|
1
|
Cillo U, Carraro A, Avolio AW, Cescon M, Di Benedetto F, Giannelli V, Magistri P, Nicolini D, Vivarelli M, Lanari J. Immunosuppression in liver transplant oncology: position paper of the Italian Board of Experts in Liver Transplantation (I-BELT). Updates Surg 2024; 76:725-741. [PMID: 38713396 DOI: 10.1007/s13304-024-01845-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 07/31/2023] [Indexed: 05/08/2024]
Abstract
Liver transplant oncology (TO) represents an area of increasing clinical and scientific interest including a heterogeneous group of clinical-pathological settings. Immunosuppressive management after LT is a key factor relevantly impacting result. However, disease-related guidance is still lacking, and many open questions remain in the field. Based on such a substantial lack of solid evidences, the Italian Board of Experts in Liver Transplantation (I-BELT) (a working group including representatives of all national transplant centers), unprecedently promoted a methodologically sound consensus conference on the topic, based on the GRADE approach. The group final recommendations are herein presented and commented. The 18 PICOs and Statements and their levels of evidence and grades of recommendation are reported and grouped into seven areas: (1) risk stratification by histopathological and bio-molecular parameters and role of mTORi post-LT; (2) steroids and HCC recurrence; (3) management of immunosuppression when HCC recurs after LT; (4) mTORi monotherapy; (5) machine perfusion and HCC recurrence after LT; (6) physiopathology of tumor-infiltrating lymphocytes and immunosuppression, the role of inflammation; (7) immunotherapy in liver transplanted patients. The interest in mammalian targets of rapamycin inhibitors (mTORi), for steroid avoidance and the need for a reduction to CNI exposure emerged from the consensus process. A selected list of unmet needs prompting further investigations have also been developed. The so far heterogeneous and granular approach to immunosuppression in oncologic patients deserves greater efforts for a more standardized therapeutic response to the different clinical scenarios. This consensus process makes a first unprecedented step in this direction, to be developed on a larger scale.
Collapse
Affiliation(s)
- Umberto Cillo
- Department of Surgical, Oncological and Gastroenterological Sciences, General Surgery 2 Hepato-Pancreato-Biliary Surgery and Liver Transplantation, Padua University Hospital, Via Giustiniani 2, 34128, Padua, PD, Italy.
| | - Amedeo Carraro
- Liver Transplant Unit, Department of Surgery and Oncology, University Hospital Trust of Verona, Verona, Italy
| | - Alfonso W Avolio
- Department of General Surgery and Liver Transplantation, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Matteo Cescon
- General Surgery and Transplantation Unit, Department of Medical and Surgical Sciences, Azienda Ospedaliero-Universitaria-Policlinico S.Orsola-Malpighi, Bologna, Italy
| | - Fabrizio Di Benedetto
- Hepatopancreatobiliary Surgery and Liver Transplantation Unit, University of Modena and Reggio Emilia, Modena, Italy
| | - Valerio Giannelli
- Liver Unit, Department of Liver Transplant, Azienda Ospedaliera San Camillo Forlanini, Rome, Italy
| | - Paolo Magistri
- Hepatopancreatobiliary Surgery and Liver Transplantation Unit, University of Modena and Reggio Emilia, Modena, Italy
| | - Daniele Nicolini
- Hepatobiliary and Abdominal Transplantation Surgery, Department of Experimental and Clinical Medicine, Riuniti Hospital, Polytechnic University of Marche, Ancona, Italy
| | - Marco Vivarelli
- Hepatobiliary and Abdominal Transplantation Surgery, Department of Experimental and Clinical Medicine, Riuniti Hospital, Polytechnic University of Marche, Ancona, Italy
| | - Jacopo Lanari
- Department of Surgical, Oncological and Gastroenterological Sciences, General Surgery 2 Hepato-Pancreato-Biliary Surgery and Liver Transplantation, Padua University Hospital, Via Giustiniani 2, 34128, Padua, PD, Italy
| |
Collapse
|
|
2
|
Zhang X, Cai L, Fang J, Chen F, Pan F, Zhang K, Huang Q, Huang Y, Li D, Lv L, Chen M, Yan R, Lai Y, Peng Y, Wu Z. Efficacy and safety of transarterial chemoembolization plus sorafenib in patients with recurrent hepatocellular carcinoma after liver transplantation. Front Oncol 2023; 12:1101351. [PMID: 36713526 PMCID: PMC9880524 DOI: 10.3389/fonc.2022.1101351] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 12/20/2022] [Indexed: 01/15/2023] Open
Abstract
Objectives To explore the benefit and safety of transarterial chemoembolization (TACE) in combination with sorafenib in patients with recurrent hepatocellular carcinoma (HCC) after orthotopic liver transplantation (OLT). Methods In this multi-center retrospective study, 106 patients with recurrent HCC after OLT were included. Fifty-two patients were treated with TACE plus sorafenib (TS group) and 54 were treated with TACE alone (TC group). Primary and secondary endpoints including overall survival (OS) and progression-free survival (PFS), and safety were assessed. Results The median OS (17 vs 10 months, P=0.035) and PFS (12 vs 6 months, P=0.004) in the TS group were longer than those in the TC group. On multivariate analysis, BCLC stage (HR [hazard ratio]=0.73 [95% CI, 0.27-0.99], P=0.036) and sorafenib medication (HR=2.26 [95% CI, 1.35-3.69], P=0.01) were identified as independent prognostic risk factors for OS. No severe adverse events related to sorafenib were noted in the TS group. Four patients discontinued sorafenib due to intolerance. Conclusion TACE in combination with sorafenib is a feasible regimen to improve the survival with mild toxicity in patients with recurrent HCC after OLT.
Collapse
Affiliation(s)
- Xia Zhang
- Department of Hepatobiliary Disease, the 900th Hospital of Joint Logistics Support Force, Fujian Medical University, Fuzhou, China
| | - Lirong Cai
- Department of Hepatobiliary Disease, the 900th Hospital of Joint Logistics Support Force, Fujian Medical University, Fuzhou, China
| | - Jian Fang
- Department of Hepatobiliary Disease, The Third People’s Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Fengsui Chen
- Department of Hepatobiliary Disease, the 900th Hospital of Joint Logistics Support Force, Fujian Medical University, Fuzhou, China
| | - Fan Pan
- Department of Hepatobiliary Surgery, the 900th Hospital of Joint Logistics Support Force, Fujian Medical University, Fuzhou, China
| | - Kun Zhang
- Department of Hepatobiliary Surgery, Xiang’an Hospital, Xiamen University, Xiamen, China
| | - Qian Huang
- Department of Hepatobiliary Surgery, the 900th Hospital of Joint Logistics Support Force, Fujian Medical University, Fuzhou, China
| | - Yuju Huang
- Department of Hepatobiliary Disease, the 900th Hospital of Joint Logistics Support Force, Fujian Medical University, Fuzhou, China
| | - Dongliang Li
- Department of Hepatobiliary Disease, the 900th Hospital of Joint Logistics Support Force, Fujian Medical University, Fuzhou, China
| | - Lizhi Lv
- Department of Hepatobiliary Surgery, the 900th Hospital of Joint Logistics Support Force, Fujian Medical University, Fuzhou, China
| | - Man Chen
- Department of Hepatobiliary Disease, the 900th Hospital of Joint Logistics Support Force, Fujian Medical University, Fuzhou, China
| | - Ruiying Yan
- Department of Hepatobiliary Disease, the 900th Hospital of Joint Logistics Support Force, Fujian Medical University, Fuzhou, China
| | - Yanhua Lai
- Department of Transplantation, People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, China,*Correspondence: Zhixian Wu, ; Yonghai Peng, ; Yanhua Lai,
| | - Yonghai Peng
- Department of Oncology, the 900th Hospital of Joint Logistics Support Force, Fujian Medica University, Fuzhou, China,*Correspondence: Zhixian Wu, ; Yonghai Peng, ; Yanhua Lai,
| | - Zhixian Wu
- Department of Hepatobiliary Disease, the 900th Hospital of Joint Logistics Support Force, Fujian Medical University, Fuzhou, China,*Correspondence: Zhixian Wu, ; Yonghai Peng, ; Yanhua Lai,
| |
Collapse
|
|
3
|
Sposito C, Citterio D, Virdis M, Battiston C, Droz Dit Busset M, Flores M, Mazzaferro V. Therapeutic strategies for post-transplant recurrence of hepatocellular carcinoma. World J Gastroenterol 2022; 28:4929-4942. [PMID: 36160651 PMCID: PMC9494935 DOI: 10.3748/wjg.v28.i34.4929] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 03/05/2022] [Accepted: 07/26/2022] [Indexed: 02/06/2023] Open
Abstract
Despite stringent selection criteria, hepatocellular carcinoma recurrence after liver transplantation (LT) still occurs in up to 20% of cases, mostly within the first 2–3 years. No adjuvant treatments to prevent such an occurrence have been developed so far. However, a balanced use of immunosuppression with minimal dose of calcineurin inhibitors and possible addition of mammalian target of rapamycin inhibitors is strongly advisable. Moreover, several pre- and post-transplant predictors of recurrence have been identified and may help determine the frequency and duration of post-transplant follow-up. When recurrence occurs, the outcomes are poor with a median survival of 12 mo according to most retrospective studies. The factor that most impacts survival after recurrence is timing (within 1–2 years from LT according to different authors). Several therapeutic options may be chosen in case of recurrence, according to timing and disease presentation. Surgical treatment seems to provide a survival benefit, especially in case of late recurrence, while the benefit of locoregional treatments has been suggested only in small retrospective studies. When systemic treatment is indicated, sorafenib has been proved safe and effective, while only few data are available for lenvatinib and regorafenib in second line. The use of immune checkpoint inhibitors is controversial in this setting, given the safety warnings for the risk of acute rejection.
