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Singh A, Singh C, Dhaliwal A, Singh N, Kumar V, Sohal A, Schneider J. Incidence, screening, and management of de novo malignancies in liver transplant patients: A review. World J Transplant 2025; 15:101046. [DOI: 10.5500/wjt.v15.i3.101046] [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: 09/03/2024] [Revised: 01/29/2025] [Accepted: 02/27/2025] [Indexed: 04/18/2025] Open
Abstract
Liver transplantation (LT) is the definitive treatment for end-stage liver disease, acute liver failure, and liver cancer. Although advancements in surgical techniques, postoperative care, and immunosuppressive therapies have significantly improved outcomes, the long-term use of immunosuppression has increased the risk of complications, including infections, cardiovascular disease, and cancer. Among these, de novo malignancies (DNMs) are a major concern, accounting for 20%-25% of deaths in LT recipients surviving beyond the early post-transplant period. Non-melanoma skin cancers, particularly squamous cell carcinoma are the most prevalent DNMs. Other significant malignancies include Kaposi's sarcoma, post-transplant lymphoproliferative disorders, and various solid organ cancers, including head and neck cancers. Compared to the general population, LT patients face a twofold increase in solid organ malignancies and a 30-fold increase in lymphoproliferative disorders. Risk factors for DNM include chronic immunosuppression, alcohol or tobacco use, viral infections, and underlying liver disease. Emerging evidence emphasizes the importance of tailored cancer screening and prevention strategies, including regular dermatological examinations, targeted screenings for high-risk cancers, and patient education on lifestyle modifications. Early detection through enhanced surveillance protocols has been shown to improve outcomes. Management of DNMs involves a combination of standard oncological therapies and adjustments to immunosuppressive regimens, with promising results from the use of mTOR inhibitors in select patients. The review highlights the critical need for ongoing research to refine risk stratification, optimize screening protocols, and improve treatment approaches to mitigate the burden of DNMs in LT recipients. By implementing personalized preventive and therapeutic strategies, we can enhance long-term outcomes and quality of life for this vulnerable population.
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Affiliation(s)
- Anmol Singh
- Department of Medicine, Tristar Centennial Medical Center, Nashville, TN 37203, United States
| | - Carol Singh
- Department of Medicine, Dayanand Medical College and Hospital, Ludhiana 141001, Punjab, India
| | - Armaan Dhaliwal
- Division of Hematology and Oncology, Lehigh Valley Health Network, Allentown, PA 18103, United States
| | - Navdeep Singh
- Department of Medicine, Government Medical College, Amritsar 143001, Punjab, India
| | - Vikash Kumar
- Division of Gastroenterology, Creighton University School of Medicine, Phoenix, AZ 85012, United States
| | - Aalam Sohal
- Division of Gastroenterology, Creighton University School of Medicine, Phoenix, AZ 85012, United States
| | - Jonathan Schneider
- Division of Gastroenterology, Tristar Centennial Medical Center, Nashville, TN 37203, United States
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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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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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4
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Lu J, Wang F, Zhang W, Ren Y, Yang T, Ratti F, Marques HP, Silva S, Soubrane O, Lam V, Poultsides GA, Popescu I, Grigorie R, Alexandrescu S, Martel G, Workneh A, Guglielmi A, Hugh T, Aldrighetti L, Endo I, Lyu Y, Zhang XF, Pawlik TM. Perioperative Changes in Serum Transaminases Levels Predicts Long-Term Survival Following Liver Resection of Hepatocellular Carcinoma. Ann Surg Oncol 2025; 32:2446-2455. [PMID: 39730966 DOI: 10.1245/s10434-024-16705-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Accepted: 12/03/2024] [Indexed: 12/29/2024]
Abstract
BACKGROUND We sought to define whether and how hepatic ischemia/reperfusion (I/R) as manifested by perioperative aspartate aminotransferase (AST) and alanine aminotransaminase (ALT) levels impact long-term outcomes after curative-intent resection of hepatocellular carcinoma (HCC). PATIENTS AND METHODS Intrasplenic injection of HCC cells was used to establish a murine model of HCC recurrence with versus without I/R injury. Patients who underwent curative resection for HCC were identified from a multi-institutional derivative cohort (DC) and separate external validation (VC) cohort. Perioperative changes of transaminase levels were examined relative to the recurrence-free (RFS) and overall survival (OS) among patients following HCC resection. RESULTS Mice exposed to hepatic I/R injury were more likely to experience tumor recurrence, as well as higher luminescence signal intensity (all p < 0.05) versus mice with no I/R injury. Relative changes between AST and ALT (sum of AST/ALT ratios, SAAR) on postoperative day (POD) 1 and POD 3AST 1 ALT 1 and AST 3 ALT 3 were calculated using the formula: SAAR = 1 2 AST 1 ALT 1 + AST 3 ALT 3 via Fourier transform theory. Among 734 patients in DC, the median SAAR was 2.1. After adjusting for other competing risk factors, SAAR ≥ 2.0 remained strongly associated with risk of postoperative recurrence (ref. SAAR < 2.0, HR 1.32, p = 0.03), whereas SAAR ≥ 3.5 was associated with risk of postoperative mortality (ref. SAAR < 3.5, HR 1.86, p < 0.01). SAAR demonstrated good accuracy to predict postoperative recurrence (c-index 0.724, 0.731) and mortality (c-index 0.655, 0.765) in DC and VC, respectively. CONCLUSIONS Use of routine labs such as AST and ALT can help identify patients at high risk of recurrence and mortality following HCC resection.
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Affiliation(s)
- Jingming Lu
- Department of Hepatobiliary Surgery and Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
- School of Future Technology, Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Fumin Wang
- Department of Hepatobiliary Surgery and Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
- School of Future Technology, Xi'an Jiaotong University, Xi'an, People's Republic of China
| | | | - Yaoxing Ren
- Department of Hepatobiliary Surgery and Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
- School of Future Technology, Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Tian Yang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Navy Medical University, Shanghai, People's Republic of China
| | | | - Hugo P Marques
- Department of Surgery, Curry Cabral Hospital, Lisbon, Portugal
| | - Silvia Silva
- Department of Surgery, Curry Cabral Hospital, Lisbon, Portugal
| | - Olivier Soubrane
- Department of Hepatobiliopancreatic Surgery, APHP, Beaujon Hospital, Clichy, France
| | - Vincent Lam
- Department of Surgery, Westmead Hospital, Sydney, Australia
| | | | - Irinel Popescu
- Department of Surgery, Fundeni Clinical Institute, Bucharest, Romania
| | - Razvan Grigorie
- Department of Surgery, Fundeni Clinical Institute, Bucharest, Romania
| | | | | | - Aklile Workneh
- Department of Surgery, University of Ottawa, Ottawa, Canada
| | | | - Tom Hugh
- Department of Surgery, School of Medicine, The University of Sydney, Sydney, Australia
| | | | - Itaru Endo
- Yokohama City University School of Medicine, Yokohama, Japan
| | - Yi Lyu
- Department of Hepatobiliary Surgery and Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
- School of Future Technology, Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Xu-Feng Zhang
- Department of Hepatobiliary Surgery and Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China.
- School of Future Technology, Xi'an Jiaotong University, Xi'an, People's Republic of China.
| | - Timothy M Pawlik
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA.
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Kojima L, Akabane M, Murray M, Fruscione M, Soma D, Snyder A, McVey J, Firl DJ, Hernandez-Alejandro R, Kubal CA, Markmann JF, Aucejo FN, Tomiyama K, Kimura S, Sasaki K. Reappraisal of tacrolimus levels after liver transplant for HCC: A multicenter study toward personalized immunosuppression regimen. Liver Transpl 2025; 31:344-354. [PMID: 39172007 DOI: 10.1097/lvt.0000000000000459] [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: 03/08/2024] [Accepted: 06/25/2024] [Indexed: 08/23/2024]
Abstract
Post-liver transplant (LT) immunosuppression is necessary to prevent rejection; however, a major consequence of this is tumor recurrence. Although recurrence is a concern after LT for patients with HCC, the oncologically optimal tacrolimus (FK) regimen is still unknown. This retrospective study included 1406 patients with HCC who underwent LT (2002-2019) at 4 US institutions using variable post-LT immunosuppression regimens. Receiver operating characteristic analyses were performed to investigate the influences of post-LT time-weighted average FK (TWA-FK) level on HCC recurrence. A competing risk analysis was employed to evaluate the prognostic influence of TWA-FK while adjusting for patient and tumor characteristics. The AUC for TWA-FK was greatest at 2 weeks (0.68), followed by 1 week (0.64) after LT. Importantly, this was consistently observed across the institutions despite immunosuppression regimen variability. In addition, the TWA-FK at 2 weeks was not associated with rejection within 6 months of LT. A competing risk regression analysis showed that TWA-FK at 2 weeks after LT is significantly associated with recurrence (HR: 1.31, 95% CI: 1.21-1.41, p < 0.001). The TWA-FK effect on recurrence varied depending on the exposure level and the individual's risk of recurrence, including vascular invasion and tumor morphology. Although previous studies have explored the influence of FK levels at 1-3 months after LT on HCC recurrence, this current study suggests that earlier time points and exposure levels must be evaluated. Each patient's oncological risk must also be considered in developing an individualized immunosuppression regimen.
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Affiliation(s)
- Lisa Kojima
- Department of Hepato-pancreato-biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA
| | - Miho Akabane
- Division of Abdominal Transplantation, Department of Surgery, Stanford University, Stanford, California, USA
| | - Matthew Murray
- Department of Surgery, Division of Abdominal Transplantation and Hepatobiliary Surgery, University of Rochester Medical Center, Rochester, New York, USA
| | - Michael Fruscione
- Transplantation Unit, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Daiki Soma
- Division of Abdominal Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Abigail Snyder
- Department of Hepato-pancreato-biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA
| | - John McVey
- Department of Hepato-pancreato-biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA
| | - Daniel J Firl
- Department of Surgery, Duke University, Durham, North Carolina, USA
| | - Roberto Hernandez-Alejandro
- Department of Surgery, Division of Abdominal Transplantation and Hepatobiliary Surgery, University of Rochester Medical Center, Rochester, New York, USA
| | - Chandrashekhar A Kubal
- Division of Abdominal Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - James F Markmann
- Transplantation Unit, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Federico N Aucejo
- Department of Hepato-pancreato-biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA
| | - Koji Tomiyama
- Department of Surgery, Division of Abdominal Transplantation and Hepatobiliary Surgery, University of Rochester Medical Center, Rochester, New York, USA
| | - Shoko Kimura
- Transplantation Unit, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Kazunari Sasaki
- Division of Abdominal Transplantation, Department of Surgery, Stanford University, Stanford, California, USA
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Brombosz EW, Hobeika MJ, Kodali S, Connor AA, Saharia A, Mobley CM, Simon CJ, Cheah YL, Abdelrahim M, Victor DW, Graviss EA, Nguyen DT, Moore LW, Ghobrial RM. Outcomes of Patients with Hepatocellular Carcinoma Undergoing Liver Transplantation Utilizing Extended Criteria Donor Grafts. Transplant Proc 2024; 56:2203-2212. [PMID: 39617682 DOI: 10.1016/j.transproceed.2024.10.039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 10/16/2024] [Indexed: 12/17/2024]
Abstract
BACKGROUND The deceased donor shortage in the United States has led to increased utilization extended criteria donor (ECD) liver grafts. Centers often utilize ECD grafts in patients with low Model for End-Stage Liver Disease (MELD) scores, like patients with hepatocellular carcinoma (HCC). However, few studies have directly examined the outcomes of using ECD grafts in patients with HCC. METHODS Adults receiving liver transplantation (LT) for HCC between 2010 and 2020 were identified in the Organ Procurement and Transplantation Network database. Recipients were categorized according to donor type: standard criteria donor (SCD), extended criteria donor, donation after brain death (ECD-DBD), and donation after circulatory death (DCD). Multivariable Cox regression analysis identified variables associated with overall or graft survival at 3 years post-LT. RESULTS Most patients received ECD-DBD grafts (51.4%); only 8.3% received DCD grafts. The time on the waitlist was similar for ECD and SCD recipients (P = .79). SCD recipients had higher 5-year overall survival post-LT than ECD-DBD or DCD recipients (79.1%, 77.1%, and 76.8%, respectively, P < .001). Similarly, 5-year graft survival was also highest in SCD recipients (SCD = 77.8%, ECD-DBD = 75.7%, and DCD = 72.2%, P < .001). In multivariable analysis, DCD grafts increased mortality risk (hazard ratio [HR] = 1.33, 95% confidence interval [CI] = 1.12-1.57, P = .001), but ECD-DBD grafts did not (HR = 1.10, 95% CI = 1.00-1.22, P = .052). CONCLUSIONS DCD and ECD-DBD recipients had significantly lower overall and graft survival. However, the survival benefit of LT for patients with HCC greatly outweighs the small differences in patient and graft survival from using ECD grafts. Further research should investigate whether treatment of ECD grafts with machine perfusion may ameliorate this discrepancy.
