60% had higher HCC recurrence after liver transplantation than the recipients with GWR ⩾60% graft. More circulating Tregs and higher intragraft TLR4/CXCL10/CXCR3 levels were detected in recipients with GWR <60% graft. These results were further validated in rat transplantation model. Foxp3+ cells and expressions of TLR4, CXCL10, TGFβ, CTLA-4 and CD274 were increased in rat liver tumor tissues from small-for-size graft group. In mouse model, the mobilization and recruitment of Tregs were decreased in TLR4-/-, CXCL10-/- and CXCR3-/- mice compared to wild-type mice. Moreover, less CXCR3+ Tregs were recruited into liver in CXCL10-/- mice after hepatic IR injury. The knockout of CXCL10 and depletion of Tregs inhibited tumor recurrence after hepatic IR injury. CONCLUSION CXCL10/CXCR3 signaling upregulated at liver graft injury directly induced the mobilization and intragraft recruitment of Tregs, which further promoted HCC recurrence after transplantation. LAY SUMMARY There were positive correlation among tumor recurrence, circulating Tregs and liver graft injury after human transplantation for HCC patients. The knockout of CXCL10 decreased hepatic recruitment of CXCR3+ Tregs and late phase tumor recurrence after hepatic IR injury.
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Affiliation(s)
- Chang Xian Li
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Chang Chun Ling
- Department of Surgery, The University of Hong Kong, Hong Kong, China; Department of General Surgery, Affiliated Hospital of Nantong University, Nantong city, 226001, China
| | - Yan Shao
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Aimin Xu
- Department of Medicine, The University of Hong Kong, Hong Kong, China
| | - Xiang Cheng Li
- Liver Transplantation Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Kevin Tak-Pan Ng
- Department of Surgery, The University of Hong Kong, Hong Kong, China; Shenzhen Institute of Research and Innovation, The University of Hong Kong, China
| | - Xiao Bing Liu
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Yuen Yuen Ma
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Xiang Qi
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Hui Liu
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Jiang Liu
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | | | - Xin Xiang Yang
- Department of Surgery, The University of Hong Kong, Hong Kong, China; Liver Transplantation Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Qing Sheng Liu
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Yin Fan Lam
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Yuan Zhai
- Department of Surgery, David Geffen School of Medicine, University of California at Los Angeles, USA
| | - Chung Mau Lo
- Department of Surgery, The University of Hong Kong, Hong Kong, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The University of Hong Kong, Hong Kong, China; Shenzhen Institute of Research and Innovation, The University of Hong Kong, China
| | - Kwan Man
- Department of Surgery, The University of Hong Kong, Hong Kong, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The University of Hong Kong, Hong Kong, China; Shenzhen Institute of Research and Innovation, The University of Hong Kong, China.
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Qi X, Ng KTP, Shao Y, Li CX, Geng W, Ling CC, Ma YY, Liu XB, Liu H, Liu J, Yeung WH, Lo CM, Man K. The Clinical Significance and Potential Therapeutic Role of GPx3 in Tumor Recurrence after Liver Transplantation. Theranostics 2016; 6:1934-46. [PMID: 27570561 PMCID: PMC4997247 DOI: 10.7150/thno.16023] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2016] [Accepted: 06/08/2016] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND AND AIMS Our previous study showed that small-for-size liver graft may provide favorable micro-environment for tumor growth. GPx3, an anti-oxidant, not only attenuates oxidative stress, but also suppresses liver tumor growth in our recent study. Here, we aimed to characterize the clinical significance and explore the functional role of GPx3 in HCC recurrence after liver transplantation. METHODS To explore the association between GPx3 expression and HCC invasiveness, a rat orthotopic liver transplantation model with tumor development was established. To investigate the clinical relevance of GPx3, 105 HCC patients who underwent liver transplantation were recruited. The suppressive role of GPx3 in HCC cells was studied using wound healing, Matrigel invasion assay and lung metastasis model. The real-time intravital imaging system was applied to directly visualize the tumor cells invasion in a living animal. The underlying mechanism was further explored. RESULTS GPx3 was identified as a down-regulated protein in small-for-size liver graft and significantly associated with invasive phenotype of tumor growth in a rat model. Plasma GPx3 was significantly lower in small-for-size graft group post-transplantation (day1: 33 vs 1147; day3: 3209 vs 4459; day7: 303 vs 2506; mU/mL, P<0.05) in rat model. Clinically, the plasma GPx3 was significantly lower in the recipients with HCC recurrence post-transplantation (day1: 4.16 vs 8.99 µg/mL, P<0.001; day7: 3.86 vs 9.99 µg/mL, P<0.001). Furthermore, lower plasma GPx3 was identified as an independent predictor (HR=4.528, P=0.046) for poor overall survival post-transplantation. Over-expression of GPx3 significantly suppressed migration, invasiveness and metastasis of HCC cells. Real-time intravital imaging showed that GPx3 significantly suppressed HCC invasiveness in a live animal. GPx3 suppressed the tumor invasiveness through inhibition of JNK-cJun-MMP2 pathway. CONCLUSION GPx3 may possess prognostic and therapeutic value for HCC patients after liver transplantation.
