|
1
|
Dasari BVM, Line PD, Sapisochin G, Hibi T, Bhangui P, Halazun KJ, Shetty S, Shah T, Magyar CTJ, Donnelly C, Chatterjee D. Liver transplantation as a treatment for cancer: comprehensive review. BJS Open 2025; 9:zraf034. [PMID: 40380811 PMCID: PMC12084677 DOI: 10.1093/bjsopen/zraf034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 01/30/2025] [Accepted: 02/07/2025] [Indexed: 05/19/2025] Open
Abstract
BACKGROUND Liver transplantation for cancer indications has gained momentum in recent years. This review is intended to optimize the care setting of liver transplant candidates by highlighting current indications, technical aspects and barriers with available solutions to facilitate the guidance of available strategies for healthcare professionals in specialized centres. METHODS A review of the most recent relevant literature was conducted for all the cancer indications of liver transplantation including colorectal cancer liver metastases, hilar cholangiocarcinoma, intrahepatic cholangiocarcinoma, neuroendocrine tumours, hepatocellular carcinoma and hepatic epitheloid haemangioendothelioma. RESULTS Transplant benefit from the best available evidence, including SECA I, SECA II, TRANSMET studies for colorectal liver metastases, various preoperative protocols for cholangiocarcinoma patients, standard, extended selection criteria for hepatocellular carcinoma and neuroendocrine tumours, are discussed. Innovative approaches to deal with organ shortages, including machine-perfused deceased grafts, living donor liver transplantation and RAPID procedures, are also explored. CONCLUSION Cancer indications for liver transplantation are here to stay, and the selection criteria among all cancer groups are likely to evolve further with improved prognostication of tumour biology using adjuncts such as radiomics, cancer genomics, and circulating DNA and RNA status. International prospective registry-based studies could overcome the limitations of smaller patient cohorts and lack of level 1 evidence.
Collapse
Affiliation(s)
- Bobby V M Dasari
- Department of Liver Transplantation and HBP Surgery, Queen Elizabeth Hospital, Birmingham, UK
- Department of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Pal-Dag Line
- Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
| | - Gonzalo Sapisochin
- Department of Surgery, Multi-Organ Transplant Program, University Health Network, Toronto, Canada
| | - Taizo Hibi
- Department of Pediatric Surgery and Transplantation, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
| | - Prashant Bhangui
- Liver Transplantation and Hepatobiliary Surgery, Medanta Institute of Liver Transplantation and Regenerative Medicine, Medanta-The Medicity, Gurgaon (Delhi NCR), India
| | - Karim J Halazun
- Department of Liver Transplantation and Hepatobiliary Surgery, NYU Grossman School of Medicine, NYU Langone Health, New York, USA
| | - Shishir Shetty
- Department of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
- Department of Hepatology, Queen Elizabeth Hospital, Birmingham, UK
| | - Tahir Shah
- Department of Hepatology, Queen Elizabeth Hospital, Birmingham, UK
| | - Christian T J Magyar
- Department of Abdominal Transplant & HBP Surgical Oncology, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Canada
| | - Conor Donnelly
- Department of Liver Transplantation and Hepatobiliary Surgery, NYU Grossman School of Medicine, NYU Langone Health, New York, USA
| | - Dev Chatterjee
- BRC Clinical Fellow Liver Medicine, University Hospitals of Birmingham, Birmingham, UK
| |
Collapse
|
|
2
|
Liu X, Du RC, Xu JY, Hu YX, Xie X, Lan QY, Hu L. Analyzing research trends in the relationship between immunosuppressants and cancer following organ transplantation: a bibliometric study from 2001 to 2023. Discov Oncol 2025; 16:366. [PMID: 40111721 PMCID: PMC11926317 DOI: 10.1007/s12672-025-02101-5] [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: 05/17/2024] [Accepted: 03/10/2025] [Indexed: 03/22/2025] Open
Abstract
BACKGROUND Recently, there has been an increasing interest in investigating the potential benefits or risks associated with using immunosuppressants for treating specific tumors post organ transplantation, with a focus on selecting appropriate drugs, doses, and treatment protocols. This study used bibliometric analysis to evaluate research trends and hotspots in this field. MATERIALS AND METHODS A systematic search was conducted on the Web of Science to identify studies focusing immunosuppressants and cancer following organ transplantation from 2001 to 2023. The search strategy utilized a variety of the keywords including "immunosuppressants", "cancer" and "transplant". Data extraction involved recording various parameters such as title, author, institution, country, publication, citation, H-index, immunosuppressant, and type of transplantation. RESULTS The analysis encompassed a total of 94 studies. The findings revealed that the period from 2005 to 2010 emerged as the most influential timeframe within this research. The United States ranked highest in the number of publications, with Vivarelli M identified as the most productive author, and the University of Bologna recognized as the most productive institute. "Immunosuppression", "rapamycin" and "kidney" were identified as the key hotspots within this field. Notably, rapamycin was identified as the predominant immunosuppressant and kidney transplantation emerged as the most prominent type of transplantation. CONCLUSIONS While immunosuppressants have been extensively utilized in organ transplant procedures, certain associated cancer risks have not been well addressed. Further long-term monitoring studies are required for numerous immunosuppressants to elucidate precise applications and potential implications for solid-organ transplant recipients.
Collapse
Affiliation(s)
- Xing Liu
- Department of Clinical Laboratory, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Honggutan District, No.566 Xuefu Road, 330036, Nanchang, Jiangxi Province, China
- Huankui Academy, Nanchang University, Nanchang, Jiangxi Province, China
| | - Ren-Chun Du
- Department of Clinical Laboratory, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Honggutan District, No.566 Xuefu Road, 330036, Nanchang, Jiangxi Province, China
- Huankui Academy, Nanchang University, Nanchang, Jiangxi Province, China
| | - Jing-Yuan Xu
- Department of Clinical Laboratory, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Honggutan District, No.566 Xuefu Road, 330036, Nanchang, Jiangxi Province, China
- Huankui Academy, Nanchang University, Nanchang, Jiangxi Province, China
| | - Yu-Xin Hu
- Department of Clinical Laboratory, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Honggutan District, No.566 Xuefu Road, 330036, Nanchang, Jiangxi Province, China
- The First Clinical Medical College, Nanchang University, Nanchang, Jiangxi Province, China
| | - Xun Xie
- Department of Clinical Laboratory, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Honggutan District, No.566 Xuefu Road, 330036, Nanchang, Jiangxi Province, China
- School of Nursing, Nanchang University, Nanchang, Jiangxi Province, China
| | - Qing-Yang Lan
- Department of Clinical Laboratory, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Honggutan District, No.566 Xuefu Road, 330036, Nanchang, Jiangxi Province, China
- The First Clinical Medical College, Nanchang University, Nanchang, Jiangxi Province, China
| | - Liaoliao Hu
- Department of Clinical Laboratory, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Honggutan District, No.566 Xuefu Road, 330036, Nanchang, Jiangxi Province, China.
| |
Collapse
|
|
3
|
Barrera FJ, Mostofsky E, Salia S, Lehman L, Liou L, Mucci L, Mittleman MA. Incidence of de novo malignancy and all-cause mortality among heart transplant recipients. Int J Cardiol 2024; 415:132455. [PMID: 39153512 PMCID: PMC11426084 DOI: 10.1016/j.ijcard.2024.132455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 07/23/2024] [Accepted: 08/13/2024] [Indexed: 08/19/2024]
Abstract
BACKGROUND Heart transplant recipients develop cancer at two-times the rate compared to the general population. However, the incidence and mortality rates and the adjusted association between cancer and mortality remains unclear. METHODS We estimated the incidence and mortality rates and the adjusted association between developing cancer (any, skin, hematologic, and solid tumor subtypes) and the all-cause mortality rates among adult heart transplant recipients from the Scientific Registry of Transplant Recipients from October 1, 1987, until June 28, 2020. RESULTS Among 51,597 adult heart transplant recipients, 13,191 (25.6%) were diagnosed with de novo malignancy throughout the follow-up period. The cumulative incidence cancer at years 1, 5, 10, and 20 was 3%, 16.4%, 32.8%, and 56.6%, respectively. Among those with cancer, the cumulative mortality was 17.5%, 42.3%, 65%, and 91% at years 1, 5, 10, and 20, respectively. The incidence rate of any de novo malignancy was 38.7 cases per 1000 person-years and the mortality rate (for those with cancer) was 115.2 cases per 1000 person-years. Compared to those without cancer, those with cancer had a higher adjusted mortality association [HR: 2.14 (2.07, 2.21)]. The strongest associations were estimated for pancreatic [10.63 (8.34, 13.54)], leukemia [8.06 (4.33, 15.00)], and esophagus [6.94 (5.43, 8.87)] malignancies. The association between de novo malignancies and mortality was higher in the earlier years of follow-up. CONCLUSION Compared to not developing cancer, those with de novo malignancy have a 2-fold higher mortality rate, on average. The strength of the association varies by cancer subtype and by follow-up time.
Collapse
Affiliation(s)
- Francisco J Barrera
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
| | - Elizabeth Mostofsky
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
| | - Soziema Salia
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Medicine, MedStar Union Memorial Hospital, Baltimore, MD, United States of America.
| | - Laura Lehman
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
| | - Lathan Liou
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Icahn School of Medicine at Mount Sinai, NY, USA
| | - Lorelei Mucci
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
| | - Murray A Mittleman
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Division of Cardiovascular Medicine, Department of Medicine, Beth, Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
| |
Collapse
|
|
4
|
Kim DS, Yoon YI, Kim BK, Choudhury A, Kulkarni A, Park JY, Kim J, Sinn DH, Joo DJ, Choi Y, Lee JH, Choi HJ, Yoon KT, Yim SY, Park CS, Kim DG, Lee HW, Choi WM, Chon YE, Kang WH, Rhu J, Lee JG, Cho Y, Sung PS, Lee HA, Kim JH, Bae SH, Yang JM, Suh KS, Al Mahtab M, Tan SS, Abbas Z, Shresta A, Alam S, Arora A, Kumar A, Rathi P, Bhavani R, Panackel C, Lee KC, Li J, Yu ML, George J, Tanwandee T, Hsieh SY, Yong CC, Rela M, Lin HC, Omata M, Sarin SK. Asian Pacific Association for the Study of the Liver clinical practice guidelines on liver transplantation. Hepatol Int 2024; 18:299-383. [PMID: 38416312 DOI: 10.1007/s12072-023-10629-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 12/18/2023] [Indexed: 02/29/2024]
Abstract
Liver transplantation is a highly complex and challenging field of clinical practice. Although it was originally developed in western countries, it has been further advanced in Asian countries through the use of living donor liver transplantation. This method of transplantation is the only available option in many countries in the Asia-Pacific region due to the lack of deceased organ donation. As a result of this clinical situation, there is a growing need for guidelines that are specific to the Asia-Pacific region. These guidelines provide comprehensive recommendations for evidence-based management throughout the entire process of liver transplantation, covering both deceased and living donor liver transplantation. In addition, the development of these guidelines has been a collaborative effort between medical professionals from various countries in the region. This has allowed for the inclusion of diverse perspectives and experiences, leading to a more comprehensive and effective set of guidelines.