Collapse
Affiliation(s)
- Carlo Sposito
- HPB Surgery, Hepatology and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan 20133, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan 20100, Italy
| | - Davide Citterio
- HPB Surgery, Hepatology and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan 20133, Italy
| | - Matteo Virdis
- HPB Surgery, Hepatology and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan 20133, Italy
| | - Carlo Battiston
- HPB Surgery, Hepatology and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan 20133, Italy
| | - Michele Droz Dit Busset
- HPB Surgery, Hepatology and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan 20133, Italy
| | - Maria Flores
- HPB Surgery, Hepatology and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan 20133, Italy
| | - Vincenzo Mazzaferro
- HPB Surgery, Hepatology and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan 20133, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan 20100, Italy
| |
Collapse
|
|
4
|
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: 21] [Impact Index Per Article: 5.3] [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
|
|
5
|
Long-term outcomes of deceased donor liver transplantation in hepatocellular carcinoma patients with portal vein tumor thrombus: A multicenter study. Eur J Surg Oncol 2021; 48:121-132. [PMID: 34456082 DOI: 10.1016/j.ejso.2021.08.014] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 07/25/2021] [Accepted: 08/09/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND The incidence of portal vein tumor thrombus (PVTT) has been reported to be as high as approximately 10%-40% in patients with hepatocellular carcinoma (HCC). The long-term prognosis of deceased donor liver transplantation (DDLT) in HCC patients with PVTT remains unknown. METHODS Data of 961 HCC patients who underwent DDLT between 2015 and 2018 in six centers were analyzed. Based on the Milan criteria (MC) and Cheng's classification of PVTT, the patients were divided into 4 groups: within MC, beyond MC without PVTT, type 1 PVTT, and type 2 PVTT groups. RESULTS 489 (50.9%) were within the MC, 296 (30.8%) beyond the MC but without PVTT, 83 (8.6%) type 1 PVTT, and 93 (9.7%) type 2 PVTT. Kaplan-Meier analysis showed that type 1 or 2 PVTT patients with alpha-fetoprotein (AFP) ≤ 100 ng/mL had overall survival (OS) similar to that of patients within the MC (P = 0.957), and superior OS (P = 0.003 and 0.009) and recurrence-free survival (RFS) (P = 0.038 and <0.001) than those of patients beyond the MC and PVTT patients with AFP > 100 ng/mL. Multivariable Cox-regression analysis identified type 1 and 2 PVTT to be independent risk factor for RFS [hazard ratio (HR) 1.523 95% confidence interval (CI) 1.162-1.997, P = 0.002], but not for OS (HR 1.283, 95%CI 0.922-1.786, P = 0.139). CONCLUSION HCC patients with type 1 or 2 PVTT may be acceptable candidates for DDLT. To achieve better outcomes, preoperative AFP levels should be seriously considered when selecting patients with PVTT for DDLT.
Collapse
|
|
6
|
Nitta H, Younès A, El-Domiaty N, Karam V, Sobesky R, Vibert E, Coilly A, Maria Antonini T, De Martin E, Cherqui D, Baba H, Rosmorduc O, Adam R, Samuel D, Saliba F. High trough levels of everolimus combined to sorafenib improve patients survival after hepatocellular carcinoma recurrence in liver transplant recipients. Transpl Int 2021; 34:1293-1305. [PMID: 33932239 DOI: 10.1111/tri.13897] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 03/19/2021] [Accepted: 04/21/2021] [Indexed: 12/21/2022]
Abstract
Recurrence of hepatocellular carcinoma (HCC) following liver transplantation (LT) occurs in 10%-20% of patients transplanted for HCC. The treatment of HCC recurrence after LT remains a challenge. Consecutive patients who underwent LT for HCC between 2005 and 2015 at our center were recruited. Characteristics of patients with recurrence, modalities of treatment and outcome were collected retrospectively. Patient survival was analyzed according to HCC recurrence therapeutic strategy. Among 306 transplanted patients, 43 patients (14.1%) developed recurrence with a median survival time after recurrence of 10.9 months (95%CI: 6.6-18.6). Survival of patients treated with Sorafenib (SOR) and everolimus (EVL) (n = 19) was significantly better than that of the group treated with other strategies (n = 24) (P = 0.001). Multivariable analysis demonstrated that SOR plus EVL therapy and absence of dissemination at diagnosis of recurrence were independent predictive factors of prolonged survival after recurrence. Among the patients who treated with EVL, survival of patients with controlled EVL blood trough levels ≥5 ng/ml was significantly better compared to those with EVL trough levels <5 ng/ml (P = 0.021). Combination therapy of sorafenib and everolimus was an independent predictor for better survival after HCC recurrence. Patients with controlled everolimus trough level ≥5 ng/ml might get the best survival benefit.
Collapse
Affiliation(s)
- Hidetoshi Nitta
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Inserm UMR-S 1193, Université Paris- Saclay, Villejuif, France
| | - Aline Younès
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Inserm UMR-S 1193, Université Paris- Saclay, Villejuif, France
| | - Nada El-Domiaty
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Inserm UMR-S 1193, Université Paris- Saclay, Villejuif, France.,Tropical Medicine Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Vincent Karam
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Inserm UMR-S 1193, Université Paris- Saclay, Villejuif, France
| | - Rodolphe Sobesky
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Inserm UMR-S 1193, Université Paris- Saclay, Villejuif, France
| | - Eric Vibert
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Inserm UMR-S 1193, Université Paris- Saclay, Villejuif, France
| | - Audrey Coilly
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Inserm UMR-S 1193, Université Paris- Saclay, Villejuif, France
| | - Teresa Maria Antonini
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Inserm UMR-S 1193, Université Paris- Saclay, Villejuif, France
| | - Eleonora De Martin
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Inserm UMR-S 1193, Université Paris- Saclay, Villejuif, France
| | - Daniel Cherqui
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Inserm UMR-S 1193, Université Paris- Saclay, Villejuif, France
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Olivier Rosmorduc
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Inserm UMR-S 1193, Université Paris- Saclay, Villejuif, France
| | - René Adam
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Inserm UMR-S 1193, Université Paris- Saclay, Villejuif, France
| | - Didier Samuel
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Inserm UMR-S 1193, Université Paris- Saclay, Villejuif, France
| | - Faouzi Saliba
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Inserm UMR-S 1193, Université Paris- Saclay, Villejuif, France
| |
Collapse
|
|
7
|
Li H, Yang Z, Li R, Lu S, Lu W. Regorafenib Combined With Sirolimus Achieves Successful Treatment of Diffuse Double Lung Metastasis After Liver Transplantation in Giant Liver Cancer Beyond Transplantation Criteria: A Case Report. Transplant Proc 2020; 52:634-637. [PMID: 32035675 DOI: 10.1016/j.transproceed.2019.12.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2019] [Revised: 11/25/2019] [Accepted: 12/15/2019] [Indexed: 02/06/2023]
Abstract
The treatment of hepatocellular carcinoma after liver transplantation (LT) is controversial because of its high recurrence rate and low survival rate. Here, we report a case of early diffuse bilateral lung metastasis after LT beyond the Milan transplantation criteria (d = 18 cm, α-fetoprotein >24,000 ng/mL) that successfully achieved 1-year tumor-free remission survival with sirolimus combined with regorafenib. The donor source of the liver is legal, and this study followed the guidelines of the Helsinki Congress in this LT. To the best of our knowledge, this is the first report of the use of regorafenib as a first-line agent combined with sirolimus to treat recurrent hepatocellular carcinoma after LT, and this case expands the indications for LT.
