|
1
|
Jang SC, Kim GA, Lim YS, Kim HL, Lee EK. Association between everolimus combination therapy and cancer risk after liver transplantation: A nationwide population-based quasi-cohort study. Am J Transplant 2025; 25:1285-1295. [PMID: 39826891 DOI: 10.1016/j.ajt.2025.01.005] [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: 06/03/2024] [Revised: 12/30/2024] [Accepted: 01/06/2025] [Indexed: 01/22/2025]
Abstract
The potential of everolimus (EVR) in reducing hepatocellular carcinoma (HCC) among recipients following liver transplantation has been reported. This nationwide population-based quasi-cohort study investigated whether combining EVR with calcineurin inhibitor therapy affects the risk of HCC and extrahepatic cancers compared to a time duration-matched cohort of recipients not receiving EVR. Using data covering the entire population from Korea, liver transplant recipients who had initiated immunosuppressants between June 2015 and February 2020 were included, and divided into 2 groups: the EVR combination and noncombination groups. We calculated adjusted hazard ratios (aHRs) and absolute risk reduction for the risk of HCC and extrahepatic cancer with EVR combination therapy using a Cox regression model. A time duration-matched retrospective cohort of 932 recipients in both of the groups was identified. The EVR combination group showed a lower risk of HCC (aHR, 0.53; 95% confidence interval, 0.30-0.94) and extrahepatic cancers (aHR, 0.30; 95% confidence interval, 0.14-0.63) compared to the noncombination group. The absolute risk reduction was 0.004 for HCC and 0.012 for extrahepatic cancer. The findings suggest that adding EVR to calcineurin inhibitor therapy reduces cancer risk in liver transplant recipients, highlighting the importance of considering cancer risk when choosing immunosuppressive therapies.
Collapse
Affiliation(s)
- Suk-Chan Jang
- School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, Republic of Korea
| | - Gi-Ae Kim
- Department of Internal Medicine, Kyung Hee University College of Medicine, Seoul, Republic of Korea
| | - Young-Suk Lim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Hye-Lin Kim
- College of Pharmacy, Sahmyook University, Seoul, Republic of Korea.
| | - Eui-Kyung Lee
- School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, Republic of Korea.
| |
Collapse
|
|
2
|
Sequeira LM, Ozturk NB, Sierra L, Gurakar M, Toruner MD, Zheng M, Simsek C, Gurakar A, Kim AK. Hepatocellular Carcinoma and the Role of Liver Transplantation: An Update and Review. J Clin Transl Hepatol 2025; 13:327-338. [PMID: 40206277 PMCID: PMC11976436 DOI: 10.14218/jcth.2024.00432] [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: 11/18/2024] [Revised: 01/25/2025] [Accepted: 02/08/2025] [Indexed: 04/11/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide. Multiple treatment modalities are available for the management of HCC, depending on its stage as determined by the Barcelona Clinic Liver Cancer staging system. Because liver transplantation (LT) theoretically removes the cancer and replaces the organ at risk for future malignancy, LT is often considered the most definitive and one of the most efficacious treatment options for HCC. Nevertheless, the success and efficacy of liver transplantation depend on various tumor characteristics. As a result, multiple criteria have been developed to assess the appropriateness of a case of HCC for LT, with the pioneering Milan Criteria established in 1996. Over the past 20 to 30 years, these criteria have been critically evaluated, expanded, and often liberalized to make LT for patients with HCC a more universally applicable option. Furthermore, the development of other treatment modalities has enabled downstaging and bridging strategies for HCC prior to LT. In this narrative and comprehensive review, we provided an update on recent trends in the epidemiology of HCC, selection criteria for LT, implementation of LT across different regions, treatment modalities available as bridges, downstaging strategies, alternatives to LT, and, finally, post-LT surveillance.
Collapse
Affiliation(s)
- Lynette M. Sequeira
- Department of Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - N. Begum Ozturk
- Department of Internal Medicine, Beaumont Hospital, Royal Oak, MI, USA
| | - Leandro Sierra
- Department of Internal Medicine, Cleveland Clinic, Cleveland, OH, USA
| | - Merve Gurakar
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | | | - Melanie Zheng
- Department of Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Cem Simsek
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ahmet Gurakar
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Amy K. Kim
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| |
Collapse
|
|
3
|
Skanthan C, Nguyen E, Somaweera L, Rabindranath M, Orchanian-Cheff A, Viau-Trudel A, Khalili M, Famure O, Kim SJ. Assessing cumulative exposure to maintenance immunosuppressive drugs: Metrics, outcomes, and implications for transplant patients. Transplant Rev (Orlando) 2025; 39:100914. [PMID: 40080995 DOI: 10.1016/j.trre.2025.100914] [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: 12/29/2024] [Revised: 03/04/2025] [Accepted: 03/05/2025] [Indexed: 03/15/2025]
Abstract
Immunosuppressive drugs are used in the management of transplant patients to prevent organ rejection. However, immunosuppression can be associated with adverse effects such as infections and cancers. This study aimed to characterize the measures of cumulative immunosuppressive drug exposure (CIDE) used in the literature and their associated outcomes in transplant patients. A literature search was conducted in Ovid MEDLINE, Ovid EMBASE, Cochrane CENTRAL, and Cochrane Database of Systematic Reviews using search terms related to maintenance immunosuppressants and CIDE. Study risk of bias was assessed using the Quality in Prognostic Studies tool. Thirty-one articles were included in this qualitative synthesis. Sixteen articles (52 %) calculated the total dose of immunosuppression over the treatment period, while eight (26 %) used area-under-the-curve of trough level concentrations to quantify CIDE. Five (16 %) articles investigated time-weighted metrics of calcineurin inhibitors and four (13 %) used other metrics that could not be categorized into the previous groups. Most studies investigated CIDE with calcineurin inhibitors and used additive dosing methods. This approach was also popular with corticosteroids and multi-drug exposures. The variety of metrics used in the literature reveals a lack of standardization in the evaluation of CIDE and long-term outcomes. Future studies should validate these metrics for clinical application, especially pertaining to infectious outcomes.
Collapse
Affiliation(s)
- Cavizshajan Skanthan
- Ajmera Transplant Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Emily Nguyen
- Ajmera Transplant Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Lakindu Somaweera
- Ajmera Transplant Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Madhumitha Rabindranath
- Ajmera Transplant Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Ani Orchanian-Cheff
- Library and Information Services, University Health Network, Toronto, Ontario, Canada
| | - Alexandra Viau-Trudel
- Department of Medicine, Division of Nephrology, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Myriam Khalili
- Department of Medicine, Division of Nephrology, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Olusegun Famure
- Ajmera Transplant Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - S Joseph Kim
- Ajmera Transplant Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada; Department of Medicine, Division of Nephrology, University Health Network, University of Toronto, Toronto, Ontario, Canada.
| |
Collapse
|
|
4
|
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.
Collapse
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
| |
Collapse
|
|
5
|
Bitzer M, Groß S, Albert J, Blödt S, Boda-Heggemann J, Borucki K, Brunner T, Caspari R, Dombrowski F, Evert M, Follmann M, Freudenberger P, Gani C, Gebert J, Geier A, Gkika E, Götz M, Helmberger T, Hoffmann RT, Huppert P, Krug D, La Fougère C, Lang H, Langer T, Lenz P, Lüdde T, Mahnken A, Nadalin S, Nguyen HHP, Nothacker M, Ockenga J, Oldhafer K, Ott J, Paprottka P, Pereira P, Persigehl T, Plentz R, Pohl J, Recken H, Reimer P, Riemer J, Ringe K, Roeb E, Rüssel J, Schellhaas B, Schirmacher P, Schlitt HJ, Schmid I, Schütte K, Schuler A, Seehofer D, Sinn M, Stengel A, Steubesand N, Stoll C, Tannapfel A, Taubert A, Trojan J, van Thiel I, Utzig M, Vogel A, Vogl T, Wacker F, Waidmann O, Wedemeyer H, Wege H, Wenzel G, Wildner D, Wörns MA, Galle P, Malek N. [Not Available]. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2025; 63:e159-e260. [PMID: 40064172 DOI: 10.1055/a-2460-6298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2025]
Affiliation(s)
- Michael Bitzer
- Abteilung für Gastroenterologie, Gastrointestinale Onkologie, Hepatologie, Infektiologie und Geriatrie, Eberhard-Karls Universität, Tübingen
| | - Sabrina Groß
- Abteilung für Gastroenterologie, Gastrointestinale Onkologie, Hepatologie, Infektiologie und Geriatrie, Eberhard-Karls Universität, Tübingen
| | - Jörg Albert
- Katharinenhospital, Klinik für Allgemeine Innere Medizin, Gastroenterologie, Hepatologie, Infektiologie und Pneumologie, Stuttgart
| | - Susanne Blödt
- Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e. V. (AWMF), Berlin
| | | | - Katrin Borucki
- Otto-von-Guericke-Universität Magdeburg, Medizinische Fakultät, Institut für Klinische Chemie und Pathobiochemie
| | - Thomas Brunner
- Universitätsklinik für Strahlentherapie-Radioonkologie, Medizinische Universität Graz
| | - Reiner Caspari
- Klinik Niederrhein Erkrankungen des Stoffwechsels der Verdauungsorgane und Tumorerkrankungen, Bad Neuenahr-Ahrweiler
| | | | | | - Markus Follmann
- Office des Leitlinienprogrammes Onkologie, Deutsche Krebsgesellschaft e.V., Berlin
| | | | - Cihan Gani
- Klinik für Radioonkologie, Universitätsklinikum Tübingen
| | - Jamila Gebert
- Abteilung für Gastroenterologie, Gastrointestinale Onkologie, Hepatologie, Infektiologie und Geriatrie, Eberhard-Karls Universität, Tübingen
| | - Andreas Geier
- Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg
| | - Eleni Gkika
- Klinik für Strahlenheilkunde, Department für Radiologische Diagnostik und Therapie, Universitätsklinikum Freiburg
| | - Martin Götz
- Medizinische Klinik IV - Gastroenterologie/Onkologie, Klinikverbund Südwest, Böblingen
| | - Thomas Helmberger
- Institut für Radiologie, Neuroradiologie und minimal invasive Therapie, München Klinik Bogenhausen
| | - Ralf-Thorsten Hoffmann
- Institut und Poliklinik für Diagnostische und Interventionelle Radiologie, Universitätsklinikum Dresden
| | - Peter Huppert
- Radiologisches Zentrum, Max Grundig Klinik, Bühlerhöhe
| | - David Krug
- Strahlentherapie Campus Kiel, Universitätsklinikum Schleswig-Holstein
| | - Christian La Fougère
- Nuklearmedizin und Klinische Molekulare Bildgebung, Eberhard-Karls Universität, Tübingen
| | - Hauke Lang
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Johannes Gutenberg-Universität, Mainz
| | - Thomas Langer
- Office des Leitlinienprogrammes Onkologie, Deutsche Krebsgesellschaft e.V., Berlin
| | - Philipp Lenz
- Zentrale Einrichtung Palliativmedizin, Universitätsklinikum Münster
| | - Tom Lüdde
- Medizinische Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universitätsklinikum Düsseldorf
| | - Andreas Mahnken
- Klinik für Diagnostische und Interventionelle Radiologie, Universitätsklinikum Marburg
| | - Silvio Nadalin
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Eberhard-Karls Universität, Tübingen
| | | | - Monika Nothacker
- Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e. V. (AWMF), Berlin
| | - Johann Ockenga
- Medizinische Klinik II, Gesundheit Nord, Klinikverbund Bremen
| | - Karl Oldhafer
- Klinik für Leber-, Gallenwegs- und Pankreaschirurgie, Asklepios Klinik Barmbek
| | - Julia Ott
- Abteilung für Gastroenterologie, Gastrointestinale Onkologie, Hepatologie, Infektiologie und Geriatrie, Eberhard-Karls Universität, Tübingen
| | - Philipp Paprottka
- Sektion für Interventionelle Radiologie, Klinikum rechts der Isar, Technische Universität München
| | - Philippe Pereira
- Zentrum für Radiologie, Minimal-invasive Therapien und Nuklearmedizin, SLK-Klinken Heilbronn
| | - Thorsten Persigehl
- Institut für Diagnostische und Interventionelle Radiologie, Universitätsklinikum Köln
| | - Ruben Plentz
- Digestive Diseases and Nutrition, Gastroenterology, University of Kentucky
| | - Jürgen Pohl
- Abteilung für Gastroenterologie, Asklepios Klinik Altona
| | | | - Peter Reimer
- Institut für Diagnostische und Interventionelle Radiologie, Städtisches Klinikum Karlsruhe
| | | | - Kristina Ringe
- Institut für Diagnostische und Interventionelle Radiologie, Medizinische Hochschule Hannover
| | - Elke Roeb
- Medizinische Klinik II Pneumologie, Nephrologie und Gastroenterologie, Universitätsklinikum Gießen
| | - Jörn Rüssel
- Medizinische Klinik IV Hämatologie und Onkologie, Universitätsklinikum Halle (Saale)
| | - Barbara Schellhaas
- Medizinische Klinik I Gastroenterologie, Pneumologie und Endokrinologie, Friedrich-Alexander-Universität, Erlangen
| | - Peter Schirmacher
- Allgemeine Pathologie und pathologische Anatomie, Universitätsklinikum Heidelberg
| | | | - Irene Schmid
- Kinderklinik und Kinderpoliklinik im Dr. von Haunerschen Kinderspital, LMU München
| | - Kerstin Schütte
- Klinik für Innere Medizin und Gastroenterologie, Niels-Stensen-Kliniken, Marienhospital Osnabrück
| | - Andreas Schuler
- Medizinische Klinik, Gastroenterologie, Alb-Fils-Kliniken, Geislingen an der Steige
| | - Daniel Seehofer
- Klinik und Poliklinik für Viszeral-, Transplantations-, Thorax- und Gefäßchirurgie, Universitätsklinikum Leipzig
| | - Marianne Sinn
- II. Medizinische Klinik und Poliklinik (Onkologie, Hämatologie, Knochenmarktransplantation mit Abteilung für Pneumologie), Universitätsklinikum Hamburg-Eppendorf
| | - Andreas Stengel
- Innere Medizin VI - Psychosomatische Medizin und Psychotherapie, Eberhard-Karls Universität, Tübingen
| | | | | | | | - Anne Taubert
- Klinische Sozialarbeit, Universitätsklinikum Heidelberg
| | - Jörg Trojan
- Medizinische Klinik 1: Gastroenterologie und Hepatologie, Pneumologie und Allergologie, Endokrinologie und Diabetologie sowie Ernährungsmedizin, Goethe-Universität, Frankfurt
| | | | - Martin Utzig
- Abteilung Zertifizierung, Deutsche Krebsgesellschaft e.V., Berlin
| | - Arndt Vogel
- Institute of Medical Science, University of Toronto
| | - Thomas Vogl
- Institut für Diagnostische und Interventionelle Radiologie, Goethe-Universität, Frankfurt
| | - Frank Wacker
- Institut für Diagnostische und Interventionelle Radiologie, Medizinische Hochschule Hannover
| | | | - Heiner Wedemeyer
- Klinik für Gastroenterologie, Hepatologie, Infektiologie und Endokrinologie, Medizinische Hochschule Hannover
| | - Henning Wege
- Klinik für Allgemeine Innere Medizin, Onkologie/Hämatologie, Gastroenterologie und Infektiologie, Klinikum Esslingen
| | - Gregor Wenzel
- Office des Leitlinienprogrammes Onkologie, Deutsche Krebsgesellschaft e.V., Berlin
| | - Dane Wildner
- Innere Medizin, Krankenhäuser Nürnberger Land GmbH, Standort Lauf
| | - Marcus-Alexander Wörns
- Klinik für Gastroenterologie, Hämatologie und internistische Onkologie und Endokrinologie, Klinikum Dortmund
| | - Peter Galle
- 1. Medizinische Klinik und Poliklinik, Gastroenterologie, Hepatologie, Nephrologie, Rheumatologie, Infektiologie, Johannes Gutenberg-Universität, Mainz
| | - Nisar Malek
- Abteilung für Gastroenterologie, Gastrointestinale Onkologie, Hepatologie, Infektiologie und Geriatrie, Eberhard-Karls Universität, Tübingen
| |
Collapse
|
|
6
|
Groß S, Bitzer M, Albert J, Blödt S, Boda-Heggemann J, Borucki K, Brunner T, Caspari R, Dombrowski F, Evert M, Follmann M, Freudenberger P, Gani C, Gebert J, Geier A, Gkika E, Götz M, Helmberger T, Hoffmann RT, Huppert P, Krug D, Fougère CL, Lang H, Langer T, Lenz P, Lüdde T, Mahnken A, Nadalin S, Nguyen HHP, Nothacker M, Ockenga J, Oldhafer K, Ott J, Paprottka P, Pereira P, Persigehl T, Plentz R, Pohl J, Recken H, Reimer P, Riemer J, Ringe K, Roeb E, Rüssel J, Schellhaas B, Schirmacher P, Schlitt HJ, Schmid I, Schütte K, Schuler A, Seehofer D, Sinn M, Stengel A, Steubesand N, Stoll C, Tannapfel A, Taubert A, Trojan J, van Thiel I, Utzig M, Vogel A, Vogl T, Wacker F, Waidmann O, Wedemeyer H, Wege H, Wenzel G, Wildner D, Wörns MA, Galle P, Malek N. [Not Available]. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2025; 63:e82-e158. [PMID: 39919781 DOI: 10.1055/a-2460-6347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2025]
Affiliation(s)
- Sabrina Groß
- Abteilung für Gastroenterologie, Gastrointestinale Onkologie, Hepatologie, Infektiologie und Geriatrie, Eberhard-Karls Universität, Tübingen
| | - Michael Bitzer
- Abteilung für Gastroenterologie, Gastrointestinale Onkologie, Hepatologie, Infektiologie und Geriatrie, Eberhard-Karls Universität, Tübingen
| | - Jörg Albert
- Katharinenhospital, Klinik für Allgemeine Innere Medizin, Gastroenterologie, Hepatologie, Infektiologie und Pneumologie, Stuttgart
| | - Susanne Blödt
- Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e. V. (AWMF), Berlin
| | | | - Katrin Borucki
- Otto-von-Guericke-Universität Magdeburg, Medizinische Fakultät, Institut für Klinische Chemie und Pathobiochemie
| | - Thomas Brunner
- Universitätsklinik für Strahlentherapie-Radioonkologie, Medizinische Universität Graz
| | - Reiner Caspari
- Klinik Niederrhein Erkrankungen des Stoffwechsels der Verdauungsorgane und Tumorerkrankungen, Bad Neuenahr-Ahrweiler
| | | | | | - Markus Follmann
- Office des Leitlinienprogrammes Onkologie, Deutsche Krebsgesellschaft e.V., Berlin
| | | | - Cihan Gani
- Klinik für Radioonkologie, Universitätsklinikum Tübingen
| | - Jamila Gebert
- Abteilung für Gastroenterologie, Gastrointestinale Onkologie, Hepatologie, Infektiologie und Geriatrie, Eberhard-Karls Universität, Tübingen
| | - Andreas Geier
- Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg
| | - Eleni Gkika
- Klinik für Strahlenheilkunde, Department für Radiologische Diagnostik und Therapie, Universitätsklinikum Freiburg
| | - Martin Götz
- Medizinische Klinik IV - Gastroenterologie/Onkologie, Klinikverbund Südwest, Böblingen
| | - Thomas Helmberger
- Institut für Radiologie, Neuroradiologie und minimal invasive Therapie, München Klinik Bogenhausen
| | - Ralf-Thorsten Hoffmann
- Institut und Poliklinik für Diagnostische und Interventionelle Radiologie, Universitätsklinikum Dresden
| | - Peter Huppert
- Radiologisches Zentrum, Max Grundig Klinik, Bühlerhöhe
| | - David Krug
- Strahlentherapie Campus Kiel, Universitätsklinikum Schleswig-Holstein
| | - Christian La Fougère
- Nuklearmedizin und Klinische Molekulare Bildgebung, Eberhard-Karls Universität, Tübingen
| | - Hauke Lang
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Johannes Gutenberg-Universität, Mainz
| | - Thomas Langer
- Office des Leitlinienprogrammes Onkologie, Deutsche Krebsgesellschaft e.V., Berlin
| | - Philipp Lenz
- Zentrale Einrichtung Palliativmedizin, Universitätsklinikum Münster
| | - Tom Lüdde
- Medizinische Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universitätsklinikum Düsseldorf
| | - Andreas Mahnken
- Klinik für Diagnostische und Interventionelle Radiologie, Universitätsklinikum Marburg
| | - Silvio Nadalin
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Eberhard-Karls Universität, Tübingen
| | | | - Monika Nothacker
- Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e. V. (AWMF), Berlin
| | - Johann Ockenga
- Medizinische Klinik II, Gesundheit Nord, Klinikverbund Bremen
| | - Karl Oldhafer
- Klinik für Leber-, Gallenwegs- und Pankreaschirurgie, Asklepios Klinik Barmbek
| | - Julia Ott
- Abteilung für Gastroenterologie, Gastrointestinale Onkologie, Hepatologie, Infektiologie und Geriatrie, Eberhard-Karls Universität, Tübingen
| | - Philipp Paprottka
- Sektion für Interventionelle Radiologie, Klinikum rechts der Isar, Technische Universität München
| | - Philippe Pereira
- Zentrum für Radiologie, Minimal-invasive Therapien und Nuklearmedizin, SLK-Klinken Heilbronn
| | - Thorsten Persigehl
- Institut für Diagnostische und Interventionelle Radiologie, Universitätsklinikum Köln
| | - Ruben Plentz
- Digestive Diseases and Nutrition, Gastroenterology, University of Kentucky
| | - Jürgen Pohl
- Abteilung für Gastroenterologie, Asklepios Klinik Altona
| | | | - Peter Reimer
- Institut für Diagnostische und Interventionelle Radiologie, Städtisches Klinikum Karlsruhe
| | | | - Kristina Ringe
- Institut für Diagnostische und Interventionelle Radiologie, Medizinische Hochschule Hannover
| | - Elke Roeb
- Medizinische Klinik II Pneumologie, Nephrologie und Gastroenterologie, Universitätsklinikum Gießen
| | - Jörn Rüssel
- Medizinische Klinik IV Hämatologie und Onkologie, Universitätsklinikum Halle (Saale)
| | - Barbara Schellhaas
- Medizinische Klinik I Gastroenterologie, Pneumologie und Endokrinologie, Friedrich-Alexander-Universität, Erlangen
| | - Peter Schirmacher
- Allgemeine Pathologie und pathologische Anatomie, Universitätsklinikum Heidelberg
| | | | - Irene Schmid
- Kinderklinik und Kinderpoliklinik im Dr. von Haunerschen Kinderspital, LMU München
| | - Kerstin Schütte
- Klinik für Innere Medizin und Gastroenterologie, Niels-Stensen-Kliniken, Marienhospital Osnabrück
| | - Andreas Schuler
- Medizinische Klinik, Gastroenterologie, Alb-Fils-Kliniken, Geislingen an der Steige
| | - Daniel Seehofer
- Klinik und Poliklinik für Viszeral-, Transplantations-, Thorax- und Gefäßchirurgie, Universitätsklinikum Leipzig
| | - Marianne Sinn
- II. Medizinische Klinik und Poliklinik (Onkologie, Hämatologie, Knochenmarktransplantation mit Abteilung für Pneumologie), Universitätsklinikum Hamburg-Eppendorf
| | - Andreas Stengel
- Innere Medizin VI - Psychosomatische Medizin und Psychotherapie, Eberhard-Karls Universität, Tübingen
| | | | | | | | - Anne Taubert
- Klinische Sozialarbeit, Universitätsklinikum Heidelberg
| | - Jörg Trojan
- Medizinische Klinik 1: Gastroenterologie und Hepatologie, Pneumologie und Allergologie, Endokrinologie und Diabetologie sowie Ernährungsmedizin, Goethe-Universität, Frankfurt
| | | | - Martin Utzig
- Abteilung Zertifizierung, Deutsche Krebsgesellschaft e.V., Berlin
| | - Arndt Vogel
- Institute of Medical Science, University of Toronto
| | - Thomas Vogl
- Institut für Diagnostische und Interventionelle Radiologie, Goethe-Universität, Frankfurt
| | - Frank Wacker
- Institut für Diagnostische und Interventionelle Radiologie, Medizinische Hochschule Hannover
| | | | - Heiner Wedemeyer
- Klinik für Gastroenterologie, Hepatologie, Infektiologie und Endokrinologie, Medizinische Hochschule Hannover
| | - Henning Wege
- Klinik für Allgemeine Innere Medizin, Onkologie/Hämatologie, Gastroenterologie und Infektiologie, Klinikum Esslingen
| | - Gregor Wenzel
- Office des Leitlinienprogrammes Onkologie, Deutsche Krebsgesellschaft e.V., Berlin
| | - Dane Wildner
- Innere Medizin, Krankenhäuser Nürnberger Land GmbH, Standort Lauf
| | - Marcus-Alexander Wörns
- Klinik für Gastroenterologie, Hämatologie und internistische Onkologie und Endokrinologie, Klinikum Dortmund
| | - Peter Galle
- 1. Medizinische Klinik und Poliklinik, Gastroenterologie, Hepatologie, Nephrologie, Rheumatologie, Infektiologie, Johannes Gutenberg-Universität, Mainz
| | - Nisar Malek
- Abteilung für Gastroenterologie, Gastrointestinale Onkologie, Hepatologie, Infektiologie und Geriatrie, Eberhard-Karls Universität, Tübingen
| |
Collapse
|
|
7
|
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.
Collapse
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
| |
Collapse
|
|
8
|
Meng F, Fu Y, Xie H, Wang H. Nanoparticle-assisted Targeting Delivery Technologies for Preventing Organ Rejection. Transplantation 2024; 108:2174-2185. [PMID: 38597913 DOI: 10.1097/tp.0000000000005025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/11/2024]
Abstract
Although organ transplantation is a life-saving medical procedure, the challenge of posttransplant rejection necessitates safe and effective immune modulation strategies. Nanodelivery approaches may have the potential to overcome the limitations of small-molecule immunosuppressive drugs, achieving efficacious treatment options for transplant tolerance without compromising overall host immunity. This review highlights recent advances in biomaterial-assisted formulations and technologies for targeted nanodrug delivery with transplant organ- or immune cell-level precision for treating graft rejection after transplantation. We provide an overview of the mechanism of transplantation rejection, current clinically approved immunosuppressive drugs, and their relevant limitations. Finally, we discuss the targeting principles and advantages of organ- and immune cell-specific delivery technologies. The development of biomaterial-assisted novel therapeutic strategies holds considerable promise for treating organ rejection and clinical translation.
Collapse
Affiliation(s)
- Fanchao Meng
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong Province, People's Republic of China
- The First Affiliated Hospital, NHC Key Laboratory of Combined Multi-Organ Transplantation, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People's Republic of China
| | - Yang Fu
- Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People's Republic of China
| | - Haiyang Xie
- The First Affiliated Hospital, NHC Key Laboratory of Combined Multi-Organ Transplantation, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People's Republic of China
| | - Hangxiang Wang
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong Province, People's Republic of China
- The First Affiliated Hospital, NHC Key Laboratory of Combined Multi-Organ Transplantation, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People's Republic of China
| |
Collapse
|
|
9
|
Liu A, Rao W, Watt KD. Lack of progress in cancer-related outcomes after liver transplantation: Mitigating risk and identifying future needs to move this needle. Liver Transpl 2024:01445473-990000000-00483. [PMID: 39724652 DOI: 10.1097/lvt.0000000000000509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Accepted: 10/06/2024] [Indexed: 12/28/2024]
Abstract
Malignancy has a crucial impact on long-term survival after liver transplantation. There have been enhanced early detection rates with refined cancer screening and improved prognosis for many cancer diagnoses in the general population with the advent of targeted anticancer therapies. Similar advancements have not occurred in the transplant population over this same timeframe. Individualized strategies to reduce the risk of cancer are needed in this high-risk population. Strict adherence to screening and surveillance specific to the transplant population is required. Lifestyle modifications and medication management (both immunosuppressive and non-immunosuppressive) that may impact cancer risk and outcome are highlighted here. As more effective anticancer therapies evolve, transplant recipients' access to these agents is paramount to truly impact cancer-related outcomes in this population. With adequate immunosuppression, rejection rates with immunotherapy are lower than previously purported. Prospective studies of immunosuppression modifications needed to minimize rejection and maximize cancer response are ongoing and will reduce the fear from oncology and transplant providers alike, allowing utilization of the most optimal therapy available to the individual. This review aims to assess current data to aid in clinical management and identify the need to facilitate further progress in this field.
Collapse
Affiliation(s)
- Alex Liu
- Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Wei Rao
- Department of Medicine, Division of Hepatology, Liver Disease Center and Organ Transplantation Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Kymberly D Watt
- Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
- Department of Internal Medicine, Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| |
Collapse
|
|
10
|
Berg T, Aehling NF, Bruns T, Welker MW, Weismüller T, Trebicka J, Tacke F, Strnad P, Sterneck M, Settmacher U, Seehofer D, Schott E, Schnitzbauer AA, Schmidt HH, Schlitt HJ, Pratschke J, Pascher A, Neumann U, Manekeller S, Lammert F, Klein I, Kirchner G, Guba M, Glanemann M, Engelmann C, Canbay AE, Braun F, Berg CP, Bechstein WO, Becker T, Trautwein C. [Not Available]. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2024; 62:1397-1573. [PMID: 39250961 DOI: 10.1055/a-2255-7246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/11/2024]
Affiliation(s)
- Thomas Berg
- Bereich Hepatologie, Medizinischen Klinik II, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Niklas F Aehling
- Bereich Hepatologie, Medizinischen Klinik II, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Tony Bruns
- Medizinische Klinik III, Universitätsklinikum Aachen, Aachen, Deutschland
| | - Martin-Walter Welker
- Medizinische Klinik I Gastroent., Hepat., Pneum., Endokrin. Universitätsklinikum Frankfurt, Frankfurt, Deutschland
| | - Tobias Weismüller
- Klinik für Innere Medizin - Gastroenterologie und Hepatologie, Vivantes Humboldt-Klinikum, Berlin, Deutschland
| | - Jonel Trebicka
- Medizinische Klinik B für Gastroenterologie und Hepatologie, Universitätsklinikum Münster, Münster, Deutschland
| | - Frank Tacke
- Charité - Universitätsmedizin Berlin, Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Campus Virchow-Klinikum (CVK) und Campus Charité Mitte (CCM), Berlin, Deutschland
| | - Pavel Strnad
- Medizinische Klinik III, Universitätsklinikum Aachen, Aachen, Deutschland
| | - Martina Sterneck
- Medizinische Klinik und Poliklinik I, Universitätsklinikum Hamburg, Hamburg, Deutschland
| | - Utz Settmacher
- Klinik für Allgemein-, Viszeral- und Gefäßchirurgie, Universitätsklinikum Jena, Jena, Deutschland
| | - Daniel Seehofer
- Klinik für Viszeral-, Transplantations-, Thorax- und Gefäßchirurgie, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Eckart Schott
- Klinik für Innere Medizin II - Gastroenterologie, Hepatologie und Diabetolgie, Helios Klinikum Emil von Behring, Berlin, Deutschland
| | | | - Hartmut H Schmidt
- Klinik für Gastroenterologie und Hepatologie, Universitätsklinikum Essen, Essen, Deutschland
| | - Hans J Schlitt
- Klinik und Poliklinik für Chirurgie, Universitätsklinikum Regensburg, Regensburg, Deutschland
| | - Johann Pratschke
- Chirurgische Klinik, Charité Campus Virchow-Klinikum - Universitätsmedizin Berlin, Berlin, Deutschland
| | - Andreas Pascher
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Universitätsklinikum Münster, Münster, Deutschland
| | - Ulf Neumann
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Universitätsklinikum Essen, Essen, Deutschland
| | - Steffen Manekeller
- Klinik und Poliklinik für Allgemein-, Viszeral-, Thorax- und Gefäßchirurgie, Universitätsklinikum Bonn, Bonn, Deutschland
| | - Frank Lammert
- Medizinische Hochschule Hannover (MHH), Hannover, Deutschland
| | - Ingo Klein
- Chirurgische Klinik I, Universitätsklinikum Würzburg, Würzburg, Deutschland
| | - Gabriele Kirchner
- Klinik und Poliklinik für Chirurgie, Universitätsklinikum Regensburg und Innere Medizin I, Caritaskrankenhaus St. Josef Regensburg, Regensburg, Deutschland
| | - Markus Guba
- Klinik für Allgemeine, Viszeral-, Transplantations-, Gefäß- und Thoraxchirurgie, Universitätsklinikum München, München, Deutschland
| | - Matthias Glanemann
- Klinik für Allgemeine, Viszeral-, Gefäß- und Kinderchirurgie, Universitätsklinikum des Saarlandes, Homburg, Deutschland
| | - Cornelius Engelmann
- Charité - Universitätsmedizin Berlin, Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Campus Virchow-Klinikum (CVK) und Campus Charité Mitte (CCM), Berlin, Deutschland
| | - Ali E Canbay
- Medizinische Klinik, Universitätsklinikum Knappschaftskrankenhaus Bochum, Bochum, Deutschland
| | - Felix Braun
- Klinik für Allgemeine Chirurgie, Viszeral-, Thorax-, Transplantations- und Kinderchirurgie, Universitätsklinikum Schlewswig-Holstein, Kiel, Deutschland
| | - Christoph P Berg
- Innere Medizin I Gastroenterologie, Hepatologie, Infektiologie, Universitätsklinikum Tübingen, Tübingen, Deutschland
| | - Wolf O Bechstein
- Klinik für Allgemein- und Viszeralchirurgie, Universitätsklinikum Frankfurt, Frankfurt, Deutschland
| | - Thomas Becker
- Klinik für Allgemeine Chirurgie, Viszeral-, Thorax-, Transplantations- und Kinderchirurgie, Universitätsklinikum Schlewswig-Holstein, Kiel, Deutschland
| | | |
Collapse
|
|
11
|
Groß S, Bitzer M, Albert J, Blödt S, Boda-Heggemann J, Brunner T, Caspari R, De Toni E, Dombrowski F, Evert M, Follmann M, Freudenberger P, Gani C, Geier A, Gkika E, Götz M, Helmberger T, Hoffmann RT, Huppert P, Krug D, La Fougère C, Lang H, Langer T, Lenz P, Lüdde T, Mahnken A, Nadalin S, Nguyen HHP, Nothacker M, Ockenga J, Oldhafer K, Paprottka P, Pereira P, Persigehl T, Plentz R, Pohl J, Recken H, Reimer P, Riemer J, Ritterbusch U, Roeb E, Rüssel J, Schellhaas B, Schirmacher P, Schlitt HJ, Schmid I, Schuler A, Seehofer D, Sinn M, Stengel A, Steubesand N, Stoll C, Tannapfel A, Taubert A, Tholen R, Trojan J, van Thiel I, Vogel A, Vogl T, Wacker F, Waidmann O, Wedemeyer H, Wege H, Wildner D, Wörns MA, Galle P, Malek N. [Not Available]. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2024; 62:e213-e282. [PMID: 38364849 DOI: 10.1055/a-2189-8567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/18/2024]
Affiliation(s)
- Sabrina Groß
- Abteilung für Gastroenterologie, Gastrointestinale Onkologie, Hepatologie, Infektiologie und Geriatrie, Eberhard-Karls Universität, Tübingen
| | - Michael Bitzer
- Abteilung für Gastroenterologie, Gastrointestinale Onkologie, Hepatologie, Infektiologie und Geriatrie, Eberhard-Karls Universität, Tübingen
| | - Jörg Albert
- Katharinenhospital, Klinik für Allgemeine Innere Medizin, Gastroenterologie, Hepatologie, Infektiologie und Pneumologie, Stuttgart
| | - Susanne Blödt
- Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e. V. (AWMF), Berlin
| | | | - Thomas Brunner
- Universitätsklinik für Strahlentherapie-Radioonkologie, Medizinische Universität Graz
| | - Reiner Caspari
- Klinik Niederrhein, Erkrankungen des Stoffwechsels der Verdauungsorgane und Tumorerkrankungen, Bad Neuenahr-Ahrweiler
| | | | | | | | - Markus Follmann
- Office des Leitlinienprogrammes Onkologie, Deutsche Krebsgesellschaft e. V., Berlin
| | | | - Cihan Gani
- Klinik für Radioonkologie, Universitätsklinikum Tübingen
| | - Andreas Geier
- Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg
| | - Eleni Gkika
- Klinik für Strahlenheilkunde, Department für Radiologische Diagnostik und Therapie, Universitätsklinikum Freiburg
| | - Martin Götz
- Medizinische Klinik IV - Gastroenterologie/Onkologie, Klinikverbund Südwest, Böblingen
| | - Thomas Helmberger
- Institut für Radiologie, Neuroradiologie und minimal invasive Therapie, München Klinik Bogenhausen
| | - Ralf-Thorsten Hoffmann
- Institut und Poliklinik für Diagnostische und Interventionelle Radiologie, Universitätsklinikum Dresden
| | - Peter Huppert
- Radiologisches Zentrum, Max Grundig Klinik, Bühlerhöhe
| | - David Krug
- Strahlentherapie Campus Kiel, Universitätsklinikum Schleswig-Holstein
| | - Christian La Fougère
- Nuklearmedizin und Klinische Molekulare Bildgebung, Eberhard-Karls Universität, Tübingen
| | - Hauke Lang
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Johannes Gutenberg-Universität, Mainz
| | - Thomas Langer
- Office des Leitlinienprogrammes Onkologie, Deutsche Krebsgesellschaft e. V., Berlin
| | - Philipp Lenz
- Zentrale Einrichtung Palliativmedizin, Universitätsklinikum Münster
| | - Tom Lüdde
- Medizinische Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universitätsklinikum Düsseldorf
| | - Andreas Mahnken
- Klinik für Diagnostische und Interventionelle Radiologie, Universitätsklinikum Marburg
| | - Silvio Nadalin
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Eberhard-Karls Universität, Tübingen
| | | | - Monika Nothacker
- Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e. V. (AWMF), Berlin
| | - Johann Ockenga
- Medizinische Klinik II, Gesundheit Nord, Klinikverbund Bremen
| | - Karl Oldhafer
- Klinik für Leber-, Gallenwegs- und Pankreaschirurgie, Asklepios Klinik Barmbek
| | - Philipp Paprottka
- Sektion für Interventionelle Radiologie, Klinikum rechts der Isar, Technische Universität München
| | - Philippe Pereira
- Zentrum für Radiologie, Minimal-invasive Therapien und Nuklearmedizin, SLK-Klinken Heilbronn
| | - Thorsten Persigehl
- Institut für Diagnostische und Interventionelle Radiologie, Universitätsklinikum Köln
| | - Ruben Plentz
- Klinik für Innere Medizin, Gesundheit Nord, Klinikverbund Bremen
| | - Jürgen Pohl
- Abteilung für Gastroenterologie, Asklepios Klinik Altona
| | | | - Peter Reimer
- Institut für Diagnostische und Interventionelle Radiologie, Städtisches Klinikum Karlsruhe
| | | | | | - Elke Roeb
- Medizinische Klinik II Pneumologie, Nephrologie und Gastroenterologie, Universitätsklinikum Gießen
| | - Jörn Rüssel
- Medizinische Klinik IV Hämatologie und Onkologie, Universitätsklinikum Halle (Saale)
| | - Barbara Schellhaas
- Medizinische Klinik I Gastroenterologie, Pneumologie und Endokrinologie, Friedrich-Alexander-Universität, Erlangen
| | - Peter Schirmacher
- Allgemeine Pathologie und pathologische Anatomie, Universitätsklinikum Heidelberg
| | - Hans J Schlitt
- Klinik und Poliklinik für Chirurgie, Universitätsklinikum Regensburg
| | - Irene Schmid
- Kinderklinik und Kinderpoliklinik im Dr. von Haunerschen Kinderspital, LMU München
| | - Andreas Schuler
- Medizinische Klinik, Gastroenterologie, Alb-Fils-Kliniken, Geislingen an der Steige
| | - Daniel Seehofer
- Klinik und Poliklinik für Viszeral-, Transplantations-, Thorax- und Gefäßchirurgie, Universitätsklinikum Leipzig
| | - Marianne Sinn
- II. Medizinische Klinik und Poliklinik (Onkologie, Hämatologie, Knochenmarktransplantation mit Abteilung für Pneumologie), Universitätsklinikum Hamburg-Eppendorf
| | - Andreas Stengel
- Innere Medizin VI - Psychosomatische Medizin und Psychotherapie, Eberhard-Karls Universität, Tübingen
| | | | | | | | - Anne Taubert
- Klinische Sozialarbeit, Universitätsklinikum Heidelberg
| | - Reina Tholen
- Deutscher Bundesverband für Physiotherapie (ZVK) e. V
| | - Jörg Trojan
- Medizinische Klinik 1: Gastroenterologie und Hepatologie, Pneumologie und Allergologie, Endokrinologie und Diabetologie sowie Ernährungsmedizin, Goethe-Universität, Frankfurt
| | | | - Arndt Vogel
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover
| | - Thomas Vogl
- Institut für Diagnostische und Interventionelle Radiologie, Goethe-Universität, Frankfurt
| | - Frank Wacker
- Institut für Diagnostische und Interventionelle Radiologie, Medizinische Hochschule Hannover
| | | | - Heiner Wedemeyer
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover
| | - Henning Wege
- Klinik für Allgemeine Innere Medizin, Onkologie/Hämatologie, Gastroenterologie und Infektiologie, Klinikum Esslingen
| | - Dane Wildner
- Innere Medizin, Krankenhäuser Nürnberger Land GmbH, Standort Lauf
| | - Marcus-Alexander Wörns
- Klinik für Gastroenterologie, Hämatologie und internistische Onkologie und Endokrinologie, Klinikum Dortmund
| | - Peter Galle
- 1. Medizinische Klinik und Poliklinik, Gastroenterologie, Hepatologie, Nephrologie, Rheumatologie, Infektiologie, Johannes Gutenberg-Universität, Mainz
| | - Nisar Malek
- Abteilung für Gastroenterologie, Gastrointestinale Onkologie, Hepatologie, Infektiologie und Geriatrie, Eberhard-Karls Universität, Tübingen
| |
Collapse
|
|
12
|
Marrone G, Leone MS, Biolato M, Liguori A, Bianco G, Spoletini G, Gasbarrini A, Miele L, Pompili M. Therapeutic Approach to Post-Transplant Recurrence of Hepatocellular Carcinoma: Certainties and Open Issues. Cancers (Basel) 2023; 15:5593. [PMID: 38067299 PMCID: PMC10705300 DOI: 10.3390/cancers15235593] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 11/03/2023] [Accepted: 11/18/2023] [Indexed: 01/12/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a growing indication for liver transplantation (LT). Careful candidate selection is a prerequisite to keep post-LT recurrence rates within acceptable percentages. In the pre-LT period, various types of locoregional treatments and/or systemic therapies can be used for bridging or downstaging purposes. In this context, one of the factors limiting the possibility of treatment is the degree of functional liver impairment. In the LT subject, no widely accepted indications are available to guide treatment of disease recurrence and heterogeneity exists between transplant centers. Improved liver function post LT makes multiple therapeutic strategies theoretically feasible, but patient management is complicated by the need to adjust immunosuppressive therapy and to assess potential toxicities and drug-drug interactions. Finally, there is controversy and uncertainty about the use of recently introduced immunotherapeutic drugs, mainly due to the risk of organ rejection. In this paper, we will review the most recent available literature on the management of post-transplant HCC recurrence, discussing evidence and controversies.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | | | - Maurizio Pompili
- Medical and Surgical Sciences Department, Policlinico Universitario A. Gemelli-IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| |
Collapse
|
|
13
|
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.
Collapse
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
| |
Collapse
|
|
14
|
Wang H, Yang R, Wang Z, Cao L, Kong D, Sun Q, Yoshida S, Ren J, Chen T, Duan J, Lu J, Shen Z, Zheng H. Metronomic capecitabine with rapamycin exerts an immunosuppressive effect by inducing ferroptosis of CD4 + T cells after liver transplantation in rat. Int Immunopharmacol 2023; 124:110810. [PMID: 37625370 DOI: 10.1016/j.intimp.2023.110810] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 08/02/2023] [Accepted: 08/14/2023] [Indexed: 08/27/2023]
Abstract
Liver transplantation is one of the most effective treatments for hepatocellular carcinoma (HCC). The balance between inhibiting immune rejection and preventing tumor recurrence after liver transplantation is the key to determining the long-term prognosis of patients with HCC after liver transplantation. In our previous study, we found that capecitabine (CAP), an effective drug for the treatment of HCC, could exert an immunosuppressive effect after liver transplantation by inducing T cell ferroptosis. Recent studies have shown that ferroptosis is highly associated with autophagy. In this study, we confirmed that the autophagy inducer rapamycin (RAPA) combined with metronomic capecitabine (mCAP) inhibits glutathione peroxidase 4 (GPX4) and promotes ferroptosis in CD4+ T cells to exert immunosuppressive effects after rat liver transplantation. Compared with RAPA or mCAP alone, the combination of RAPA and mCAP could adequately reduce liver injury in rats with acute rejection after transplantation. The CD4+ T cell counts in peripheral blood, spleen, and transplanted liver of recipient rats significantly decreased, and the oxidative stress level and ferrous ion concentration of CD4+ T cells significantly increased in the combination group. In vitro, the combination of drugs significantly promoted autophagy, decreased GPX4 protein expression, and induced ferroptosis in CD4+ T cells. In conclusion, the autophagy inducer RAPA improved the mCAP-induced ferroptosis in CD4+ T cells. Our results support the concept of ferroptosis as an autophagy-dependent cell death and suggest that the combination of ferroptosis inducers and autophagy inducers is a new research direction for improving immunosuppressive regimens after liver transplantation.
Collapse
Affiliation(s)
- Hao Wang
- The First Central Clinical School, Tianjin Medical University, Tianjin, China
| | - Ruining Yang
- The First Central Clinical School, Tianjin Medical University, Tianjin, China
| | - Zhenglu Wang
- Organ Transplant Department, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China; Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin, China
| | - Lei Cao
- Research Institute of Transplant Medicine, Nankai University, Tianjin, China; Tianjin Key Laboratory for Organ Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
| | - Dejun Kong
- School of Medicine, Nankai University, Tianjin, China
| | - Qian Sun
- The First Central Clinical School, Tianjin Medical University, Tianjin, China
| | - Sei Yoshida
- Research Institute of Transplant Medicine, Nankai University, Tianjin, China
| | - Jiashu Ren
- The First Central Clinical School, Tianjin Medical University, Tianjin, China
| | - Tao Chen
- School of Medicine, Nankai University, Tianjin, China
| | - Jinliang Duan
- School of Medicine, Nankai University, Tianjin, China
| | - Jianing Lu
- The First Central Clinical School, Tianjin Medical University, Tianjin, China
| | - Zhongyang Shen
- Organ Transplant Department, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China; Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin, China; Research Institute of Transplant Medicine, Nankai University, Tianjin, China; Tianjin Key Laboratory for Organ Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China; National Health Commission's Key Laboratory for Critical Care Medicine, Tianjin, China
| | - Hong Zheng
- Organ Transplant Department, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China; Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin, China; Research Institute of Transplant Medicine, Nankai University, Tianjin, China; Tianjin Key Laboratory for Organ Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China; National Health Commission's Key Laboratory for Critical Care Medicine, Tianjin, China.
| |
Collapse
|
|
15
|
Cuadrado A, Fortea JI, Rodríguez-Lope C, Puente Á, Fernández-Vilchez V, Echavarria VJ, Castillo Suescun FJ, Fernández R, Echeverri JA, Achalandabaso M, Toledo E, Pellón R, Rodríguez Sanjuan JC, Crespo J, Fábrega E. Risk of Recurrence of Hepatocarcinoma after Liver Transplantation: Performance of Recurrence Predictive Models in a Cohort of Transplant Patients. J Clin Med 2023; 12:5457. [PMID: 37685524 PMCID: PMC10488177 DOI: 10.3390/jcm12175457] [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: 07/06/2023] [Revised: 08/09/2023] [Accepted: 08/20/2023] [Indexed: 09/10/2023] Open
Abstract
Liver transplantation (LT) is a curative treatment for early-stage hepatocellular carcinoma (HCC) unsuitable for surgical resection. However, tumor recurrence (TR) rates range from 8% to 20% despite strict selection criteria. The validation of new prognostic tools, such as pre-MORAL or RETREAT risks, is necessary to improve recurrence prediction. A retrospective study was conducted at Marqués de Valdecilla University Hospital in Cantabria, Spain, between 2010 and 2019 to determine the rate of TR in LT patients and identify associated factors. Patients with liver-kidney transplantation, re-transplantation, HIV infection, survival less than 90 days, or incidental HCC were excluded. Data on demographic, liver disease-related, LT, and tumor-related variables, as well as follow-up records, including TR and death, were collected. TR was analyzed using the Log-Rank test, and a multivariate Cox regression analysis was performed. The study was approved by the IRB of Cantabria. TR occurred in 13.6% of LT patients (95% CI = 7.3-23.9), primarily as extrahepatic recurrence (67%) within the first 5 years (75%). Increased TR was significantly associated with higher Body Mass Index (BMI) (HR = 1.3 [95% CI = 1.1-1.5]), vascular micro-invasion (HR = 8.8 [1.6-48.0]), and medium (HR = 20.4 [3.0-140.4]) and high pre-MORAL risk (HR = 30.2 [1.6-568.6]). TR also showed a significant correlation with increased mortality. Conclusions: LT for HCC results in a 13.6% rate of tumor recurrence. Factors such as BMI, vascular micro-invasion, and medium/high pre-MORAL risk are strongly associated with TR following LT.
Collapse
Affiliation(s)
- Antonio Cuadrado
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla University Hospital, 39011 Santander, Spain
| | - José Ignacio Fortea
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla University Hospital, 39011 Santander, Spain
| | - Carlos Rodríguez-Lope
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla University Hospital, 39011 Santander, Spain
| | - Ángela Puente
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla University Hospital, 39011 Santander, Spain
| | - Vanesa Fernández-Vilchez
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla University Hospital, 39011 Santander, Spain
| | - Victor Jose Echavarria
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla University Hospital, 39011 Santander, Spain
| | | | - Roberto Fernández
- General Surgery Service, Marqués de Valdecilla University Hospital, 39008 Santander, Spain
| | - Juan Andrés Echeverri
- General Surgery Service, Marqués de Valdecilla University Hospital, 39008 Santander, Spain
| | - Mar Achalandabaso
- General Surgery Service, Marqués de Valdecilla University Hospital, 39008 Santander, Spain
| | - Enrique Toledo
- General Surgery Service, Marqués de Valdecilla University Hospital, 39008 Santander, Spain
| | - Raúl Pellón
- Radiology Service, Marqués de Valdecilla University Hospital, 39008 Santander, Spain
| | | | - Javier Crespo
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla University Hospital, 39011 Santander, Spain
| | - Emilio Fábrega
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla University Hospital, 39011 Santander, Spain
| |
Collapse
|
|
16
|
Durkin C, Schaubel DE, Xu Y, Mahmud N, Kaplan DE, Abt PL, Bittermann T. Induction Immunosuppression Does Not Worsen Tumor Recurrence After Liver Transplantation for Hepatocellular Carcinoma. Transplantation 2023; 107:1524-1534. [PMID: 36695564 PMCID: PMC11972139 DOI: 10.1097/tp.0000000000004487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
BACKGROUND Prior studies are inconsistent regarding the impact of antibody induction therapy on outcomes after liver transplantation (LT) for hepatocellular carcinoma (HCC). METHODS Adults transplanted with HCC exception priority were identified from February 27, 2002, to March 31, 2019, using the United Network for Organ Sharing database. Time-to-event analyses evaluated the association of antibody induction therapy (none, nondepleting induction [NDI], depleting induction [DI]) with overall post-LT patient survival and HCC recurrence. Separate multivariable models adjusted for tumor characteristics on either last exception or on explant. The interaction of induction and maintenance regimen at LT discharge was investigated. RESULTS Among 22 535 LTs for HCC, 17 688 (78.48%) received no antibody induction, 2984 (13.24%) NDI, and 1863 (8.27%) DI. Minimal differences in patient and tumor characteristics were noted between induction groups, and there was significant center variability in practices. NDI was associated with improved survival, particularly when combined with a calcineurin inhibitor (CNI) and antimetabolite (hazard ratio [HR] 0.73 versus no induction plus 3-drug therapy in the last exception model [ P < 0.001]; HR 0.64 in the explant model [ P = 0.011]). The combination of DI with CNI alone was also protective (HR 0.43; P = 0.003). Neither NDI nor DI was associated with tumor recurrence (all P > 0.1). However, increased HCC recurrence was observed with no induction plus CNI monotherapy (HR 1.47, P = 0.019; versus no induction plus 3-drug therapy). CONCLUSIONS In conclusion, induction immunosuppression was not associated with worse post-LT outcomes in patients transplanted with HCC exception priority. An improvement in survival was possibly observed with NDI.
Collapse
Affiliation(s)
- Claire Durkin
- Division of Gastroenterology and Hepatology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Douglas E. Schaubel
- Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA
| | - Yuwen Xu
- Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA
| | - Nadim Mahmud
- Division of Gastroenterology and Hepatology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
- Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA
- Section of Gastroenterology and Hepatology, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA
| | - David E. Kaplan
- Division of Gastroenterology and Hepatology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
- Section of Gastroenterology and Hepatology, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA
| | - Peter L. Abt
- Division of Transplant Surgery, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Therese Bittermann
- Division of Gastroenterology and Hepatology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
- Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA
| |
Collapse
|
|
17
|
Li J, Yang F, Li J, Huang ZY, Cheng Q, Zhang EL. Postoperative adjuvant therapy for hepatocellular carcinoma with microvascular invasion. World J Gastrointest Surg 2023; 15:19-31. [PMID: 36741072 PMCID: PMC9896490 DOI: 10.4240/wjgs.v15.i1.19] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 10/29/2022] [Accepted: 12/21/2022] [Indexed: 01/17/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most lethal tumors in the world. Liver resection (LR) and liver transplantation (LT) are widely considered as radical treatments for early HCC. However, the recurrence rates after curative treatment are still high and overall survival is unsatisfactory. Microvascular invasion (MVI) is considered to be one of the important prognostic factors affecting postoperative recurrence and long-term survival. Unfortunately, whether HCC patients with MVI should receive postoperative adjuvant therapy remains unknown. In this review, we summarize the therapeutic effects of transcatheter arterial chemoembolization, hepatic arterial infusion chemotherapy, tyrosine protein kinase inhibitor-based targeted therapy, and immune checkpoint inhibitors in patients with MVI after LR or LT, aiming to provide a reference for the best adjuvant treatment strategy for HCC patients with MVI after LT or LR.