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Xu LN, Xu YY, Gao DW. Impact of operative and peri-operative factors on the long-term prognosis of primary liver cancer patients undergoing hepatectomy. ACTA ACUST UNITED AC 2016; 36:523-528. [DOI: 10.1007/s11596-016-1619-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Accepted: 05/30/2016] [Indexed: 12/17/2022]
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Hu Z, Zhong X, Zhou J, Xiang J, Li Z, Zhang M, Wu J, Jiang W, Zheng S. Smaller grafts do not imply early recurrence in recipients transplanted for hepatocellular carcinoma: A Chinese experience. Sci Rep 2016; 6:26487. [PMID: 27225666 PMCID: PMC4880903 DOI: 10.1038/srep26487] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Accepted: 04/29/2016] [Indexed: 02/08/2023] Open
Abstract
Liver graft size has long been a critical issue in adult-to-adult living donor liver transplantation (LDLT). We analyzed China Liver Transplant Registry data (January 2007-December 2009), identifying 295 patients who underwent LDLT for hepatocellular carcinoma (HCC). The recipients were divided into two groups: A, graft-to-recipient body weight ratio (GRWR) ≤ 0.8% (n = 56); B, GRWR > 0.8% (n = 239). We evaluated donor, recipient, and operative factors and analyzed survival outcome and the risk factors affecting overall and recurrence survival. As a result, the overall survival rates of group B were significantly higher than that of group A (p = 0.009); the corresponding tumor-free survival rates did not differ significantly (p = 0.133). The overall survival rates among the 151 recipients who met the Hangzhou criteria did not differ significantly (p = 0.953), nor did the corresponding tumor-free survival rates (p = 0.893). Multivariate analysis determined that GRWR was a significant risk factor for poor survival but not for early recurrence. In conclusion, small grafts may predict poorer survival outcome but do not indicate earlier HCC recurrence in recipients transplanted for HCC, and survival outcome with smaller grafts is merely acceptable in selected recipients.