Collapse
Affiliation(s)
- Dong-Sik Kim
- Department of Surgery, Korea University College of Medicine, Seoul, Republic of Korea
| | - Young-In Yoon
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | | | | | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jongman Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Dong Hyun Sinn
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Dong Jin Joo
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - YoungRok Choi
- Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jeong-Hoon Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Ho Joong Choi
- Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Ki Tae Yoon
- Department of Internal Medicine, Pusan National University College of Medicine, Yangsan, Republic of Korea
| | - Sun Young Yim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Cheon-Soo Park
- Department of Surgery, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Deok-Gie Kim
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hae Won Lee
- Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea
| | - Won-Mook Choi
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Young Eun Chon
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Woo-Hyoung Kang
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jinsoo Rhu
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jae Geun Lee
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yuri Cho
- Center for Liver and Pancreatobiliary Cancer, National Cancer Center, Ilsan, Republic of Korea
| | - Pil Soo Sung
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Han Ah Lee
- Department of Internal Medicine, Ewha Womans University, Seoul, Republic of Korea
| | - Ji Hoon Kim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Si Hyun Bae
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jin Mo Yang
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
| | - Kyung-Suk Suh
- Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
| | - Mamun Al Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Soek Siam Tan
- Department of Medicine, Hospital Selayang, Batu Caves, Selangor, Malaysia
| | - Zaigham Abbas
- Sindh Institute of Urology and Transplantation, Karachi, Pakistan
| | - Ananta Shresta
- Department of Hepatology, Alka Hospital, Lalitpur, Nepal
| | - Shahinul Alam
- Crescent Gastroliver and General Hospital, Dhaka, Bangladesh
| | - Anil Arora
- Department of Gastroenterology and Hepatology, Sir Ganga Ram Hospital New Delhi, New Delhi, India
| | - Ashish Kumar
- Department of Gastroenterology and Hepatology, Sir Ganga Ram Hospital New Delhi, New Delhi, India
| | - Pravin Rathi
- TN Medical College and BYL Nair Hospital, Mumbai, India
| | - Ruveena Bhavani
- University of Malaya Medical Centre, Petaling Jaya, Selangor, Malaysia
| | | | - Kuei Chuan Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Jun Li
- College of Medicine, Zhejiang University, Hangzhou, China
| | - Ming-Lung Yu
- Department of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | | | | | | | | | | | - H C Lin
- Endoscopy Center for Diagnosis and Treatment, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Masao Omata
- Department of Gastroenterology, Yamanashi Central Hospital, Yamanashi, Japan
- University of Tokyo, Bunkyo City, Japan
| | | |
Collapse
|
|
5
|
Zou WW, Mok HP, Zhu QK, Luo J, Yang S, Cen JZ, Gao Q. Perioperative corticosteroids for reducing postoperative complications following esophagectomy: an updated systematic review and meta-analysis. BMC Surg 2024; 24:57. [PMID: 38360649 PMCID: PMC10870429 DOI: 10.1186/s12893-024-02342-1] [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: 08/18/2023] [Accepted: 02/01/2024] [Indexed: 02/17/2024] Open
Abstract
BACKGROUND This updated systematic review and meta-analysis aims to evaluate the efficacy and safety of perioperative corticosteroid administration versus placebo for esophageal cancer patients following scheduled esophagectomy. METHODS We searched databases through June 30, 2023. We included articles on randomized controlled trials (RCTs) comparing perioperative corticosteroid administration with placebo in esophageal cancer patients with esophagectomy. The outcomes were the death rate during hospitalization, length of hospital stay, and short-term complications. Risk ratios (RRs) and corresponding 95% confidence interval (CIs) for each estimated effect size were applied for dichotomous outcomes, and the mean difference (MD) and corresponding 95% CIs for each estimated effect size were applied for continuous outcomes. We used GRADE to evaluate the quality of each of the outcome and the level of recommendations. RESULTS Nine RCTs with 508 participants were included in this study. Severe outcomes, including the length of hospital stay, leakage, mortality during the hospitalization period in the corticosteroid group was comparable to that in the control group, but positive effects of corticosteroid administration were observed on the length of intensive care unit stay (MD -3.1, 95% CI - 5.43 to - 0.77), cardiovascular disorders (RR 0.44, 95% CI 0.21-0.94) and other general complications (RR 0.49, 95% CI 0.29-0.85). CONCLUSIONS Peri-operative intravenous corticosteroid administration may reduce cardiovascular disorders, other general complications and the length of ICU stay without carrying severe outcomes. More high quality RCTs are warranted to further investigate the effects of corticosteroids on postoperative mortality and complications for esophageal cancer patients with esophagectomy. SYSTEMATIC REVIEW REGISTRATION Cochrane, registration number: 196.
Collapse
Affiliation(s)
- Wan-Wan Zou
- School of Medicine South China University of Technology, Guangzhou, 510006, People's Republic of China
- Department of Cardiovascular Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, 510080, People's Republic of China
- Guangdong Provincial Key Laboratory of South China Structural Heart Disease, Guangzhou, 510080, People's Republic of China
| | - Hsiao-Pei Mok
- Department of Breast Cancer, Cancer Center, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, 510080, People's Republic of China
| | - Qi-Kun Zhu
- Department of Cardiovascular Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, 510080, People's Republic of China
- Guangdong Provincial Key Laboratory of South China Structural Heart Disease, Guangzhou, 510080, People's Republic of China
| | - Jing Luo
- Department of Cardiovascular Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, 510080, People's Republic of China
- Guangdong Provincial Key Laboratory of South China Structural Heart Disease, Guangzhou, 510080, People's Republic of China
| | - Song Yang
- Department of Cardiovascular Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, 510080, People's Republic of China
- Guangdong Provincial Key Laboratory of South China Structural Heart Disease, Guangzhou, 510080, People's Republic of China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, People's Republic of China
| | - Jian-Zheng Cen
- Department of Cardiovascular Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, 510080, People's Republic of China
- Guangdong Provincial Key Laboratory of South China Structural Heart Disease, Guangzhou, 510080, People's Republic of China
| | - Qiang Gao
- Department of Cardiovascular Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, 510080, People's Republic of China.
- Guangdong Provincial Key Laboratory of South China Structural Heart Disease, Guangzhou, 510080, People's Republic of China.
| |
Collapse
|
|
6
|
Domouchtsidou A, Beckmann F, Marenbach B, Mueller SP, Best J, Herrmann K, Horn PA, Barsegian V, Lindemann M. In Patients Treated by Selective Internal Radiotherapy, Cellular In Vitro Immune Function Is Predictive of Survival. Cancers (Basel) 2023; 15:4055. [PMID: 37627082 PMCID: PMC10452121 DOI: 10.3390/cancers15164055] [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: 07/03/2023] [Revised: 07/28/2023] [Accepted: 08/10/2023] [Indexed: 08/27/2023] Open
Abstract
In patients with liver malignancies, the cellular immune function was impaired in vitro after selective internal radiotherapy (SIRT). Because immunosuppression varied substantially, in the current study, we investigated in 25 SIRT patients followed up for ten years whether the lymphocyte function was correlated with survival. Peripheral blood mononuclear cells were stimulated with four microbial antigens (tuberculin, tetanus toxoid, Candida albicans and CMV) before therapy and at four time points thereafter, and lymphocyte proliferation was determined by H3-thymidine uptake. The median sum of the responses to these four antigens decreased from 39,464 counts per minute (CPM) increment (range 1080-204,512) before therapy to a minimum of 700 CPM increment on day 7 after therapy (0-93,187, p < 0.0001). At all five time points, the median survival in patients with weaker responses was 2- to 3.5-fold shorter (p < 0.05). On day 7, the median survival in patients with responses below and above the cutoff of a 2 CPM increment was 185 and 523 days, respectively (χ2 = 9.4, p = 0.002). In conclusion, lymphocyte function could be a new predictor of treatment outcome after SIRT.
Collapse
Affiliation(s)
- Aglaia Domouchtsidou
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Virchowstraße 179, 45147 Essen, Germany; (A.D.); (F.B.); (B.M.); (P.A.H.)
- Department of Microbiology, General Anticancer Oncological Hospital “Agios Savvas”, 115 22 Athens, Greece
| | - Ferdinand Beckmann
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Virchowstraße 179, 45147 Essen, Germany; (A.D.); (F.B.); (B.M.); (P.A.H.)
| | - Beate Marenbach
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Virchowstraße 179, 45147 Essen, Germany; (A.D.); (F.B.); (B.M.); (P.A.H.)
| | - Stefan P. Mueller
- Department of Nuclear Medicine, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany; (S.P.M.); (K.H.); (V.B.)
| | - Jan Best
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany;
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus Bochum, Ruhr University Bochum, 44892 Bochum, Germany
| | - Ken Herrmann
- Department of Nuclear Medicine, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany; (S.P.M.); (K.H.); (V.B.)
| | - Peter A. Horn
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Virchowstraße 179, 45147 Essen, Germany; (A.D.); (F.B.); (B.M.); (P.A.H.)
| | - Vahé Barsegian
- Department of Nuclear Medicine, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany; (S.P.M.); (K.H.); (V.B.)
- Institute of Nuclear Medicine, Helios Kliniken, 19049 Schwerin, Germany
| | - Monika Lindemann
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Virchowstraße 179, 45147 Essen, Germany; (A.D.); (F.B.); (B.M.); (P.A.H.)
| |
Collapse
|
|
7
|
Kang M, Cho JY, Han HS, Yoon YS, Lee HW, Lee B, Park Y, Kim J, Yoon CJ. Comparative Study of Long-Term Outcomes of Laparoscopic Liver Resection versus Radiofrequency Ablation for Single Small Hepatocellular Carcinoma Located in Left Lateral Segments of the Liver. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1063. [PMID: 37374267 DOI: 10.3390/medicina59061063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 05/23/2023] [Accepted: 05/26/2023] [Indexed: 06/29/2023]
Abstract
Background and Objectives: Laparoscopic liver resection (LLR) is now widely recognized as the primary surgical option for hepatocellular carcinomas (HCC) smaller than 3 cm located in the left lateral segment of the liver. Nevertheless, there is a scarcity of studies comparing laparoscopic liver resection with radiofrequency ablation (RFA) in these cases. Materials and Methods: We retrospectively compared the short- and long-term outcomes of Child-Pugh class A patients who underwent LLR (n = 36) or RFA (n = 40) for a newly diagnosed single small (≤3 cm) HCC located in the left lateral segment of the liver. Results: Overall survival (OS) was not significantly different between the LLR and RFA groups (94.4% vs. 80.0%, p = 0.075). However, disease-free survival (DFS) was better in the LLR group than in the RFA group (p < 0.001), with 1-, 3-, and 5-year DFS rates of 100%, 84.5%, and 74.4%, respectively, in the LLR group vs. 86.9%, 40.2%, and 33.4%, respectively, in the RFA group. The hospital stay was significantly shorter in the RFA group than in the LLR (2.4 vs. 4.9 days, p < 0.001). The overall complication rate was higher in the RFA group than in the LLR group (15% vs. 5.6%). In patients with an α-fetoprotein level of ≥20 ng/mL, the 5-year OS (93.8% vs. 50.0%, p = 0.031) and DFS (68.8% vs. 20.0%, p = 0.002) rates were greater in the LLR group. Conclusions: LLR showed superior OS and DFS compared to RFA in patients with a single small HCC situated in the left lateral segment of the liver. LLR can be considered for patients with an α-fetoprotein level of ≥20 ng/mL.