Collapse
Affiliation(s)
- Jiang Li
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, College of Medicine, Shihezi University, Shihezi 832000, Xinjiang Uygur Autonomous Regions, China
| | - Fan Yang
- Department of General Surgery, Affiliated Hospital of Hubei Minzu University, Enshi 445000, Hubei Province, China
| | - Jian Li
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Zhi-Yong Huang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Qi Cheng
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Er-Lei Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| |
Collapse
|
|
18
|
Cisneros-Garza LE, González-Huezo MS, Moctezuma-Velázquez C, Ladrón de Guevara-Cetina L, Vilatobá M, García-Juárez I, Alvarado-Reyes R, Álvarez-Treviño GA, Allende-Pérez S, Bornstein-Quevedo L, Calderillo-Ruiz G, Carrillo-Martínez MA, Castillo-Barradas M, Cerda-Reyes E, Félix-Leyva JA, Gabutti-Thomas JA, Guerrero-Ixtlahuac J, Higuera-de la Tijera F, Huitzil-Melendez D, Kimura-Hayama E, López-Hernández PA, Malé-Velázquez R, Méndez-Sánchez N, Morales-Ruiz MA, Ruíz-García E, Sánchez-Ávila JF, Torrecillas-Torres L. The second Mexican consensus on hepatocellular carcinoma. Part II: Treatment. REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2022; 87:362-379. [PMID: 35778341 DOI: 10.1016/j.rgmx.2022.01.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 01/20/2022] [Indexed: 01/03/2025]
Abstract
Hepatocellular carcinoma (HCC) is more frequently manifesting as one of the main complications of cirrhosis of the liver, its principal risk factor. There have been modifications in its incidence over the past decade, related to an epidemiologic transition in the etiology of cirrhosis, with a decrease in the prevalence of hepatitis C and an increase in nonalcoholic fatty liver disease (NAFLD) as a cause, as well as the development of HCC in the non-cirrhotic liver due to NAFLD. Genetic markers associated with the disease have been identified, and surveillance and diagnosis have improved. Regarding treatment, surgical techniques, in both resection and transplantation, have advanced and radiologic techniques, at the curative stage of the disease, have enhanced survival in those patients. And finally, there have been radical changes in the systemic approach, with much more optimistic expectations, when compared with the options available a decade ago. Therefore, the Asociación Mexicana de Hepatología decided to carry out the Second Mexican Consensus on Hepatocellular Carcinoma, which is an updated review of the available national and international evidence on the epidemiology, risk factors, surveillance, diagnosis, and treatment of the disease, to offer the Mexican physician current information on the different topics regarding hepatocellular carcinoma. In this second part of the document, the topics related to the treatment of HCC are presented.
Collapse
Affiliation(s)
- L E Cisneros-Garza
- Hospital Christus Muguerza Alta Especialidad, Monterrey, Nuevo León, Mexico.
| | | | | | | | - M Vilatobá
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, CDMX, Mexico
| | - I García-Juárez
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, CDMX, Mexico
| | | | | | | | - L Bornstein-Quevedo
- InmunoQ, Laboratorio de Patología, Inmunohistoquímica y Biología Molecular, CDMX, Mexico
| | | | | | | | | | | | - J A Gabutti-Thomas
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, CDMX, Mexico
| | | | | | - D Huitzil-Melendez
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, CDMX, Mexico
| | | | | | - R Malé-Velázquez
- Instituto de Salud Digestiva y Hepática SA de CV, Guadalajara, Jalisco, Mexico
| | | | - M A Morales-Ruiz
- Centro Oncológico Estatal Issemym, Toluca, Estado de México, Mexico
| | | | - J F Sánchez-Ávila
- Escuela de Medicina y Ciencias de la Salud, Tecnológico de Monterrey, Monterrey, Nuevo León, Mexico
| | | |
Collapse
|
|
19
|
Cisneros-Garza L, González-Huezo M, Moctezuma-Velázquez C, Ladrón de Guevara-Cetina L, Vilatobá M, García-Juárez I, Alvarado-Reyes R, Álvarez-Treviño G, Allende-Pérez S, Bornstein-Quevedo L, Calderillo-Ruiz G, Carrillo-Martínez M, Castillo-Barradas M, Cerda-Reyes E, Félix-Leyva J, Gabutti-Thomas J, Guerrero-Ixtlahuac J, Higuera-de la Tijera F, Huitzil-Melendez D, Kimura-Hayama E, López-Hernández P, Malé-Velázquez R, Méndez-Sánchez N, Morales-Ruiz M, Ruíz-García E, Sánchez-Ávila J, Torrecillas-Torres L. The second Mexican consensus on hepatocellular carcinoma. Part II: Treatment. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO (ENGLISH EDITION) 2022; 87:362-379. [DOI: 10.1016/j.rgmxen.2022.01.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 01/20/2022] [Indexed: 10/25/2022] Open
|
|
20
|
Yan X, Huang S, Yang Y, Lu Z, Li F, Jiang L, Jiang Y, Liu J. Sirolimus or Everolimus Improves Survival After Liver Transplantation for Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis. Liver Transpl 2022; 28:1063-1077. [PMID: 34919773 DOI: 10.1002/lt.26387] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Revised: 11/29/2021] [Accepted: 12/13/2021] [Indexed: 01/13/2023]
Abstract
The effects of mammalian target of rapamycin (mTOR) inhibitors (sirolimus [SRL] and everolimus [EVL]) on survival in liver transplantation (LT) recipients with hepatocellular carcinoma (HCC) remain the subject of intense research. Therefore, we performed this systematic review and meta-analysis to investigate the potential survival benefits of mTOR inhibitors (mTORis). Embase, PubMed, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for all randomized controlled trials (RCTs) and cohort studies investigating effects of SRL or EVL on LT recipients for HCC. The primary outcomes were 1-, 2-, 3-, and 5-year overall survival (OS), and the secondary outcomes were 1-, 2-, and 3-year recurrence-free survival (RFS) and adverse effects. Pooled relative risks (RRs) with 95% confidence interval (CI) were calculated by a fixed or random effects model with Mantel-Haenszel weighting. Subgroup analyses were performed according to crucial clinical characteristics. We also conducted sensitivity analyses to assess the reliability of our findings. A total of 17 studies were included. OS was improved in both RCTs (1 year: RR, 1.04; 95% CI, 1.00-1.08; 2 years: RR, 1.09; 95% CI, 1.02-1.16; 3 years: RR, 1.13; 95% CI, 1.04-1.24; 5 years: RR, 1.13; 95% CI, 1.02-1.26) and cohort studies (1 year: RR, 1.13; 95% CI, 1.06-1.20; 2 years: RR, 1.24; 95% CI, 1.16-1.32; 3 years: RR, 1.24; 95% CI, 1.15-1.34; 5 years: RR, 1.17; 95% CI, 1.10-1.24), with a lower risk of renal toxicity (RR, 0.75; 95% CI, 0.60 to 0.93). The 1-, 2-, and 3-year RFS were also improved. Current evidence indicates that SRL- or EVL-based immunosuppression improves OS and RFS with a lower risk of renal toxicity compared with mTORi-free immunosuppression. Nevertheless, results must be interpreted with caution.
Collapse
Affiliation(s)
- Xiangyu Yan
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China.,Department of Hepatobiliary Surgery and Center of Organ Transplantation, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Songhan Huang
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China.,Department of Hepatobiliary Surgery and Center of Organ Transplantation, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Yang Yang
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China.,Department of Hepatobiliary Surgery and Center of Organ Transplantation, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Ziwen Lu
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China.,Department of Hepatobiliary Surgery and Center of Organ Transplantation, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Feiyu Li
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China.,Department of Hepatobiliary Surgery and Center of Organ Transplantation, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Liyong Jiang
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China.,Department of Hepatobiliary Surgery and Center of Organ Transplantation, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Yong Jiang
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China.,Department of Hepatobiliary Surgery and Center of Organ Transplantation, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Jun Liu
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China.,Department of Hepatobiliary Surgery and Center of Organ Transplantation, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| |
Collapse
|
|
21
|
Azhie A, Grant RC, Herman M, Wang L, Knox JJ, Bhat M. Phase II clinical trial of cabozantinib for the treatment of recurrent hepatocellular carcinoma after liver transplantation. Future Oncol 2022; 18:2173-2191. [PMID: 35287469 DOI: 10.2217/fon-2021-1635] [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] [Indexed: 12/24/2022] Open
Abstract
Recurrent hepatocellular carcinoma (HCC) develops in 15-20% of liver transplant recipients, and it tends to be more aggressive due to underlying immunosuppression. The multikinase inhibitor cabozantinib has been shown to be effective for the treatment of advanced HCC. However, there is no study evaluating this medication in patients with recurrent HCC. Adult patients with measurable biopsy-proven recurrent HCC are eligible for enrollment provided they are not amenable to curative treatments and no prior treatment with cabozantinib. In this study, 60 mg once daily cabozantinib will be administered orally. Participants will receive study treatment as long as they continue to experience clinical benefit or until there is unacceptable toxicity. Tumor measurements will be repeated every 8 weeks to evaluate response. The primary end point of this study will be the disease control rate at 4 months after treatment. The secondary end points will be overall survival, progression-free survival and safety profile of cabozantinib. Furthermore, potential biomarkers will be evaluated to identify their role in tumor progression. The total duration of this trial is expected to be 3 years. We anticipate that this trial will show the effectiveness and safety of cabozantinib in the treatment of post-liver transplant recurrent HCC. Cabozantinib is expected to be an effective treatment due to its activity against many protein kinases, including MET and AXL which are not inhibited by sorafenib.
Collapse
Affiliation(s)
- Amirhossein Azhie
- Ajmera Transplant Program, University Health Network, Toronto, Ontario, M5G 2N2, Canada
| | - Robert C Grant
- Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, M5G 2M9, Canada
| | - Michael Herman
- Oakville Trafalgar Memorial Hospital, Oakville, Ontario, L6M 0L8, Canada
| | - Lisa Wang
- Biostatistics Division, Princess Margaret Cancer Centre, University Health Network, Toronto, M5G 2M9, Canada
| | - Jennifer J Knox
- Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, M5G 2M9, Canada
| | - Mamatha Bhat
- Ajmera Transplant Program, University Health Network, Toronto, Ontario, M5G 2N2, Canada
- Division of Gastroenterology & Hepatology, Department of Medicine, University of Toronto, Ontario, M5S 1A8, Canada
| |
Collapse
|
|
22
|
Agarwal PD, Lucey MR. Management of hepatocellular carcinoma recurrence after liver transplantation. Ann Hepatol 2022; 27:100654. [PMID: 34929349 DOI: 10.1016/j.aohep.2021.100654] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 11/30/2021] [Accepted: 11/30/2021] [Indexed: 02/04/2023]
Abstract
Despite careful selection for liver transplantation (LT) of patients with hepatocellular carcinoma (HCC), HCC may still recur after LT and is frequently associated with dismal outcome. Tumor factors, including serum alpha-fetoprotein (AFP), the presence of microvascular invasion, tumor grade/differentiation, and largest tumor size are amongst the most important predictors of recurrence after transplantation. The nature of recurrence can be highly variable, but often presents with extra-hepatic involvement. As such, management of patients with HCC can be challenging, and consensus guidelines are lacking. Curative options, with surgery or ablation, which may be applicable in patients with isolated intra-or extrahepatic metastases, offer the best chance for improved long-term outcome in patients with HCC recurrence after transplantation. Most patients with recurrence have unresectable disease, and may benefit from palliative treatments, including intra-arterial therapies and/or systemic therapy.
Collapse
Affiliation(s)
- Parul D Agarwal
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, 1685 Highland Avenue, Suite 4224, Madison, WI 53705, United States.
| | - Michael R Lucey
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, 1685 Highland Avenue, Suite 4224, Madison, WI 53705, United States
| |
Collapse
|
|
23
|
Abrahamsson J, Sternby Eilard M, Rizell M, Bennett W, Åberg F. Reduced calcineurin inhibitor exposure with antibody induction and recurrent hepatocellular carcinoma after liver transplantation. Scand J Gastroenterol 2022; 57:325-332. [PMID: 34871120 DOI: 10.1080/00365521.2021.2010799] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a common indication for liver transplantation (LT), but post-LT tumor recurrence remains a concern. Early post-LT immunosuppression is suggested to affect recurrence risk. We evaluated the impact on HCC recurrence of an immunosuppression protocol introduced in 2010 with interleukin-2 receptor antibody (IL-2RA) induction and delayed-introduction of reduced-dose tacrolimus with mycophenolate. METHODS We included consecutive HCC patients transplanted 2000-2017 in Gothenburg. The impact on HCC recurrence of IL-2RA induction and mean tacrolimus trough concentration during the first 20 post-LT days was analyzed by multivariable Cox regression and propensity score-adjusted analyses. RESULTS The study comprised 235 patients (mean age 57 yrs, men 80%, mean MELD 13, within Milan criteria 57%). The cumulative 5-yr HCC recurrence rate among patients transplanted before and after 2010 were 28.6% and 19.7%, respectively. IL-2RA induction had no independent effect on HCC recurrence. High tacrolimus exposure (mean 20-day tacrolimus concentration ≥8ng/mL) was associated with increased HCC recurrence risk on univariable analysis (HR 2.22, 95% CI 1.23-4.01, p = .008), but was non-significant on multivariable analysis (p = .17). Outside Milan criteria, high tacrolimus exposure was significant for HCC recurrence (HR 3.68, 95% CI 1.34-10.11, p = .012) independently of tumor characteristics and AFP level. This was confirmed on multivariable propensity score-adjusted analysis. CONCLUSIONS Reduced early tacrolimus exposure, facilitated by IL-2RA induction, was associated with reduced risk for HCC recurrence among patients outside Milan criteria. Prospective studies are needed to confirm if early tacrolimus-minimization strategies can help reduce HCC recurrence rates and help extend transplant criteria.
