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Mauro E, Rodríguez-Perálvarez M, D'Alessio A, Crespo G, Piñero F, De Martin E, Colmenero J, Pinato DJ, Forner A. New Scenarios in Liver Transplantation for Hepatocellular Carcinoma. Liver Int 2025; 45:e16142. [PMID: 39494583 DOI: 10.1111/liv.16142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Revised: 10/03/2024] [Accepted: 10/09/2024] [Indexed: 11/05/2024]
Abstract
BACKGROUND AND AIMS Despite liver transplantation (LT) is considered the optimal treatment for hepatocellular carcinoma (HCC), particularly in patients with impaired liver function, the shortage of donors has forced the application of very restrictive criteria for selecting ideal candidates for whom LT can offer the best outcome. With the evolving LT landscape due to the advent of direct-acting antivirals (DAAs) and the steady increase in donors, major efforts have been made to expand the transplant eligibility criteria for HCC. In addition, the emergence of immune checkpoint inhibitors (ICIs) for the treatment of HCC, with demonstrated efficacy in earlier stages, has revolutionized the therapeutic approach for these patients, and their integration in the setting of LT is challenging. Management of immunological compromise from ICIs, including the wash-out period before LT and post-LT immunosuppression adjustments, is crucial to balance the risk of graft rejection against HCC recurrence. Additionally, the effects of increased immunosuppression on non-hepatic complications must be understood to prevent them from becoming obstacles to long-term OS. METHODS AND RESULTS In this review, we will evaluate the emerging evidence and its implications for the future of LT in HCC. Addressing these novel challenges and opportunities, while integrating the current clinical evidence with predictive algorithms, would ensure a fair balance between individual patient needs and the overall population benefit in the LT system.
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Affiliation(s)
- Ezequiel Mauro
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, ICMDM, Hospital Clinic Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Manuel Rodríguez-Perálvarez
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
- Department of Hepatology and Liver Transplantation, Hospital Universitario Reina Sofía, Universidad de Córdoba, IMIBIC, CIBERehd, Córdoba, Spain
| | - Antonio D'Alessio
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
- Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Gonzalo Crespo
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
- Liver Transplant Unit, Liver Unit, ICMDM, Hospital Clinic Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Federico Piñero
- School of Medicine, Hospital Universitario Austral, Austral University, Buenos Aires, Argentina
| | - Eleonora De Martin
- AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, INSERM Unit 1193, Université Paris-Saclay, FHU Hepatinov, Villejuif, France
| | - Jordi Colmenero
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
- Liver Transplant Unit, Liver Unit, ICMDM, Hospital Clinic Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - David James Pinato
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
- Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Alejandro Forner
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, ICMDM, Hospital Clinic Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
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Sha M, Wang J, Cao J, Zou ZH, Qu XY, Xi ZF, Shen C, Tong Y, Zhang JJ, Jeong S, Xia Q. Criteria and prognostic models for patients with hepatocellular carcinoma undergoing liver transplantation. Clin Mol Hepatol 2025; 31:S285-S300. [PMID: 39159949 PMCID: PMC11925443 DOI: 10.3350/cmh.2024.0323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 08/12/2024] [Indexed: 08/21/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-associated death globally. Liver transplantation (LT) has emerged as a key treatment for patients with HCC, and the Milan criteria have been adopted as the cornerstone of the selection policy. To allow more patients to benefit from LT, a number of expanded criteria have been proposed, many of which use radiologic morphological characteristics with larger and more tumors as surrogates to predict outcomes. Other groups developed indices incorporating biological variables and dynamic markers of response to locoregional treatment. These expanded selection criteria achieved satisfactory results with limited liver supplies. In addition, a number of prognostic models have been developed using clinicopathological characteristics, imaging radiomics features, genetic data, and advanced techniques such as artificial intelligence. These models could improve prognostic estimation, establish surveillance strategies, and bolster long-term outcomes in patients with HCC. In this study, we reviewed the latest findings and achievements regarding the selection criteria and post-transplant prognostic models for LT in patients with HCC.
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Affiliation(s)
- Meng Sha
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jun Wang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jie Cao
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zhi-Hui Zou
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Military Medical University, Shanghai, China
| | - Xiao-Ye Qu
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zhi-Feng Xi
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Chuan Shen
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ying Tong
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jian-Jun Zhang
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Seogsong Jeong
- Department of Biomedical Informatics, Korea University College of Medicine, Seoul, Korea
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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3
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Zhou Z, Liu Q, Liu J, Li W, Cao S, Xu J, Chen J, Xu X, Chen C. Research progress of protein induced by vitamin K absence or antagonist II in liver transplantation for hepatocellular carcinoma. Heliyon 2024; 10:e30622. [PMID: 38726103 PMCID: PMC11079398 DOI: 10.1016/j.heliyon.2024.e30622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Revised: 04/30/2024] [Accepted: 04/30/2024] [Indexed: 05/12/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common pathologic type of primary liver cancer. Liver transplantation (LT) is a radical strategy for treating patients with early-stage HCC, which may lead to a better prognosis compared to hepatectomy and ablation. However, survival of patients who develop HCC recurrence after LT is short, and early recurrence is the most common cause of death. Thus, efficient biomarkers are also needed in LT to guide precision therapy to improve patient prognosis and 5-year survival. Protein induced by vitamin K absence or antagonist II (PIVKA-II) is an abnormal prothrombin that cannot activate coagulation, and it is significantly increased in patients with HCC, obstructive jaundice, and those taking vitamin K antagonists. Over the past decades, substantial progress has been made in the study of PIVKA-II in diagnosing, surveilling, and treating HCC, but its role in LT still needs to be elaborated. In this review, we focused on the role of PIVKA-II as a biomarker in LT for HCC, especially its relationship with clinicopathologic features, early recurrence, long-term survival, and donor-recipient selection.
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Affiliation(s)
- Zheyu Zhou
- Department of General Surgery, Nanjing Drum Tower Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Graduate School of Peking Union Medical College, Nanjing, China
| | - Qiaoyu Liu
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jinsong Liu
- Department of Colorectal and Anal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Colorectal Cancer Research Center, Shanghai, China
| | - Wenwen Li
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing, China
| | - Shuya Cao
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Science, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, China
| | - Jiawei Xu
- Department of Hepatobiliary and Transplantation Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Jun Chen
- Department of Pathology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Xiaoliang Xu
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Chaobo Chen
- Department of General Surgery, Xishan People's Hospital of Wuxi City, Wuxi, China
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Lai Q, Ito T, Iesari S, Ikegami T, Nicolini D, Larghi Laureiro Z, Rossi M, Vivarelli M, Yoshizumi T, Hatano E, Lerut J. Role of protein induced by vitamin-K absence-II in transplanted patients with HCC not producing alpha-fetoprotein. Liver Transpl 2024; 30:472-483. [PMID: 37729520 DOI: 10.1097/lvt.0000000000000259] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 08/30/2023] [Indexed: 09/22/2023]
Abstract
Elevated Protein Induced by Vitamin-K Absence-II (PIVKA-II) has been shown to be an adverse prognostic factor in HCC patients undergoing liver transplantation (LT). No definitive data are available about the impact of PIVKA-II concerning post-LT recurrence in patients not secreting (≤ 20 ng/mL) alpha-fetoprotein (AFP). An observational retrospective study of the East-West HCC-LT consortium is reported. Between 2000 and 2019, 639 HCC patients were enrolled in 5 collaborative European and Japanese centers. To minimize the initial selection bias, an inverse probability therapy weighting method was adopted to analyze the data. In the post-inverse probability therapy weighting population, PIVKA-II (HR = 2.00; 95% CI: 1.52-2.64; p < 0.001) and AFP (HR=1.82; 95% CI: 1.48-2.24; p < 0.001) were the most relevant independent risk factors for post-LT recurrence. A sub-analysis focusing only on patients who are AFP non-secreting confirmed the negative role of PIVKA-II (HR=2.06, 95% CI: 1.26-3.35; p =0.004). When categorizing the entire population into 4 groups according to the AFP levels (≤ or > 20 ng/mL) and PIVKA (≤ or > 300 mUA/mL) at the time of LT, the lowest recurrence rates were observed in the low AFP-PIVKA-II group (5-year recurrence rate = 8.0%). Conversely, the high AFP-PIVKA-II group had the worst outcome (5-year recurrence rate = 35.1%). PIVKA-II secretion is a relevant risk factor for post-LT HCC recurrence. The role of this marker is independent of the AFP status. Combining both tumor markers, especially in the setting of LT, should be of great relevance for adding information about predicting the post-LT risk of tumor recurrence and selecting these patients for transplantation.
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Affiliation(s)
- Quirino Lai
- Department of General and Specialistic Surgery, General Surgery and Organ Transplantation Unit, Sapienza University of Rome, Rome, Italy
| | - Takashi Ito
- Department of Surgery, Kyoto University, Kyoto, Japan
| | - Samuele Iesari
- Department of Surgery, Universitè catholique de Louvain, Brussels, Belgium
| | - Toru Ikegami
- Department of Surgery and Science, Kyushu University, Fukuoka, Japan
| | - Daniele Nicolini
- Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Ancona, Italy
| | - Zoe Larghi Laureiro
- Department of General and Specialistic Surgery, General Surgery and Organ Transplantation Unit, Sapienza University of Rome, Rome, Italy
| | - Massimo Rossi
- Department of General and Specialistic Surgery, General Surgery and Organ Transplantation Unit, Sapienza University of Rome, Rome, Italy
| | - Marco Vivarelli
- Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Ancona, Italy
| | | | | | - Jan Lerut
- Institute for Experimental and Clinical Research IREC-Université catholique de Louvain, Brussels, Belgium
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Piñero F, Mauro E, Casciato P, Forner A. From evidence to clinical practice: Bridging the gap of new liver cancer therapies in Latin America. Ann Hepatol 2024; 29:101185. [PMID: 38042481 DOI: 10.1016/j.aohep.2023.101185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Accepted: 10/26/2023] [Indexed: 12/04/2023]
Abstract
The most common primary liver tumors are hepatocellular carcinoma and cholangiocarcinoma. They constitute the sixth most common neoplasia and the third cause of cancer-related deaths worldwide. Although both tumors may share etiologic factors, diagnosis, prognostic factors, and treatments, they differ substantially in determining distinctive clinical management. In recent years, significant advances have been made in the management of these neoplasms, particularly in advanced stages. In this review, we focus on the most relevant diagnostic, prognostic, and treatment aspects of both, hepatocellular carcinoma and cholangiocarcinoma, underlying their applicability in Latin America.
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Affiliation(s)
- Federico Piñero
- Hospital Universitario Austral, Austral University, School of Medicine, Buenos Aires, Argentina.
| | - Ezequiel Mauro
- Barcelona Clinic Liver Cancer (BCLC) group. IDIBAPS. Barcelona. Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain; Liver Unit. Liver Oncology Unit. ICMDM. Hospital Clinic Barcelona. Barcelona, Spain
| | | | - Alejandro Forner
- Barcelona Clinic Liver Cancer (BCLC) group. IDIBAPS. Barcelona. Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain; Liver Unit. Liver Oncology Unit. ICMDM. Hospital Clinic Barcelona. Barcelona, Spain; University of Barcelona, Barcelona, Spain.
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Chabert S, Iesari S, Dahlqvist G, Komuta M, Baldin P, Favi E, Coubeau L. Association of Serum Levels and Immunohistochemical Labelling of Des-Gamma-Carboxy-Prothrombin in Patients Undergoing Liver Transplantation for Hepatocellular Carcinoma. Diagnostics (Basel) 2024; 14:894. [PMID: 38732309 PMCID: PMC11083058 DOI: 10.3390/diagnostics14090894] [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: 03/07/2024] [Revised: 04/18/2024] [Accepted: 04/21/2024] [Indexed: 05/13/2024] Open
Abstract
Hepatocellular cancer (HCC) is one of the main reasons for liver transplantation (LT). Biomarkers, such as alpha-foetoprotein (AFP) and Des-gamma-carboxy-prothrombin (DCP), can be helpful in defining the recurrence risk post LT. This study aims to evaluate the association between the intensity of DCP immunohistochemical labelling and serum DCP levels in patients undergoing LT for HCC. We carried out a prospective monocentric study including patients who all underwent LT for cirrhosis between 2016 and 2018 and all fell under the Milan criteria. The accepted diagnostic criteria for HCC were contrast-enhanced imaging and histology. Thirty-nine patients were followed for a median of 21 months, with HCC lesions categorized into negative, focally positive, and diffusely positive groups based on DCP immunohistochemistry. The serum DCP levels were significantly higher in the positive groups (258 mAU/mL for the focally and 257 mAU/mL for the diffusely positive) than in the negative group (48 mAU/mL) (p = 0.005) at diagnosis and at the time of liver transplantation (220 mAU/mL for the diffuse positive group). Microvascular invasion (58.8% vs. 19.0% for the diffusely positive and negative groups, respectively, p < 0.001) and lesion size (20 mm in the diffusely labelled group versus 12 mm in the other groups, p = 0.002) were significantly correlated with DCP labelling. Late recurrence occurred only in the positive groups; in the negative group, it occurred within the first 3 months after transplantation. DCP labelling in liver lesions correlates with serum levels and a more aggressive tumour profile. Further investigation is needed to determine if highly DCP-labelled tumours allow for the better selection of high-risk patients before LT.
