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Endo Y, Bekki Y, Hernandez-Alejandro R, Tomiyama K. Recent Strategies to Attenuate Hepatocellular Carcinoma Recurrence After Liver Transplantation: A Narrative Review. Cancers (Basel) 2025; 17:1650. [PMID: 40427147 PMCID: PMC12110414 DOI: 10.3390/cancers17101650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Revised: 05/03/2025] [Accepted: 05/09/2025] [Indexed: 05/29/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of liver transplant worldwide. While liver transplantation offers a survival advantage for early-stage HCC patients, post-transplant recurrence remains a significant concern, affecting up to 15% of recipients. We sought to conduct a comprehensive review related to HCC recurrence after liver transplant. Tumor-related factors such as poor differentiation, vascular invasion, and elevated tumor biomarkers like alpha-fetoprotein are key predictors of recurrence. Donor-related factors, including graft type and surgical procedures, can also influence outcomes, though their effects are less conclusive. Advancements in patient selection criteria and scoring systems, such as the Milan Criteria and RETREAT score, have improved risk stratification by incorporating tumor size, biomarkers, and response to pre-transplant treatment. Despite these measures, recurrent HCC after transplantation poses treatment challenges. Curative approaches such as resection are feasible for localized or oligometastatic recurrence and offer the best outcomes when applicable. Locoregional treatments, including ablation and transarterial chemoembolization, provide options for unresectable cases but have limited long-term efficacy. Systemic therapies, including targeted agents like sorafenib, regorafenib, and lenvatinib, have shown modest benefits in managing advanced recurrent HCC. Emerging immunotherapy approaches hold promise but face unique challenges due to the required immunosuppression in transplant recipients. Multidisciplinary evaluation remains essential for tailoring treatment plans. Future efforts should focus on refining predictive tools and exploring novel therapies to improve survival outcomes for patients with recurrent HCC after liver transplantation.
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Affiliation(s)
| | | | | | - Koji Tomiyama
- Department of Transplant Surgery, University of Rochester Medical Center, Rochester, NY 14626, USA; (Y.E.); (Y.B.); (R.H.-A.)
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Pinheiro RS, Fonseca GM, Andraus W, Coelho FF, Rocha-Santos V, Pirola Kruger JA, Waisberg DR, Jeismann V, de Martino RB, Ferrari Makdissi F, Ducatti L, Arantes Junior RM, Franca Bezerra RO, Rocha-Filho JA, de Souza Rocha M, Carneiro D'Albuquerque LA, Herman P. Analysis of the survival of patients with hepatocellular carcinoma and indications for liver transplantation or hepatic resection. BMC Surg 2025; 25:166. [PMID: 40251550 PMCID: PMC12007291 DOI: 10.1186/s12893-025-02899-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Accepted: 04/03/2025] [Indexed: 04/20/2025] Open
Abstract
BACKGROUND Hepatic resection (HR) and liver transplantation (LT) are potentially curative treatments for Hepatocellular carcinoma (HCC). The aim of this study was to analyze the survival of patients with HCC and indications for surgical treatment (HR or LT) in a high-volume center. METHODS This was a retrospective cohort study of consecutive patients with HCC and indications for LT or HR from May 2006 to July 2019. Analysis of overall survival (OS) and disease-free survival (DFS) rates, univariate analysis and construction of a multivariable model to identify risk factors were performed. RESULTS A total of 744 patients with HCC were evaluated, 563 (75.6%) of whom were enrolled in waiting list for LT and 181 (24.4%) of whom underwent HR. Among the patients enrolled in the waiting list, 362 (64.3%) underwent LT, whereas 201 (35.7%) remained on the waiting list (WL). From the group of 201 patients on the waiting list, 97 (48.2%) were removed from the list due to tumor progression beyond the Milan criteria (MC), and 83 (41.3%) died while waiting for the transplant. In the WL group, 97 (48.2%) patients were removed from the list due to tumor progression beyond the MC, another 83 (41.3%) patients died while waiting for the LT. The OS rates of the LT group were 77.4%, 67.5% and 56.8%, whereas those of the WL + LT (intention-to-treat) group were 59.9%, 47.3%, and 39.9%, and the HRs were 82.8%, 49.3%, and 33.4% at 1, 5 and 10 years, respectively (p = 0.001). Donor age (p = 0.002) and cold ischemia time (p < 0.001) were independent factors related to OS in the LT group, whereas the presence of significant portal hypertension (p < 0.001), alpha-fetoprotein (AFP) value (p < 0.001) and MC (p = 0.002) were independent factors for HR. The DFS rates for HR were 74.9%, 40.0% and 31.0%, and those for LT were 97.9%, 92.0% and 90.9% at 1, 5 and 10 years, respectively (p < 0.001). Higher AFP levels were identified as an independent factor for lower DFS in both groups. CONCLUSIONS The present study revealed that the OS of patients listed for LT was greater in the first year than in the second year and that the results were similar to those of the HR in an intention-to-treat analysis. However, patients who achieve LT have better long-term outcomes, especially disease-free survival.
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Affiliation(s)
- Rafael Soares Pinheiro
- Departamento de Gastroenterologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Gilton Marques Fonseca
- Departamento de Gastroenterologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Wellington Andraus
- Departamento de Gastroenterologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil.
| | - Fabricio Ferreira Coelho
- Departamento de Gastroenterologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Vinicius Rocha-Santos
- Departamento de Gastroenterologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Jaime Arthur Pirola Kruger
- Departamento de Gastroenterologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Daniel R Waisberg
- Departamento de Gastroenterologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Vagner Jeismann
- Departamento de Gastroenterologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Rodrigo Bronze de Martino
- Departamento de Gastroenterologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Fabio Ferrari Makdissi
- Departamento de Gastroenterologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Liliana Ducatti
- Departamento de Gastroenterologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Rubens Macedo Arantes Junior
- Departamento de Gastroenterologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Regis Otaviano Franca Bezerra
- Departamento de Radiologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Instituto do Cancer do Estado de São Paulo, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Joel Avancini Rocha-Filho
- Departamento de Anestesiologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Manoel de Souza Rocha
- Departamento de Radiologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Instituto do Cancer do Estado de São Paulo, Universidade de Sao Paulo, Sao Paulo, Brazil
| | | | - Paulo Herman
- Departamento de Gastroenterologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
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Wang K, Dong L, Wang X, Wang Z, Qiu X, Xu H, Xu X. Outcomes and risk factors for liver transplantation using steatotic grafts for hepatocellular carcinoma: a multicenter study. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2025; 51:110061. [PMID: 40288219 DOI: 10.1016/j.ejso.2025.110061] [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: 10/29/2024] [Revised: 04/09/2025] [Accepted: 04/15/2025] [Indexed: 04/29/2025]
Abstract
INTRODUCTION A growing number of steatotic grafts have been used in liver transplantation (LT), including hepatocellular carcinoma (HCC) patients. However, the impact of steatotic grafts on the prognosis of HCC recipients remains unclear. This study aims to evaluate the impact of steatotic graft in long-term prognosis for HCC recipients and development an algorithm for minimizing the risk of these grafts. MATERIALS AND METHODS The clinicopathologic data of HCC patients undergoing LT from 2003 to 2022 in the United Network for Organ Sharing database was analyzed. The disease-free survival (DFS) and overall survival (OS) of recipients were compared between non-steatotic (macrosteatosis <30 %) and steatotic (macrosteatosis ≥30 %) graft groups after propensity score matching (PSM). Interaction analysis was conducted to identify factors that amplified the negative impact of steatotic grafts on DFS. RESULTS A total of 8345 eligible HCC patients were included. Three factors exhibited significant interaction effect with steatotic grafts: cold ischemia time ≥6h (HR = 1.447; P = 0.023), donor body mass index ≥40 (HR = 1.771; P = 0.018) and recipient with non-alcoholic fatty liver disease (HR = 1.632; P = 0.032). Hazard Associated with Macrosteatotic Liver (HAML) score was created based on these three factors. In HAML ≥1 cohort, the DFS and OS of steatotic graft group were significantly reduced compared to non-steatotic graft group. But in HAML = 0 cohort, no significant differences in DFS and OS were observed between the two groups. CONCLUSIONS The risk of steatotic grafts in LT for HCC could be minimized through evaluating HAML score.
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Affiliation(s)
- Kai Wang
- Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), School of Clinical Medicine, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China
| | - Libin Dong
- Zhejiang University School of Medicine, Hangzhou, 310058, Zhejiang, China
| | - Xiaobo Wang
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, China
| | - Zhoucheng Wang
- Zhejiang University School of Medicine, Hangzhou, 310058, Zhejiang, China
| | - Xun Qiu
- Zhejiang University School of Medicine, Hangzhou, 310058, Zhejiang, China
| | - Hanzhi Xu
- Zhejiang University School of Medicine, Hangzhou, 310058, Zhejiang, China
| | - Xiao Xu
- Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), School of Clinical Medicine, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China.
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Matevish LE, Guo J, Shubin AD, MacConmara M, Hwang CS, Raschzok N, Rich NE, Mufti AR, Singal AG, Vagefi PA, Patel MS. Transplantation of Patients with Hepatocellular Carcinoma Through Increased Utilization of Machine Perfusion Technology. Transplant Direct 2025; 11:e1777. [PMID: 40078822 PMCID: PMC11896107 DOI: 10.1097/txd.0000000000001777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 01/27/2025] [Accepted: 01/28/2025] [Indexed: 03/14/2025] Open
Abstract
Background With the intent to mitigate waitlist disparities, the median model for end-stage liver disease (MELD) at transplant minus 3 policy nevertheless decreased access to liver transplant for patients with hepatocellular carcinoma (HCC). However, the adoption of machine perfusion (MP) technologies has shown promise in improving deceased donor graft yield and utilization. To understand current use for patients with HCC, we examined liver transplant patterns with MP and the characteristics of patients with HCC receiving an MP liver. Methods Adult patients with HCC undergoing deceased donor liver transplant from September 29, 2021, to March 30, 2024, were identified using the United Network for Organ Sharing Standard Transplant Analysis and Research files. Patients were excluded if listed as status 1A or they underwent multiorgan or split liver transplant. Multivariate analysis compared patients with HCC receiving an MP liver with those receiving a static cold storage liver. Results Of 3774 liver recipients with HCC, 593 (15.7%) underwent transplant with an MP graft. Compared with patients donation after circulatory death graft receiving a graft with static cold storage preservation, those with MP had less advanced disease (ie, Child-Pugh class C cirrhosis 22.9% versus 29.9%, P < 0.01) and lower median match MELD (13 versus 17, P < 0.001). Tumor characteristics were similar between groups, including alpha-fetoprotein level, maximum tumor size, and locoregional treatments. Donor factors, and not tumor burden, were most predictive of receipt of an MP liver (donation after circulatory death graft: odds ratio [OR], 14.81; macrosteatosis >30%; OR, 3.85; donor age older than 60 y; OR, 2.34). A shorter waitlist time (6.5 versus 7.2 mo, P < 0.01), with similar 1-y patient survival (93.6% versus 93.2%, P = 0.82) and graft survival (92.0% versus 91.6%, P = 0.84), was also noted in patients undergoing MP transplant. Conclusions The strategic use of MP livers may improve graft utilization and access to liver transplants, helping offset the disadvantages of the MELD at transplant minus 3 policy for patients with HCC.
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Affiliation(s)
- Lauren E. Matevish
- Division of Surgical Transplantation, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX
| | - Jason Guo
- Division of Surgical Transplantation, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX
| | - Andrew D. Shubin
- Division of Surgical Transplantation, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX
| | | | - Christine S. Hwang
- Division of Surgical Transplantation, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX
| | - Nathanael Raschzok
- Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute of Health at Charité – Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Clinician Scientist Program, Berlin, Germany
| | - Nicole E. Rich
- Division of Digestive and Liver Diseases, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX
| | - Arjmand R. Mufti
- Division of Digestive and Liver Diseases, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX
| | - Amit G. Singal
- Division of Digestive and Liver Diseases, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX
| | - Parsia A. Vagefi
- Division of Surgical Transplantation, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX
| | - Madhukar S. Patel
- Division of Surgical Transplantation, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX
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Lai Q, Melandro F, Vitale A, Ghinolfi D, Coubeau L, Pravisani R, Nowak G, Mocchegiani F, Vivarelli M, Rossi M, Ericzon BG, Baccarani U, De Simone P, Cillo U, Lerut J. The role of the comprehensive complication index in the prediction of tumor-related death in transplanted patients with hepatocellular carcinoma. Updates Surg 2025:10.1007/s13304-025-02101-8. [PMID: 39928277 DOI: 10.1007/s13304-025-02101-8] [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: 11/18/2024] [Accepted: 01/07/2025] [Indexed: 02/11/2025]
Abstract
Liver transplantation (LT) is the primary treatment for selected patients with hepatocellular carcinoma (HCC). However, HCC-related mortality post-LT remains a significant concern, with up to 10% of cases reported in international series. Identifying risk factors for adverse clinical outcomes is essential. We hypothesized that post-LT HCC-related mortality rates are higher in patients with a high (≥ 42) Comprehensive Complication Index (CCI) calculated at discharge. This study aims to compare post-LT HCC-related mortality rates between two groups of patients with high versus low CCI following LT for HCC. This study included data from seven collaborative European centers. A cohort of 1121 HCC patients transplanted between 2005 and 2019, surviving more than six months post-LT, was analyzed retrospectively. Patients were divided into two groups based on the CCI at discharge: Low-CCI Group (n = 942, 84.0%) and High-CCI Group (n = 179, 16.0%). An inverse probability of treatment weighting (IPTW) approach was applied for analysis. In the post-IPTW cohort, four multivariable logistic regression models with mixed effects identified independent risk factors for HCC-related death, overall death, recurrence, and early recurrence. A CCI score of ≥ 42 emerged as an independent risk factor across all models. Specifically, CCI ≥ 42 was associated with increased odds of HCC-related death (OR = 3.35; P < 0.0001), overall death (OR = 2.63; P < 0.0001), overall recurrence (OR = 2.09; P = 0.001), and early recurrence (OR = 1.88; P = 0.02). A CCI score at discharge should be considered a critical factor for recurrence and HCC-related mortality risk. Incorporating CCI into standard post-LT predictive models may enhance prognostic accuracy for adverse HCC outcomes.