Collapse
Affiliation(s)
- Jenny Abrahamsson
- Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden
| | | | - Magnus Rizell
- Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - William Bennett
- Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Fredrik Åberg
- Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden.,Transplantation and Liver Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| |
Collapse
|
|
24
|
Sabrina V, Michael B, Jörg A, Peter B, Wolf B, Susanne B, Thomas B, Frank D, Matthias E, Markus F, Christian LF, Paul F, Andreas G, Eleni G, Martin G, Elke H, Thomas H, Ralf-Thorsten H, Wolf-Peter H, Peter H, Achim K, Gabi K, Jürgen K, David K, Frank L, Hauke L, Thomas L, Philipp L, Andreas M, Alexander M, Oliver M, Silvio N, Huu Phuc N, Johann O, Karl-Jürgen O, Philipp P, Kerstin P, Philippe P, Thorsten P, Mathias P, Ruben P, Jürgen P, Jutta R, Peter R, Johanna R, Ulrike R, Elke R, Barbara S, Peter S, Irene S, Andreas S, Dietrich VS, Daniel S, Marianne S, Alexander S, Andreas S, Nadine S, Christian S, Andrea T, Anne T, Jörg T, Ingo VT, Reina T, Arndt V, Thomas V, Hilke V, Frank W, Oliver W, Heiner W, Henning W, Dane W, Christian W, Marcus-Alexander W, Peter G, Nisar M. S3-Leitlinie: Diagnostik und Therapie des hepatozellulären Karzinoms. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2022; 60:e56-e130. [PMID: 35042248 DOI: 10.1055/a-1589-7568] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- Voesch Sabrina
- Medizinische Klinik I, Universitätsklinikum Tübingen, Tübingen
| | - Bitzer Michael
- Medizinische Klinik I, Universitätsklinikum Tübingen, Tübingen
| | - Albert Jörg
- Abteilung für Gastroenterologie, Hepatologie und Endokrinologie, Stuttgart
| | | | - Bechstein Wolf
- Klinik für Allgemein-, Viszeral-, Transplantations- und Thoraxchirurgie, Universitätsklinikum Frankfurt, Frankfurt am Main
| | | | - Brunner Thomas
- Klinik für Strahlentherapie, Universitätsklinikum Magdeburg A. ö. R., Magdeburg
| | - Dombrowski Frank
- Institut für Pathologie, Universitätsmedizin Greifswald, Greifswald
| | | | - Follmann Markus
- Office des Leitlinienprogrammes Onkologie, c/o Deutsche Krebsgesellschaft e.V. Berlin
| | | | | | - Geier Andreas
- Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg
| | - Gkika Eleni
- Klinik für Strahlenheilkunde, Department für Radiologische Diagnostik und Therapie, Universitätsklinikum Freiburg, Freiburg
| | | | - Hammes Elke
- Lebertransplantierte Deutschland e. V., Ansbach
| | - Helmberger Thomas
- Institut für Radiologie, Neuroradiologie und minimal-invasive Therapie, München Klinik Bogenhausen, München
| | | | - Hofmann Wolf-Peter
- Gastroenterologie am Bayerischen Platz, medizinisches Versorgungszentrum, Berlin
| | | | | | - Knötgen Gabi
- Konferenz onkologischer Kranken- und Kinderkrankenpflege, Hamburg
| | - Körber Jürgen
- Klinik Nahetal, Fachklinik für onkologische Rehabilitation und Anschlussrehabilitation, (AHB), Bad Kreuznach
| | - Krug David
- Klinik für Strahlentherapie, Universitätsklinikum Schleswig-Holstein, Kiel
| | | | - Lang Hauke
- Klinik für Allgemein-, Viszeral und Transplantationschirurgie, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz
| | - Langer Thomas
- Office des Leitlinienprogrammes Onkologie, c/o Deutsche Krebsgesellschaft e.V. Berlin
| | - Lenz Philipp
- Universitätsklinikum Münster, Zentrale Einrichtung Palliativmedizin, Münster
| | - Mahnken Andreas
- Klinik für Diagnostische und Interventionelle Radiologie, Universitätsklinikum Gießen und Marburg GmbH, Marburg
| | - Meining Alexander
- Medizinische Klinik und Poliklinik II des Universitätsklinikums Würzburg, Würzburg
| | - Micke Oliver
- Klinik für Strahlentherapie und Radioonkologie, Franziskus Hospital Bielefeld, Bielefeld
| | - Nadalin Silvio
- Universitätsklinik für Allgemein-, Viszeral- und Transplantationschirurgie, Universitätsklinikum Tübingen, Tübingen
| | | | | | - Oldhafer Karl-Jürgen
- Klinik für Leber-, Gallenwegs- und Pankreaschirurgie, Semmelweis Universität, Asklepios Campus Hamburg, Hamburg
| | - Paprottka Philipp
- Abteilung für interventionelle Radiologie, Klinikum rechts der Isar der Technischen Universität München, München
| | - Paradies Kerstin
- Konferenz onkologischer Kranken- und Kinderkrankenpflege, Hamburg
| | - Pereira Philippe
- Zentrum für Radiologie, Minimal-invasive Therapien und Nuklearmedizin, Klinikum am Gesundbrunnen, SLK-Kliniken Heilbronn GmbH, Heilbronn
| | - Persigehl Thorsten
- Institut für Diagnostische und Interventionelle Radiologie, Universitätsklinikum Köln, Köln
| | | | | | - Pohl Jürgen
- Interventionelles Endoskopiezentrum und Schwerpunkt Gastrointestinale Onkologie, Asklepios Klinik Altona, Hamburg
| | - Riemer Jutta
- Lebertransplantierte Deutschland e. V., Bretzfeld
| | - Reimer Peter
- Institut für diagnostische und interventionelle Radiologie, Städtisches Klinikum Karlsruhe gGmbH, Karlsruhe
| | - Ringwald Johanna
- Psychosomatische Medizin und Psychotherapie, Universitätsklinikum Tübingen, Tübingen
| | | | - Roeb Elke
- Medizinische Klinik II, Universitätsklinikum Gießen und Marburg GmbH, Gießen
| | - Schellhaas Barbara
- Medizinische Klinik I, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen
| | - Schirmacher Peter
- Pathologisches Institut, Universitätsklinikum Heidelberg, Heidelberg
| | - Schmid Irene
- Zentrum Pädiatrische Hämatologie und Onkologie, Dr. von Haunersches Kinderspital, Klinikum der Universität München, München
| | | | | | - Seehofer Daniel
- Klinik und Poliklinik für Viszeral-, Transplantations-, Thorax- und Gefäßchirurgie, Universitätsklinikum Leipzig, Leipzig
| | - Sinn Marianne
- Medizinische Klinik II, Universitätsklinikum Hamburg-Eppendorf, Hamburg
| | | | - Stengel Andreas
- Psychosomatische Medizin und Psychotherapie, Universitätsklinikum Tübingen, Tübingen
| | | | | | - Tannapfel Andrea
- Institut für Pathologie der Ruhr-Universität Bochum am Berufsgenossenschaftlichen Universitätsklinikum Bergmannsheil, Bochum
| | - Taubert Anne
- Kliniksozialdienst, Universitätsklinikum Heidelberg, Bochum
| | - Trojan Jörg
- Medizinische Klinik I, Universitätsklinikum Frankfurt, Frankfurt am Main
| | | | - Tholen Reina
- Deutscher Verband für Physiotherapie e. V., Köln
| | - Vogel Arndt
- Klinik für Gastroenterologie, Hepatologie, Endokrinologie der Medizinischen Hochschule Hannover, Hannover
| | - Vogl Thomas
- Universitätsklinikum Frankfurt, Institut für Diagnostische und Interventionelle Radiologie, Frankfurt
| | - Vorwerk Hilke
- Klinik für Strahlentherapie, Universitätsklinikum Gießen und Marburg GmbH, Marburg
| | - Wacker Frank
- Institut für Diagnostische und Interventionelle Radiologie der Medizinischen Hochschule Hannover, Hannover
| | - Waidmann Oliver
- Medizinische Klinik I, Universitätsklinikum Frankfurt, Frankfurt am Main
| | - Wedemeyer Heiner
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie Medizinische Hochschule Hannover, Hannover
| | - Wege Henning
- I. Medizinische Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg
| | - Wildner Dane
- Innere Medizin, Krankenhäuser Nürnberger Land GmbH, Lauf an der Pegnitz
| | | | | | - Galle Peter
- I. Medizinische Klinik und Poliklinik, Universitätsklinikum Mainz, Mainz
| | - Malek Nisar
- Medizinische Klinik I, Universitätsklinikum Tübingen, Tübingen
| |
Collapse
|
|
25
|
Yilmaz S, Ince V. The Importance of the Immunosuppressive Regime on Hepatocellular Carcinoma Recurrence After Liver Transplantation. J Gastrointest Cancer 2021; 52:1350-1355. [PMID: 34611833 DOI: 10.1007/s12029-021-00716-9] [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] [Accepted: 09/20/2021] [Indexed: 11/26/2022]
Abstract
PURPOSE Hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) occurs in approximately 20% of recipients and these patients have median about one year survival after diagnosis. Some immunosuppressive drugs can cause development of HCC recurrence, on the other hand some immunosuppressive drugs may have a positive effect for preventing HCC recurrence. Thus, immunosuppression (IS) modification may play a role in preventing HCC recurrence. METHODS In this review, we analyzed IS treatment strategy in two parts: before HCC recurrence following LT and after HCC recurrence following LT, and after HCC recurrence following LT. RESULTS There is no proven, optimal IS protocol to prevent HCC recurrence after transplantation. Therefore, individualized immunosuppressive treatments should be tailored to the biological behaviour of HCC. Forcing the immune tolerance in terms of recurrence can probably be expressed as the most appropriate post LT period. Once HCC recurrence has developed after transplantation, again, there is no commonly accepted, optimal IS treatment, but there is a tendency to switch to IS modifications that include mTORi by minimizing CNIs and MMF. CONCLUSION There is a need for well-designed, randomized, controlled clinical studies with larger numbers of patients on this subject.
Collapse
Affiliation(s)
- Sezai Yilmaz
- Department of Surgery, Liver Transplant Institute, Inonu University, Malatya, Turkey
| | - Volkan Ince
- Department of Surgery, Liver Transplant Institute, Inonu University, Malatya, Turkey.
| |
Collapse
|
|
26
|
Magro B, Pinelli D, De Giorgio M, Lucà MG, Ghirardi A, Carrobio A, Baronio G, Del Prete L, Nounamo F, Gianatti A, Colledan M, Fagiuoli S. Pre-Transplant Alpha-Fetoprotein > 25.5 and Its Dynamic on Waitlist Are Predictors of HCC Recurrence after Liver Transplantation for Patients Meeting Milan Criteria. Cancers (Basel) 2021; 13:5976. [PMID: 34885087 PMCID: PMC8656660 DOI: 10.3390/cancers13235976] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 11/22/2021] [Accepted: 11/25/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND AND AIM Hepatocellular carcinoma (HCC) recurrence rates after liver transplantation (LT) range between 8 and 20%. Alpha-fetoprotein (AFP) levels at transplant can predict HCC recurrence, however a defined cut-off value is needed to better stratify patients. The aim of this study was to evaluate the rate of HCC recurrence at our centre and to identify predictors, focusing on AFP. METHODS We retrospectively analysed 236 consecutive patients that were waitlisted for HCC who all met the Milan criteria from January 2001 to December 2017 at our liver transplant centre. A total of twenty-nine patients dropped out while they were waitlisted, and 207 patients were included in the final analysis. All survival analyses included the competing-risk model. RESULTS The mean age was 56.8 ± 6.8 years. A total of 14% were female (n = 29/207). The median MELD (model for end-stage liver disease) at LT was 12 (9-16). The median time on the waitlist was 92 (41-170) days. The HCC recurrence rate was 16.4% (n = 34/208). The mean time to recurrence was 3.3 ± 2.8 years. The median AFP levels at transplant were higher in patients with HCC recurrence (p < 0.001). At multivariate analysis, the AFP value at transplant that was greater than 25.5 ng/mL (AUC 0.69) was a strong predictor of HCC recurrence after LT [sHR 3.3 (1.6-6.81); p = 0.001]. The HCC cumulative incidence function (CIF) of recurrence at 10 years from LT was significantly higher in patients with AFP > 25.5 ng/mL [34.3% vs. 11.5% (p = 0.001)]. Moreover, an increase in AFP > 20.8%, was significantly associated with HCC recurrence (p = 0.034). CONCLUSIONS In conclusion, in our retrospective study, the AFP level at transplant > 25.5 ng/mL and its increase greater than 20.8% on the waitlist were strong predictors of HCC recurrence after LT in a cohort of patients that were waitlisted within the Milan criteria. However further studies are needed to validate these data.
Collapse
Affiliation(s)
- Bianca Magro
- Gastroenterology, Hepatology and Liver Transplantation, Department of Medicine-Papa Giovanni, XXIII Hospital, 24122 Bergamo, Italy; (M.D.G.); (M.G.L.); (S.F.)
| | - Domenico Pinelli
- Unit of Hepato-Biliary Surgery and Liver Transplantation, ASST Papa Giovanni XXIII, 24122 Bergamo, Italy; (D.P.); (G.B.); (L.D.P.); (F.N.); (M.C.)
| | - Massimo De Giorgio
- Gastroenterology, Hepatology and Liver Transplantation, Department of Medicine-Papa Giovanni, XXIII Hospital, 24122 Bergamo, Italy; (M.D.G.); (M.G.L.); (S.F.)
| | - Maria Grazia Lucà
- Gastroenterology, Hepatology and Liver Transplantation, Department of Medicine-Papa Giovanni, XXIII Hospital, 24122 Bergamo, Italy; (M.D.G.); (M.G.L.); (S.F.)
| | - Arianna Ghirardi
- FROM Research Foundation, Papa Giovanni XXIII Hospital, 24122 Bergamo, Italy; (A.G.); (A.C.)
| | - Alessandra Carrobio
- FROM Research Foundation, Papa Giovanni XXIII Hospital, 24122 Bergamo, Italy; (A.G.); (A.C.)
| | - Giuseppe Baronio
- Unit of Hepato-Biliary Surgery and Liver Transplantation, ASST Papa Giovanni XXIII, 24122 Bergamo, Italy; (D.P.); (G.B.); (L.D.P.); (F.N.); (M.C.)
| | - Luca Del Prete
- Unit of Hepato-Biliary Surgery and Liver Transplantation, ASST Papa Giovanni XXIII, 24122 Bergamo, Italy; (D.P.); (G.B.); (L.D.P.); (F.N.); (M.C.)
| | - Franck Nounamo
- Unit of Hepato-Biliary Surgery and Liver Transplantation, ASST Papa Giovanni XXIII, 24122 Bergamo, Italy; (D.P.); (G.B.); (L.D.P.); (F.N.); (M.C.)
| | - Andrea Gianatti
- Pathology Unit, ASST Papa Giovanni XXIII, 24122 Bergamo, Italy;
| | - Michele Colledan
- Unit of Hepato-Biliary Surgery and Liver Transplantation, ASST Papa Giovanni XXIII, 24122 Bergamo, Italy; (D.P.); (G.B.); (L.D.P.); (F.N.); (M.C.)
| | - Stefano Fagiuoli
- Gastroenterology, Hepatology and Liver Transplantation, Department of Medicine-Papa Giovanni, XXIII Hospital, 24122 Bergamo, Italy; (M.D.G.); (M.G.L.); (S.F.)
| |
Collapse
|
|
27
|
L R, T I, Mpaw C, H M, G S. THE MANAGEMENT OF POST-TRANSPLANTATION RECURRENCE OF HEPATOCELLULAR CARCINOMA. Clin Mol Hepatol 2021; 28:1-16. [PMID: 34610652 PMCID: PMC8755475 DOI: 10.3350/cmh.2021.0217] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 10/03/2021] [Indexed: 11/15/2022] Open
Abstract
The annual incidence of hepatocellular carcinoma (HCC) continues to rise. Over the last two decades, liver transplantation (LT) has become the preferable treatment of HCC, when feasible and strict selection criteria are met. With the rise in HCC-related LT, compounded by downstaging techniques and expansion of transplant selection criteria, a parallel increase in number of post-transplantation HCC recurrence is expected. Additionally, in the context of an immunosuppressed transplant host, recurrences may behave aggressively and more challenging to manage, resulting in poor prognosis. Despite this, no consensus or best practice guidelines for post-transplantation cancer surveillance and recurrence management for HCC currently exist. Studies with adequate population sizes and high-level evidence are lacking, and the role of systemic and locoregional therapies for graft and extrahepatic recurrences remains under debate. This review seeks to summarize the existing literature on post-transplant HCC surveillance and recurrence management. It highlights the value of early tumour detection, re-evaluating the immunosuppression regimen, and staging to differentiate disseminated recurrence from intrahepatic or extrahepatic oligo-recurrence. This ultimately guides decision-making and maximizes treatment effect. Treatment recommendations specific to recurrence type are provided based on currently available locoregional and systemic therapies.
Collapse
Affiliation(s)
- Rajendran L
- Division of General Surgery, University of Toronto, Toronto, Ontario, Canada
| | - Ivanics T
- Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada.,Department of Surgery, Henry Ford Hospital, Detroit, MI, USA.,Department of Surgical Sciences, Akademiska Sjukhuset, Uppsala University, Uppsala, Sweden
| | - Claasen Mpaw
- Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada.,Department of Surgery, Erasmus MC, University Medical Centre, Rotterdam, the Netherlands
| | - Muaddi H
- Division of General Surgery, University of Toronto, Toronto, Ontario, Canada
| | - Sapisochin G
- Division of General Surgery, University of Toronto, Toronto, Ontario, Canada.,Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
| |
Collapse
|
|
28
|
Kang I, Lee JG, Choi SH, Kim HJ, Han DH, Choi GH, Kim MS, Choi JS, Kim SI, Joo DJ. Impact of everolimus on survival after liver transplantation for hepatocellular carcinoma. Clin Mol Hepatol 2021; 27:589-602. [PMID: 34293849 PMCID: PMC8524068 DOI: 10.3350/cmh.2021.0038] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 06/09/2021] [Accepted: 07/22/2021] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND/AIMS This study aimed to investigate whether everolimus (EVR) affects long-term survival after liver transplantation (LT) in patients with hepatocellular carcinoma (HCC). METHODS The data from 303 consecutive patients with HCC who had undergone LT from January 2012 to July 2018 were retrospectively reviewed. The patients were divided into two groups: 1) patients treated with EVR in combination with calcineurin inhibitors (CNIs) (EVR group; n=114) and 2) patients treated with CNI-based therapy without EVR (non-EVR group; n=189). Time to recurrence (TTR) and overall survival (OS) after propensity score (PS) matching were compared between the groups, and prognostic factors for TTR and OS were evaluated. RESULTS The EVR group exhibited more aggressive tumor biology than the non-EVR group, such as a higher number of tumors (P=0.003), a higher prevalence of microscopic vascular invasion (P=0.017) and exceeding Milan criteria (P=0.029). Compared with the PS-matched non-EVR group, the PS-matched EVR group had significantly better TTR (P<0.001) and OS (P<0.001). In multivariable analysis, EVR was identified as an independent prognostic factor for TTR (hazard ratio [HR], 0.248; P=0.001) and OS (HR, 0.145; P<0.001). CONCLUSION Combined with CNIs, EVR has the potential to prolong long-term survival in patients undergoing LT for HCC. These findings warrant further investigation in a well-designed prospective study.
Collapse
Affiliation(s)
- Incheon Kang
- Department of Surgery, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea
| | - Jae Geun Lee
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
- The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, Korea
| | - Sung Hoon Choi
- Department of Surgery, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea
| | - Hyun Jeong Kim
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
- The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, Korea
| | - Dai Hoon Han
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
- The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, Korea
| | - Gi Hong Choi
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
- The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, Korea
| | - Myoung Soo Kim
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
- The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, Korea
| | - Jin Sub Choi
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
- The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, Korea
| | - Soon Il Kim
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
- The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, Korea
| | - Dong Jin Joo
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
- The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, Korea
| |
Collapse
|
|
29
|
Pelizzaro F, Gambato M, Gringeri E, Vitale A, Cillo U, Farinati F, Burra P, Russo FP. Management of Hepatocellular Carcinoma Recurrence after Liver Transplantation. Cancers (Basel) 2021; 13:4882. [PMID: 34638365 PMCID: PMC8508053 DOI: 10.3390/cancers13194882] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 09/19/2021] [Accepted: 09/24/2021] [Indexed: 02/06/2023] Open
Abstract
Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT), occurring in 10-15% of cases, is a major concern. A lot of work has been done in order to refine the selection of LT candidates with HCC and to improve the outcome of patients with recurrence. Despite this, the prognosis of these patients remains poor, partly due to the several areas of uncertainty in their management. Even if surveillance for HCC recurrence is crucial for early detection, there is currently no evidence to support a specific and cost-effective post-LT surveillance strategy. Concerning preventive measures, consensus on the best immunosuppressive drugs has not been reached and not enough data to support adjuvant therapy are present. Several therapeutic approaches (surgical, locoregional and systemic treatments) are available in case of recurrence, but there are still few data in the post-LT setting. Moreover, the use of immune checkpoint inhibitors is controversial in transplant recipients considered the risk of rejection. In this paper, the available evidence on the management of HCC recurrence after LT is comprehensively reviewed, considering pre- and post-transplant risk stratification, post-transplant surveillance, preventive strategies and treatment options.
Collapse
Affiliation(s)
- Filippo Pelizzaro
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (F.P.); (M.G.); (F.F.); (P.B.)
| | - Martina Gambato
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (F.P.); (M.G.); (F.F.); (P.B.)
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy
| | - Enrico Gringeri
- Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (E.G.); (A.V.); (U.C.)
| | - Alessandro Vitale
- Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (E.G.); (A.V.); (U.C.)
| | - Umberto Cillo
- Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (E.G.); (A.V.); (U.C.)
| | - Fabio Farinati
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (F.P.); (M.G.); (F.F.); (P.B.)
| | - Patrizia Burra
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (F.P.); (M.G.); (F.F.); (P.B.)
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy
| | - Francesco Paolo Russo
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (F.P.); (M.G.); (F.F.); (P.B.)