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Affiliation(s)
- Suzanne Chabert
- Department of Hepatogastroenterology, Cliniques Universitaires Saint-Luc, 1200 Brussels, Belgium; (S.C.); (G.D.)
| | - Samuele Iesari
- General Surgery and Kidney Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (S.I.); (E.F.)
| | - Geraldine Dahlqvist
- Department of Hepatogastroenterology, Cliniques Universitaires Saint-Luc, 1200 Brussels, Belgium; (S.C.); (G.D.)
| | - Mina Komuta
- Department of Pathology, Keio University, Tokyo 223-8522, Japan;
| | - Pamela Baldin
- Department of Pathology, Université Catholique de Louvain, 1200 Brussels, Belgium;
| | - Evaldo Favi
- General Surgery and Kidney Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (S.I.); (E.F.)
| | - Laurent Coubeau
- Pôle de Chirurgie Expérimentale et Transplantation, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, 1200 Brussels, Belgium
- Service de Chirurgie et Transplantation Abdominale, Cliniques Universitaires Saint-Luc, 1200 Brussels, Belgium
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Devillers MJC, Pluimers JKF, van Hooff MC, Doukas M, Polak WG, de Man RA, Sonneveld MJ, Boonstra A, den Hoed CM. The Role of PIVKA-II as a Predictor of Early Hepatocellular Carcinoma Recurrence-Free Survival after Liver Transplantation in a Low Alpha-Fetoprotein Population. Cancers (Basel) 2023; 16:4. [PMID: 38201435 PMCID: PMC10778448 DOI: 10.3390/cancers16010004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 12/13/2023] [Accepted: 12/13/2023] [Indexed: 01/12/2024] Open
Abstract
INTRODUCTION AFP and the RETREAT score are currently used to predict HCC recurrence after LT. However, superior discriminating models are needed for low AFP populations. The aim of this study is to investigate the predictive value of PIVKA-II on recurrence-free survival after LT in a low AFP population and microvascular invasion on explant. METHODS A retrospective cohort study including all consecutive patients transplanted for HCC between 1989 and 2019 in the Erasmus MC University Medical Center in Rotterdam, the Netherlands, was used. AFP and PIVKA-II levels were determined in serum samples collected at the time of transplantation. Data on tumor load and microvascular invasion were retrieved from patients' records. RESULTS The study cohort consisted of 121 patients, with HCC recurrence in 15 patients (12.4%). The median AFP was 7.7 ng/mL (4.4-20.2), and the median PIVKA-II was 72.0 mAU/mL (41.0-213.5). Patients with low AFP (≤8 ng/mL) and PIVKA-II (≤90 mAU/mL) had a 5-year recurrence-free survival of 100% compared to 85.7% in patients with low AFP and high PIVKA-II (p = 0.026). Regardless of the AFP level, patients within the Milan criteria (based on explant pathology) with a low PIVKA-II level had a 5-year recurrence-free survival of 100% compared to patients with a high PIVKA-II level of 81.1% (p = 0.002). In patients with microvascular invasion, the AUC for PIVKA-II was slightly better than the AUC for AFP (0.775 vs. 0.687). CONCLUSIONS The dual model of PIVKA-II ≤ 90 mAU/mL with either AFP ≤ 8 ng/mL or with patients within the Milan criteria identifies patient groups which can be exempted from HCC surveillance after LT in a low AFP population. PIVKA-II may be a better predictor for explant microvascular invasion than AFP and could play a role in future models identifying LT candidates with the highest risk for HCC recurrence.
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Affiliation(s)
- Monique J. C. Devillers
- Department of Gastroenterology and Hepatology, Erasmus MC Transplant Institute, Erasmus MC University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands; (M.J.C.D.); (J.K.F.P.); (M.C.v.H.); (R.A.d.M.); (M.J.S.); (A.B.)
| | - Johanna K. F. Pluimers
- Department of Gastroenterology and Hepatology, Erasmus MC Transplant Institute, Erasmus MC University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands; (M.J.C.D.); (J.K.F.P.); (M.C.v.H.); (R.A.d.M.); (M.J.S.); (A.B.)
| | - Maria C. van Hooff
- Department of Gastroenterology and Hepatology, Erasmus MC Transplant Institute, Erasmus MC University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands; (M.J.C.D.); (J.K.F.P.); (M.C.v.H.); (R.A.d.M.); (M.J.S.); (A.B.)
| | - Michail Doukas
- Department of Pathology, Erasmus MC University Medical Center, 3000 CA Rotterdam, The Netherlands;
| | - Wojciech G. Polak
- Department of Surgery, Division of Hepatopancreatobiliary and Transplant Surgery, Erasmus MC Transplant Institute, Erasmus MC University Medical Center, 3000 CA Rotterdam, The Netherlands;
| | - Robert A. de Man
- Department of Gastroenterology and Hepatology, Erasmus MC Transplant Institute, Erasmus MC University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands; (M.J.C.D.); (J.K.F.P.); (M.C.v.H.); (R.A.d.M.); (M.J.S.); (A.B.)
| | - Milan J. Sonneveld
- Department of Gastroenterology and Hepatology, Erasmus MC Transplant Institute, Erasmus MC University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands; (M.J.C.D.); (J.K.F.P.); (M.C.v.H.); (R.A.d.M.); (M.J.S.); (A.B.)
| | - Andre Boonstra
- Department of Gastroenterology and Hepatology, Erasmus MC Transplant Institute, Erasmus MC University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands; (M.J.C.D.); (J.K.F.P.); (M.C.v.H.); (R.A.d.M.); (M.J.S.); (A.B.)
| | - Caroline M. den Hoed
- Department of Gastroenterology and Hepatology, Erasmus MC Transplant Institute, Erasmus MC University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands; (M.J.C.D.); (J.K.F.P.); (M.C.v.H.); (R.A.d.M.); (M.J.S.); (A.B.)
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8
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Yoon JH, Choi SK. Management of early-stage hepatocellular carcinoma: challenges and strategies for optimal outcomes. JOURNAL OF LIVER CANCER 2023; 23:300-315. [PMID: 37734717 PMCID: PMC10565545 DOI: 10.17998/jlc.2023.08.27] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 08/24/2023] [Accepted: 08/27/2023] [Indexed: 09/23/2023]
Abstract
Although hepatocellular carcinoma (HCC) is associated with a poor prognosis, management of early-stage HCC is often successful with highly efficacious treatment modalities such as liver transplantation, surgical resection, and radiofrequency ablation. However, unfavorable clinical outcomes have been observed under certain circumstances, even after efficient treatment. Factors that predict unsuitable results after treatment include tumor markers, inflammatory markers, imaging findings reflecting tumor biology, specific outcome indicators for each treatment modality, liver functional reserve, and the technical feasibility of the treatment modalities. Various strategies may overcome these challenges, including the application of reinforced treatment indication criteria with predictive markers reflecting tumor biology, compensation for technical issues with up-to-date technologies, modification of treatment modalities, downstaging with locoregional therapies (such as transarterial chemotherapy or radiotherapy), and recently introduced combination immunotherapies. In this review, we discuss the challenges to achieving optimal outcomes in the management of early-stage HCC and suggest strategies to overcome these obstacles.
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Affiliation(s)
- Jae Hyun Yoon
- Department of Gastroenterology and hepatology, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, Korea
| | - Sung Kyu Choi
- Department of Gastroenterology and hepatology, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, Korea
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Yu J, Park R, Kim R. Promising Novel Biomarkers for Hepatocellular Carcinoma: Diagnostic and Prognostic Insights. J Hepatocell Carcinoma 2023; 10:1105-1127. [PMID: 37483311 PMCID: PMC10362916 DOI: 10.2147/jhc.s341195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Accepted: 07/07/2023] [Indexed: 07/25/2023] Open
Abstract
The systemic therapy landscape for hepatocellular carcinoma is rapidly evolving, as the recent approvals of checkpoint inhibitor-based regimens such as atezolizumab-bevacizumab and durvalumab-tremelimumab in advanced disease have led to an expanding therapeutic armamentarium. The development of biomarkers, however, has not kept up with the approvals of new agents. Nevertheless, biomarker research for hepatocellular carcinoma has recently been growing at a rapid pace. The most active areas of research are biomarkers for early detection and screening, accurate prognostication, and detection of minimal residual disease following curative intent therapies, and, perhaps most importantly, predictive markers to guide selection and sequencing of the individual agents, including tyrosine kinase inhibitors and immunotherapy. In this review, we briefly summarize the recent developments in systemic therapeutics for hepatocellular carcinoma, introduce the key completed and ongoing prospective and retrospective studies evaluating diagnostic, prognostic, and predictive biomarkers with high clinical relevance, highlight several potentially important areas of future research, and share our insights for each biomarker.
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Affiliation(s)
- James Yu
- Division of Hematology and Medical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Robin Park
- Division of Hematology and Medical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Richard Kim
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
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10
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Pommergaard HC. Prognostic biomarkers in and selection of surgical patients with hepatocellular carcinoma. APMIS 2023; 131 Suppl 146:1-39. [PMID: 37186326 DOI: 10.1111/apm.13309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/17/2023]
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11
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Villalba-López F, Sáenz-Mateos LF, Sánchez-Lorencio MI, De La Orden-García V, Alconchel-Gago F, Cascales-Campos PA, García-Bernardo C, Noguera-Velasco JA, Baroja-Mazo A, Ramírez-Romero P. Usefulness of PIVKA-II for monitoring after liver transplantation in patients with hepatocellular carcinoma. Sci Rep 2023; 13:5621. [PMID: 37024609 PMCID: PMC10079651 DOI: 10.1038/s41598-023-32879-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 04/04/2023] [Indexed: 04/08/2023] Open
Abstract
The high morbidity and mortality of hepatocellular carcinoma (HCC) has encouraged the search for new biomarkers to be used alongside alpha-foetoprotein (AFP) and imaging tests. The aim of this study was to evaluate the clinical contribution of protein induced by vitamin K absence or antagonist-II (PIVKA-II) for HCC monitoring after liver transplantation (LT) and compare it with AFP, a routinely used tumour marker. A total of 46 HCC patients (Milan criteria) were enrolled in this study. Serum levels of PIVKA-II and AFP were measured before and after transplantation. Clinical features were determined for all the patients that were included. Significant correlations were found between PIVKA-II expression levels and some clinicopathological features, such as tumour size and number of pre-transplant transarterial chemoembolizations (TACEs). Serum levels of PIVKA-II and AFP decreased significantly after LT and increased in patients with tumour recurrence. Serum PIVKA-II levels may play an important role in predicting disease severity. Furthermore, monitoring PIVKA-II levels in HCC transplant recipients reflects the tumor early recurrence after transplantation and could be used, complementing AFP and imaging tests, as a novel biomarker of this pathology.