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Affiliation(s)
- Quirino Lai
- Organ Transplantation Unit, Department of General and Specialty Surgery, Sapienza University of Rome, AOU Policlinico Umberto I, Viale del Policlinico 155, 00161, Rome, Italy.
| | - Fabio Melandro
- Organ Transplantation Unit, Department of General and Specialty Surgery, Sapienza University of Rome, AOU Policlinico Umberto I, Viale del Policlinico 155, 00161, Rome, Italy
| | | | | | | | | | - Greg Nowak
- Karolinska University Hospital Huddinge, Solna, Sweden
| | | | | | - Massimo Rossi
- Organ Transplantation Unit, Department of General and Specialty Surgery, Sapienza University of Rome, AOU Policlinico Umberto I, Viale del Policlinico 155, 00161, Rome, Italy
| | | | | | | | | | - Jan Lerut
- Université Catholique de Louvain, Brussels, Belgium
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Li Y, Liu X, Zhang C, Tao R, Pan B, Liu W, Jiang D, Hu F, Xu Z, Tan D, Ou Y, Li X, You Y, Zhang L. A Brief Model Evaluated Outcomes After Liver Transplantation Based on the Matching of Donor Graft and Recipient. Clin Transl Gastroenterol 2025; 16:e00761. [PMID: 39166764 PMCID: PMC11756882 DOI: 10.14309/ctg.0000000000000761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Accepted: 07/31/2024] [Indexed: 08/23/2024] Open
Abstract
INTRODUCTION A precise model for predicting outcomes is needed to guide perioperative management. With the development of the liver transplantation (LT) discipline, previous models may become inappropriate or noncomprehensive. Thus, we aimed to develop a novel model integrating variables from donors and recipients for quick assessment of transplant outcomes. METHODS The risk model was based on Cox regression in a randomly selected derivation cohort and verified in a validation cohort. Perioperative data and overall survival were compared between stratifications grouped by X-tile. Receiver-operating characteristic curve and decision curve analysis were used to compare the models. Violin and raincloud plots were generated to present post-LT complications distributed in different stratifications. RESULTS Overall, 528 patients receiving LT from 2 centers were included with 2/3 in the derivation cohort and 1/3 in the validation cohort. Cox regression analysis showed that cold ischemia time (CIT) ( P = 0.012) and Model for End-Stage Liver Disease (MELD) ( P = 0.007) score were predictors of survival. After comparison with the logarithmic models, the primitive algorithms of CIT and MELD were defined as the CIT-MELD Index (CMI). CMI was stratified by X-tile (grade 1 ≤1.06, 1.06 < grade 2 ≤ 1.87, grade 3 >1.87). In both cohorts, CMI performed better in calculating transplant outcomes than the balance of risk score, including perioperative incidents and prevalence of complications. DISCUSSION The model integrating variables from graft donors and recipients made the prediction more accurate and available. CMI provided new insight into outcome evaluation and risk factor management of LT.
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Affiliation(s)
- Yuancheng Li
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Xingchao Liu
- Department of Hepatobiliary Surgery, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Chengcheng Zhang
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Ran Tao
- Department of Organ Transplantation, Liaocheng People's Hospital, Liaocheng, China
| | - Bi Pan
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Wei Liu
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Di Jiang
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Feng Hu
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Zeliang Xu
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Dehong Tan
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Yanjiao Ou
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Xun Li
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Yuemei You
- Department of Surgery and Anesthesiology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Leida Zhang
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
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Garcia KB, Hussein A, Satish S, Wehrle CJ, Karakaya O, Panconesi R, Sun K, Jiao C, Fernandes E, Pinna A, Hashimoto K, Miller C, Aucejo F, Schlegel A. Machine Perfusion as a Strategy to Decrease Ischemia-Reperfusion Injury and Lower Cancer Recurrence Following Liver Transplantation. Cancers (Basel) 2024; 16:3959. [PMID: 39682147 DOI: 10.3390/cancers16233959] [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: 08/05/2024] [Revised: 11/12/2024] [Accepted: 11/13/2024] [Indexed: 12/18/2024] Open
Abstract
Liver transplantation (LT) is a key treatment for primary and secondary liver cancers, reducing tumor burden with concurrent improvement of liver function. While significant improvement in survival is noted with LT, cancer recurrence rates remain high. Mitochondrial dysfunction caused by ischemia-reperfusion injury (IRI) is known to drive tumor recurrence by creating a favorable microenvironment rich in pro-inflammatory and angiogenic factors. Therefore, strategies that decrease reperfusion injury and mitochondrial dysfunction may also decrease cancer recurrence following LT. Machine perfusion techniques are increasingly used in routine clinical practice of LT with improved post-transplant outcomes and increased use of marginal grafts. Normothermic (NMP) and hypothermic oxygenated machine perfusion (HOPE) provide oxygen to ischemic tissues, and impact IRI and potential cancer recurrence through different mechanisms. This article discussed the link between IRI-associated inflammation and tumor recurrence after LT. The current literature was screened for the role of machine perfusion as a strategy to mitigate the risk of cancer recurrence. Upfront NMP ("ischemia free organ transplantation") and end-ischemic HOPE were shown to reduce hepatocellular carcinoma recurrence in retrospective studies. Three prospective randomized controlled trials are ongoing in Europe to provide robust evidence on the impact of HOPE on cancer recurrence in LT.
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Affiliation(s)
- Karla Bracho Garcia
- Department of Liver Transplantation, Cleveland Clinic Weston Hospital, Weston, FL 33331, USA
| | - Ahmed Hussein
- Department of Liver Transplantation, Cleveland Clinic Weston Hospital, Weston, FL 33331, USA
| | - Sangeeta Satish
- Transplantation Center, Department of Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH 44195, USA
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Chase J Wehrle
- Transplantation Center, Department of Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Omer Karakaya
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Rebecca Panconesi
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Keyue Sun
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Chunbao Jiao
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Eduardo Fernandes
- Department of Liver Transplantation, Cleveland Clinic Weston Hospital, Weston, FL 33331, USA
| | - Antonio Pinna
- Department of Liver Transplantation, Cleveland Clinic Weston Hospital, Weston, FL 33331, USA
| | - Koji Hashimoto
- Transplantation Center, Department of Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH 44195, USA
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Charles Miller
- Transplantation Center, Department of Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Federico Aucejo
- Transplantation Center, Department of Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Andrea Schlegel
- Transplantation Center, Department of Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH 44195, USA
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
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Yu J, Yunhua T, Guo Y, Dong Y, Gong JL, Wang T, Chen Z, Chen M, Ju W, He X. Beyond graft function impairment after liver transplantation: the prolonged cold ischemia time impact on recurrence of hepatocellular carcinoma after liver transplantation-a single-center retrospective study. PeerJ 2024; 12:e18126. [PMID: 39376229 PMCID: PMC11457873 DOI: 10.7717/peerj.18126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 08/28/2024] [Indexed: 10/09/2024] Open
Abstract
Purpose Hepatocellular carcinoma (HCC) is one of the malignant tumors responsible for high mortality and recurrence rates. Although liver transplantation (LT) is an effective treatment option for HCC, ischemia-reperfusion injury (IRI) is a contributor to HCC recurrence after LT. Moreover, prolonged cold ischemia time (CIT) is a risk factor for IRI during LT, and there is insufficient clinical evidence regarding the impact of CIT on HCC recurrence after LT. Patients and Methods This retrospective study analyzed 420 patients who underwent LT for HCC between February 2015 and November 2020 at The First Affiliated Hospital, Sun Yat-sen University. The duration of CIT was defined as the time from clamping of the donor aorta until portal reperfusion. Results A total of 133 patients (31.7%) experienced tumor recurrence after LT, and CIT > 568 min was the independent risk factor for HCC recurrence (OR, 2.406; 95% CI [1.371-4.220]; p = 0.002). Multivariate Cox's regression analysis revealed that the recipients' gender, exceeding Milan criteria, poor differentiation, and alpha-fetoprotein (AFP) ≥400 ng/ml in CIT > 568 min group were independent risk factors for disease-free survival. The peak 7-day postoperative alanine aminotransferase (ALT) level (p < 0.001), the peak 7-day postoperative aspartate aminotransferase (AST) level (p < 0.001), the peak 7-day postoperative peak total bilirubin (TBIL) level (p = 0.012), and the incidence of early allograft dysfunction (EAD) (p = 0.006) were significantly higher in the CIT > 568 min group compared to the CIT ≤ 568 min group. Moreover, the amount of fresh frozen plasma (FFP) infusion during the operation increased (p = 0.02), and the time of mechanical ventilation postoperative was longer (p = 0.045). Conclusion An effective strategy to improve the prognosis is to reduce CIT; this strategy lowers the recurrence of HCC in patients undergoing LT, especially those within the Milan criteria.
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Affiliation(s)
- Jia Yu
- First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science & Technology (Organ Transplantation), Guangzhou, China
- The First Affiliated Hospital of University of South China, Hengyang, China
| | - Tang Yunhua
- First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science & Technology (Organ Transplantation), Guangzhou, China
| | - Yiwen Guo
- First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science & Technology (Organ Transplantation), Guangzhou, China
| | - Yuqi Dong
- First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science & Technology (Organ Transplantation), Guangzhou, China
| | | | - Tielong Wang
- First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science & Technology (Organ Transplantation), Guangzhou, China
| | - Zhitao Chen
- First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science & Technology (Organ Transplantation), Guangzhou, China
| | - Maogen Chen
- First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science & Technology (Organ Transplantation), Guangzhou, China
| | - Weiqiang Ju
- First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science & Technology (Organ Transplantation), Guangzhou, China
| | - Xiaoshun He
- First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science & Technology (Organ Transplantation), Guangzhou, China
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9
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Badwei N. Challenges related to clinical decision-making in hepatocellular carcinoma recurrence post-liver transplantation: Is there a hope? World J Transplant 2024; 14:96637. [PMID: 39295978 PMCID: PMC11317853 DOI: 10.5500/wjt.v14.i3.96637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Revised: 06/08/2024] [Accepted: 06/24/2024] [Indexed: 07/31/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a common liver malignancy and represents a serious cause of cancer-related mortality and morbidity. One of the favourable curative surgical therapeutic options for HCC is liver transplantation (LT) in selected patients fulfilling the known standard Milan/University of California San Francisco criteria which have shown better outcomes and longer-term survival. Despite careful adherence to the strict HCC selection criteria for LT in different transplant centres, the recurrence rate still occurs which could negatively affect HCC patients' survival. Hence HCC recurrence post-LT could predict patients' survival and prognosis, depending on the exact timing of recurrence after LT (early or late), and whether intra/extrahepatic HCC recurrence. Several factors may aid in such a complication, particularly tumour-related criteria including larger sizes, higher grades or poor tumour differentiation, microvascular invasion, and elevated serum alpha-fetoprotein. Therefore, managing such cases is challenging, different therapeutic options have been proposed, including curative surgical and ablative treatments that have shown better outcomes, compared to the palliative locoregional and systemic therapies, which may be helpful in those with unresectable tumour burden. To handle all these issues in our review.
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Affiliation(s)
- Nourhan Badwei
- Department of Tropical Medicine, Gastroenterology and Hepatology, Hepatoma Group, Ain Shams University, Cairo 11517, Egypt
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10
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Chen X, Jiang C, Chen M, Li X, Yu W, Qiu A, Sun L, Pu L, Shi Y. SYK promotes the formation of neutrophil extracellular traps by inducing PKM2 nuclear translocation and promoting STAT3 phosphorylation to exacerbate hepatic ischemia-reperfusion injury and tumor recurrence. Mol Med 2024; 30:146. [PMID: 39261768 PMCID: PMC11391729 DOI: 10.1186/s10020-024-00907-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Accepted: 08/22/2024] [Indexed: 09/13/2024] Open
Abstract
BACKGROUND At present, hepatic ischemia-reperfusion injury (IRI) is an important complication of partial hepatectomy and liver transplantation, and it is an important cause of poor prognosis. Spleen tyrosine kinase(SYK) plays an important role in a variety of signaling pathways in the liver, but its role in hepatic IRI is still unclear. This study aims to investigate the role and mechanism of SYK in hepatic IRI and tumor recurrence. METHODS We first observed the activation of SYK in the liver of mice in response to hepatic IRI. Subsequently, Pharmacological inhibitions of SYK were used to evaluated the effect of SYK on neutrophil recruitment and NETosis, and further explored the effect of SYK on IRI and tumor recurrence. RESULTS Our study shows that SYK is activated in response to hepatic IRI and aggravates liver injury. On the one hand, neutrophils SYK during the early stage of liver reperfusion increases neutrophil extracellular traps (NETs) production by promoting Pyruvate kinase M2(PKM2) nuclear translocation leading to upregulation of phosphorylated STAT3, thereby exacerbating liver inflammation and tumor recurrence. On the other hand, macrophages SYK can promote the recruitment of neutrophils and increase the activation of NLRP3 inflammasome and IL1β, which further promotes the formation of NETs. CONCLUSIONS Our study demonstrates that neutrophil and macrophage SYK synergistically promote hepatic IRI and tumor recurrence, and SYK may be a potential target to improve postoperative hepatic IRI and tumor recurrence.
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Affiliation(s)
- Xuejiao Chen
- Department of General Surgery, The Yancheng School of Clinical Medicine of Nanjing Medical University, 75 Theater Road, Yancheng, 224000, Jiangsu province, China
| | - Chuanwei Jiang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210003, Jiang Su province, China
| | - Minhao Chen
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210003, Jiang Su province, China
| | - Xiangdong Li
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210003, Jiang Su province, China
| | - Wenjie Yu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210003, Jiang Su province, China
| | - Aigang Qiu
- Department of General Surgery, The Yancheng School of Clinical Medicine of Nanjing Medical University, 75 Theater Road, Yancheng, 224000, Jiangsu province, China
| | - Linfeng Sun
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210003, Jiang Su province, China
| | - Liyong Pu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210003, Jiang Su province, China.
| | - Yuhua Shi
- Department of General Surgery, The Yancheng School of Clinical Medicine of Nanjing Medical University, 75 Theater Road, Yancheng, 224000, Jiangsu province, China.
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11
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Dajti G, Germinario G, Prosperi E, Siniscalchi A, Vasuri F, Valente S, Odaldi F, Maroni L, Serenari M, Bertuzzo V, Laurenzi A, Del Gaudio M, Cescon M, Ravaioli M. The role of cold ischemia time and hypothermic perfusion in predicting early hepatocellular carcinoma recurrences after liver transplantation. Artif Organs 2024; 48:619-625. [PMID: 38270476 DOI: 10.1111/aor.14715] [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: 09/23/2023] [Revised: 12/28/2023] [Accepted: 01/08/2024] [Indexed: 01/26/2024]
Abstract
AIM The aim of the study was to identify predictors of early tumor recurrence in patients with hepatocellular carcinoma (HCC) after liver transplantation (LT). METHODS Retrospective cohort study in 237 consecutive liver recipients with HCC between 2016 and 2021. Multivariate logistic analysis was performed to identify predictors of early HCC recurrences. The impact of hypothermic-oxygenated perfusion (HOPE) on outcome was analyzed after propensity score weighting. RESULTS Early recurrences were observed in 15 cases. Microvascular invasion (OR 3.737, 95% CI 1.246-11.206, p = 0.019) and cold ischemia time (OR 1.155, 95% CI 1.001-1.333, p = 0.049) were independently associated with a lower risk of HCC recurrences. After balancing for relevant variables, patients in the HOPE group had lower rates of tumor recurrence (weighted OR 0.126, 95% CI 0.016-0.989, p = 0.049) and higher recurrence free survival (weighted HR 0.132, 95% CI 0.017-0.999, p = 0.050). CONCLUSION Reducing cold ischemia time and graft perfusion with HOPE can lead to lower rates of early HCC recurrences and higher recurrence-free survival.