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy
| |
Collapse
|
|
30
|
Zhao Y, Liu Y, Zhou L, Du GS, He Q. Trends of rapamycin in survival benefits of liver transplantation for hepatocellular carcinoma. World J Gastrointest Surg 2021; 13:953-966. [PMID: 34621472 PMCID: PMC8462078 DOI: 10.4240/wjgs.v13.i9.953] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 05/17/2021] [Accepted: 07/26/2021] [Indexed: 02/06/2023] Open
Abstract
The proportion of liver transplantation (LT) for hepatocellular carcinoma (HCC) has kept on increasing over the past years and account for 20%-40% of all LT. Post-transplant HCC recurrence is considered the most important factor affecting the long-term survival of patients. The use of different types of immunosuppressive agents after LT is closely associated with an increased risk for HCC recurrence. The most commonly used conventional immunosuppressive drugs include the calcineurin inhibitors tacrolimus (FK506) and mammalian target of rapamycin inhibitor rapamycin (RAPA). Compared with tacrolimus, RAPA may carry an advantage in survival benefit because of its anti-tumor effects. However, no sufficient evidence to date has proven that RAPA could increase long-term recurrence-free survival and its anti-tumor mechanism of combined therapy remains incompletely clear. In this review, we will focus on recent advances in clinical application experience and basic research results of RAPA in patients undergoing LT for HCC to further guide the clinical practice.
Collapse
Affiliation(s)
- Yang Zhao
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
| | - Yu Liu
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
| | - Lin Zhou
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
| | - Guo-Sheng Du
- Department of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital, Beijing 100853, China
| | - Qiang He
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
| |
Collapse
|
|
31
|
Lee SK, Lee SW, Jang JW, Bae SH, Choi JY, Yoon SK. Immunological Markers, Prognostic Factors and Challenges Following Curative Treatments for Hepatocellular Carcinoma. Int J Mol Sci 2021; 22:10271. [PMID: 34638613 PMCID: PMC8508906 DOI: 10.3390/ijms221910271] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 09/20/2021] [Accepted: 09/21/2021] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortalities worldwide. Patients with early-stage HCC are eligible for curative treatments, such as surgical resection, liver transplantation (LT) and percutaneous ablation. Although curative treatments provide excellent long-term survival, almost 70-80% of patients experience HCC recurrence after curative treatments. Tumor-related factors, including tumor size, number and differentiation, and underlying liver disease, are well-known risk factors for recurrence following curative therapies. Moreover, the tumor microenvironment (TME) also plays a key role in the recurrence of HCC. Many immunosuppressive mechanisms, such as an increase in regulatory T cells and myeloid-derived suppressor cells with a decrease in cytotoxic T cells, are implicated in HCC recurrence. These suppressive TMEs are also modulated by several factors and pathways, including mammalian target of rapamycin signaling, vascular endothelial growth factor, programmed cell death protein 1 and its ligand 1. Based on these mechanisms and the promising results of immune checkpoint blockers (ICBs) in advanced HCC, there have been several ongoing adjuvant studies using a single or combination of ICB following curative treatments in HCC. In this review, we strive to provide biologic and immunological markers, prognostic factors, and challenges associated with clinical outcomes after curative treatments, including resection, LT and ablation.
Collapse
Affiliation(s)
- Soon Kyu Lee
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (S.K.L.); (J.W.J.); (S.H.B.); (J.Y.C.); (S.K.Y.)
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Sung Won Lee
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (S.K.L.); (J.W.J.); (S.H.B.); (J.Y.C.); (S.K.Y.)
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Jeong Won Jang
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (S.K.L.); (J.W.J.); (S.H.B.); (J.Y.C.); (S.K.Y.)
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Si Hyun Bae
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (S.K.L.); (J.W.J.); (S.H.B.); (J.Y.C.); (S.K.Y.)
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Jong Young Choi
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (S.K.L.); (J.W.J.); (S.H.B.); (J.Y.C.); (S.K.Y.)
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Seung Kew Yoon
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (S.K.L.); (J.W.J.); (S.H.B.); (J.Y.C.); (S.K.Y.)
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| |
Collapse
|
|
32
|
Na BG, Kim YK, Hwang S, Lee KJ, Park GC, Ahn CS, Kim KH, Moon DB, Ha TY, Song GW, Jung DH, Yang H, Yoon YI, Tak E, Park YH, Lee SG. Absence of association between pretransplant serum soluble programmed death protein-1 level and prognosis following living donor liver transplantation in patients with hepatocellular carcinoma. Medicine (Baltimore) 2021; 100:e25640. [PMID: 33907121 PMCID: PMC8084037 DOI: 10.1097/md.0000000000025640] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 03/20/2021] [Accepted: 03/22/2021] [Indexed: 11/26/2022] Open
Abstract
ABSTRACT Programmed death protein 1 (PD-1) pathway is one of the most critical mechanisms in tumor biology of hepatocellular carcinoma (HCC). The study aimed to assess the prognostic influence of pretransplant serum soluble PD-1 (sPD-1) in patients undergoing liver transplantation for treatment of HCC.Data from 229 patients with HCC who underwent living donor liver transplantation between January 2010 and December 2015 were retrospectively evaluated. Stored serum samples were used to measure sPD-1 concentrations.Overall survival (OS) and disease-free survival (DFS) rates were 94.3% and 74.5% at 1 year; 78.2% and 59.2% at 3 years; and 75.4% and 55.5% at 5 years, respectively. Prognostic analysis using pretransplant serum sPD-1 with a cut-off of 93.6 μg/mL (median value of the study cohort) did not have significant prognostic influence on OS (P = .69) and DFS (P = .26). Prognostic analysis using sPD-1 with a cut-off of 300 μg/mL showed similar OS (P = .46) and marginally lower DFS (P = .070). Combination of Milan criteria and sPD-1 with a cutoff of 300 μg/mL showed similar outcomes of OS and DFS in patients within and beyond Milan criteria. Multivariate analysis revealed that only Milan criteria was an independent prognostic for OS and DFS, but pretransplant sPD1 with a cut-off of 300 μg/mL did not become a prognostic factor.The results of this study demonstrate that pretransplant serum sPD-1 did not show significant influences on post-transplant outcomes in patients with HCC. Further large-scale, multicenter studies are necessary to clarify the role of serum sPD-1 in liver transplantation recipients.
Collapse
Affiliation(s)
- Byeong-Gon Na
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation
| | - Yun Kyu Kim
- Asan Institute of Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul
| | - Shin Hwang
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation
| | - Kyung Jin Lee
- Asan Institute of Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul
| | - Gil-Chun Park
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation
| | - Chul-Soo Ahn
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation
| | - Ki-Hun Kim
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation
| | - Deok-Bog Moon
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation
| | - Tae-Yong Ha
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation
| | - Gi-Won Song
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation
| | - Dong-Hwan Jung
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation
| | - Hunji Yang
- Asan Institute of Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul
| | - Young-In Yoon
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation
| | - Eunyoung Tak
- Asan Institute of Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul
| | - Yo-Han Park
- Department of Surgery, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea
| | - Sung-Gyu Lee
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation
| |
Collapse
|
|
33
|
Minimization of Immunosuppressive Therapy Is Associated with Improved Survival of Liver Transplant Patients with Recurrent Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:cancers13071617. [PMID: 33807392 PMCID: PMC8037838 DOI: 10.3390/cancers13071617] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/23/2021] [Accepted: 03/24/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Liver transplantation is a curative treatment option for a subset of patients with hepatocellular carcinoma (HCC). However, about twenty percent of patients develop recurrence in the graft or at extrahepatic sites, which is associated with limited therapeutic options and poor survival. To date, management of the immunosuppressive regimen after recurrence and its impact on survival are unknown. In this retrospective study, we analyzed a cohort of liver recipients with HCC recurrence. Our findings indicate that reduction of immunosuppressive therapy after diagnosis of recurrence has a beneficial impact on patient survival. Therefore, we propose further investigation into the management of immunosuppressive therapy following recurrence. Abstract Introduction: Recurrence of hepatocellular carcinoma (rHCC) after liver transplantation (LT) is associated with limited survival. Therefore, identification of factors that prolong survival in these patients is of great interest. Surgical resection, radiotherapy, and transarterial chemoembolization (TACE) are established interventions to improve outcomes in these patients; however, the impact of immunosuppression is unknown. Methods: All patients diagnosed with rHCC in the follow-up after LT were identified from a database of liver recipients transplanted between 1988 and 2019 at our institution (Charité Universitätsmedizin Berlin, Germany). Based on the immunosuppressive regimen following diagnosis of rHCC and the oncological treatment approach, survival analysis was performed. Results: Among 484 patients transplanted for HCC, 112 (23.1%) developed rHCC in the follow-up. Recurrent HCC was diagnosed at a median interval of 16.0 months (range 1.0–203.0), with the majority presenting early after transplantation (63.0%, <2 years). Median survival after rHCC diagnosis was 10.6 months (0.3–228.7). Reduction of immunosuppression was associated with improved survival, particularly in patients with palliative treatment (8.4 versus 3.0 months). In addition, greater reduction of immunosuppression seemed to be associated with greater prolongation of survival. Graft rejection after reduction was uncommon (n = 7, 6.8%) and did not result in any graft loss. Patients that underwent surgical resection showed improved survival rates (median 19.5 vs. 8.7 months). Conclusion: Reduction of immunosuppressive therapy after rHCC diagnosis is associated with prolonged survival in LT patients. Therefore, reduction of immunosuppression should be an early intervention following diagnosis. In addition, surgical resection should be attempted, if technically feasible and oncologically meaningful.
Collapse
|
|
34
|
Lee S, Kim KW, Jeong WK, Jeong SY, Hwang JA, Choi JS, Lee SG, Joh JW. Liver Imaging Reporting and Data System Category on Magnetic Resonance Imaging Predicts Recurrence of Hepatocellular Carcinoma After Liver Transplantation Within the Milan Criteria: A Multicenter Study. Ann Surg Oncol 2021; 28:6782-6789. [PMID: 33751296 DOI: 10.1245/s10434-021-09772-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 02/07/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND This study was designed to investigate the association between Liver Imaging Reporting and Data System (LI-RADS) category and recurrence of hepatocellular carcinoma (HCC) after primary liver transplantation (LT) within the Milan criteria. METHODS This multicenter, retrospective study included 140 recipients who underwent living donor LT (LDLT) for treatment-naïve HCC and pretransplant contrast-enhanced magnetic resonance imaging (MRI) between 2009 and 2013. LI-RADS categories were assigned using LI-RADS version 2018. Recurrence-free survival (RFS) and associated factors were evaluated using Cox proportional hazards regression analysis, Kaplan-Meier analysis, and log-rank test. Histological grading and microvascular invasion (MVI) were analyzed on the pathologic examinations of explanted livers. RESULTS The overall 1-, 3-, 5-, and 7-year RFS rates were 95.6%, 92.6%, 90.2%, and 89.3%, respectively. In the multivariable analysis, independent predictors of recurrence included HCCs categorized as LR-M (hazard ratio [HR], 18.68; 95% confidence interval [CI], 5.79-60.23; P < 0.001) and the largest tumor size of ≥ 3 cm on MRI (HR, 4.18; 95% CI, 1.42-12.37; P = 0.010). The 5-year RFS rate was significantly lower in patients with HCCs categorized as LR-M than in those with HCCs categorized as LR-5 or 4 (LR-5/4) (36.9% vs. 95.8%, respectively; P < 0.001). HCCs categorized as LR-M exhibited significantly more MVI than HCCs categorized as LR-5/4 (57.1% vs. 17.5%, respectively; P = 0.002). CONCLUSIONS Patients with HCCs categorized as LR-M using LI-RADS version 2018 may have a worse prognosis after primary LT within the Milan criteria than those with HCCs categorized as LR-5/4.
Collapse
Affiliation(s)
- Sunyoung Lee
- Department of Radiology and Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Kyoung Won Kim
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
| | - Woo Kyoung Jeong
- Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - So Yeong Jeong
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jeong Ah Hwang
- Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jin Sub Choi
- Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sung-Gyu Lee
- Departments of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jae-Won Joh
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| |
Collapse
|
|
35
|
Lee SK, Jang JW, Nam H, Sung PS, Kim HY, Kwon JH, Lee SW, Song DS, Kim CW, Song MJ, Choi HJ, You YK, Bae SH, Choi JY, Yoon SK. Sorafenib for advanced hepatocellular carcinoma provides better prognosis after liver transplantation than without liver transplantation. Hepatol Int 2021; 15:137-145. [PMID: 33496932 DOI: 10.1007/s12072-020-10131-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 12/26/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND Although sorafenib has been used to treat advanced hepatocellular carcinoma (HCC), the efficacy of sorafenib in patients with recurrent HCCs after liver transplantation (LT) has not been compared with that in patients without LT (non-LT). METHODS Between 2008 and 2019, a total of 832 consecutive HCC patients treated with sorafenib (790 in the non-LT group and 42 in the LT group) were enrolled. The primary outcome was overall survival (OS). Secondary outcomes were time-to-progression (TTP), objective response rate (ORR) and disease control rate (DCR). Treatment outcomes were assessed by multiple subgroup analyses and propensity-score matching (PSM). RESULTS The median follow-up duration was 152.5 days. The LT group was younger and had smaller intrahepatic HCC than the non-LT group. The LT group showed significantly better OS (16.8 vs. 7.1 months, p < 0.001), TTP, ORR and DCR than the non-LT group. The superior efficacy of sorafenib in the LT group was corroborated in multiple subgroup analyses stratified by metastasis, effective sorafenib maintenance dose, or Child-Turcotte-Pugh class A. LT was identified as an independent factor for favorable OS. Intrahepatic HCC was the strongest tumor-related factor for both OS and TTP and was significantly associated with tumor response and hepatic function. Finally, subanalyses including only patients with small intrahepatic HCC or PSM modeling showed no difference in sorafenib efficacy between the LT and the non-LT groups. CONCLUSION Sorafenib provides better outcomes in the LT setting than the non-LT setting. This benefit may be associated with the smaller intrahepatic HCC coupled with preserved hepatic function in LT recipients.
Collapse
Affiliation(s)
- Soon Kyu Lee
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, #222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea
- The Catholic University Liver Research Center, Seoul, Republic of Korea
| | - Jeong Won Jang
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, #222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea.
- The Catholic University Liver Research Center, Seoul, Republic of Korea.
| | - Heechul Nam
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, #222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea
- The Catholic University Liver Research Center, Seoul, Republic of Korea
| | - Pil Soo Sung
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, #222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea
- The Catholic University Liver Research Center, Seoul, Republic of Korea
| | - Hee Yeon Kim
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, #222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea
- The Catholic University Liver Research Center, Seoul, Republic of Korea
| | - Jung Hyun Kwon
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, #222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea
- The Catholic University Liver Research Center, Seoul, Republic of Korea
| | - Sung Won Lee
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, #222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea
- The Catholic University Liver Research Center, Seoul, Republic of Korea
| | - Do Seon Song
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, #222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea
- The Catholic University Liver Research Center, Seoul, Republic of Korea
| | - Chang Wook Kim
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, #222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea
- The Catholic University Liver Research Center, Seoul, Republic of Korea
| | - Myeong Jun Song
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, #222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea
- The Catholic University Liver Research Center, Seoul, Republic of Korea
| | - Ho Joong Choi
- Department of Surgery, The Catholic University of Korea, Seoul, Republic of Korea
| | - Young Kyoung You
- Department of Surgery, The Catholic University of Korea, Seoul, Republic of Korea
| | - Si Hyun Bae
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, #222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea
- The Catholic University Liver Research Center, Seoul, Republic of Korea
| | - Jong Young Choi
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, #222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea
- The Catholic University Liver Research Center, Seoul, Republic of Korea
| | - Seung Kew Yoon
- Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, #222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea
- The Catholic University Liver Research Center, Seoul, Republic of Korea
| |
Collapse
|
|
36
|
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) is an increasingly common disease with liver transplant (LT) the best long-term therapy for early stage disease. We will review the data for assessing risk and managing recurrence for patients undergoing LT for HCC. AREAS COVERED In this review, we will provide an overview of methods of patient risk stratification in the post-transplant period, the data around surveillance for HCC recurrence, and the evidence for and against post-LT adjuvant treatment strategies. Finally, we will provide data regarding treatment options for patients with HCC recurrence after LT. Using an extensive search of original papers and society guidelines, this paper provides a comprehensive review of the data for assessing risk and managing recurrence for patients undergoing LT for HCC. EXPERT OPINION The development of multiple post-transplant prognostic scoring systems have allowed for improved assessment of recurrence risk and stratification of patients. However, the ability to translate this information into surveillance and therapeutic strategies that improve patient outcomes still have to be fully demonstrated. Post-LT immunosuppression strategies have been implemented in order to attempt to reduce this risk. Evidence-based strategies for managing recurrent HCC are evolving. We expect that with further understanding of individual patient characteristics will allow for optimal therapeutic selection.
Collapse
Affiliation(s)
- Daniel Hoffman
- Department of Surgery, University of California , San Francisco, CA, USA
| | - Neil Mehta
- Division of Gastroenterology, Department of Medicine, University of California , San Francisco, CA, USA
| |
Collapse
|
|
37
|
Posttransplant Management of Recipients Undergoing Liver Transplantation for Hepatocellular Carcinoma. Working Group Report From the ILTS Transplant Oncology Consensus Conference. Transplantation 2020; 104:1143-1149. [PMID: 32217940 DOI: 10.1097/tp.0000000000003196] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Although liver transplantation (LT) is the best treatment for patients with localized hepatocellular carcinoma (HCC), recurrence occurs in 6%-18% of patients. Several factors, particularly morphological criteria combined with dynamic parameters, known before LT modify this risk and combined in prediction models may be used to stratify patients at need of variable surveillance strategies. Additional variables though likely explain differences in recurrence rates in patients with the same pre-LT HCC status. One of these variables is possibly immunosuppression (IS). Once recurrence takes place, management is highly heterogenous. Within the International Liver Transplantation Society Consensus Conference on Liver Transplant Oncology, working group 4 aim was to analyze the data regarding posttransplant management of recipients undergoing LT for HCC. Three areas of research were considered: (1) cancer prediction models and surveillance strategies; (2) tailored IS for cancer recipients; and (3) new adjuvant therapies for HCC recurrence. Following formulation of several questions, a literature search was undertaken with abstract review followed by article retrieval and full-data extraction. The grading of recommendations assessment, development and evaluation (GRADE) system was used for evidence rating incorporating strength of recommendation and quality of evidence.