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Affiliation(s)
| | - Mark J Hobeika
- Department of Surgery, Houston Methodist Hospital, Houston, Texas; JC Walter Jr Transplant Center, Houston Methodist Hospital, Houston, Texas; Department of Surgery, Weill Cornell Medical College, New York, New York
| | - Sudha Kodali
- JC Walter Jr Transplant Center, Houston Methodist Hospital, Houston, Texas; Department of Medicine, Houston Methodist Hospital, Houston, Texas; Department of Medicine, Weill Cornell Medical College, New York, New York
| | - Ashton A Connor
- Department of Surgery, Houston Methodist Hospital, Houston, Texas; JC Walter Jr Transplant Center, Houston Methodist Hospital, Houston, Texas; Department of Surgery, Weill Cornell Medical College, New York, New York
| | - Ashish Saharia
- Department of Surgery, Houston Methodist Hospital, Houston, Texas; JC Walter Jr Transplant Center, Houston Methodist Hospital, Houston, Texas; Department of Surgery, Weill Cornell Medical College, New York, New York
| | - Constance M Mobley
- Department of Surgery, Houston Methodist Hospital, Houston, Texas; JC Walter Jr Transplant Center, Houston Methodist Hospital, Houston, Texas; Department of Surgery, Weill Cornell Medical College, New York, New York
| | - Caroline J Simon
- Department of Surgery, Houston Methodist Hospital, Houston, Texas; JC Walter Jr Transplant Center, Houston Methodist Hospital, Houston, Texas
| | - Yee Lee Cheah
- Department of Surgery, Houston Methodist Hospital, Houston, Texas; JC Walter Jr Transplant Center, Houston Methodist Hospital, Houston, Texas
| | - Maen Abdelrahim
- JC Walter Jr Transplant Center, Houston Methodist Hospital, Houston, Texas; Department of Medicine, Houston Methodist Hospital, Houston, Texas; Department of Medicine, Weill Cornell Medical College, New York, New York; Dr. Mary and Ron Neal Cancer Center, Houston Methodist Hospital, Houston, Texas
| | - David W Victor
- JC Walter Jr Transplant Center, Houston Methodist Hospital, Houston, Texas; Department of Medicine, Houston Methodist Hospital, Houston, Texas; Department of Medicine, Weill Cornell Medical College, New York, New York
| | - Edward A Graviss
- JC Walter Jr Transplant Center, Houston Methodist Hospital, Houston, Texas; Department of Surgery, Weill Cornell Medical College, New York, New York; Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas
| | - Duc T Nguyen
- Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Linda W Moore
- Department of Surgery, Houston Methodist Hospital, Houston, Texas; JC Walter Jr Transplant Center, Houston Methodist Hospital, Houston, Texas; Department of Surgery, Weill Cornell Medical College, New York, New York
| | - R Mark Ghobrial
- Department of Surgery, Houston Methodist Hospital, Houston, Texas; JC Walter Jr Transplant Center, Houston Methodist Hospital, Houston, Texas; Department of Surgery, Weill Cornell Medical College, New York, New York.
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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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8
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Akabane M, Esquivel CO, Kim WR, Sasaki K. The Future Frontier of Liver Transplantation Exploring Young Donor Allocation Strategies for HCC Recipients. Transplant Direct 2024; 10:e1657. [PMID: 38881743 PMCID: PMC11177833 DOI: 10.1097/txd.0000000000001657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 02/21/2024] [Accepted: 02/23/2024] [Indexed: 06/18/2024] Open
Abstract
Background The role of donor age in liver transplantation (LT) outcomes for hepatocellular carcinoma (HCC) is controversial. Given the significant risk of HCC recurrence post-LT, optimizing donor/recipient matching is crucial. This study reassesses the impact of young donors on LT outcomes in patients with HCC. Methods A retrospective review of 11 704 LT cases from the United Network for Organ Sharing database (2012-2021) was conducted. The study focused on the effect of donor age on recurrence-free survival, using hazard associated with LT for HCC (HALT-HCC) and Metroticket 2.0 scores to evaluate post-LT survival in patients with HCC. Results Of 4706 cases with young donors, 11.0% had HCC recurrence or death within 2 y, and 18.3% within 5 y. These outcomes were comparable with those of non-young donors. A significant correlation between donor age and post-LT recurrence or mortality (P = 0.04) was observed, which became statistically insignificant after tumor-related adjustments (P = 0.32). The Kaplan-Meier curve showed that recipients with lower HALT-HCC scores (<9) and Metroticket 2.0 scores (<2.2) significantly benefited from young donors, unlike those exceeding these score thresholds. Cox regression analysis showed that donor age significantly influenced outcomes in recipients below certain score thresholds but was less impactful for higher scores. Conclusions Young donors are particularly beneficial for LT recipients with less aggressive HCC, as indicated by their HALT-HCC and Metroticket 2.0 scores. These findings suggest strategically allocating young donors to recipients with less aggressive tumor profiles, which could foster more efficient use of the scarce donor supply and potentially enhance post-LT outcomes.
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Affiliation(s)
- Miho Akabane
- Division of Abdominal Transplant, Department of Surgery, Stanford University Medical Center, Stanford, CA
| | - Carlos O Esquivel
- Division of Abdominal Transplant, Department of Surgery, Stanford University Medical Center, Stanford, CA
| | - W Ray Kim
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford, CA
| | - Kazunari Sasaki
- Division of Abdominal Transplant, Department of Surgery, Stanford University Medical Center, Stanford, CA
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9
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El Hajji S, Lacotte S, Moeckli B, Cauchy F, Compagnon P, Toso C. Transjugular Intrahepatic Portosystemic Shunt Is Associated With Better Waitlist Management of Liver Transplant Candidates With Hepatocellular Carcinoma. Transpl Int 2024; 37:12781. [PMID: 39044902 PMCID: PMC11265282 DOI: 10.3389/ti.2024.12781] [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: 01/31/2024] [Accepted: 06/12/2024] [Indexed: 07/25/2024]
Abstract
Transjugular intrahepatic portosystemic shunt (TIPS) reduces portal hypertension complications. Its impact on hepatocellular carcinoma (HCC) remains unclear. We evaluated 42,843 liver transplant candidates with HCC from the Scientific Registry of Transplant Recipients (2002-2022). 4,484 patients with and without TIPS were propensity score-matched 1:3. Analysing wait-list changes in total tumor volume, HCC count, and alpha-fetoprotein levels, and assessing survival from listing and transplantation; TIPS correlated with a decreased nodule count (-0.24 vs. 0.04, p = 0.028) over a median wait period of 284 days (IQR 195-493) and better overall survival from listing (95.6% vs. 91.5% at 1 year, p < 0.0001). It was not associated with changes in tumor volume (0.28 vs. 0.11 cm³/month, p = 0.58) and AFP (14.37 vs. 20.67 ng/mL, p = 0.42). Post-transplant survival rates (91.8% vs. 91.7% at 1 year, p = 0.25) and HCC recurrence (5.1% vs. 5.9% at 5 years, p = 0.14) were similar, with a median follow-up of 4.98 years (IQR 2.5-8.08). While TIPS was associated with a reduced nodule count and improved waitlist survival, it did not significantly impact HCC growth or aggressiveness. These findings suggest potential benefits of TIPS in HCC management, but further studies need to confirm TIPS safety.
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Affiliation(s)
- Sofia El Hajji
- Division of Abdominal Surgery, Department of Surgery, Geneva University Hospitals, Geneva, Switzerland
- Laboratory of Transplantation and Hepatology, University of Geneva, Geneva, Switzerland
| | - Stéphanie Lacotte
- Division of Abdominal Surgery, Department of Surgery, Geneva University Hospitals, Geneva, Switzerland
- Laboratory of Transplantation and Hepatology, University of Geneva, Geneva, Switzerland
| | - Beat Moeckli
- Division of Abdominal Surgery, Department of Surgery, Geneva University Hospitals, Geneva, Switzerland
- Laboratory of Transplantation and Hepatology, University of Geneva, Geneva, Switzerland
| | - François Cauchy
- Division of Abdominal Surgery, Department of Surgery, Geneva University Hospitals, Geneva, Switzerland
| | - Philippe Compagnon
- Division of Abdominal Surgery, Department of Surgery, Geneva University Hospitals, Geneva, Switzerland
- Division of Transplantation, Department of Surgery, Geneva University Hospitals, Geneva, Switzerland
| | - Christian Toso
- Division of Abdominal Surgery, Department of Surgery, Geneva University Hospitals, Geneva, Switzerland
- Laboratory of Transplantation and Hepatology, University of Geneva, Geneva, Switzerland
- Division of Transplantation, Department of Surgery, Geneva University Hospitals, Geneva, Switzerland
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10
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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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11
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Zhou J, Ye D, Zhang S, Ding J, Zhang T, Chen Z, Xu F, Ren S, Hu Z. The impact of Karnofsky performance status on prognosis of patients with hepatocellular carcinoma in liver transplantation. BMC Gastroenterol 2024; 24:85. [PMID: 38408903 PMCID: PMC10895807 DOI: 10.1186/s12876-024-03161-7] [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: 10/24/2022] [Accepted: 02/06/2024] [Indexed: 02/28/2024] Open
Abstract
BACKGROUND Functional performance as measured by the Karnofsky Performance Status (KPS) scale has been linked to the outcomes of liver transplant patients; however, the effect of KPS on the outcomes of the hepatocellular carcinoma (HCC) liver transplant population has not been fully elucidated. We aimed to investigate the association between pre-transplant KPS score and long-term outcomes in HCC patients listed for liver transplantation. METHODS Adult HCC candidates listed on the Scientific Registry of Transplant Recipients (SRTR) database from January 1, 2011 to December 31, 2017 were grouped into group I (KPS 80-100%, n = 8,379), group II (KPS 50-70%, n = 8,091), and group III (KPS 10-40%, n = 1,256) based on percentage KPS score at listing. Survival was compared and multivariable analysis was performed to identify independent predictors. RESULTS Patients with low KPS score had a higher risk of removal from the waiting list. The 5-year intent-to-treat survival was 57.7% in group I, 53.2% in group II and 46.7% in group III (P < 0.001). The corresponding overall survival was 77.6%, 73.7% and 66.3% in three groups, respectively (P < 0.001). Multivariable analysis demonstrated that KPS was an independent predictor of intent-to-treat survival (P < 0.001, reference group I; HR 1.19 [95%CI 1.07-1.31] for group II, P = 0.001; HR 1.63 [95%CI 1.34-1.99] for group III, P < 0.001) and overall survival(P < 0.001, reference group I; HR 1.16 [95%CI 1.05-1.28] for group II, P = 0.004; HR 1.53 [95%CI 1.26-1.87] for group III, P < 0.001). The cumulative 5-year recurrence rates was higher in group III patients (7.4%), compared with 5.2% in group I and 5.5% in group II (P = 0.037). However, this was not significant in the competing regression analysis. CONCLUSIONS Low pre-transplant KPS score is associated with inferior long-term survival in liver transplant HCC patients, but is not significantly associated with post-transplant tumor recurrence.
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Affiliation(s)
- Jie Zhou
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Afliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Danni Ye
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Afliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Siyao Zhang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Fourth Affiliated Hospital, School of Medicine, Zhejiang University, Yiwu, China
| | - Jiawei Ding
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Fourth Affiliated Hospital, School of Medicine, Zhejiang University, Yiwu, China
| | - Tao Zhang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Fourth Affiliated Hospital, School of Medicine, Zhejiang University, Yiwu, China
| | - Zheng Chen
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Fourth Affiliated Hospital, School of Medicine, Zhejiang University, Yiwu, China
| | - Fangshen Xu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Fourth Affiliated Hospital, School of Medicine, Zhejiang University, Yiwu, China
| | - Shenli Ren
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Fourth Affiliated Hospital, School of Medicine, Zhejiang University, Yiwu, China
| | - Zhenhua Hu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Afliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Fourth Affiliated Hospital, School of Medicine, Zhejiang University, Yiwu, China.