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Affiliation(s)
| | | | | | | | - Felipe Alconchel-Gago
- Liver Transplant Unit, University Hospital Virgen de la Arrixaca, 30120, Murcia, Spain
| | | | | | | | | | - Pablo Ramírez-Romero
- Liver Transplant Unit, University Hospital Virgen de la Arrixaca, 30120, Murcia, Spain
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12
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Ishii M, Ibuki S, Morinaga J, Shimata K, Hirukawa K, Isono K, Honda M, Sugawara Y, Inomata Y, Hibi T. Elevated Alfa-Fetoprotein and Des-Gamma-Carboxy Prothrombin Levels Predict Poor Outcomes After Liver Transplantation for Hepatocellular Carcinoma Beyond the Japan Criteria. Transplant Proc 2023; 55:606-612. [PMID: 37005157 DOI: 10.1016/j.transproceed.2023.02.047] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Accepted: 02/24/2023] [Indexed: 04/03/2023]
Abstract
AIM The Japan criteria (Milan criteria + 5-5-500 rule) was established recently to select cirrhotic patients with hepatocellular carcinoma for liver transplantation. We evaluated factors associated with poor prognosis after liver transplantation and investigated whether a further extension of the criteria would be worthwhile. METHODS We retrospectively analyzed 86 patients who underwent liver transplantation for hepatocellular carcinoma at Kumamoto University Hospital since 2004; 69 patients (80.2%) met the Japan criteria (the JCIN group), and 17 patients (19.8%) did not (the JCOUT group). RESULTS The 5-year cancer-specific survival rates of the JCIN group (92.2%) were significantly better than that of the JCOUT group (39.2%; P < .001). In univariable analysis, alfa-fetoprotein and des-gamma-carboxy prothrombin were significant independent factors associated with cancer-specific survival rates. According to the receiver operating characteristic curves, the cutoff values of alfa-fetoprotein and des-gamma-carboxy prothrombin that predicted hepatocellular carcinoma recurrence after liver transplantation were 756 ng/mL and 1976 mAU/mL, respectively. The JCOUT group was divided into 2 subgroups according to alfa-fetoprotein and des-gamma-carboxy prothrombin: low risk (alfa-fetoprotein level <756 ng/mL and des-gamma-carboxy prothrombin level <1976 mAU/mL) and high risk (alfa-fetoprotein level ≥756 ng/mL and/or des-gamma-carboxy prothrombin level ≥1976 mAU/mL). The 5-year cancer-specific survival rate in the low-risk group (67.5%) was significantly better than that in the high-risk group (0%; P < .001). CONCLUSIONS Alfa-fetoprotein levels of <756 ng/mL and des-gamma-carboxy prothrombin levels of <1976 mAU/mL may help identify cirrhotic patients with hepatocellular carcinoma who do not meet the Japan criteria but still benefit from liver transplantation.
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13
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Kim MJ, Kang WH, Hwang S, Ahn CS, Moon DB, Ha TY, Song GW, Jung DH, Park GC. Expression Patterns of Tumor Markers in Liver Transplant Recipients Showing Complete Pathological Response of Hepatocellular Carcinoma. J Clin Med 2022; 11:jcm11195897. [PMID: 36233764 PMCID: PMC9573247 DOI: 10.3390/jcm11195897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 10/03/2022] [Accepted: 10/03/2022] [Indexed: 11/28/2022] Open
Abstract
Complete pathological response (CPR) is achieved with various pretransplant locoregional treatments for hepatocellular carcinoma (HCC). This study aimed to investigate pretransplant expression of HCC tumor markers in liver transplantation (LT) recipients showing CPR. For the CPR group, 166 patients were selected from a single-institution LT database. Two control groups of 332 patients without HCC and 184 patients with partial pathological response (PPR) were also selected. The model for end-stage liver disease score in the CPR group was 11.5 ± 7.7. The number of transcatheter arterial chemoembolization sessions before LT was one in 68 patients (14.0%), two in 38 patients (22.9%), and three or more in 60 patients (36.1%). A solitary non-viable tumor was identified in 120 (86.4%) of the explant livers and the largest tumor size was 2.4 ± 1.3 cm. Living-donor and deceased-donor LTs were performed in 152 (91.6%) and 14 (8.4%) patients, respectively. The median levels of α-fetoprotein (AFP) and protein induced by Vitamin K absence or antagonist-II (PIVKA-II) measured within two weeks before LT were 4.2 ng/mL and 20 mAU/mL, respectively. These tumor marker levels were comparable to those in the no-HCC control group, but much lower than those in the PPR group (p < 0.001). Receiver operating characteristic curve analysis of AFP and PIVKA-II showed no definite cutoff values for CPR in the cohort of CPR and no-HCC patients, but significant cutoffs of 6.5 ng/mL for AFP and 29 mAU/mL for PIVKA-II were obtained in the cohort of CPR and PPR patients. The 1-, 3- and 5-year HCC recurrence and overall patient survival rates of the CPR group were 5.1% and 93.3%, 7.6% and 89.6%, and 7.6% and 89.6%, respectively. These tumor recurrence rates were much lower than those in the PPR group (p < 0.001). In conclusion, the present study results suggest that normalizing AFP and PIVKA-II after locoregional treatment is indicative of CPR. However, some CPR patients showed high expression of tumor markers; thus, pretransplant values of HCC tumor markers should be interpreted with caution.
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Affiliation(s)
| | | | - Shin Hwang
- Correspondence: ; Tel.: +82-2-3010-3930; Fax: +82-2-3010-6701
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14
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Shimamura T, Goto R, Watanabe M, Kawamura N, Takada Y. Liver Transplantation for Hepatocellular Carcinoma: How Should We Improve the Thresholds? Cancers (Basel) 2022; 14:cancers14020419. [PMID: 35053580 PMCID: PMC8773688 DOI: 10.3390/cancers14020419] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/06/2022] [Accepted: 01/10/2022] [Indexed: 02/01/2023] Open
Abstract
Simple Summary The ideal treatment for hepatocellular carcinoma (HCC) is liver transplantation (LT), which both eliminates the HCC and cures the diseased liver. Once considered an experimental treatment with dismal survival rates, LT for HCC entered a new era with the establishment of the Milan criteria over 20 years ago. However, over the last two decades, the Milan criteria, which are based on tumor morphology, have come under intense scrutiny and are now largely regarded as too restrictive, and limit the access of transplantation for many patients who would otherwise achieve good clinical outcomes. The liver transplant community has been making every effort to reach a goal of establishing more reliable selection criteria. This article addresses how the criteria have been extended, as well as the concept of pre-transplant down-staging to maximize the eligibility. Abstract Hepatocellular carcinoma (HCC) is the third highest cause of cancer-related mortality, and liver transplantation is the ideal treatment for this disease. The Milan criteria provided the opportunity for HCC patients to undergo LT with favorable outcomes and have been the international gold standard and benchmark. With the accumulation of data, however, the Milan criteria are not regarded as too restrictive. After the implementation of the Milan criteria, many extended criteria have been proposed, which increases the limitations regarding the morphological tumor burden, and incorporates the tumor’s biological behavior using surrogate markers. The paradigm for the patient selection for LT appears to be shifting from morphologic criteria to a combination of biologic, histologic, and morphologic criteria, and to the establishment of a model for predicting post-transplant recurrence and outcomes. This review article aims to characterize the various patient selection criteria for LT, with reference to several surrogate markers for the biological behavior of HCC (e.g., AFP, PIVKA-II, NLR, 18F-FDG PET/CT, liquid biopsy), and the response to locoregional therapy. Furthermore, the allocation rules in each country and the present evidence on the role of down-staging large tumors are addressed.
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Affiliation(s)
- Tsuyoshi Shimamura
- Division of Organ Transplantation, Hokkaido University Hospital, N-14, W-5, Kita-ku, Sapporo 060-8648, Hokkaido, Japan
- Correspondence:
| | - Ryoichi Goto
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, N-15, W-7, Kita-ku, Sapporo 060-8638, Hokkaido, Japan;
| | - Masaaki Watanabe
- Department of Transplant Surgery, Hokkaido University Graduate School of Medicine, N-15, W-7, Kita-ku, Sapporo 060-8638, Hokkaido, Japan; (M.W.); (N.K.)
| | - Norio Kawamura
- Department of Transplant Surgery, Hokkaido University Graduate School of Medicine, N-15, W-7, Kita-ku, Sapporo 060-8638, Hokkaido, Japan; (M.W.); (N.K.)
| | - Yasutsugu Takada
- Department of HBP and Breast Surgery, Ehime University Graduate School of Medicine, Shitsukawa, Toon 791-0295, Ehime, Japan;
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15
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Mouchli M, Reddy S, Gerrard M, Boardman L, Rubio M. Usefulness of neutrophil-to-lymphocyte ratio (NLR) as a prognostic predictor after treatment of hepatocellular carcinoma." Review article. Ann Hepatol 2021; 22:100249. [PMID: 32896610 DOI: 10.1016/j.aohep.2020.08.067] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 08/07/2020] [Accepted: 08/08/2020] [Indexed: 02/06/2023]
Abstract
The neutrophil-to-lymphocyte ratio (NLR) is an inflammatory marker which has been investigated as a prognostic indicator in post-therapeutic recurrence and survival of patients with HCC. Our aim was to review all studies that assessed the prognostic value of pre-treatment NLR in predicting patient survival, cancer recurrence, and graft survival in patients undergoing various therapies for HCC. We searched the database of PubMed and Google Scholar to review all studies that have the word "NLR" and the word "HCC." We included all studies that assessed pre-treatment NLR as a prognostic factor in predicting outcomes in HCC patients. We excluded studies that assessed the correlation between post-treatment NLR or dynamic changes in NLR after treatment and HCC outcomes in an effort to minimize the confounding effect of each treatment on NLR. We reviewed 123 studies that studied the correlation between pre-treatment NLR and patient survival, 72 studies that evaluated the correlation between pre-treatment NLR and tumor recurrence, 21 studies that evaluated the correlation between NLR and tumor behavior, and 4 studies that assessed the correlation between NLR and graft survival. We found a remarkable heterogeneity between the methods of the studies, which is likely responsible for the differences in outcomes. The majority of the studies suggested a correlation between higher levels of pre-treatment NLR and poor outcomes. We concluded that NLR is a reliable and inexpensive biomarker and should be incorporated into other prognostic models to help determine outcomes following HCC treatment.
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Affiliation(s)
- Mohamad Mouchli
- Virginia Tech Carilion School of Medicine Department of Internal Medicine, Division of Gastroenterology & Hepatology, Roanoke, VA, United States; Virginia Tech Carilion School of Medicine Department of Internal Medicine, Roanoke, VA, United States; Mayo Clinic, Division of Gastroenterology & Hepatology, Rochester, MN, United States; Cleveland Clinic Foundation, Division of Gastroenterology & Hepatology, Cleveland, OH, United States.
| | - Shravani Reddy
- Virginia Tech Carilion School of Medicine Department of Internal Medicine, Roanoke, VA, United States
| | - Miranda Gerrard
- Virginia Tech Carilion School of Medicine, Roanoke, VA, United States
| | - Lisa Boardman
- Mayo Clinic, Division of Gastroenterology & Hepatology, Rochester, MN, United States
| | - Marrieth Rubio
- Virginia Tech Carilion School of Medicine Department of Internal Medicine, Division of Gastroenterology & Hepatology, Roanoke, VA, United States; Virginia Tech Carilion School of Medicine Department of Internal Medicine, Roanoke, VA, United States
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16
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Badwei N, Monsef WA, Montasser I, Bahaa M, El Meteini M, Kamel SY. Role of inflammatory markers in predicting hepatocellular carcinoma recurrence after liver transplantation. EGYPTIAN LIVER JOURNAL 2021. [DOI: 10.1186/s43066-021-00105-8] [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
Liver transplantation (LT) is the best treatment for selected patients with cirrhosis and small hepatocellular carcinoma (HCC) who are not candidates for resection. The proinflammatory effects of systemic inflammatory response have been linked with HCC. Therefore, the measurement of inflammatory markers represents a significant tool to limit recurrence after LT.
Results
There are eleven patients with HCC recurrence post-transplantation. Pre-transplantation AFP can predict HCC recurrence with the best cutoff value of > 17.8 ng/ml with a sensitivity of 82% and specificity of 70%. Post-transplantation CRP can predict HCC recurrence with the best cutoff value of > 0.85 (mg/dl) with a sensitivity of 73% and specificity of 71%. Other inflammatory markers NLR and PLR were not significant in predicting HCC recurrence. Moreover, HCC recurrence significantly affects the outcome of patients undergoing LT (p value < 0.001) with a worse prognosis.
Conclusion
Our results showed additional benefits of inflammatory markers as CRP to standard parameters in predicting HCC recurrence to refine recipient selection and achieve better survival outcomes post-LT.
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17
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Lerut J, Foguenne M, Lai Q. Hepatocellular cancer selection systems and liver transplantation: from the tower of babel to an ideal comprehensive score. Updates Surg 2021; 73:1599-1614. [PMID: 34003479 PMCID: PMC8500859 DOI: 10.1007/s13304-021-01078-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Accepted: 05/03/2021] [Indexed: 12/13/2022]
Abstract
The Milan criteria (MC) remain the cornerstone for the selection of patients with hepatocellular cancer (HCC) to be listed for liver transplantation (LT). Recently, several expanded criteria have been proposed to increase the transplantability of HCC patients without compromising their (oncologic) outcome. This paper aims to systematically review the different reported HCC-LT selection systems looking thereby at their ability to increase the number of transplantable patients and the overall survival and oncological outcome. A systematic review of the literature covering the period 1993 (date of the first reported HCC-LT selection system)-2021 identified 59 different inclusion criteria of HCC for LT. Among the 59 studies reporting HCC-LT selection systems, 15 (28.3%) were exclusively based on morphological aspects of the tumor; 29 (54.7%) included biologic, seven (13.2%) radiological, and two (3.8%) only included pathological tumor features. Overall, 31% more patients could be transplanted when adhering to the new HCC-LT selection systems. Despite the increased number of LT, 5-year patient and disease-free survival rates were similar between MC-IN and MC-OUT/new HCC-LT-IN criteria. A careful extension of the inclusion criteria should allow many more patients to access a potentially curative LT without compromising their outcome. The development of a widely accepted "comprehensive" HCC-LT Score able to offer a fair chance of justified transplantation to more patients should become a priority within the liver transplant community. Further studies are needed to develop internationally accepted, expanded selection criteria for liver transplantation of HCC patients.