Collapse
Affiliation(s)
- Huixin Li
- Department of Hepatobiliary Surgery, First Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China
| | - Zhanyu Yang
- Department of Hepatobiliary Surgery, First Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China
| | - Ruofan Li
- Department of Hepatobiliary Surgery, First Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China
| | - Shichun Lu
- Department of Hepatobiliary Surgery, First Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China
| | - Wenping Lu
- Department of Hepatobiliary Surgery, First Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China.
| |
Collapse
|
|
8
|
Fang J, Pan L, Gu QX, Juengpanich S, Zheng JH, Tong CH, Wang ZY, Nan JJ, Wang YF. Scientometric analysis of mTOR signaling pathway in liver disease. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:93. [PMID: 32175386 DOI: 10.21037/atm.2019.12.110] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Background The mTOR pathway is vital for homeostasis, metabolism, cancer transplantation and regeneration in the liver. The aim of this study is to use a bibliometric method to reveal current research hotspots and promising future trends in mTOR signaling in liver diseases. Methods Publications were searched and downloaded from the Web of Science Core Collection (WOSCC) Database. CiteSpace, Carrot2, and VOSviewer programs were utilized to analyze the contribution of various countries/regions, institutes, and authors; and to reveal research hotspots and promising future trends in this research area. Results Until May 21, 2019, a total of 2,232 papers regarding mTOR signaling pathway in liver disease were included, and each paper was cited 23.21 times on average. The most active country was the USA. 5 landmark articles with centrality and burstiness were determined by co-citation analysis. Research hotspots included "liver transplantation" "hepatic stellate cell proliferation" "NAFLD" "therapy of HCC". Moreover, six key clusters were discovered during the procedure of "clustering", including "liver transplantation" "protein synthesis" "mTOR inhibitor" "following early cyclosporine withdrawal" "srebp-1 activation", and "hepatocellular cancer". Conclusions Various scientific methods were applied to reveal scientific productivity, collaboration, and research hotspots in the mTOR signaling pathway in liver disease. Liver transplantation, hepatic stellate cell proliferation, non-alcoholic fatty liver disease (NAFLD), therapy of hepatocellular carcinoma (HCC), cell growth and autophagy, are research hotspots and are likely to be promising in the next few years. Further studies in this field are needed.
Collapse
Affiliation(s)
- Jing Fang
- Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.,Zhejiang Province Medical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases, Hangzhou 310016, China.,Institute of Minimally Invasive Surgery of Zhejiang University, Hangzhou 310016, China
| | - Long Pan
- Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.,Zhejiang Province Medical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases, Hangzhou 310016, China.,Institute of Minimally Invasive Surgery of Zhejiang University, Hangzhou 310016, China
| | - Qiu-Xia Gu
- Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.,Zhejiang Province Medical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases, Hangzhou 310016, China.,Institute of Minimally Invasive Surgery of Zhejiang University, Hangzhou 310016, China
| | - Sarun Juengpanich
- Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.,Zhejiang Province Medical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases, Hangzhou 310016, China.,Institute of Minimally Invasive Surgery of Zhejiang University, Hangzhou 310016, China
| | - Jun-Hao Zheng
- Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.,Zhejiang Province Medical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases, Hangzhou 310016, China.,Institute of Minimally Invasive Surgery of Zhejiang University, Hangzhou 310016, China
| | - Chen-Hao Tong
- Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.,Zhejiang Province Medical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases, Hangzhou 310016, China.,Department of General Surgery, Shaoxing People's Hospital, Zhejiang University School of Medicine, Shaoxing 312000, China
| | - Zi-Yuan Wang
- Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.,Zhejiang Province Medical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases, Hangzhou 310016, China
| | - Jun-Jie Nan
- Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.,Zhejiang Province Medical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases, Hangzhou 310016, China
| | - Yi-Fan Wang
- Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.,Zhejiang Province Medical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases, Hangzhou 310016, China.,Institute of Minimally Invasive Surgery of Zhejiang University, Hangzhou 310016, China
| |
Collapse
|
|
9
|
Hong SK, Lee K, Yoon KC, Kim H, Ahn S, Kim H, Lee J, Cho J, Yi N, Suh K. Different prognostic factors and strategies for early and late recurrence after adult living donor liver transplantation for hepatocellular carcinoma. Clin Transplant 2019; 33:e13703. [DOI: 10.1111/ctr.13703] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 08/23/2019] [Indexed: 12/15/2022]
Affiliation(s)
- Suk Kyun Hong
- Department of Surgery Seoul National University College of Medicine Seoul Korea
| | - Kwang‐Woong Lee
- Department of Surgery Seoul National University College of Medicine Seoul Korea
| | - Kyung Chul Yoon
- Department of Surgery Division of HBP Surgery & Liver Transplantation Anam Hospital Korea University College of Medicine Seoul Korea
| | - Hyo‐Sin Kim
- Department of Surgery Chonnam National University Medical School and Hospital Gwangju Korea
| | - Sung‐Woo Ahn
- Department of Surgery Chonbuk National University College of Medicine Jeonju Korea
| | - Hyeyoung Kim
- Department of Surgery Eulji University Hospital Eulji University College of Medicine Daejeon Korea
| | - Jeong‐Moo Lee
- Department of Surgery Seoul National University College of Medicine Seoul Korea
| | - Jae‐Hyung Cho
- Department of Surgery Seoul National University College of Medicine Seoul Korea
| | - Nam‐Joon Yi
- Department of Surgery Seoul National University College of Medicine Seoul Korea
| | - Kyung‐Suk Suh
- Department of Surgery Seoul National University College of Medicine Seoul Korea
| |
Collapse
|
|
10
|
Wang X, Wu F, Li G, Zhang N, Song X, Zheng Y, Gong C, Han B, He G. Lipid-modified cell-penetrating peptide-based self-assembly micelles for co-delivery of narciclasine and siULK1 in hepatocellular carcinoma therapy. Acta Biomater 2018; 74:414-429. [PMID: 29787814 DOI: 10.1016/j.actbio.2018.05.030] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Revised: 05/05/2018] [Accepted: 05/18/2018] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer, and one therapeutic approach is to target both the AMPK and autophagy pathways in order to synergistically promote programmed cell death. Here, a series of amphiphilic, lipid-modified cell-penetrating peptides were synthesized and allowed to self-assemble into micelles loaded with the AMPK activator narciclasine (Narc) and short interfering RNA targeting the unc-51-like kinase 1 (siULK1). The size of these micelles, their efficiency of transfection into cells, and their ability to release drug or siRNA cargo in vitro were pH-sensitive, such that drug release was facilitated in the acidic microenvironment of the tumor. Transfecting the micelles into HCC cells significantly inhibited protective autophagy within tumor cells, and delivering the micelles into mice carrying HCC xenografts induced apoptosis, slowed tumor growth, and inhibited autophagy. Our results indicate that co-delivering Narc and siULK1 in biocompatible micelles can safely inhibit tumor growth and protective autophagy, justifying further studies into this promising therapeutic approach against HCC. STATEMENT OF SIGNIFICANCE We have focused on the targeted therapy of HCC via synergistically inhibiting the autophagy and inducing apoptosis. The lipid-modified cell-penetrating peptide can not only aggregate into micelles to load natural product narciclasine and ULK1 siRNA simultaneously, but also facilitate uptake and endosome escape with a pH-sensitive manner in HepG2 cells. HepG2 cell treated with siULK1-M-Narc has increased apoptotic levels and declined autophagy via the targeted regulation of AMPK-ULK1 signaling axis. The in vivo studies have confirmed that siULK1-M-Narc efficiently reduce the growth of tumor on HCC xenograft models with good safety. Thus, we suppose the lipid-modified cell-penetrating peptide has good application prospects in the targeted combinational therapy of HCC.