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12
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Xiang Z, Li J, Zeng H, Xiang X, Gao F, Wang K, Wei X, Zheng S, Xu X. Current Understanding of Marginal Grafts in Liver Transplantation. Aging Dis 2024; 16:1036-1058. [PMID: 38607739 PMCID: PMC11964436 DOI: 10.14336/ad.2024.0214] [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: 11/11/2023] [Accepted: 02/14/2024] [Indexed: 04/14/2024] Open
Abstract
End-stage liver disease (ESLD), stemming from a spectrum of chronic liver pathologies including chronic liver failure, acute cirrhosis decompensation and hepatocellular carcinoma, imposes a significant global healthcare burden. Liver transplantation (LT) remains the only treatment for ESLD. However, the escalating mortality on transplant waitlists has prompted the utilization of marginal liver grafts in LT procedures. These grafts primarily encompass elderly livers, steatotic livers, livers from donation after circulatory death, split livers and those infected with the hepatitis virus. While the expansion of the donor pool offers promise, it also introduces concomitant risks. These encompass graft failure, biliary and cardiovascular complications, the recurrence of liver disease and reduced patient and graft survival. Consequently, various established strategies, ranging from improved donor-recipient matching to surgical interventions, have emerged to mitigate these risks. This article undertakes a comprehensive assessment of the current landscape, evaluating the viability of diverse marginal liver grafts. Additionally, it synthesizes approaches aimed at enhancing the quality of such marginal liver grafts. The overarching objective is to augment the donor pool and ameliorate the risk factors associated with the shortage of liver grafts.
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Affiliation(s)
- Ze Xiang
- Department of Hepatobiliary and Pancreatic Surgery, Hangzhou First People's Hospital, Hangzhou 310006, China.
- Zhejiang University School of Medicine, Hangzhou 310058, China.
| | - Jiarui Li
- Zhejiang University School of Medicine, Hangzhou 310058, China.
| | - Huixuan Zeng
- Zhejiang University School of Medicine, Hangzhou 310058, China.
| | - Xiaonan Xiang
- Zhejiang University School of Medicine, Hangzhou 310058, China.
- Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, Cambridgeshire, UK.
| | - Fengqiang Gao
- Department of Hepatobiliary and Pancreatic Surgery, Hangzhou First People's Hospital, Hangzhou 310006, China.
- Zhejiang University School of Medicine, Hangzhou 310058, China.
| | - Kai Wang
- Department of Hepatobiliary and Pancreatic Surgery, Hangzhou First People's Hospital, Hangzhou 310006, China.
- Zhejiang University School of Medicine, Hangzhou 310058, China.
| | - Xuyong Wei
- Department of Hepatobiliary and Pancreatic Surgery, Hangzhou First People's Hospital, Hangzhou 310006, China.
| | - Shusen Zheng
- Zhejiang University School of Medicine, Hangzhou 310058, China.
- Shulan (Hangzhou) Hospital, Zhejiang Shuren University School of Medicine, Hangzhou 310022, China.
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China.
| | - Xiao Xu
- Zhejiang University School of Medicine, Hangzhou 310058, China.
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China.
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13
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Yang M, Shu W, Zhai X, Yang X, Zhou H, Pan B, Li C, Lu D, Cai J, Zheng S, Jin B, Wei X, Xu X. Integrated multi-omic analysis identifies fatty acid binding protein 4 as a biomarker and therapeutic target of ischemia-reperfusion injury in steatotic liver transplantation. Cell Mol Life Sci 2024; 81:83. [PMID: 38341383 PMCID: PMC10858962 DOI: 10.1007/s00018-023-05110-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 12/25/2023] [Accepted: 12/27/2023] [Indexed: 02/12/2024]
Abstract
BACKGROUND AND AIMS Due to a lack of donor grafts, steatotic livers are used more often for liver transplantation (LT). However, steatotic donor livers are more sensitive to ischemia-reperfusion (IR) injury and have a worse prognosis after LT. Efforts to optimize steatotic liver grafts by identifying injury targets and interventions have become a hot issue. METHODS Mouse LT models were established, and 4D label-free proteome sequencing was performed for four groups: normal control (NC) SHAM, high-fat (HF) SHAM, NC LT, and HF LT to screen molecular targets for aggravating liver injury in steatotic LT. Expression detection of molecular targets was performed based on liver specimens from 110 donors to verify its impact on the overall survival of recipients. Pharmacological intervention using small-molecule inhibitors on an injury-related target was used to evaluate the therapeutic effect. Transcriptomics and metabolomics were performed to explore the regulatory network and further integrated bioinformatics analysis and multiplex immunofluorescence were adopted to assess the regulation of pathways and organelles. RESULTS HF LT group represented worse liver function compared with NC LT group, including more apoptotic hepatocytes (P < 0.01) and higher serum transaminase (P < 0.05). Proteomic results revealed that the mitochondrial membrane, endocytosis, and oxidative phosphorylation pathways were upregulated in HF LT group. Fatty acid binding protein 4 (FABP4) was identified as a hypoxia-inducible protein (fold change > 2 and P < 0.05) that sensitized mice to IR injury in steatotic LT. The overall survival of recipients using liver grafts with high expression of FABP4 was significantly worse than low expression of FABP4 (68.5 vs. 87.3%, P < 0.05). Adoption of FABP4 inhibitor could protect the steatotic liver from IR injury during transplantation, including reducing hepatocyte apoptosis, reducing serum transaminase (P < 0.05), and alleviating oxidative stress damage (P < 0.01). According to integrated transcriptomics and metabolomics analysis, cAMP signaling pathway was enriched following FABP4 inhibitor use. The activation of cAMP signaling pathway was validated. Microscopy and immunofluorescence staining results suggested that FABP4 inhibitors could regulate mitochondrial membrane homeostasis in steatotic LT. CONCLUSIONS FABP4 was identified as a hypoxia-inducible protein that sensitized steatotic liver grafts to IR injury. The FABP4 inhibitor, BMS-309403, could activate of cAMP signaling pathway thereby modulating mitochondrial membrane homeostasis, reducing oxidative stress injury in steatotic donors.
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Affiliation(s)
- Mengfan Yang
- Department of Organ Transplantation, Qilu Hospital of Shandong University, Jinan, 250012, China
- Zhejiang University School of Medicine, Hangzhou, 310058, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China
| | - Wenzhi Shu
- Zhejiang University School of Medicine, Hangzhou, 310058, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China
| | - Xiangyu Zhai
- Department of Hepatobiliary Surgery, The Second Hospital, Shandong University, Jinan, 250033, China
| | - Xinyu Yang
- Zhejiang University School of Medicine, Hangzhou, 310058, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China
| | - Huaxin Zhou
- Department of Hepatobiliary Surgery, The Second Hospital, Shandong University, Jinan, 250033, China
| | - Binhua Pan
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Changbiao Li
- Zhejiang University School of Medicine, Hangzhou, 310058, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China
| | - Di Lu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Jinzhen Cai
- Organ Transplantation Center, Affiliated Hospital of Qingdao University, Qingdao, 266035, China
| | - Shusen Zheng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Hangzhou, 310003, China
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Bin Jin
- Department of Organ Transplantation, Qilu Hospital of Shandong University, Jinan, 250012, China.
- Department of Hepatobiliary Surgery, The Second Hospital, Shandong University, Jinan, 250033, China.
| | - Xuyong Wei
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China.
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China.
| | - Xiao Xu
- Zhejiang University School of Medicine, Hangzhou, 310058, China.
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China.
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Hangzhou, 310003, China.
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14
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Incarbone N, De Carlis R, Centonze L, Bernasconi DP, Valsecchi MG, Lauterio A, De Carlis L. The impact of postoperative complications on oncological outcomes of liver transplantation for hepatocellular carcinoma: A competing risk analysis. Dig Liver Dis 2023; 55:1690-1698. [PMID: 37316362 DOI: 10.1016/j.dld.2023.05.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 05/18/2023] [Accepted: 05/22/2023] [Indexed: 06/16/2023]
Abstract
OBJECTIVE To investigate the influence of postoperative complications on tumor-related (TRD), disease-free survival (DFS) and overall survival (OS) in patients undergoing liver transplant (LT) for hepatocellular carcinoma (HCC). METHODS We retrospectively evaluated 425 LTs for HCC from 2010 to 2019. Postoperative complications were classified according to Comprehensive Complication Index (CCI) and the posttransplant risk of TRD assessed through Metroticket 2.0 calculator. The population was stratified into high-risk and low-risk cohorts based on the predicted TRD risk of 80%. In a second step, we re-evaluated TRD, DFS and OS of both cohorts according to a further stratification based on 47.3 points of CCI cut-off. RESULTS In the low-risk cohort, we observed a significantly better DFS (84% vs. 46%, p<0.001), TRD (3% vs. 26%, p<0.001) and OS (89% vs. 62%, p<0.001) in the group with CCI < 47.3. In the high-risk cohort, patients with CCI < 47.3 had significantly better DFS (50% vs. 23%, p = 0.003) and OS (68% vs. 42%, p = 0.02) and a comparable TRD (22% vs. 31%, p = 0.142). CONCLUSIONS A complicated postoperative course negatively influenced long-term survival. This poorer oncological outcome associated with in-hospital postoperative complications suggests that every effort should be made to improve the early posttransplant course in HCC patients, including a careful donor-to recipient match and use of new perfusion technologies.
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Affiliation(s)
- Niccolò Incarbone
- Department of General Surgery and Transplantation, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy; School of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy
| | - Riccardo De Carlis
- Department of General Surgery and Transplantation, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy; PhD Course in Clinical and Experimental Sciences, University of Padua, Padua, Italy
| | - Leonardo Centonze
- Department of General Surgery and Transplantation, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy; Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, Modena, Italy.
| | - Davide Paolo Bernasconi
- Bicocca Bioinformatics Biostatistics and Bioimaging Center - B4, School of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy
| | - Maria Grazia Valsecchi
- Bicocca Bioinformatics Biostatistics and Bioimaging Center - B4, School of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy
| | - Andrea Lauterio
- Department of General Surgery and Transplantation, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy; School of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy
| | - Luciano De Carlis
- Department of General Surgery and Transplantation, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy; School of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy
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15
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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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16
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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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17
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Al-Ameri AAM, Zhou Z, Zheng S. Comparative Analysis of Donor Liver Allograft Outcomes in Hepatocellular Carcinoma Patients Who Underwent Liver Transplant. EXP CLIN TRANSPLANT 2023; 21:664-670. [PMID: 37698401 DOI: 10.6002/ect.2023.0119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/13/2023]
Abstract
OBJECTIVES Liver transplant for patients with hepatocellular carcinoma involves 3 main types of donor allografts: donation after brain death, donation after cardiac death, and donation after brain and cardiac death. Data on this topic are limited, and controversies exist regarding liver transplant outcomes in hepatocellular carcinoma patients who have received these allografts. MATERIALS AND METHODS Data from 490 hepatocellular carcinoma patients who received liver transplant from 2015 to 2021 at the Shulan (Hangzhou) Hospital were retrospectively analyzed. Participants were divided into 3 cohorts according to allograft type: donation after brain death, donation after cardiac death, and donation after brain and cardiac death. Kaplan-Meier and Cox regression methods were used to evaluate patient survival, graft survival, and recurrence-free survival rates after liver transplant. RESULTS Kaplan-Meier analysis revealed that 3-year patient survival rates were 69.2% for donations after brain death, 69.2% for donations after cardiac death, and 46.6% for donations after brain and cardiac death (P = .42); the 3-year graft survival rates were 53.3% for donations after brain death, 56.4% for donations after cardiac death, and 46.6% for donations after brain and cardiac death (P = .44); and 3-year recurrence-free survival rates were 55% for donations after brain death, 56.6% for donations after cardiac death, and 39.5% for donations after brain and cardiac death (P = .46). Complications were also similar across the 3 cohorts (P = .36). Multivariable analysis showed that intraoperative red blood cell transfusion (hazard ratio: 1.820; P = .042) and early allograft dysfunction (hazard ratio: 3.240; P = .041) were independent risk factors for graft survival. CONCLUSIONS Similar outcomes can be achieved for hepatocellular carcinoma patients who undergo liver transplant with donations after brain death, donations after cardiac death, or donations after brain and cardiac death allografts, especially when strict donor selection criteria are applied.