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Affiliation(s)
- Jan Lerut
- Institute for Experimental and Clinical Research (IREC), Université Catholique de Louvain (UCL), Avenue Hippocrates 55, 1200 Brussels, Belgium
| | - Maxime Foguenne
- University Hospitals Saint-Luc Université Catholique de Louvain (UCL), Brussels, Belgium
| | - Quirino Lai
- General Surgery and Organ Transplantation Unit, Sapienza University of Rome, Rome, Italy
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18
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Isik B, Gonultas F, Sahin T, Yilmaz S. Microvascular Venous Invasion in Hepatocellular Carcinoma: Why Do Recurrences Occur? J Gastrointest Cancer 2021; 51:1133-1136. [PMID: 32839943 DOI: 10.1007/s12029-020-00487-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE Hepatocellular carcinoma is the most common primary cancer of the liver. It is almost always associated with cirrhosis and it is usually diagnosed in later stages of the disease. Furthermore, recurrence rate following liver transplantation ranges between 15 and 30%. The most important factor determining the recurrence is vascular invasion. METHODS In this review, the issue of microvascular invasion causing hepatocellular carcinoma recurrence is reviewed. Macroscopic vascular invasion is almost easy to diagnose on radiologic evaluation. However, microscopic vascular invasion is almost always diagnosed with pathologic evaluation. On the other hand, microscopic vascular invasion is associated with early recurrences and reduced disease-free survival. The type of vessel that is invaded determines the nature of the spread of the tumor cells. Invasion of the hepatic venous tributaries leads to systemic metastasis whereas portal venous invasions lead to intrahepatic spread of the tumor. Microscopic vascular invasion should be diagnosed before liver transplantation or liver resection in order to deliver the appropriate therapy to the patients. RESULTS Yet, there is no ideal marker to suggest microscopic vascular invasion before any intervention. Markers such as alpha-fetoprotein, des carboxy prothrombin, or gamma-glutamyl transferase have been found to be correlated with microscopic vascular invasion. These parameters are not very efficient to be used in routine clinical practice. CONCLUSION Therefore, further research is needed to define ideal marker associated with microscopic vascular invasion.
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Affiliation(s)
- Burak Isik
- Department of Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, 244280, Malatya, Turkey
| | - Fatih Gonultas
- Department of Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, 244280, Malatya, Turkey
| | - Tolga Sahin
- Department of Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, 244280, Malatya, Turkey
| | - Sezai Yilmaz
- Department of Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, 244280, Malatya, Turkey. .,Department of Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, Elazig Yolu 10. Km, 44280, Malatya, Turkey.
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19
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Akbulut S, Koc C. Do We Need to Be Limited by Matching Milan Criteria for Survival in Living Donor Liver Transplantation? J Gastrointest Cancer 2020; 51:1107-1113. [PMID: 32857265 DOI: 10.1007/s12029-020-00482-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE Hepatocellular carcinoma (HCC) is the second leading cause of cancer deaths and the 7th most common cancer. It has two characteristic features: being advanced stage at diagnosis and association with liver cirrhosis. Liver transplantation (LT) offers the only curative option to treat both components of the disease. The Milan criteria have been extensively used for selecting patients with HCC for LT. However, using Milan criteria, we can only transplant 30% of the patients. The aim of the present review is to evaluate the role of LT in HCC beyond the Milan criteria. METHODS We evaluated the studies that have introduced extended criteria to select patients with HCC beyond the Milan criteria. We evaluated the outcomes in terms of disease-free survival rates and HCC recurrences. RESULTS There are patients with tumors that are beyond Milan criteria that could benefit from LT. Selection of these patients has paramount importance in the era of living donor liver transplantation. Current expanded criteria depend on either the bulk of the tumor or the additional surrogate markers of tumor biology such as alpha-fetoprotein (AFP) and des-gamma carboxyprothrombin (DCP). CONCLUSION There is no ideal marker or an extended criterion for selecting patients with HCC beyond the Milan criteria and it needs further research to find an effective biomarker that has prognostic significance to select patients with advanced tumors.
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Affiliation(s)
- Sami Akbulut
- Department of Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, Elazig Yolu 10. Km, 244280, Malatya, Turkey.
| | - Cemalettin Koc
- Department of Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, Elazig Yolu 10. Km, 244280, Malatya, Turkey
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20
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Piñero F, Dirchwolf M, Pessôa MG. Biomarkers in Hepatocellular Carcinoma: Diagnosis, Prognosis and Treatment Response Assessment. Cells 2020; 9:E1370. [PMID: 32492896 PMCID: PMC7349517 DOI: 10.3390/cells9061370] [Citation(s) in RCA: 293] [Impact Index Per Article: 58.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 05/28/2020] [Accepted: 05/28/2020] [Indexed: 02/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the main cancer-related causes of death worldwide. Thus, there is a constant search for improvement in screening, diagnosis, and treatment strategies to improve the prognosis of this malignancy. The identification of useful biomarkers for surveillance and early HCC diagnosis is still deficient, with available serum biomarkers showing low sensitivity and heterogeneous specificity despite different cut-off points, even when assessed longitudinally, or with a combination of serum biomarkers. In contrast, HCC biomarkers used for prognostic (when associated with clinical outcomes) or predictive purposes (when associated with treatment response) may have an increased clinical role in the near future. Furthermore, some serum biomarkers are already implicated as a treatment selection tool, whether to provide access to certain therapies or to assess clinical benefit after treatment. In the present review we will discuss the clinical utility and foreseen future of HCC biomarkers implicated in surveillance, diagnosis, prognosis, and post-treatment assessment.
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Affiliation(s)
- Federico Piñero
- Hepatology and Liver Transplant Unit, Hospital Universitario Austral, School of Medicine, Austral University, B1629AHJ Buenos Aires, Argentina;
- Latin American Liver Research Educational and Awareness Network (LALREAN), B1629AHJ Buenos Aires, Argentina
| | - Melisa Dirchwolf
- Liver Unit, Hospital Privado de Rosario, 2000 Rosario, Santa Fe, Argentina;
| | - Mário G. Pessôa
- Division of Gastroenterology and Hepatology, University of São Paulo School of Medicine, 05403-000 São Paulo, Brazil
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21
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Sanghera C, Teh JJ, Pinato DJ. The systemic inflammatory response as a source of biomarkers and therapeutic targets in hepatocellular carcinoma. Liver Int 2019; 39:2008-2023. [PMID: 31433891 DOI: 10.1111/liv.14220] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Revised: 08/10/2019] [Accepted: 08/13/2019] [Indexed: 12/12/2022]
Abstract
The pathogenesis of hepatocellular carcinoma (HCC) strongly relates to inflammation, with chronic up-regulation of pro-inflammatory mediators standing as a potential unifying mechanism that underscores the origin and progression of HCC independent of aetiology. Activation of the diverse pro-inflammatory mediators either within the tumour or its microenvironment is part of an active cross-talk between the progressive HCC and the host, which is known to influence clinical outcomes including recurrence after radical treatments and long-term survival. A number of clinical biomarkers to measure the severity of cancer-related inflammation are now available, most of which emerge from routine blood parameters including neutrophil, lymphocyte, platelet counts, as well as albuminaemia and C-reactive protein levels. In this review, we summarise the body of evidence supporting the biologic qualification of inflammation-based scores in HCC and review their potential in facilitating the prognostic assessment and treatment allocation in the individual patient. We also discuss the evidence to suggest modulation of tumour-promoting inflammation may act as a source of novel therapeutic strategies in liver cancer.
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Affiliation(s)
| | - Jhia J Teh
- Department of Medicine, Imperial College London, London, UK
| | - David J Pinato
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK
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22
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Citores MJ, Lucena JL, de la Fuente S, Cuervas-Mons V. Serum biomarkers and risk of hepatocellular carcinoma recurrence after liver transplantation. World J Hepatol 2019; 11:50-64. [PMID: 30705718 PMCID: PMC6354126 DOI: 10.4254/wjh.v11.i1.50] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 11/13/2018] [Accepted: 12/05/2018] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation (LT) is the only potentially curative treatment for selected patients with cirrhosis and hepatocellular carcinoma (HCC) who are not candidates for resection. When the Milan criteria are strictly applied, 75% to 85%of 3- to 4-year actuarial survival rates are achieved, but up to 20% of the patients experience HCC recurrence after transplantation. The Milan criteria are based on the preoperative tumor macromorphology, tumor size and number on computed tomography or magnetic resonance imaging that neither correlate well with posttransplant histological study of the liver explant nor accurately predict HCC recurrence after LT, since they do not include objective measures of tumor biology. Preoperative biological markers, including alpha-fetoprotein, des-gamma-carboxiprothrombin or neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio, can predict the risk for HCC recurrence after transplantation. These biomarkers have been proposed as surrogate markers of tumor differentiation and vascular invasion, with varied risk magnitudes depending on the defined cutoffs. Different studies have shown that the combination of one or several biomarkers integrated into prognostic models predict the risk of HCC recurrence after LT more accurately than Milan criteria alone. In this review, we focus on the potential utility of these serum biological markers to improve the performance of Milan criteria to identify patients at high risk of tumoral recurrence after LT.
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Affiliation(s)
- Maria J Citores
- Department of Internal Medicine, Instituto de Investigación Sanitaria Puerta de Hierro-Segovia de Arana, Majadahonda 28222, Spain
| | - Jose L Lucena
- Liver Transplantation Unit, Hospital Universitario Puerta de Hierro-Majadahonda, Majadahonda 28222, Spain
- Department of Surgery, Hospital Universitario Puerta de Hierro-Majadahonda, Majadahonda 28222, Spain
| | - Sara de la Fuente
- Department of Internal Medicine, Hospital Universitario Puerta de Hierro-Majadahonda, Majadahonda 28222, Spain
| | - Valentin Cuervas-Mons
- Department of Internal Medicine, Hospital Universitario Puerta de Hierro-Majadahonda, Majadahonda 28222, Spain
- Department of Medicine, Universidad Autónoma de Madrid, Madrid 28029, Spain
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23
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Amado V, Rodríguez-Perálvarez M, Ferrín G, De la Mata M. Selecting patients with hepatocellular carcinoma for liver transplantation: incorporating tumor biology criteria. J Hepatocell Carcinoma 2018; 6:1-10. [PMID: 30613572 PMCID: PMC6306074 DOI: 10.2147/jhc.s174549] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Liver transplantation (LT) is the optimal therapeutic option for patients with liver cirrhosis and hepatocellular carcinoma (HCC). Due to universal donor shortage, only the patients with limited tumor burden (under the so-called Milan criteria) are considered as potential candidates for LT in most institutions. It is expected that in the near future, more liver grafts will be available for patients with HCC due to the implementation of new direct antivirals against hepatitis C, leaving a prone scenario to consider expanding Milan criteria. A moderate expansion of Milan criteria could be implemented without increasing the risk of tumor recurrence if patients with favorable biological behavior are carefully selected. Incorporating information regarding tumor biology in the decision-making algorithm would result in a more rational use of LT in patients with HCC. In the present review, surrogate markers of tumor biology are critically evaluated as potential tools to be combined with existing radiological criteria. In addition, the current state of liquid biopsy is discussed, as this cutting-edge technology may reshape the management of HCC in the upcoming years.