Collapse
Affiliation(s)
- Xiaoyun Wang
- Department of Pharmacy and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
| | - Fengbo Wu
- Department of Pharmacy and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
| | - Guoyou Li
- Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610065, China.
| | - Nan Zhang
- Department of Pharmacy and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
| | - Xiangrong Song
- Department of Pharmacy and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
| | - Yu Zheng
- Department of Pharmacy and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
| | - Changyang Gong
- Department of Pharmacy and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
| | - Bo Han
- State Key Laboratory Breeding Base of Systematic Research Development and Utilization of Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| | - Gu He
- Department of Pharmacy and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
| |
Collapse
|
|
11
|
Ravaioli M, Cucchetti A, Pinna AD, De Pace V, Neri F, Barbera MA, Maroni L, Frega G, Palloni A, De Lorenzo S, Ripoli MC, Pantaleo MA, Cescon M, Del Gaudio M, Brandi G. The role of metronomic capecitabine for treatment of recurrent hepatocellular carcinoma after liver transplantation. Sci Rep 2017; 7:11305. [PMID: 28900245 PMCID: PMC5595852 DOI: 10.1038/s41598-017-11810-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Accepted: 08/14/2017] [Indexed: 12/17/2022] Open
Abstract
The management of recurrent hepatocellular carcinoma untreatable with surgical options is based on systemic therapy with sorafenib. Due to the high rates of adverse events connected to the therapy with sorafenib, metronomic capecitabine seems a promising strategy for these patients. We analyzed the data of 38 patients with hepatocellular carcinoma recurrent after liver transplantation performed at our center. We compared the outcome of 17 patients receiving metronomic capecitabine versus 20 patients experiencing best supportive care and versus the data of the literature about treatment with sorafenib. In the group treated with metronomic capecitabine we observed an increased survival after tumor recurrence at the univariate and multivariate analysis compared to the group of best supportive care (median 22 months vs. 7 months, p < 0.01). Data from the literature on the use of sorafenib showed outcomes like our study group, with similar patient and tumoral features. The episodes of acute rejection and the tumor stage at the recurrence showed a correlation with patient survival at the univariate analysis. The metronomic capecitabine for hepatocellular cancer recurrent after liver transplantation seems effective without important adverse events and comparable results to sorafenib.
Collapse
Affiliation(s)
- Matteo Ravaioli
- Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, Alma Mater Studiorum, University of Bologna, V. Massarenti 9, 40138, Bologna, Italy.
| | - Alessandro Cucchetti
- Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, Alma Mater Studiorum, University of Bologna, V. Massarenti 9, 40138, Bologna, Italy
| | - Antonio Daniele Pinna
- Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, Alma Mater Studiorum, University of Bologna, V. Massarenti 9, 40138, Bologna, Italy
| | - Vanessa De Pace
- Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, Alma Mater Studiorum, University of Bologna, V. Massarenti 9, 40138, Bologna, Italy
| | - Flavia Neri
- Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, Alma Mater Studiorum, University of Bologna, V. Massarenti 9, 40138, Bologna, Italy
| | - Maria Aurelia Barbera
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Alma Mater Studiorum, Bologna University, V. Massarenti 9, 40138, Bologna, Italy
| | - Lorenzo Maroni
- Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, Alma Mater Studiorum, University of Bologna, V. Massarenti 9, 40138, Bologna, Italy
| | - Giorgio Frega
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Alma Mater Studiorum, Bologna University, V. Massarenti 9, 40138, Bologna, Italy
| | - Andrea Palloni
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Alma Mater Studiorum, Bologna University, V. Massarenti 9, 40138, Bologna, Italy
| | - Stefania De Lorenzo
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Alma Mater Studiorum, Bologna University, V. Massarenti 9, 40138, Bologna, Italy
| | - Maria Cristina Ripoli
- Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, Alma Mater Studiorum, University of Bologna, V. Massarenti 9, 40138, Bologna, Italy
| | - Maria Abbondanza Pantaleo
- "G. Prodi" Interdepartmental Center for Cancer Research (C.I.R.C.), University of Bologna, V. Massarenti 9, 40138, Bologna, Italy
| | - Matteo Cescon
- Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, Alma Mater Studiorum, University of Bologna, V. Massarenti 9, 40138, Bologna, Italy
| | - Massimo Del Gaudio
- Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, Alma Mater Studiorum, University of Bologna, V. Massarenti 9, 40138, Bologna, Italy
| | - Giovanni Brandi
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Alma Mater Studiorum, Bologna University, V. Massarenti 9, 40138, Bologna, Italy
| |
Collapse
|
|
12
|
Giakoustidis AE, Giakoustidis DE. Immunosuppression strategies in liver transplantation patient; patients with hepatocellular carcinoma. Immunotherapy 2017; 9:197-206. [PMID: 28128716 DOI: 10.2217/imt-2016-0110] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) consists the main primary malignant tumor of the liver. There is an underlining liver cirrhosis mainly attributed to chronic hepatitis B virus or hepatitis C virus, alcoholic liver disease, nonalcoholic steatohepatitis and other pathologic conditions. Liver transplantation consists a radical management, treating both cancer and cirrhosis. By introducing the Milan Criteria for liver transplantation in HCC patients there was a 5-year survival escalation. Even though there is a careful selection of patients with HCC for transplantation, recurrent disease is still high. The role of immusuppression therapy is of paramount importance, in order to avoid acute and chronic graft rejection while protecting the patient from tumor recurrence. In recent years newer immunosuppressive agents such as the mTOR inhibitors are proposed, having dual properties, as both immunosuppressive and antitumors agents.
Collapse
Affiliation(s)
- Alexander E Giakoustidis
- Hepato-Pancreato-Biliary Surgery Department, The Royal London Hospital, Barts Health, Whitechapel Road, London E1 1BB, UK
| | - Dimitrios E Giakoustidis
- Division of Transplant Surgery, Department of Surgery, School of Health Sciences, Aristotle University of Thessaloniki & Hippokration General Hospital, Thessaloniki, Greece
| |
Collapse
|
|
13
|
Weiler N, Bilge N, Troetschler S, Vermehren J, Schnitzbauer AA, Herrmann E, Sarrazin C, Zeuzem S, Welker MW. Conversion From Sirolimus to Everolimus in Long-Term Liver Graft Recipients. J Clin Pharmacol 2017; 57:837-845. [PMID: 28134984 DOI: 10.1002/jcph.871] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Accepted: 12/13/2016] [Indexed: 12/20/2022]
Abstract
Immunosuppression by inhibition of the mechanistic target of rapamycin (mTOR) is a promising approach after liver transplantation. The mTOR inhibitor sirolimus was used in selected liver graft recipients despite safety concerns and lack of approval. Everolimus is another mTOR inhibitor approved after liver transplantation. It is currently unknown, whether conversion of sirolimus to everolimus is safe in long-term liver graft recipients. Long-term liver graft recipients treated with sirolimus were converted to everolimus. A systematical analysis of biochemical and clinical data before and after conversion was performed. Sixteen patients were included (female/male, 8/8). Median (range) age at conversion was 66 years (49-78 years), and patients were converted at a median (range) of 10.1 years (4.0-22.3 years) after liver transplantation. In the majority of patients, no dose adjustment was needed after conversion. No rejection and no cytomegalovirus replication episodes were observed. Furthermore, no differences were found with respect to kidney function, diabetes mellitus, or blood pressure before and after conversion. Bilirubin serum concentration was lower, whereas aspartate aminotransaminase, alanine aminotransferase, and triglycerides serum concentrations were higher after conversion to everolimus. Neither clinical- nor graft-associated significant complications were observed after conversion from sirolimus to everolimus in long-term liver graft recipients. Everolimus-based immunosuppression may be offered to patients after liver transplantation formerly treated with sirolimus.
