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Sequeira LM, Ozturk NB, Sierra L, Gurakar M, Toruner MD, Zheng M, Simsek C, Gurakar A, Kim AK. Hepatocellular Carcinoma and the Role of Liver Transplantation: An Update and Review. J Clin Transl Hepatol 2025; 13:327-338. [PMID: 40206277 PMCID: PMC11976436 DOI: 10.14218/jcth.2024.00432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 01/25/2025] [Accepted: 02/08/2025] [Indexed: 04/11/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide. Multiple treatment modalities are available for the management of HCC, depending on its stage as determined by the Barcelona Clinic Liver Cancer staging system. Because liver transplantation (LT) theoretically removes the cancer and replaces the organ at risk for future malignancy, LT is often considered the most definitive and one of the most efficacious treatment options for HCC. Nevertheless, the success and efficacy of liver transplantation depend on various tumor characteristics. As a result, multiple criteria have been developed to assess the appropriateness of a case of HCC for LT, with the pioneering Milan Criteria established in 1996. Over the past 20 to 30 years, these criteria have been critically evaluated, expanded, and often liberalized to make LT for patients with HCC a more universally applicable option. Furthermore, the development of other treatment modalities has enabled downstaging and bridging strategies for HCC prior to LT. In this narrative and comprehensive review, we provided an update on recent trends in the epidemiology of HCC, selection criteria for LT, implementation of LT across different regions, treatment modalities available as bridges, downstaging strategies, alternatives to LT, and, finally, post-LT surveillance.
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Affiliation(s)
- Lynette M. Sequeira
- Department of Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - N. Begum Ozturk
- Department of Internal Medicine, Beaumont Hospital, Royal Oak, MI, USA
| | - Leandro Sierra
- Department of Internal Medicine, Cleveland Clinic, Cleveland, OH, USA
| | - Merve Gurakar
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | | | - Melanie Zheng
- Department of Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Cem Simsek
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ahmet Gurakar
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Amy K. Kim
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Gryziak M, Stec R, Woźniak K, Szczepankiewicz B, Krasnodębski M, Grąt M, Kraj L. Prognostic factors for hepatocellular carcinoma recurrence after liver transplantation or resection - single-center experience. Heliyon 2024; 10:e40228. [PMID: 39641063 PMCID: PMC11617879 DOI: 10.1016/j.heliyon.2024.e40228] [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: 03/17/2024] [Revised: 10/01/2024] [Accepted: 11/06/2024] [Indexed: 12/07/2024] Open
Abstract
INTRODUCTION The aim of the study was to assess prognostic factors associated with an increased risk of recurrence of hepatocellular carcinoma (HCC) after radical treatment. MATERIALS AND METHODS This is a retrospective, single-center analysis of data on HCC recurrence in patients who underwent radical treatment. Molecular tumor characteristics, baseline laboratory results and hepatic viral status were analyzed. RESULTS Data from 111 patients were included in the analysis. The most important prognostic factors for recurrence were vascular microinvasion (HR 4.54; 95 % CI 1.769-11.681; p 0.001), baseline white blood count (HR 2.13; 95 % CI 1.261-3.567; p 0.004) and baseline alpha-fetoprotein (HR 1.00009; 95 % CI 1.000001-1.00002; p 0.034). Microvascular invasion was only prognostic factor which correlate significantly with the overall survival (HR 5.04, 95 % CI 2.352-12.413; p < 0.001). PD-L1 expression was confirmed in 4 patients and all of them developed a disease recurrence. However, there was no statistically significant assosciation with prognosis. The presence of CD68 tumor-associated macrophages was confirmed in 62 patients, ranging from 5 % to 40 %. Analysis showed that CD68 was not associated with the risk of recurrence of HCC. CONCLUSIONS The results confirm that microvascular invasion is the most important factor associated with an increased risk of hepatocellular carcinoma recurrence and death, while PD-L1 and CD68 expression did not have an impact on patient prognosis.
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Affiliation(s)
- Maciej Gryziak
- Medical University of Warsaw, ul. Żwirki i Wigury 61, 02-091, Warsaw, Poland
| | - Rafał Stec
- Medical University of Warsaw, ul. Żwirki i Wigury 61, 02-091, Warsaw, Poland
| | - Krzysztof Woźniak
- Medical University of Warsaw, ul. Żwirki i Wigury 61, 02-091, Warsaw, Poland
| | | | - Maciej Krasnodębski
- Medical University of Warsaw, ul. Żwirki i Wigury 61, 02-091, Warsaw, Poland
| | - Michał Grąt
- Medical University of Warsaw, ul. Żwirki i Wigury 61, 02-091, Warsaw, Poland
| | - Leszek Kraj
- Medical University of Warsaw, ul. Żwirki i Wigury 61, 02-091, Warsaw, Poland
- Department of Molecular Biology, Institute of Genetics and Animal Biotechnology, Polish Academy of Sci-ences, 05-552, Garbatka, Poland
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Jiao N, Yan C, He L, Jin HL, Oiu S, Li C, Zheng ZS, Lu B, Wu FD, Yang Y, Chen XG, Zhang Q. Liver transplantation for hepatocellular carcinoma: a proposal for including preoperative serological indicators improves the Milan criteria expanded. Transl Gastroenterol Hepatol 2024; 9:63. [PMID: 39503026 PMCID: PMC11535812 DOI: 10.21037/tgh-24-40] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Accepted: 07/22/2024] [Indexed: 11/08/2024] Open
Abstract
Background Liver transplantation (LT) is the most effective and radical treatment for hepatocellular carcinoma (HCC). Most LT criteria are based on the morphological characteristics of tumors, which are not enough to predict the risk of tumor recurrence. It is found that some serological biomarkers can predict tumor recurrence and may be a good indicator for selecting suitable HCC patients for LT. This article aims to evaluate the predictive effect of preoperative serological indicators on long-term overall survival (OS) and tumor recurrence-free survival (TFS) of patients with HCC after LT, and to explore its significance for expanding the Milan criteria. Methods Clinical data of 253 patients after LT in HCC were collected retrospectively. The receiver operating characteristic curve was used to calculate the best cut-off value. χ2 test was used to analyze the correlation between preoperative serological indicators and tumor pathological features. Univariate and multivariate analyses were used to analyze the risk factors affecting the OS and TFS rates and the predictive values of different LT criteria were compared. Nomogram model was used to predict the OS and TFS rates of patients exceeding Milan criteria. Results Independent risk factors for poor OS and TFS rates were alpha-fetoprotein (AFP) >200 ng/mL, gamma-glutamyl transpeptidase (GGT) >80 IU/L, total tumor diameter (TTD) >8 cm and microsatellite lesions. Nomogram model showed patients beyond Milan criteria had better survival when AFP ≤200 ng/mL and GGT ≤80 IU/L or AFP >200 ng/mL, GGT ≤80 IU/L and TTD ≤8 cm. According to Milan criteria, AFP, GGT and TTD, Milan-AFP-GGT-TTD (M-AGT) criteria was established. There was no significant difference in OS and TFS rates among patients in M-AGT, Milan, Hangzhou, Malaya and the University of California at San Francisco (UCSF) criteria. Conclusions Preoperative serological indicators AFP and GGT can effectively predict long-term OS and TFS in HCC patients after LT. Establishing M-AGT criteria based on serological indicators is helpful to supplement the Milan criteria.