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Affiliation(s)
- Víctor Amado
- Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, IMIBIC, CIBERehd, Córdoba, Spain,
| | - Manuel Rodríguez-Perálvarez
- Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, IMIBIC, CIBERehd, Córdoba, Spain,
| | - Gustavo Ferrín
- Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, IMIBIC, CIBERehd, Córdoba, Spain,
| | - Manuel De la Mata
- Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, IMIBIC, CIBERehd, Córdoba, Spain,
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24
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Lorente L. New prognostic biomarkers of mortality in patients undergoing liver transplantation for hepatocellular carcinoma. World J Gastroenterol 2018; 24:4230-4242. [PMID: 30310256 PMCID: PMC6175764 DOI: 10.3748/wjg.v24.i37.4230] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Revised: 08/18/2018] [Accepted: 08/24/2018] [Indexed: 02/06/2023] Open
Abstract
The outcome prediction of hepatocellular carcinoma (HCC) patients undergoing liver transplantation (LT) was classically established using various macromorphological factors and serum alpha-fetoprotein levels prior to LT. However, other biomarkers have recently been reported to be associated with the prognosis of HCC patients undergoing to LT. This review summarizes clinical data on these new biomarkers. High blood levels of malondialdehyde, total antioxidant capacity, caspase-cleaved cytokeratin-18, soluble CD40 ligand, substance P, C-reactive protein, and vascular endothelial growth factor, increased neutrophil to lymphocyte ratio and platelet to lymphocyte ratio in blood, high peripheral blood expression of human telomerase reverse transcriptase messenger ribonucleic acid, and high HCC expression of dickkopf-1 have recently been associated with decreased survival rates. In addition, high blood levels of des-gamma-carboxy prothrombin, and high HCC expression of glypican-3, E-cadherin and beta-catenin have been associated with increased HCC recurrence. Additional research is necessary to establish the prognostic role of these biomarkers in HCC prior to LT. Furthermore, some of these biomarkers are also interesting because their potential modulation could help to create new research lines for improving the outcomes of those patients.
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Affiliation(s)
- Leonardo Lorente
- Intensive Care Unit, Hospital Universitario de Canarias, Santa Cruz de Tenerife 38320, Spain
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25
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Najjar M, Agrawal S, Emond JC, Halazun KJ. Pretreatment neutrophil-lymphocyte ratio: useful prognostic biomarker in hepatocellular carcinoma. J Hepatocell Carcinoma 2018; 5:17-28. [PMID: 29404284 PMCID: PMC5779314 DOI: 10.2147/jhc.s86792] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common liver malignancy and the third most common cause of cancer-related deaths. Liver resection (LR) and liver transplantation (LT) are the only curative modalities for HCC. Despite recent advances and the adoption of the Milan and University of California, San Francisco, criteria, HCC recurrence after LR and LT remains a challenge. Several markers and prognostic scores have been proposed to predict tumor aggressiveness and supplement radiological data; among them, neutrophil–lymphocyte ratio (NLR) has recently gained significant interest. An elevated NLR is thought to predispose to HCC recurrence by creating a protumorigenic microenvironment through both relative neutrophilia and lymphocytopenia. In the present review, we attempted to summarize the published work on the role of pretreatment NLR as a prognostic marker for HCC following LR and LT. A total of 13 LT and 18 LR studies were included from 2008 to 2015. Pretransplant NLR was most often predictive of HCC recurrence, recurrence-free survival, and overall survival. NLR was, however, more variably and less clearly associated with worse outcomes following LR.
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Affiliation(s)
- Marc Najjar
- Department of Surgery, Center for Liver Disease and Transplantation, Columbia University Medical Center, New York Presbyterian Hospital, New York, NY, USA
| | - Surbhi Agrawal
- Department of Surgery, Center for Liver Disease and Transplantation, Columbia University Medical Center, New York Presbyterian Hospital, New York, NY, USA
| | - Jean C Emond
- Department of Surgery, Center for Liver Disease and Transplantation, Columbia University Medical Center, New York Presbyterian Hospital, New York, NY, USA
| | - Karim J Halazun
- Department of Surgery, Center for Liver Disease and Transplantation, Columbia University Medical Center, New York Presbyterian Hospital, New York, NY, USA.,Department of Surgery, Division of Liver Transplantation and Hepatobiliary Surgery, Weill Cornell Medical College, New York, NY, USA
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26
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Xu ZG, Ye CJ, Liu LX, Wu G, Zhao ZX, Wang YZ, Shi BQ, Wang YH. The pretransplant neutrophil-lymphocyte ratio as a new prognostic predictor after liver transplantation for hepatocellular cancer: a systematic review and meta-analysis. Biomark Med 2018; 12:189-199. [PMID: 29327595 DOI: 10.2217/bmm-2017-0307] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
AIM Recently, many reports showed that the pretransplant neutrophil-lymphocyte ratio (NLR) may be correlated with the prognosis of patients undergoing liver transplantation (LT) for hepatocellular cancer (HCC). However, their results still remained controversial. Thus we performed a meta-analysis of 13 studies to estimate the prognostic value of pretransplant NLR. METHODS Databases including PubMed, Embase, Cochrane Library and Web of Science were searched to September 2017. Hazard ratio (HR) or odds ratio (OR) with its 95% CI was used to evaluate the association between elevated NLR and the prognosis or clinical features of liver cancer patients. RESULTS A total of 13 studies including 1936 patients were included in this meta-analysis. Elevated pretransplant NLR had a close association with the overall survival (HR: 2.22; 95% CI: 1.34-3.68), recurrence-free survival (HR: 3.77; 95% CI: 2.01-7.06) and disease-free survival (HR: 2.51; 95% CI: 1.22-5.15) of patients undergoing LT for HCC, respectively. In addition, elevated NLR was associated with the presence of vascular invasion (OR: 2.39; 95% CI: 1.20-4.77) and Milan criteria (OR: 0.26; 95% CI: 0.17-0.40). CONCLUSION The results of this meta-analysis showed that elevated pretransplant NLR may be used as a new prognostic predictor after LT for HCC.
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Affiliation(s)
- Zheng-Guang Xu
- Department of General Surgery, Qinghai Provincial People's Hospital, Xi'ning 810000, China
| | - Cheng-Jie Ye
- Department of General Surgery, Qinghai Provincial People's Hospital, Xi'ning 810000, China
| | - Lin-Xun Liu
- Department of General Surgery, Qinghai Provincial People's Hospital, Xi'ning 810000, China
| | - Gang Wu
- Department of General Surgery, Qinghai Provincial People's Hospital, Xi'ning 810000, China
| | - Zhan-Xue Zhao
- Department of General Surgery, Qinghai Provincial People's Hospital, Xi'ning 810000, China
| | - Yong-Zhen Wang
- Department of General Surgery, Qinghai Provincial People's Hospital, Xi'ning 810000, China.,Department of Clinical Medicine, The Clinical Medical College of Qinghai University, Xi'ning 810000, China
| | - Bing-Qiang Shi
- Department of General Surgery, Qinghai Provincial People's Hospital, Xi'ning 810000, China.,Department of Clinical Medicine, The Clinical Medical College of Qinghai University, Xi'ning 810000, China
| | - Yong-Hong Wang
- Department of General Surgery, Qinghai Provincial People's Hospital, Xi'ning 810000, China
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27
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Des-gamma-carboxy prothrombin in hepatocellular cancer patients waiting for liver transplant: a systematic review and meta-analysis. Int J Biol Markers 2017; 32:e370-e374. [PMID: 28561879 DOI: 10.5301/ijbm.5000276] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/27/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND The use of des-gamma-carboxy prothrombin (DCP) as a predictor of the risk of recurrence of hepatocellular cancer (HCC) after liver transplant (LT) has recently gained interest, especially in view of the recent extension of the eligibility criteria of these patients for LT. The aim of the present study is to look into this important matter based on a systematic review and meta-analysis. METHODS A systematic literature review about the role of DCP in the specific setting of LT for HCC has been conducted. RESULTS Three selected studies, which showed a high rate of homogeneity (I2 = 0.0%), confirmed that the tumor marker DCP is a useful predictive factor, indicating a 5-fold increased risk for HCC recurrence after LT (p<0.001). CONCLUSIONS The meta-analysis enabled us to underline the importance of DCP in the refinement of the eligibility criteria of HCC patients for LT. This information, based on Japanese studies performed in the setting of living-donor LT only, needs further validation in the Western world both in the setting of post-mortem and living-donor LT.
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28
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Takada Y, Kaido T, Shirabe K, Nagano H, Egawa H, Sugawara Y, Taketomi A, Takahara T, Wakabayashi G, Nakanishi C, Kawagishi N, Kenjo A, Gotoh M, Toyoki Y, Hakamada K, Ohtsuka M, Akamatsu N, Kokudo N, Takeda K, Endo I, Takamura H, Okajima H, Wada H, Kubo S, Kuramitsu K, Ku Y, Ishiyama K, Ohdan H, Ito E, Maehara Y, Honda M, Inomata Y, Furukawa H, Uemoto S, Yamaue H, Miyazaki M, Takada T. Significance of preoperative fluorodeoxyglucose-positron emission tomography in prediction of tumor recurrence after liver transplantation for hepatocellular carcinoma patients: a Japanese multicenter study. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2017; 24:49-57. [PMID: 27806426 DOI: 10.1002/jhbp.412] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Accepted: 10/31/2016] [Indexed: 12/13/2022]
Abstract
BACKGROUND In the present study, we conducted a multicenter nationwide survey to investigate the effects of preoperative fluorine-18-fluorodeoxyglucose (FDG) positron emission tomography (PET) on the prediction of hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT). METHODS From 16 Japanese LT centers, data were collected on 182 recipients with HCC who underwent living donor liver transplantation (LDLT) between February 2005 and November 2013. PET-positive status was defined as increased uptake of FDG in the tumor compared to the surrounding non-tumor liver tissue. The median follow-up after LDLT was 54.5 months (range 1-125 months). RESULTS Postoperative HCC recurrence occurred in 23 patients. Multivariate analysis revealed that exceeding the Milan criteria (MC), alpha-fetoprotein (AFP) level ≥115 ng/ml, and PET-positive status were significant and independent risk factors for recurrence. In the over-MC group, a subgroup of patients with AFP level <115 ng/ml and PET-negative status (n = 22) had a significantly lower 5-year recurrence rate than the other patients (n = 27, 19% vs. 53%, P = 0.019). CONCLUSIONS These results suggest that preoperative FDG-PET status offers additional information on HCC recurrence risk after LT. Over-MC patients with PET-negative status and lower AFP level may achieve successful outcome comparable to that of within-MC patients.
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Affiliation(s)
- Yasutsugu Takada
- Department of HBP and Breast Surgery, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Toshimi Kaido
- Division of HBP Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Ken Shirabe
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Gunma, Japan
| | - Hiroaki Nagano
- Department of Gastroenterological Surgery, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | - Hiroto Egawa
- Department of Surgery, Tokyo Women's Medical University, Tokyo, Japan
| | - Yasuhiko Sugawara
- Department of Transplantation and Pediatric Surgery, Postgraduate School of Life Science, Kumamoto University, Kumamoto, Japan
| | - Akinobu Taketomi
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Hokkaido, Japan
| | - Takeshi Takahara
- Department of Surgery, Iwate Medical University School of Medicine, Iwate, Japan
| | - Go Wakabayashi
- Center for Advanced Treatment of Hepatobiliary and Pancreatic Diseases, Surgical Services, Ageo Central General Hospital, Saitama, Japan
| | - Chikashi Nakanishi
- Department of Transplantation, Reconstruction and Endoscopic Surgery, Tohoku University Hospital, Miyagi, Japan
| | - Naoki Kawagishi
- Department of Transplantation, Reconstruction and Endoscopic Surgery, Tohoku University Hospital, Miyagi, Japan
| | - Akira Kenjo
- Department of Regenerative Surgery, Fukushima Medical University, Fukushima, Japan
| | - Mitsukazu Gotoh
- Department of Regenerative Surgery, Fukushima Medical University, Fukushima, Japan
| | - Yoshikazu Toyoki
- Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Aomori, Japan
| | - Kenichi Hakamada
- Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Aomori, Japan
| | - Masayuki Ohtsuka
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Nobuhisa Akamatsu
- Artificial Organ and Transplantation Surgery Division, Department of Surgery, The University of Tokyo, Tokyo, Japan
| | - Norihiro Kokudo
- Artificial Organ and Transplantation Surgery Division, Department of Surgery, The University of Tokyo, Tokyo, Japan
| | - Kazuhisa Takeda
- National Hospital Organization Yokohama Medical Center, Kanagawa, Japan
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Kanagawa, Japan
| | - Hiroyuki Takamura
- Department of Gastroenterological Surgery, Kanazawa University, Ishikawa, Japan
| | - Hideaki Okajima
- Division of HBP Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hiroshi Wada
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Shoji Kubo
- Department of Hepato-Biliary-Pancreatic Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Kaoru Kuramitsu
- Hepato-Biliary-Pancreatic Surgery, Kobe University Hospital, Hyogo, Japan
| | - Yonson Ku
- Hepato-Biliary-Pancreatic Surgery, Kobe University Hospital, Hyogo, Japan
| | - Kohei Ishiyama
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hideki Ohdan
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Eitaro Ito
- Department of HBP and Breast Surgery, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Yoshihiko Maehara
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masaki Honda
- Department of Transplantation and Pediatric Surgery, Postgraduate School of Life Science, Kumamoto University, Kumamoto, Japan
| | - Yukihiro Inomata
- Department of Transplantation and Pediatric Surgery, Postgraduate School of Life Science, Kumamoto University, Kumamoto, Japan
| | - Hiroyuki Furukawa
- Division of Gastroenterologic Surgery, Department of Surgery, Asahikawa Medical University, Hokkaido, Japan
| | - Shinji Uemoto
- Division of HBP Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hiroki Yamaue
- Second Department of Surgery, Wakayama Medical University School of Medicine, Wakayama, Japan
| | - Masaru Miyazaki
- International University of Health and Welfare, Mita Hospital, Tokyo, Japan
| | - Tadahiro Takada
- Japanese Society of Hepato-biliary-Pancreatic Surgery, Department of Surgery, Teikyo University School of Medicine, Tokyo, Japan
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Liver transplantation for hepatocellular carcinoma: outcomes and novel surgical approaches. Nat Rev Gastroenterol Hepatol 2017; 14:203-217. [PMID: 28053342 DOI: 10.1038/nrgastro.2016.193] [Citation(s) in RCA: 312] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Liver transplantation for hepatocellular carcinoma (HCC) is the best treatment option for patients with early-stage tumours and accounts for ∼20-40% of all liver transplantations performed at most centres worldwide. The Milan criteria are the most common criteria to select patients with HCC for transplantation but they can be seen as too restrictive. Several proposals have been made for a moderate expansion of the criteria, which result in good outcomes but with an increase in the risk of tumour recurrence. In this Review, we provide a comprehensive overview of the outcomes after liver transplantation for HCC, focusing on tumour recurrence in terms of surveillance, prevention and treatment. Additionally, novel surgical techniques have been developed to increase the available pool of organs for liver transplantation (such as living donor liver transplantation, donation after circulatory death and split livers), but the effect of these techniques on patients with HCC is still under debate. Thus, we will describe these techniques and expose the benefits and disadvantages of each surgical approach. Finally, we will comment on the limitations of the current priority policies for liver transplantation and the need to further refine them to better serve the population.