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Affiliation(s)
- Gerti Dajti
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
| | - Giuliana Germinario
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
- General Surgery and Transplantation Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Enrico Prosperi
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
- General Surgery and Transplantation Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Antonio Siniscalchi
- Intensive Care Unit, IRCSS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Francesco Vasuri
- Department of Specialized, Experimental and Diagnostic Medicine (DIMES), University of Bologna, Bologna, Italy
| | - Sabrina Valente
- Department of Specialized, Experimental and Diagnostic Medicine (DIMES), University of Bologna, Bologna, Italy
| | - Federica Odaldi
- General Surgery and Transplantation Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Lorenzo Maroni
- General Surgery and Transplantation Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Matteo Serenari
- General Surgery and Transplantation Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Valentina Bertuzzo
- General Surgery and Transplantation Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Andrea Laurenzi
- General Surgery and Transplantation Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Massimo Del Gaudio
- General Surgery and Transplantation Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Matteo Cescon
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
- General Surgery and Transplantation Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Matteo Ravaioli
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
- General Surgery and Transplantation Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
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12
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Faleiro MD, Mir ZM, Azizieh Y, Hiebert SE, Livingstone SM, Walsh MJ, Gala-Lopez BL. Oncologic Outcomes of Interventions to Decrease Allograft Ischemia-Reperfusion Injury within Patients Undergoing Liver Transplantation for Hepatocellular Carcinoma: A Systematic Review. Curr Oncol 2024; 31:2895-2906. [PMID: 38920705 PMCID: PMC11202749 DOI: 10.3390/curroncol31060221] [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: 03/31/2024] [Revised: 05/12/2024] [Accepted: 05/17/2024] [Indexed: 06/27/2024] Open
Abstract
Ischemia-reperfusion injury (IRI) during liver transplantation has been implicated in the recurrence of hepatocellular carcinoma (HCC). This systematic review aimed to evaluate interventions to reduce IRI during liver transplantation for HCC and their impact on oncologic outcomes. A comprehensive literature search retrieved four retrospective studies involving 938 HCC patients, utilising interventions such as post-operative prostaglandin administration, hypothermic machine perfusion, and normothermic machine perfusion. Overall, treated patients exhibited reduced post-operative hepatocellular injury and inflammation and significantly enhanced recurrence-free survival. Despite these promising results, the impact of these interventions on overall survival remains unclear. This underscores the imperative for further prospective research to comprehensively understand the efficacy of these interventions in HCC patients undergoing transplantation. The findings highlight the potential benefits of these strategies while emphasising the need for continued investigation into their overall impact.
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Affiliation(s)
- Matheus D. Faleiro
- Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte 31270-901, MG, Brazil
| | - Zuhaib M. Mir
- Department of Surgery, Dalhousie University, Halifax, NS B3H 4R2, Canada
| | - Yara Azizieh
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada
| | | | | | - Mark J. Walsh
- Department of Surgery, Dalhousie University, Halifax, NS B3H 4R2, Canada
| | - Boris L. Gala-Lopez
- Department of Surgery, Dalhousie University, Halifax, NS B3H 4R2, Canada
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada
- Beatrice Hunter Cancer Research Institute, Halifax, NS B3H 0A2, Canada
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13
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Al-Ameri AAM, Zheng S. Outcomes of liver transplantation for hepatocellular carcinoma in donation after circulatory death compared with donation after brain death: A systematic review and meta-analysis. Ann Hepatol 2024; 29:101484. [PMID: 38417629 DOI: 10.1016/j.aohep.2024.101484] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 02/04/2024] [Accepted: 02/05/2024] [Indexed: 03/01/2024]
Abstract
INTRODUCTION AND OBJECTIVES Due to organ shortages, liver transplantation (LT) using donation-after-circulatory-death (DCD) grafts has become more common. There is limited and conflicting evidence on LT outcomes using DCD grafts compared to those using donation-after-brain death (DBD) grafts for patients with hepatocellular carcinoma (HCC). We aimed to summarize the current evidence on the outcomes of DCD-LT and DBD-LT in patients with HCC. MATERIALS AND METHODS Online databases were searched for studies comparing DCD-LT and DBD-LT outcomes in patients with HCC and a meta-analysis was conducted using fixed- or random-effects models. RESULTS Five studies involving 487 (33.4%) HCC DCD-LT patients and 973 (66.6%) DBD-LT patients were included. The meta-analysis showed comparable 1-year [relative risk (RR)=0.99, 95%CI:0.95 to 1.03, p=0.53] and 3-year [RR=0.99, 95%CI:0.89 to 1.09, p=0.79] recurrence-free survival. The corresponding 1-year [RR=0.98, 95%CI:0.93 to 1.03, p=0.35] and 3-year [RR=0.94, 95%CI:0.87 to 1.01, p=0.08] patient survival and 1-year [RR=0.91, 95%CI:0.71 to 1.16, p=0.43] and 3-year [RR=0.92, 95%CI:0.67 to 1.26, p=0.59] graft survival were also comparable. There were no significant differences between the two cohorts regarding the tumor characteristics, donor/recipient risk factors and the incidence of post-operative complications, including acute rejection, primary non-function, biliary complications and retransplantation. CONCLUSIONS Based on the current evidence, it has been found that comparable outcomes can be achieved in HCC patients using DCD-LT compared to DBD-LT, particularly when employing good quality graft, strict donor and recipient selection, and effective surgical management. The decision to utilize DCD-LT for HCC patients should be personalized, taking into consideration the risk of post-LT HCC recurrence. (PROSPERO ID: CRD42023445812).
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Affiliation(s)
- Abdulahad Abdulrab Mohammed Al-Ameri
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital, Hangzhou, China; NHC Key Laboratory of Combined Multi-Organ Transplantation, China; Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences, China; Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, Zhejiang 310003, China
| | - Shusen Zheng
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital, Hangzhou, China; NHC Key Laboratory of Combined Multi-Organ Transplantation, China; Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences, China; Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, Zhejiang 310003, China.
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14
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Wehrle CJ, Raj R, Maspero M, Satish S, Eghtesad B, Pita A, Kim J, Khalil M, Calderon E, Orabi D, Zervos B, Modaresi Esfeh J, Whitsett Linganna M, Diago-Uso T, Fujiki M, Quintini C, Kwon CD, Miller C, Pinna A, Aucejo F, Hashimoto K, Schlegel A. Risk assessment in liver transplantation for hepatocellular carcinoma: long-term follow-up of a two-centre experience. Int J Surg 2024; 110:2818-2831. [PMID: 38241354 PMCID: PMC11093438 DOI: 10.1097/js9.0000000000001104] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Accepted: 01/08/2024] [Indexed: 01/21/2024]
Abstract
BACKGROUND Liver transplantation (LT) is a well-established treatment for hepatocellular carcinoma (HCC), but there are ongoing debates regarding outcomes and selection. This study examines the experience of LT for HCC at a high-volume centre. METHODS A prospectively maintained database was used to identify HCC patients undergoing LT from 2000 to 2020 with more than or equal to 3-years follow-up. Data were obtained from the centre database and electronic medical records. The Metroticket 2.0 HCC-specific 5-year survival scale was calculated for each patient. Kaplan-Meier and Cox-regression analyses were employed assessing survival between groups based on Metroticket score and individual donor and recipient risk factors. RESULTS Five hundred sixty-nine patients met criteria. Median follow-up was 96.2 months (8.12 years; interquartile range 59.9-147.8). Three-year recurrence-free (RFS) and overall survival (OS) were 88.6% ( n =504) and 86.6% ( n =493). Five-year RFS and OS were 78.9% ( n =449) and 79.1% ( n =450). Median Metroticket 2.0 score was 0.9 (interquartile range 0.9-0.95). Tumour size greater than 3 cm ( P =0.012), increasing tumour number on imaging ( P =0.001) and explant pathology ( P <0.001) was associated with recurrence. Transplant within Milan ( P <0.001) or UCSF criteria ( P <0.001) had lower recurrence rates. Increasing alpha-fetoprotein (AFP)-values were associated with more HCC recurrence ( P <0.001) and reduced OS ( P =0.008). Chemoembolization was predictive of recurrence in the overall population ( P =0.043) and in those outside-Milan criteria ( P =0.038). A receiver-operator curve using Metroticket 2.0 identified an optimal cut-off of projected survival greater than or equal to 87.5% for predicting recurrence. This cut-off was able to predict RFS ( P <0.001) in the total cohort and predict both, RFS ( P =0.007) and OS ( P =0.016) outside Milan. Receipt of donation after brain death (DBD) grafts (55/478, 13%) or living-donor grafts (3/22, 13.6%) experienced better survival rates compared to donation after cardiac death (DCD) grafts ( n =15/58, 25.6%, P =0.009). Donor age was associated with a higher HCC recurrence ( P =0.006). Both total ischaemia time (TIT) greater than 6hours ( P =0.016) and increasing TIT correlated with higher HCC recurrence ( P =0.027). The use of DCD grafts for outside-Milan candidates was associated with increased recurrence ( P =0.039) and reduced survival ( P =0.033). CONCLUSION This large two-centre analysis confirms favourable outcomes after LT for HCC. Tumour size and number, pre-transplant AFP, and Milan criteria remain important recipient HCC-risk factors. A higher donor risk (i.e. donor age, DCD grafts, ischaemia time) was associated with poorer outcomes.
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Affiliation(s)
- Chase J. Wehrle
- Transplantation Center, Department of Surgery, Digestive Disease Institute
| | - Roma Raj
- Transplantation Center, Department of Surgery, Digestive Disease Institute
| | - Marianna Maspero
- Transplantation Center, Department of Surgery, Digestive Disease Institute
| | - Sangeeta Satish
- Transplantation Center, Department of Surgery, Digestive Disease Institute
| | - Bijan Eghtesad
- Transplantation Center, Department of Surgery, Digestive Disease Institute
| | - Alejandro Pita
- Transplantation Center, Department of Surgery, Digestive Disease Institute
| | - Jaekeun Kim
- Transplantation Center, Department of Surgery, Digestive Disease Institute
| | - Mazhar Khalil
- Transplantation Center, Department of Surgery, Digestive Disease Institute
| | - Esteban Calderon
- Transplantation Center, Department of Surgery, Digestive Disease Institute
| | - Danny Orabi
- Transplantation Center, Department of Surgery, Digestive Disease Institute
| | - Bobby Zervos
- Cleveland Clinic Weston Hospital, Department of Liver Transplantation, Weston, FL, USA
| | | | | | - Teresa Diago-Uso
- Transplantation Center, Department of Surgery, Digestive Disease Institute
| | - Masato Fujiki
- Transplantation Center, Department of Surgery, Digestive Disease Institute
| | - Cristiano Quintini
- Transplantation Center, Department of Surgery, Digestive Disease Institute
| | - Choon David Kwon
- Transplantation Center, Department of Surgery, Digestive Disease Institute
| | - Charles Miller
- Transplantation Center, Department of Surgery, Digestive Disease Institute
| | - Antonio Pinna
- Cleveland Clinic Weston Hospital, Department of Liver Transplantation, Weston, FL, USA
| | - Federico Aucejo
- Transplantation Center, Department of Surgery, Digestive Disease Institute
| | - Koji Hashimoto
- Transplantation Center, Department of Surgery, Digestive Disease Institute
| | - Andrea Schlegel
- Transplantation Center, Department of Surgery, Digestive Disease Institute
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, OH
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15
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Sim JH, Kim KW, Ko Y, Moon YJ, Kwon HM, Jun IG, Kim SH, Kim KS, Song JG, Hwang GS. Association between visceral obesity and tumor recurrence in hepatocellular carcinoma recipients undergoing liver transplantation. Int J Obes (Lond) 2023; 47:1214-1223. [PMID: 37640894 DOI: 10.1038/s41366-023-01367-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 07/28/2023] [Accepted: 08/16/2023] [Indexed: 08/31/2023]
Abstract
BACKGROUND Excessive visceral obesity in recipients of living donor liver transplantation (LDLT) is associated with mortality, and a recent study reported the correlation between visceral adiposity of male LDLT recipients and hepatocellular carcinoma (HCC) recurrence. However, there is no study on the relationship between the donor's visceral adiposity and surgical outcomes in LDLT recipients. We investigated the association of the visceral-to-subcutaneous fat area ratio (VSR) in donors and recipients with HCC recurrence and mortality in LDLT. METHODS We analyzed 1386 sets of donors and recipients who underwent LDLT between January 2008 and January 2018. The maximal chi-square method was used to determine the optimal cutoff values for VSR for predicting overall HCC recurrence and mortality. Cox regression analyses were performed to evaluate the association of donor VSR and recipient VSR with overall HCC recurrence and mortality in recipients. RESULTS The cutoff values of VSR was determined as 0.73 in males and 0.31 in females. High donor VSR was significantly associated with overall HCC recurrence (adjusted hazard ratio [HR]: 1.43, 95% confidence interval [CI]: 1.06-1.93, p = 0.019) and mortality (HR: 1.35, 95% CI: 1.03-1.76, p = 0.030). High recipient VSR was significantly associated with overall HCC recurrence (HR: 1.40, 95% CI: 1.04-1.88, p = 0.027) and mortality (HR: 1.50, 95% CI: 1.14-1.96, p = 0.003). CONCLUSIONS Both recipient VSR and donor VSR were significant risk factors for HCC recurrence and mortality in LDLT recipients. Preoperative donor VSR and recipient VSR may be strong predictors of the surgical outcomes of LDLT recipients with HCC.
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Affiliation(s)
- Ji-Hoon Sim
- Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Kyung-Won Kim
- Department of Radiology, Asan Image Metrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea
| | - YouSun Ko
- Department of Radiology, Asan Image Metrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea
| | - Young-Jin Moon
- Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Hye-Mee Kwon
- Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - In-Gu Jun
- Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Sung-Hoon Kim
- Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Kyoung-Sun Kim
- Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jun-Gol Song
- Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
| | - Gyu-Sam Hwang
- Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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16
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Hu L, Wang A, Qiao Y, Huang X. Effect of intermittent Pringle maneuver on perioperative outcomes and long-term survival following liver resection in patients with hepatocellular carcinoma: a meta-analysis and systemic review. World J Surg Oncol 2023; 21:359. [PMID: 37986187 PMCID: PMC10662549 DOI: 10.1186/s12957-023-03244-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Accepted: 11/13/2023] [Indexed: 11/22/2023] Open
Abstract
BACKGROUND Intermittent Pringle maneuver (IPM) is commonly used to control bleeding during liver resection. IPM can cause ischemia-reperfusion injury, which may affect the prognosis of patients with hepatocellular carcinoma (HCC). The present meta-analysis was conducted to evaluate the effect of IPM use on perioperative outcomes and long-term survival in patients with HCC. METHODS A systemic literature search was performed in the PubMed, Embase, Web of Science, and Cochrane Library databases to identify randomized controlled trials and retrospective studies that compared the effect of IPM with no Pringle maneuver during liver resection in patients with HCC. Hazard ratio (HR), risk ratio, standardized mean difference, and their 95% confidence interval (CI) values were calculated based on the type of variables. RESULTS This meta-analysis included nine studies comprising one RCT and eight retrospective studies and involved a total of 3268 patients. Perioperative outcomes, including operation time, complications, and length of hospital stay, except for blood loss, were comparable between the two groups. After removing the studies that led to heterogeneity, the results showed that IPM was effective in reducing blood loss. Five studies reported overall survival (OS) and disease-free survival (DFS) data and eight studies reported perioperative outcomes. No significant difference in OS and DFS was observed between the two groups (OS: HR, 1.01; 95% CI, 0.85-1.20; p = 0.95; DFS: HR, 1.01; 95% CI, 0.88-1.17; p = 0.86). CONCLUSION IPM is a useful technique to control blood loss during liver resection and does not affect the long-term survival of patients with HCC.