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Affiliation(s)
- Abdulahad Abdulrab Mohammed Al-Ameri
- >From the Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; the Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital, Hangzhou, China; and the NHC Key Laboratory of Combined Multi-organ Transplantation, the 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, and the Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Zhejiang Province, Hangzhou China
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18
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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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19
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Lacotte S, Slits F, Moeckli B, Peloso A, Koenig S, Tihy M, El Hajji S, Gex Q, Rubbia-Brandt L, Toso C. Anti-CD122 antibody restores specific CD8 + T cell response in nonalcoholic steatohepatitis and prevents hepatocellular carcinoma growth. Oncoimmunology 2023; 12:2184991. [PMID: 36891258 PMCID: PMC9988345 DOI: 10.1080/2162402x.2023.2184991] [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] [Indexed: 03/06/2023] Open
Abstract
Nonalcoholic steatohepatitis (NASH) can lead to hepatocellular carcinoma (HCC). Although immunotherapy is used as first-line treatment for advanced HCC, the impact of NASH on anticancer immunity is only partially characterized. We assessed the tumor-specific T cell immune response in the context of NASH. In a mouse model of NASH, we observed an expansion of the CD44+CXCR6+PD-1+CD8+ T cells in the liver. After intra-hepatic injection of RIL-175-LV-OVA-GFP HCC cells, NASH mice had a higher percentage of peripheral OVA-specific CD8+ T cells than control mice, but these cells did not prevent HCC growth. In the tumor, the expression of PD-1 on OVA-specific CD44+CXCR6+CD8+ cells was higher in NASH mice suggesting lowered immune activity. Treating mice with an anti-CD122 antibody, which reduced the number of CXCR6+PD-1+ cells, we restored OVA-specific CD8 activity, and reduced HCC growth compared to untreated NASH mice. Human dataset confirmed that NASH-affected livers, NASH tissues adjacent to HCC and HCC in patients with NASH exhibited gene expression patterns supporting mouse observations. Our findings demonstrate the immune system fails to prevent HCC growth in NASH, primarily linked to a higher representation of CD44+CXCR6+PD-1+CD8+ T cells. Treatment with an anti-CD122 antibody reduces the number of these cells and prevents HCC growth.
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Affiliation(s)
- Stéphanie Lacotte
- Transplantation and Hepatology Laboratory, Department of Surgery, University of Geneva, Geneva, Switzerland
| | - Florence Slits
- Transplantation and Hepatology Laboratory, Department of Surgery, University of Geneva, Geneva, Switzerland
| | - Beat Moeckli
- Transplantation and Hepatology Laboratory, Department of Surgery, University of Geneva, Geneva, Switzerland.,Division of Abdominal Surgery, Department of Surgery, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
| | - Andrea Peloso
- Transplantation and Hepatology Laboratory, Department of Surgery, University of Geneva, Geneva, Switzerland.,Division of Abdominal Surgery, Department of Surgery, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
| | - Stéphane Koenig
- Department of Physiology, University of Geneva, Geneva, Switzerland
| | - Matthieu Tihy
- Division of Clinical Pathology, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
| | - Sofia El Hajji
- Transplantation and Hepatology Laboratory, Department of Surgery, University of Geneva, Geneva, Switzerland
| | - Quentin Gex
- Transplantation and Hepatology Laboratory, Department of Surgery, University of Geneva, Geneva, Switzerland
| | - Laura Rubbia-Brandt
- Division of Clinical Pathology, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
| | - Christian Toso
- Transplantation and Hepatology Laboratory, Department of Surgery, University of Geneva, Geneva, Switzerland.,Division of Abdominal Surgery, Department of Surgery, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
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20
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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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21
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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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22
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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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23
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An Update on Usage of High-Risk Donors in Liver Transplantation. J Clin Med 2021; 11:jcm11010215. [PMID: 35011956 PMCID: PMC8746244 DOI: 10.3390/jcm11010215] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 12/01/2021] [Accepted: 12/28/2021] [Indexed: 12/13/2022] Open
Abstract
The ideal management for end stage liver disease, acute liver failure, and hepatocellular carcinoma (HCC), within specific criteria, is liver transplantation (LT). Over the years, there has been a steady increase in the candidates listed for LT, without a corresponding increase in the donor pool. Therefore, due to organ shortage, it has been substantially difficult to reduce waitlist mortality among patients awaiting LT. Thus, marginal donors such as elderly donors, steatotic donors, split liver, and donors after cardiac death (DCD), which were once not commonly used, are now considered. Furthermore, it is encouraging to see the passing of Acts, such as the HIV Organ Policy Equity (HOPE) Act, enabling further research and development in utilizing HIV grafts. Subsequently, the newer antivirals have aided in successful post-transplant period, especially for hepatitis C positive grafts. However, currently, there is no standardization, and protocols are center specific in the usage of marginal donors. Therefore, studies with longer follow ups are required to standardize its use.
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24
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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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25
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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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26
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Cusumano C, De Carlis L, Centonze L, Lesourd R, Levi Sandri GB, Lauterio A, De Carlis R, Ferla F, Di Sandro S, Camus C, Jézéquel C, Bardou-Jacquet E, Rayar M. Advanced donor age does not increase risk of hepatocellular carcinoma recurrence after liver transplantation: a retrospective two-centre analysis using competing risk analysis. Transpl Int 2021; 34:1948-1958. [PMID: 34145653 DOI: 10.1111/tri.13950] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 04/15/2021] [Accepted: 04/22/2021] [Indexed: 12/30/2022]
Abstract
The impact of donor age on the recurrence of hepatocellular carcinoma (HCC) after liver transplantation is still debated. Between 2002 and 2014, all patients transplanted for HCC in 2 European liver transplantation tertiary centres were retrospectively reviewed. Risk factors for HCC recurrence were assessed using competing risk analysis, and the impact of donor age < or ≥65 years and < or ≥80 years was specifically evaluated after propensity score matching. 728 patients transplanted with a median follow-up of 86 months were analysed. The 1-, 3- and 5-year recurrence rates were 4.9%, 10.7% and 13.9%, respectively. In multivariable analysis, recipient age (sHR: 0.96 [0.93; 0.98], P < 0.01), number of lesions (sHR: 1.05 [1.04; 1.06], P < 0.001), maximum size of the lesions (sHR: 1.37 [1.27; 1.48], P < 0.01), presence of a hepatocholangiocarcinoma (sHR: 6.47 [2.91; 14.38], P < 0.01) and microvascular invasion (sHR: 3.48 [2.42; 5.02], P < 0.01) were significantly associated with HCC recurrence. After propensity score matching, neither donor age ≥65 (P = 0.29) nor donor age ≥80 (P = 0.84) years increased the risk of HCC recurrence. In conclusion, donor age was not found to be a risk factor for HCC recurrence. Patients listed for HCC can receive a graft from an elderly donor without compromising the outcome.
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Affiliation(s)
- Caterina Cusumano
- Service de Chirurgie Hépatobiliaire et Digestive, CHU Rennes, Rennes, France
| | - Luciano De Carlis
- Department of General Surgery and Transplantation, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy
| | - Leonardo Centonze
- Department of General Surgery and Transplantation, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Romain Lesourd
- Service de Chirurgie Hépatobiliaire et Digestive, CHU Rennes, Rennes, France
- Faculté de médecine, Université Rennes1, Rennes, France
| | | | - Andrea Lauterio
- Department of General Surgery and Transplantation, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Riccardo De Carlis
- Department of General Surgery and Transplantation, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Fabio Ferla
- Department of General Surgery and Transplantation, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Stefano Di Sandro
- Department of General Surgery and Transplantation, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Christophe Camus
- Service de Maladies Infectieuses et Réanimation Médicale, CHU Rennes, Rennes, France
- CIC 1414, INSERM, Rennes, France
| | | | - Edouard Bardou-Jacquet
- Faculté de médecine, Université Rennes1, Rennes, France
- Service des Maladies du foie, CHU Rennes, Rennes, France
| | - Michel Rayar
- Service de Chirurgie Hépatobiliaire et Digestive, CHU Rennes, Rennes, France
- Faculté de médecine, Université Rennes1, Rennes, France
- CIC 1414, INSERM, Rennes, France
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27
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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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28
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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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29
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Zhou J, Huang Z, Chen Z, Xu F, Tong R, Zheng S. Impact of donor age on liver transplant outcomes in patients with hepatocellular carcinoma: analysis of the SRTR database. BMC Gastroenterol 2021; 21:195. [PMID: 33931011 PMCID: PMC8086097 DOI: 10.1186/s12876-021-01786-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Accepted: 04/21/2021] [Indexed: 12/26/2022] Open
Abstract
Background Donor age is an important predictor for liver transplant recipients. Studies have not fully explored its impact on transplant outcomes in hepatocellular carcinoma (HCC) patients as well as its involvement in tumor recurrence. Methods HCC patients who received liver transplants during 2010–2017 from the Scientific Registry of Transplant Recipients database were included. The recipients were divided into four groups based on donor age: I (≤ 34 years), II (35–49 years), III (50–64 years), and IV (≥ 65 years). Transplant outcomes, including the overall survival (OS), tumor recurrence, and risks, were evaluated. Results A total of 13,276 HCC recipients were included in this study. Statistical significant differences were observed in OS among the four groups. The best 5-year survival was 76.0% in group I, followed by 73.5% in group II, 72.8% in group III, and 69.2% in group IV (P < 0.001). However, the liver-specific survival did not differ among these groups (P = 0.260). Donor age was found to be the independent predictor of OS after adjusting for other variables (P < 0.001, ref. group I; 1.087 (0.979–1.208) for group II, P = 0.119; 1.124 (1.015–1.246) for group III, P = 0.025; 1.395 (1.215–1.602) for group IV, P < 0.001). In subgroup analysis, OS was significantly different in recipients with hepatitis C virus (HCV), but there was no significant difference for recipients with hepatitis B virus (HBV), alcoholic liver diseases and nonalcoholic steatohepatitis (NASH). The post-transplant cumulative tumor recurrence rates were similar among the four groups (P = 0.382). Conclusions Older donor age was associated with decreased OS but not liver-specific survival as well as post-transplant tumor recurrence in HCC recipients. Donor age also had different effects in patients with different underlying liver diseases. Supplementary Information The online version contains supplementary material available at 10.1186/s12876-021-01786-6.
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Affiliation(s)
- Jie Zhou
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, China.,NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 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 (2019RU019), Hangzhou, China.,Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, 310003, Zhejiang Province, China
| | - Zhichao Huang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, China
| | - Zheng Chen
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, China
| | - Fangshen Xu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, China
| | - Rongliang Tong
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, China.,NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 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 (2019RU019), Hangzhou, China.,Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, 310003, Zhejiang Province, China
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, China. .,NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 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 (2019RU019), Hangzhou, China. .,Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, 310003, Zhejiang Province, China.
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30
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Sapisochin G, Hibi T, Toso C, Man K, Berenguer M, Heimbach J, Greten TF, Pugh TJ, Dawson LA, Mazzaferro V. Transplant Oncology in Primary and Metastatic Liver Tumors: Principles, Evidence, and Opportunities. Ann Surg 2021; 273:483-493. [PMID: 33065633 DOI: 10.1097/sla.0000000000004071] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Transplant oncology defines any application of transplant medicine and surgery aimed at improving cancer patients' survival and/or quality of life. In practice, liver transplantation for selected hepato-biliary cancers is the only solid organ transplant with demonstrated efficacy in curing cancer. Four are the proposed future contributions of transplant oncology in hepato-biliary cancer (4-e). (1) evolutionary approach to cancer care that includes liver transplantation; (2) elucidation of self and non-self recognition systems, by linking tumor and transplant immunology; (3) exploration of innovative endpoints both in clinical and experimental settings taking advantage from the access to the entire liver explant; (4) extension of surgical limitation in the multidisciplinary approach to hepato-biliary oncology. The aim of this review is to define the principles of transplant oncology that may be applied to hepato-biliary cancer treatment and research, attempting to balance current evidences with future opportunities.