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30
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Grąt M, Stypułkowski J, Patkowski W, Bik E, Krasnodębski M, Wronka KM, Lewandowski Z, Wasilewicz M, Grąt K, Masior Ł, Ligocka J, Krawczyk M. Limitations of predicting microvascular invasion in patients with hepatocellular cancer prior to liver transplantation. Sci Rep 2017; 7:39881. [PMID: 28057916 PMCID: PMC5216407 DOI: 10.1038/srep39881] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Accepted: 11/29/2016] [Indexed: 02/08/2023] Open
Abstract
Microvascular invasion (MVI) is well known to negatively influence outcomes following surgical treatment of hepatocellular cancer (HCC) patients. The aim of this study was to evaluate the rationale for prediction of MVI before liver transplantation (LT). Data of 200 HCC patients after LT were subject to retrospective analysis. MVI was present in 57 patients (28.5%). Tumor number (p = 0.001) and size (p = 0.009), and alpha-fetoprotein (p = 0.049) were independent predictors of MVI used to create a prediction model, defined as: 0.293x(tumor number) + 0.283x(tumor size in cm) + 0.164xloge(alpha-fetoprotein in ng/ml) (c statistic = 0.743). The established cut-off (≥2.24) was associated with sensitivity and specificity of 72%. MVI was not an independent risk factor for recurrence (p = 0.307), in contrast to tumor number (p = 0.047) and size (p < 0.001), alpha-fetoprotein (p < 0.001) and poor differentiation (p = 0.039). Recurrence-free survival at 5 years for patients without MVI was 85.9% as compared to 83.3% (p = 0.546) and 55.3% (p = 0.001) for patients with false negative and true positive prediction of MVI, respectively. The use of both morphological and biological tumor features enables effective pre-transplant prediction of high-risk MVI. Provided that these parameters are combined in selection of HCC patients for LT, pre-transplant identification of all patients with MVI does not appear necessary.
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Affiliation(s)
- Michał Grąt
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Poland
| | - Jan Stypułkowski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Poland
| | - Waldemar Patkowski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Poland
| | - Emil Bik
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Poland
| | - Maciej Krasnodębski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Poland
| | - Karolina M Wronka
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Poland
| | | | - Michał Wasilewicz
- Hepatology and Internal Medicine Unit, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Poland
| | - Karolina Grąt
- Second Department of Clinical Radiology, Medical University of Warsaw, Poland
| | - Łukasz Masior
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Poland
| | - Joanna Ligocka
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Poland
| | - Marek Krawczyk
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Poland
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31
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Xing H, Yan C, Cheng L, Wang N, Dai S, Yuan J, Lu W, Wang Z, Han J, Zheng Y, Yang T. Clinical application of protein induced by vitamin K antagonist-II as a biomarker in hepatocellular carcinoma. Tumour Biol 2016; 37:15447–15456. [PMID: 27739028 DOI: 10.1007/s13277-016-5443-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Accepted: 09/23/2016] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide. Early diagnosis improves the prognosis. Protein induced by vitamin K antagonist-II (PIVKA-II) is an effective serum biomarker for HCC diagnosis and prognosis. Combined with another serum biomarker α-fetoprotein (AFP), the sensitivity and specificity of HCC diagnosis can be improved to a maximum of 94 and 98.5 %, respectively. PIVKA-II alone or in combination with AFP and/or AFP-L3 was effective in predicting the treatment response and clinical outcome of curative hepatic resection, chemotherapy, targeted therapy, radiotherapy, and liver transplantation. Japanese clinical guidelines recommend the combined use of PIVKA-II and AFP for the diagnosis of HCC, management of high-risk population, and prognosis of anticancer treatment. Further, PIVKA-II as a functional target promoted HCC cell proliferation, invasion, and metastasis by activating c-Met and other signal transduction pathways. Inhibition of PIVKA-II may provide a selective and effective therapy for HCC.
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Affiliation(s)
- Hao Xing
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China
| | - Cunling Yan
- Department of Clinical Laboratory, Peking University First Hospital, Beijing, China
| | - Liming Cheng
- Department of Clinical Laboratory, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Nianyue Wang
- The Second Hospital of Nanjing, Affiliated to Medical School of Southeast University, Nanjing, China
| | - Shuyang Dai
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China
| | - Jianyong Yuan
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China
| | - Wenfeng Lu
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China
| | - Zhouchong Wang
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China
| | - Jun Han
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China
| | - Yijie Zheng
- Medical Scientific Affairs, Abbott Diagnostics, Shanghai, 200003, China.
| | - Tian Yang
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China.
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32
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Development and Applicability of the A-P 200 Criteria for Liver Transplantation for Hepatocellular Carcinoma. Transplant Proc 2016; 48:3317-3322. [PMID: 27931576 DOI: 10.1016/j.transproceed.2016.08.050] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Revised: 07/28/2016] [Accepted: 08/22/2016] [Indexed: 02/07/2023]
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33
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Lee HW, Suh KS. Advancements of liver transplantation for hepatocellular carcinoma in Korea. Jpn J Clin Oncol 2016; 47:93-100. [DOI: 10.1093/jjco/hyw168] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2016] [Revised: 09/21/2016] [Accepted: 11/14/2016] [Indexed: 02/06/2023] Open
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34
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Lee HW, Suh KS. Liver transplantation for advanced hepatocellular carcinoma. Clin Mol Hepatol 2016; 22:309-318. [PMID: 27729631 PMCID: PMC5066382 DOI: 10.3350/cmh.2016.0042] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Accepted: 08/10/2016] [Indexed: 12/12/2022] Open
Abstract
There has been ongoing debate that the Milan criteria may be too strict that a significant number of patients who could benefit from liver transplantation (LT) might have been excluded. Based on this idea, various studies have been conducted to further expand the Milan criteria and give more HCC patients a chance of cure. In deceased donor LT (DDLT) setting, expansion of the criteria is relatively tempered because the results of LT for HCC should be comparable to those of patients with non-malignant indications. On the other hand, in living donor LT (LDLT) situation, liver grafts are not public resources. The acceptable target outcomes for LDLT might be much lower than those for DDLT. Patients with biologically favorable tumors might have excellent survivals after LT despite morphological advanced HCCs. Therefore, the significance and utility of biological tumor parameters for selecting suitable LT candidates have been increased to predict HCC recurrence after LT. Although there is no consensus regarding the use of prognostic biomarkers in LT selection criteria for HCC, the combination of conventional morphological parameters and new promising biomarkers could help us refine and expand the LT criteria for HCC in the near future.
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Affiliation(s)
- Hae Won Lee
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.,Department of Surgery, Seoul National University Boramae Medical Center, Seoul, Korea
| | - Kyung-Suk Suh
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
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35
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Expansion of the criteria for living donor liver transplantation for hepatocellular carcinoma. Curr Opin Organ Transplant 2016; 21:231-7. [PMID: 26918880 DOI: 10.1097/mot.0000000000000294] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW Several expanded criteria for liver transplantation for hepatocellular carcinoma (HCC) have been suggested out of concern that the Milan criteria may be too strict, and thereby exclude patients who could benefit from this surgical procedure. However, most expanded criteria were designed for deceased donor liver transplantation. Living donor liver transplantation (LDLT) differs from that of deceased donor liver transplantation primarily because LDLT liver grafts are not public resources. RECENT FINDINGS In Asian countries, where HCC is endemic, LDLT is the main currently available treatment option for HCC. High-volume LDLT centers throughout Asia have adopted their own expanded selection criteria for LDLT for HCC with acceptable long-term results. Some centers utilize tumor markers as one of the criterion to help select suitable candidates. Indeed, such adjunctive biomarkers may have prognostic relevance for patients with HCC. The use of both biological and histomorphologic parameters may increase the number of transplantable patients. SUMMARY The overall chance of survival, and recipient/donor preferences as well as the risk of recurrence are considered in the LDLT setting. Therefore, the selection criteria for liver transplantation for HCC could benefit from expansion for LDLT.
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36
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Grąt M, Wronka KM, Stypułkowski J, Bik E, Krasnodębski M, Masior Ł, Lewandowski Z, Grąt K, Patkowski W, Krawczyk M. The Warsaw Proposal for the Use of Extended Selection Criteria in Liver Transplantation for Hepatocellular Cancer. Ann Surg Oncol 2016; 24:526-534. [PMID: 27531306 PMCID: PMC5215188 DOI: 10.1245/s10434-016-5500-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2016] [Indexed: 12/18/2022]
Abstract
BACKGROUND Combination of the University of California, San Francisco (UCSF) and the up-to-7 criteria with alpha-fetoprotein (AFP) cutoff of 100 ng/ml was proposed as the Warsaw expansion of the Milan criteria in selection of hepatocellular cancer (HCC) patients for liver transplantation. The purpose of this retrospective study was to validate this proposal. METHODS A total of 240 HCC patients after liver transplantation were included. Recurrence-free survival and overall survival at 5 years were set as the primary and secondary outcome measures, respectively. RESULTS The Warsaw expansion increased transplant eligibility rate by 20.3 %. AFP >100 ng/ml significantly increased the recurrence risk in patients within the Milan criteria (p = 0.025) and in those beyond, yet within either the UCSF or the up-to-7 criteria (p < 0.001). Recurrence-free survival at 5 years was 90.8 % for patients within the Milan criteria, 100.0 % in patients within the Warsaw expansion, 54.9 % in patients beyond the Warsaw expansion but within either the UCSF or the up-to-7 criteria, and 45.1 % in patients beyond both the UCSF and the up-to-7 criteria (p < 0.001). The corresponding overall survival rates were 71.6, 82.4, 64.3, and 55.3 %, respectively (p = 0.027). CONCLUSIONS The Warsaw expansion of the Milan criteria substantially increases the recipient pool without compromising outcomes.