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Affiliation(s)
- Lingbo Hu
- Department of Hepatopancreatobiliary Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Zhejiang, China
- Department of Hepatopancreatobiliary Surgery, Taizhou Enze Medical Center (Group), Enze Hospital, Zhejiang, China
| | - Aidong Wang
- Department of Hepatopancreatobiliary Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Zhejiang, China
| | - Yingli Qiao
- Department of Hepatopancreatobiliary Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Zhejiang, China
- Department of Hepatopancreatobiliary Surgery, Taizhou Enze Medical Center (Group), Enze Hospital, Zhejiang, China
| | - Xiandan Huang
- Department of Hepatopancreatobiliary Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Zhejiang, China.
- Department of Hepatopancreatobiliary Surgery, Taizhou Enze Medical Center (Group), Enze Hospital, Zhejiang, China.
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17
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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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18
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Wu J, Chan YT, Lu Y, Wang N, Feng Y. The tumor microenvironment in the postsurgical liver: Mechanisms and potential targets of postoperative recurrence in human hepatocellular carcinoma. Med Res Rev 2023; 43:1946-1973. [PMID: 37102365 DOI: 10.1002/med.21967] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 03/23/2023] [Accepted: 04/13/2023] [Indexed: 04/28/2023]
Abstract
Surgery remains to be the mainstay of treatment for hepatocellular carcinoma (HCC). Nonetheless, its therapeutic efficacy is significantly impaired by postoperative recurrence, which occurs in more than half of cases as a result of intrahepatic metastasis or de novo tumorigenesis. For decades, most therapeutic strategies on inhibiting postoperative HCC recurrence have been focused on the residual tumor cells but satisfying therapeutic outcomes are barely observed in the clinic. In recent years, a better understanding of tumor biology allows us to shift our focus from tumor cells toward the postoperative tumor microenvironment (TME), which is gradually identified to play a pivotal role in tumor recurrence. In this review, we describe various surgical stress and surgical perturbation on postoperative TME. Besides, we discuss how such alternations in TME give rise to postoperative recurrence of HCC. Based on its clinical significance, we additionally highlight the potential of the postoperative TME as a target for postoperative adjuvant therapeutics.
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Affiliation(s)
- Junyu Wu
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Yau-Tuen Chan
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Yuanjun Lu
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Ning Wang
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Yibin Feng
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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19
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Paul C, Besch C, Artzner T, Michard B, Cusumano C, Addeo P, Bachellier P, Faitot F. Additional value of interleukin-6 level to predict histopathological features of hepatocellular carcinoma before liver transplantation. Cytokine 2023; 169:156286. [PMID: 37385083 DOI: 10.1016/j.cyto.2023.156286] [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: 04/10/2023] [Revised: 06/13/2023] [Accepted: 06/24/2023] [Indexed: 07/01/2023]
Abstract
BACKGROUND & AIMS Inflammatory biomarkers are increasingly used as outcome predictors in the field of oncology and liver transplantation for HCC, but no study has shown the prognostic value of IL6 after LT. The goal of this study was to evaluate the predictive value of IL-6 on histopathological features of HCC on explant, its predictive value on recurrence risk and its additional value to other scores and inflammatory markers at the time of transplantation. METHODS From 2009 to 2019, all adults transplanted with a first liver graft and diagnosed with HCC on the explant analysis were retrospectively included (n = 229). Only patients who had a pre-LT IL6 level determination were analysed in this study (n = 204). RESULTS High IL-6 level at transplantation was associated with a significantly higher risk of vascular invasion (15% vs 6%; p = 0.023), microsatellitosis (11% vs 3%; p = 0.013), lower rate of histological response both in terms of complete response (2% vs 14%, p = 0.004) and of necrosis (p = 0.010). Patients with pre-LT IL-6 level > 15 ng/ml had a lower overall and cancer-specific survival (p = 0.013). Recurrence-free survival was lower in patients with IL-6 > 15 ng/ml with a 3-year recurrence-free survival of 88% versus 78% (p = 0.034). IL6 levels were significantly higher in patients with early recurrence compared to patients without (p = 0.002) or with late recurrence (p = 0.044). CONCLUSIONS IL6 level at transplantation is an independent predictor of pejorative histological features of HCC and is associated to the risk of recurrence.
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Affiliation(s)
- Chloé Paul
- Service de Chirurgie Hépatique et Pancréatique, Chirurgie Générale et Transplantation, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, 1 avenue Molière, 67200 Strasbourg, France; University of Strasbourg, 4 Rue Kirschleger, 67000 Strasbourg, France
| | - Camille Besch
- Service de Chirurgie Hépatique et Pancréatique, Chirurgie Générale et Transplantation, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, 1 avenue Molière, 67200 Strasbourg, France
| | - Thierry Artzner
- Service de Chirurgie Hépatique et Pancréatique, Chirurgie Générale et Transplantation, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, 1 avenue Molière, 67200 Strasbourg, France
| | - Baptiste Michard
- Service de Chirurgie Hépatique et Pancréatique, Chirurgie Générale et Transplantation, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, 1 avenue Molière, 67200 Strasbourg, France
| | - Caterina Cusumano
- Service de Chirurgie Hépatique et Pancréatique, Chirurgie Générale et Transplantation, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, 1 avenue Molière, 67200 Strasbourg, France
| | - Pietro Addeo
- Service de Chirurgie Hépatique et Pancréatique, Chirurgie Générale et Transplantation, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, 1 avenue Molière, 67200 Strasbourg, France; ICube Laboratory, University of Strasbourg, 300 Bd Sébastien Brant, 67400 Illkirch-Graffenstaden, France
| | - Philippe Bachellier
- Service de Chirurgie Hépatique et Pancréatique, Chirurgie Générale et Transplantation, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, 1 avenue Molière, 67200 Strasbourg, France; University of Strasbourg, 4 Rue Kirschleger, 67000 Strasbourg, France
| | - François Faitot
- Service de Chirurgie Hépatique et Pancréatique, Chirurgie Générale et Transplantation, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, 1 avenue Molière, 67200 Strasbourg, France; University of Strasbourg, 4 Rue Kirschleger, 67000 Strasbourg, France; ICube Laboratory, University of Strasbourg, 300 Bd Sébastien Brant, 67400 Illkirch-Graffenstaden, France.
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20
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Badwei N. Molecular Clues for Prediction of Hepatocellular Carcinoma Recurrence After Liver Transplantation. J Clin Exp Hepatol 2023; 13:804-812. [PMID: 37693263 PMCID: PMC10482986 DOI: 10.1016/j.jceh.2023.02.006] [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: 12/11/2022] [Accepted: 02/15/2023] [Indexed: 09/12/2023] Open
Abstract
Recurrence after liver transplantation (LT) for hepatocellular carcinoma (HCC) is one of the commonest causes of cancer-related mortality. Thus, advances in the HCC molecular features have paid researchers great attention to identifying the different risk factors that could aid in liver cancer initiation and progression for earlier prediction of post-operative HCC recurrence risk. Our review has focused on the possible molecular onco-drivers' for HCC recurrence post-LT that may represent diagnostic/prognostic tools and scoring models for the proper selection of LT candidates with HCC.
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Affiliation(s)
- Nourhan Badwei
- Tropical Medicine, Gastroenterology and Hepatology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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21
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Nakamura T, Sasaki K, Kojima L, Teo R, Inaba Y, Yamamoto T, Kimura S, Dageforde LA, Yeh H, Elias N, Bozorgzadeh A, Kawai T, Markmann JF. Impact of donor sex on hepatocellular carcinoma recurrence in liver transplantation after brain death. Clin Transplant 2023; 37:e14989. [PMID: 37039506 DOI: 10.1111/ctr.14989] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 03/17/2023] [Accepted: 04/02/2023] [Indexed: 04/12/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is predominantly seen in males but has a better prognosis in females. No prior studies have investigated HCC recurrence based on sex combination following liver transplant donated after brain death (DBDLT). This study sought to elucidate the effects of donor and recipient sex on HCC recurrence rates. METHODS 9232 adult recipients from the United Network for Organ Sharing (UNOS) database who underwent DBDLT for HCC from 2012 to 2018 were included. Donor-recipient pairs were divided into (1) female donor/female recipient (F-F) (n = 1089); (2) male donor/female recipient (M-F) (n = 975); (3) female donor/male recipient (F-M) (n = 2691); (4) male donor/male recipient (M-M) (n = 4477). The primary prognostic outcome was HCC recurrence. A multivariable competing risk regression analysis was used to assess prognostic influences. RESULTS The median recipient age and model for end-stage liver disease (MELD) scores were similar among the four groups. Livers of male recipients demonstrated greater in size and number of HCC (both p-values were <.0001). There was also a higher rate of vascular invasion in male recipients compared to female (p < .0001). Competing risk analyses showed that the cumulative HCC recurrence rate was significantly lower in the M-F group (p = .013). After adjusting for tumor characteristics, liver grafts from male donors were associated with a lower HCC recurrence rate in female recipients (HR: .62 95%CI: .42-.93) (p = .021). CONCLUSION In DBDLT, male donor to female recipient pairing exhibited lower HCC recurrence rates. SUMMARY Lowest rates of HCC recurrence were confirmed among the female recipients of male donor grafts group in the deceased donor LT cohort. A competing risk multivariable regression analysis demonstrated that male donor sex was significantly associated with low HCC recurrence in female but not male recipients.
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Affiliation(s)
- Tsukasa Nakamura
- Division of Transplant Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Kazunari Sasaki
- Division of Abdominal Transplantation, Stanford University, Stanford, California, USA
| | - Lisa Kojima
- Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA
| | - Richard Teo
- Division of Transplant Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Yosuke Inaba
- Biostatistics Section, Chiba University Hospital Clinical Research Center, Chiba, Japan
| | - Takayuki Yamamoto
- Division of Transplant Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Shoko Kimura
- Division of Transplant Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Leigh Anne Dageforde
- Division of Transplant Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Heidi Yeh
- Division of Transplant Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Nahel Elias
- Division of Transplant Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Adel Bozorgzadeh
- Division of Transplant Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Tatsuo Kawai
- Division of Transplant Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - James F Markmann
- Division of Transplant Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
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22
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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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23
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Shimada S, Shamaa T, Ivanics T, Kitajima T, Adhnan M, Collins K, Rizzari M, Yoshida A, Abouljoud M, Salgia R, Nagai S. Multiple Pretransplant Treatments for Patients Without Pathological Complete Response may Worsen Posttransplant Outcomes in Patients with Hepatocellular Carcinoma. Ann Surg Oncol 2023; 30:1408-1419. [PMID: 36434482 DOI: 10.1245/s10434-022-12789-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 10/28/2022] [Indexed: 11/27/2022]
Abstract
BACKGROUND Liver transplant (LT) candidates with hepatocellular carcinoma (HCC) often receive cancer treatment before transplant. We investigated the impact of pre-transplant treatment for HCC on the risk of posttransplant recurrence. METHODS Adult HCC patients with LT at our institution between 2013 and 2020 were included. The impact of pre-LT cancer treatments on the cumulative recurrence was evaluated, using the Gray and Fine-Gray methods adjusted for confounding factors. Outcomes were considered in two ways: 1) by pathologically complete response (pCR) status within patients received pre-LT treatment; and 2) within patients without pCR, grouped by pre-LT treatment as A) none; B) one treatment; C) multiple treatments. RESULTS The sample included 179 patients, of whom 151 (84%) received pretreatment and 42 (28% of treated) demonstrated pCR. Overall, 22 (12%) patients experienced recurrence. The 5-year cumulative post-LT recurrence rate was significantly lower in patients with pCR than those without pCR (4.8% vs. 19.2%, P = 0.03). In bivariable analyses, pCR significantly decreased risk of recurrence. Among the 137 patients without pCR (viable HCC in the explant), 28 (20%) had no pretreatment (A), 70 (52%) had one treatment (B), and 39 (20%) had multiple treatments (C). Patients in Group C had higher 5-year recurrence rates than those in A or B (39.6% vs. 8.2%, 6.5%, P = 0.004 and P < 0.001, respectively). In bivariable analyses, multiple treatments was significantly associated with recurrence. CONCLUSIONS pCR is a favorable prognostic factor after LT. When pCR was not achieved by pre-LT treatment, the number of treatments might be associated with post-LT oncological prognosis.
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Affiliation(s)
- Shingo Shimada
- Division of Transplant and Hepatobiliary Surgery, Henry Ford Health System, Detroit, MI, USA
| | - Tayseer Shamaa
- Division of Transplant and Hepatobiliary Surgery, Henry Ford Health System, Detroit, MI, USA
| | - Tommy Ivanics
- Division of Transplant and Hepatobiliary Surgery, Henry Ford Health System, Detroit, MI, USA
| | - Toshihiro Kitajima
- Division of Transplant and Hepatobiliary Surgery, Henry Ford Health System, Detroit, MI, USA
| | - Mohamed Adhnan
- Division of Transplant and Hepatobiliary Surgery, Henry Ford Health System, Detroit, MI, USA
| | - Kelly Collins
- Division of Transplant and Hepatobiliary Surgery, Henry Ford Health System, Detroit, MI, USA
| | - Michael Rizzari
- Division of Transplant and Hepatobiliary Surgery, Henry Ford Health System, Detroit, MI, USA
| | - Atsushi Yoshida
- Division of Transplant and Hepatobiliary Surgery, Henry Ford Health System, Detroit, MI, USA
| | - Marwan Abouljoud
- Division of Transplant and Hepatobiliary Surgery, Henry Ford Health System, Detroit, MI, USA
| | - Reena Salgia
- Division of Gastroenterology and Hepatology, Henry Ford Health System, Detroit, MI, USA
| | - Shunji Nagai
- Division of Transplant and Hepatobiliary Surgery, Henry Ford Health System, Detroit, MI, USA.
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24
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Kim J, Zimmerman MA, Shin WY, Boettcher BT, Lee JS, Park JI, Ali M, Yang M, Mishra J, Hagen CE, McGraw JE, Mathison A, Woehlck HJ, Lomberk G, Camara AKS, Urrutia RA, Stowe DF, Hong JC. Effects of Subnormothermic Regulated Hepatic Reperfusion on Mitochondrial and Transcriptomic Profiles in a Porcine Model. Ann Surg 2023; 277:e366-e375. [PMID: 34387201 PMCID: PMC8840998 DOI: 10.1097/sla.0000000000005156] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE We sought to investigate the biological effects of pre-reperfusion treatments of the liver after warm and cold ischemic injuries in a porcine donation after circulatory death model. SUMMARY OF BACKGROUND DATA Donation after circulatory death represents a severe form of liver ischemia and reperfusion injury that has a profound impact on graft function after liver transplantation. METHODS Twenty donor pig livers underwent 60 minutes of in situ warm ischemia after circulatory arrest and 120 minutes of cold static preservation prior to simulated transplantation using an ex vivo perfusion machine. Four reperfusion treatments were compared: Control-Normothermic (N), Control- Subnormothermic (S), regulated hepatic reperfusion (RHR)-N, and RHR-S (n = 5 each). The biochemical, metabolic, and transcriptomic profiles, as well as mitochondrial function were analyzed. RESULTS Compared to the other groups, RHR-S treated group showed significantly lower post-reperfusion aspartate aminotransferase levels in the reperfusion effluent and histologic findings of hepatocyte viability and lesser degree of congestion and necrosis. RHR-S resulted in a significantly higher mitochondrial respiratory control index and calcium retention capacity. Transcriptomic profile analysis showed that treatment with RHR-S activated cell survival and viability, cellular homeostasis as well as other biological functions involved in tissue repair such as cytoskeleton or cytoplasm organization, cell migration, transcription, and microtubule dynamics. Furthermore, RHR-S inhibited organismal death, morbidity and mortality, necrosis, and apoptosis. CONCLUSION Subnormothermic RHR mitigates IRI and preserves hepatic mitochondrial function after warm and cold hepatic ischemia. This organ resuscitative therapy may also trigger the activation of protective genes against IRI. Sub- normothermic RHR has potential applicability to clinical liver transplantation.