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Affiliation(s)
- Gonzalo Sapisochin
- Multi-Organ Transplant and HPB Surgical Oncology, Division of General Surgery, University Health Network, Department of Surgery, University of Toronto, Toronto, Ontario, Canada
| | - Taizo Hibi
- Department of Pediatric Surgery and Transplantation, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
| | - Christian Toso
- Division of Abdominal Surgery and Hepato-pancreato-biliary Center, Department of Surgery, Geneva University Hospitals, Geneva, Switzerland
| | - Kwan Man
- Department of Surgery, HKU-SZH and LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Marina Berenguer
- Hepatology and Liver Transplantation Unit, Ciberehd, IISLaFe and Facultad de Medicina, La Fe University Hospital, Valencia, Spain
| | - Julie Heimbach
- Department of Surgery Liver Transplant Program, Mayo Clinic, Rochester, Minnesota
| | - Tim F Greten
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research and NCI-CCR Liver Cancer Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Trevor J Pugh
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
- Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Laura A Dawson
- Radiation Medicine Program, Princess Margaret Cancer Centre, Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada
| | - Vincenzo Mazzaferro
- HPB Surgery and Liver Transplantation, Department of Oncology, University of Milan, Milan, Italy and Istituto Nazionale Tumori, Fondazione IRCCS, Milan, Italy
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31
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Association between Liver Cirrhosis and Diabetes Mellitus: A Review on Hepatic Outcomes. J Clin Med 2021; 10:jcm10020262. [PMID: 33445629 PMCID: PMC7827383 DOI: 10.3390/jcm10020262] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 01/07/2021] [Accepted: 01/11/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Liver cirrhosis (LC) is largely associated with diabetes mellitus (DM). More than 80% of patients with LC manifest glucose intolerance and about 30% have type 2 DM. A particular and yet unrecognized entity is hepatogenous diabetes (HD), defined as impaired glucose regulation caused by altered liver function following LC. Numerous studies have shown that DM could negatively influence liver-related outcomes. AIM We aimed to investigate whether patients with LC and DM are at higher risk for hepatic encephalopathy (HE), variceal hemorrhage (VH), infections and hepatocellular carcinoma (HCC). The impact of DM on liver transplant (LT) outcomes was also addressed. METHODS Literature search was performed in PubMed, Ovid, and Elsevier databases. Population-based observational studies reporting liver outcomes in patients with LC were included. RESULTS Diabetics are at higher risk for HE, including post-transjugular intrahepatic portosystemic shunt HE. DM also increases the risk of VH and contributes to elevated portal pressure and variceal re-bleeding, while uncontrolled DM is associated with increased risk of bacterial infections. DM also increases the risk of HCC and contributes to adverse LT outcomes. CONCLUSIONS Patients with DM and LC may benefit from close follow-up in order to reduce readmissions and mortality. Due to the heterogeneity of available research, prospective multicenter clinical trials are needed to further validate these findings.
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32
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Hasan B, Colak Y, Khalid RA, Castillo M, Castaneda D, Tandon K, Shaw JJ, Erim T, Zervos XB, Castro FJ, Al-Khalloufi K. Early Detection of Hepatocellular Carcinoma Recurrence in the Posttransplant Population: A Comparison of RETREAT and Cleveland Clinic Florida Scoring System. Transplant Proc 2021; 53:193-199. [PMID: 33069486 DOI: 10.1016/j.transproceed.2020.09.015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 08/10/2020] [Accepted: 09/21/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Liver transplantation (LT) for hepatocellular carcinoma (HCC) is curative in most cases; however, recurrence is observed in some patients. The Risk Estimation of Tumor Recurrence After Transplant (RETREAT) score is an externally validated scoring system for prediction of post-LT HCC recurrence. The Cleveland Clinic Florida Scoring System (CCFSS) is a potential new scoring system for prediction of HCC recurrence. Our study aimed to compare the RETREAT and CCFSS. METHODS We conducted a retrospective cohort study of 52 adult patients with HCC who underwent LT at a tertiary care center. Mantel-Haenszel chi-square analyses were conducted to compare the RETREAT and CCFSS classifications for detecting HCC recurrence. RESULTS A total of 52 patients underwent LT. The median follow-up period was 37 months. Four patients had post-LT HCC recurrence, with all recurrences occurring within 2 years of LT. The RETREAT score was better able to detect low, moderate, and high levels of risk (P < .001), compared to the CCFSS score (P = 0.480). Both risk scores had a sensitivity of 75%; the specificity of the RETREAT score was 95.8%, whereas the specificity of the CCFSS was 60.4%. Alpha-fetoprotein level at the time of LT was associated with HCC recurrence (P = .014). CONCLUSIONS This is the first study to evaluate the CCFSS as a potential new scoring system to predict HCC recurrence after LT. The RETREAT score is more specific than the CCFSS. The incorporation of alpha-fetoprotein level at the time of LT improves the estimation of HCC recurrence in the post-LT period.
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Affiliation(s)
- Badar Hasan
- Department of Gastroenterology, Cleveland Clinic Florida, Weston, Florida.
| | - Yasar Colak
- Department of Gastroenterology, Cleveland Clinic Florida, Weston, Florida
| | - Rumman A Khalid
- Department of Gastroenterology, Cleveland Clinic Florida, Weston, Florida
| | - Michael Castillo
- Department of Gastroenterology, Cleveland Clinic Florida, Weston, Florida
| | - Daniel Castaneda
- Department of Gastroenterology, Cleveland Clinic Florida, Weston, Florida
| | - Kanwarpreet Tandon
- Department of Gastroenterology, Cleveland Clinic Florida, Weston, Florida
| | - Joshua J Shaw
- Department of Transplant Hepatology, Cleveland Clinic Florida, Weston, Florida
| | - Tolga Erim
- Department of Gastroenterology, Cleveland Clinic Florida, Weston, Florida
| | - Xaralambos B Zervos
- Department of Transplant Hepatology, Cleveland Clinic Florida, Weston, Florida
| | - Fernando J Castro
- Department of Gastroenterology, Cleveland Clinic Florida, Weston, Florida
| | - Kawtar Al-Khalloufi
- Department of Transplant Hepatology, Cleveland Clinic Florida, Weston, Florida
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Matsushima H, Acevedo-Moreno LA, Sasaki K, Fujiki M, Kwon CHD, Uso TD, D'Amico G, Aucejo F, Eghtesad B, Miller C, Quintini C, Hashimoto K. Does graft hemodynamics affect the risk of hepatocellular carcinoma recurrence after liver transplantation? Clin Transplant 2020; 34:e14004. [PMID: 32515016 DOI: 10.1111/ctr.14004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 05/15/2020] [Accepted: 05/29/2020] [Indexed: 12/11/2022]
Abstract
Although experimental studies have reported that hepatic ischemia-reperfusion injury promotes tumor growth and metastases, the impact of graft hemodynamics on the recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) is unclear. To investigate the association between graft hemodynamics and HCC recurrence after LT, we conducted a retrospective analysis of 279 patients who underwent LT for HCC. Graft hemodynamics including portal vein flow (PVF), hepatic artery flow (HAF), and total hepatic flow (THF) was analyzed as a predictor of HCC recurrence, using competing risk regression analyses. The cutoff values of PVF, HAF, and THF were set at the lower quartile of distribution. A cumulative recurrence curve demonstrated that low THF (<1511 mL/min, P = .005) was significantly associated with increased recurrence, whereas neither low PVF (<1230 mL/min, P = .150) nor low HAF (<164 mL/min, P = .110) was significant. On multivariate analysis, outside Milan criteria (sub-hazard ratio [SHR] = 3.742; P < .001), microvascular invasion (SHR = 3.698; P < .001), and low THF (SHR = 2.359; P = .010) were independently associated with increased HCC recurrence. In conclusion, our findings suggest that graft hemodynamics may play an important role in HCC recurrence after LT.
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Affiliation(s)
- Hajime Matsushima
- Department of General Surgery, Digestive Disease & Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Lou-Anne Acevedo-Moreno
- Department of General Surgery, Digestive Disease & Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Kazunari Sasaki
- Department of General Surgery, Digestive Disease & Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Masato Fujiki
- Department of General Surgery, Digestive Disease & Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Choon Hyuck David Kwon
- Department of General Surgery, Digestive Disease & Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Teresa Diago Uso
- Department of General Surgery, Digestive Disease & Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Giuseppe D'Amico
- Department of General Surgery, Digestive Disease & Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Federico Aucejo
- Department of General Surgery, Digestive Disease & Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Bijan Eghtesad
- Department of General Surgery, Digestive Disease & Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Charles Miller
- Department of General Surgery, Digestive Disease & Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Cristiano Quintini
- Department of General Surgery, Digestive Disease & Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Koji Hashimoto
- Department of General Surgery, Digestive Disease & Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
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Orci LA, Kreutzfeldt M, Goossens N, Rubbia-Brandt L, Slits F, Hammad K, Delaune V, Oldani G, Negro F, Clément S, Gonelle-Gispert C, Buhler LH, Toso C, Lacotte S. Tolerogenic properties of liver macrophages in non-alcoholic steatohepatitis. Liver Int 2020; 40:609-621. [PMID: 31872499 DOI: 10.1111/liv.14336] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 12/13/2019] [Accepted: 12/15/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Our understanding of non-alcoholic fatty liver disease (NAFLD) pathogenesis is improving, but there is still limited data on the function of resident liver macrophages in this context, especially when considering their contribution in dampening liver inflammation. METHODS Liver macrophages were studied in mouse models of prolonged diet-induced liver steatohepatitis and carbon tetrachloride-induced liver injury. We assessed liver macrophages phenotype and costimulatory/inhibitory properties upon exposure to lipopolysaccharide or interleukin 4. We did phagocytosis and antigen presentation assays to investigate liver macrophages function as scavengers and immune response initiators. Using immunofluorescence staining, we further determined, in human liver tissue of patients with simple steatosis, non-alcoholic steatohepatitis and chronic hepatitis B infection, the expression of the co-inhibitory protein CD274 (Programmed-death ligand 1) and major histocompatibility complex (MHC) class II. RESULTS Both in humans and mice, within chronically inflamed fatty livers, liver macrophages acquired immunomodulatory properties by reducing the expression of MHC class II, and by enhancing co-inhibitory signalling. Liver macrophages circumscribed endotoxin-mediated inflammatory response by upregulating anti-inflammatory genes arginase 1 and interleukin-10. While hepatic macrophages isolated from mice with normal livers were capable of achieving endotoxin tolerance, our results indicated an impairment of this protective mechanism in the presence NASH-like parenchymal abnormalities. CONCLUSIONS Liver macrophages can achieve endotoxin tolerance, but in the chronically inflamed fatty liver, while they acquire an immunomodulatory phenotype, liver macrophages fail to dampen immune-mediated damage. Therefore, loss of tolerogenicity induced by ongoing liver insult may be a mechanism contributing to the worsening of NAFLD.