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Affiliation(s)
- Ning Jiao
- Department of Organ Transplantation, Third Medical Center of Chinese PLA General Hospital, Beijing, China
- School of Clinical Medicine, Shandong Second Medical University, Weifang, China
- Department of Health Statistics, Fourth Military Medical University, Xi’an, China
- Department of Gastroenterology, People’s Hospital of Jiyang County, Jinan, China
| | - Cheng Yan
- Department of Organ Transplantation, Third Medical Center of Chinese PLA General Hospital, Beijing, China
- School of Clinical Medicine, Shandong Second Medical University, Weifang, China
| | - Li He
- Department of Organ Transplantation, Third Medical Center of Chinese PLA General Hospital, Beijing, China
- School of Clinical Medicine, Shandong Second Medical University, Weifang, China
| | - Hai-Long Jin
- Department of Organ Transplantation, Third Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Shuang Oiu
- Department of Organ Transplantation, Third Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Chao Li
- Department of Organ Transplantation, Third Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Zhi-Sheng Zheng
- Department of Orthopaedics, People’s Hospital of Jiyang County, Jinan, China
| | - Bin Lu
- Department of Organ Transplantation, Third Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Feng-Dong Wu
- Department of Organ Transplantation, Third Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yang Yang
- Department of Organ Transplantation, Third Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Xin-Guo Chen
- Department of Organ Transplantation, Third Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Qing Zhang
- Department of Organ Transplantation, Third Medical Center of Chinese PLA General Hospital, Beijing, China
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Yeo YH, Lee YT, Tseng HR, Zhu Y, You S, Agopian VG, Yang JD. Alpha-fetoprotein: Past, present, and future. Hepatol Commun 2024; 8:e0422. [PMID: 38619448 PMCID: PMC11019827 DOI: 10.1097/hc9.0000000000000422] [Citation(s) in RCA: 24] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Accepted: 01/29/2024] [Indexed: 04/16/2024] Open
Abstract
Alpha-fetoprotein (AFP) is a glycoprotein that plays an important role in immune regulation with critical involvement in early human development and maintaining the immune balance during pregnancy. Postfetal development, the regulatory mechanisms controlling AFP undergo a shift and AFP gene transcription is suppressed. Instead, these enhancers refocus their activity to maintain albumin gene transcription throughout adulthood. During the postnatal period, AFP expression can increase in the setting of hepatocyte injury, regeneration, and malignant transformation. It is the first oncoprotein discovered and is routinely used as part of a screening strategy for HCC. AFP has been shown to be a powerful prognostic biomarker, and multiple HCC prognosis models confirmed the independent prognostic utility of AFP. AFP is also a useful predictive biomarker for monitoring the treatment response of HCC. In addition to its role as a biomarker, AFP plays important roles in immune modulation to promote tumorigenesis and thus has been investigated as a therapeutic target in HCC. In this review article, we aim to provide an overview of AFP, encompassing the discovery, biological role, and utility as an HCC biomarker in combination with other biomarkers and how it impacts clinical practice and future direction.
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Affiliation(s)
- Yee Hui Yeo
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Yi-Te Lee
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Hsian-Rong Tseng
- Department of Molecular and Medical Pharmacology, California NanoSystems Institute, Crump Institute for Molecular Imaging, University of California, Los Angeles, California, USA
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California, USA
| | - Yazhen Zhu
- Department of Molecular and Medical Pharmacology, California NanoSystems Institute, Crump Institute for Molecular Imaging, University of California, Los Angeles, California, USA
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California, USA
- Department of Pathology and Laboratory Medicine, Ronald Reagan Medical Center, David Geffen School of Medicine, University of California, Los Angeles, California, USA
| | - Sungyong You
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
- Department of Surgery, Division of Cancer Biology and Therapeutics, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Vatche G. Agopian
- Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, California, USA
| | - Ju Dong Yang
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California, USA
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California, USA
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Mahmud N, Yagan L, Hoteit MA, Reddy KR, Abt PL, Abu-Gazala S. Significant Reduction in Posttransplant Hepatocellular Carcinoma Recurrence in the Post 6-Mo Waiting Policy Era. Transplantation 2024; 108:1172-1178. [PMID: 37953481 PMCID: PMC12036739 DOI: 10.1097/tp.0000000000004860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2023]
Abstract
BACKGROUND In 2015, the United Network for Organ Sharing implemented a policy introducing a 6-mo waiting period before granting model for end-stage liver disease exception points to liver transplant (LT) candidates with hepatocellular carcinoma (HCC). This study analyzes the policy impact on post-LT HCC recurrence. METHODS This was a United Network for Organ Sharing retrospective cohort study of patients with HCC who underwent LT from January 1, 2010, to May 31, 2019. HCC-specific data included alpha-fetoprotein, tumor characteristics, locoregional therapy (LRT), and explant data used to calculate the Risk Estimation of Tumor Recurrence After Transplant score. The primary exposure was pre-/post-policy era, divided on October 8, 2015. Survival analysis techniques were used to evaluate the unadjusted and sequentially adjusted association between policy era and HCC recurrence, accounting for competing risks. RESULTS A total of 7940 patients were included, 5879 (74.0%) pre-policy era and 2061 (26.0%) post-policy era. Post-policy patients were older, received more LRT, and had lower alpha-fetoprotein levels and smaller tumor sizes at transplant. Incidence rates of HCC recurrence were 19.8 and 13.7 events per 1000 person-years for pre- and post-policy eras, respectively. Post-policy era was associated with an unadjusted 35% reduction in the risk of HCC recurrence ( P < 0.001). After adjusting for recipient, donor, and tumor characteristics at listing this association remained (subhazard ratio 0.69; 95% confidence interval, 0.55-0.86; P = 0.001); however, after additionally adjusting for LRT episodes and Risk Estimation of Tumor Recurrence After Transplant score, there was no longer a statistically significant association (subhazard ratio 0.77; 95% confidence interval, 0.59-1.00; P = 0.054). CONCLUSIONS We observed a significant reduction in post-LT HCC recurrence after policy implementation. This may be due to waitlist selection of healthier patients, increased LRT utilization, and potential selection of favorable tumor biology.