Collapse
Affiliation(s)
- MeeYoung Kang
- Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul 13620, Republic of Korea
| | - Jai Young Cho
- Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul 13620, Republic of Korea
| | - Ho-Seong Han
- Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul 13620, Republic of Korea
| | - Yoo-Seok Yoon
- Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul 13620, Republic of Korea
| | - Hae Won Lee
- Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul 13620, Republic of Korea
| | - Boram Lee
- Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul 13620, Republic of Korea
| | - Yeshong Park
- Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul 13620, Republic of Korea
| | - Jinju Kim
- Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul 13620, Republic of Korea
| | - Chang Jin Yoon
- Department of Radiology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul 13620, Republic of Korea
| |
Collapse
|
|
8
|
Rovgaliyev B, Tan MY, Lee KW, Oh SC, Park MY, Seo S, Choi HS, Hong SK, Cho JH, Lee JM, Yi NJ, Suh KS. Sirolimus Attenuates Calcineurin Inhibitor-Induced Epithelial-Mesenchymal Transition in Hepatocellular Carcinoma. Transplant Proc 2022; 54:2025-2034. [PMID: 35977851 DOI: 10.1016/j.transproceed.2022.04.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 03/17/2022] [Accepted: 04/13/2022] [Indexed: 10/15/2022]
Abstract
BACKGROUND Calcineurin inhibitors (CNIs), which are potent immunosuppressants (ISs), increase the risk for hepatocellular carcinoma (HCC) recurrence after liver transplantation (LTx). Epithelial-mesenchymal transition (EMT) is a key process in which epithelial cancer cells lose their polarity, resulting in cancer progression and metastasis. The aim of this study was to evaluate the effect of sirolimus (SRL) individually and in combination with other ISs to reduce EMT. METHODS HCC SK-Hep1 cells were used and various ISs (SRL, tacrolimus, cyclosporine A, or mycophenolate mofetil) were administered at 2 dosages and in combination therapies. Mice were transplanted with SK-Hep1 cells (in the liver) and were monitored after 2 weeks. RESULTS The in vitro treatment with SRL showed a dose-dependent attenuation of cell proliferation and migration in case of the individual and IS combination treatments; further, decreased levels of pro-EMT proteins, namely, N-cadherin, transforming growth factor-β, ZEB1, Slug, and Snail were observed. In contrast, E-cadherin expression was upregulated after both the individual and IS combination treatments. These results were also observed in the samples from mice transplanted with the SK-Hep1 cells. CONCLUSION The present study demonstrated that SRL reduced HCC metastasis by inhibiting EMT. Thus, our findings provide a rationale for the use of SRL in combination with ISs in HCC LTx patients.
Collapse
Affiliation(s)
- Berik Rovgaliyev
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Ming Yuan Tan
- 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.
| | - Seung Cheol Oh
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Min Young Park
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Sooin Seo
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Hyo-Sun Choi
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Suk Kyun Hong
- 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
| | - Jeong-Moo Lee
- 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
|
|
9
|
Kornberg A, Kaschny L, Kornberg J, Friess H. Preoperative Prognostic Nutritional Index May Be a Strong Predictor of Hepatocellular Carcinoma Recurrence Following Liver Transplantation. J Hepatocell Carcinoma 2022; 9:649-660. [PMID: 35923612 PMCID: PMC9342250 DOI: 10.2147/jhc.s366107] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Accepted: 06/23/2022] [Indexed: 12/12/2022] Open
Abstract
Purpose Malnutrition is a major risk factor of immune dysfunction and poor outcome in cancer patients. The prognostic nutritional index (PNI), which is established by serum albumin level and peripheral lymphocyte count, was shown to correlate with prognosis of hepatocellular carcinoma (HCC) patients following liver resection and non-surgical interventions. The aim of this study was to analyze the predictive value of preoperative PNI in liver transplantation (LT) patients with HCC. Patients and Methods A total of 123 HCC patients that underwent LT were included in the analysis. The prognostic impact of preoperatively assessed clinical factors including the PNI on post-LT outcome was analyzed by uni- and multivariate analysis. Results Post-transplant tumor recurrence rates were 5.1% in high-PNI (> 42) and 55.6% in low-PNI (≤ 42) patients (p < 0.001). Preoperative high-PNI could be identified as a significant and independent promoter of both recurrence-free survival (hazard ratio [HR] = 10.12, 95% CI: 3.40–30.10; p < 0.001) and overall survival (HR = 1.69, 95% CI: 1.02–2.79; p = 0.004) following LT. Apart from that low-PNI proved to be a significant and independent predictor of microvascular tumor invasion (OR = 7.71, 95% CI: 3.17–18.76; p < 0.001). In contrast, no tumor morphology features including the Milan criteria revealed an independent prognostic value. Conclusion Our data indicate that preoperative PNI correlates with biological tumor aggressiveness and outcome following LT in HCC patients and may therefore be useful for refining oncologic risk stratification.
Collapse
Affiliation(s)
- Arno Kornberg
- Technical University of Munich, School of Medicine, Klinikum rechts der Isar, Department of Surgery, Munich, Germany
- Correspondence: Arno Kornberg, Technical University of Munich, Medical School, Klinikum rechts der Isar, Department of Surgery, Ismaningerstr. 22, Munich, D-81675, Germany, Tel +49 89 41405087, Fax +49 89 41404884, Email
| | - Linda Kaschny
- Technical University of Munich, School of Medicine, Klinikum rechts der Isar, Department of Surgery, Munich, Germany
| | - Jennifer Kornberg
- Technical University of Munich, School of Medicine, Klinikum rechts der Isar, Department of Surgery, Munich, Germany
| | - Helmut Friess
- Technical University of Munich, School of Medicine, Klinikum rechts der Isar, Department of Surgery, Munich, Germany
| |
Collapse
|
|
10
|
Dakua SP, Nayak A. A review on treatments of hepatocellular carcinoma—role of radio wave ablation and possible improvements. EGYPTIAN LIVER JOURNAL 2022. [DOI: 10.1186/s43066-022-00191-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Currently, several treatment options are available for liver cancer depending on various factors such as location, size, shape, and liver function. Image fusion is required for the diagnosis, intervention, and follow-up of certain HCCs. Presently, mental fusion is the only way while diagnosing liver lesions by comparing the ultrasound (US) image with the computed tomography (CT) image. Nevertheless, mental fusion is bound to have errors. The objective of this paper is to study the present treatment options for hepatocellular carcinoma and review the present treatment options, list out their potential limitations, and present a possible alternative solution based on the findings to reduce errors and mistargeting.
Methods
This is a systematic review on the present treatment options for hepatocellular carcinoma, especially radio wave ablation.
Results
It is found that computer fusion is the possible alternative to the present mental registration.
Conclusions
Although computer fusion is the best alternative to use radio wave ablation, there have been a few open-ended questions to further explore.
Collapse
|
|
11
|
Tsai YF, Liu FC, Chen CY, Lin JR, Yu HP. Effect of Mycophenolate Mofetil Therapy on Recurrence of Hepatocellular Carcinoma after Liver Transplantation: A Population-Based Cohort Study. J Clin Med 2021; 10:jcm10081558. [PMID: 33917215 PMCID: PMC8068064 DOI: 10.3390/jcm10081558] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 03/11/2021] [Accepted: 03/18/2021] [Indexed: 12/23/2022] Open
Abstract
Hepatocellular carcinoma (HCC) recurrence after liver transplantation is associated with immunosuppressants. However, the appropriate immunosuppressant for HCC recipients is still debated. Data for this nationwide population-based cohort study were extracted from the National Health Insurance Research Database of Taiwan. A total of 1250 liver transplant recipients (LTRs) with HCC were included. We analyzed the risk factors for post-transplant HCC recurrences. Cumulative defined daily dose (cDDD) represented the exposure duration and was calculated as the amount of dispensed defined daily dose (DDD) of mycophenolate mofetil (MMF). The dosage effects of MMF on HCC recurrence and liver graft complication rates were investigated. A total of 155 LTRs, having experienced post-transplant HCC recurrence, exhibited low survival probability at 1-, 3-, 5-, and 10-year observations. Our results demonstrated increased HCC recurrence rate after liver transplantation (p = 0.0316) following MMF administration; however, no significant increase was demonstrated following cyclosporine, tacrolimus, or sirolimus administration. Notably, our data demonstrated significantly increased HCC recurrence rate following MMF administration with cDDD > 0.4893 compared with cDDD ≤ 0.4893 or no administration of MMF (p < 0.0001). MMF administration significantly increases the risk of HCC recurrence. Moreover, a MMF-minimizing strategy (cDDD ≤ 0.4893) is recommended for recurrence-free survival.
Collapse
Affiliation(s)
- Yung-Fong Tsai
- Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (Y.-F.T.); (F.-C.L.); (C.-Y.C.)
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Fu-Chao Liu
- Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (Y.-F.T.); (F.-C.L.); (C.-Y.C.)
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Chun-Yu Chen
- Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (Y.-F.T.); (F.-C.L.); (C.-Y.C.)
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Jr-Rung Lin
- Clinical Informatics and Medical Statistics Research Center, Chang Gung University, Taoyuan 333, Taiwan;
- Graduate Institute of Clinical Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Huang-Ping Yu
- Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; (Y.-F.T.); (F.-C.L.); (C.-Y.C.)
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
- Correspondence: ; Tel.: +86-886-3-3281200 (ext. 2324)
| |
Collapse
|
|
12
|
Adoptive Cell Therapy in Hepatocellular Carcinoma: Biological Rationale and First Results in Early Phase Clinical Trials. Cancers (Basel) 2021; 13:cancers13020271. [PMID: 33450845 PMCID: PMC7828372 DOI: 10.3390/cancers13020271] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 01/07/2021] [Accepted: 01/08/2021] [Indexed: 12/13/2022] Open
Abstract
The mortality of hepatocellular carcinoma (HCC) is quickly increasing worldwide. In unresectable HCC, the cornerstone of systemic treatments is switching from tyrosine kinase inhibitors to immune checkpoints inhibitors (ICI). Next to ICI, adoptive cell transfer represents another promising field of immunotherapy. Targeting tumor associated antigens such as alpha-fetoprotein (AFP), glypican-3 (GPC3), or New York esophageal squamous cell carcinoma-1 (NY-ESO-1), T cell receptor (TCR) engineered T cells and chimeric antigen receptors (CAR) engineered T cells are emerging as potentially effective therapies, with objective responses reported in early phase trials. In this review, we address the biological rationale of TCR/CAR engineered T cells in advanced HCC, their mechanisms of action, and results from recent clinical trials.
Collapse
|
|
13
|
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
|
|
14
|
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
|
|
15
|
Wang Y, Zhang P, Yuan M, Li X. Overexpression of miRNA-21 Promotes the Proliferation and Invasion in Hepatocellular Carcinoma Cells via Suppressing SMAD7. Technol Cancer Res Treat 2020; 18:1533033819878686. [PMID: 31554487 PMCID: PMC6763940 DOI: 10.1177/1533033819878686] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Purpose: This study aimed to explore the molecular mechanism of microRNA-21 and smad family member 7 in hepatocellular carcinoma. Method: A total of 57 participants were divided into control group (healthy participants, n = 10) and hepatocellular carcinoma group (hepatocellular carcinoma patients, n = 37). The expression of microRNA-21 levels were first detected in these two groups. Cell transfection was performed on hepatoma cell lines, followed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Transwell assay to reveal proliferation and invasion ability. Furthermore, the relation between microRNA-21 and smad family member 7 was revealed by luciferase reporter gene and RNA immunoprecipitation assay. Finally, a transplantation tumor model of breast cancer in mice was constructed. Results: The serum indicators including α-alanine aminotransferase, aspartate aminotransferase, and albumin were differentially expressed between hepatocellular carcinoma group and control group. Compared to the control group, there was a high expression of microRNA-21 in hepatocellular carcinoma group. Low expression of microRNA-21 inhibited the proliferation and invasion of HepG2.2.15 and Huh7-1.3 cells. Luciferase reporter gene and RNA innumoprecipitation assay showed that smad family member 7 was the target gene of microRNA-21. Moreover, mice model analysis showed that microRNA-21 might regulate the growth of the transplanted tumors in mice by targeting smad family member 7. Conclusion: The upregulated microRNA-21 might participate in the proliferation and migration in cells of hepatocellular carcinoma via suppression of smad family member 7. Furthermore, serum indicators such as alanine aminotransferase, aspartate aminotransferase, and albumin might be used as serum diagnostic markers for hepatocellular carcinoma.