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Affiliation(s)
- Zhenhua Hu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery First Affiliated Hospital, School of Medicine, Zhejiang University; Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou 310003, China
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 310003 Hangzhou, China
| | - Xun Zhong
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery First Affiliated Hospital, School of Medicine, Zhejiang University; Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou 310003, China
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 310003 Hangzhou, China
| | - Jie Zhou
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery First Affiliated Hospital, School of Medicine, Zhejiang University; Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou 310003, China
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 310003 Hangzhou, China
| | - Jie Xiang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery First Affiliated Hospital, School of Medicine, Zhejiang University; Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou 310003, China
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 310003 Hangzhou, China
| | - Zhiwei Li
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery First Affiliated Hospital, School of Medicine, Zhejiang University; Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou 310003, China
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 310003 Hangzhou, China
| | - Min Zhang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery First Affiliated Hospital, School of Medicine, Zhejiang University; Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou 310003, China
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 310003 Hangzhou, China
| | - Jian Wu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery First Affiliated Hospital, School of Medicine, Zhejiang University; Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou 310003, China
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 310003 Hangzhou, China
| | - Wenshi Jiang
- China Liver Transplant Registry, Hong Kong, 999077, China
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery First Affiliated Hospital, School of Medicine, Zhejiang University; Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou 310003, China
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 310003 Hangzhou, China
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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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35
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Liu S, Li X, Li H, Guo L, Zhang B, Gong Z, Zhang J, Ye Q. Longer duration of the Pringle maneuver is associated with hepatocellular carcinoma recurrence following curative resection. J Surg Oncol 2016; 114:112-8. [PMID: 27122256 DOI: 10.1002/jso.24271] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Accepted: 04/09/2016] [Indexed: 12/23/2022]
Affiliation(s)
- Shuang Liu
- Liver Cancer Institute, Zhongshan Hospital; Fudan University; Shanghai P. R. China
- Key Laboratory of Carcinogenesis and Cancer Invasion; Fundan University, Ministry of Education; Shanghai P. R. China
| | - Xiaoqiang Li
- Liver Cancer Institute, Zhongshan Hospital; Fudan University; Shanghai P. R. China
- Key Laboratory of Carcinogenesis and Cancer Invasion; Fundan University, Ministry of Education; Shanghai P. R. China
| | - Hui Li
- Liver Cancer Institute, Zhongshan Hospital; Fudan University; Shanghai P. R. China
- Key Laboratory of Carcinogenesis and Cancer Invasion; Fundan University, Ministry of Education; Shanghai P. R. China
| | - Lei Guo
- Liver Cancer Institute, Zhongshan Hospital; Fudan University; Shanghai P. R. China
- Key Laboratory of Carcinogenesis and Cancer Invasion; Fundan University, Ministry of Education; Shanghai P. R. China
| | - Bo Zhang
- Liver Cancer Institute, Zhongshan Hospital; Fudan University; Shanghai P. R. China
- Key Laboratory of Carcinogenesis and Cancer Invasion; Fundan University, Ministry of Education; Shanghai P. R. China
| | - Zijun Gong
- Liver Cancer Institute, Zhongshan Hospital; Fudan University; Shanghai P. R. China
- Key Laboratory of Carcinogenesis and Cancer Invasion; Fundan University, Ministry of Education; Shanghai P. R. China
| | - Jubo Zhang
- Liver Cancer Institute, Zhongshan Hospital; Fudan University; Shanghai P. R. China
- Key Laboratory of Carcinogenesis and Cancer Invasion; Fundan University, Ministry of Education; Shanghai P. R. China
| | - Qinghai Ye
- Liver Cancer Institute, Zhongshan Hospital; Fudan University; Shanghai P. R. China
- Key Laboratory of Carcinogenesis and Cancer Invasion; Fundan University, Ministry of Education; Shanghai P. R. China
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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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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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Xu X, Ling Q, Wang J, Xie H, Wei X, Lu D, Hu Q, Zhang X, Wu L, Zhou L, Zheng S. Donor miR-196a-2 polymorphism is associated with hepatocellular carcinoma recurrence after liver transplantation in a Han Chinese population. Int J Cancer 2016; 138:620-629. [PMID: 26365437 DOI: 10.1002/ijc.29821] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2015] [Accepted: 07/28/2015] [Indexed: 01/05/2023]
Abstract
Recurrence of hepatocellular carcinoma (HCC) is one of the leading causes of death after liver transplantation (LT). We aim to evaluate the association of donor and recipient single nucleotide polymorphisms (SNPs) with the risk of HCC recurrence after LT. A total of 155 adult patients who underwent primary LT for HCC were enrolled. Ten SNPs associated with HCC susceptibility were genotyped. Patients who received donor livers with the rs11614913 homozygous CC variant presented significantly higher recurrence rates of HCC (41.7 vs. 15.3%, p = 0.009) and lower cumulative tumor-free survival (p = 0.005) than those who received TT wild-type donor livers. The donor rs11614913 genetic variant was an independent risk factor for HCC recurrence (odds ratio = 2 per each C allele, p < 0.05) and could significantly improve the predictive abilities of clinical models (Milan, UCSF and Hangzhou criteria). Donor livers homozygous for rs11614913 CC were associated with a higher miR-196a expression than TT (p = 0.002). In a lentiviral infection of mouse liver and orthotopic mouse model of HCC, the liver miR-196a overexpression group showed a significantly larger tumor size than the control group (p = 0.001). There is a close association between the tumor size and expression of miR-196a in the liver (r = 0.693, p = 0.001). In conclusion, the donor miR-196a-2 rs11614913 polymorphism is associated with HCC recurrence after LT and improves the predictive value of clinical models. The overexpression of miR-196a in the liver might provide a tumor-favorable environment for the development of HCC.