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Affiliation(s)
- Joohyun Kim
- Division of Transplant Surgery, Department of Surgery, Medical College of Wisconsin, Milwaukee WI
- Transplant Center, Froedtert & the Medical College of Wisconsin, and Children's Wisconsin, Milwaukee, WI
| | - Michael A Zimmerman
- Division of Transplant Surgery, Department of Surgery, Medical College of Wisconsin, Milwaukee WI
- Transplant Center, Froedtert & the Medical College of Wisconsin, and Children's Wisconsin, Milwaukee, WI
| | - Woo Young Shin
- Department of Surgery, inha University School of Medicine, incheon, South Korea
| | - Brent T Boettcher
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI
| | - Ju-Seog Lee
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Jong-In Park
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI
| | - Muhammed Ali
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI
| | - Meiying Yang
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI
| | - Jyotsna Mishra
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI
| | | | - Joseph E McGraw
- Department of Pharmacology, Concordia University, Mequon, WI
| | - Angela Mathison
- Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI; and
- Division of Research, Department of Surgery, Medical College of Wisconsin, Milwaukee WI
| | - Harvey J Woehlck
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI
| | - Gwen Lomberk
- Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI; and
- Division of Research, Department of Surgery, Medical College of Wisconsin, Milwaukee WI
| | - Amadou K S Camara
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI
| | - Raul A Urrutia
- Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI; and
- Division of Research, Department of Surgery, Medical College of Wisconsin, Milwaukee WI
| | - David F Stowe
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI
| | - Johnny C Hong
- Division of Transplant Surgery, Department of Surgery, Medical College of Wisconsin, Milwaukee WI
- Transplant Center, Froedtert & the Medical College of Wisconsin, and Children's Wisconsin, Milwaukee, WI
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25
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Influence of Perioperative Anesthesia on Cancer Recurrence: from Basic Science to Clinical Practice. Curr Oncol Rep 2023; 25:63-81. [PMID: 36512273 PMCID: PMC9745294 DOI: 10.1007/s11912-022-01342-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/02/2022] [Indexed: 12/15/2022]
Abstract
PURPOSEOF REVIEW In this review, we will summarize the effects of these perioperative anesthetics and anesthetic interventions on the immune system and tumorigenesis as well as address the related clinical evidence on cancer-related mortality and recurrence. RECENT FINDINGS Cancer remains a leading cause of morbidity and mortality worldwide. For many solid tumors, surgery is one of the major therapies. Unfortunately, surgery promotes angiogenesis, shedding of circulating cancer cells, and suppresses immunity. Hence, the perioperative period has a close relationship with cancer metastases or recurrence. In the perioperative period, patients require multiple anesthetic management including anesthetics, anesthetic techniques, and body temperature control. Preclinical and retrospective studies have found that these anesthetic agents and interventions have complex effects on cancer outcomes. Therefore, well-planned, prospective, randomized controlled trials are required to explore the effects of different anesthetics and techniques on long-term outcomes after cancer surgery. Due to the conflicting effects of anesthetic management on cancer recurrence, further preclinical and clinical trials are required and beneficial to the development of systemic cancer therapies.
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Kurihara T, Harada N, Morinaga A, Tomiyama T, Toshida K, Kosai Y, Tomino T, Toshima T, Nagao Y, Morita K, Itoh S, Yoshizumi T. Predictive Factors for the Resectable Type of Hepatocellular Carcinoma Recurrence After Living Donor Liver Transplant. Transplant Proc 2023; 55:191-196. [PMID: 36564321 DOI: 10.1016/j.transproceed.2022.09.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 09/19/2022] [Accepted: 09/20/2022] [Indexed: 12/24/2022]
Abstract
Recurrence of hepatocellular carcinoma (HCC) after living donor liver transplant (LDLT) is an essential factor defining prognosis, and surgical resection is the only curative treatment. However, the factors that define whether surgical resection is possible remain unclear. Here, we compared resectable and unresectable HCC recurrence cases after LDLT and examined factors that determine whether surgical resection is possible. Resectable (n = 17) and unresectable (n = 14) groups among 264 patients who underwent LDLT for HCC from January 1999 to March 2020 were compared and examined for recurrence type, prognosis, and clinicopathologic factors. Overall survival after LDLT (median, 8.5 vs 1.7 years, P < .01) was significantly longer in the resectable group. In univariate analysis, female recipient rate, lymphocyte to monocyte ratio (LMR) ≥2.75, and tumor size ≤5.0 cm were significantly higher in the resectable group. Younger donors, lower Model for End-Stage Liver Disease scores, lower graft volume, and lower graft volume to standard liver volume ratio were evident in the resectable group. In multivariate analysis, female recipient rate (P = .0034) and LMR ≥2.75 (P = .0203) were independent predictive factors for resectable HCC recurrence after LDLT. Female recipient and LMR ≥2.75 before transplant could predict the surgically resectable type of HCC recurrence after LDLT.
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Affiliation(s)
- Takeshi Kurihara
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Noboru Harada
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Akinari Morinaga
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takahiro Tomiyama
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Katsuya Toshida
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yukiko Kosai
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takahiro Tomino
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takeo Toshima
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshihiro Nagao
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kazutoyo Morita
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shinji Itoh
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tomoharu Yoshizumi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
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Suo L, Liang X, Zhang W, Ma T, Gao Z. Risk Factors Related to Early Biliary Complications After Liver Transplantation: a Single-Center Analysis. Transplant Proc 2023; 55:164-169. [PMID: 36707363 DOI: 10.1016/j.transproceed.2022.12.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Revised: 11/19/2022] [Accepted: 12/07/2022] [Indexed: 01/27/2023]
Abstract
BACKGROUND The aim of this study was to evaluate the risk factors of early biliary complications (EBC) after liver transplantation (LT) and seek effective treatments based on our single-center experience. METHODS A total of 124 adult patients were divided into a non-EBC group and EBC group. EBC usually accounts for biliary leakage, biliary stricture, biliary stones, sphincter of Oddi dysfunction, and transient jaundice within 3 months after LT. Statistical analysis including logistic regression was performed to determine EBC risk factors. All procedures complied with the Helsinki Congress and the Declaration of Istanbul. RESULTS Non-EBC (n = 95) and EBC (n = 29) were finally compared, which had no difference in their general characteristics. EBC occurred in 29 patients (26.92%): 1 biliary hemorrhage (3.45%), 7 biliary leakage (24.13%), and 16 biliary stricture (55.18%), and 5 others (17.24%). Of all EBC patients, endoscopic retrograde cholangiopancreatography (68.96%) was higher used to deal with complications than conservative treatment (10.35%), percutaneous transhepatic cholangial drainage (17.24%), and surgical treatment (3.45%). On univariate analyses, risk factors for EBC were bilirubin (P = .014), warm ischemia time (WIT) (P = .020), second WIT (P = .042), and operative time (OT) (P = .033). On multivariate analysis, independent risk factors for BC were WIT (P = .011) and OT (P = .049). CONCLUSIONS The presence of WIT and OT were the independent risk factors for the development of EBC. In addition, we also confirmed that endoscopic retrograde cholangiopancreatography was beneficial and safe in the management of EBC after LT.
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Affiliation(s)
- Lida Suo
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Hospital of Dalian Medical University, Dalian, China; Organ Transplantation Center, The Second Hospital of Dalian Medical University, Dalian, China
| | - Xiangnan Liang
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Hospital of Dalian Medical University, Dalian, China; Organ Transplantation Center, The Second Hospital of Dalian Medical University, Dalian, China
| | - Weibin Zhang
- Organ Transplantation Center, The Second Hospital of Dalian Medical University, Dalian, China
| | - Taiheng Ma
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Hospital of Dalian Medical University, Dalian, China
| | - Zhenming Gao
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Hospital of Dalian Medical University, Dalian, China; Organ Transplantation Center, The Second Hospital of Dalian Medical University, Dalian, China.
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Deng Y, Yang J, Chen Y, Wang J, Fu B, Zhang T, Yi S, Yang Y. Development of a Risk Classifier to Predict Tumor Recurrence and Lenvatinib Benefits in Hepatocellular Carcinoma After Liver Transplantation. Transplant Proc 2023; 55:153-163. [PMID: 36522222 DOI: 10.1016/j.transproceed.2022.11.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Revised: 10/22/2022] [Accepted: 11/16/2022] [Indexed: 12/14/2022]
Abstract
BACKGROUND Current selection tools were not precise enough to predict recurrence of hepatocellular carcinoma (HCC) and benefit of adjuvant lenvatinib for patients who received liver transplant (LT) for HCC. Thus, we aim at developing a risk classifier to predict recurrence of HCC and benefit of adjuvant Lenvatinib for those who underwent LT for HCC. METHODS Cox regression model was applied to selected predictors and created the final model in a training cohort of 287 patients who underwent LT for HCC, which was tested in an internal validation cohort of 72 patients by using C-statistic and net classification index (NRI) compared with the following HCC selection criteria: the Milan criteria, the Up-to-7 criteria, and the University of California, San Francisco criteria. RESULTS We built a Risk Classifier of South China Cohort (RCOSC) based on 4 variables: the maximum diameter plus number of viable tumors, alpha-fetoprotein, microvascular invasion, and highest alanine aminotransferase in 7 days after LT. In validation analyses, our RCOSC showed good predictive performance (C-statistic, 0.866; 95% confidence interval [CI], 0.833-0.899) and had better prognostic value than Milan criteria (NRI, 0.406; P < .001), University of California, San Francisco (NRI, 0.497; P < .001), and Up-to-7 (NRI, 0.527; P < .001). By applying the RCOSC, we were able to accurately categorize patients into high-risk and low-risk groups. Further survival analysis revealed that the patients in the high-risk group might have a better therapeutic response to preventive regimen of lenvatinib after LT for HCC (hazard ratio, 0.38; 95% CI, 0.161-0.871, P = .018). CONCLUSIONS Our RCOSC presented favorable predictive performance for HCC recurrence. It might be capable of sifting out patients who benefit from adjuvant therapy after LT for HCC, providing a reliable tool for precise clinical decision-making of patients with HCC with LT.
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Affiliation(s)
- Yinan Deng
- Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jianming Yang
- Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yewu Chen
- Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jiangfeng Wang
- Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Binsheng Fu
- Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Tong Zhang
- Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Shuhong Yi
- Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
| | - Yang Yang
- Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China.
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29
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Pretzsch E, Nieß H, Khaled NB, Bösch F, Guba M, Werner J, Angele M, Chaudry IH. Molecular Mechanisms of Ischaemia-Reperfusion Injury and Regeneration in the Liver-Shock and Surgery-Associated Changes. Int J Mol Sci 2022; 23:12942. [PMID: 36361725 PMCID: PMC9657004 DOI: 10.3390/ijms232112942] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 10/16/2022] [Accepted: 10/20/2022] [Indexed: 09/01/2023] Open
Abstract
Hepatic ischemia-reperfusion injury (IRI) represents a major challenge during liver surgery, liver preservation for transplantation, and can cause hemorrhagic shock with severe hypoxemia and trauma. The reduction of blood supply with a concomitant deficit in oxygen delivery initiates various molecular mechanisms involving the innate and adaptive immune response, alterations in gene transcription, induction of cell death programs, and changes in metabolic state and vascular function. Hepatic IRI is a major cause of morbidity and mortality, and is associated with an increased risk for tumor growth and recurrence after oncologic surgery for primary and secondary hepatobiliary malignancies. Therapeutic strategies to prevent or treat hepatic IRI have been investigated in animal models but, for the most part, have failed to provide a protective effect in a clinical setting. This review focuses on the molecular mechanisms underlying hepatic IRI and regeneration, as well as its clinical implications. A better understanding of this complex and highly dynamic process may allow for the development of innovative therapeutic approaches and optimize patient outcomes.
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Affiliation(s)
- Elise Pretzsch
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
| | - Hanno Nieß
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
| | - Najib Ben Khaled
- Department of Medicine II, University Hospital, LMU Munich, 81377 Munich, Germany
| | - Florian Bösch
- Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, 37075 Goettingen, Germany
| | - Markus Guba
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
| | - Jens Werner
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
| | - Martin Angele
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
| | - Irshad H. Chaudry
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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30
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Zhang F, Li Y, Wu J, Zhang J, Cao P, Sun Z, Wang W. The role of extracellular traps in ischemia reperfusion injury. Front Immunol 2022; 13:1022380. [PMID: 36211432 PMCID: PMC9533173 DOI: 10.3389/fimmu.2022.1022380] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 08/31/2022] [Indexed: 11/29/2022] Open
Abstract
In response to strong signals, several types of immune cells release extracellular traps (ETs), which are web-like structures consisting of DNA decorated with various protein substances. This process is most commonly observed in neutrophils. Over the past two decades, ET formation has been recognized as a unique mechanism of host defense and pathogen destruction. However, the role of ETs in sterile inflammation has only been studied extensively in recent years. Ischemia reperfusion injury (IRI) is a type of sterile inflammatory injury. Several studies have reported that ETs have an important role in IRI in various organs. In this review, we describe the release of ETs by various types of immune cells and focus on the mechanism underlying the formation of neutrophil ETs (NETs). In addition, we summarize the role of ETs in IRI in different organs and their effects on tumors. Finally, we discuss the value of ETs as a potential therapeutic target for organ IRI and present possible challenges in conducting studies on IRI-related ETs as well as future research directions and prospects.