Collapse
Affiliation(s)
- Yan Wang
- Chronic Disease Management Center, Qingdao Sixth People's Hospital, Qingdao City, Shandong Province, China
| | - Ping Zhang
- Department of Clinical Lab, Qingdao Sixth People's Hospital, Qingdao City, Shandong Province, China
| | - Mei Yuan
- Department of Clinical Lab, Qingdao Sixth People's Hospital, Qingdao City, Shandong Province, China
| | - Xiaojie Li
- Department of The 7th Inpatient Ward, Qingdao Sixth People's Hospital, Qingdao City, Shandong Province, China
| |
Collapse
|
|
16
|
Can Mycophenolic Acid-based Immunosuppression Benefit Liver Transplant Patients With HCC? Transplantation 2019; 103:873-874. [PMID: 30720687 DOI: 10.1097/tp.0000000000002648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
|
|
17
|
Ma KW, Chok KSH, Fung JYY, Lo CM. Liver Transplantation for Hepatitis B Virus-related Hepatocellular Carcinoma in Hong Kong. J Clin Transl Hepatol 2018; 6:283-288. [PMID: 30271740 PMCID: PMC6160307 DOI: 10.14218/jcth.2017.00058] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Revised: 01/09/2018] [Accepted: 01/31/2018] [Indexed: 01/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer-related deaths worldwide. Curative resection is frequently limited in Hong Kong by hepatitis B virus-related cirrhosis, and liver transplantation is the treatment of choice. Liver transplantation has been shown to produce superior oncological benefits, when compared to hepatectomy for HCC. New developments in the context of patient selection criteria, modification of organ allocation, bridging therapy, salvage liver transplantation and pharmaceutical breakthrough have improved the survival of HCC patients. In this article, we will share our experience in transplanting hepatitis B virus-related HCC patients in Hong Kong and discuss the recent progress in several areas of liver transplantation.
Collapse
Affiliation(s)
- Ka Wing Ma
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Kenneth Siu Ho Chok
- Department of Surgery, The University of Hong Kong, Hong Kong, China
- State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China
| | - James Yan Yue Fung
- State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China
- Department of Medicine, The University of Hong Kong, Hong Kong, China
| | - Chung Mau Lo
- Department of Surgery, The University of Hong Kong, Hong Kong, China
- State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China
| |
Collapse
|
|
18
|
Foerster F, Mittler J, Darstein F, Heise M, Marquardt JU, Wörns MA, Weinmann A, Sälter L, Hoppe-Lotichius M, Heinrich S, Kloeckner R, Pitton MB, Schattenberg JM, Sprinzl MF, Düber C, Otto G, Lang H, Galle PR, Zimmermann T. Recipient liver function before liver transplantation influences post-transplantation survival in patients with HCC. Eur J Intern Med 2018; 55:57-65. [PMID: 29859798 DOI: 10.1016/j.ejim.2018.05.024] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2018] [Revised: 05/05/2018] [Accepted: 05/20/2018] [Indexed: 01/10/2023]
Abstract
BACKGROUND Liver transplantation (LT) is a complex yet curative treatment for a subset of patients with hepatocellular carcinoma (HCC). Due to donor organ shortage, patients with HCC need to be carefully selected for LT. In European countries, selection of patients is based on the Milan criteria, and donor organs are allocated by Eurotransplant. In order to optimize the utilization of available liver grafts, the outcome of HCC patients after LT needs to be closely monitored and evaluated. METHODS We assessed the outcome of 304 HCC patients who underwent LT at a tertiary medical center over a period of nearly 20 years (February 1998 until June 2017). RESULTS The 5-, 10- and 15-year survival rates were 62, 47 and 30%, respectively. The strongest survival-determining factor was tumour recurrence. Apart from a high tumour grading, the pre-LT MELD score was significantly and negatively associated with survival after LT. CONCLUSION Our results confirm the importance of recurrence for the outcome of HCC patients after LT and highlight the relevance of HCC patients' liver function before LT. Our findings encourage efforts to identify prognostically relevant factors for LT in HCC with the overall goal of refining the organ allocation system and maximizing the survival benefit after LT.
Collapse
Affiliation(s)
- Friedrich Foerster
- Department of Internal Medicine I, University Medical Center Mainz, Germany; Interdiscliplinary Transplantation Center (ITx), Mainz, Germany
| | - Jens Mittler
- Department of General and Abdominal Surgery, University Medical Center Mainz, Germany; Interdiscliplinary Transplantation Center (ITx), Mainz, Germany
| | - Felix Darstein
- Department of Internal Medicine I, University Medical Center Mainz, Germany; Interdiscliplinary Transplantation Center (ITx), Mainz, Germany
| | - Michael Heise
- Department of General and Abdominal Surgery, University Medical Center Mainz, Germany; Interdiscliplinary Transplantation Center (ITx), Mainz, Germany
| | - Jens U Marquardt
- Department of Internal Medicine I, University Medical Center Mainz, Germany; Interdiscliplinary Transplantation Center (ITx), Mainz, Germany
| | - Marcus-Alexander Wörns
- Department of Internal Medicine I, University Medical Center Mainz, Germany; Interdiscliplinary Transplantation Center (ITx), Mainz, Germany
| | - Arndt Weinmann
- Department of Internal Medicine I, University Medical Center Mainz, Germany; Interdiscliplinary Transplantation Center (ITx), Mainz, Germany
| | - Lina Sälter
- Department of Internal Medicine I, University Medical Center Mainz, Germany; Interdiscliplinary Transplantation Center (ITx), Mainz, Germany
| | - Maria Hoppe-Lotichius
- Department of General and Abdominal Surgery, University Medical Center Mainz, Germany; Interdiscliplinary Transplantation Center (ITx), Mainz, Germany
| | - Stefan Heinrich
- Department of General and Abdominal Surgery, University Medical Center Mainz, Germany; Interdiscliplinary Transplantation Center (ITx), Mainz, Germany
| | - Roman Kloeckner
- Department of Diagnostic and Interventional Radiology, University Medical Center Mainz, Germany; Interdiscliplinary Transplantation Center (ITx), Mainz, Germany
| | - Michael B Pitton
- Department of Diagnostic and Interventional Radiology, University Medical Center Mainz, Germany; Interdiscliplinary Transplantation Center (ITx), Mainz, Germany
| | - Jörn M Schattenberg
- Department of Internal Medicine I, University Medical Center Mainz, Germany; Interdiscliplinary Transplantation Center (ITx), Mainz, Germany
| | - Martin F Sprinzl
- Department of Internal Medicine I, University Medical Center Mainz, Germany; Interdiscliplinary Transplantation Center (ITx), Mainz, Germany
| | - Christoph Düber
- Department of Diagnostic and Interventional Radiology, University Medical Center Mainz, Germany; Interdiscliplinary Transplantation Center (ITx), Mainz, Germany
| | - Gerd Otto
- Department of General and Abdominal Surgery, University Medical Center Mainz, Germany; Interdiscliplinary Transplantation Center (ITx), Mainz, Germany
| | - Hauke Lang
- Department of General and Abdominal Surgery, University Medical Center Mainz, Germany; Interdiscliplinary Transplantation Center (ITx), Mainz, Germany
| | - Peter R Galle
- Department of Internal Medicine I, University Medical Center Mainz, Germany; Interdiscliplinary Transplantation Center (ITx), Mainz, Germany
| | - Tim Zimmermann
- Department of Internal Medicine I, University Medical Center Mainz, Germany; Interdiscliplinary Transplantation Center (ITx), Mainz, Germany.
| |
Collapse
|
|
19
|
Acuna SA. Etiology of increased cancer incidence after solid organ transplantation. Transplant Rev (Orlando) 2018; 32:218-224. [PMID: 30017342 DOI: 10.1016/j.trre.2018.07.001] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Revised: 06/28/2018] [Accepted: 07/05/2018] [Indexed: 01/15/2023]
Abstract
Over the past decades, there has been an encouraging increase in survival after solid organ transplantation. However, with longer life spans, more transplant recipients are at risk of dying with functioning grafts from illnesses such as cancer and cardiovascular conditions. Malignancy has emerged as an important cause of death in transplant recipients and is expected to become the leading cause of death in transplanted patients within the next decade. While it is known that solid organ transplant recipients have a three to five-fold increased risk of developing cancer compared with the general population, the mechanisms that lead to the observed excess risk in transplant recipients are less clear. This review explores the etiology of the increased cancer incidence in solid organ transplant including the effect of immunosuppressants on immunosurveillance and activation of oncogenic viruses, and carcinogenic effects of these medications; the role of chronic stimulation of the immune system on the development of cancer; and the impact of pre-existing cancer risk factors and factors related to end-stage organ disease on the cancer excess incidence in solid organ transplant recipients.
Collapse
Affiliation(s)
- Sergio A Acuna
- Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada; Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada; Department of Surgery, St. Michael's Hospital, Toronto, Canada; Division of General Surgery, Department of Surgery, University of Toronto, Toronto, Canada.
| |
Collapse
|
|
20
|
Yoon YI, Song GW, Lee SG, Hwang S, Kim KH, Kim SH, Kang WH, Cho HD, Jwa EK, Kwon JH, Tak EY, Kirchner VA. Outcome of ABO-incompatible adult living-donor liver transplantation for patients with hepatocellular carcinoma. J Hepatol 2018; 68:1153-1162. [PMID: 29452208 DOI: 10.1016/j.jhep.2018.02.002] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Revised: 02/01/2018] [Accepted: 02/04/2018] [Indexed: 01/10/2023]
Abstract
BACKGROUND & AIMS Living-donor liver transplantation (LDLT) can simultaneously cure hepatocellular carcinoma (HCC) and underlying liver cirrhosis, improving long-term results in patients with HCC. ABO-incompatible LDLT could expand the living-donor pool, reduce waiting times for deceased-donor liver transplantation, and improve long-term survival for some patients with HCC. METHODS We retrospectively reviewed the medical records of patients undergoing LDLT for HCC from November 2008 to December 2015 at a single institution in Korea. In total, 165 patients underwent ABO-incompatible and 753 patients underwent ABO-compatible LDLT for HCC. ABO-incompatible recipients underwent desensitization to overcome the ABO blood group barrier, including pretransplant plasma exchange and rituximab administration (300-375 mg/m2 /body surface area). RESULTS We performed 1:1 propensity score matching and included 165 patients in each group. 82.4% of ABO-incompatible and 83.0% of -compatible LDLT groups had HCC within conventional Milan criteria, respectively, and 92.1% and 92.7% of patients in each group had a Child-Pugh score of A or B. ABO-incompatible and -compatible LDLT groups were followed up for 48.0 and 48.7 months, respectively, with both groups showing comparable recurrence-free survival rates (hazard ratio [HR] 1.14; 95% CI 0.68-1.90; p = 0.630) and overall patient-survival outcomes (HR 1.10; 95% CI 0.60-2.00; p = 0.763). CONCLUSIONS These findings suggested that ABO-incompatible liver transplantation is a feasible option for patients with HCC, especially for those with compensated cirrhosis with HCC within conventional Milan criteria. LAY SUMMARY Despite hypothetical immunological concerns that the desensitization protocol for breaking through the ABO blood group barrier might have a negative impact on the recurrence of hepatocellular carcinoma, our experience demonstrated no significant differences in the long-term overall survival and recurrence-free survival rates between patients receiving ABO-compatible or ABO-incompatible liver transplantation. In conclusion, results from our institution indicated that ABO-incompatible living-donor liver transplantation constitutes a potentially feasible option for patients with hepatocellular carcinoma, especially those with compensated cirrhosis with hepatocellular carcinoma within conventional Milan criteria.