Collapse
Affiliation(s)
- Nina Weiler
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt, Germany
| | - Nigar Bilge
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt, Germany
| | - Sven Troetschler
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt, Germany
| | - Johannes Vermehren
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt, Germany
| | | | - Eva Herrmann
- Institut für Biostatistik und mathematische Modellierung, Goethe-Universität Frankfurt, Frankfurt, Germany
| | - Christoph Sarrazin
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt, Germany
| | - Stefan Zeuzem
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt, Germany
| | | |
Collapse
|
|
14
|
Khorsandi SE, Heaton N. Optimization of immunosuppressive medication upon liver transplantation against HCC recurrence. Transl Gastroenterol Hepatol 2016; 1:25. [PMID: 28138592 DOI: 10.21037/tgh.2016.03.18] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Accepted: 02/01/2016] [Indexed: 12/12/2022] Open
Abstract
The introduction of liver transplant listing criteria for hepatocellular cancer (HCC) has significantly improved oncological outcomes and survival. But despite this HCC recurrence is still problematic. There is emerging evidence that the choice of immunosuppression (IS) after transplant for HCC can influence oncological survival and HCC recurrence. The following is a short summary of what has been published on HCC recurrence with the different classes of immunosuppressive agents in present use, concluding with the possible rationalization of the use of these immunosuppressive agents in the post-transplant patient at high risk of recurrence.
Collapse
Affiliation(s)
- Shirin Elizabeth Khorsandi
- Institute of Liver Studies, King's Healthcare Partners at Denmark Hill, King's College Hospital NHSFT, London, SE5 9RS, UK
| | - Nigel Heaton
- Institute of Liver Studies, King's Healthcare Partners at Denmark Hill, King's College Hospital NHSFT, London, SE5 9RS, UK
| |
Collapse
|
|
15
|
de’Angelis N, Landi F, Carra MC, Azoulay D. Managements of recurrent hepatocellular carcinoma after liver transplantation: A systematic review. World J Gastroenterol 2015; 21:11185-11198. [PMID: 26494973 PMCID: PMC4607916 DOI: 10.3748/wjg.v21.i39.11185] [Citation(s) in RCA: 126] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2015] [Revised: 04/06/2015] [Accepted: 08/25/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the efficacy (survival) and safety of treatments for recurrent hepatocellular carcinoma (HCC) in liver transplantation (LT) patients.
METHODS: Literature search was performed on available online databases without a time limit until January 2015. Clinical studies describing survival after HCC recurrence in LT patients were retrieved for a full-text evaluation. A total of 61 studies were selected: 13 case reports, 41 retrospective case series, and 7 retrospective comparative studies.
RESULTS: Based on all included studies, the mean HCC recurrence rate was 16% of all LTs for HCC. A total of 1021 LT patients experienced HCC recurrence. The median time from LT to HCC recurrence was 13 mo (range 2-132 mo). The majority of patients (67%) presented with HCC extra-hepatic recurrences, involving lung, bone, adrenal gland, peritoneal lymph nodes, and rarely the brain. Overall survival after HCC recurrence was 12.97 mo. Surgical resection of localized HCC recurrence and Sorafenib for controlling systemic spread of HCC recurrence were associated with the higher survival rates (42 and 18 mo, respectively). However, Sorafenib, especially when combined with mTOR, was frequently associated with severe side effects that required dose reduction or discontinuation
CONCLUSION: Management of recurrent HCC in LT patients is challenging and associated with poor prognosis independently of the type of treatment.
Collapse
|
|
16
|
Abstract
Hepatocellular carcinoma (HCC) is an increasing problem in the USA and worldwide. Current treatments for HCC include chemoembolization, radioembolization, liver resection, and liver transplantation in the setting of selected cirrhotic patients. Liver transplantation for HCC was controversial initially, but is now widely accepted as a curative approach. Cirrhotic patients who meet standards for transplantation and have a tumor burden within Milan criteria are eligible for transplantation and receive Model for End-Stage Liver Disease (MELD) exception points once listed. Given the decline in availability of donor organs, rewarding MELD exception points and performing liver transplants in these patients remain controversial. Despite this, various guidelines propose expanding eligibility criteria for cirrhotics with HCC, due to post-transplant outcomes comparable to patients transplanted without HCC. Following the transplant, issues include optimizing the type and amount of immunosuppression and screening for and treating recurrence of HCC.
Collapse
Affiliation(s)
- M Katherine Rude
- Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8124, St. Louis, MO, 63110, USA,
| | | |
Collapse
|
|
17
|
Xiang ZW, Sun L, Li GH, Maharjan R, Huang JH, Li CX. Progress in the treatment of pulmonary metastases after liver transplantation for hepatocellular carcinoma. World J Hepatol 2015; 7:2309-2314. [PMID: 26380655 PMCID: PMC4568491 DOI: 10.4254/wjh.v7.i20.2309] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Revised: 06/19/2015] [Accepted: 09/07/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world, and is the third leading cause of cancer-related death. Liver transplantation (LT) has become a curative treatment for patients with HCC. However, recurrence and metastasis after LT are the main factors reducing long-term survival in patients, and the lung is the most common site of metastasis after LT for HCC, although metastasis to liver, para-aortic lymph nodes and renal periphery are observed. Thus, the treatment of pulmonary metastases after LT for HCC has become a hot research topic, the successful treatment of pulmonary metastases can significantly prolong the survival of LT patients. Although single conventional treatment (chemotherapy, surgery and external beam radiation therapy), immunosuppression, image-guided minimally invasive therapy (radiofrequency ablation, microwave ablation, cryoablation, and brachytherapy) and molecular targeted drugs have had a significant effect, patients do not have durable remission and the long-term survival rate is disappointing. Therefore, improving existing treatments and identifying a more effective combination therapy are important research issues in the prevention and treatment of pulmonary metastases after LT for HCC. The paper reviewed single conventional treatments, new treatments, and combination therapy, to provide a basis for the best treatment of these patients.
Collapse
|
|
18
|
Wang ZY, Geng L, Zheng SS. Current strategies for preventing the recurrence of hepatocellular carcinoma after liver transplantation. Hepatobiliary Pancreat Dis Int 2015; 14:145-9. [PMID: 25865686 DOI: 10.1016/s1499-3872(15)60345-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Liver transplantation is the optimal treatment for a selected group of patients with moderate to severe cirrhosis and hepatocellular carcinoma (HCC). Despite the strict selection of candidates, post-transplant recurrence often occurs and markedly reduces the long-term survival of patients with HCC. The present review focuses on the current strategies on preventing the recurrence of HCC after liver transplantation. DATA SOURCES Relevant articles were identified by extensive searching of PubMed using the keywords "hepatocellular carcinoma", "recurrence" and "liver transplantation" between January 1996 and January 2014. Additional papers were searched manually from the references in key articles. RESULTS The current theories of HCC recurrence after liver transplantation are: (i) the growth of pre-transplant occult metastases; (ii) the engraftment of circulating tumor cells released at the time of transplantation. Pre-transplant treatment aims to control local tumor by radiofrequency ablation, transarterial embolization and transarterial chemoembolization. The main objective during the operation is to prevent tumor cell dissemination. Post-transplant treatment includes systemic anticancer therapy, antiviral therapy, and most recently, immunotherapy. These strategies concentrate on the control of the tumor when the patients are waiting for transplant, to reduce the release of HCC cells during surgical procedures and to clear the occult HCC cells after transplantation. CONCLUSIONS Much can be done to prevent HCC recurrence after liver transplantation. In future, effort is likely to be directed towards combining multidisciplinary approaches and various treatment modalities.