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Affiliation(s)
- Feilong Zhang
- Department of Urology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China
- Institute of Urology, Capital Medical University, Beijing, China
| | - Yuqing Li
- Department of Urology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China
- Institute of Urology, Capital Medical University, Beijing, China
| | - Jiyue Wu
- Department of Urology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China
- Institute of Urology, Capital Medical University, Beijing, China
| | - Jiandong Zhang
- Department of Urology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China
- Institute of Urology, Capital Medical University, Beijing, China
| | - Peng Cao
- Department of Urology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China
- Institute of Urology, Capital Medical University, Beijing, China
| | - Zejia Sun
- Department of Urology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China
- Institute of Urology, Capital Medical University, Beijing, China
| | - Wei Wang
- Department of Urology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China
- Institute of Urology, Capital Medical University, Beijing, China
- *Correspondence: Wei Wang,
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31
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Parente A, Flores Carvalho M, Eden J, Dutkowski P, Schlegel A. Mitochondria and Cancer Recurrence after Liver Transplantation-What Is the Benefit of Machine Perfusion? Int J Mol Sci 2022; 23:9747. [PMID: 36077144 PMCID: PMC9456431 DOI: 10.3390/ijms23179747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 08/23/2022] [Accepted: 08/24/2022] [Indexed: 11/16/2022] Open
Abstract
Tumor recurrence after liver transplantation has been linked to multiple factors, including the recipient's tumor burden, donor factors, and ischemia-reperfusion injury (IRI). The increasing number of livers accepted from extended criteria donors has forced the transplant community to push the development of dynamic perfusion strategies. The reason behind this progress is the urgent need to reduce the clinical consequences of IRI. Two concepts appear most beneficial and include either the avoidance of ischemia, e.g., the replacement of cold storage by machine perfusion, or secondly, an endischemic organ improvement through perfusion in the recipient center prior to implantation. While several concepts, including normothermic perfusion, were found to reduce recipient transaminase levels and early allograft dysfunction, hypothermic oxygenated perfusion also reduced IRI-associated post-transplant complications and costs. With the impact on mitochondrial injury and subsequent less IRI-inflammation, this endischemic perfusion was also found to reduce the recurrence of hepatocellular carcinoma after liver transplantation. Firstly, this article highlights the contributing factors to tumor recurrence, including the surgical and medical tissue trauma and underlying mechanisms of IRI-associated inflammation. Secondly, it focuses on the role of mitochondria and associated interventions to reduce cancer recurrence. Finally, the role of machine perfusion technology as a delivery tool and as an individual treatment is discussed together with the currently available clinical studies.
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Affiliation(s)
- Alessandro Parente
- The Liver Unit, Queen Elizabeth University Hospital Birmingham, Birmingham B15 2GW, UK
| | - Mauricio Flores Carvalho
- Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Centre of Preclinical Research, 20122 Milan, Italy
| | - Janina Eden
- Department of Surgery and Transplantation, Swiss HPB Centre, University Hospital Zurich, 8091 Zurich, Switzerland
| | - Philipp Dutkowski
- Department of Surgery and Transplantation, Swiss HPB Centre, University Hospital Zurich, 8091 Zurich, Switzerland
| | - 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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Utilization of elderly donors in liver transplantation for patients with hepatocellular carcinoma: A national retrospective cohort study of China. Int J Surg 2022; 105:106839. [PMID: 35987333 DOI: 10.1016/j.ijsu.2022.106839] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Revised: 08/07/2022] [Accepted: 08/11/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUND Profound organ shortages worldwide have led to the increased utilization of marginal organs from older individuals. However, the effectiveness of liver transplantation (LT) with organs from elderly donors for patients with hepatocellular carcinoma (HCC) remains controversial. The objective of the current study was to assess the overall survival (OS) and disease-free survival (DFS) of patients with HCC following LT using grafts from deceased donors over 60 years old. MATERIAL AND METHODS Patients with HCC who underwent LT between 2015 and 2018 were identified in the China Liver Transplant Registry database. The overall survival and disease-free survival of older liver donors (OLDs) were compared with those of younger liver donors (YLDs) after propensity score matching. RESULTS From January 2015 to December 2018, a total of 4971 HCC patients were enrolled in the study according to the screening criteria. The absolute and relative utilization of liver grafts from elderly patients over 60 years for HCC patients increased every year, from 65 (9.3%) in 2015 to 268 (14.5%) in 2018. Disease-free survival (DFS) was significantly lower in HCC patients with elderly donors (both P < 0.05) after propensity score matching. The OLD group had worse DFS than YLD group if patients had tumors beyond the Milan criteria (P < 0.05). CONCLUSIONS The use of older donors for LT has been growing quickly in the last few years in China. Grafts from older donors can be safely used in HCC recipients with similar OS and comparable perioperative complications. However, further investigation into whether older donor has an impact on recurrence is warranted, especially among those with tumors beyond the Milan criteria.
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Liver perfusion strategies: what is best and do ischemia times still matter? Curr Opin Organ Transplant 2022; 27:285-299. [PMID: 35438271 DOI: 10.1097/mot.0000000000000963] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
PURPOSE OF REVIEW This review describes recent developments in the field of liver perfusion techniques. RECENT FINDINGS Dynamic preservation techniques are increasingly tested due to the urgent need to improve the overall poor donor utilization. With their exposure to warm ischemia, livers from donors after circulatory death (DCD) transmit additional risk for severe complications after transplantation. Although the superiority of dynamic approaches compared to static-cold-storage is widely accepted, the number of good quality studies remains limited. Most risk factors, particularly donor warm ischemia, and accepted thresholds are inconsistently reported, leading to difficulties to assess the impact of new preservation technologies. Normothermic regional perfusion (NRP) leads to good outcomes after DCD liver transplantation, with however short ischemia times. While randomized controlled trials (RCT) with NRP are lacking, results from the first RCTs with ex-situ perfusion were reported. Hypothermic oxygenated perfusion was shown to protect DCD liver recipients from ischemic cholangiopathy. In contrast, endischemic normothermic perfusion seems to not impact on the development of biliary complications, although this evidence is only available from retrospective studies. SUMMARY Dynamic perfusion strategies impact posttransplant outcomes and are increasingly commissioned in various countries along with more evidence from RCTs. Transparent reporting of risk and utilization with uniform definitions is required to compare the role of different preservation strategies in DCD livers with prolonged ischemia times.
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34
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Mao Y, Han CY, Hao L, Lee Y, Son JB, Choi H, Lee MR, Yang JD, Hong SK, Suh KS, Yu HC, Kim ND, Bae EJ, Park BH. p21-activated kinase 4 inhibition protects against liver ischemia/reperfusion injury: Role of nuclear factor erythroid 2-related factor 2 phosphorylation. Hepatology 2022; 76:345-356. [PMID: 35108418 DOI: 10.1002/hep.32384] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 01/28/2022] [Accepted: 01/29/2022] [Indexed: 12/23/2022]
Abstract
BACKGROUND AND AIMS p21-activated kinase 4 (PAK4), an oncogenic protein, has emerged as a promising target for anticancer drug development. Its role in oxidative stress conditions, however, remains elusive. We investigated the effects of PAK4 signaling on hepatic ischemia/reperfusion (I/R) injury. APPROACH AND RESULTS Hepatocyte- and myeloid-specific Pak4 knockout (KO) mice and their littermate controls were subjected to a partial hepatic I/R (HIR) injury. We manipulated the catalytic activity of PAK4, either through genetic engineering (gene knockout, overexpression of wild-type [WT] or dominant-negative kinase) or pharmacological inhibitor, coupled with a readout of nuclear factor erythroid 2-related factor 2 (Nrf2) activity, to test the potential function of PAK4 on HIR injury. PAK4 expression was markedly up-regulated in liver during HIR injury in mice and humans. Deletion of PAK4 in hepatocytes, but not in myeloid cells, ameliorated liver damages, as demonstrated in the decrease in hepatocellular necrosis and inflammatory responses. Conversely, the forced expression of WT PAK4 aggravated the pathological changes. PAK4 directly phosphorylated Nrf2 at T369, and it led to its nuclear export and proteasomal degradation, all of which impaired antioxidant responses in hepatocytes. Nrf2 silencing in liver abolished the protective effects of PAK4 deficiency. A PAK4 inhibitor protected mice from HIR injury. CONCLUSIONS PAK4 phosphorylates Nrf2 and suppresses its transcriptional activity. Genetic or pharmacological suppression of PAK4 alleviates HIR injury. Thus, PAK4 inhibition may represent a promising intervention against I/R-induced liver injury.
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Affiliation(s)
- Yuancheng Mao
- Department of Biochemistry and Molecular Biology, Jeonbuk National University Medical School, Jeonju, Republic of Korea
| | - Chang Yeob Han
- School of Pharmacy, Jeonbuk National University, Jeonju, Republic of Korea
| | - Lihua Hao
- Department of Biochemistry and Molecular Biology, Jeonbuk National University Medical School, Jeonju, Republic of Korea
| | | | | | | | - Mi Rin Lee
- Department of Surgery, Jeonbuk National University Medical School, Jeonju, Republic of Korea
| | - Jae Do Yang
- Department of Surgery, Jeonbuk National University Medical School, Jeonju, Republic of Korea
| | - Suk Kyun Hong
- Department of Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Kyung-Suk Suh
- Department of Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hee Chul Yu
- Department of Surgery, Jeonbuk National University Medical School, Jeonju, Republic of Korea
| | | | - Eun Ju Bae
- School of Pharmacy, Jeonbuk National University, Jeonju, Republic of Korea
| | - Byung-Hyun Park
- Department of Biochemistry and Molecular Biology, Jeonbuk National University Medical School, Jeonju, Republic of Korea
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35
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Yu J, Shi X, Yu H, Wu J, Ma J, Dong S, Lu S, Zheng S, Li L, Xu X, Cao H. Impact of hepatitis B surface antigen positive grafts on liver transplantation in patients with benign and malignant liver disease. J Med Virol 2022; 94:3338-3348. [PMID: 35257389 DOI: 10.1002/jmv.27703] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 02/14/2022] [Accepted: 03/04/2022] [Indexed: 02/05/2023]
Abstract
Hepatitis B surface antigen (HBsAg) persists after liver transplantation in almost all patients receiving HBsAg-positive grafts. Chronic hepatitis B virus (HBV) infection is one of the main causes of hepatocellular carcinoma (HCC). We aimed to investigate possible interactions between HBsAg-positive donors, HCC, HBV-related transplant indication, and long-term outcomes. This retrospective study enrolled 1176 patients from two centers between January 2015 and May 2019, of which 135 (11.5%) were HBsAg-positive and 1041 (88.5%) were HBsAg-negative donors. Cox regression models were fitted to study the association between variables and patient and graft survival. In univariate and multivariate analyses, the donor HBsAg status was not significantly associated with patient and graft survival in the entire cohort, but there was a significant interaction between HBsAg-positive donors and HCC, independent of HBV-related transplant indication. The cumulative incidence of patient and graft survival was significantly lower in the subgroup of HCC recipients receiving HBsAg-positive grafts, but no significant difference was found in recipients with benign liver disease. In a subgroup analysis of HCC recipients, HBsAg-positive donors were significantly associated with an increased risk of HCC recurrence (hazard ratio: 1.73; 95% confidence interval: 1.20-2.48; p = 0.003) and similar results were obtained after propensity score matching analysis. We showed excellent outcomes of using HBsAg-positive grafts in patients with benign liver disease, regardless of HBV-related transplant indications. However, positive grafts should be used with caution in recipients with HCC, which are associated with an increased risk of HCC recurrence.
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Affiliation(s)
- Jiong Yu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, China
- National Clinical Research Center for Infectious Diseases, Hangzhou City, China
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, Hangzhou City, China
| | - Xiaowei Shi
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, Zhejiang, China
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Haiying Yu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, China
- National Clinical Research Center for Infectious Diseases, Hangzhou City, China
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, Hangzhou City, China
| | - Jian Wu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, China
- National Clinical Research Center for Infectious Diseases, Hangzhou City, China
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, Hangzhou City, China
| | - Jing Ma
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, China
- National Clinical Research Center for Infectious Diseases, Hangzhou City, China
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, Hangzhou City, China
| | - Siyi Dong
- NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, Zhejiang, China
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Sen Lu
- Department of Colorectal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Shusen Zheng
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, Zhejiang, China
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Lanjuan Li
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, China
- National Clinical Research Center for Infectious Diseases, Hangzhou City, China
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, Hangzhou City, China
| | - Xiao Xu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, Zhejiang, China
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Hongcui Cao
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, China
- National Clinical Research Center for Infectious Diseases, Hangzhou City, China
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, Hangzhou City, China
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36
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Chen H, Lu D, Yang X, Hu Z, He C, Li H, Lin Z, Yang M, Xu X. One Shoot, Two Birds: Alleviating Inflammation Caused by Ischemia/Reperfusion Injury to Reduce the Recurrence of Hepatocellular Carcinoma. Front Immunol 2022; 13:879552. [PMID: 35634295 PMCID: PMC9130551 DOI: 10.3389/fimmu.2022.879552] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Accepted: 04/15/2022] [Indexed: 12/12/2022] Open
Abstract
Inflammation is crucial to tumorigenesis and the development of metastasis. Hepatic ischemia/reperfusion injury (IRI) is an unresolved problem in liver resection and transplantation which often establishes and remodels the inflammatory microenvironment in liver. More and more experimental and clinical evidence unmasks the role of hepatic IRI and associated inflammation in promoting the recurrence of hepatocellular carcinoma (HCC). Meanwhile, approaches aimed at alleviating hepatic IRI, such as machine perfusion, regulating the gut-liver axis, and targeting key inflammatory components, have been proved to prevent HCC recurrence. This review article highlights the underlying mechanisms and promising therapeutic strategies to reduce tumor recurrence through alleviating inflammation induced by hepatic IRI.
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Affiliation(s)
- Hao Chen
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Health Commission (NHC) Key Laboratory of Combined Multi-organ Transplantation, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Institute of Organ Transplantation, Zhejiang University, Hangzhou, China
| | - Di Lu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Health Commission (NHC) Key Laboratory of Combined Multi-organ Transplantation, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Institute of Organ Transplantation, Zhejiang University, Hangzhou, China
| | - Xinyu Yang
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Health Commission (NHC) Key Laboratory of Combined Multi-organ Transplantation, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Institute of Organ Transplantation, Zhejiang University, Hangzhou, China
| | - Zhihang Hu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Health Commission (NHC) Key Laboratory of Combined Multi-organ Transplantation, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Institute of Organ Transplantation, Zhejiang University, Hangzhou, China
| | - Chiyu He
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Health Commission (NHC) Key Laboratory of Combined Multi-organ Transplantation, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Institute of Organ Transplantation, Zhejiang University, Hangzhou, China.,Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital, Hangzhou, China
| | - Huigang Li
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Health Commission (NHC) Key Laboratory of Combined Multi-organ Transplantation, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Institute of Organ Transplantation, Zhejiang University, Hangzhou, China
| | - Zuyuan Lin
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Health Commission (NHC) Key Laboratory of Combined Multi-organ Transplantation, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Institute of Organ Transplantation, Zhejiang University, Hangzhou, China
| | - Modan Yang
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Health Commission (NHC) Key Laboratory of Combined Multi-organ Transplantation, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Institute of Organ Transplantation, Zhejiang University, Hangzhou, China
| | - Xiao Xu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Health Commission (NHC) Key Laboratory of Combined Multi-organ Transplantation, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Institute of Organ Transplantation, Zhejiang University, Hangzhou, China.,Westlake Laboratory of Life Sciences and Biomedicine, Westlake University, Hangzhou, China
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Taura K, Shimamura T, Akamatsu N, Umeshita K, Fujiyoshi M, Abe H, Morita S, Uemoto S, Eguchi S, Furukawa H, Takada Y, Egawa H, Ohdan H, Hatano E. No impact of donor sex on the recurrence of hepatocellular carcinoma after liver transplantation. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2022; 29:570-584. [PMID: 35279950 DOI: 10.1002/jhbp.1134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Revised: 12/28/2021] [Accepted: 01/23/2022] [Indexed: 11/12/2022]
Abstract
BACKGROUND/PURPOSE We aimed to verify a recent theory that female donors reduced the risk of hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT). METHODS A total of 1118 recipients registered in the Japanese Liver Transplantation Society database were evaluated for HCC, of whom 446 received a graft from female donors (F-D group) and 672 from male donors (M-D group). RESULTS Between the groups, donor age, recipient age and sex, positivity of hepatitis viruses, and graft type were different, whereas tumor-related factors were all comparable. The 5-year overall recurrence rates were 14% and 16% in the F-D and M-D groups, respectively (P = 0.59). The 5-year graft recurrence rate was also comparable between the groups (4% and 6%, respectively, P = 0.17). Neither univariate nor multivariate analysis identified donor sex as a significant risk factor for recurrence. Propensity score matching showed similar 5-year overall recurrence rates (15% in the F-D group and 14% in the M-D group, P = 0.63) and graft recurrence rates (5% and 5%, respectively, P = 0.94) between the groups. CONCLUSION Donor sex did not affect post-LT recurrence of HCC in the Japanese cohort and should not be considered in the process of donor selection or organ allocation.