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Affiliation(s)
- Michał Grąt
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland.
| | - Karolina M Wronka
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Jan Stypułkowski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Emil Bik
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Maciej Krasnodębski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Łukasz Masior
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | | | - Karolina Grąt
- Second Department of Clinical Radiology, Medical University of Warsaw, Warsaw, Poland
| | - Waldemar Patkowski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Marek Krawczyk
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
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Qi X, Li J, Deng H, Li H, Su C, Guo X. Neutrophil-to-lymphocyte ratio for the prognostic assessment of hepatocellular carcinoma: A systematic review and meta-analysis of observational studies. Oncotarget 2016; 7:45283-45301. [PMID: 27304193 PMCID: PMC5216723 DOI: 10.18632/oncotarget.9942] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2016] [Accepted: 05/16/2016] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND AND AIMS Neutrophil to lymphocyte ratio (NLR) is an inflammatory-based marker. A systematic review and meta-analysis was performed to explore the prognostic role of NLR in patients with hepatocellular carcinoma (HCC). RESULTS Overall, 598 papers were identified, of which 90 papers including 20,475 HCC patients were finally included. Low baseline NLR was significantly associated with better overall survival (HR = 1.80, 95% CI: 1.59-2.04, p < 0.00001) and recurrence-free or disease-free survival (HR = 2.23, 95% CI: 1.80-2.76, p < 0.00001). Low post- treatment NLR was significantly associated with better overall survival (HR = 1.90, 95% CI: 1.22-2.94, p = 0.004). Decreased NLR was significantly associated with overall survival (HR = 2.23, 95%CI: 1.83-2.72, p < 0.00001) and recurrence-free or disease-free survival (HR = 2.23, 95% CI: 1.83-2.72, p < 0.00001). The findings from most of subgroup meta-analyses were consistent with those from the overall meta-analyses. MATERIALS AND METHODS All relevant literatures were identified via PubMed, EMBASE, and Cochrane library databases. Hazard ratio (HR) with 95% confidence interval (95%CI) was calculated. Subgroup meta-analyses were performed according to the treatment options, NLR cut-off value ranges, and regions. CONCLUSIONS NLR should be a major prognostic factor for HCC patients. NLR might be further incorporated into the prognostic model of HCC.
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Affiliation(s)
- Xingshun Qi
- Department of Gastroenterology, General Hospital of Shenyang Military Area, Shenyang, Liaoning 110840, China
| | - Jianjun Li
- Department of Radiotherapy, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning 110001, China
| | - Han Deng
- Department of Gastroenterology, General Hospital of Shenyang Military Area, Shenyang, Liaoning 110840, China
| | - Hongyu Li
- Department of Gastroenterology, General Hospital of Shenyang Military Area, Shenyang, Liaoning 110840, China
| | - Chunping Su
- Library of Fourth Military Medical University, Xi'an, Shaanxi 710032 China
| | - Xiaozhong Guo
- Department of Gastroenterology, General Hospital of Shenyang Military Area, Shenyang, Liaoning 110840, China
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Ogawa K, Takada Y. Living vs. deceased-donor liver transplantation for patients with hepatocellular carcinoma. Transl Gastroenterol Hepatol 2016; 1:35. [PMID: 28138602 DOI: 10.21037/tgh.2016.04.03] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Accepted: 04/07/2016] [Indexed: 12/12/2022] Open
Abstract
With the scarcity of deceased donor liver grafts, living donor liver transplantation (LDLT) is gaining popularity as an alternative to deceased donor liver transplantation (DDLT) for patients with hepatocellular carcinoma (HCC). However, as the evidence of cases of LDLT accumulates, several authors have reported higher HCC recurrence rates after LDLT. The suggested reasons for the higher recurrence rates following LDLT are related to the small-for-size graft in LDLT, surgical procedures that are specific to LDLT, and the fast-track to LDLT. Fast-tracking to LDLT may not allow sufficient time for evaluation of the biological aggressiveness of tumors, which may result in high recurrence rates due to inclusion of patients with more inherently aggressive tumors. Actually, some studies that reported higher recurrence rates with LDLT included a larger number of cases of HCC with microvascular invasion or poorly differentiated HCC. In order to exclude biologically aggressive HCC preoperatively, selection criteria incorporating tumor markers, such as alpha-fetoprotein (AFP) and des-gamma-carboxyprothrombin (DCP), as well as morphological tumor number and size have been proposed. With more reliable selection criteria incorporating biological markers to eliminate biologically aggressive HCC, LDLT can be a viable treatment option for patients with HCC, providing similar recurrence rates as those achieved with DDLT.
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Affiliation(s)
- Kohei Ogawa
- Department of HBP and Breast Surgery, Ehime University, Ehime, Japan
| | - Yasutsugu Takada
- Department of HBP and Breast Surgery, Ehime University, Ehime, Japan
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Liver transplantation for hepatobiliary malignancies: a new era of "Transplant Oncology" has begun. Surg Today 2016; 47:403-415. [PMID: 27130463 DOI: 10.1007/s00595-016-1337-1] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Accepted: 04/06/2016] [Indexed: 01/10/2023]
Abstract
The indications of liver transplantation for hepatobiliary malignancies have been carefully expanded in a stepwise fashion, despite the fundamental limitations in oncological, immunological, and technical aspects. A new era of "Transplant Oncology," the fusion of transplant surgery and surgical oncology, has begun, and we stand at the dawn of a paradigm shift in multidisciplinary cancer treatment. For hepatocellular carcinoma, new strategies have been undertaken to select recipients based on biological and dynamic markers instead of conventional morphological and static parameters, opening the doors for a more deliberate expansion of the Milan criteria and locoregional therapies before liver transplantation. Neoadjuvant chemoradiation therapy followed by liver transplantation for unresectable perihilar cholangiocarcinoma developed by the Mayo Clinic provided excellent outcomes in a US multicenter study; however, the surgical indications are not necessarily universal and await international validation. Similarly, an aggressive multidisciplinary approach has been applied for other tumors, including intrahepatic cholangiocarcinoma, hepatoblastoma, liver metastases from colorectal and neuroendocrine primary and gastrointestinal stromal tumors as well as rare tumors, such as hepatic undifferentiated embryonal sarcoma and infantile choriocarcinoma. In conclusion, liver transplantation is an important option for hepatobiliary malignancies; however, prospective studies are urgently needed to ensure the appropriate patient selection, organ allocation and living donation policies, and administration of antineoplastic immunosuppression.
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Pommergaard HC, Burcharth J, Rosenberg J, Rasmussen A. Serologic and molecular biomarkers for recurrence of hepatocellular carcinoma after liver transplantation: A systematic review and meta-analysis. Transplant Rev (Orlando) 2016; 30:171-7. [PMID: 27118303 DOI: 10.1016/j.trre.2016.03.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Revised: 03/13/2016] [Accepted: 03/25/2016] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Recurrence after liver transplantation (LT) for hepatocellular carcinoma (HCC) is a major cause of mortality. Knowledge on biomarkers may contribute to better surveillance based on the patients' risk of recurrence. Reviewing the literature, we aimed to identify serological and molecular biomarkers for recurrence of hepatocellular carcinoma after liver transplantation. METHODS A literature search was performed in the databases PubMed and Scopus to identify observational studies evaluating serological or molecular biomarkers for recurrence of HCC after LT using adjusted analysis to correct for confounding. RESULTS Of 502 records, 69 mainly retrospective studies were included with a total of 15,213 patients. Of these, 41 studies were suitable for meta-analyses, which showed that the serum markers pre-transplant α-fetoprotein (AFP) (hazard ratio (HR) 2.69 [2.08-3.47]), pre-transplant des-gamma-carboxy prothrombin (DCP) (HR 5.99 [3.27-10.98]), and allelic imbalance in microsatellites in DNA of tumor tissue (HR 13.49 [3.17-57.30]) were related to recurrence. CONCLUSIONS AFP, DCP and allelic imbalance in microsatellites may be used to predict recurrence. Together with other modalities, biomarkers may be used in future transplantation criteria to optimize selection of suitable patients.
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Affiliation(s)
- Hans-Christian Pommergaard
- Hvidovre Hospital - University of Copenhagen, Department of Surgery, Kettegård Allé 30, 2650 Hvidovre, Denmark.
| | - Jakob Burcharth
- Herlev Hospital - University of Copenhagen, Department of Surgery, Herlev Ringvej 75, 2730 Herlev, Denmark
| | - Jacob Rosenberg
- Herlev Hospital - University of Copenhagen, Department of Surgery, Herlev Ringvej 75, 2730 Herlev, Denmark
| | - Allan Rasmussen
- Rigshospitalet - University of Copenhagen, Department of Surgical Gastroenterology and Transplantation, Abdominal Centre, Blegdamsvej 9, 2100 Copenhagen, Denmark
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Xu DW, Wan P, Xia Q. Liver transplantation for hepatocellular carcinoma beyond the Milan criteria: A review. World J Gastroenterol 2016; 22:3325-34. [PMID: 27022214 PMCID: PMC4806190 DOI: 10.3748/wjg.v22.i12.3325] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Revised: 12/14/2015] [Accepted: 01/30/2016] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation (LT) has been accepted as an effective therapy for hepatocellular carcinoma (HCC). The Milan criteria (MC) are widely used across the world to select LT candidates in HCC patients. However, the MC may be too strict because a substantial subset of patients who have HCC exceed the MC and who would benefit from LT may be unnecessarily excluded from the waiting list. In recent years, many extended criteria beyond the MC were raised, which were proved to be able to yield similar outcomes compared with those patients meeting the MC. Because the simple use of tumor size and number was insufficient to indicate HCC biological features and to predict the risk of tumor recurrence, some biological markers such as Alpha-fetoprotein, Des-Gamma-carboxy prothrombin and the neutrophil-to-lymphocyte ratio were useful in selecting LT candidates in HCC patients beyond the MC. For patients with advanced HCC, downstaging therapy is an effective way to reduce the tumor stage to fulfill the MC by using liver-directed therapy such as transarterial chemoembolization, radiofrequency ablation and percutaneous ethanol injection. This article reviews the recent advances in LT for HCC beyond the MC.
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Cillo U, Giuliani T, Polacco M, Herrero Manley LM, Crivellari G, Vitale A. Prediction of hepatocellular carcinoma biological behavior in patient selection for liver transplantation. World J Gastroenterol 2016; 22:232-252. [PMID: 26755873 PMCID: PMC4698488 DOI: 10.3748/wjg.v22.i1.232] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Revised: 08/14/2015] [Accepted: 11/09/2015] [Indexed: 02/06/2023] Open
Abstract
Morphological criteria have always been considered the benchmark for selecting hepatocellular carcinoma (HCC) patients for liver transplantation (LT). These criteria, which are often inappropriate to express the tumor’s biological behavior and aggressiveness, offer only a static view of the disease burden and are frequently unable to correctly stratify the tumor recurrence risk after LT. Alpha-fetoprotein (AFP) and its progression as well as AFP-mRNA, AFP-L3%, des-γ-carboxyprothrombin, inflammatory markers and other serological tests appear to be correlated with post-transplant outcomes. Several other markers for patient selection including functional imaging studies such as 18F-FDG-PET imaging, histological evaluation of tumor grade, tissue-specific biomarkers, and molecular signatures have been outlined in the literature. HCC growth rate and response to pre-transplant therapies can further contribute to the transplant evaluation process of HCC patients. While AFP, its progression, and HCC response to pre-transplant therapy have already been used as a part of an integrated prognostic model for selecting patients, the utility of other markers in the transplant setting is still under investigation. This article intends to review the data in the literature concerning predictors that could be included in an integrated LT selection model and to evaluate the importance of biological aggressiveness in the evaluation process of these patients.
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Elevated Preoperative Neutrophil-Lymphocyte Ratio Is Associated with Poor Prognosis in Hepatocellular Carcinoma Patients Treated with Liver Transplantation: A Meta-Analysis. Gastroenterol Res Pract 2015; 2016:4743808. [PMID: 26843858 PMCID: PMC4710922 DOI: 10.1155/2016/4743808] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2015] [Revised: 10/24/2015] [Accepted: 10/27/2015] [Indexed: 12/12/2022] Open
Abstract
This study aims to investigate the prognostic value of neutrophil to lymphocyte ratio (NLR) in hepatocellular carcinoma (HCC) patients treated with liver transplantation (LT) through meta-analysis. Relevant articles were sought in PubMed, Embase, and Wangfang databases up to July 2015. A total of 1687 patients from 10 studies were included in this meta-analysis. Meta-analysis results showed that elevated NLR was significantly associated with poorer overall survival (OS) (HR = 2.71, 95% CI: 1.91-3.83) and poorer disease-free survival (DFS) (HR = 3.61, 95% CI: 2.23-5.84) in HCC patients treated with LT. Moreover, subgroup analysis showed the significant association between elevated preoperative NLR and poor prognosis was not altered by cutoff values of NLR or types of LT. Therefore, elevated preoperative NLR is associated with poor prognosis in HCC patients treated with LT. Preoperative NLR should be used to predict the prognosis of HCC after LT in our clinical work.