Collapse
Affiliation(s)
- Young-In Yoon
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Gi-Won Song
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
| | - Sung-Gyu Lee
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Shin Hwang
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Ki-Hun Kim
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Seok-Hwan Kim
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Woo-Hyoung Kang
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Hwui-Dong Cho
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Eun-Kyoung Jwa
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jae-Hyun Kwon
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Eun-Young Tak
- Asan Institute for Life Sciences and Asan-Minnesota Institute for Innovating Transplantation, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Varvara A Kirchner
- Division of Transplantation, Department of Surgery and Asan-Minnesota Institute for Innovating Transplantation, University of Minnesota, Minneapolis, MN, USA
| |
Collapse
|
|
21
|
Benjamin AJ, Baker TB, Talamonti MS, Bodzin AS, Schneider AB, Winschester DJ, Roggin KK, Bentrem DJ, Suss NR, Baker MS. Liver transplant offers a survival benefit over margin negative resection in patients with small unifocal hepatocellular carcinoma and preserved liver function. Surgery 2018; 163:582-586. [PMID: 29370929 DOI: 10.1016/j.surg.2017.12.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2017] [Revised: 12/04/2017] [Accepted: 12/05/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND Studies comparing orthotopic liver transplantation to margin negative resection for patients with small unifocal hepatocellular carcinoma have not controlled for degree of cirrhosis. METHODS The National Cancer Database was used to identify patients with preserved liver function (Model for End-stage Liver Disease score ≤12) who underwent orthotopic liver transplantation or margin negative resection for American Joint Committee on Cancer stage I hepatocellular carcinoma lesions <3 cm between 2010 and 2013. Multivariable and Cox regression adjusting for age, demographics, comorbid disease burden, Model for End-stage Liver Disease score, tumor size, and operation were used to compare overall survival between cohorts. RESULTS In the study, 241 (53%) patients underwent orthotopic liver transplantation. In addition, 219 (47%) underwent margin negative resection. On multivariable regression, patients having a Charlson comorbidity score ≥2 were more likely to undergo orthotopic liver transplantation, (odds ratio 1.94, P=.03). African American patients (odds ratio 0.44, P=.02), and patients of advanced age (odds ratio 0.92, P<.001) were more likely to undergo margin negative resection. Patients undergoing orthotopic liver transplantation had longer overall survival than those undergoing margin negative resection (median OS not reached versus 67.6 months, P<.001). Multivariable Cox regression identified surgical procedure as the only independent determinant of survival with margin negative resection conferring a nearly 3-fold increased risk of death (hazard ratio 2.86, P<.001). CONCLUSION Orthotopic liver transplantation offers a survival advantage relative to margin negative resection for patients with small unifocal hepatocellular carcinoma and preserved liver function.
Collapse
Affiliation(s)
| | - Talia B Baker
- Department of Surgery, University of Chicago, Chicago, IL
| | - Mark S Talamonti
- Department of Surgery, Northshore University HealthSystem, Evanston, IL
| | - Adam S Bodzin
- Department of Surgery, University of Chicago, Chicago, IL
| | | | | | - Kevin K Roggin
- Department of Surgery, University of Chicago, Chicago, IL
| | | | - Nicholas R Suss
- Department of Surgery, Northshore University HealthSystem, Evanston, IL
| | - Marshall S Baker
- Department of Surgery, Northshore University HealthSystem, Evanston, IL.
| |
Collapse
|
|
22
|
Huang CP, Chen CC, Shyr CR. Xenogeneic cell therapy provides a novel potential therapeutic option for cancers by restoring tissue function, repairing cancer wound and reviving anti-tumor immune responses. Cancer Cell Int 2018; 18:9. [PMID: 29371832 PMCID: PMC5771064 DOI: 10.1186/s12935-018-0501-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Accepted: 01/03/2018] [Indexed: 12/13/2022] Open
Abstract
Conventional cancer treatments such as surgery, radiotherapy, chemotherapy and targeted therapy, not only destruct tumors, but also injure the normal tissues, resulting in limited efficacy. Recent advances in cancer therapy have aimed at changing the host milieu of cancer against its development and progression by targeting tumor microenvironment and host immune system to eradicate tumors. To the host body, tumors arise in tissues. They impair the normal healthy tissue physiological function, become chronically inflamed and develop non-healing or overhealing wounds as well as drive immuno-suppressive activity to escape immunity attack. Therefore, the rational therapeutic strategies for cancers should treat both the tumors and the host body for the best efficacy to turn the deadly malignant disease to a manageable one. Xenogeneic cell therapy (i.e. cellular xenotransplantation) using cells from non-human source animals such as pigs has shown promising results in animal studies and clinical xenotransplantation in restoring lost tissue physiological function and repairing the wound. However, the major hurdle of xenogeneic cell therapy is the host immunological barriers that are induced by transplanted xenogeneic cells to reject xenografts. Possibly, the immunological barriers of xenogeneic cells could be used as immunological boosters to activate the host immune system. Here, we hypothesized that because of the biological properties of xenogeneic cells to the recipient humans, the transplantation of xenogeneic cells (i.e. cellular xenotransplantation) into cancer patients' organs of the same origin with developed tumors may restore the impaired function of organs, repair the wound, reduce chronic inflammation and revive the anti-tumor immunity to achieve beneficial outcome for patients.
Collapse
Affiliation(s)
- Chi-Ping Huang
- Department of Urology, Graduate Institute of Clinical Medical Science, China Medical University and Hospital, 40454, Taichung, Taiwan
| | - Chi-Cheng Chen
- Department of Urology, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung 404, Taiwan
| | - Chih-Rong Shyr
- Department of Urology, Graduate Institute of Clinical Medical Science, China Medical University and Hospital, 40454, Taichung, Taiwan
- Sex Hormone Research Center, Department of Laboratory Science and Biotechnology, China Medical University and Hospital, 6 Hsiuh-Shih Rd, Taichung, 40454 Taiwan
| |
Collapse
|
|
23
|
Lerut J, Iesari S, Foguenne M, Lai Q. Hepatocellular cancer and recurrence after liver transplantation: what about the impact of immunosuppression? Transl Gastroenterol Hepatol 2017; 2:80. [PMID: 29167827 PMCID: PMC5676205 DOI: 10.21037/tgh.2017.09.06] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Accepted: 09/05/2017] [Indexed: 12/12/2022] Open
Abstract
Liver transplantation (LT) has originally been designed to treat hepatobiliary malignancies. The initial results of LT for hepatocellular cancer (HCC) were, however, dismal this mainly due to the poor patient selection procedure. Better surgical and perioperative care and, especially, the refinement of selection criteria led to a major improvement of results, making HCC nowadays (again!) one of the leading indications for LT. This evolution is clearly shown by the innumerable reports aiming to further extend inclusion criteria for LT in HCC patients. Nonetheless, the vast majority of papers only deals with morphologic (tumour diameter and number) and (only recently) biologic (tumour markers and response to locoregional treatment) parameters to do so. Curiously enough, the role of both the immune competent state of the recipient as well as the impact of both immunosuppression (IS) type and load has been very poorly addressed in this context, even if it has been shown for a long time, based on both basic and clinical research, that they all play a key role in the outcome of any oncologic treatment and in the development of de novo as well as recurrent tumours. This chapter aims to give, after a short introductive note about the currently used inclusion criteria of HCC patients for LT and about the role of IS in carcinogenesis, a comprehensive overview of the actual literature related to the impact of different immunosuppressive drugs and schemes on outcome of LT in HCC recipients. Unfortunately, up to now solid conclusions cannot be drawn due to the lack of high-level evidence studies caused by the heterogeneity of the studied patient cohorts and the lack of prospectively designed and randomized studies. Based on long-term personal experience with immunosuppressive handling in LT some proposals for further clinical research and practice are put forward. The strategy of curtailing and minimising IS should be explored in the growing field of transplant oncology taking thereby into account the immunological privilege of the liver allograft. These strategies will become more and more compelling when further extending the indications in which adjuvant chemotherapy will probably become an inherent part of the therapeutic scheme of HCC liver recipients.
Collapse
Affiliation(s)
- Jan Lerut
- Starzl Unit Abdominal Transplantation, University Hospitals Saint Luc, Université Catholique de Louvain, Brussels, Belgium
| | - Samuele Iesari
- General Surgery and Organ Transplantation, Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy
| | - Maxime Foguenne
- Starzl Unit Abdominal Transplantation, University Hospitals Saint Luc, Université Catholique de Louvain, Brussels, Belgium
| | - Quirino Lai
- Hepato-bilio-pancreatic and Liver Transplant Unit, Department of Surgery, La Sapienza University, Rome, Italy
| |
Collapse
|
|
24
|
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
|
|
25
|
Marino IR, Carr BI. New Developments in Orthotopic Liver Transplant for Hepatocellular Carcinoma. EXP CLIN TRANSPLANT 2017; 15:1-6. [PMID: 28301991 DOI: 10.6002/ect.tond16.l2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
The use of orthotopic liver transplant for hepatocellular carcinoma was a major advance, pioneered by Thomas E. Starzl as a way to circumvent the limitations imposed on the liver surgeon by the presence of cirrhosis and liver failure. Patients with a few small tumors, whatever their degree of liver damage, may expect prolonged survival (70% at 5 years). Patients with more advanced tumors have high recurrence rates and more limited survival, possibly due to immune suppression or pretransplant understaging of their tumors. Another possibility is that patients with micrometastases have a longer survival time, during which the metastases eventually become evident. Recent advances include the identification of patients using levels of tumor markers to allow more careful patient selection with better outcomes. The contributions of molecular signatures and the new, effective antiviral agents are possibly significant.
Collapse
|
|
26
|
Ma KW, Cheung TT. When to consider liver transplantation in hepatocellular carcinoma patients? Hepat Oncol 2017; 4:15-24. [PMID: 30191050 PMCID: PMC6095144 DOI: 10.2217/hep-2016-0010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2016] [Accepted: 04/06/2017] [Indexed: 12/12/2022] Open
Abstract
Orthotopic liver transplantation (LT) has been regarded as the best cure among the three curative treatment modalities. However, when to consider LT in hepatocellular carcinoma (HCC) patients remains a complicated clinical question. In this article, we will look into the recent updates in the context of LT for HCC, including the timing of orthotopic LT (primary or salvage LT), patient selection criteria, newer prognostic markers and scoring systems, down-staging and bridging therapy, salvage LT and treatment option of post-LT HCC recurrence. Evolution of immunosuppressive therapy and future development of the LT for HCC will also be discussed.