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Affiliation(s)
- Kojiro Taura
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Tsuyoshi Shimamura
- Division of Organ Transplantation, Hokkaido University Hospital, Sapporo, Japan
| | - Nobuhisa Akamatsu
- Artificial Organ and Transplantation Surgery Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Koji Umeshita
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Masato Fujiyoshi
- Division of Organ Transplantation, Hokkaido University Hospital, Sapporo, Japan
| | - Hiroyasu Abe
- Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan
| | - Satoshi Morita
- Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan
| | | | - Susumu Eguchi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Hiroyuki Furukawa
- Division of Gastroenterological Surgery, Department of Surgery, Asahikawa Medical University, Asahikawa, Japan
| | - Yasutsugu Takada
- Department of Hepato-Pancreatic-Biliary and Breast Surgery, Ehime University Graduate School of Medicine, Shitsukawa, Japan
| | - Hiroto Egawa
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
| | - Hideki Ohdan
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Etsuro Hatano
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
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Li JH, Chen T, Xing H, Li RD, Shen CH, Zhang QB, Tao YF, Wang ZX. The AGH score is a predictor of disease-free survival and targeted therapy efficacy after liver transplantation in patients with hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int 2022; 22:245-252. [PMID: 35534342 DOI: 10.1016/j.hbpd.2022.04.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 04/18/2022] [Indexed: 02/05/2023]
Abstract
BACKGROUND Liver transplantation (LT) is the "cure" therapy for patients with hepatocellular carcinoma (HCC). However, some patients encounter HCC recurrence after LT. Unfortunately, there is no effective methods to identify the LT patients who have high risk of HCC recurrence and would benefit from adjuvant targeted therapy. The present study aimed to establish a scoring system to predict HCC recurrence of HCC patients after LT among the Chinese population, and to evaluate whether these patients are suitable for adjuvant targeted therapy. METHODS Clinical data of HCC patients who underwent LT from March 2015 to June 2019 were retrospectively collected and analyzed. RESULTS A total of 201 patients were included in the study. The multivariate Cox analysis suggested that preoperative alpha fetoprotein (AFP) > 200 µg/L (HR = 2.666, 95% CI: 1.515-4.690; P = 0.001), glutamyl transferase (GGT) > 96 U/L (HR = 1.807, 95% CI: 1.012-3.224; P = 0.045), and exceeding the Hangzhou criteria (HR = 2.129, 95% CI: 1.158-3.914; P = 0.015) were independent risk factors for poor disease-free survival (DFS) in patients with HCC who underwent LT. We established an AFP-GGT-Hangzhou (AGH) scoring system based on these factors, and divided cases into high-, moderate-, and low-risk groups. The differences in overall survival (OS) and disease-free survival (DFS) rates among the three groups were significant (P < 0.05). The efficacy of the AGH scoring system to predict DFS was better than that of the Hangzhou criteria, UCSF criteria, Milan criteria, and TNM stage. Only in the high-risk group, we found that lenvatinib significantly improved prognosis compared with that of the control group (P < 0.05). CONCLUSIONS The AGH scoring system provides a convenient and effective way to predict HCC recurrence after LT in HCC patients in China. Patients with a high-risk AGH score may benefit from lenvatinib adjuvant therapy after LT.
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Affiliation(s)
- Jian-Hua Li
- Department of General Surgery, Huashan Hospital, Fudan University, 12 Urumqi Road(M), Shanghai 200040, China
| | - Tuo Chen
- Department of General Surgery, Huashan Hospital, Fudan University, 12 Urumqi Road(M), Shanghai 200040, China
| | - Hao Xing
- Department of General Surgery, Huashan Hospital, Fudan University, 12 Urumqi Road(M), Shanghai 200040, China
| | - Rui-Dong Li
- Department of Intensive Care Unit, Huashan Hospital, Fudan University, 12 Urumqi Road(M), Shanghai 200040, China
| | - Cong-Huan Shen
- Department of General Surgery, Huashan Hospital, Fudan University, 12 Urumqi Road(M), Shanghai 200040, China
| | - Quan-Bao Zhang
- Department of General Surgery, Huashan Hospital, Fudan University, 12 Urumqi Road(M), Shanghai 200040, China
| | - Yi-Feng Tao
- Department of General Surgery, Huashan Hospital, Fudan University, 12 Urumqi Road(M), Shanghai 200040, China
| | - Zheng-Xin Wang
- Department of General Surgery, Huashan Hospital, Fudan University, 12 Urumqi Road(M), Shanghai 200040, China.
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Tang Y, Wang T, Ju W, Li F, Zhang Q, Chen Z, Gong J, Zhao Q, Wang D, Chen M, Guo Z, He X. Ischemic-Free Liver Transplantation Reduces the Recurrence of Hepatocellular Carcinoma After Liver Transplantation. Front Oncol 2021; 11:773535. [PMID: 34966679 PMCID: PMC8711268 DOI: 10.3389/fonc.2021.773535] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 11/22/2021] [Indexed: 12/12/2022] Open
Abstract
Ischemia reperfusion injury (IRI) is an adverse factor for hepatocellular carcinoma (HCC) recurrence after liver transplantation. Ischemic-free liver transplantation (IFLT) is a novel transplant procedure that can largely reduce or even prevent IRI, but the clinical relevance of IFLT and the recurrence of HCC after liver transplantation are still unknown. This retrospective study compared survival outcomes, HCC recurrence, perioperative data and IRI severity following liver transplantation (LT). 30 patients received IFLT and 196 patients received conventional liver transplantation (CLT) were chosen for the entire cohort between June 2017 and August 2020. A 1:3 propensity score matching was performed, 30 IFLT recipients and 85 matched CLT patients were enrolled in propensity-matched cohorts. An univariate and multivariate Cox regression analysis was performed, and showed surgical procedure (CLT vs IFLT) was an independent prognostic factor (HR 3.728, 95% CI 1.172-11.861, P=0.026) for recurrence free survival (RFS) in HCC patients following liver transplantation. In the Kaplan–Meier analysis, the RFS rates at 1 and 3 years after LT in recipients with HCC in the IFLT group were significantly higher than those in the CLT group both in the entire cohort and propensity-matched cohort (P=0.006 and P=0.048, respectively). In addition, patients in the IFLT group had a lower serum lactate level, lower serum ALT level and serum AST level on postoperative Day 1. LT recipients with HCC in the IFLT group had a lower incidence of early allograft dysfunction than LT recipients with HCC in the CLT group. Histological analysis showed no obvious hepatocyte necrosis or apoptosis in IFLT group. In conclusion, IFLT can significantly reduce IRI damage and has the potential to be a useful strategy to reduce HCC recurrence after liver transplantation.
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Affiliation(s)
- Yunhua Tang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Tielong Wang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Weiqiang Ju
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Fangcong Li
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Qi Zhang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Zhitao Chen
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Jinlong Gong
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Qiang Zhao
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Dongping Wang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Maogen Chen
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Zhiyong Guo
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Xiaoshun He
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
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Magro B, Pinelli D, De Giorgio M, Lucà MG, Ghirardi A, Carrobio A, Baronio G, Del Prete L, Nounamo F, Gianatti A, Colledan M, Fagiuoli S. Pre-Transplant Alpha-Fetoprotein > 25.5 and Its Dynamic on Waitlist Are Predictors of HCC Recurrence after Liver Transplantation for Patients Meeting Milan Criteria. Cancers (Basel) 2021; 13:5976. [PMID: 34885087 PMCID: PMC8656660 DOI: 10.3390/cancers13235976] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 11/22/2021] [Accepted: 11/25/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND AND AIM Hepatocellular carcinoma (HCC) recurrence rates after liver transplantation (LT) range between 8 and 20%. Alpha-fetoprotein (AFP) levels at transplant can predict HCC recurrence, however a defined cut-off value is needed to better stratify patients. The aim of this study was to evaluate the rate of HCC recurrence at our centre and to identify predictors, focusing on AFP. METHODS We retrospectively analysed 236 consecutive patients that were waitlisted for HCC who all met the Milan criteria from January 2001 to December 2017 at our liver transplant centre. A total of twenty-nine patients dropped out while they were waitlisted, and 207 patients were included in the final analysis. All survival analyses included the competing-risk model. RESULTS The mean age was 56.8 ± 6.8 years. A total of 14% were female (n = 29/207). The median MELD (model for end-stage liver disease) at LT was 12 (9-16). The median time on the waitlist was 92 (41-170) days. The HCC recurrence rate was 16.4% (n = 34/208). The mean time to recurrence was 3.3 ± 2.8 years. The median AFP levels at transplant were higher in patients with HCC recurrence (p < 0.001). At multivariate analysis, the AFP value at transplant that was greater than 25.5 ng/mL (AUC 0.69) was a strong predictor of HCC recurrence after LT [sHR 3.3 (1.6-6.81); p = 0.001]. The HCC cumulative incidence function (CIF) of recurrence at 10 years from LT was significantly higher in patients with AFP > 25.5 ng/mL [34.3% vs. 11.5% (p = 0.001)]. Moreover, an increase in AFP > 20.8%, was significantly associated with HCC recurrence (p = 0.034). CONCLUSIONS In conclusion, in our retrospective study, the AFP level at transplant > 25.5 ng/mL and its increase greater than 20.8% on the waitlist were strong predictors of HCC recurrence after LT in a cohort of patients that were waitlisted within the Milan criteria. However further studies are needed to validate these data.
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Affiliation(s)
- Bianca Magro
- Gastroenterology, Hepatology and Liver Transplantation, Department of Medicine-Papa Giovanni, XXIII Hospital, 24122 Bergamo, Italy; (M.D.G.); (M.G.L.); (S.F.)
| | - Domenico Pinelli
- Unit of Hepato-Biliary Surgery and Liver Transplantation, ASST Papa Giovanni XXIII, 24122 Bergamo, Italy; (D.P.); (G.B.); (L.D.P.); (F.N.); (M.C.)
| | - Massimo De Giorgio
- Gastroenterology, Hepatology and Liver Transplantation, Department of Medicine-Papa Giovanni, XXIII Hospital, 24122 Bergamo, Italy; (M.D.G.); (M.G.L.); (S.F.)
| | - Maria Grazia Lucà
- Gastroenterology, Hepatology and Liver Transplantation, Department of Medicine-Papa Giovanni, XXIII Hospital, 24122 Bergamo, Italy; (M.D.G.); (M.G.L.); (S.F.)
| | - Arianna Ghirardi
- FROM Research Foundation, Papa Giovanni XXIII Hospital, 24122 Bergamo, Italy; (A.G.); (A.C.)
| | - Alessandra Carrobio
- FROM Research Foundation, Papa Giovanni XXIII Hospital, 24122 Bergamo, Italy; (A.G.); (A.C.)
| | - Giuseppe Baronio
- Unit of Hepato-Biliary Surgery and Liver Transplantation, ASST Papa Giovanni XXIII, 24122 Bergamo, Italy; (D.P.); (G.B.); (L.D.P.); (F.N.); (M.C.)
| | - Luca Del Prete
- Unit of Hepato-Biliary Surgery and Liver Transplantation, ASST Papa Giovanni XXIII, 24122 Bergamo, Italy; (D.P.); (G.B.); (L.D.P.); (F.N.); (M.C.)
| | - Franck Nounamo
- Unit of Hepato-Biliary Surgery and Liver Transplantation, ASST Papa Giovanni XXIII, 24122 Bergamo, Italy; (D.P.); (G.B.); (L.D.P.); (F.N.); (M.C.)
| | - Andrea Gianatti
- Pathology Unit, ASST Papa Giovanni XXIII, 24122 Bergamo, Italy;
| | - Michele Colledan
- Unit of Hepato-Biliary Surgery and Liver Transplantation, ASST Papa Giovanni XXIII, 24122 Bergamo, Italy; (D.P.); (G.B.); (L.D.P.); (F.N.); (M.C.)
| | - Stefano Fagiuoli
- Gastroenterology, Hepatology and Liver Transplantation, Department of Medicine-Papa Giovanni, XXIII Hospital, 24122 Bergamo, Italy; (M.D.G.); (M.G.L.); (S.F.)
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Orci LA, Combescure C, Fink M, Oldani G, Compagnon P, Andres A, Berney T, Toso C. Predicting recurrence of hepatocellular carcinoma after liver transplantation using a novel model that incorporates tumor and donor-related factors. Transpl Int 2021; 34:2875-2886. [PMID: 34784081 DOI: 10.1111/tri.14161] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 08/31/2021] [Accepted: 09/03/2021] [Indexed: 01/11/2023]
Abstract
Evidence suggests that liver graft quality impacts on posttransplant recurrence of hepatocellular carcinoma (HCC). As of today, selection criteria only use variables related to tumor characteristics. Within the Scientific Registry of Transplant Recipients, we identified patients with HCC who underwent liver transplantation between 2004 and 2016 (development cohort, n = 10 887). Based on tumor recurrence rates, we fitted a competing-risk regression incorporating tumor- and donor-related factors, and we developed a prognostic score. Results were validated both internally and externally in the Australia and New Zealand Liver Transplant Registry. Total tumor diameter (subhazard ratio [sub-HR] 1.52 [1.28-1.81]), alpha-feto protein (sub-HR 1.27 [1.23-1.32], recipient male gender (sub-HR 1.43 [1.18-1.74]), elevated donor body mass index (sub-HR 1.26 [1.01-1.58]), and shared graft allocation policy (sub-HR 1.20 [1.01-1.43]) were independently associated with tumor recurrence. We next developed the Darlica score (sub-HR 2.72 [2.41-3.08] P < 0.001) that allows identifying risky combinations between a given donor and a given recipient. Results were validated internally (n = 3 629) and externally in the Australia and New Zealand Liver Transplant Registry (n = 370). The current score is based on variables that are readily available at the time of graft offer. It allows identifying hazardous donor-recipient combinations in terms of risk of tumor recurrence and overall survival.