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Postoperative neutrophil-to-lymphocyte ratio of living-donor liver transplant: Association with graft size. Asian J Surg 2015; 39:103-8. [PMID: 26699814 DOI: 10.1016/j.asjsur.2015.10.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Revised: 09/30/2015] [Accepted: 10/21/2015] [Indexed: 02/07/2023] Open
Abstract
Issues related to small-for-size grafts in living donor liver transplantation (LDLT) are highly important. The neutrophil lymphocyte ratio (NLR) has been reported to be an inexpensive index of systemic inflammation for various diseases. We retrospectively evaluated the relationship between NLR and clinical course of 61 adult LDLT recipients in our institute until post-operative day 14. Patients were classified into two groups based on the graft volume divided by standard liver volume, as over 35% of graft volume divided by standard liver volume (GV/SLV) (Group L; n = 55) and under 35% of GV/SLV (Group S; n = 6). No differences were seen in background of the patients between the two groups. Also, absolute neutrophil, lymphocyte and platelet counts in both the groups showed no significant differences. In contrast, the NLR between the groups differed significantly from post-operative day 3 to 10, being higher in the Group S. In addition, the incidence of prolonged hyperbilirubinemia and small for size graft syndrome differed significantly between the two groups. Therefore, the elevation of post-operative NLR in the smaller graft group reflect suggestive pathophysiology of endothelial injuries that related to small for size graft syndrome in LDLT.
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Kornberg A, Witt U, Kornberg J, Müller K, Friess H, Thrum K. Postoperative peak serum C-reactive protein is a predictor of outcome following liver transplantation for hepatocellular carcinoma. Biomarkers 2015; 21:152-9. [PMID: 26643974 DOI: 10.3109/1354750x.2015.1118548] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
CONTEXT C-reactive protein (CRP), a biomarker of inflammation, may correlate with prognosis in several malignancies. OBJECTIVE To investigate the prognostic impact of early postoperative peak serum levels of CRP on tumor-specific outcome in 106 liver transplant patients with hepatocellular carcinoma (HCC). METHODS AND RESULTS In multivariate Cox regression analysis, a posttransplant elevated peak CRP level (>versus ≤ 3.5 mg/dl) was identified as an independent predictor of poor recurrence-free survival (p = 0.01; HR = 4.04; CI = 1.399-11.640). CONCLUSION Early postoperative serum CRP may serve as a useful inflammation-based biomarker of outcome in liver transplant patients with HCC.
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Affiliation(s)
- Arno Kornberg
- a Department of Surgery, Klinikum Rechts Der Isar, Technical University , Munich , Germany
| | - Ulrike Witt
- a Department of Surgery, Klinikum Rechts Der Isar, Technical University , Munich , Germany
| | - Jennifer Kornberg
- b Department of Anaesthesiology , Klinikum Großhadern, LMU Munich , Germany
| | | | - Helmut Friess
- a Department of Surgery, Klinikum Rechts Der Isar, Technical University , Munich , Germany
| | - Katharina Thrum
- d Institute of Pathology , Helios Klinikum, Berlin , Germany
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Nagai S, Mangus RS, Kubal CA, Ekser B, Fridell JA, Klingler KR, Maluccio MA, Tector AJ. Prognosis after recurrence of hepatocellular carcinoma in liver transplantation: predictors for successful treatment and survival. Clin Transplant 2015; 29:1156-63. [PMID: 26458066 DOI: 10.1111/ctr.12644] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/04/2015] [Indexed: 12/12/2022]
Abstract
There are no established prognostic factors or standardized therapies for hepatocellular carcinoma (HCC) recurrence in liver transplantation (LT). The aim of this study was to investigate impact of underlying patient condition on treatment and outcomes of recurrence of HCC after LT. The medical records of 268 LT patients with HCC were evaluated. Potential prognostic factors for survival after recurrence were evaluated, including recurrent tumor characteristics, medical/radiological/surgical therapies for recurrence, and an inflammatory marker (neutrophil/lymphocyte ratio). Laboratory tests at recurrence, including albumin, absolute lymphocyte count (ALC), prognostic nutritional index (PNI: ALC(/μL) × 0.005 + Albumin(g/dL) × 10), were evaluated as surrogate markers for underlying patient conditions. A total of 51 (19%) patients developed HCC recurrence. The use of sirolimus and sorafenib significantly improved outcome (p = 0.007 and 0.04), and better nutritional status (PNI ≥ 40) enhanced their efficacy. On multivariate analysis, low ALC (<500/μL) and albumin (<2.8 g/L) remained independent prognostic factors (p = 0.03 and 0.02; hazard ratio = 3.61 [Ref. >1000/μL] and 4.97 [Ref. >3.5 g/dL], respectively). Low PNI (<40) showed significantly lower survival rate after adjusting the risk (p = 0.006, hazard ratio = 3.29). Underlying patient conditions and nutritional status, represented by ALC and albumin, are important to successful cancer treatment and strong prognostic markers for survival after HCC recurrence.
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Affiliation(s)
- Shunji Nagai
- Division of Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Richard S Mangus
- Division of Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Chandrashekhar A Kubal
- Division of Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Burcin Ekser
- Division of Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Jonathan A Fridell
- Division of Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Kendell R Klingler
- Division of Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Mary A Maluccio
- Division of Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - A Joseph Tector
- Division of Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
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Andreou A, Bahra M, Guel S, Struecker B, Sauer IM, Klein F, Pascher A, Pratschke J, Seehofer D. Tumor DNA Index and α-Fetoprotein Level Define Outcome following Liver Transplantation for Advanced Hepatocellular Carcinoma. Eur Surg Res 2015; 55:302-318. [PMID: 26440793 DOI: 10.1159/000439565] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2015] [Accepted: 08/20/2015] [Indexed: 11/19/2022]
Abstract
BACKGROUND Patients with hepatocellular carcinoma (HCC) beyond the Milan criteria are expected to have inferior outcome after liver transplantation (LT) and are therefore currently not considered for LT in many countries. The purpose of this study was to identify predictive factors for overall survival following LT for HCC that may support the Milan criteria in the selection of appropriate transplant candidates. METHODS Clinicopathological data on 364 patients with HCC who underwent LT between 1989 and 2010 were retrospectively evaluated. Predictors of overall survival in the entire cohort as well as in subsets of patients within (n = 214) and beyond (n = 150) the Milan criteria were analyzed. RESULTS Multivariate analysis in the entire cohort identified DNA index >1.5 (p < 0.0001), α-fetoprotein level (AFP) >200 ng/ml (p = 0.005), and HCC beyond the Milan criteria (p = 0.002) to be associated with worse overall survival. In patients within the Milan criteria (median survival: 170 months), DNA index >1.5 (p < 0.0001) was the only predictor of worse overall survival in multivariate analysis. In patients beyond the Milan criteria (median survival: 44 months), DNA index >1.5, AFP >200 ng/ml, microvascular invasion, patient age >60 years, and DNA index >1.5 concomitant with AFP >200 ng/ml were associated with worse overall survival in univariate analysis. Multivariate analysis identified DNA index >1.5 concomitant with AFP >200 ng/ml (p < 0.0001) as the only independent predictor of worse overall survival. Consequently, patients beyond the Milan criteria with a combined favorable DNA index ≤1.5 and AFP ≤200 ng/ml had a median survival (147 months) comparable to that of patients within the Milan criteria. CONCLUSIONS DNA index and AFP level predict overall survival following LT in patients with advanced HCC beyond the Milan criteria. A combined assessment of these markers during the evaluation of transplant candidates can contribute to the selection of patients with HCC who may benefit from LT independently of their tumor burden.
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Affiliation(s)
- Andreas Andreou
- Department of General, Visceral and Transplant Surgery, Charitx00E9; - Universitx00E4;tsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany
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Hepatocellular Carcinoma Progression While on Waiting List for Liver Transplantation. Transplantation 2015; 99:e155-6. [PMID: 26308419 DOI: 10.1097/tp.0000000000000826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Combination of morphologic criteria and α-fetoprotein in selection of patients with hepatocellular carcinoma for liver transplantation minimizes the problem of posttransplant tumor recurrence. World J Surg 2015; 38:2698-707. [PMID: 24858191 PMCID: PMC4161934 DOI: 10.1007/s00268-014-2647-3] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Background Serum α-fetoprotein concentration (AFP) might be a useful addition to morphologic criteria for selecting patients with hepatocellular carcinoma (HCC) for liver transplantation (LT). The aim of this study was to evaluate the role of AFP in selecting HCC patients at minimal risk of posttransplant tumor recurrence in the setting of existing criteria. Methods This retrospective cohort study was based on 121 HCC patients after LT performed at a single institution. AFP was evaluated as a predictor of posttransplant tumor recurrence with respect to fulfillment of the Milan, University of California, San Francisco (UCSF), and Up-to-7 criteria. Results There was a nearly linear association between AFP and the risk of HCC recurrence (p < 0.001 for linear effect; p = 0.434 for nonlinear effect). AFP predicted HCC recurrence in patients (1) beyond the Milan criteria (p < 0.001; optimal cutoff 200 ng/ml); (2) within the UCSF criteria (p = 0.001; optimal cutoff 100 ng/ml) and beyond them (p = 0.015; optimal cutoff 200 ng/ml); and (3) within the Up-to-7 criteria (p = 0.001; optimal cutoff 100 ng/ml) and beyond them (p = 0.023; optimal cutoff 100 ng/ml) but not in patients within the Milan criteria (p = 0.834). Patients within either UCSF and Up-to-7 criteria with AFP level <100 ng/ml exhibited superior (100 %) 5-year recurrence-free survival—significantly higher than those within UCSF (p = 0.005) or Up-to-7 (p = 0.001) criteria with AFP levels higher than the estimated cutoffs or beyond with AFP levels less than the estimated cutoffs. Conclusions Combining the UCSF and Up-to-7 criteria with an AFP level <100 ng/ml is associated with minimal risk of tumor recurrence. Hence, this combination might be useful for selecting HCC patients for LT.
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50
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Toso C, Meeberg G, Hernandez-Alejandro R, Dufour JF, Marotta P, Majno P, Kneteman NM. Total tumor volume and alpha-fetoprotein for selection of transplant candidates with hepatocellular carcinoma: A prospective validation. Hepatology 2015; 62:158-65. [PMID: 25777590 DOI: 10.1002/hep.27787] [Citation(s) in RCA: 219] [Impact Index Per Article: 21.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2014] [Accepted: 03/10/2015] [Indexed: 01/10/2023]
Abstract
UNLABELLED The selection of liver transplantation (LT) candidates with hepatocellular carcinoma (HCC) is currently validated based on Milan criteria. The use of extended criteria has remained a matter of debate, mainly because of the absence of prospective validation. The present prospective study recruited patients according to the previously proposed total tumor volume (TTV; ≤115 cm(3) )/alpha-fetoprotein (AFP; ≤400 ng/mL) score. Patients with AFP >400 ng/mL were excluded, and, as such, the Milan group was modified to include only patients with AFP <400 ng/mL; these patients were compared to patients beyond Milan, but within TTV/AFP. From January 2007 to March 2013, 233 patients with HCC were listed for LT. Of them, 195 patients were within Milan and 38 beyond Milan, but within TTV/AFP. The average follow-up from listing was 33.9 ± 24.9 months. Risk of dropout was higher for patients beyond Milan, but within TTV/AFP (16 of 38; 42.1%), than for those within Milan (49 of 195 [25.1%]; P = 0.033). In parallel, intent-to-treat survival from listing was lower in patients beyond Milan (53.8% vs. 71.6% at 4 years; P < 0.001). After a median waiting time of 8 months, 166 patients were transplanted, 134 within Milan criteria, and 32 beyond Milan but within TTV/AFP. They demonstrated acceptable and similar recurrence rates (4.5% vs. 9.4%; P = 0.138) and post-transplant survivals (78.7% vs. 74.6% at 4 years; P = 0.932). CONCLUSION Based on the present prospective study, HCC LT candidate selection could be expanded to the TTV (≤115 cm(3) )/AFP (≤400 ng/mL) criteria in centers with at least 8-month waiting time. An increased risk of dropout on the waiting list can be expected, but with equivalent and satisfactory post-transplant survival.
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Affiliation(s)
- Christian Toso
- Divisions of Transplant and Abdominal Surgery, Department of Surgery, University of Geneva Hospitals, Geneva, Switzerland
| | - Glenda Meeberg
- Division of Transplantation, Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
| | - Roberto Hernandez-Alejandro
- Multi-Organ Transplant Program, London Health Sciences Center, The University of Western Ontario, London, Ontario, Canada
| | - Jean-François Dufour
- University Clinic for Visceral Surgery and Medicine, Inselspital, University of Bern, Bern, Switzerland
| | - Paul Marotta
- Multi-Organ Transplant Program, London Health Sciences Center, The University of Western Ontario, London, Ontario, Canada
| | - Pietro Majno
- Divisions of Transplant and Abdominal Surgery, Department of Surgery, University of Geneva Hospitals, Geneva, Switzerland
| | - Norman M Kneteman
- Division of Transplantation, Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
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