Collapse
Affiliation(s)
- Ka Wing Ma
- Department of Surgery, Queen Mary Hospital, the University of Hong Kong, Hong Kong
| | - Tan To Cheung
- Department of Surgery, Queen Mary Hospital, the University of Hong Kong, Hong Kong
| |
Collapse
|
|
27
|
Gu L, Jin W, Kan L, Wang X, Shan C, Fan H. A retrospective study to compare the use of tacrolimus and cyclosporine in combination with adriamycin in post-transplant liver cancer patients. Cell Biochem Biophys 2016; 71:565-70. [PMID: 25287673 DOI: 10.1007/s12013-014-0235-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
The aim of this study was to compare the clinical effect of tacrolimus (TAC) versus cyclosporine (CycA) in post-transplant hepatic cancer patients undergoing adriamycin hydrochloride (ADM) chemotherapy. Patients with advanced hepatic cancer who underwent liver transplant and subsequent therapy between March 2007 and March 2009 in our hospital were selected for this study. All of these patients were treated with chemotherapeutic agent adriamycin, with respect to immunosuppressant, whereas they received either TAC or CycA, and hence represented two groups, TAC and controls, respectively. The short- and long-term outcomes of two therapies, ADM + TAC and ADM + CsA, were compared. The TAC group patients showed improved remission compared to the control group (40 cases with 46.0 % versus 32 cases with 31.1 % remission, respectively). The 5-year survival in TAC group was significantly prolonged (20.7 %) compared to that of the controls (8.7 %). The short-term outcomes, such as serum levels of calcium, biomarkers of cardiac toxicity/functioning, and regulatory T lymphocytes counts (markers of immune functioning), were found to be significantly more auspicious with TAC treatment than with CycA. Our study showed that use of TAC plus ADM resulted in improved patient survival, tolerance of the graft, and remission compared to CycA combined with ADM. The serum levels of various markers in the short follow-up analysis indicated a better cardiac and immune functioning with TAC than with CycA treatment.
Collapse
Affiliation(s)
- Liangfeng Gu
- Department of Pharmacy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China
| | | | | | | | | | | |
Collapse
|
|
28
|
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
|
|
29
|
|
|
30
|
Mok HP, Lu F, Zhang HY, Gao Q. Perioperative corticosteroids for reducing postoperative complications following esophagectomy. Hippokratia 2015. [DOI: 10.1002/14651858.cd011955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Affiliation(s)
- Hsiao-Pei Mok
- Southern Medical University; Department of Plastic and Cosmetic Surgery, Southern Hospital; Guangzhou Guangdong China
- Southern Medical University; Guangzhou China
| | - Feng Lu
- Southern Medical University; Department of Plastic and Cosmetic Surgery, Southern Hospital; Guangzhou Guangdong China
| | - Hong-Yu Zhang
- Guangdong General Hospital, Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences; Department of Cardiovascular Surgery; Guangzhou China
| | - Qiang Gao
- Guangdong General Hospital, Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences; Department of Cardiovascular Surgery; Guangzhou China
| |
Collapse
|
|
31
|
Mazzola A, Costantino A, Petta S, Bartolotta TV, Raineri M, Sacco R, Brancatelli G, Cammà C, Cabibbo G. Recurrence of hepatocellular carcinoma after liver transplantation: an update. Future Oncol 2015; 11:2923-36. [PMID: 26414336 DOI: 10.2217/fon.15.239] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Liver transplantation is the only curative alternative for selected patients with hepatocellular carcinoma (HCC) who are not eligible for resection and/or with decompensated cirrhosis. According to Milan criteria the 5-year survival rate is 70-85%, with a recurrence-free survival of 75%. However, HCC recurrence rate after liver transplantation remains a significant problem in the clinical practice. The prognosis in patients with HCC recurrence is poor. The treatment of choice for HCC recurrence is surgery, but it seems that a systemic treatment based on combination of an mTOR inhibitor with sorafenib can be used. Data on safety and efficacy are limited, clinical monitoring is necessary. The aim of this review is to underline the main concerns, pitfalls and warnings for these patients.
Collapse
Affiliation(s)
- Alessandra Mazzola
- Section of Gastroenterology - Di.Bi.M.I.S., University of Palermo, Palermo, Italy.,Unité Médicale de Transplantation Hépatique AP-HP, Hôpital Pitié-Salpêtrière, UPMC Paris, Paris, France
| | - Andrea Costantino
- Section of Gastroenterology - Di.Bi.M.I.S., University of Palermo, Palermo, Italy
| | - Salvatore Petta
- Section of Gastroenterology - Di.Bi.M.I.S., University of Palermo, Palermo, Italy
| | | | - Maurizio Raineri
- Section of Anesthesiology, Analgesia, Intensive Care & Emergency, Department of Biopathology, Medical & Forensic Biotechnologies (DIBIMEF), Policlinico 'P Giaccone', University of Palermo, Palermo, Italy
| | - Rodolfo Sacco
- Gastroenterology Unit, Cisanello Hospital, Pisa, Italy
| | | | - Calogero Cammà
- Section of Gastroenterology - Di.Bi.M.I.S., University of Palermo, Palermo, Italy
| | - Giuseppe Cabibbo
- Section of Gastroenterology - Di.Bi.M.I.S., University of Palermo, Palermo, Italy
| |
Collapse
|
|
32
|
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
|
|
33
|
Abstract
Hepatocellular carcinoma (HCC) is an epithelial tumor derived from hepatocytes; it accounts for 80% of all primary liver cancers and ranks globally as the fourth leading cause of cancer-related deaths. HCC treatment is a multidisciplinary and a multimodal task, with surgery in the form of liver resection and liver transplantation (LT) representing the only potentially curative modality. However, there are variable opinions and discussions about applying these surgical options and using other supporting treatments. This article is a narrative review that includes articles published from 1984 to 2013 located by searching scientific databases such as PubMed, SCOPUS, and Elsevier, with the main keyword of hepatocellular carcinoma in addition to other keywords such as liver transplantation, liver resection, transarterial chemoembolization, portal vein embolization, bridging therapy, and downstaging. In this review, we focus mainly on the surgical treatment options offered for HCC, in order to illustrate the current relevant data available in the literature to help in applying these surgical options and to use other supporting treatment modalities when appropriate.
Collapse
Affiliation(s)
- Ahmad A. Madkhali
- Department of Surgery, College of Medicine, King Saud University, Riyadh, Saudi Arabia,Section of Hepatopancreatobilairy and Transplant, Transplant, McGill University, Montreal, Canada
| | - Zahir T. Fadel
- Section of Hepatopancreatobilairy and Transplant, Transplant, McGill University, Montreal, Canada,Department of Surgery, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Murad M. Aljiffry
- Department of Surgery, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mazen M. Hassanain
- Department of Surgery, College of Medicine, King Saud University, Riyadh, Saudi Arabia,Department of Oncology, McGill University, Montreal, Canada,Address for correspondence: Dr. Mazen Hassanain, Assistant Professor of Surgery and Consultant HPB and Transplant Surgery, Department of Surgery, College of Medicine, Scientific Director Liver Disease Research Centre, King Saud University, P.O.Box 25179, Riyadh, 11466, Saudi Arabia. E-mail:
| |
Collapse
|
|
34
|
De novo hepatocellular carcinoma of liver allograft: a neglected issue. Cancer Lett 2014; 357:47-54. [PMID: 25444925 DOI: 10.1016/j.canlet.2014.11.032] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2014] [Revised: 11/13/2014] [Accepted: 11/14/2014] [Indexed: 12/19/2022]
Abstract
De novo hepatocellular carcinoma (HCC) is a rare neoplasm, ensuing after liver transplantation. Its definitive identification requires sophisticated molecular analyses. Hence, some cases, particularly those ensuing in patients who have been transplanted with HCC, are probably misclassified as recurrences of the primary tumor. Nevertheless, a tumor recurrence cannot be excluded in patients transplanted without apparent malignancy, because of an occult HCC. The main risk factor for de novo HCC is the recurrence of hepatitis/cirrhosis in the allograft. All the described de novo HCCs occurred at least 2 years after OLT, whereas most recurrent HCCs develop within 2 years from surgery. The treatment of this tumor can follow the recommendations of guidelines for primary HCC and, unlike recurrent HCC, re-transplant can be considered a therapeutic option for these patients. Prevention of this tumor relies on the prevention/cure of recurrent liver disease in the allograft and on judicious post-transplant immunosuppression. The present review analyzes this topic by addressing seven key questions. An algorithm based on clinical factors - regarding primary and secondary tumors - to trigger the suspicion of de novo origin of a post-transplant HCC is proposed.
Collapse
|
|
35
|
Lan X, Liu MG, Chen HX, Liu HM, Zeng W, Wei D, Chen P. Efficacy of immunosuppression monotherapy after liver transplantation: A meta-analysis. World J Gastroenterol 2014; 20:12330-12340. [PMID: 25232269 PMCID: PMC4161820 DOI: 10.3748/wjg.v20.i34.12330] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2014] [Revised: 02/17/2014] [Accepted: 04/29/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess the advantages and disadvantages of immunosuppression monotherapy after transplantation and the impact of monotherapy on hepatitis C virus (HCV) recurrence.
METHODS: Articles from Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded, including non-English literature identified in these databases, were searched up to January 2013. We included randomized clinical trials comparing various immunosuppression monotherapy and prednisone-based immunosuppression combinations for liver transplantation. The modified Jadad scale score or the Oxford quality scoring system was used. Meta-analyses were performed with weighted random-effects models.
RESULTS: A total of 14 randomized articles including 1814 patients were identified. Eight trials including 1214 patients compared tacrolimus monotherapy (n = 610) vs tacrolimus plus steroids or triple therapy regarding acute rejection and adverse events (n = 604). Five trials, including 285 patients, compared tacrolimus monotherapy (n = 143) vs tacrolimus plus steroids or triple therapy regarding hepatitis C recurrence (n = 142). Four trials including 273 patients compared cyclosporine monotherapy (n = 148) vs cyclosporine and steroids regarding acute rejection and adverse events (n = 125). Two trials including 170 patients compared mycophenolate mofetil monotherapy (n = 86) vs combinations regarding acute rejection (n = 84). There were no significant differences in the acute rejection rates between tacrolimus monotherapy (RR = 1.04, P = 0.620), and cyclosporine monotherapy (RR = 0.89, P = 0.770). Mycophenolate mofetil monotherapy had a significant increase in the acute rejection rate (RR = 4.50, P = 0.027). Tacrolimus monotherapy had no significant effects on the recurrence of hepatitis C (RR = 1.03, P = 0.752). More cytomegalovirus infection (RR = 0.48, P = 0.000) and drug-related diabetes mellitus (RR = 0.54, P = 0.000) were observed in the immunosuppression combination therapy groups.
CONCLUSION: Tacrolimus and cyclosporine monotherapy may be as effective as immunosuppression combination therapy. Mycophenolate mofetil monotherapy was not considerable. Tacrolimus monotherapy does not increase recurrence of HCV.
Collapse
|
|
36
|
Lee JY, Kim YH, Yi NJ, Kim HS, Lee HS, Lee BK, Kim H, Choi YR, Hong G, Lee KW, Suh KS. Impact of immunosuppressant therapy on early recurrence of hepatocellular carcinoma after liver transplantation. Clin Mol Hepatol 2014; 20:192-203. [PMID: 25032186 PMCID: PMC4099335 DOI: 10.3350/cmh.2014.20.2.192] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2014] [Revised: 06/07/2014] [Accepted: 06/10/2014] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND/AIMS The most commonly used immunosuppressant therapy after liver transplantation (LT) is a combination of tacrolimus and steroid. Basiliximab induction has recently been introduced; however, the most appropriate immunosuppression for hepatocellular carcinoma (HCC) patients after LT is still debated. METHODS Ninety-three LT recipients with HCC who took tacrolimus and steroids as major immunosuppressants were included. Induction with basiliximab was implemented in 43 patients (46.2%). Mycophenolate mofetil (MMF) was added to reduce the tacrolimus dosage (n=28, 30.1%). The 1-year tacrolimus exposure level was 7.2 ± 1.3 ng/mL (mean ± SD). RESULTS The 1- and 3-year recurrence rates of HCC were 12.9% and 19.4%, respectively. Tacrolimus exposure, cumulative steroid dosages, and MMF dosages had no impact on HCC recurrence. Induction therapy with basiliximab, high alpha fetoprotein (AFP; >400 ng/mL) and protein induced by vitamin K absence/antagonist-II (PIVKA-II; >100 mAU/mL) levels, and microvascular invasion were significant risk factors for 1-year recurrence (P<0.05). High AFP and PIVKA-II levels, and positive (18)fluoro-2-deoxy-d-glucose positron-emission tomography findings were significantly associated with 3-year recurrence (P<0.05). CONCLUSIONS Induction therapy with basiliximab, a strong immunosuppressant, may have a negative impact with respect to early HCC recurrence (i.e., within 1 year) in high-risk patients.