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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.,Hepato-pancreato-biliary centre, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland
| | - Mario Kreutzfeldt
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.,Division of Clinical Pathology, Geneva University Hospital, Geneva, Switzerland
| | - Nicolas Goossens
- Hepato-pancreato-biliary centre, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland.,Division of Gastroenterology and Hepatology, Department of Medicine, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland
| | - Laura Rubbia-Brandt
- Hepato-pancreato-biliary centre, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland.,Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.,Division of Clinical Pathology, Geneva University Hospital, Geneva, Switzerland
| | - Florence Slits
- Division of Abdominal and Transplantation Surgery, Department of Surgery, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland
| | - Karim Hammad
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
| | - Vaihere Delaune
- Division of Abdominal and Transplantation Surgery, Department of Surgery, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland.,Hepato-pancreato-biliary centre, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland
| | - Graziano Oldani
- Division of Abdominal and Transplantation Surgery, Department of Surgery, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland.,Hepato-pancreato-biliary centre, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland
| | - Francesco Negro
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.,Division of Clinical Pathology, Geneva University Hospital, Geneva, Switzerland
| | - Sophie Clément
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
| | - Carmen Gonelle-Gispert
- Division of Abdominal and Transplantation Surgery, Department of Surgery, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland
| | - Léo H Buhler
- Division of Abdominal and Transplantation Surgery, Department of Surgery, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland
| | - Christian Toso
- Division of Abdominal and Transplantation Surgery, Department of Surgery, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland.,Hepato-pancreato-biliary centre, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland
| | - Stéphanie Lacotte
- Division of Abdominal and Transplantation Surgery, Department of Surgery, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland
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Yang F, Zhang Y, Ren H, Wang J, Shang L, Liu Y, Zhu W, Shi X. Ischemia reperfusion injury promotes recurrence of hepatocellular carcinoma in fatty liver via ALOX12-12HETE-GPR31 signaling axis. J Exp Clin Cancer Res 2019; 38:489. [PMID: 31831037 PMCID: PMC6909624 DOI: 10.1186/s13046-019-1480-9] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 11/13/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Ischemia reperfusion injury (IRI) has been shown to increase the risk of tumor recurrence after liver surgery. Also, nonalcoholic fatty liver disease (NAFLD) is associated with increased HCC recurrence. ALOX12-12-HETE pathway is activated both in liver IRI and NASH. Also, ALOX12-12-HETE has been shown to mediate tumorigenesis and progression. Therefore, our study aims to investigate whether the ALOX12-12-HETE-GPR31 pathway involved in IRI induced HCC recurrence in NAFLD. METHODS HCC mouse model was used to mimic the HCC recurrence in NAFLD. Western Blot, qPCR, Elisa and Immunofluorescence analysis were conducted to evaluate the changes of multiple signaling pathways during HCC recurrence, including ALOX12-12-HETE axis, EMT, MMPs and PI3K/AKT/NF-κB signaling pathway. We also measured the expression and functional changes of GPR31 by siRNA. RESULTS ALOX12-12-HETE pathway was activated in liver IRI and its activation was further enhanced in NAFLD, which induced more severe HCC recurrence in fatty livers than normal livers. Inhibition of ALOX12-12-HETE by ML355 reduced the HCC recurrence in fatty livers. In vitro studies showed that 12-HETE increased the expression of GPR31 and induced epithelial-mesenchymal transition (EMT) and matrix metalloprotein (MMPs) by activating PI3K/AKT/NF-κB pathway. Furthermore, knockdown of GPR31 in cancer cells inhibited the HCC recurrence in NAFLD. CONCLUSIONS ALOX12-12-HETE-GPR31 played an important role in HCC recurrence and might be a potential therapeutic target to reduce HCC recurrence after surgery in fatty livers.
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Affiliation(s)
- Faji Yang
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321, Zhongshan Road, 210008 Nanjing, Jiangsu Province, China
| | - Yuheng Zhang
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321, Zhongshan Road, 210008 Nanjing, Jiangsu Province, China
| | - Haozhen Ren
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321, Zhongshan Road, 210008 Nanjing, Jiangsu Province, China
| | - Jinglin Wang
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321, Zhongshan Road, 210008 Nanjing, Jiangsu Province, China
| | - Longcheng Shang
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321, Zhongshan Road, 210008 Nanjing, Jiangsu Province, China
| | - Yang Liu
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321, Zhongshan Road, 210008 Nanjing, Jiangsu Province, China
| | - Wei Zhu
- Department of Anesthesiology, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321, Zhongshan Road, 210008 Nanjing, Jiangsu Province, China
| | - Xiaolei Shi
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321, Zhongshan Road, 210008 Nanjing, Jiangsu Province, China
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Recent advances in liver transplantation for cancer: The future of transplant oncology. JHEP Rep 2019; 1:377-391. [PMID: 32039389 PMCID: PMC7005652 DOI: 10.1016/j.jhepr.2019.07.004] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Revised: 07/15/2019] [Accepted: 07/16/2019] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation is widely indicated as a curative treatment for selected patients with hepatocellular carcinoma. However, with recent therapeutic advances, as well as efforts to increase the donor pool, liver transplantation has been carefully expanded to patients with other primary or secondary malignancies in the liver. Cholangiocarcinoma, colorectal and neuroendocrine liver metastases, and hepatic epithelioid haemangioendothelioma are amongst the most relevant new indications. In this review we discuss the fundamental concepts of this ambitious undertaking, as well as the newest indications for liver transplantation, with a special focus on future perspectives within the recently established concept of transplant oncology.
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Grąt M, Krasnodębski M, Krawczyk M, Stypułkowski J, Morawski M, Wasilewicz M, Lewandowski Z, Grąt K, Patkowski W, Zieniewicz K. Extremes of Liver Transplantation for Hepatocellular Carcinoma. J Clin Med 2019; 8:787. [PMID: 31163668 PMCID: PMC6616997 DOI: 10.3390/jcm8060787] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Revised: 05/28/2019] [Accepted: 05/30/2019] [Indexed: 12/12/2022] Open
Abstract
The aim of this retrospective observational study was to evaluate outcomes of patients with extremely advanced hepatocellular carcinoma (HCC) after liver transplantation. A total of 285 HCC patients after liver transplantation were screened for eligibility based on either intrahepatic dissemination (≥10 tumors) or macrovascular invasion. Tumor recurrence was the primary end-point. The study cohort comprised 26 patients. Median recurrence-free survival was 23.2 months with hepatitis B virus (HBV) infection (p = 0.038), higher AFP model score (p = 0.001), prolonged graft ischemia (p = 0.004), and younger donor age (p = 0.016) being significant risk factors. Median recurrence-free survival of HBV-negative and HBV-positive patients was 29.8 and 9.3 months, respectively (p = 0.053). In patients with macrovascular invasion, recurrence-free survival at 3 years was 46.3% with no specific predictors. Tumor size (p = 0.044), higher AFP model score (p = 0.019), prolonged graft ischemia (p = 0.016), and younger donor age (p = 0.041) were significant risk factors in patients with intrahepatic dissemination. Superior 3-year outcomes were observed in patients with intrahepatic dissemination and tumor size <3.5 cm (83.3%, p = 0.027) and HBV-negative patients with ischemia <9.7 h (85.7%, p = 0.028). In conclusion, patients with extremely advanced HCCs are remarkably heterogeneous with respect to their profile of tumor recurrence risk. This heterogeneity is largely driven by factors other than standard predictors of post-transplant HCC recurrence.
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Affiliation(s)
- Michał Grąt
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, 1A Banacha Street, 02-091 Warsaw, Poland.
| | - Maciej Krasnodębski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, 1A Banacha Street, 02-091 Warsaw, Poland.
| | - Marek Krawczyk
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, 1A Banacha Street, 02-091 Warsaw, Poland.
| | - Jan Stypułkowski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, 1A Banacha Street, 02-091 Warsaw, Poland.
| | - Marcin Morawski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, 1A Banacha Street, 02-091 Warsaw, Poland.
| | - Michał Wasilewicz
- Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, 02-091 Warsaw, Poland.
| | - Zbigniew Lewandowski
- Department of Epidemiology and Biostatistics, Medical University of Warsaw, 3 Oczki Street, 02-007 Warsaw, Poland.
| | - Karolina Grąt
- Second Department of Clinical Radiology, Medical University of Warsaw, 02-091 Warsaw, Poland.
| | - Waldemar Patkowski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, 1A Banacha Street, 02-091 Warsaw, Poland.
| | - Krzysztof Zieniewicz
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, 1A Banacha Street, 02-091 Warsaw, Poland.
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Wang C, Lu D, Ling Q, Chen J, Liu Z, Guo H, Xu X, Zheng S. Donor one‑carbon metabolism gene single nucleotide polymorphisms predict the susceptibility of cancer recurrence after liver transplantation. Gene 2019; 689:97-101. [PMID: 30529095 DOI: 10.1016/j.gene.2018.11.035] [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: 07/26/2018] [Revised: 11/05/2018] [Accepted: 11/13/2018] [Indexed: 10/27/2022]
Abstract
BACKGROUND Many enzymes involved in one‑carbon metabolism (OCM) are considered to have important roles in carcinogenesis, especially in hepatocellular carcinoma (HCC). However, the influence of polymorphisms in OCM genes on recurrence in HCC patients with liver transplantation has yet not been reported. The aim of this study was to explore the impact of donor liver graft OCM gene polymorphism on the prognosis of liver transplant recipients with HCC. METHODS This study enrolled 100 liver transplantation patients from a Chinese Han population to detect the association between donor OCM genes polymorphisms and post-transplant HCC recurrence. Nine SNPs from seven OCM genes (MTHFD1, MTR, MTRR, DHFR, ALDH1L1, SHMT1, and CBS) were evaluated by Chi-square test and Kaplan-Meier survival analysis. RESULT None of the nine SNPs were significantly associated with cancer recurrence after liver transplantation. However, tumor-free survival for recipients with the AA genotype of rs1801394 polymorphism was significantly shorter than patients with AG/GG genotype (1097 ± 155 vs. 1657 ± 173 days, P < 0.05) among patients with alpha-fetoprotein < 400 ng/ml. Kaplan-Meier survival curves showed that recipients with donor rs1127717 homozygous TT had a significantly longer tumor-free survival and overall survival than heterozygous CT/CC recipients (tumor-free survival 1395 ± 128 vs. 671 ± 233 days, P < 0.05; overall survival 1540 ± 114 vs. 925 ± 242 days, P < 0.05) in the patient subgroup with well or moderately differentiated HCC. CONCLUSION This is the first genetic study to examine the relation between donor liver graft OCM gene polymorphisms and the risk of HCC recurrence after liver transplantation. Our findings support the hypothesis that polymorphisms of donor genes related to OCM play important roles in post-transplant HCC recurrence. Furthermore, donor rs1801394 and rs1127717 polymorphism may serve as promising prognostic biomarkers for HCC recurrence in liver transplant recipients.
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Affiliation(s)
- Chao Wang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China.
| | - Di Lu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Qi Ling
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Jun Chen
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China.
| | - Zhikun Liu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Haijun Guo
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Xiao Xu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China.
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China.
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Li Z, Gao Z, Xiang J, Zhou J, Yan S, Hu Z. Intention-to-treat analysis of liver transplantation for hepatocellular carcinoma: The impact of pre-existing diabetes mellitus. Liver Int 2019; 39:361-370. [PMID: 30276959 DOI: 10.1111/liv.13982] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2018] [Revised: 09/22/2018] [Accepted: 09/25/2018] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Diabetes mellitus is known to negatively impact the outcome of liver transplant; however, data are scarce regarding risk of waitlist dropout and tumour recurrence in patients with hepatocellular carcinoma. We examined the impact of diabetes mellitus on the outcomes of candidates with hepatocellular carcinoma on an intention-to-treat basis. METHODS Our study included 15 776 candidates with hepatocellular carcinoma diagnosis on the Scientific Registry of Transplant Recipients database from 2008 to 2015 to evaluate the risk of waitlist dropout, hepatocellular carcinoma recurrence and overall survival. RESULTS There were more patients dropped out from the waiting list owing to patient disease deterioration or tumour progression in the diabetes mellitus group (15.1% vs 13.7%, P = 0.024). The mean waiting time was similar in the two groups (233 days vs 230 days, P = 0.631). The recurrence rate was higher in the diabetes mellitus group (9.0% vs 6.2%, P < 0.001); however, the mean time to recurrence in the two groups was similar (23.7 months vs 22.6 months, P = 0.371). Diabetes mellitus, tumours exceeding Milan criteria, and AFP >400 ng/mL were independent predictive factors for recurrence. On an intention-to-treat basis, diabetes mellitus was also an independent poor prognostic factor for overall survival; however, the overall survival was comparable with tumours beyond Milan criteria. CONCLUSIONS Diabetes mellitus was associated with poor survival outcomes and an increased risk of waitlist dropout and tumour recurrence rates in hepatocellular carcinoma patients. Those patients should be paid more attention to cardiovascular and oncological examination when determining waitlist and post-transplant surveillance strategies.