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Affiliation(s)
- Nadim Mahmud
- Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Medicine, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA
- Leonard David Institute of Health Economics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
- Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics, Epidemiology & Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Lina Yagan
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Maarouf A. Hoteit
- Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - K. Rajender Reddy
- Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Peter L. Abt
- Division of Transplant Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Samir Abu-Gazala
- Division of Transplant Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Incarbone N, De Carlis R, Centonze L, Bernasconi DP, Valsecchi MG, Lauterio A, De Carlis L. The impact of postoperative complications on oncological outcomes of liver transplantation for hepatocellular carcinoma: A competing risk analysis. Dig Liver Dis 2023; 55:1690-1698. [PMID: 37316362 DOI: 10.1016/j.dld.2023.05.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 05/18/2023] [Accepted: 05/22/2023] [Indexed: 06/16/2023]
Abstract
OBJECTIVE To investigate the influence of postoperative complications on tumor-related (TRD), disease-free survival (DFS) and overall survival (OS) in patients undergoing liver transplant (LT) for hepatocellular carcinoma (HCC). METHODS We retrospectively evaluated 425 LTs for HCC from 2010 to 2019. Postoperative complications were classified according to Comprehensive Complication Index (CCI) and the posttransplant risk of TRD assessed through Metroticket 2.0 calculator. The population was stratified into high-risk and low-risk cohorts based on the predicted TRD risk of 80%. In a second step, we re-evaluated TRD, DFS and OS of both cohorts according to a further stratification based on 47.3 points of CCI cut-off. RESULTS In the low-risk cohort, we observed a significantly better DFS (84% vs. 46%, p<0.001), TRD (3% vs. 26%, p<0.001) and OS (89% vs. 62%, p<0.001) in the group with CCI < 47.3. In the high-risk cohort, patients with CCI < 47.3 had significantly better DFS (50% vs. 23%, p = 0.003) and OS (68% vs. 42%, p = 0.02) and a comparable TRD (22% vs. 31%, p = 0.142). CONCLUSIONS A complicated postoperative course negatively influenced long-term survival. This poorer oncological outcome associated with in-hospital postoperative complications suggests that every effort should be made to improve the early posttransplant course in HCC patients, including a careful donor-to recipient match and use of new perfusion technologies.
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Affiliation(s)
- Niccolò Incarbone
- Department of General Surgery and Transplantation, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy; School of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy
| | - Riccardo De Carlis
- Department of General Surgery and Transplantation, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy; PhD Course in Clinical and Experimental Sciences, University of Padua, Padua, Italy
| | - Leonardo Centonze
- Department of General Surgery and Transplantation, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy; Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, Modena, Italy.
| | - Davide Paolo Bernasconi
- Bicocca Bioinformatics Biostatistics and Bioimaging Center - B4, School of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy
| | - Maria Grazia Valsecchi
- Bicocca Bioinformatics Biostatistics and Bioimaging Center - B4, School of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy
| | - Andrea Lauterio
- Department of General Surgery and Transplantation, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy; School of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy
| | - Luciano De Carlis
- Department of General Surgery and Transplantation, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy; School of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy
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Abdelhamed W, El-Kassas M. Hepatocellular carcinoma recurrence: Predictors and management. LIVER RESEARCH (BEIJING, CHINA) 2023; 7:321-332. [PMID: 39958776 PMCID: PMC11791921 DOI: 10.1016/j.livres.2023.11.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Revised: 09/14/2023] [Accepted: 11/17/2023] [Indexed: 02/18/2025]
Abstract
Hepatocellular carcinoma (HCC), the sixth most common cancer globally, is associated with high mortality rates and more than 830,000 annual deaths. Despite advances in the available management options including surgical resection and local ablative therapies, recurrence rates after the initial treatment exceed 50%, even among patients who have undergone curative-intent therapy. Moreover, postsurgical HCC recurrence occurs in about 70% of cases five years postoperatively. The management of recurrent HCC remains undefined. This review discusses different predictors for HCC recurrence after each treatment modality and different approaches available to stratify these patients. More specific guidelines for managing HCC recurrence and strict surveillance protocols for such recurrence after initial HCC management are needed.
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Affiliation(s)
| | - Mohamed El-Kassas
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt
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Durkin C, Schaubel DE, Xu Y, Mahmud N, Kaplan DE, Abt PL, Bittermann T. Induction Immunosuppression Does Not Worsen Tumor Recurrence After Liver Transplantation for Hepatocellular Carcinoma. Transplantation 2023; 107:1524-1534. [PMID: 36695564 PMCID: PMC11972139 DOI: 10.1097/tp.0000000000004487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
BACKGROUND Prior studies are inconsistent regarding the impact of antibody induction therapy on outcomes after liver transplantation (LT) for hepatocellular carcinoma (HCC). METHODS Adults transplanted with HCC exception priority were identified from February 27, 2002, to March 31, 2019, using the United Network for Organ Sharing database. Time-to-event analyses evaluated the association of antibody induction therapy (none, nondepleting induction [NDI], depleting induction [DI]) with overall post-LT patient survival and HCC recurrence. Separate multivariable models adjusted for tumor characteristics on either last exception or on explant. The interaction of induction and maintenance regimen at LT discharge was investigated. RESULTS Among 22 535 LTs for HCC, 17 688 (78.48%) received no antibody induction, 2984 (13.24%) NDI, and 1863 (8.27%) DI. Minimal differences in patient and tumor characteristics were noted between induction groups, and there was significant center variability in practices. NDI was associated with improved survival, particularly when combined with a calcineurin inhibitor (CNI) and antimetabolite (hazard ratio [HR] 0.73 versus no induction plus 3-drug therapy in the last exception model [ P < 0.001]; HR 0.64 in the explant model [ P = 0.011]). The combination of DI with CNI alone was also protective (HR 0.43; P = 0.003). Neither NDI nor DI was associated with tumor recurrence (all P > 0.1). However, increased HCC recurrence was observed with no induction plus CNI monotherapy (HR 1.47, P = 0.019; versus no induction plus 3-drug therapy). CONCLUSIONS In conclusion, induction immunosuppression was not associated with worse post-LT outcomes in patients transplanted with HCC exception priority. An improvement in survival was possibly observed with NDI.
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Affiliation(s)
- Claire Durkin
- Division of Gastroenterology and Hepatology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Douglas E. Schaubel
- Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA
| | - Yuwen Xu
- Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA
| | - Nadim Mahmud
- Division of Gastroenterology and Hepatology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
- Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA
- Section of Gastroenterology and Hepatology, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA
| | - David E. Kaplan
- Division of Gastroenterology and Hepatology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
- Section of Gastroenterology and Hepatology, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA
| | - Peter L. Abt
- Division of Transplant Surgery, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Therese Bittermann
- Division of Gastroenterology and Hepatology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
- Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA
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Ding Q, Wang K, Li Y, Peng P, Zhang D, Chang D, Wang W, Ren L, Tang F, Li Z. Clinical Characteristics and Survival Analysis of Patients With Second Primary Malignancies After Hepatocellular Carcinoma Liver Transplantation: A SEER-based Analysis. Am J Clin Oncol 2023; 46:284-292. [PMID: 37145881 PMCID: PMC10281177 DOI: 10.1097/coc.0000000000001004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/07/2023]
Abstract
BACKGROUND Second primary malignancies (SPMs) after liver transplantation (LT) are becoming the leading causes of death in LT recipients. The purpose of this study was to explore prognostic factors for SPMs and to establish an overall survival nomogram. METHODS A retrospective analysis was conducted of data from the Surveillance, Epidemiology, and End Results (SEER) database on adult patients with primary hepatocellular carcinoma who had undergone LT between 2004 and 2015. Cox regression analysis was used to explore the independent prognostic factors for SPMs. Nomogram was constructed using R software to predict the overall survival at 2, 3, and 5 years. The concordance index, calibration curves, and decision curve analysis were used to evaluate the clinical prediction model. RESULTS Data from a total of 2078 patients were eligible, of whom 221 (10.64%) developed SPMs. A total of 221 patients were split into a training cohort (n=154) or a validation cohort (n=67) with a 7:3 ratio. The 3 most common SPMs were lung cancer, prostate cancer, and non-Hodgkin lymphoma. Age at initial diagnosis, marital status, year of diagnosis, T stage, and latency were the prognostic factors for SPMs. The C-index of the nomogram for overall survival in the training and validation cohorts were 0.713 and 0.729, respectively. CONCLUSIONS We analyzed the clinical characteristics of SPMs and developed a precise prediction nomogram, with a good predictive performance. The nomogram we developed may help clinicians provide personalized decisions and clinical treatment for LT recipients.