Collapse
Affiliation(s)
- Ju-Yeun Lee
- Department of Pharmacy, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea. ; College of Pharmacy, Hanyang University, Gyeonggi-do, Korea
| | - Yul Hee Kim
- Ewha Graduate School of Clinical Health Sciences, Ewha Women's University, Seoul, Korea
| | - Nam-Joon Yi
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Hyang Sook Kim
- Department of Pharmacy, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Hye Suk Lee
- Department of Pharmacy, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Byung Koo Lee
- Ewha Graduate School of Clinical Health Sciences, Ewha Women's University, Seoul, Korea
| | - Hyeyoung Kim
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Young Rok Choi
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Geun Hong
- Department of Surgery, Ewha Women's University College of Medicine, Seoul, Korea
| | - Kwang-Woong Lee
- 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
|
|
37
|
Zhu H, Sun Q, Tan C, Xu M, Dai Z, Wang Z, Fan J, Zhou J. Tacrolimus promotes hepatocellular carcinoma and enhances CXCR4/SDF‑1α expression in vivo. Mol Med Rep 2014; 10:585-92. [PMID: 24912495 PMCID: PMC4094770 DOI: 10.3892/mmr.2014.2302] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2013] [Accepted: 03/12/2014] [Indexed: 12/13/2022] Open
Abstract
The aim of our study was to elucidate the effect of tacrolimus (FK506) and of C-X-C chemokine receptor type 4 (CXCR4), which is a receptor specific to the stromal cell-derived factor-1α (SDF-1α), on growth and metastasis of hepatocellular carcinoma (HCC). Following treatment with different concentrations of FK506, AMD3100 or normal saline (NS), the proliferation of Morris rat hepatoma 3924A (MH3924A) cells was measured by the MTT assay, the expression of CXCR4 was analyzed with immunohistochemistry, and the morphological changes and the invasiveness of cells were studied with a transwell assay and under a scanning electron microscope, respectively. In addition, August Copenhagen Irish rat models implanted with tumor were used to examine the pathological changes and invasiveness of tumor in vivo, the expression of CXCR4 in tumor tissues and the expression of SDF-1α in the adjacent tissues to the HCC ones, using immunohistochemistry. In vitro, FK506 (100–1,000 μg/l) significantly promoted the proliferation of MH3924A cells (P<0.01), and increased the expression of CXCR4 in MH3924A cells, albeit with no significance (P>0.05). By contrast, AMD3100 had no effect on the proliferation of MH3924A cells, but significantly reduced the expression of CXCR4 (P<0.05). The invasiveness of MH3924A cells was significantly (P<0.01) enhanced following treatment with FK506, SDF-1α, FK506 + AMD3100, FK506 + SDF-1α or FK506 + AMD3100 + SDF-1α. In vivo, tumor weight (P=0.041), lymph node metastasis (P=0.002), the number of pulmonary nodules (P=0.012), the expression of CXCR4 in tumor tissues (P=0.048) and that of SDF-1α in adjacent tissues (P=0.026) were significantly different between the FK506-treated and the NS group. Our results suggest that FK506 promotes the proliferation of MH3924A cells and the expression of CXCR4 and SDF-1α in vivo. Therefore, inhibiting the formation of the CXCR4/SDF-1α complex may partly reduce the promoting effect of FK506 on HCC.
Collapse
Affiliation(s)
- Huaqi Zhu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Qiman Sun
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Changjun Tan
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Min Xu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Zhi Dai
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Zheng Wang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Jia Fan
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Jian Zhou
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| |
Collapse
|
|
38
|
Kornberg A. Liver Transplantation for Hepatocellular Carcinoma beyond Milan Criteria: Multidisciplinary Approach to Improve Outcome. ISRN HEPATOLOGY 2014; 2014:706945. [PMID: 27335840 PMCID: PMC4890913 DOI: 10.1155/2014/706945] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/15/2013] [Accepted: 01/03/2014] [Indexed: 12/12/2022]
Abstract
The implementation of the Milan criteria (MC) in 1996 has dramatically improved prognosis after liver transplantation (LT) in patients with hepatocellular carcinoma (HCC). Liver transplantation has, thereby, become the standard therapy for patients with "early-stage" HCC on liver cirrhosis. The MC were consequently adopted by United Network of Organ Sharing (UNOS) and Eurotransplant for prioritization of patients with HCC. Recent advancements in the knowledge about tumor biology, radiographic imaging techniques, locoregional interventional treatments, and immunosuppressive medications have raised a critical discussion, if the MC might be too restrictive and unjustified keeping away many patients from potentially curative LT. Numerous transplant groups have, therefore, increasingly focussed on a stepwise expansion of selection criteria, mainly based on tumor macromorphology, such as size and number of HCC nodules. Against the background of a dramatic shortage of donor organs, however, simple expansion of tumor macromorphology may not be appropriate to create a safe extended criteria system. In contrast, rather the implementation of reliable prognostic parameters of tumor biology into selection process prior to LT is mandatory. Furthermore, a multidisciplinary approach of pre-, peri-, and posttransplant modulating of the tumor and/or the patient has to be established for improving prognosis in this special subset of patients.
Collapse
Affiliation(s)
- A. Kornberg
- Department of Surgery, Klinikum rechts der Isar, Technical University Munich, Ismaningerstraße 22, D-81675 Munich, Germany
| |
Collapse
|
|
39
|
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
|
|
40
|
Pei F, Shang K, Jiang B, Wang H, Mei F, Zhang Y, Du J, Zhong H, You J. Clinicopathologic study on complications of orthotopic liver transplantation in 54 patients with chronic hepatitis B viral infection. Hepatol Int 2013; 7:468-476. [DOI: 10.1007/s12072-013-9422-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
|
|
41
|
Miyagi S, Kawagishi N, Sekiguchi S, Akamatsu Y, Sato K, Takeda I, Kobayashi Y, Tokodai K, Fujimori K, Satomi S. The relationship between recurrences and immunosuppression on living donor liver transplantation for hepatocellular carcinoma. Transplant Proc 2012; 44:797-801. [PMID: 22483499 DOI: 10.1016/j.transproceed.2012.01.012] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
OBJECTIVES Living donor liver transplantation (LDLT) offers timely transplantation for patients with hepatocellular carcinoma (HCC). If ABO-incompatible LDLT is feasible, the needs for pretransplantation treatments may be eliminated. It is known that negative impacts of immunosuppression are limited among LDLT for HCC, however, we believe that excessive immunosuppression is one of the risk factors for recurrence. We compared the impacts of immunosuppression for LDLT with hepatectomy outcomes for HCC. METHODS From 1991 to 2010, we performed 144 LDLTs including 14 patients with HCC. Seven met the Milan criteria. Immunosuppressive therapies were based on tacrolimus plus methylprednisolone plus CD25 antibody. For ABO-incompatible cases, we also used mycophenolate mofetil and rituximab. Five cases underwent strong imunosuppressive therapy (steroid pulse or rituximab) within 180 days. In addition, we performed hepatectomy for 180 HCC cases from 1997 to 2010. RESULTS Overall survival rates of the LDLT cohort and hepatectomy groups were similar, but disease-free 5-year survival rates (DFS) of the LDLT cohort were significantly better than those of the hepatectomy group (total = 54.4% versus 27.4%, within the Milan criteria cases, 71.4% versus 33.8%). Thus, the negative impact of immunosuppression on recurrence was less than the benefit of a whole liver resection. Among strongly immunosuppressed cases, 5-years DFS rates were significantly worse than among other immunosuppressed cases (20.0% versus 76.2%). Upon univariate analysis, the factors associated with HCC recurrence were alpha-fetoprotein levels and steroid doses within 180 days, but multivariate analysis did not show a predictor for recurrence. CONCLUSION Patients who are strongly immunosuppressed may have several negative impacts for recurrences. More careful indications must be selected for ABO-incompatible cases.
Collapse
Affiliation(s)
- S Miyagi
- Department of Transplantation, Reconstruction and Endoscopic Surgery, Tohoku University, Aoba-ku, Sendai, Japan.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
42
|
Rubín A, Berenguer M. [Liver transplantation: personalized immunosuppression in patients with hepatitis C virus infection and hepatocellular carcinoma]. GASTROENTEROLOGIA Y HEPATOLOGIA 2012; 36:48-57. [PMID: 22578313 DOI: 10.1016/j.gastrohep.2012.03.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2012] [Accepted: 03/06/2012] [Indexed: 11/20/2022]
Abstract
Transplantation has become the treatment of choice in end-stage liver disease, with 5-year survival rates of around 68-74% in European and North-American registries (www.unos.org, www.eltr.org, www.ont.es). These results are largely due to the development of powerful immunosuppressive agents, mainly calcineurin inhibitors. However, these immunosuppressive drugs are not free of adverse effects, especially nephrotoxicity. Moreover, two of the most frequent indications for transplantation, cirrhosis due to hepatitis C virus and hepatocellular carcinoma, can recur in the transplanted graft. Whether specific immunosuppression could be less harmful in these conditions is the subject of debate. With the greater use of suboptimal donors and of expanded criteria for liver transplantation in patients with hepatocellular carcinoma, aggressive recurrences can be expected to increase. The present review attempts to elucidate whether there is an immunosuppression strategy that could minimize the risk of aggressive tumoral recurrence or recurrence of hepatitis C.
Collapse
Affiliation(s)
- Angel Rubín
- Unidad de Hepatología y Trasplante Hepático, Hospital La Fe, Valencia, España
| | | |
Collapse
|
|
43
|
Kim HR, Cheon SH, Rha SY, Lee S, Han KH, Chon CY, Lee JD, Sung JS, Chung HC. Treatment of recurrent hepatocellular carcinoma after liver transplantation. Asia Pac J Clin Oncol 2012; 7:258-69. [PMID: 21884437 DOI: 10.1111/j.1743-7563.2011.01425.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
AIM Liver transplantation (LT) is a curative treatment for localized hepatocellular carcinoma (HCC), but the recurrence rate after LT is about 10-20%, with a dismal prognosis. Little data exist as to the natural history, treatment outcome and optimal treatment of recurrent HCC after LT. We reviewed various treatment modalities given to patients with recurrent HCC after LT. METHODS Among 132 patients who underwent LT for localized HCC, we retrospectively reviewed medical records of 39 of the 132 patients who developed recurrent HCC after LT. We analyzed the clinical outcome of various treatment modalities and treatment-related adverse events. RESULTS A total of 39 (29%) of the original 132 patients had recurrent HCC, most recurrences (82%) having occurred within 1 year after LT and involved extrahepatic lesions. Only seven patients had recurrent disease limited to the liver. The median overall survival from the initial treatment of all relapsed patients was 6.9 months. There were various initial treatment modalities, namely palliative systemic chemotherapy, trans-catheter arterial chemo-embolization/infusion (TACE/I), radiation therapy (RT), surgical resection and no treatment. The median overall survival was 9.5 months for first-line chemotherapy, including those who had prior local therapy, 6.3 months TACE/I and 6.9 months for RT. CONCLUSION Various clinical approaches have been used to treat patients with recurrent HCC after LT in a clinical setting. More effective strategies and clinical guidelines for recurrent HCC following LT must be established.