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Affiliation(s)
- Zhiwei Li
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, School of Medicine, First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Zhenzhen Gao
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, School of Medicine, First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Jie Xiang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, School of Medicine, First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Jie Zhou
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, School of Medicine, First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Sheng Yan
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, School of Medicine, First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Zhenhua Hu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, School of Medicine, First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang Province, China.,Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, Zhejiang Province, China
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Ata N, Ayloo S, Tsung A, Molinari M. Recipient obesity does not affect survival after deceased donor liver transplantation for hepatocellular carcinoma. A national retrospective cohort study in the United States. HPB (Oxford) 2019; 21:67-76. [PMID: 30691592 DOI: 10.1016/j.hpb.2018.06.1797] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Revised: 04/24/2018] [Accepted: 06/03/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND The oncological effects of obesity on liver transplant (LT) patients with hepatocellular carcinoma (HCC) remains unclear. We investigated patient overall survival and tested two-way interactions between donor and recipient obesity status. METHODS Using the UNOS database, a total of 8352 LT recipients with HCC were included. Donors and recipients were stratified in normal weight (NW), overweight (OW) and obese (OB). Hazard ratios (HR) for any cause of death and interactions between recipient and donor BMI were estimated by multivariate flexible parametric models. RESULTS Five-year overall survival was 66% for NW, 67% for OW and 68% for OB recipients. The HRs of death from all causes were 0.96 (95% CI: 0.86-1.08) for OW and 0.93 (95% CI: 0.82-1.05) for OB recipients when compared to NW patients. At multivariate analysis, predictors of inferior survival were recipient age (≥65 years), donor age (≥45 years), need for pre-operative dialysis, HCV infection, transplants performed before 2007, and UNOS regions 2,3,9,10, and 11. The lowest adjusted HR was measured for recipients with BMI between 25 and 35 and there were no interactions between recipient and donor BMI. CONCLUSIONS the overall survival of LT recipients with HCC was not affected by donor or recipient obesity.
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Affiliation(s)
- Nicole Ata
- Division of Surgery, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Subhashini Ayloo
- Division of Transplant Surgery, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Alan Tsung
- Division of Hepatobiliary and Pancreatic Surgery, University of Pittsburgh Medical Centre, Pittsburgh, PA, USA
| | - Michele Molinari
- Division of Transplant Surgery, University of Pittsburgh Medical Centre, Pittsburgh, PA, USA.
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Galle PR, Forner A, Llovet JM, Mazzaferro V, Piscaglia F, Raoul JL, Schirmacher P, Vilgrain V. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol 2018; 69:182-236. [PMID: 29628281 DOI: 10.1016/j.jhep.2018.03.019] [Citation(s) in RCA: 5925] [Impact Index Per Article: 846.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 03/20/2018] [Indexed: 02/06/2023]
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Grąt M, Krawczyk M, Wronka KM, Stypułkowski J, Lewandowski Z, Wasilewicz M, Krawczyk P, Grąt K, Patkowski W, Zieniewicz K. Ischemia-reperfusion injury and the risk of hepatocellular carcinoma recurrence after deceased donor liver transplantation. Sci Rep 2018; 8:8935. [PMID: 29895820 PMCID: PMC5997656 DOI: 10.1038/s41598-018-27319-y] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2018] [Accepted: 06/01/2018] [Indexed: 02/07/2023] Open
Abstract
This study aimed to evaluate the effects of ischemia-reperfusion injury (IRI) on the risk of hepatocellular carcinoma (HCC) recurrence after liver transplantation. Data of 195 patients were retrospectively analysed. Post-reperfusion aspartate (AST), alanine transaminase, and lactate dehydrogenase (LDH) levels were the primary measures of IRI. Tumour recurrence was the primary endpoint. Post-reperfusion AST was a continuous risk factor for tumour recurrence in patients within Milan criteria (p = 0.035), with an optimal cut-off of 1896 U/L. Recurrence-free survival of patients within Milan criteria and post-reperfusion AST of <1896 and ≥1896 U/L was 96.6% and 71.9% at 5 and 3.7 years, respectively (p = 0.006). Additionally, post-reperfusion AST and LDH exceeding the upper quartile significantly increased the risk of HCC recurrence in patients within Milan criteria (p = 0.039, hazard ratio [HR] = 5.99 and p = 0.040, HR = 6.08, respectively) and to a lesser extent, in patients within Up-to-7 criteria (p = 0.028, HR = 3.58 and p = 0.039, HR = 3.33, respectively). No other significant IRI effects were found in patients beyond the Up-to-7 criteria and in analyses stratified for independent risk factors for recurrence: tumour number and differentiation, alpha-fetoprotein, and microvascular invasion. Thus, IRI exerts major negative effects on the risk of HCC recurrence after liver transplantation in patients within standard and extended criteria.
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Affiliation(s)
- Michał Grąt
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland.
| | - Marek Krawczyk
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Karolina M Wronka
- Hepatology and Internal Medicine Unit, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Jan Stypułkowski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Zbigniew Lewandowski
- Department of Epidemiology and Biostatistics, Medical University of Warsaw, Warsaw, Poland
| | - Michał Wasilewicz
- Hepatology and Internal Medicine Unit, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Piotr Krawczyk
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Karolina Grąt
- Second Department of Clinical Radiology, Medical University of Warsaw, Warsaw, Poland
| | - Waldemar Patkowski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Krzysztof Zieniewicz
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
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Orci LA, Lacotte S, Delaune V, Slits F, Oldani G, Lazarevic V, Rossetti C, Rubbia-Brandt L, Morel P, Toso C. Effects of the gut-liver axis on ischaemia-mediated hepatocellular carcinoma recurrence in the mouse liver. J Hepatol 2018; 68:978-985. [PMID: 29331341 DOI: 10.1016/j.jhep.2017.12.025] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Revised: 12/06/2017] [Accepted: 12/22/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS There is growing evidence that liver graft ischemia-reperfusion (I/R) is a risk factor for hepatocellular carcinoma (HCC) recurrence, but the mechanisms involved are unclear. Herein, we tested the hypothesis that mesenteric congestion resulting from portal blood flow interruption induces endotoxin-mediated Toll-like receptor 4 (Tlr4) engagement, resulting in elevated liver cancer burden. We also assessed the role of remote ischemic preconditioning (RIPC) in this context. METHODS C57Bl/6j mice were exposed to standardized models of liver I/R injury and RIPC, induced by occluding the hepatic and femoral blood vessels. HCC was induced by injecting RIL-175 cells into the portal vein. We further evaluated the impact of the gut-liver axis (lipopolysaccharide (LPS)-Tlr4 pathway) in this context by studying mice with enhanced (lipopolysaccharide infusion) or defective (Tlr4-/- mice, gut sterilization, and Tlr4 antagonist) Tlr4 responses. RESULTS Portal triad clamping provoked upstream mesenteric venous engorgement and increased bacterial translocation, resulting in aggravated tumor burden. RIPC prevented this mechanism by preserving intestinal integrity and reducing bacterial translocation, thereby mitigating HCC recurrence. These observations were linked to the LPS-Tlr4 pathway, as supported by the high and low tumor burden displayed by mice with enhanced or defective Tlr4 responses, respectively. CONCLUSIONS Modulation of the gut-liver axis and the LPS-Tlr4 response by RIPC, gut sterilization, and Tlr4 antagonism represents a potential therapeutic target to prevent I/R lesions, and to alleviate HCC recurrence after liver transplantation and resection. LAY SUMMARY Cancer recurrence can occur after liver resection or liver transplantation for hepatocellular carcinoma (HCC). This study suggests that intestinal venous congestion, which often occurs during liver surgery, favors the translocation of gut-derived bacterial products in the portal vein, thereby facilitating cancer recurrence by enhancing the signaling of Toll-like receptor 4 in the liver. Using a mouse model of HCC recurrence, we show that strategies that (i) reduce bacterial translocation (by gut decontamination, or by protecting the intestine from venous ischemia damage) or (ii) inhibit Tlr4 signaling in the liver, could reduce cancer recurrence.
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Affiliation(s)
- Lorenzo A Orci
- Division of Abdominal and Transplantation Surgery, Department of Surgery, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland; Hepato-Pancreato-Biliary Centre, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland.
| | - Stéphanie Lacotte
- Division of Abdominal and Transplantation Surgery, Department of Surgery, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Vaihere Delaune
- Division of Abdominal and Transplantation Surgery, Department of Surgery, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland; Hepato-Pancreato-Biliary Centre, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Florence Slits
- Division of Abdominal and Transplantation Surgery, Department of Surgery, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Graziano Oldani
- Division of Abdominal and Transplantation Surgery, Department of Surgery, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland; Hepato-Pancreato-Biliary Centre, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Vladimir Lazarevic
- Genomic Research Laboratory, Geneva University Hospitals, Geneva, University of Geneva, Switzerland
| | - Carlo Rossetti
- Dipartimento di Biotecnologie e Scienze della Vita, Università degli Studi dell'Insubria, Varese, Italy
| | - Laura Rubbia-Brandt
- Hepato-Pancreato-Biliary Centre, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland; Division of Clinical Pathology, Department of Pathology and Immunology, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
| | - Philippe Morel
- Division of Abdominal and Transplantation Surgery, Department of Surgery, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland; Hepato-Pancreato-Biliary Centre, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Christian Toso
- Division of Abdominal and Transplantation Surgery, Department of Surgery, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland; Hepato-Pancreato-Biliary Centre, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland
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Ling Q, Liu J, Zhuo J, Zhuang R, Huang H, He X, Xu X, Zheng S. Development of models to predict early post-transplant recurrence of hepatocellular carcinoma that also integrate the quality and characteristics of the liver graft: A national registry study in China. Surgery 2018; 164:S0039-6060(18)30079-5. [PMID: 29709370 DOI: 10.1016/j.surg.2018.01.022] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Revised: 01/11/2018] [Accepted: 01/29/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Donor characteristics and graft quality were recently reported to play an important role in the recurrence of hepatocellular carcinoma after liver transplantation. Our aim was to establish a prognostic model by using both donor and recipient variables. METHODS Data of 1,010 adult patients (training/validation: 2/1) undergoing primary liver transplantation for hepatocellular carcinoma were extracted from the China Liver Transplant Registry database and analyzed retrospectively. A multivariate competing risk regression model was developed and used to generate a nomogram predicting the likelihood of post-transplant hepatocellular carcinoma recurrence. RESULTS Of 673 patients in the training cohort, 70 (10.4%) had hepatocellular carcinoma recurrence with a median recurrence time of 6 months (interquartile range: 4-25 months). Cold ischemia time was the only independent donor prognostic factor for predicting hepatocellular carcinoma recurrence (hazard ratio = 2.234, P = .007). The optimal cutoff value was 12 hours when patients were grouped according to cold ischemia time at 2-hour intervals. Integrating cold ischemia time into the Milan criteria (liver transplantation candidate selection criteria) improved the accuracy for predicting hepatocellular carcinoma recurrence in both training and validation sets (P < .05). A nomogram composed of cold ischemia time, tumor burden, differentiation, and α-fetoprotein level proved to be accurate and reliable in predicting the likelihood of 1-year hepatocellular carcinoma recurrence after liver transplantation. Additionally, donor anti-hepatitis B core antibody positivity, prolonged cold ischemia time, and anhepatic time were linked to the intrahepatic recurrence, whereas older donor age, prolonged donor warm ischemia time, cold ischemia time, and ABO incompatibility were relevant to the extrahepatic recurrence. CONCLUSION The graft quality integrated models exhibited considerable predictive accuracy in early hepatocellular carcinoma recurrence risk assessment. The identification of donor risks can further help understand the mechanism of different patterns of recurrence.
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Affiliation(s)
- Qi Ling
- Department of Surgery, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, China
| | - Jimin Liu
- Department of Surgery, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Department of Pathology and Molecular Medicine, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
| | - Jianyong Zhuo
- Department of Surgery, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Runzhou Zhuang
- Department of Surgery, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Haitao Huang
- Department of Surgery, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | | | - Xiao Xu
- Department of Surgery, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, China; China Liver Transplant Registry, Hangzhou, China
| | - Shusen Zheng
- Department of Surgery, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, China; China Liver Transplant Registry, Hangzhou, China.