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Affiliation(s)
| | | | | | - Peng Peng
- Center for Big Data Research in Health and Medicine, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, Shandong Province, China
| | | | | | | | - Lei Ren
- Department of General Surgery
| | - Fang Tang
- Center for Big Data Research in Health and Medicine, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, Shandong Province, China
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Hepatocellular Carcinoma, Alpha Fetoprotein, and Liver Allocation for Transplantation: Past, Present and Future. Curr Oncol 2022; 29:7537-7551. [PMID: 36290870 PMCID: PMC9600271 DOI: 10.3390/curroncol29100593] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Revised: 10/01/2022] [Accepted: 10/02/2022] [Indexed: 11/05/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading indications for liver transplantation and has been the treatment of choice due to the oncologic benefit for patients with advanced chronic liver disease (AdvCLD) and small tumors for the last 25 years. For HCC patients undergoing liver transplantation, alpha fetoprotein (AFP) has increasingly been applied as an independent predictor for overall survival, disease free recurrence, and waitlist drop out. In addition to static AFP, newer studies evaluating the AFP dynamic response to downstaging therapy show enhanced prognostication compared to static AFP alone. While AFP has been utilized to select HCC patients for transplant, despite years of allocation policy changes, the US allocation system continues to take a uniform approach to HCC patients, without discriminating between those with favorable or unfavorable tumor biology. We aim to review the history of liver allocation for HCC in the US, the utility of AFP in liver transplantation, the implications of weaving AFP as a biomarker into policy. Based on this review, we encourage the US transplant community to revisit its HCC organ allocation model, to incorporate more precise oncologic principles for patient selection, and to adopt AFP dynamics to better stratify waitlist dropout risk.
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Goldman ML, Zhou K, Dodge JL, Yao F, Mehta N. Lower Alpha-Fetoprotein Threshold of 500 ng/mL for Liver Transplantation May Improve Posttransplant Outcomes in Patients With Hepatocellular Carcinoma. Liver Transpl 2022; 28:763-773. [PMID: 34927344 PMCID: PMC9295312 DOI: 10.1002/lt.26392] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 12/02/2021] [Accepted: 12/11/2021] [Indexed: 01/13/2023]
Abstract
Under current United Network for Organ Sharing (UNOS) policy, patients with hepatocellular carcinoma (HCC) and alpha-fetoprotein (AFP) levels ≥1000 ng/mL are required to show a reduction in AFP level to <500 ng/mL before liver transplantation (LT). However, effects of AFP reduction on post-LT HCC outcomes among patients with HCC with moderately elevated AFP levels between 100 and <1000 ng/mL are unclear. Adults in the UNOS registry who underwent LTs from January 2005 to September 2015 with initial AFP levels of 100 to 999 ng/mL at listing for Model for End-Stage Liver Disease exceptions were included. Primary predictor was AFP level at LT, categorized as <100, 100 to 499, or ≥500 ng/mL, and patients with only 1 recorded pre-LT AFP value (AFP 1-value). Survival was compared using the Kaplan-Meier curve method. Factors associated with post-LT survival and HCC recurrence were assessed in a multivariable Cox regression model. Among 1766 included patients, 50.2% had AFP 1-value, followed by 24.7%, 18.9%, and 6.2% with AFP levels <100, 100 to 499, and ≥500 ng/mL, respectively. The 5-year post-LT survival rate was lowest in the AFP ≥500 category, at 56.1%, compared with 72.7%, 70.4%, and 65.6% in the AFP <100, 100 to 499 ng/mL, and AFP 1-value categories, respectively. In multivariable analysis, AFP ≥500 ng/mL at LT was associated with a greater risk of post-LT death (hazard ratio [HR], 1.5; 95% confidence interval [CI], 1.1-2.1) and HCC recurrence (HR, 1.9; 95% CI, 1.1-3.1) when compared with the AFP <100 ng/mL category; other significant variables included donor risk index, age, race/ethnicity, Child-Turcotte-Pugh class, and tumor diameter. Among AFP levels ≥500 ng/mL at LT, 40.4% had AFP levels ≥1000, but no difference in post-LT survival or recurrence was seen between those patients with AFP levels < or ≥1000 ng/mL. Mandating AFP <500 ng/mL at LT for all patients, not only for those with initial AFP levels ≥1000 ng/mL, may improve post-LT outcomes and can be considered in future UNOS policy.
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Affiliation(s)
- Max L. Goldman
- Department of Medicine, University of California, San Francisco, San Francisco, CA
| | - Kali Zhou
- Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Jennifer L. Dodge
- Department of Medicine, University of California, San Francisco, San Francisco, CA,Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Francis Yao
- Department of Medicine, University of California, San Francisco, San Francisco, CA
| | - Neil Mehta
- Department of Medicine, University of California, San Francisco, San Francisco, CA
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12
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Iavarone M, Invernizzi F, Ivanics T, Mazza S, Zavaglia C, Sanduzzi-Zamparelli M, Fraile-López M, Czauderna C, Di Costanzo G, Bhoori S, Pinter M, Manini MA, Amaddeo G, Yunquera AF, Piñero F, Blanco Rodríguez MJ, Anders M, Aballay Soteras G, Villadsen GE, Yoon PD, Cesarini L, Díaz-González Á, González-Diéguez ML, Tortora R, Weinmann A, Mazzaferro V, Romero Cristóbal M, Crespo G, Regnault H, De Giorgio M, Varela M, Prince R, Scudeller L, Donato MF, Wörns MA, Bruix J, Sapisochin G, Lampertico P, Reig M. Regorafenib Efficacy After Sorafenib in Patients With Recurrent Hepatocellular Carcinoma After Liver Transplantation: A Retrospective Study. Liver Transpl 2021; 27:1767-1778. [PMID: 34388851 DOI: 10.1002/lt.26264] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 06/28/2021] [Accepted: 07/06/2021] [Indexed: 12/13/2022]
Abstract
Safety of regorafenib in hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) has been recently demonstrated. We aimed to assess the survival benefit of regorafenib compared with best supportive care (BSC) in LT patients after sorafenib discontinuation. This observational multicenter retrospective study included LT patients with HCC recurrence who discontinued first-line sorafenib. Group 1 comprised regorafenib-treated patients, whereas the control group was selected among patients treated with BSC due to unavailability of second-line options at the time of sorafenib discontinuation and who were sorafenib-tolerant progressors (group 2). Primary endpoint was overall survival (OS) of group 1 compared with group 2. Secondary endpoints were safety and OS of sequential treatment with sorafenib + regorafenib/BSC. Among 132 LT patients who discontinued sorafenib included in the study, 81 were sorafenib tolerant: 36 received regorafenib (group 1) and 45 (group 2) received BSC. Overall, 24 (67%) patients died in group 1 and 40 (89%) in group 2: the median OS was significantly longer in group 1 than in group 2 (13.1 versus 5.5 months; P < 0.01). Regorafenib treatment was an independent predictor of reduced mortality (hazard ratio, 0.37; 95% confidence interval [CI], 0.16-0.89; P = 0.02). Median treatment duration with regorafenib was 7.0 (95% CI, 5.5-8.5) months; regorafenib dose was reduced in 22 (61%) patients for adverse events and discontinued for tumor progression in 93% (n = 28). The median OS calculated from sorafenib start was 28.8 months (95% CI, 17.6-40.1) in group 1 versus 15.3 months (95% CI, 8.8-21.7) in group 2 (P < 0.01). Regorafenib is an effective second-line treatment after sorafenib in patients with HCC recurrence after LT.