Collapse
|
|
38
|
Di Maira T, Little EC, Berenguer M. Immunosuppression in liver transplant. Best Pract Res Clin Gastroenterol 2020; 46-47:101681. [PMID: 33158467 DOI: 10.1016/j.bpg.2020.101681] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 08/31/2020] [Indexed: 02/07/2023]
Abstract
The increasing potency of immunosuppression (IS) agents resulted in significantly decreased rates of steroid resistant rejection and rejection related graft loss in liver transplantation (LT). Currently, more than two thirds of late mortality after LT is unrelated to graft function. However, the increased benefit of more potent IS drugs, coupled with the prolonged survival of transplant recipients led to longer patients exposure to these drugs and their unwanted adverse effects, creating a double-edged sword. In this article the authors describe the mechanism of action and the adverse effects of the most commonly used immunosuppressed drugs, and the most commonly used IS regimens for both induction and maintenance regimens. The balance between the ideal IS regimen to prevent rejection and the need to minimize the dose of IS drugs in order to prevent the adverse effects related to its use requires the knowledge of the science and the experience with the art of medicine. The different protocols aimed at protecting renal function and preventing the development of de novo cancer and metabolic syndrome are discussed here. The main causes of mortality late after liver transplant are associated with prolonged use of IS medications, and clear evidence exists about over-immunosuppression of recipients of liver transplant. The current status of strategies of IS minimization and withdrawal are reviewed in this article, with evaluation of its benefits and pitfalls.
Collapse
Affiliation(s)
- Tommaso Di Maira
- Liver Transplantation and Hepatology Unit, Hospital Universitari I Politècnic La Fe, Avda Fernando Abril Martorell, 106 (Torre F5), Valencia, 46026, Spain; CIBERehd, Instituto de Salud Carlos III, Madrid, 28029, Spain; ISS La Fe, Valencia, 46026, Spain.
| | - Ester Coelho Little
- University of Arizona, College of Medicine, 3110 East Minnesona Avenue, Phoenix, AZ, 85016, USA.
| | - Marina Berenguer
- Liver Transplantation and Hepatology Unit, Hospital Universitari I Politècnic La Fe, Avda Fernando Abril Martorell, 106 (Torre F5), Valencia, 46026, Spain; CIBERehd, Instituto de Salud Carlos III, Madrid, 28029, Spain; ISS La Fe, Valencia, 46026, Spain; Universidad de Valencia, Facultad de Medicina, Valencia, 46010, Spain.
| |
Collapse
|
|
39
|
Au KP, Chok KSH. Mammalian target of rapamycin inhibitors after post-transplant hepatocellular carcinoma recurrence: Is it too late? World J Gastrointest Surg 2020; 12:149-158. [PMID: 32426094 PMCID: PMC7215969 DOI: 10.4240/wjgs.v12.i4.149] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 03/21/2020] [Accepted: 03/26/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Mammalian target of rapamycin (mTOR) inhibitors have been shown to reduce the risk of tumour recurrence after liver transplantation for hepatocellular carcinoma (HCC). However, their role in established post-transplant HCC recurrence is uncertain. AIM To investigate whether mTOR inhibitor offers a survival benefit in post-transplant HCC recurrence. METHODS A retrospective study of 143 patients who developed HCC recurrence after liver transplantation was performed. They were divided into 2 groups based on whether they had received mTOR inhibitor-based immunosuppression. The primary endpoint was post-recurrence survival. RESULTS Seventy-nine (55%) patients received an mTOR inhibitor-based immunosuppressive regime, while 64 (45%) patients did not. The mTOR inhibitor group had a lower number of recurrent tumours (2 vs 5, P = 0.02) and received more active treatments including radiotherapy (39 vs 22%, P = 0.03) and targeted therapy (59 vs 23%, P < 0.001). The median post-recurrence survival was 21.0 ± 4.1 mo in the mTOR inhibitor group and 11.2 ± 2.5 mo in the control group. Multivariate Cox regression analysis confirmed that mTOR inhibitor therapy was independently associated with improved post-recurrence survival (P = 0.04, OR = 0.482, 95%CI: 0.241-0.966). The number of recurrent tumours and use of other treatment modalities did not affect survival. No survival difference was observed between mTOR inhibitor monotherapy and combination therapy with calcineurin inhibitor. CONCLUSION mTOR inhibitors prolonged survival after post-transplant HCC recurrence.
Collapse
Affiliation(s)
- Kin Pan Au
- Department of Surgery, Queen Mary Hospital, Hong Kong 999077, China
| | - Kenneth Siu Ho Chok
- Department of Surgery and State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong 999077, China
| |
Collapse
|
|
40
|
Verna EC, Patel YA, Aggarwal A, Desai AP, Frenette C, Pillai AA, Salgia R, Seetharam A, Sharma P, Sherman C, Tsoulfas G, Yao FY. Liver transplantation for hepatocellular carcinoma: Management after the transplant. Am J Transplant 2020; 20:333-347. [PMID: 31710773 DOI: 10.1111/ajt.15697] [Citation(s) in RCA: 102] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 10/03/2019] [Accepted: 10/21/2019] [Indexed: 02/05/2023]
Abstract
Hepatocellular carcinoma (HCC) is an increasingly common indication for liver transplantation (LT) in the United States and in many parts of the world. In the last decade, significant work has been done to better understand how to risk stratify LT candidates for recurrence of HCC following transplant using a combination of biomarker and imaging findings. However, despite the high frequency of HCC in the LT population, guidance regarding posttransplant management is lacking. In particular, there is no current evidence to support specific post-LT surveillance strategies, leading to significant heterogeneity in practices. In addition, there are no current recommendations regarding recurrence prevention, including immunosuppression regimen or secondary prevention with adjuvant chemotherapy. Finally, guidance on treatment of disease recurrence is also lacking and there is significant controversy about the use of immunotherapy in transplant recipients due to the risk of rejection. Thus, outcomes for patients with recurrence are poor. This paper therefore provides a comprehensive review of the current literature on post-LT management of patients with HCC and identifies gaps in our current knowledge that are in urgent need of further investigation.
Collapse
Affiliation(s)
- Elizabeth C Verna
- Center for Liver Disease and Transplantation, Columbia University, New York, New York, USA
| | - Yuval A Patel
- Division of Gastroenterology, Department of Medicine, Duke University, Durham, North Carolina, USA
| | - Avin Aggarwal
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Arizona College of Medicine, Tuscon, Arizona, USA
| | - Archita P Desai
- Division of Gastroenterology, Department of Medicine, Indiana University, Indianapolis, Indiana, USA
| | - Catherine Frenette
- Scripps Center for Organ Transplantation, Scripps Green Hospital, La Jolla, California, USA
| | - Anjana A Pillai
- Center for Liver Diseases, University of Chicago Medicine, Chicago, Illinois, USA
| | - Reena Salgia
- Department of Gastroenterology/Hepatology, Henry Ford Hospital, Detroit, Michigan, USA
| | - Anil Seetharam
- Transplant Hepatology, University of Arizona College of Medicine, Phoenix, Arizona, USA
| | - Pratima Sharma
- Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Courtney Sherman
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, California, USA
| | - Georgios Tsoulfas
- Department of Surgery, Aristotle University School of Medicine, Thessaloniki, Greece
| | - Francis Y Yao
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, California, USA
| |
Collapse
|
|
41
|
Nakano T, Chen IH, Wang CC, Chen PJ, Tseng HP, Huang KT, Hu TH, Li LC, Goto S, Cheng YF, Lin CC, Chen CL. Circulating exosomal miR-92b: Its role for cancer immunoediting and clinical value for prediction of posttransplant hepatocellular carcinoma recurrence. Am J Transplant 2019; 19:3250-3262. [PMID: 31162867 DOI: 10.1111/ajt.15490] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Revised: 05/08/2019] [Accepted: 05/11/2019] [Indexed: 01/25/2023]
Abstract
A recurrence of hepatocellular carcinoma (HCC) after living donor liver transplantation (LDLT) is one of the major concerns reflecting the higher mortality of HCC. This study aimed to explore the impact of circulating exosomes on HCC development and recurrence. One-shot transfusion of hepatoma serum to naïve rats induced liver cancer development with gradual elevation of alpha-fetoprotein (AFP), but exosome-free hepatoma serum failed to induce AFP elevation. The microarray analysis revealed miR-92b as one of the highly expressing microribonucleic acids in hepatoma serum exosomes. Overexpression of miR-92b enhanced the migration ability of liver cancer cell lines with active release of exosomal miR-92b. The hepatoma-derived exosomal miR-92b transferred to natural killer (NK) cells, resulting in the downregulation of CD69 and NK cell-mediated cytotoxicity. Furthermore, higher expression of miR-92b in serum exosomes was confirmed in HCC patients before LDLT, and its value at 1 month after LDLT was maintained at a higher level in the patients with posttransplant HCC recurrence. In summary, we demonstrated the impact of circulating exosomes on liver cancer development, partly through the suppression of CD69 on NK cells by hepatoma-derived exosomal miR-92b. The value of circulating exosomal miR-92b may predict the risk of posttransplant HCC recurrence.
Collapse
Affiliation(s)
- Toshiaki Nakano
- Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Liver Transplantation Center and Division of General Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - I-Hsuan Chen
- Liver Transplantation Center and Division of General Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Chih-Chi Wang
- Liver Transplantation Center and Division of General Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Po-Jung Chen
- Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Hui-Peng Tseng
- Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Kuang-Tzu Huang
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Tsung-Hui Hu
- Liver Transplantation Center and Division of Hepato-Gastroenterology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Lung-Chih Li
- Liver Transplantation Center and Division of Nephrology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Shigeru Goto
- Liver Transplantation Center and Division of General Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.,Nobeoka Medical Check Center, Fukuoka Institution of Occupational Health, Nobeoka, Miyazaki, Japan.,Faculty of Nursing, Department of Nursing, Josai International University, Togane, Chiba, Japan
| | - Yu-Fan Cheng
- Liver Transplantation Center and Department of Diagnostic Radiology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Chih-Che Lin
- Liver Transplantation Center and Division of General Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Chao-Long Chen
- Liver Transplantation Center and Division of General Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| |
Collapse
|
|
42
|
Lai Q, Iesari S, Finkenstedt A, Hoppe-Lotichius M, Foguenne M, Lehner K, Otto G, Lerut J. Hepatocellular carcinoma recurrence after acute liver allograft rejection treatment: A multicenter European experience. Hepatobiliary Pancreat Dis Int 2019; 18:517-524. [PMID: 31151807 DOI: 10.1016/j.hbpd.2019.05.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Accepted: 05/10/2019] [Indexed: 02/05/2023]
Abstract
BACKGROUND During the last decades, several risk factors for the recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) have been investigated. However, the impact of two important drivers of oncogenesis, namely the immunosuppression and the treatment of acute cellular rejection (ACR) have been marginally addressed. This study aimed at investigating the impact of ACR treatment on the incidence of tumor recurrence in a large European HCC-LT population. METHODS Seven hundred and eighty-one adult patients transplanted between February 1, 1985 and June 30, 2016 were retrospectively analyzed. After propensity score match, 116 patients treated for ACR using steroid boluses were compared with 115 patients who did not present any ACR or a histologic but clinical irrelevant ACR. RESULTS Steroid boluses treated patients had a 18-fold higher overall incidence of HCC recurrence than those non-treated patients (16.4% vs. 0.9%; P<0.0001). At multivariate Cox regression analysis, steroid boluses used to treat ACR were an independent risk factor for HCC recurrence (HR=14.2; 95% CI: 1.8-110.4; P = 0.010). CONCLUSIONS The decision to treat ACR as well as to reinforce immunosuppression load should be cautiously taken in view of the presented results. Prospective studies are needed to further elucidate the clinical impact of immunosuppression on HCC recurrence after transplantation.
Collapse
Affiliation(s)
- Quirino Lai
- Starzl Unit of Abdominal Transplantation, University Hospitals Saint Luc, Université catholique Louvain, Brussels, Belgium; Hepato-biliary Surgery and Liver Transplantation Unit, Sapienza University of Rome, Umberto I Hospital, Rome, Italy.
| | - Samuele Iesari
- Starzl Unit of Abdominal Transplantation, University Hospitals Saint Luc, Université catholique Louvain, Brussels, Belgium; Department of Bio-technological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - Armin Finkenstedt
- Department of Internal Medicine I, Innsbruck Medical University, Innsbruck, Austria
| | - Maria Hoppe-Lotichius
- Department of Transplantation and Hepatobiliary Surgery, University of Mainz, Mainz, Germany
| | - Maxime Foguenne
- Starzl Unit of Abdominal Transplantation, University Hospitals Saint Luc, Université catholique Louvain, Brussels, Belgium
| | - Konrad Lehner
- Department of Internal Medicine I, Innsbruck Medical University, Innsbruck, Austria
| | - Gerd Otto
- Department of Transplantation and Hepatobiliary Surgery, University of Mainz, Mainz, Germany
| | - Jan Lerut
- Starzl Unit of Abdominal Transplantation, University Hospitals Saint Luc, Université catholique Louvain, Brussels, Belgium
| |
Collapse
|
|
43
|
Suppression of Hepatocellular Carcinoma by Mycophenolic Acid in Experimental Models and in Patients. Transplantation 2019; 103:929-937. [PMID: 30747839 DOI: 10.1097/tp.0000000000002647] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND Tumor recurrence is a major complication following liver transplantation (LT) as treatment for hepatocellular carcinoma (HCC). Immunosuppression is an important risk factor for HCC recurrence, but conceivably may depend on the type of immunosuppressive medication. Mycophenolic acid (MPA) is a currently widely used immunosuppressant. This study investigated the effects of MPA on HCC. METHODS Three human HCC cell lines and organoids from mouse primary liver tumor were used as experimental models. MTT, Alamar Blue assay, cell cycle analysis, colony formation, and [3H]-thymidine assays were performed. An LT database was used for retrospective analysis of the effect of mycophenolate mofetil, the prodrug of MPA, on HCC recurrence. RESULTS With clinically achievable concentrations, MPA effectively inhibited HCC cell proliferation and single-cell colony-forming unit. In short-term experiments, MPA effectively elicited S phase arrest in HCC cell lines. In addition, the initiation and growth of liver tumor organoids were effectively inhibited by MPA. Most importantly, the use of mycophenolate mofetil in patients with HCC-related LT was significantly associated with less tumor recurrence and improved patient survival. CONCLUSIONS MPA can specifically counteract HCC growth in vitro and tumor recurrence in LT patients. These results warrant prospective clinical trials into the role of MPA-mediated immunosuppression following LT of patients with HCC.
Collapse
|
|
44
|
Cholongitas Ε, Koukoufiki A, Pipili C, Antoniadis N, Fouzas I, Haidich AB, Goulis I. Is everolimus linked to metabolic syndrome in liver transplant recipients? Indian J Gastroenterol 2019; 38:348-355. [PMID: 31515763 DOI: 10.1007/s12664-019-00971-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Accepted: 07/03/2019] [Indexed: 02/04/2023]
Abstract
BACKGROUND As the mortality rates after liver transplantation (LT) have been reduced, the attention has shifted to additional conditions which still compromise the quality of life and the survival of these patients, such as the post-LT metabolic syndrome (MS). In order to determine the prevalence and the factors associated with the post-LT MS, we carried out the present study. METHODS One hundred and six LT recipients, after completing at least 1 year follow up after LT, were included in the study. Data on clinical, laboratory parameters and immunosuppressive therapy before and after LT were recorded. MS was defined as per current diagnostic criteria. RESULTS MS was prevalent in 47.2% (50 of 106 patients) and was not associated with the LT indications and the time period after LT. Univariate analysis showed that history of diabetes mellitus before (odds ratio [OR] 3.2, 95% confidence interval [CI] 1.046-9.918, p = 0.042) and after LT (OR 6.03, 95% CI 2.18-16.67, p = 0.001), the age at the time of baseline visit (OR 1.077, 95% CI 1.033-1.124, p = 0.001) and the everolimus-based immunosuppression (OR 1.23, 95% CI 1.003-1.33, p = 0.019) were significantly associated with MS. Notably, everolimus administration was the only factor independently associated with the presence of post-LT MS (OR 1.026, 95% CI 1.004-1.047, p = 0.019). More specifically, everolimus was linked to the presence of arterial hypertension (OR 1.02, 95% CI 1.0-1.03, p = 0.05) and hyperlipidemia (OR 2.87, 95% CI 1.28-6.56, p = 0.011). CONCLUSIONS Our study demonstrated for the first time that everolimus was independently associated with post-LT MS. Nevertheless, more robust studies are required to confirm these findings.
Collapse
Affiliation(s)
- Εvangelos Cholongitas
- 4th Department of Internal Medicine, Medical School of Aristotle University, Hippokration General Hospital of Thessaloniki, Thessaloniki, Greece. .,First Department of Internal Medicine, Laiko General Hospital, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Agiou Thoma 17, 115 27, Athens, Greece.
| | - Argyro Koukoufiki
- 4th Department of Internal Medicine, Medical School of Aristotle University, Hippokration General Hospital of Thessaloniki, Thessaloniki, Greece
| | - Chrysoula Pipili
- Renal Clinical Fellow, Queen Elizabeth University Hospital, Glasgow, UK
| | - Nikolaos Antoniadis
- Department of Transplant Surgery, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Ioannis Fouzas
- Department of Transplant Surgery, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Anna-Bettina Haidich
- Department of Hygiene and Epidemiology, Medical School of Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Ioannis Goulis
- 4th Department of Internal Medicine, Medical School of Aristotle University, Hippokration General Hospital of Thessaloniki, Thessaloniki, Greece
| |
Collapse
|
|
45
|
de la Fuente S, Citores MJ, Lucena JL, Muñoz P, Cuervas-Mons V. TLR9-1486C/T polymorphism is associated with hepatocellular carcinoma recurrence after liver transplantation. Biomark Med 2019; 13:995-1004. [PMID: 31317790 DOI: 10.2217/bmm-2019-0030] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Accepted: 06/10/2019] [Indexed: 02/07/2023] Open
Abstract
Aim: To determine whether TLR9 polymorphisms are associated with tumor recurrence after liver transplantation for hepatocellular carcinoma (HCC). Patients & methods: All patients who underwent liver transplantation, and had viable HCC in the explanted liver were included. TLR9-1237C/T and -1486C/T polymorphisms were analyzed by real-time PCR and melting curves analysis. Results: 20 of 159 patients (12.6%) developed post-transplant HCC recurrence. Tumors exceeding Milan criteria, moderately-to-poorly differentiated tumors and microvascular invasion on explants, and pretransplant α-fetoprotein level (all p < 0.01) were associated with an increased risk, while TLR9-1486TT genotype was associated with a decreased risk of HCC recurrence (p = 0.03). Conclusion: TLR9-1486C/T might help to preoperatively identify patients at low risk of post-transplant HCC recurrence.