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45
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Wang C, Xie H, Lu D, Ling Q, Jin P, Li H, Zhuang R, Xu X, Zheng S. The MTHFR polymorphism affect the susceptibility of HCC and the prognosis of HCC liver transplantation. Clin Transl Oncol 2018; 20:448-456. [PMID: 29185200 DOI: 10.1007/s12094-017-1729-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Accepted: 07/28/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND Methylenetetrahyfrofolate reductase (MTHFR) is the key enzyme for one carbon and folate metabolism. Previous studies have drawn different conclusions about the relationship between the mutation of MTHFR and hepatocellular carcinoma (HCC) occurrence. MTHFR polymorphisms' influence on liver transplantation for HCC recurrence has yet not been reported. Aim of this study was to clarify the impact of MTHFR polymorphism on hepatocarcinogenesis and the prognosis of liver transplant recipient with HCC. METHODS This study enrolled 244 HCC patients and 487 healthy individuals in Chinese Han population to analyze the influence of MTHFR polymorphism on HCC susceptibility first. Furthermore, this research choose another 100 donors' and 104 recipients' specimens to detect the association between polymorphism of MTHFR and post-transplant HCC recurrence. RESULT rs1801131 polymorphism A to C was associated with the occurrence of HCC in Chinese Han population (p < 0.05), especially in age exceeding 50 years (p < 0.01). No association was observed with rs1801133 polymorphism and HCC occurrence. The mean tumor-free survival for recipients with donor liver graft rs1801133 C to T variants was shorter than CC type (12.63 ± 3.84 vs 22.43 ± 4.74 months, p < 0.05). Multivariate analysis revealed that Donor rs1801133 and Hangzhou criteria were two independent prognostic factors for tumor-free survival (p < 0.05). Neither donor rs1801131 polymorphism nor recipients' MTHFR polymorphisms was associated with HCC recurrence. CONCLUSION This study demonstrated that MTHFR polymorphism was associated with HCC occurrence and post-transplant HCC recurrence. rs1801131 mutation A to C is a valuable molecular biomarker for predicting HCC occurrence in Chinese Han population. Donor MTHFR rs1801133 C to T polymorphism could present as a promising prognostic biomarkers for HCC recurrence in liver transplant recipients.
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Affiliation(s)
- C Wang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - H Xie
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - D Lu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Q Ling
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - P Jin
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - H Li
- Shenzhen Key Laboratory of Hepatobiliary Disease, Shenzhen Third People's Hospital, Shenzhen, China
| | - R Zhuang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - X Xu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - S Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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Abstract
Liver transplantation is the most effective treatment for selected patients with hepatocellular carcinoma. However, cancer recurrence, posttransplantation, remains to be the critical issue that affects the long-term outcome of hepatocellular carcinoma recipients. In addition to tumor biology itself, increasing evidence demonstrates that acute-phase liver graft injury is a result of hepatic ischemia reperfusion injury (which is an inevitable consequence during liver transplantation) and may promote cancer recurrence at late phase posttransplantation. The liver grafts from living donors, donors after cardiac death, and steatotic donors have been considered as promising sources of organs for liver transplantation and are associated with high incidence of liver graft injury. The acute-phase liver graft injury will trigger a series of inflammatory cascades, which may not only activate the cell signaling pathways regulating the tumor cell invasion and migration but also mobilize the circulating progenitor and immune cells to facilitate tumor recurrence and metastasis. The injured liver graft may also provide the favorable microenvironment for tumor cell growth, migration, and invasion through the disturbance of microcirculatory barrier function, induction of hypoxia and angiogenesis. This review aims to summarize the latest findings about the role and mechanisms of liver graft injury resulted from hepatic ischemia reperfusion injury on tumor recurrence posttransplantation, both in clinical and animal cohorts.
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Vining CC, Ecker BL, Abt PL, Olthoff KM. Donation after cardiac death in the hepatocellular carcinoma patient: Same indication? Liver Transpl 2017; 23:S27-S33. [PMID: 28846212 DOI: 10.1002/lt.24862] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Revised: 08/14/2017] [Accepted: 08/24/2017] [Indexed: 02/07/2023]
Affiliation(s)
- Charles C Vining
- Department of Surgery, University of Pennsylvania, Philadelphia, PA
| | - Brett L Ecker
- Department of Surgery, University of Pennsylvania, Philadelphia, PA
| | - Peter L Abt
- Department of Surgery, University of Pennsylvania, Philadelphia, PA
| | - Kim M Olthoff
- Department of Surgery, University of Pennsylvania, Philadelphia, PA
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48
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Liver transplantation for hepatocellular carcinoma: outcomes and novel surgical approaches. Nat Rev Gastroenterol Hepatol 2017; 14:203-217. [PMID: 28053342 DOI: 10.1038/nrgastro.2016.193] [Citation(s) in RCA: 322] [Impact Index Per Article: 40.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Liver transplantation for hepatocellular carcinoma (HCC) is the best treatment option for patients with early-stage tumours and accounts for ∼20-40% of all liver transplantations performed at most centres worldwide. The Milan criteria are the most common criteria to select patients with HCC for transplantation but they can be seen as too restrictive. Several proposals have been made for a moderate expansion of the criteria, which result in good outcomes but with an increase in the risk of tumour recurrence. In this Review, we provide a comprehensive overview of the outcomes after liver transplantation for HCC, focusing on tumour recurrence in terms of surveillance, prevention and treatment. Additionally, novel surgical techniques have been developed to increase the available pool of organs for liver transplantation (such as living donor liver transplantation, donation after circulatory death and split livers), but the effect of these techniques on patients with HCC is still under debate. Thus, we will describe these techniques and expose the benefits and disadvantages of each surgical approach. Finally, we will comment on the limitations of the current priority policies for liver transplantation and the need to further refine them to better serve the population.
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Orci LA, Lacotte S, Oldani G, Slits F, De Vito C, Crowe LA, Rubbia-Brandt L, Vallée JP, Morel P, Toso C. Effect of ischaemic preconditioning on recurrence of hepatocellular carcinoma in an experimental model of liver steatosis. Br J Surg 2016; 103:417-26. [PMID: 26891212 DOI: 10.1002/bjs.10080] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2015] [Revised: 08/31/2015] [Accepted: 11/17/2015] [Indexed: 12/25/2022]
Abstract
BACKGROUND Livers with parenchymal abnormalities tolerate ischaemia-reperfusion (IR) injury poorly. IR injury is a risk factor for hepatocellular carcinoma (HCC) recurrence. This study assessed the link between liver parenchymal abnormalities and HCC recurrence, and evaluated the protective effect of ischaemic preconditioning. METHODS C57BL/6 mice were fed a choline-deficient diet for 6 and 12 weeks, or standard chow. Hepatic IR and ischaemic preconditioning were achieved by clamping liver blood inflow. Hepa 1-6 HCC cells were inoculated through the spleen. Thereafter, tumour burden, serum α-fetoprotein and cancer cell aggressiveness were compared among groups. RESULTS Hepatocellular damage and expression of inflammatory genes (encoding interleukin 6, tumour necrosis factor α, hypoxia inducible factor 1α and E-selectin) were exacerbated after IR injury in mice with severe steatosis. Compared with control livers or those with minimal steatosis, livers exposed to a prolonged choline-deficient diet developed larger tumour nodules and had higher serum α-fetoprotein levels. Non-ischaemic liver lobes from mice with steatosis were not protected from accelerated tumour growth mediated by IR injury. This remote effect was linked to promotion of the aggressiveness of HCC cells. Ischaemic preconditioning before IR injury reduced the tumour burden to the level of that in non-ischaemic steatotic controls. This protective effect was associated with decreased cancer cell motility. CONCLUSION Livers with steatosis tolerated IR poorly, contributing to more severe HCC recurrence patterns in mice with increasingly severe steatosis. IR injury also had a remote effect on cancer cell aggressiveness. Ischaemic preconditioning before IR injury reduced tumour load and serum α-fetoprotein levels. SURGICAL RELEVANCE Liver ischaemia-reperfusion (IR) injury is associated with organ dysfunction and surgical morbidity. Livers with steatosis tolerate IR injury poorly in the setting of both liver resection and liver transplantation. Ischaemic preconditioning is a simple method to mitigate IR injury. This study shows that ischaemic preconditioning of mouse livers with steatosis reduces ischaemia-mediated tumour growth acceleration. Liver parenchymal abnormalities such as warm IR injury and liver steatosis should be taken into account to predict accurately the risk of liver cancer recurrence after surgical management. Ischaemic preconditioning strategies may hold therapeutic potential not only to mitigate surgical morbidity but also to reduce postoperative recurrence of liver cancer.
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Affiliation(s)
- L A Orci
- Division of Abdominal and Transplantation Surgery, Hepato-pancreato-biliary Centre, Geneva, Switzerland.,Department of Surgery, Hepato-pancreato-biliary Centre, Geneva, Switzerland
| | - S Lacotte
- Division of Abdominal and Transplantation Surgery, Hepato-pancreato-biliary Centre, Geneva, Switzerland
| | - G Oldani
- Division of Abdominal and Transplantation Surgery, Hepato-pancreato-biliary Centre, Geneva, Switzerland.,Department of Surgery, Hepato-pancreato-biliary Centre, Geneva, Switzerland
| | - F Slits
- Division of Abdominal and Transplantation Surgery, Hepato-pancreato-biliary Centre, Geneva, Switzerland
| | - C De Vito
- Department of Surgery, Hepato-pancreato-biliary Centre, Geneva, Switzerland.,Division of Clinical Pathology, Department of Pathology and Immunology, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - L A Crowe
- Division of Radiology, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - L Rubbia-Brandt
- Department of Surgery, Hepato-pancreato-biliary Centre, Geneva, Switzerland.,Division of Clinical Pathology, Department of Pathology and Immunology, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - J-P Vallée
- Division of Radiology, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - P Morel
- Division of Abdominal and Transplantation Surgery, Hepato-pancreato-biliary Centre, Geneva, Switzerland.,Department of Surgery, Hepato-pancreato-biliary Centre, Geneva, Switzerland
| | - C Toso
- Division of Abdominal and Transplantation Surgery, Hepato-pancreato-biliary Centre, Geneva, Switzerland.,Department of Surgery, Hepato-pancreato-biliary Centre, Geneva, Switzerland
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Ferla F, Mariani A, di Sandro S, Buscemi V, Lauterio A, Mangoni J, Covucci E, Giacomoni A, De Carlis L. Do Older Liver Grafts Have Worse Survival? The Niguarda Experience. Transplant Proc 2016; 48:362-365. [PMID: 27109956 DOI: 10.1016/j.transproceed.2015.12.043] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Accepted: 12/30/2015] [Indexed: 01/14/2023]
Abstract
BACKGROUND Elderly donor livers are thought to be marginal graft. In the present study, we aimed to identify an age threshold to consider a graft as elderly to identify the trend (if any) of the donor age in our series and to identify an efficient allocation criteria for elderly grafts. METHODS We reviewed in a retrospective manner our series of 1520 liver transplants, comparing graft survival under and over a certain age. On the basis of the results of this analysis, we identified a threshold of 70 years to define a graft as old. The donor age trend analysis showed an increasing rate of transplants from elderly donors. RESULTS To identify efficient allocation criteria for elderly graft, we stratified the series by the disease of the recipient: 556 patients underwent transplants for hepatocellular carcinoma (HCC+ group) and 964 for other diseases (HCC- group). Two hundred twenty-one patients of 556 of the HCC+ group were hepatitis c virus (HCV) negative (HCC+/HCV- group), and 312 of 964 of the HCC- group were HCV positive (HCC-/HCV+). The survival analysis showed no significant differences in comparing the outcome for elderly and young grafts in the HCC+ (P = .135) and HCC- (P = .055) groups. CONCLUSIONS When comparing the survival of old and young livers in the HCC+/HCV- group, the elderly livers appear to have a better outcome (P = .05); on the other hand, the same analysis in the HCC-/HCV+ group shows a worse outcome for old-aged grafts (P = .026). Therefore, the present study suggests that elderly livers should be allocated to hepatocellular carcinoma (HCC) patients and should be avoided in HCV+ recipients.
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Affiliation(s)
- F Ferla
- Chirurgia Generale e dei Trapianti, Ospedale Niguarda, Milano, Italy.
| | - A Mariani
- Chirurgia Generale e dei Trapianti, Ospedale Niguarda, Milano, Italy
| | - S di Sandro
- Chirurgia Generale e dei Trapianti, Ospedale Niguarda, Milano, Italy
| | - V Buscemi
- Chirurgia Generale e dei Trapianti, Ospedale Niguarda, Milano, Italy
| | - A Lauterio
- Chirurgia Generale e dei Trapianti, Ospedale Niguarda, Milano, Italy
| | - J Mangoni
- Chirurgia Generale e dei Trapianti, Ospedale Niguarda, Milano, Italy
| | - E Covucci
- Chirurgia Generale e dei Trapianti, Ospedale Niguarda, Milano, Italy
| | - A Giacomoni
- Chirurgia Generale e dei Trapianti, Ospedale Niguarda, Milano, Italy
| | - L De Carlis
- Chirurgia Generale e dei Trapianti, Ospedale Niguarda, Milano, Italy
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