Collapse
Affiliation(s)
- Zhuo-Yi Wang
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; Division of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
| | | | | |
Collapse
|
|
19
|
Hong YM, Yoon KT, Cho M, Kang DH, Kim HW, Choi CW, Park SB, Heo J, Woo HY, Lim W. Sorafenib in the Treatment of Recurrent Hepatocellular Carcinoma after Liver Transplantation: A Report of Four Cases. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2015; 65:246-51. [DOI: 10.4166/kjg.2015.65.4.246] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Young Mi Hong
- Department of Internal Medicine, Pusan National University Yangsan Hospital, Yangsan, Korea
- Department of Internal Medicine, Pusan National University School of Medicine, Yangsan, Korea
- Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Korea
| | - Ki Tae Yoon
- Department of Internal Medicine, Pusan National University Yangsan Hospital, Yangsan, Korea
- Department of Internal Medicine, Pusan National University School of Medicine, Yangsan, Korea
- Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Korea
| | - Mong Cho
- Department of Internal Medicine, Pusan National University Yangsan Hospital, Yangsan, Korea
- Department of Internal Medicine, Pusan National University School of Medicine, Yangsan, Korea
- Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Korea
| | - Dae Hwan Kang
- Department of Internal Medicine, Pusan National University Yangsan Hospital, Yangsan, Korea
- Department of Internal Medicine, Pusan National University School of Medicine, Yangsan, Korea
- Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Korea
| | - Hyung Wook Kim
- Department of Internal Medicine, Pusan National University Yangsan Hospital, Yangsan, Korea
- Department of Internal Medicine, Pusan National University School of Medicine, Yangsan, Korea
- Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Korea
| | - Cheol Woong Choi
- Department of Internal Medicine, Pusan National University Yangsan Hospital, Yangsan, Korea
- Department of Internal Medicine, Pusan National University School of Medicine, Yangsan, Korea
- Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Korea
| | - Su Bum Park
- Department of Internal Medicine, Pusan National University Yangsan Hospital, Yangsan, Korea
- Department of Internal Medicine, Pusan National University School of Medicine, Yangsan, Korea
- Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Korea
| | - Jeong Heo
- Department of Internal Medicine, Pusan National University Hospital, Busan, Korea
- Department of Internal Medicine, Pusan National University School of Medicine, Yangsan, Korea
| | - Hyun Young Woo
- Department of Internal Medicine, Pusan National University Hospital, Busan, Korea
- Department of Internal Medicine, Pusan National University School of Medicine, Yangsan, Korea
| | - Won Lim
- Department of Internal Medicine, Pusan National University Hospital, Busan, Korea
- Department of Internal Medicine, Pusan National University School of Medicine, Yangsan, Korea
| |
Collapse
|
|
20
|
Kang SH, Hwang S, Ha TY, Song GW, Jung DH, Kim KH, Ahn CS, Moon DB, Park GC, Jung BH, Yoon YI, Lee SG. Tailored long-term immunosuppressive regimen for adult liver transplant recipients with hepatocellular carcinoma. KOREAN JOURNAL OF HEPATO-BILIARY-PANCREATIC SURGERY 2014; 18:48-51. [PMID: 26155248 PMCID: PMC4492313 DOI: 10.14701/kjhbps.2014.18.2.48] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/15/2014] [Revised: 05/15/2014] [Accepted: 05/18/2014] [Indexed: 02/06/2023]
Abstract
Backgrounds/Aims There are few guidelines for tailored immunosuppressive regimens for liver transplantation (LT) recipients with hepatocellular carcinoma (HCC). To establish long-term immunosuppressive regimens suitable for Korean adult LT recipients, we analyzed those that were currently in use at a single high-volume institution. Methods This cross-sectional study comprises three parts including review of the immunosuppressive regimens used to manage 2,147 adult LT outpatients, review of LT recipients who were diagnosed of HCC at LT, and review of LT recipients who suffered from HCC recurrence. Results In 1,000 adult LT recipients who were living more than 5 years with no adverse events, 916 received a calcineurin inhibitor (CNI)-based therapy (CNI only in 520; CNI with mycophenolate mofetil [MMF] in 396) and 84 were receiving an MMF-based therapy (MMF only in 45; MMF with minimal CNI in 39). Tacrolimus was preferred over cyclosporine for both monotherapy and combination therapy along the passage of posttransplant period. There was no difference in selection of immunosuppressants, target blood concentration, and rate of combination therapy between LT recipients with and without HCC, except for the first 1 year. Sirolimus-based regimens were applied in 21 patients who showed HCC recurrence. Sorafenib was often used after conversion to sirolimus. Conclusions Tailored immunosuppressive regimen covering the long-term posttransplant period should be established after consideration of individualized patient profiles including HCC.
Collapse
Affiliation(s)
- Sung-Hwa Kang
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Shin Hwang
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Tae-Yong Ha
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Gi-Won Song
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Dong-Hwan Jung
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Ki-Hun Kim
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Chul-Soo Ahn
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Deok-Bog Moon
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Gil-Chun Park
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Bo-Hyun Jung
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Young-In Yoon
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Sung-Gyu Lee
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| |
Collapse
|
|
21
|
Yan S, Ding Y, Tian Y, Lu Z, Wang Y, Zhang Q, Ye Y, Zhou L, Xie H, Chen H, Zheng M, Zheng S. MHC-mismatched mice liver transplantation promotes tumor growth in liver graft. Cancer Lett 2014; 351:162-71. [PMID: 24880081 DOI: 10.1016/j.canlet.2014.05.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2014] [Revised: 04/19/2014] [Accepted: 05/11/2014] [Indexed: 12/18/2022]
Abstract
Liver transplantation is a final therapeutic option for treatment of hepatic malignancies, but local recurrence remains high after surgery. However, the underlying mechanisms of local tumor recurrence are still unknown. We speculated that immunological status of transplanted liver may contribute to the progress of tumor development. CT-26 tumor cells are injected into graft after allogeneic or syngeneic liver transplantation. The growth pattern of tumor and the co-relationship of regulatory T cell and effector T cells in liver graft were observed and investigated at 3d, 6d, 9d and 15d post-transplantation. The Hepatic Replacement Area of tumor in allogeneic grafts was significantly larger than that in syngeneic grafts. The activation of tumor growth in allografts was due to the dysfunction of effector T cells mediated by regulatory T cells in liver graft. Using nude mice model, we further confirmed that regulatory T cells from allograft significantly weaken the function of effector T cells in vivo. Our data has showed that MHC-mismatched mice liver transplantation can promote tumor growth in liver graft. For the first time, we demonstrated that susceptibility to tumor development in liver graft is due to the down-regulation of effector T cells' function mediated by the regulatory T cells.
Collapse
Affiliation(s)
- Sheng Yan
- Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, PR China; Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, PR China; Key Laboratory of Organ Transplantation Zhejiang Province, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, PR China
| | - Yuan Ding
- Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, PR China; Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, PR China; Key Laboratory of Organ Transplantation Zhejiang Province, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, PR China
| | - Yang Tian
- Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, PR China; Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, PR China; Key Laboratory of Organ Transplantation Zhejiang Province, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, PR China
| | - Zhongjie Lu
- Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, PR China; Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, PR China; Key Laboratory of Organ Transplantation Zhejiang Province, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, PR China
| | - Yan Wang
- Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, PR China; Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, PR China; Key Laboratory of Organ Transplantation Zhejiang Province, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, PR China
| | - Qiyi Zhang
- Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, PR China; Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, PR China; Key Laboratory of Organ Transplantation Zhejiang Province, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, PR China
| | - Yufu Ye
- Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, PR China; Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, PR China; Key Laboratory of Organ Transplantation Zhejiang Province, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, PR China
| | - Lin Zhou
- Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, PR China; Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, PR China; Key Laboratory of Organ Transplantation Zhejiang Province, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, PR China
| | - Haiyang Xie
- Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, PR China; Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, PR China; Key Laboratory of Organ Transplantation Zhejiang Province, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, PR China
| | - Hui Chen
- Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, PR China; Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, PR China; Key Laboratory of Organ Transplantation Zhejiang Province, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, PR China
| | - Minghao Zheng
- Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, PR China; Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, PR China; Key Laboratory of Organ Transplantation Zhejiang Province, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, PR China; Centre for Orthopaedic Research, School of Surgery, University of Western Australia, Western Australia 6009, Australia.
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, PR China; Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, PR China; Key Laboratory of Organ Transplantation Zhejiang Province, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, PR China.
| |
Collapse
|
|
22
|
Use of adjuvant sorafenib in liver transplant recipients with high-risk hepatocellular carcinoma. J Transplant 2014; 2014:913634. [PMID: 24818010 PMCID: PMC4003738 DOI: 10.1155/2014/913634] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2014] [Accepted: 02/24/2014] [Indexed: 02/06/2023] Open
Abstract
The efficacy of liver transplantation (LT) for hepatocellular (HCC) is limited by tumor recurrence rates of 10–15%. We undertook this pilot study to examine the use of sorafenib as adjuvant therapy in high-risk LT recipients. Methods. We prospectively enrolled patients transplanted for HCC into a treatment protocol utilizing sorafenib if their explant examination showed evidence of viable tumor exceeding Milan criteria. We utilized as historical controls patients transplanted previously, whose explant tumor characteristics exceeded Milan criteria, but who were not “preemptively” treated with sorafenib. Wilcoxon two-sample test and Fisher's exact test were used to compare survival and recurrence rates between the two groups. Results. Seven patients were treated with sorafenib and compared to 12 historical “controls.” Two of 7 treated patients suffered from HCC recurrence. Of the comparison group, 9 experienced HCC recurrence and all succumbed to disease. Dose reduction improved tolerance of drug. The overall rate of HCC recurrence was decreased in the adjuvant therapy group compared to historical controls (29% versus 75%, P = 0.07). Disease free 1-year survival for the treated versus untreated group was 100% versus 66%, respectively. Conclusion. Adjuvant use of sorafenib is safe and decreases risk of HCC recurrence in high-risk LT recipients.