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Affiliation(s)
- Xiao Xu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Qi Ling
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Jianguo Wang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Haiyang Xie
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, China
| | - Xuyong Wei
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Di Lu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Qichao Hu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Xuanyu Zhang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Liming Wu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Lin Zhou
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, China
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, China
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Kornberg A, Witt U, Kornberg J, Müller K, Friess H, Thrum K. Postoperative peak serum C-reactive protein is a predictor of outcome following liver transplantation for hepatocellular carcinoma. Biomarkers 2015; 21:152-9. [PMID: 26643974 DOI: 10.3109/1354750x.2015.1118548] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
CONTEXT C-reactive protein (CRP), a biomarker of inflammation, may correlate with prognosis in several malignancies. OBJECTIVE To investigate the prognostic impact of early postoperative peak serum levels of CRP on tumor-specific outcome in 106 liver transplant patients with hepatocellular carcinoma (HCC). METHODS AND RESULTS In multivariate Cox regression analysis, a posttransplant elevated peak CRP level (>versus ≤ 3.5 mg/dl) was identified as an independent predictor of poor recurrence-free survival (p = 0.01; HR = 4.04; CI = 1.399-11.640). CONCLUSION Early postoperative serum CRP may serve as a useful inflammation-based biomarker of outcome in liver transplant patients with HCC.
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Affiliation(s)
- Arno Kornberg
- a Department of Surgery, Klinikum Rechts Der Isar, Technical University , Munich , Germany
| | - Ulrike Witt
- a Department of Surgery, Klinikum Rechts Der Isar, Technical University , Munich , Germany
| | - Jennifer Kornberg
- b Department of Anaesthesiology , Klinikum Großhadern, LMU Munich , Germany
| | | | - Helmut Friess
- a Department of Surgery, Klinikum Rechts Der Isar, Technical University , Munich , Germany
| | - Katharina Thrum
- d Institute of Pathology , Helios Klinikum, Berlin , Germany
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Geng W, Lo CM, Ng KT, Ling CC, Qi X, Li CX, Zhai Y, Liu XB, Ma YY, Man K. Interferon-gamma inducible protein 10 (IP10) induced cisplatin resistance of HCC after liver transplantation through ER stress signaling pathway. Oncotarget 2015; 6:28042-56. [PMID: 26336986 PMCID: PMC4695043 DOI: 10.18632/oncotarget.4832] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Accepted: 07/31/2015] [Indexed: 12/12/2022] Open
Abstract
Tumor recurrence remains an obstacle after liver surgery, especially in living donor liver transplantation (LDLT) for patients with hepatocellular carcinoma (HCC). The acute-phase liver graft injury might potentially induce poor response to chemotherapy in recurrent HCC after liver transplantation. We here intended to explore the mechanism and to identify a therapeutic target to overcome such chemoresistance. The associations among graft injury, overexpression of IP10 and multidrug resistant genes were investigated in a rat liver transplantation model, and further validated in clinical cohort. The role of IP10 on HCC cell proliferation and tumor growth under chemotherapy was studied both in vitro and in vivo. The underlying mechanism was revealed by detecting the activation of endoplasmic reticulum (ER) stress signaling pathways. Moreover, the effect of IP10 neutralizing antibody sensitizing cisplatin treatment was further explored. In rat liver transplantation model, significant up-regulation of IP10 associated with multidrug resistant genes was found in small-for-size liver graft. Clinically, high expression of circulating IP10 was significant correlated with tumor recurrence in HCC patients underwent LDLT. Overexpression of IP10 promoted HCC cell proliferation and tumor growth under cisplatin treatment by activation of ATF6/Grp78 signaling. IP10 neutralizing antibody sensitized cisplatin treatment in nude mice. The overexpression of IP10, which induced by liver graft injury, may lead to cisplatin resistance via ATF6/Grp78 ER stress signaling pathway. IP10 neutralizing antibody could be a potential adjuvant therapy to sensitize cisplatin treatment.