Collapse
Affiliation(s)
- Sara de la Fuente
- Liver Transplantation Unit, Hospital Universitario Puerta de Hierro-Majadahonda, Manuel de Falla 1, 28022 Majadahonda, Madrid, Spain
- Department of Internal Medicine, Hospital Universitario Puerta de Hierro-Majadahonda, Manuel de Falla 1, 28022 Majadahonda, Madrid, Spain
| | - María-Jesús Citores
- Department of Internal Medicine, Instituto de Investigación Sanitaria Puerta de Hierro-Segovia de Arana, Joaquin Rodrigo 2, 28022 Majadahonda, Madrid, Spain
| | - José-Luis Lucena
- Liver Transplantation Unit, Hospital Universitario Puerta de Hierro-Majadahonda, Manuel de Falla 1, 28022 Majadahonda, Madrid, Spain
- Department of Surgery, Hospital Universitario Puerta de Hierrdo-Majadahonda, Manuel de Falla 1, 28022 Majadahonda, Madrid, Spain
| | - Pablo Muñoz
- Department of Internal Medicine, Instituto de Investigación Sanitaria Puerta de Hierro-Segovia de Arana, Joaquin Rodrigo 2, 28022 Majadahonda, Madrid, Spain
| | - Valentín Cuervas-Mons
- Liver Transplantation Unit, Hospital Universitario Puerta de Hierro-Majadahonda, Manuel de Falla 1, 28022 Majadahonda, Madrid, Spain
- Department of Internal Medicine, Hospital Universitario Puerta de Hierro-Majadahonda, Manuel de Falla 1, 28022 Majadahonda, Madrid, Spain
- Department of Medicine, Universidad Autónoma de Madrid, Arzobispo Morcillo, s/n, 28029 Madrid, Spain
| |
Collapse
|
|
46
|
Santopaolo F, Lenci I, Milana M, Manzia TM, Baiocchi L. Liver transplantation for hepatocellular carcinoma: Where do we stand? World J Gastroenterol 2019; 25:2591-2602. [PMID: 31210712 PMCID: PMC6558441 DOI: 10.3748/wjg.v25.i21.2591] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 04/09/2019] [Accepted: 04/29/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma represents an important cause of morbidity and mortality worldwide. It is the sixth most common cancer and the fourth leading cause of cancer death. Liver transplantation is a key tool for the treatment of this disease in human therefore hepatocellular carcinoma is increasing as primary indication for grafting. Although liver transplantation represents an outstanding therapy for hepatocellular carcinoma, due to organ shortage, the careful selection and management of patients who may have a major survival benefit after grafting remains a fundamental question. In fact, only some stages of the disease seem amenable of this therapeutic option, stimulating the debate on the appropriate criteria to select candidates. In this review we focused on current criteria to select patients with hepatocellular carcinoma for liver transplantation as well as on the strategies (bridging) to avoid disease progression and exclusion from grafting during the stay on wait list. The treatments used to bring patients within acceptable criteria (down-staging), when their tumor burden exceeds the standard criteria for transplant, are also reported. Finally, we examined tumor reappearance following liver transplantation. This occurrence is estimated to be approximately 8%-20% in different studies. The possible approaches to prevent this outcome after transplant are reported with the corresponding results.
Collapse
Affiliation(s)
- Francesco Santopaolo
- Hepatology Unit, Department of Medicine, Policlinico Universitario Tor Vergata, Rome 00133, Italy
| | - Ilaria Lenci
- Hepatology Unit, Department of Medicine, Policlinico Universitario Tor Vergata, Rome 00133, Italy
| | - Martina Milana
- Hepatology Unit, Department of Medicine, Policlinico Universitario Tor Vergata, Rome 00133, Italy
| | - Tommaso Maria Manzia
- Transplant Surgery Unit, Department of Surgery, Policlinico Universitario Tor Vergata, Rome 00133, Italy
| | - Leonardo Baiocchi
- Hepatology Unit, Department of Medicine, Policlinico Universitario Tor Vergata, Rome 00133, Italy
| |
Collapse
|
|
47
|
Chou YC, Lao IH, Hsieh PL, Su YY, Mak CW, Sun DP, Sheu MJ, Kuo HT, Chen TJ, Ho CH, Kuo YT. Gadoxetic acid-enhanced magnetic resonance imaging can predict the pathologic stage of solitary hepatocellular carcinoma. World J Gastroenterol 2019; 25:2636-2649. [PMID: 31210715 PMCID: PMC6558433 DOI: 10.3748/wjg.v25.i21.2636] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Revised: 04/30/2019] [Accepted: 05/08/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Although important for determining long-term outcome, pathologic stage of hepatocellular carcinoma (HCC) is difficult to predict before surgery. Current state-of-the-art magnetic resonance imaging (MRI) using gadoxetic acid provides many imaging features that could potentially be used to classify single HCC as pT1 or pT2.
AIM To determine which gadoxetic acid-enhanced MRI (EOB-MRI) findings predict pathologic stage T2 in patients with solitary HCC (cT1).
METHODS Pre-operative EOB-MRI findings were reviewed in a retrospective cohort of patients with solitary HCC. The following imaging features were examined: Hyperintensity in unenhanced T2-weighted images, hypointensity in unenhanced T1-weighted images, arterial enhancement, corona enhancement, washout appearance, capsular appearance, hypointensity in the tumor tissue during the hepatobiliary (HB) phase, peritumoral hypointensity in the HB phase, hypointense rim in the HB phase, intratumoral fat, hyperintensity on diffusion-weighted imaging, hypointensity on apparent diffusion coefficient map, mosaic appearance, nodule-in-nodule appearance, and the margin (smooth or irregular). Surgical pathology was used as the reference method for tumor staging. Univariate and multivariate analyses were performed to identify predictors of microvascular invasion or satellite nodules.
RESULTS There were 39 (34.2%; 39 of 114) and 75 (65.8%; 75 of 114) pathological stage T2 and T1 HCCs, respectively. Large tumor size (≥ 2.3 cm) and two MRI findings, i.e., corona enhancement [odds ratio = 2.67; 95% confidence interval: 1.101-6.480] and peritumoral hypointensity in HB phase images (odds ratio = 2.203; 95% confidence interval: 0.961-5.049) were associated with high risk of pT2 HCC. The positive likelihood ratio was 6.25 (95% confidence interval: 1.788-21.845), and sensitivity of EOB-MRI for detecting pT2 HCC was 86.2% when two or three of these MRI features were present. Small tumor size and hypointense rim in the HB phase were regarded as benign features. Small HCCs with hypointense rim but not associated with aggressive features were mostly pT1 lesions (specificity, 100%).
CONCLUSION Imaging features on EOB-MRI could potentially be used to predict the pathologic stage of solitary HCC (cT1) as pT1 or pT2.
Collapse
Affiliation(s)
- Yi-Chen Chou
- Department of Medical Imaging, Chi Mei Medical Center, Tainan 710, Taiwan
| | - I-Ha Lao
- Department of Medical Imaging, Chi Mei Medical Center, Tainan 710, Taiwan
- Biomedical Sciences, National Sun Yat-sen University, Kaohsiung 804, Taiwan
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Pei-Ling Hsieh
- Department of Medical Imaging, Chi Mei Medical Center, Tainan 710, Taiwan
| | - Ying-Ying Su
- Department of Medical Imaging, Chi Mei Medical Center, Tainan 710, Taiwan
| | - Chee-Wai Mak
- Department of Medical Imaging, Chi Mei Medical Center, Tainan 710, Taiwan
| | - Ding-Ping Sun
- Department of Surgery, Chi Mei Medical Center, Tainan 710, Taiwan
- Department of Food Science and Technology, Chia Nan University of Pharmacy and Science, Tainan 717, Taiwan
| | - Ming-Jen Sheu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chi Mei Medical Center, Tainan 710, Taiwan
- Department of Medicinal Chemistry, Chia Nan University of Pharmacy and Science, Tainan 717, Taiwan
| | - Hsing-Tao Kuo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chi Mei Medical Center, Tainan 710, Taiwan
- Department of Senior Citizen Service Management, Chia Nan University of Pharmacy and Science, Tainan 717, Taiwan
| | - Tzu-Ju Chen
- Department of Pathology, Chi-Mei Medical Center, Tainan 710, Taiwan
- Department of Optometry, Chung Hwa University of Medical Technology, Tainan 717, Taiwan
- Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung 804, Taiwan
| | - Chung-Han Ho
- Department of Medical Research, Chi-Mei Medical Center, Tainan 710, Taiwan
- Department of Hospital and Health Care Administration, Chia Nan University of Pharmacy and Science, Tainan 717, Taiwan
| | - Yu-Ting Kuo
- Department of Medical Imaging, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
- Department of Radiology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| |
Collapse
|
|
48
|
Nitta H, Allard MA, Sebagh M, Karam V, Ciacio O, Pittau G, Vibert E, Sa Cunha A, Cherqui D, Castaing D, Bismuth H, Guettier C, Samuel D, Baba H, Adam R. Predictive model for microvascular invasion of hepatocellular carcinoma among candidates for either hepatic resection or liver transplantation. Surgery 2019; 165:1168-1175. [PMID: 30878140 DOI: 10.1016/j.surg.2019.01.012] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Revised: 01/05/2019] [Accepted: 01/21/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND Microvascular invasion is the strongest prognostic factor of survival in patients with hepatocellular carcinoma. We therefore developed a predictive model for microvascular invasion of hepatocellular carcinoma to help guide treatment strategies in patients scheduled for either hepatic resection or liver transplantation. METHODS Patients with hepatocellular carcinoma who underwent hepatic resection or liver transplantation from 1994 to 2016 were divided into training and validation cohorts. A predictive model for microvascular invasion was developed based on microvascular invasion risk factors in the training cohort and validated in the validation cohort. RESULTS A total of 910 patients (425 having received hepatic resection, 485 having received liver transplantation) were included in the training (n = 637) and validation (n = 273) cohorts. Multivariate analysis identified α-fetoprotein ≥100 ng/mL (relative risk 3.05, P < .0001), tumor size ≥40 mm (relative risk 1.98, P = .0002), nonboundary hepatocellular carcinoma type (relative risk 1.91, P = .001), neutrophil-to-lymphocyte ratio (relative risk 1.86, P = .002), and aspartate aminotransferase (relative risk 1.53, P = .02) as associated with microvascular invasion. The estimated probability of microvascular invasion ranged from 17.0% in patients with none of these factors to 86.9% in the presence of all factors. This model achieved a C-index of 0.732 in the validation cohort. The 5-year overall survival of patients with ≥50% probability of microvascular invasion was poorer than that of patients with <50% probability (hepatic resection; 39.1% vs 61.2%, P < .0001, liver transplantation; 5-year overall survival, 54.8% vs 79.0%, P = .05). CONCLUSION This model developed from preoperative data allows reliable prediction of microvascular invasion in candidates for either hepatic resection or liver transplantation.
Collapse
Affiliation(s)
- Hidetoshi Nitta
- Centre Hépato-Biliaire, AP-HP, Hôpital Paul Brousse, Université Paris-Sud, Inserm U 935 and U 1193, Villejuif, France; Departement of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Japan.
| | - Marc-Antoine Allard
- Centre Hépato-Biliaire, AP-HP, Hôpital Paul Brousse, Université Paris-Sud, Inserm U 935 and U 1193, Villejuif, France
| | - Mylène Sebagh
- Departement of Pathology, Hôpital Paul Brousse, Assistance Publique-Hôpitaux de Paris, Villejuif, France
| | - Vincent Karam
- Centre Hépato-Biliaire, AP-HP, Hôpital Paul Brousse, Université Paris-Sud, Inserm U 935 and U 1193, Villejuif, France
| | - Oriana Ciacio
- Centre Hépato-Biliaire, AP-HP, Hôpital Paul Brousse, Université Paris-Sud, Inserm U 935 and U 1193, Villejuif, France
| | - Gabriella Pittau
- Centre Hépato-Biliaire, AP-HP, Hôpital Paul Brousse, Université Paris-Sud, Inserm U 935 and U 1193, Villejuif, France
| | - Eric Vibert
- Centre Hépato-Biliaire, AP-HP, Hôpital Paul Brousse, Université Paris-Sud, Inserm U 935 and U 1193, Villejuif, France
| | - Antonio Sa Cunha
- Centre Hépato-Biliaire, AP-HP, Hôpital Paul Brousse, Université Paris-Sud, Inserm U 935 and U 1193, Villejuif, France
| | - Daniel Cherqui
- Centre Hépato-Biliaire, AP-HP, Hôpital Paul Brousse, Université Paris-Sud, Inserm U 935 and U 1193, Villejuif, France
| | - Denis Castaing
- Centre Hépato-Biliaire, AP-HP, Hôpital Paul Brousse, Université Paris-Sud, Inserm U 935 and U 1193, Villejuif, France
| | - Henri Bismuth
- Centre Hépato-Biliaire, AP-HP, Hôpital Paul Brousse, Université Paris-Sud, Inserm U 935 and U 1193, Villejuif, France
| | - Catherine Guettier
- Departement of Pathology, Bicêtre University Hospital, Université Paris-Sud, Le Kremlin-Bicêtre, Ile-de-France, France
| | - Didier Samuel
- Centre Hépato-Biliaire, AP-HP, Hôpital Paul Brousse, Université Paris-Sud, Inserm U 935 and U 1193, Villejuif, France
| | - Hideo Baba
- Departement of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Japan
| | - René Adam
- Centre Hépato-Biliaire, AP-HP, Hôpital Paul Brousse, Université Paris-Sud, Inserm U 935 and U 1193, Villejuif, France
| |
Collapse
|
|
49
|
Tan PS, Muthiah MD, Koh T, Teoh YL, Chan A, Kow A, Zheng Q, Kwon CHD, Lee GH, Lesmana CRA, de Villa V, Fung J, Lim K. Asian Liver Transplant Network Clinical Guidelines on Immunosuppression in Liver Transplantation. Transplantation 2019; 103:470-480. [PMID: 30422953 DOI: 10.1097/tp.0000000000002532] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Most management guidelines and much of the available clinical trial evidence for immunosuppressants in liver transplantation (LT) pertain to Western practice. While evidence from Western studies may not translate to Asian settings, there is a paucity of Asian randomized controlled trials of immunosuppression in liver recipients. Nonetheless, there are notable differences in the indications and procedures for LT between Western and Asian settings. The Asian Liver Transplant Network held its inaugural meeting in Singapore in November 2016 and aimed to provide an Asian perspective on aspects of immunosuppression following LT. Because of their importance to outcome following LT, the meeting focused on (1) reducing the impact of renal toxicity, (2) hepatocellular carcinoma recurrence, and (3) nonadherence with immunosuppressant therapy.
Collapse
Affiliation(s)
- Poh Seng Tan
- Division of Gastroenterology and Hepatology, National University Hospital, National University Health System, Singapore
- National University Centre for Organ Transplantation, National University Hospital, National University Health System, Singapore
| | - Mark D Muthiah
- Division of Gastroenterology and Hepatology, National University Hospital, National University Health System, Singapore
- National University Centre for Organ Transplantation, National University Hospital, National University Health System, Singapore
| | - Tsingyi Koh
- Department of Pharmacy, National University Hospital, National University Health System, Singapore
| | | | - Albert Chan
- Division of Hepatobiliary and Pancreatic Surgery, and Liver Transplantation, Department of Surgery, Queen Mary Hospital, Hong Kong
| | - Alfred Kow
- National University Centre for Organ Transplantation, National University Hospital, National University Health System, Singapore
- Division of Hepatopancreatobiliary Surgery and Division of Liver Transplantation, Department of Surgery, University Surgical Cluster, National University Health System, National University of Singapore, Singapore
| | - Qishi Zheng
- Singapore Clinical Research Institute, Singapore
| | - Choon Hyuck David Kwon
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Guan Huei Lee
- Division of Gastroenterology and Hepatology, National University Hospital, National University Health System, Singapore
- National University Centre for Organ Transplantation, National University Hospital, National University Health System, Singapore
| | - Cosmas Rinaldi A Lesmana
- Hepatobiliary Division, Department of Internal Medicine, Cipto Mangunkusumo Hospital, Universitas Indonesia, Jakarta, Indonesia
- Digestive Disease & GI Oncology Center, Medistra Hospital, Jakarta, Indonesia
| | - Vanessa de Villa
- Department of Surgery and Center for Liver Disease Management and Transplantation, The Medical City, Pasig City, Philippines
| | - James Fung
- Department of Medicine, Queen Mary Hospital, Hong Kong
| | - Kieron Lim
- Division of Gastroenterology and Hepatology, National University Hospital, National University Health System, Singapore
- National University Centre for Organ Transplantation, National University Hospital, National University Health System, Singapore
| |
Collapse
|
|
50
|
Lou LL, Zhang Y, Huang X, Zhang LX, Ji HF, Li X, Guo XL. Solitary nasopharynx metastasis from hepatocellular carcinoma after liver transplantation: A case report. Medicine (Baltimore) 2019; 98:e14368. [PMID: 30762736 PMCID: PMC6408045 DOI: 10.1097/md.0000000000014368] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
RATIONALE Hepatocellular carcinoma (HCC) is the fifth most common cancer and third leading cause of cancer-related deaths worldwide. Nasopharyngeal metastasis of hepatocellular carcinoma is very rare. This is the first report of posttransplantation nasopharyngeal metastasis. PATIENT CONCERNS A 45-year-old man with a history of hepatitis B related hepatocellular carcinoma (HCC) in the right segment of the liver received an orthotopic liver transplant. Two year after the transplantation, he suffered from severe headache, and head contrast enhanced CT scans did not show clues for brain or skull metastasis. Then he developed hoarseness and dysphagia. DIAGNOSIS The nasopharyngeal cancer was confirmed to be metastatic tumor from liver histologically according to biopsy. INTERVENTIONS This patient underwent radiotherapy (RT) of the metastatic nasopharyngeal tumor, and there was significant symptomatic relief. OUTCOMES The patient died 3 months after nasopharyngeal metastasis was diagnosed. LESSONS Recurrence of hepatocellular carcinoma with metastasis of nasopharyngeal carcinoma after liver transplantation is rare, but the prognosis is very poor. Close follow-up of patients should be paid attention to prevent the occurrence of such diseases.
Collapse
Affiliation(s)
- Li-Li Lou
- Department of Hepatology, The First Hospital of Jilin University, Chang Chun 130021, China
| | | | | | | | | | | | | |
Collapse
|