Collapse
|
|
23
|
Chen K, Man K, Metselaar HJ, Janssen HLA, Peppelenbosch MP, Pan Q. Rationale of personalized immunosuppressive medication for hepatocellular carcinoma patients after liver transplantation. Liver Transpl 2014; 20:261-9. [PMID: 24376158 DOI: 10.1002/lt.23806] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2013] [Accepted: 11/24/2013] [Indexed: 12/12/2022]
Abstract
Liver transplantation is the only potentially curative treatment for hepatocellular carcinoma (HCC) that is not eligible for surgical resection. However, disease recurrence is the main challenge to the success of this treatment. Immunosuppressants that are universally used after transplantation to prevent graft rejection could potentially have a significant impact on HCC recurrence. Nevertheless, current research is exclusively focused on mammalian target of rapamycin inhibitors, which are thought to be the only class of immunosuppressive agents that can reduce HCC recurrence. In fact, substantial evidence from the bench to the bedside indicates that other classes of immunosuppressants may also exert diverse effects; for example, inosine monophosphate dehydrogenase inhibitors potentially have antitumor effects. In this article, we aim to provide a comprehensive overview of the potential effects of different types of immunosuppressants on HCC recurrence and their mechanisms of action from both experimental and clinical perspectives. To ultimately improve the outcomes of HCC patients after transplantation, we propose a concept and approaches for developing personalized immunosuppressive medication to be used either as immunosuppression maintenance or during the prevention/treatment of HCC recurrence.
Collapse
Affiliation(s)
- Kan Chen
- Bio-X Center, College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, China; Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | | | | | | | | | | |
Collapse
|
|
24
|
Sposito C, Mariani L, Germini A, Flores Reyes M, Bongini M, Grossi G, Bhoori S, Mazzaferro V. Comparative efficacy of sorafenib versus best supportive care in recurrent hepatocellular carcinoma after liver transplantation: a case-control study. J Hepatol 2013; 59:59-66. [PMID: 23500153 DOI: 10.1016/j.jhep.2013.02.026] [Citation(s) in RCA: 113] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2012] [Revised: 02/19/2013] [Accepted: 02/22/2013] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS The efficacy of sorafenib in the post-liver transplantation (LT) setting has been scarcely studied. The aim of this study was to evaluate the efficacy of sorafenib, compared to best supportive care (BSC), in two cohorts of patients which presented with hepatocellular carcinoma (HCC) recurrence after LT. METHODS Data from patients who developed presentation or progression of HCC recurrence after LT not amenable to surgical/locoregional treatments (untreatable presentation/progression, UP) were retrieved. The cohort of patients receiving sorafenib starting from 2007 was compared to that of patients receiving BSC in the previous era. Disease outcome was investigated in terms of survival from recurrence or from UP by means of univariate and multivariate Cox regression models with event times left-truncated at the date of UP. RESULTS Of a total of 39 patients, 24 received BSC and 15 sorafenib. The two groups were well matched at baseline, with time-related imbalances regarding mTOR-based immunosuppression and median time from LT to recurrence, significantly higher in the sorafenib group. Patients' outcome in the sorafenib group was significantly improved (median survival from recurrence 21.3 vs.11.8 months, HR=5.2, p=0.0009; median survival from UP 10.6 vs. 2.2 months, HR=21.1, p<0.0001). The only factor associated with survival after HCC recurrence in multivariate analysis was treatment with sorafenib (HR=4.0; p=0.0325). No severe adverse event was registered in this post-LT setting. CONCLUSIONS Although the use of historical controls weakens final interpretation, sorafenib seems to be associated with an acceptable safety profile and benefit in survival in HCC patients suffering recurrence after LT.
Collapse
Affiliation(s)
- Carlo Sposito
- The Hepato-Oncology Group, Gastro-Intestinal Surgery, Liver Transplantation and Hepatology, Fondazione IRCCS Istituto Nazionale Tumori (National Cancer Institute), Milan, Italy
| | | | | | | | | | | | | | | |
Collapse
|
|
25
|
Integrating sorafenib into an algorithm for the management of post-transplant hepatocellular carcinoma recurrence. J Hepatol 2013; 59:3-5. [PMID: 23567081 DOI: 10.1016/j.jhep.2013.03.029] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2013] [Revised: 03/22/2013] [Accepted: 03/27/2013] [Indexed: 12/12/2022]
|
|
26
|
Sotiropoulos GC, Nowak KW, Fouzas I, Vernadakis S, Kykalos S, Klein CG, Paul A. Sorafenib treatment for recurrent hepatocellular carcinoma after liver transplantation. Transplant Proc 2013; 44:2754-6. [PMID: 23146514 DOI: 10.1016/j.transproceed.2012.09.022] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND With an increasing number of patients with hepatocellular carcinoma (HCC) undergoing liver transplantation (OLT), HCC recurrence remains the main limiting factor for long-term survival. We herein report our experience with sorafenib treatment for HCC recurrence post-OLT. PATIENTS AND METHODS We reviewed data on transplanted HCC patients receiving sorafenib for HCC recurrence. RESULTS Fourteen patients were included for the period November 2006 to February 2011. There were 9 men and 5 women of median age of 57 years. Twelve patients (86%) received rescue grafts through Eurotransplant allocation. Median values for alpha fetoprotein levels, Model for End-Stage Liver Disease score, sorafenib daily dose, and length of treatment were 97 ng/mL, 10, 400 mg, and 6.5 months, respectively. Sorafenib side effects led to discontinuation (n = 4) or reduction (n = 2) of the daily dose. Four patients experienced tumor progression during treatment. Seven patients are currently alive, 3 patients died of tumor progression, and 4 patients of non-tumor-related causes of death. Median survival was 25 months. CONCLUSION Sorafenib treatment for HCC recurrence in transplant recipients represents a challenging oncologic approach that requires further validation in prospective, multicenter studies.
Collapse
Affiliation(s)
- G C Sotiropoulos
- Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany.
| | | | | | | | | | | | | |
Collapse
|
|
27
|
Sorafenib for the treatment of recurrent hepatocellular carcinoma after liver transplantation? Transplant Proc 2013; 44:1989-91. [PMID: 22974889 DOI: 10.1016/j.transproceed.2012.06.046] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND There are scarce data on the use of sorafenib for the treatment of recurrent hepatocellular carcinoma (HCC) after orthotopic liver transplantation (OLT). PATIENTS AND METHODS Ten patients were treated with sorafenib after OLT following the Italian Drug Agency guidelines: they had well-compensated liver function (Child-Pugh class A in the case of cirrhosis), intermediate-or advanced-stage HCC, good general condition (performance status 0), and not suitable for loco-regional therapies. Patients with HCC recurrence after OLT were treated with sorafenib (400 mg twice daily). Adverse events (AEs) were assessed using National Cancer Institute Common Toxicity Criteria of Adverse Events (NCI-CTCAE) v3.0 with tumor responses evaluated acording to modified Response Evaluation Criteria in Select Tumors) criteria. RESULTS Median duration of treatment was 10 months (range, 2-18). Seven patients (70%) received an additionally targeted therapy with mTOR inhibitors as part of their immunosuppressive regimen. Most common grade 3 AEs included diarrhea (50%), hand-foot skin reaction (30%), and fatigue (20%). Sorafenib had to be discontinued in 3 patients (30%) due to AEs and 4 additional patients (40%) required a dose adjustment. No deterioration of liver graft function occurred. Three patients (30%) stopped treatment due to radiological progression of HCC, whereas 3 are still using the drug. Median time to progression was 8 months (range, 2-16). Median survival from start of therapy was 18 months (range, 4- 36). CONCLUSION Our preliminary results suggest that sorafenib is a safe effective therapy for recurrent HCC after OLT.