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Affiliation(s)
- Wei Geng
- Department of Surgery, The University of Hong Kong, Hong Kong, China
- Department of Transplantation and Hepatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Chung-Mau Lo
- Department of Surgery, The University of Hong Kong, Hong Kong, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Kevin T.P. Ng
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Chang-Chun Ling
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Xiang Qi
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Chang-Xian Li
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Yuan Zhai
- Department of Surgery, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
| | - Xiao-Bing Liu
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Yuen-Yuen Ma
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Kwan Man
- Department of Surgery, The University of Hong Kong, Hong Kong, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
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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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42
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Huang J, Tang W, Hernandez-Alejandro R, Bertens KA, Wu H, Liao M, Li J, Zeng Y. Intermittent hepatic inflow occlusion during partial hepatectomy for hepatocellular carcinoma does not shorten overall survival or increase the likelihood of tumor recurrence. Medicine (Baltimore) 2014; 93:e288. [PMID: 25526466 PMCID: PMC4603114 DOI: 10.1097/md.0000000000000288] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2014] [Revised: 10/28/2014] [Accepted: 10/29/2014] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate whether the long-term outcomes of hepatocellular carcinoma (HCC) was adversely impacted by intermittent hepatic inflow occlusion (HIO) during hepatic resection. METHODS 1549 HCC patients who underwent hepatic resection between 1998 and 2008 were identified from a prospectively maintained database. Intermittent HIO was performed in 931 patients (HIO group); of which 712 patients had a Pringle maneuver as the mechanism for occlusion (PM group), and 219 patients had selective hemi-hepatic occlusion (SO group). There were 618 patients that underwent partial hepatectomy without occlusion (occlusion-free, OF group). RESULTS The 1-, 3-, and 5- year overall survival (OS) rates were 79%, 59%, and 42% in the HIO group, and 83%, 53%, and 35% in the OF group, respectively. The corresponding recurrence free survival (RFS) rates were 68%, 39%, and 22% in the HIO group, and 74%, 41%, and 18% in the OF group, respectively. There was no significant difference between the 2 groups in OS or RFS (P=0.325 and P=0.416). Subgroup analysis showed patients with blood loss over 3000 mL and those requiring transfusion suffered significantly shorter OS and RFS. Blood loss over 3000 mL and blood transfusion were independent risk factors to OS and RFS. CONCLUSIONS The application of intermittent HIO (PM and SO) during hepatic resection did not adversely impact either OS or RFS in patients with HCC. Intermittent HIO is still a valuable tool in hepatic resection, because high intraoperative blood loss resulting in transfusion is associated with a reduction in both OS and RFS.