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Affiliation(s)
- Lorenzo A Orci
- Division of Abdominal and Transplantation Surgery, Department of Surgery, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland.,Faculty of Medicine, Hepato-pancreato-biliary Centre, Geneva University Hospitals, Geneva, Switzerland
| | | | - Michael Fink
- Department of Surgery, Austin Health, Medicine Dentistry and Health Sciences, The University of Melbourne, Melbourne, Victoria, Australia
| | - Graziano Oldani
- Division of Abdominal and Transplantation Surgery, Department of Surgery, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland.,Faculty of Medicine, Hepato-pancreato-biliary Centre, Geneva University Hospitals, Geneva, Switzerland
| | - Philippe Compagnon
- Division of Abdominal and Transplantation Surgery, Department of Surgery, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland.,Faculty of Medicine, Hepato-pancreato-biliary Centre, Geneva University Hospitals, Geneva, Switzerland
| | - Axel Andres
- Division of Abdominal and Transplantation Surgery, Department of Surgery, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland.,Faculty of Medicine, Hepato-pancreato-biliary Centre, Geneva University Hospitals, Geneva, Switzerland
| | - Thierry Berney
- Division of Abdominal and Transplantation Surgery, Department of Surgery, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland.,Faculty of Medicine, Hepato-pancreato-biliary Centre, Geneva University Hospitals, Geneva, Switzerland
| | - Christian Toso
- Division of Abdominal and Transplantation Surgery, Department of Surgery, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland.,Faculty of Medicine, Hepato-pancreato-biliary Centre, Geneva University Hospitals, Geneva, Switzerland
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42
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The effect of leg ischemia/reperfusion injury on the liver in an experimental breast cancer model. JOURNAL OF SURGERY AND MEDICINE 2021. [DOI: 10.28982/josam.1003837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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Schlegel A, Foley DP, Savier E, Flores Carvalho M, De Carlis L, Heaton N, Taner CB. Recommendations for Donor and Recipient Selection and Risk Prediction: Working Group Report From the ILTS Consensus Conference in DCD Liver Transplantation. Transplantation 2021; 105:1892-1903. [PMID: 34416750 DOI: 10.1097/tp.0000000000003825] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Although the utilization of donation after circulatory death donors (DCDs) for liver transplantation (LT) has increased steadily, much controversy remains, and no common acceptance criteria exist with regard to donor and recipient risk factors and prediction models. A consensus conference was organized by International Liver Transplantation Society on January 31, 2020, in Venice, Italy, to review the current clinical practice worldwide regarding DCD-LT and to develop internationally accepted guidelines. The format of the conference was based on the grade system. International experts in this field were allocated to 6 working groups and prepared evidence-based recommendations to answer-specific questions considering the currently available literature. Working group members and conference attendees served as jury to edit and confirm the final recommendations presented at the end of the conference by each working group separately. This report presents the final statements and recommendations provided by working group 2, covering the entire spectrum of donor and recipient risk factors and prediction models in DCD-LT.
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Affiliation(s)
- Andrea Schlegel
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Edgbaston, Birmingham, United Kingdom
- Hepatobiliary Unit, Department of Clinical and Experimental Medicine, University of Florence, AOU Careggi, Florence, Italy
| | - David P Foley
- University of Wisconsin School of Medicine and Public Health, William S. Middleton VA Medical Center, Madison, WI
| | - Eric Savier
- Department of Hepatobiliary Surgery and Liver Transplantation, Sorbonne Université Pitié-Salpêtrière Hospital, Paris, France
| | - Mauricio Flores Carvalho
- Hepatobiliary Unit, Department of Clinical and Experimental Medicine, University of Florence, AOU Careggi, Florence, Italy
| | - Luciano De Carlis
- Department of General Surgery and Transplantation, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
- School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
| | - Nigel Heaton
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - C Burcin Taner
- Department of Transplant, Mayo Clinic Florida, Jacksonville, FL
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Uzuni A, El-Bashir J, Galusca D, Yeddula S, Nagai S, Yoshida A, Abouljoud MS, Otrock ZK. Transfusion requirements and alloimmunization to red blood cell antigens in orthotopic liver transplantation. Vox Sang 2021; 117:408-414. [PMID: 34387366 DOI: 10.1111/vox.13190] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 07/09/2021] [Accepted: 07/23/2021] [Indexed: 01/28/2023]
Abstract
BACKGROUND AND OBJECTIVES Orthotopic liver transplantation (OLT) has been associated with high blood transfusion requirements. We evaluated the transfusion needs and frequency of alloimmunization to RBC antigens among OLT recipients pre- and post-transplantation. MATERIALS AND METHODS We reviewed the medical records of patients who underwent a first OLT between January 2007 and June 2017. Transfusions given only during the perioperative period, defined by 1 week before OLT until 2 weeks following OLT, were included in this study. Records were reviewed in June 2019 for updated antibody testing results. RESULTS A total of 970 patients underwent OLT during the study period. The median age of patients was 57 years; 608(62.7%) were male. During the perioperative period, transfused patients received an average of 10.7 (±10.7) RBC units, 15.6 (±16.2) thawed plasma units and 4.1 (±4.3) platelet units. At the time of OLT, a total of 101 clinically significant RBC alloantibodies were documented in 58(5.98%) patients. Fifty-three of these antibodies were directed against Rh blood group antigens. Twenty-two (37.9%) patients had more than one alloantibody. Patients with alloimmunization before OLT (N = 58) received perioperatively comparable number of RBCs to non-alloimmunized patients (10.5 ± 10.6 vs. 9.6 ± 10.7; p = 0.52). There was no significant difference in perioperative or intraoperative RBC transfusion between patients with one alloantibody and those with multiple alloantibodies. Only 16 patients (16/737; 2.17%) developed new alloantibodies at a median of 61 days after OLT. The overall alloimmunization rate was 9.8% (72/737), and female patients were more likely to be alloimmunized. CONCLUSION Blood transfusion requirements in OLT remain high. However, the rate of RBC alloimmunization was not higher than the general patient population.
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Affiliation(s)
- Ajna Uzuni
- Department of Pathology, Wayne State University School of Medicine, Transfusion Medicine, Henry Ford Hospital, Detroit, Michigan, USA
| | - Jaber El-Bashir
- Department of Anesthesiology, Pain Management and Perioperative Medicine, Henry Ford Hospital, Detroit, Michigan, USA
| | - Dragos Galusca
- Department of Anesthesiology, Pain Management and Perioperative Medicine, Henry Ford Hospital, Detroit, Michigan, USA
| | - Sirisha Yeddula
- Transplant and Hepatobiliary Surgery, Henry Ford Hospital, Detroit, Michigan, USA
| | - Shunji Nagai
- Transplant and Hepatobiliary Surgery, Henry Ford Hospital, Detroit, Michigan, USA
| | - Atsushi Yoshida
- Transplant and Hepatobiliary Surgery, Henry Ford Hospital, Detroit, Michigan, USA
| | - Marwan S Abouljoud
- Transplant and Hepatobiliary Surgery, Henry Ford Hospital, Detroit, Michigan, USA
| | - Zaher K Otrock
- Department of Pathology, Wayne State University School of Medicine, Transfusion Medicine, Henry Ford Hospital, Detroit, Michigan, USA
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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: 60] [Impact Index Per Article: 15.0] [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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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: 17] [Impact Index Per Article: 4.3] [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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Liver transplantation for hepatocellular carcinoma using grafts from uncontrolled circulatory death donation. Sci Rep 2021; 11:13520. [PMID: 34188156 PMCID: PMC8241826 DOI: 10.1038/s41598-021-92976-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 06/11/2021] [Indexed: 11/26/2022] Open
Abstract
Controversy exists regarding whether the rate of hepatocellular carcinoma (HCC) recurrence after orthotopic liver transplantation (OLT) differs when using livers from donation after controlled circulatory death (DCD) versus livers from donation after brain death (DBD). The aim of this cohort study was to analyze rates of HCC recurrence, patient survival, and graft survival after OLT for HCC, comparing recipients of DBD livers (n = 103) with recipients of uncontrolled DCD livers (uDCD; n = 41). No significant differences in tumor size, tumor number, serum alpha-fetoprotein, proportion of patients within Milan criteria, or pre-OLT bridging therapies were identified between groups, although the waitlist period was significantly shorter in the uDCD group (p = 0.040). HCC recurrence was similar between groups. Patient survival was similar between groups, but graft survival was lower in the uDCD group. Multivariate analysis identified recipient age (p = 0.031), pre-OLT bridging therapy (p = 0.024), and HCC recurrence (p = 0.048) as independent risk factors for patient survival and pre-OLT transarterial chemoembolization (p = 0.045) as the single risk factor for HCC recurrence. In conclusion, similar patient survival and lower graft survival were observed in the uDCD group. However, the use of uDCD livers appears to be justified due to a shorter waitlist time, and lower waitlist dropout and HCC recurrence rates.
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Jiang Z, Jiang Q, Fang X, Wang P, Que W, Li H, Yu Y, Liu X, Wang C, Zhong L. Recipient C7 rs9292795 genotype and the risk of hepatocellular carcinoma recurrence after orthotopic liver transplantation in a Han Chinese population. BMC Cancer 2021; 21:521. [PMID: 33964921 PMCID: PMC8106183 DOI: 10.1186/s12885-021-08269-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Accepted: 04/26/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Complement component(C7) gene has been shown to influence the prognosis in Hepatocellular carcinoma (HCC) patients. The association between C7 and HCC recurrence after orthotopic liver transplantation (OLT), however, is still unknown. The purpose of this study was to evaluate whether the donor and recipient C7 gene polymorphisms are related to HCC recurrence after OLT in the Han Chinese population. METHODS A total of 73 consecutive patients with HCC who had undergone OLT, both donors and recipients, were involved in this research. A single nucleotide polymorphism of C7, rs9292795, was genotyped using Sequenom MassARRAY in the cohort. The expression of C7 and the association between C7 gene polymorphisms and HCC recurrence following OLT were analyzed by bioinformatics and statistical analysis, respectively. RESULTS As shown in database, the expression of C7 was higher in HCC tissues than that in normal tissues, and represented a worse prognosis. We also found that recipient C7 rs9292795 polymorphism, rather than the donor, was significantly associated with HCC recurrence after OLT. Multivariate logistic regression analysis confirmed that TNM stage (P = 0.001), Milan criteria (P = 0.000) and recipient rs9292795 genotype (TT vs AA/AT, P = 0.008) were independent risk factors for HCC recurrence. Furthermore, the recipient carrying AA/AT showed higher recurrence-free survival (RFS) and overall survival (OS) than that carrying TT (P < 0.05). In Cox proportional hazards model, TNM stage, recipient rs9292795 genotype, and Milan criteria were identified as independent factors for RFS and OS (P < 0.05) as well as pre-OLT serum alpha fetoprotein (AFP) level was associated with OS (P < 0.05). CONCLUSIONS Recipient C7 rs9292795 gene polymorphism is related to the recurrence of HCC after OLT, which may be a helpful prognostic marker for HCC patients who receive OLT.
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Affiliation(s)
- Zhongyi Jiang
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai, 200080, China
| | - Qianwei Jiang
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai, 200080, China
| | - Xu Fang
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai, 200080, China
| | - Pusen Wang
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai, 200080, China
| | - Weitao Que
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai, 200080, China
| | - Hao Li
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai, 200080, China
| | - Yang Yu
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai, 200080, China
| | - Xueni Liu
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai, 200080, China
| | - Chunguang Wang
- Emergency & Critical Care Department, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 650 New Songjiang Road, Songjiang District, Shanghai, China.
| | - Lin Zhong
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai, 200080, China.
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Gül-Klein S, Kästner A, Haber PK, Krenzien F, Wabitsch S, Krannich A, Andreou A, Eurich D, Tacke F, Horst D, Pratschke J, Schmelzle M. Recurrence of Hepatocellular Carcinoma After Liver Transplantation is Associated with Episodes of Acute Rejections. J Hepatocell Carcinoma 2021; 8:133-143. [PMID: 33777855 PMCID: PMC7987264 DOI: 10.2147/jhc.s292010] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 01/21/2021] [Indexed: 12/24/2022] Open
Abstract
Purpose The impact of acute rejection (AR) after liver transplantation (LT) for hepatocellular carcinoma (HCC) on patient outcome is uncertain. This aim of this study is to investigate whether AR is associated with HCC relapse and overall survival. Patients and Methods Patients undergoing LT for HCC between 2001 and 2015 were retrospectively analyzed with regard to histopathological proven AR within the median time until recurrence. Cox’s regression analysis was conducted revealing risk factors for HCC recurrence. Results HCC recurred in 47 of 252 analyzed patients with a median time to recurrence of 20 months. Patients with AR (28.6%) had a significantly higher frequency of recurrence compared to patients without AR (13.0%, p=0.002). Multiple Cox regression analyses identified AR within 20 months to be an independent risk factor for HCC recurrence both as dichotomized (HR=2.91, 95%CI: 1.30–6.53; p=0.009) and as a continuous variable (HR=1.81, 95%CI: 1.28–2.54; p=0.001). HCC recurrence and AR were associated with higher grades of liver fibrosis one year after LT, when compared to patients without AR (p=0.019). Conclusion Our results demonstrate an association of AR with HCC recurrence after LT with implications for intervals of monitoring in tumor surveillance. Graft fibrosis and immune mechanisms are potentially related and causal interactions are worth further investigation.
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Affiliation(s)
- Safak Gül-Klein
- Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Anika Kästner
- Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Philipp Konstantin Haber
- Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Felix Krenzien
- Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Simon Wabitsch
- Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Alexander Krannich
- Clinical Study Center, Clinical Trial Office, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Andreas Andreou
- Division of Acute Care Surgery, Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, Bern, Switzerland
| | - Dennis Eurich
- Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Frank Tacke
- Department of Hepatology/Gastroenterology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - David Horst
- Institute of Pathology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Johann Pratschke
- Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Moritz Schmelzle
- Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
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Complement 5 Inhibition Ameliorates Hepatic Ischemia/reperfusion Injury in Mice, Dominantly via the C5a-mediated Cascade. Transplantation 2021; 104:2065-2077. [PMID: 32384381 DOI: 10.1097/tp.0000000000003302] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Hepatic ischemia/reperfusion injury (IRI) is a serious complication in liver surgeries, including transplantation. Complement activation seems to be closely involved in hepatic IRI; however, no complement-targeted intervention has been clinically applied. We investigated the therapeutic potential of Complement 5 (C5)-targeted regulation in hepatic IRI. METHODS C5-knockout (B10D2/oSn) and their corresponding wild-type mice (WT, B10D2/nSn) were exposed to 90-minute partial (70%) hepatic ischemia/reperfusion with either anti-mouse-C5 monoclonal antibody (BB5.1) or corresponding control immunoglobulin administration 30 minutes before ischemia. C5a receptor 1 antagonist was also given to WT to identify which cascade, C5a or C5b-9, is dominant. RESULTS C5-knockout and anti-C5-Ab administration to WT both significantly reduced serum transaminase release and histopathological damages from 2 hours after reperfusion. This improvement was characterized by significantly reduced CD41+ platelet aggregation, maintained F4/80+ cells, and decreased high-mobility group box 1 release. After 6 hours of reperfusion, the infiltration of CD11+ and Ly6-G+ cells, cytokine/chemokine expression, single-stranded DNA+ cells, and cleaved caspase-3 expression were all significantly alleviated by anti-C5-Ab. C5a receptor 1 antagonist was as effective as anti-C5-Ab for reducing transaminases. CONCLUSIONS Anti-C5 antibody significantly ameliorated hepatic IRI, predominantly via the C5a-mediated cascade, not only by inhibiting platelet aggregation during the early phase but also by attenuating the activation of infiltrating macrophages/neutrophils and hepatocyte apoptosis in the late phase of reperfusion. Given its efficacy, clinical availability, and controllability, C5-targeted intervention may provide a novel therapeutic strategy against hepatic IRI.
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