Collapse
|
|
28
|
Welker MW, Bechstein WO, Zeuzem S, Trojan J. Recurrent hepatocellular carcinoma after liver transplantation - an emerging clinical challenge. Transpl Int 2012; 26:109-18. [PMID: 22994652 DOI: 10.1111/j.1432-2277.2012.01562.x] [Citation(s) in RCA: 110] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
In western countries, hepatocellular carcinoma (HCC) is a major reason for orthotopic liver transplantation (OLT) with estimated recurrence rates between 15% and 20%. This selective literature review addresses follow-up care after OLT in HCC and current treatment options. Recurrence prediction is based on pathological tumor stage, vascular invasion, serum alfafetoprotein levels, and histological differentiation, but further advances are expected by molecular profiling techniques. Lower levels of immunosuppressive agents are associated with a lower risk for HCC recurrence. Retrospective studies indicate that mammalian target of rapamycin (mTOR) inhibitors as immunosuppression reduce the risk of HCC recurrence. However, prospective studies supporting this potential advantage of mTOR inhibitors are still lacking, and higher rejection rates were reported for sirolimus after OLT in HCC. Prognosis is poor in recurrent HCC, a longer interval between OLT and recurrence and feasibility of surgical resection are associated with improved survival. Systemic treatment with sorafenib is the current standard of care in patients with advanced-stage HCC not suitable for locoregional therapy. After OLT, combination of an mTOR inhibitor with sorafenib is feasible and frequently used in clinical practice. As safety and efficacy data are still limited, close clinical monitoring is mandatory.
Collapse
Affiliation(s)
- Martin-Walter Welker
- Medizinische Klinik 1, Klinikum der Johann-Wolfgang Goethe-Universität, Frankfurt am Main, Germany
| | | | | | | |
Collapse
|
|
29
|
Weinmann A, Niederle IM, Koch S, Hoppe-Lotichius M, Heise M, Düber C, Schuchmann M, Otto G, Galle PR, Wörns MA. Sorafenib for recurrence of hepatocellular carcinoma after liver transplantation. Dig Liver Dis 2012; 44:432-7. [PMID: 22265328 DOI: 10.1016/j.dld.2011.12.009] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2011] [Revised: 12/02/2011] [Accepted: 12/12/2011] [Indexed: 12/11/2022]
Abstract
BACKGROUND Recurrence of hepatocellular carcinoma after orthotopic liver transplantation not amenable to surgical approaches is associated with poor outcome. AIMS Retrospective evaluation of the safety and efficacy of sorafenib in patients with post-transplant hepatocellular carcinoma recurrence. METHODS Patients with post-transplant hepatocellular carcinoma recurrence were treated with sorafenib. Adverse events were assessed using National Cancer Institute Common Toxicity Criteria of AEs version 3.0, tumour response was evaluated according to Response Evaluation Criteria in Solid Tumours. RESULTS First-line therapy after recurrence was surgery (n=6), radiation therapy (n=1), chemotherapy (n=1), and sorafenib (n=3). Finally, 11 patients were treated with sorafenib. Nine patients (82%) received an additionally targeted therapy with sirolimus as part of their immunosuppressive regimen. Most common grade 3 adverse events included diarrhoea (46%), hand-foot skin reaction (27%), nausea, fatigue, and leucopoenia (all 18%). Sorafenib had to be discontinued in two patients due to adverse events and six additional patients required a dose adjustment. No deterioration of liver graft function occurred. Median time to progression was 4.1 months; however, patients were treated with ongoing sorafenib in case of clinical benefit (median 8.9 months). Median overall survival after initiation of sorafenib treatment was 20.1 months. CONCLUSION Sorafenib in combination with immunosuppression including sirolimus may be administered to patients with post-transplant hepatocellular carcinoma recurrence with acceptable toxicity and without deterioration of liver graft function.
Collapse
Affiliation(s)
- Arndt Weinmann
- Department of Internal Medicine I, University Medicine of the Johannes Gutenberg University, Mainz, Germany
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
30
|
Gomez-Martin C, Bustamante J, Castroagudin JF, Salcedo M, Garralda E, Testillano M, Herrero I, Matilla A, Sangro B. Efficacy and safety of sorafenib in combination with mammalian target of rapamycin inhibitors for recurrent hepatocellular carcinoma after liver transplantation. Liver Transpl 2012; 18:45-52. [PMID: 21932373 DOI: 10.1002/lt.22434] [Citation(s) in RCA: 119] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
There is currently no consensus on the most suitable treatment for the recurrence of hepatocellular carcinoma (HCC) after liver transplantation. This open, multicenter, retrospective, uncontrolled cohort study was designed to evaluate the safety and preliminary efficacy of the combined use of a mammalian target of rapamycin (mTOR) inhibitor and sorafenib in this setting. In 31 patients who suffered from HCC recurrence after liver transplantation, the immunosuppressive therapy was changed to mTOR inhibitors, and systemic treatment with sorafenib was initiated. This combination was maintained until symptomatic tumor progression, death, hepatic decompensation, or unacceptable toxicity occurred. Primary treatment efficacy was determined by overall survival and progression-free survival, and secondary efficacy was determined by the overall response rate. Toxicity parameters associated with the use of sorafenib and mTOR inhibitors were also analyzed. The overall response rate according to the Response Evaluation Criteria in Solid Tumors was 3.8% (1/26), and there was sustained stabilization of the disease in 13 additional cases (50.0%). The median overall survival was 19.3 months [95% confidence interval (CI) = 13.4-25.1 months], and the median time to progression was 6.77 months (95% CI = 2.3-11.1 months). Only 2 grade 3/4 cases of hyperglycemia and 1 case of grade 3/4 mucositis were reported, and they were possibly related to mTOR inhibitors. The most common severe adverse event probably related to sorafenib was diarrhea (12.9%). In conclusion, the coadministration of sorafenib and an mTOR inhibitor could be effective despite notable toxicity in patients with post-liver transplant HCC recurrence not suitable for radical therapy. The toxicity and efficacy need to be further evaluated in randomized controlled studies for this combination to be considered a valid option.
Collapse
Affiliation(s)
- Carlos Gomez-Martin
- Gastrointestinal Cancer Unit, Spanish National Cancer Research Center, Fuenlabrada University Hospital, Camino del Molino 2, Fuenlabrada, Madrid, Spain.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
31
|
Pignataro G, Capone D, Polichetti G, Vinciguerra A, Gentile A, Di Renzo G, Annunziato L. Neuroprotective, immunosuppressant and antineoplastic properties of mTOR inhibitors: current and emerging therapeutic options. Curr Opin Pharmacol 2011; 11:378-394. [PMID: 21646048 DOI: 10.1016/j.coph.2011.05.003] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2011] [Revised: 05/12/2011] [Accepted: 05/13/2011] [Indexed: 02/05/2023]
Abstract
The acronym mTOR defines a family of serine-threonine protein kinase called mammalian target of rapamycin. The major role of these kinases in the cell is to merge extracellular instructions with information about cellular metabolic resources and to control the rate of anabolic and catabolic processes accordingly. In mammalian cells mTOR is present in two distinct heteromeric protein complexes commonly referred to as mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), involved in the control of a wide variety of cellular processes. It has been recently reported that compounds acting modulating mTOR activity, beside mediating the well recognized processes exploited in the anticancer and immunosuppressant effects, are provided with neuroprotective properties. In fact, mTOR is involved in the mechanism of PI3K/Akt-induced upregulation of glutamate transporter 1, GLT1, that is linked to several neuronal disorders such as stroke, Alzheimer's disease, and amyotrophic lateral sclerosis. Furthermore, in adult brain mTOR is crucial for numerous physiological processes such as synaptic plasticity, learning, memory, and brain control of food uptake. Moreover, the activation of mTOR pathway is involved in neuronal development, dendrite development and spine morphogenesis.
Collapse
Affiliation(s)
- Giuseppe Pignataro
- Division of Pharmacology, Department of Neuroscience, School of Medicine, Federico II University of Naples, Via Pansini, 5, 80131 Naples, Italy
| | | | | | | | | | | | | |
Collapse
|