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Affiliation(s)
- Jiwei Huang
- From the Department of Liver Surgery, Division of Liver Transplantation, West China Hospital, Sichuan University, Chengdu, China (JH, HW, ML, JL, YZ); Department of Hepato-Biliary-Pancreatic Surgery, University of Tokyo Hospital, University of Tokyo, Tokyo, Japan (WT); Department of Hepato-Biliary-Pancreatic Surgery, London Health Sciences Centre, Western University, London, Canada (RHA, KAB)
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43
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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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46
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The impact of posthepatectomy liver failure on the recurrence of hepatocellular carcinoma. World J Surg 2014; 38:150-8. [PMID: 24132820 DOI: 10.1007/s00268-013-2247-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Patients with hepatocellular carcinoma (HCC) who underwent hepatectomy often developed an intrahepatic recurrence, even though it was a curative one. The relationship between surgery-induced liver damage and the recurrence of HCC has not been described. This study evaluated whether posthepatectomy liver failure, as defined by the International Study Group of Liver Surgery, affected the recurrence of HCC. METHODS We performed a retrospective cohort study of 488 patients with HCC who underwent hepatectomy between 2004 and 2012 at Kyoto University Hospital. Early posthepatectomy liver failure (EPLF) was defined as liver failure occurring between postoperative days 5 and 10. The patients were divided into an EPLF group and a non-EPLF group. Disease-free survival (DFS) was compared between these groups. The influences of host-related, surgery-related, and tumor-related factors on patient outcomes were evaluated using multivariate analyses. RESULTS The EPLF group and the non-EPLF group contained 153 and 335 patients, respectively. The probability of DFS was significantly increased in the non-EPLF group (median: 574 days) compared to the EPLF group (median: 348 days) (hazard ratio, HR [95 % confidence interval, CI] 1.61 [1.29-2.00]). The multivariate analysis revealed that EPLF was an independent factor for DFS (HR [95 % CI] 1.43 [1.13-1.81]), besides the factors previously described, including fibrosis (1.32 [1.05-1.67]), stage (1.85 [1.34-2.51]), tumor differentiation (1.46 [1.11-1.89]), and des-γ-carboxyprothrombin (1.39 [1.10-1.74]). CONCLUSIONS EPLF was associated with postoperative HCC recurrence. The prevention of EPLF might improve the prognosis of patients with HCC.
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Abstract
Liver transplantation (LT) is the most effective treatment for small and unresectable hepatocellular carcinomas (HCCs). With scarcity of deceased donor livers, living donor LT (LDLT) is the alternative to deceased donor LT (DDLT). Animal studies have suggested that regeneration of the partial liver graft encourages HCC recurrence. Increased recurrence was observed in a few studies. Thus, there is the belief that the use of small-for-size graft carries the potential risk of disease recurrence. Nevertheless, those studies were retrospective, with sample sizes not large enough for conclusions.Living donor LT can be performed when a suitable donor is available. The fast tracking of patients for transplantation without a period of observation is an issue. Meta-analyses, however, showed no significant increase in HCC recurrence after LDLT. Patients listed for DDLT and without suitable living donors have to endure a long wait, during which the aggressiveness of their HCC is observed. Such observation almost guarantees slow disease progression when they get transplanted. Nevertheless, a long wait has the disadvantage of transplanting patients with more advanced tumors, although still within standard criteria. Judicious use of deceased donor grafts is the responsibility of the transplant community.Living donor LT for HCC should only be performed after careful assessment of the recipient and tumor status. Although tumor size and number are references widely adopted in tumor staging, biological staging of tumors using positron emission tomography could provide additional information of tumor behavior. A high level of serum α-fetoprotein also warns against LT because it is predictive of a high HCC recurrence rate.
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48
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Kornberg A. Liver Transplantation for Hepatocellular Carcinoma beyond Milan Criteria: Multidisciplinary Approach to Improve Outcome. ISRN HEPATOLOGY 2014; 2014:706945. [PMID: 27335840 PMCID: PMC4890913 DOI: 10.1155/2014/706945] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/15/2013] [Accepted: 01/03/2014] [Indexed: 12/12/2022]
Abstract
The implementation of the Milan criteria (MC) in 1996 has dramatically improved prognosis after liver transplantation (LT) in patients with hepatocellular carcinoma (HCC). Liver transplantation has, thereby, become the standard therapy for patients with "early-stage" HCC on liver cirrhosis. The MC were consequently adopted by United Network of Organ Sharing (UNOS) and Eurotransplant for prioritization of patients with HCC. Recent advancements in the knowledge about tumor biology, radiographic imaging techniques, locoregional interventional treatments, and immunosuppressive medications have raised a critical discussion, if the MC might be too restrictive and unjustified keeping away many patients from potentially curative LT. Numerous transplant groups have, therefore, increasingly focussed on a stepwise expansion of selection criteria, mainly based on tumor macromorphology, such as size and number of HCC nodules. Against the background of a dramatic shortage of donor organs, however, simple expansion of tumor macromorphology may not be appropriate to create a safe extended criteria system. In contrast, rather the implementation of reliable prognostic parameters of tumor biology into selection process prior to LT is mandatory. Furthermore, a multidisciplinary approach of pre-, peri-, and posttransplant modulating of the tumor and/or the patient has to be established for improving prognosis in this special subset of patients.