Collapse
Affiliation(s)
- Hye Ryun Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | | | | | | | | | | | | | | | | |
Collapse
|
|
44
|
Zhou S, Tan C, Dai Z, Zhu H, Xu M, Zhou Z, Wang W, Zhao Y, Fu X, Zhou J, Fan J. Tacrolimus enhances the invasion potential of hepatocellular carcinoma cells and promotes lymphatic metastasis in a rat model of hepatocellular carcinoma: involvement of vascular endothelial growth factor-C. Transplant Proc 2012; 43:2747-54. [PMID: 21911157 DOI: 10.1016/j.transproceed.2011.06.040] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2011] [Revised: 05/20/2011] [Accepted: 06/13/2011] [Indexed: 01/06/2023]
Abstract
PURPOSE The purpose of this study was to elucidate the effect of tacrolimus treatment on tumor growth and metastasis of hepatocellular carcinoma (HCC). METHODS The effect of tacrolimus was investigated on tumor growth and lymph node metastasis in a rat model of HCC. Angiogenesis and lymphangiogenesis were assessed by CD31 and vascular endothelial growth factor receptor 3 (VEGFR-3) immunostaining. Cell proliferation and invasion were monitored in vitro using the Cell Counting Kit-8 (CCK8) and Matrigel Invasion Chambers, respectively. Levels of vascular endothelial growth factor-C (VEGF-C) expression were measured using quantitative real-time polymerase chain reaction (qRT-PCR), immunohistochemisty and Western blots. RESULTS Tacrolimus had no effect on the proliferation of HCC in vitro or in vivo. Treatment with tacrolimus resulted in a dose-dependent increase in the invasive potential of HCC cells in vitro, in the density of peritumoral lymphatic vessels, and in the number and volume of metastatic lymph nodes in August Copenhagen Irish (ACI) rats. qRT-PCR, immunohistochemisty, and Western blot revealed that tacrolimus increased the levels of expression of VEGF-C in HCC. CONCLUSIONS Tacrolimus enhanced the invasive potential of HCC cells, facilitating HCC lymphangiogenesis and promoting lymphatic metastasis in a rat model of HCC. This influence may be the result of an increase in VEGF-C expression by HCC cells. Targeting the VEGF-C/Fms-related tyrosine kinase 4 axis may be a novel treatment for HCC patients after liver transplantation.
Collapse
Affiliation(s)
- S Zhou
- Liver Cancer Institute, Zhong Shan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis & Cancer Invasion, Chinese Ministry of Education, Shanghai, People's Republic of China
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
45
|
Li L, Zhang J, Liu X, Li X, Jiao B, Kang T. Clinical outcomes of radiofrequency ablation and surgical resection for small hepatocellular carcinoma: a meta-analysis. J Gastroenterol Hepatol 2012; 27:51-8. [PMID: 22004366 DOI: 10.1111/j.1440-1746.2011.06947.x] [Citation(s) in RCA: 89] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND AIM To evaluate the evidence comparing radiofrequency ablation (RFA) and surgical resection (RES) on the treatment of hepatocellular carcinoma (HCC) using meta-analytical techniques. METHODS Literature search was undertaken until March 2011 to identify comparative studies evaluating survival rates, recurrence rates, and complications. Pooled odds ratios (OR) and 95% confidence intervals (95% CI) were calculated with either the fixed or random effect model. RESULTS These studies included a total of 877 patients: 441 treated with RFA and 436 treated with RES. The overall survival was significantly higher in patients treated with RES than RFA at 1, 3 and 5 years (respectively: OR: 0.50, 95% CI: 0.29-0.86; OR: 0.51, 95% CI: 0.28-0.94; OR: 0.62, 95% CI: 0.45-0.84). In the RES group the 1, 3, and 5 years recurrence-free survival rates were significantly higher than the RFA group (respectively: OR: 0.65, 95% CI: 0.44-0.97; OR: 0.65, 95% CI: 0.47-0.89; OR: 0.52, 95% CI: 0.35-0.77). RFA had a higher rate of local recurrence (OR: 4.08, 95% CI: 2.03-8.20). For tumors ≤ 3 cm RES was better than RFA in the 3-year overall survival rates (OR: 0.38, 95% CI: 0.16-0.89). CONCLUSIONS Surgical resection was superior to RFA in the treatment of HCC. However, the findings have to be carefully interpreted due to the lower level of evidence.
Collapse
Affiliation(s)
- Le Li
- Department of General Surgery, First Affiliated Hospital, China Medical University, Shenyang, Liaoning Province, China
| | | | | | | | | | | |
Collapse
|
|
46
|
Vivarelli M, Risaliti A. Liver transplantation for hepatocellular carcinoma on cirrhosis: strategies to avoid tumor recurrence. World J Gastroenterol 2011; 17:4741-4746. [PMID: 22147974 PMCID: PMC3229622 DOI: 10.3748/wjg.v17.i43.4741] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2011] [Revised: 06/21/2011] [Accepted: 06/28/2011] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most frequent neoplasms worldwide and in most cases it is associated with chronic liver disease. Liver transplantation (LT) is potentially the optimal treatment for those patients with HCC who have a poor functional hepatic reserve due to their underlying chronic liver disease. However, due to the limited availability of donors, only those patients whose oncologic profile is favorable can be considered for LT. Despite the careful selection of candidates based on strict rules, 10 to 20% of liver transplant recipients who have HCC in the native cirrhotic liver develop tumor recurrence after transplantation. The selection criteria presently employed to minimize the risk of recurrence are based on gross tumor characteristics defined by imaging techniques; unfortunately, the accuracy of imaging is far from being optimal. Furthermore, microscopic tumor features that are strictly linked with prognosis can not be assessed prior to transplantation. Pre-transplantation tumor downstaging may allow transplantation in patients initially outside the selection criteria and seems to improve the prognosis; it also provides information on tumor biology. The main peculiarity of the transplantation setting, when this is compared with other modalities of treatment, is the need for pharmacological immunosuppression: this is based on drugs that have been demonstrated to increase the risk of tumor development. As HCC is an aggressive malignancy, immunosuppression has to be handled carefully in patients who have HCC at the time of transplantation and new categories of immunosuppressive agents should be considered. Adjuvant chemotherapy following transplantation has failed to show any significant advantage. The aim of the present study is to review the possible strategies to avoid recurrence of HCC after liver transplantation based on the current clinical evidence and the more recent developments and to discuss possible future directions.
Collapse
|
|
47
|
Mazzaferro V, Bhoori S, Sposito C, Bongini M, Langer M, Miceli R, Mariani L. Milan criteria in liver transplantation for hepatocellular carcinoma: an evidence-based analysis of 15 years of experience. Liver Transpl 2011; 17 Suppl 2:S44-57. [PMID: 21695773 DOI: 10.1002/lt.22365] [Citation(s) in RCA: 435] [Impact Index Per Article: 31.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Vincenzo Mazzaferro
- Units of Gastrointestinal Surgery and Liver Transplantation, National Cancer Institute of Milan, Milan, Italy.
| | | | | | | | | | | | | |
Collapse
|
|
48
|
Castroagudín JF, Molina-Pérez E, Ferreiro-Iglesias R, Varo-Pérez E. Strategies of immunosuppression for liver transplant recipients with hepatocellular carcinoma. Transplant Proc 2011; 43:711-3. [PMID: 21486580 DOI: 10.1016/j.transproceed.2011.01.090] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Liver transplantation is considered to be the most efficient therapeutic option for patients with liver cirrhosis and early stage hepatocellular carcinoma (HCC) in terms of overall survival and recurrence rate. The application of restrictive selection criteria based on tumor size and number of nodules is advised to obtain optimal results. Nevertheless, tumor recurrence occurs in 3.5% to 21% of recipients, despite careful pretransplant staging and patient selection. Post transplant recurrence of hepatocarcinoma clearly has a major negative impact on prognosis. Intuitively, an immunosupressed state is undesirable in cancer patients. Inversely, modulation or minimization of immunosuppressive therapy could influence tumor progression and reduce the negative impact of recurrence on posttransplant survival. Experimental evidence shows that mammalian target of rapamycin (mTOR) inhibitors have antiangiogenic and antiproliferative effects. Thus, their application has been proposed as antineoplastic agents for immunosuppressive protocols in liver transplant recipients with HCC and may reduce the rate or the impact of tumor recurrence. Clinical data about efficacy and safety of mTOR-based immunosuppressant protocols in liver transplant recipients with HCC show promising results, namely low recurrence and higher survival rates compared with standard calcineurin inhibitor-based immunosuppressive protocols, even among patients with extended morphological criteria. The safety profile is regarded generally as adequate.
Collapse
|
|
49
|
Influence of immunosuppressive drugs on the recurrence of hepatocellular carcinoma after liver transplantation: a gap between basic science and clinical evidence. Transplantation 2011; 91:1173-6. [PMID: 21427632 DOI: 10.1097/tp.0b013e318215e72b] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Effects of immunosuppressive drug on tumor development in transplantation are understudied. Tumors are especially concerning when liver transplantation recipients have a pretransplant hepatocellular carcinoma (HCC). Because immunosuppressive drugs likely influence HCC recurrence, with mammalian target of rapamycin inhibitors showing antineoplastic properties especially experimentally, we sought for practical medical guidance from published clinical studies. Although the current literature review revealed 14 studies regarding immunosuppression in this context, suggesting antitumor effects for mammalian target of rapamycin inhibitors, the quality of evidence is low. Therefore, randomized controlled trials investigating effects of immunosuppression on HCC recurrence in liver transplantation are lacking, exposing a gap between basic science knowledge and clinical evidence.
Collapse
|
|
50
|
Theodoropoulos J, Brooks A. Inconsistency in the Management of Patients with Hepatocellular Carcinoma: The Need for a Strict Protocol. Am Surg 2011. [DOI: 10.1177/000313481107700223] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
As more therapies become available for the treatment of hepatocellular carcinoma (HCC), the management of patients with HCC is more complex, and the indications for the various therapeutic modalities are less clear. Although all of the treatment options have shown a certain efficacy in well-selected patient groups, their everyday use, especially in nonspecialized centers, is not always appropriate. We report our experience with 81 individuals who were diagnosed and treated in our institution between 2001 and 2007. Only patients who received transplants had good long-term outcomes, and we noted significant inconsistencies in the management of patients with similar stages of disease and degrees of cirrhosis. Despite recent progress, HCC still carries an overall dismal prognosis, making the optimization of the therapeutic plan mandatory to improve outcomes. We believe that a unified protocol, as well as the early involvement of the hepatology and transplant teams, can help physicians optimize the care of these patients.
Collapse
Affiliation(s)
- John Theodoropoulos
- Hahnemann University Hospital, Philadelphia, Pennsylvania and the Department of Surgery, Drexel University College of Medicine, Philadelphia, Pennsylvania
| | - Ari Brooks
- Hahnemann University Hospital, Philadelphia, Pennsylvania and the Department of Surgery, Drexel University College of Medicine, Philadelphia, Pennsylvania
| |
Collapse
|