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Affiliation(s)
- Massimo Iavarone
- Division of Gastroenterology and HepatologyFoundation IRCCS Ca' Granda Ospedale Maggiore PoliclinicoMilanItaly
| | - Federica Invernizzi
- Division of Gastroenterology and HepatologyFoundation IRCCS Ca' Granda Ospedale Maggiore PoliclinicoMilanItaly
| | - Tommy Ivanics
- Multi-Organ Transplant Program, Division of General SurgeryToronto General HospitalUniversity Health NetworkUniversity of TorontoTorontoCanada
| | - Stefano Mazza
- Division of Gastroenterology and HepatologyFoundation IRCCS Ca' Granda Ospedale Maggiore PoliclinicoMilanItaly
| | - Claudio Zavaglia
- Hepatology and Gastroenterology DepartmentNiguarda Ca' Granda HospitalMilanItaly
| | - Marco Sanduzzi-Zamparelli
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver UnitHospital Clínic, IDIBAPS, CIBEREHD, University of BarcelonaBarcelonaSpain
| | - Miguel Fraile-López
- Liver UnitHospital Universitario Central de AsturiasOviedoSpain
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA)OviedoSpain
| | - Carolin Czauderna
- Department of Internal Medicine IUniversity Medical Centre of the Johannes Gutenberg-UniversityMainzGermany
| | | | - Sherrie Bhoori
- G. I. Surgery and Liver Transplantation UnitFondazione IRCCS Istituto Nazionale dei TumoriMilanItaly
| | - Matthias Pinter
- Department of Internal Medicine IIIDivision of Gastroenterology & HepatologyMedical University of ViennaViennaAustria
| | - Matteo Angelo Manini
- Gastroenterology, Hepatology and Transplant UnitDepartment of Specialty and Transplant MedicineAzienda Socio Sanitaria Territoriale (ASST) Papa Giovanni XXIIIBergamoItaly
| | - Giuliana Amaddeo
- Service d'HepatologieHôpital Henri Mondor, Equipe 18, INSERM U955, Virus Immunité CancerCréteilFrance
| | | | - Federico Piñero
- School of MedicineLatin American Liver Research Educational and Awareness Network (LALREAN)Hospital Universitario AustralBuenos AiresArgentina
| | | | - Margarita Anders
- Unidad de Hepatología y Trasplante Hepático, Hospital AlemanBuenos AiresArgentina
| | | | | | - Peter Daechul Yoon
- Multi-Organ Transplant Program, Division of General SurgeryToronto General HospitalUniversity Health NetworkUniversity of TorontoTorontoCanada
| | - Lucia Cesarini
- Hepatology and Gastroenterology DepartmentNiguarda Ca' Granda HospitalMilanItaly
| | - Álvaro Díaz-González
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver UnitHospital Clínic, IDIBAPS, CIBEREHD, University of BarcelonaBarcelonaSpain
| | | | - Raffaella Tortora
- Department of Transplantation, Liver UnitCardarelli HospitalNaplesItaly
| | - Arndt Weinmann
- Department of Internal Medicine IUniversity Medical Centre of the Johannes Gutenberg-UniversityMainzGermany
| | - Vincenzo Mazzaferro
- G. I. Surgery and Liver Transplantation UnitFondazione IRCCS Istituto Nazionale dei Tumori and University of MilanMilanItaly
| | | | - Gonzalo Crespo
- Liver Transplant Unit, Liver UnitHospital Clínic, IDIBAPS, CIBEREHD, University of BarcelonaBarcelonaSpain
| | - Helene Regnault
- Service d'HepatologieHôpital Henri Mondor, Equipe 18, INSERM U955, Virus Immunité CancerCréteilFrance
| | - Massimo De Giorgio
- Gastroenterology, Hepatology and Transplant UnitDepartment of Specialty and Transplant MedicineAzienda Socio Sanitaria Territoriale (ASST) Papa Giovanni XXIIIBergamoItaly
| | - Maria Varela
- Liver UnitHospital Universitario Central de AsturiasOviedoSpain
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA)OviedoSpain
| | - Rebecca Prince
- Division of Medical Oncology and HematologyPrincess Margaret HospitalUniversity of TorontoTorontoCanada
| | - Luigia Scudeller
- Scientific DirectionClinical Trial CenterFoundation IRCCS Ca' Granda Ospedale Maggiore PoliclinicoMilanItaly
| | - Maria Francesca Donato
- Division of Gastroenterology and HepatologyFoundation IRCCS Ca' Granda Ospedale Maggiore PoliclinicoMilanItaly
| | - Marcus-Alexander Wörns
- Department of Internal Medicine IUniversity Medical Centre of the Johannes Gutenberg-UniversityMainzGermany
| | - Jordi Bruix
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver UnitHospital Clínic, IDIBAPS, CIBEREHD, University of BarcelonaBarcelonaSpain
| | - Gonzalo Sapisochin
- Multi-Organ Transplant Program, Division of General SurgeryToronto General HospitalUniversity Health NetworkUniversity of TorontoTorontoCanada
| | - Pietro Lampertico
- Division of Gastroenterology and HepatologyFoundation IRCCS Ca' Granda Ospedale Maggiore PoliclinicoMilanItaly
- Department of Pathophysiology and TransplantationCRC "A. M. and A. Migliavacca" Center for Liver DiseaseUniversity of MilanMilanItaly
| | - Maria Reig
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver UnitHospital Clínic, IDIBAPS, CIBEREHD, University of BarcelonaBarcelonaSpain
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Magro B, Pinelli D, De Giorgio M, Lucà MG, Ghirardi A, Carrobio A, Baronio G, Del Prete L, Nounamo F, Gianatti A, Colledan M, Fagiuoli S. Pre-Transplant Alpha-Fetoprotein > 25.5 and Its Dynamic on Waitlist Are Predictors of HCC Recurrence after Liver Transplantation for Patients Meeting Milan Criteria. Cancers (Basel) 2021; 13:5976. [PMID: 34885087 PMCID: PMC8656660 DOI: 10.3390/cancers13235976] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 11/22/2021] [Accepted: 11/25/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND AND AIM Hepatocellular carcinoma (HCC) recurrence rates after liver transplantation (LT) range between 8 and 20%. Alpha-fetoprotein (AFP) levels at transplant can predict HCC recurrence, however a defined cut-off value is needed to better stratify patients. The aim of this study was to evaluate the rate of HCC recurrence at our centre and to identify predictors, focusing on AFP. METHODS We retrospectively analysed 236 consecutive patients that were waitlisted for HCC who all met the Milan criteria from January 2001 to December 2017 at our liver transplant centre. A total of twenty-nine patients dropped out while they were waitlisted, and 207 patients were included in the final analysis. All survival analyses included the competing-risk model. RESULTS The mean age was 56.8 ± 6.8 years. A total of 14% were female (n = 29/207). The median MELD (model for end-stage liver disease) at LT was 12 (9-16). The median time on the waitlist was 92 (41-170) days. The HCC recurrence rate was 16.4% (n = 34/208). The mean time to recurrence was 3.3 ± 2.8 years. The median AFP levels at transplant were higher in patients with HCC recurrence (p < 0.001). At multivariate analysis, the AFP value at transplant that was greater than 25.5 ng/mL (AUC 0.69) was a strong predictor of HCC recurrence after LT [sHR 3.3 (1.6-6.81); p = 0.001]. The HCC cumulative incidence function (CIF) of recurrence at 10 years from LT was significantly higher in patients with AFP > 25.5 ng/mL [34.3% vs. 11.5% (p = 0.001)]. Moreover, an increase in AFP > 20.8%, was significantly associated with HCC recurrence (p = 0.034). CONCLUSIONS In conclusion, in our retrospective study, the AFP level at transplant > 25.5 ng/mL and its increase greater than 20.8% on the waitlist were strong predictors of HCC recurrence after LT in a cohort of patients that were waitlisted within the Milan criteria. However further studies are needed to validate these data.