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Affiliation(s)
- A. Kornberg
- Department of Surgery, Klinikum rechts der Isar, Technical University Munich, Ismaningerstraße 22, D-81675 Munich, Germany
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49
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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: 64] [Impact Index Per Article: 5.8] [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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50
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Ling CC, Ng KTP, Shao Y, Geng W, Xiao JW, Liu H, Li CX, Liu XB, Ma YY, Yeung WH, Qi X, Yu J, Wong N, Zhai Y, Chan SC, Poon RTP, Lo CM, Man K. Post-transplant endothelial progenitor cell mobilization via CXCL10/CXCR3 signaling promotes liver tumor growth. J Hepatol 2014; 60:103-9. [PMID: 23994383 DOI: 10.1016/j.jhep.2013.08.017] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2013] [Revised: 08/01/2013] [Accepted: 08/14/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Patients with hepatocellular carcinoma (HCC) receiving living donor liver transplantation appear to possess significantly higher tumor recurrence than the recipients receiving deceased donor liver transplantation. The underlying mechanism for HCC recurrence after transplantation remains unclear. Here, we aim to investigate the impact of small-for-size liver graft injury on HCC recurrence after transplantation. METHODS The correlation between tumor recurrence, liver graft injury, CXCL10 expression and endothelial progenitor cell (EPC) mobilization was studied in 115 liver transplant recipients and rat orthotopic liver transplantation (OLT) models. The direct role of CXCL10/CXCR3 signaling on EPC mobilization was investigated in CXCL10(-/-) mice and CXCR3(-/-) mice. The role of EPCs on tumor growth and angiogenesis was further investigated in an orthotopic liver tumor model. RESULTS Clinically, patients with small-for-size liver grafts (<60% of standard liver weight, SLW) had significantly higher HCC recurrence (p=0.04), accompanied by more circulating EPCs and higher early-phase intragraft and plasma CXCL10 levels, than the recipients with large grafts (≥60% of SLW), which were further validated in rat OLT models. Circulatory EPC mobilization was reduced after liver injury both in CXCL10(-/-) mice and CXCR3(-/-) mice in comparison to wild-type controls. CXCL10 recruited EPCs in dose-dependent and CXCR3-dependent manners in vitro. Early-phase EPC/CXCL10 injection enhanced orthotopic liver tumor growth, angiogenesis and metastasis in nude mice. CONCLUSIONS Post-transplant enhanced CXCL10/CXCR3 signaling in small-for-size liver grafts directly induced EPC mobilization, differentiation and neovessel formation, which further promotes tumor growth. Targeting CXCL10/CXCR3 signaling may attenuate early-phase liver graft injury and prevent late-phase tumor recurrence/metastasis after transplantation.
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Affiliation(s)
- Chang-Chun Ling
- Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, China
| | - Kevin T P Ng
- Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, China
| | - Yan Shao
- Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, China
| | - Wei Geng
- Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, China
| | - Jiang-Wei Xiao
- Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, China
| | - Hui Liu
- Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, China
| | - Chang-Xian Li
- Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, China
| | - Xiao-Bing Liu
- Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, China
| | - Yuen-Yuen Ma
- Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, China
| | - Wai-Ho Yeung
- Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, China
| | - Xiang Qi
- Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, China
| | - Jun Yu
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, China
| | - Nathalie Wong
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, China
| | - Yuan Zhai
- Department of Surgery, David Geffen School of Medicine, University of California at Los Angeles, USA
| | - See-Ching Chan
- Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, China
| | - Ronnie T P Poon
- Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, China; Center for Cancer Research, LKS Faculty of Medicine, The University of Hong Kong, China
| | - Chung-Mau Lo
- Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, China
| | - Kwan Man
- Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, China; Center for Cancer Research, LKS Faculty of Medicine, The University of Hong Kong, China.
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