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Affiliation(s)
- Bianca Magro
- Gastroenterology, Hepatology and Liver Transplantation, Department of Medicine-Papa Giovanni, XXIII Hospital, 24122 Bergamo, Italy; (M.D.G.); (M.G.L.); (S.F.)
| | - Domenico Pinelli
- Unit of Hepato-Biliary Surgery and Liver Transplantation, ASST Papa Giovanni XXIII, 24122 Bergamo, Italy; (D.P.); (G.B.); (L.D.P.); (F.N.); (M.C.)
| | - Massimo De Giorgio
- Gastroenterology, Hepatology and Liver Transplantation, Department of Medicine-Papa Giovanni, XXIII Hospital, 24122 Bergamo, Italy; (M.D.G.); (M.G.L.); (S.F.)
| | - Maria Grazia Lucà
- Gastroenterology, Hepatology and Liver Transplantation, Department of Medicine-Papa Giovanni, XXIII Hospital, 24122 Bergamo, Italy; (M.D.G.); (M.G.L.); (S.F.)
| | - Arianna Ghirardi
- FROM Research Foundation, Papa Giovanni XXIII Hospital, 24122 Bergamo, Italy; (A.G.); (A.C.)
| | - Alessandra Carrobio
- FROM Research Foundation, Papa Giovanni XXIII Hospital, 24122 Bergamo, Italy; (A.G.); (A.C.)
| | - Giuseppe Baronio
- Unit of Hepato-Biliary Surgery and Liver Transplantation, ASST Papa Giovanni XXIII, 24122 Bergamo, Italy; (D.P.); (G.B.); (L.D.P.); (F.N.); (M.C.)
| | - Luca Del Prete
- Unit of Hepato-Biliary Surgery and Liver Transplantation, ASST Papa Giovanni XXIII, 24122 Bergamo, Italy; (D.P.); (G.B.); (L.D.P.); (F.N.); (M.C.)
| | - Franck Nounamo
- Unit of Hepato-Biliary Surgery and Liver Transplantation, ASST Papa Giovanni XXIII, 24122 Bergamo, Italy; (D.P.); (G.B.); (L.D.P.); (F.N.); (M.C.)
| | - Andrea Gianatti
- Pathology Unit, ASST Papa Giovanni XXIII, 24122 Bergamo, Italy;
| | - Michele Colledan
- Unit of Hepato-Biliary Surgery and Liver Transplantation, ASST Papa Giovanni XXIII, 24122 Bergamo, Italy; (D.P.); (G.B.); (L.D.P.); (F.N.); (M.C.)
| | - Stefano Fagiuoli
- Gastroenterology, Hepatology and Liver Transplantation, Department of Medicine-Papa Giovanni, XXIII Hospital, 24122 Bergamo, Italy; (M.D.G.); (M.G.L.); (S.F.)
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14
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Hepatocellular Carcinoma Staging: Differences Between Radiologic and Pathologic Systems and Relevance to Patient Selection and Outcomes in Liver Transplantation. AJR Am J Roentgenol 2021; 218:77-86. [PMID: 34406054 DOI: 10.2214/ajr.21.26436] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Liver transplant is indicated with curative intent for patients with early-stage hepatocellular carcinoma (HCC). The radiologic T category is used to determine candidacy and priority of patients on the waiting list. After transplant, the explant liver pathologic TNM stage is used as a predictor of postoperative outcomes and overall prognosis. Although the comparison of radiologic and pathologic T categories for concordance is often considered to be straightforward, the staging conventions significantly differ. Not accounting for these differences is in part the reason for the high rates of radiologic-pathologic discordance reported in the literature, with inconsistent terminology being an additional source of confusion when evaluating concordance. These factors may affect the understanding of important radiopathologic phenotypes of disease and the adequate investigation of their prognostic capabilities. The aims of this article are to provide an overview of the pathologic and radiologic TNM staging systems for HCC while describing staging procedures, emphasize the differences between these staging systems to highlight the limitations of radiologic-pathologic stage correlation, present a review of the literature on the prognostic value of individual features used for HCC staging; and signal significant aspects of preoperative risk stratification that could be improved to positively impact posttransplant outcomes.
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15
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YANKOL Y, HOŞ G, KANMAZ T, MECİT N, ÇAKALOĞLU Y, KALAYOĞLU M, ACARLI KS. Are the criteria always right? Assessment of hepatocellular carcinoma cases in living donor liver transplantation at a high-volume center. Turk J Med Sci 2021; 51:2383-2395. [PMID: 33754656 PMCID: PMC8742484 DOI: 10.3906/sag-2101-51] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 03/20/2021] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND/AIM With the increased experience in living donor liver transplantation (LDLT), it has been adopted for the treatment of hepatocellular carcinoma (HCC), with emerging discussions of criteria beyond tumor size and number. In contrast to deceased donor liver transplantation (DDLT), recipient selection for LDLT is not limited by organ allocation systems. We discuss herein the assessment, criteria, and experience with liver transplantation (LT) in HCC cases at a high-volume LDLT center. MATERIAL AND METHODS Between August 2006 and December 2017, 191 adult LT HCC recipients with at least one-year follow-up were retrospectively analyzed. RESULTS In 191 patients, one-, three- and five-year survival rates were 87.2%, 81.6%, and 76.2%, respectively, including early postoperative mortality. In 174 patients with long-term follow-up, one-, three- and five-year disease-free survival rates were 91.6%, 87.7%, and 84.4%, respectively. When multivariate analysis was utilized, tumor differentiation was the only factor which statistically affected survival (p = 0.025). CONCLUSION LDLT allows us to push the limits forward and the question “Are the criteria always right?” is always on the table. We can conclude that, with the advantage of LDLT, every HCC patient deserves a case-by-case basis discussion for LT under scientific literature support. In borderline cases, tumor biopsy might help determine the decision for LT.
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Affiliation(s)
- Yücel YANKOL
- Division of Transplantation, Department of Surgery, School of Medicine and Public Health, University of Wisconsin, Madison, WIUnited States
- Organ Transplant Center, Memorial Şişli Hospital, İstanbulTurkey
| | - Gültekin HOŞ
- Division of Transplantation, Department of Surgery, School of Medicine and Public Health, University of Wisconsin, Madison, WIUnited States
- Department of Surgery, Şişli Etfal Training and Research Hospital, İstanbulTurkey
| | - Turan KANMAZ
- Division of Transplantation, Department of Surgery, School of Medicine and Public Health, University of Wisconsin, Madison, WIUnited States
- Organ Transplant Center, School of Medicine, Koç University, İstanbulTurkey
| | - Nesimi MECİT
- Division of Transplantation, Department of Surgery, School of Medicine and Public Health, University of Wisconsin, Madison, WIUnited States
- Organ Transplant Center, School of Medicine, Koç University, İstanbulTurkey
| | - Yılmaz ÇAKALOĞLU
- Division of Transplantation, Department of Surgery, School of Medicine and Public Health, University of Wisconsin, Madison, WIUnited States
| | - Münci KALAYOĞLU
- Division of Transplantation, Department of Surgery, School of Medicine and Public Health, University of Wisconsin, Madison, WIUnited States
- Organ Transplant Center, School of Medicine, Koç University, İstanbulTurkey
| | - Koray S. ACARLI
- Division of Transplantation, Department of Surgery, School of Medicine and Public Health, University of Wisconsin, Madison, WIUnited States
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16
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Núñez KG, Sandow T, Fort D, Patel J, Hibino M, Carmody I, Cohen AJ, Thevenot P. Baseline Alpha-Fetoprotein, Alpha-Fetoprotein-L3, and Des-Gamma-Carboxy Prothrombin Biomarker Status in Bridge to Liver Transplant Outcomes for Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:4765. [PMID: 34638251 PMCID: PMC8507524 DOI: 10.3390/cancers13194765] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 09/08/2021] [Accepted: 09/20/2021] [Indexed: 11/16/2022] Open
Abstract
The biomarkers α-fetoprotein (AFP), Lens culinaris agglutinin-reactive AFP fraction (AFP-L3), and des-γ-carboxy prothrombin (DCP) have emerging implications in hepatocellular carcinoma (HCC) surveillance, overall prognosis, and post-surgical recurrence risk. This retrospective study investigated treatment and bridge to liver transplant (LT) prognosis associated with AFP, AFP-L3%, and DCP biomarker profiles prior to liver-directed therapy (LDT). In a 140-patient cohort, each biomarker was associated with HCC progression risk using the established thresholds of AFP > 20 ng/mL, AFP-L3 > 15%, and DCP > 7.5 ng/mL. Over 60% of the cohort expressed at least one biomarker at baseline. Although most biomarker-positive patients expressed the clinical standard AFP (57/87), only 32% were positive for AFP alone. Biomarker accumulation increased HCC progression risk but was not associated with demographic factors or preserved liver function. Biomarker triple negative patients had smaller index HCC (p = 0.003), decreased multifocal burden (p = 0.010), and a higher objective response rate (ORR, 62% compared to 46%, p = 0.011). Expressing all three biomarkers at baseline was associated with dismal first-line ORR (12%) with a median time to progression (TTP) of only 181 days post-LDT. Patients with triple negative status for the HCC biomarkers AFP, AFP-L3%, and DCP have the highest first-line ORR with < 5% HCC progression 1-year post-LDT. Biomarker profiling can establish baseline prognosis for identifying optimal bridge to LT and downstaging to LT candidates with triple negative biomarker status and providing an ideal post-LDT target as a compliment to radiographic response.
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Affiliation(s)
- Kelley G. Núñez
- Institute of Translational Research, Ochsner Health, New Orleans, LA 70121, USA; (K.G.N.); (J.P.); (M.H.); (A.J.C.)
| | - Tyler Sandow
- Department of Radiology, Ochsner Health, New Orleans, LA 70121, USA;
| | - Daniel Fort
- Center for Outcomes and Health Services Research, Ochsner Health, New Orleans, LA 70121, USA;
| | - Jai Patel
- Institute of Translational Research, Ochsner Health, New Orleans, LA 70121, USA; (K.G.N.); (J.P.); (M.H.); (A.J.C.)
| | - Mina Hibino
- Institute of Translational Research, Ochsner Health, New Orleans, LA 70121, USA; (K.G.N.); (J.P.); (M.H.); (A.J.C.)
| | - Ian Carmody
- Multi-Organ Transplant Institute, Ochsner Health, New Orleans, LA 70121, USA;
| | - Ari J. Cohen
- Institute of Translational Research, Ochsner Health, New Orleans, LA 70121, USA; (K.G.N.); (J.P.); (M.H.); (A.J.C.)
- Multi-Organ Transplant Institute, Ochsner Health, New Orleans, LA 70121, USA;
- Faculty of Medicine, The University of Queensland, New Orleans, LA 70121, USA
| | - Paul Thevenot
- Institute of Translational Research, Ochsner Health, New Orleans, LA 70121, USA; (K.G.N.); (J.P.); (M.H.); (A.J.C.)
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17
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Ince V, Carr BI, Bag HG, Ersan V, Usta S, Koc C, Gonultas F, Sarici BK, Karakas S, Kutluturk K, Baskiran A, Yilmaz S. Liver transplant for large hepatocellular carcinoma in Malatya: The role of gamma glutamyl transferase and alpha-fetoprotein, a retrospective cohort study. World J Gastrointest Surg 2020; 12:520-533. [PMID: 33437403 PMCID: PMC7769743 DOI: 10.4240/wjgs.v12.i12.520] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 11/03/2020] [Accepted: 11/13/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND There is increasing interest in transplanting patients with hepatocellular carcinoma (HCC) with tumors greater than 5 cm (Milan criteria). AIM To investigate possible prognostically-useful factors for liver transplantation in HCC patients with large tumors. METHODS In this clinical study, 50 patients with HCC who were transplanted at our Liver Transplant Center between April 2006 and August 2019 and had tumors greater than 6 cm maximum diameter were retrospectively analyzed. Their survival and full clinical characteristics were examined, with respect to serum alpha-fetoprotein (AFP) and gamma glutamyl transpeptidase (GGT) levels. Kaplan-Meier survival estimates were used to determine overall survival and disease-free survival in these patients. The inclusion criterion was evidence of HCC. Exclusion criteria were the presence of macroscopic portal vein thrombosis or metastasis and a follow-up period of less than 90 d. RESULTS Using receiver operating characteristic curve (ROC) analysis, cutoff values of AFP 200 ng/mL and GGT 104 IU/L were identified and used in this study. Significantly longer overall survival (OS) and disease-free-survival (DFS) were found in patients who had lower values of either parameter, compared with higher values. Even greater differences in survival were found when the 2 parameters were combined. Two tumor size bands were identified, in searching for the limits of this approach with larger tumors, namely 6-10 cm and > 10 cm. Combination parameters in the 6-10 cm band reflected 5-year OS of 76.2% in patients with low AFP plus low GGT vs 0% for all other groups. Patients with tumors greater than 10 cm, did not have low AFP plus low GGT. The most consistent clinical correlates for longer survival were degree of tumor differentiation and absence of microscopic portal venous invasion. CONCLUSION Serum levels of AFP and GGT, both alone and combined, represent a simple prognostic identifier in patients with large HCCs undergoing liver transplant-ation.
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Affiliation(s)
- Volkan Ince
- Department of General Surgery, Inonu University, Liver Transplantation Institute, Malatya 44280, Turkey
| | - Brian I Carr
- Department of General Surgery, Inonu University, Liver Transplantation Institute, Malatya 44280, Turkey
| | - Harika Gozukara Bag
- Department of Biostatistics, Inonu University, School of Medicine, Malatya 44280, Turkey
| | - Veysel Ersan
- Department of General Surgery, Inonu University, Liver Transplantation Institute, Malatya 44280, Turkey
| | - Sertac Usta
- Department of General Surgery, Inonu University, Liver Transplantation Institute, Malatya 44280, Turkey
| | - Cemalettin Koc
- Department of General Surgery, Inonu University, Liver Transplantation Institute, Malatya 44280, Turkey
| | - Fatih Gonultas
- Department of General Surgery, Inonu University, Liver Transplantation Institute, Malatya 44280, Turkey
| | - Baris Kemal Sarici
- Department of General Surgery, Inonu University, Liver Transplantation Institute, Malatya 44280, Turkey
| | - Serdar Karakas
- Department of General Surgery, Inonu University, Liver Transplantation Institute, Malatya 44280, Turkey
| | - Koray Kutluturk
- Department of General Surgery, Inonu University, Liver Transplantation Institute, Malatya 44280, Turkey
| | - Adil Baskiran
- Department of General Surgery, Inonu University, Liver Transplantation Institute, Malatya 44280, Turkey
| | - Sezai Yilmaz
- Department of General Surgery, Inonu University, Liver Transplantation Institute, Malatya 44280, Turkey
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Zhang T, Barrett S, Cotton R, Galvan NTN, O'Mahony C, Moore Vierling J, Goss JA, Rana A. Pediatric length-of-stay index following liver transplantation. Pediatr Transplant 2020; 24:e13779. [PMID: 32720748 DOI: 10.1111/petr.13779] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 04/21/2020] [Accepted: 06/10/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND PELD scores are used to reduce waitlist mortality, but they do not accurately predict likelihood of prolonged length-of-stay or higher costs associated with it. This study aims to create a pediatric length-of-stay (LOS) index to predict increased risk of prolonged stay following liver transplantation. METHODS The scoring system generated predicts length-of-stay following pediatric liver transplantation. With univariate and multivariate analyses on data from 5669 pediatric liver transplant recipients, independent recipient/donor risk factors for prolonged stay (>30 days) were identified. Multiple imputations accounted for missing variables. RESULTS The most significant factors were ICU admission (OR 2.92, CI 2.27-3.75), recipient bilirubin >32 (OR 2.35, CI 1.70-3.25), and hemodialysis 1 week before transplantation (OR 2.27, CI 1.57-3.27). The LOS index assigns weighted scoring points to factors to predict prolonged stay (C-statistic of .72). The index demonstrated discrimination across the population after dividing it into quartiles for prolonged stay. CONCLUSIONS The pediatric LOS index, utilizing 13 donor/recipient factors, can assess the risk for pediatric liver transplantation prolonged stay. Important predictive factors are hemodialysis, ICU admission, recipient weight and bilirubin, and recipient life support status.
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Affiliation(s)
- Theodore Zhang
- Department of Student Affairs, Baylor College of Medicine, Houston, TX, USA
| | - Spencer Barrett
- Department of Student Affairs, Baylor College of Medicine, Houston, TX, USA
| | - Ronald Cotton
- Division of Abdominal Transplantation, Michael E DeBakey Department of General Surgery, Baylor College of Medicine, Houston, TX, USA
| | - Nhu Thao Nguyen Galvan
- Division of Abdominal Transplantation, Michael E DeBakey Department of General Surgery, Baylor College of Medicine, Houston, TX, USA
| | - Christine O'Mahony
- Division of Abdominal Transplantation, Liver Center, Department of General Surgery, Baylor College of Medicine, Houston, TX, USA
| | - John Moore Vierling
- Division of Gastroenterology, Nutrition & Hepatology, Baylor College of Medicine, Houston, TX, USA
| | - John A Goss
- Division of Abdominal Transplantation, Liver Center, Department of General Surgery, Baylor College of Medicine, Houston, TX, USA
| | - Abbas Rana
- Division of Abdominal Transplantation, Michael E DeBakey Department of General Surgery, Baylor College of Medicine, Houston, TX, USA
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T2 Hepatocellular Carcinoma Exception Policies That Prolong Waiting Time Improve the Use of Evidence-based Treatment Practices. Transplant Direct 2020; 6:e597. [PMID: 32904026 PMCID: PMC7447448 DOI: 10.1097/txd.0000000000001039] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 06/18/2020] [Indexed: 02/06/2023] Open
Abstract
Supplemental Digital Content is available in the text. Background. A United Network for Organ Sharing policy change in 2015 created a 6-mo delay in the receipt of T2 hepatocellular carcinoma exception points. It was hypothesized that the policy changed locoregional therapy (LRT) practices and explant findings because of longer expected waiting time. Methods. Patients transplanted with a first T2 hepatocellular carcinoma exception application between January 1, 2010 and December 31, 2014 (prepolicy; N = 6562), and those between August 10, 2015 and December 2, 2019 (postpolicy; N = 2345), were descriptively compared using data from United Network for Organ Sharing. Results. Median time from first application to transplantation was more homogenous across the US postpolicy, due to greater absolute increases in Regions 3, 6, 10, and 11 (>120 d). During waitlisting, postpolicy candidates received more LRT overall (P < 0.001), with more notable increases in previously short-wait regions. Postpolicy explants were overall more likely to have ≥1 tumor with complete necrosis (23.9 versus 18.4%; P < 0.001) and less likely have ≥1 tumor with no necrosis (32.6% versus 38.5%; P < 0.001). Significant geographic variability in explant treatment response was observed prepolicy with recipients in previously short-wait regions having more frequent tumor viability at transplant. Postpolicy, there were no differences in the prevalence of recipients with ≥1 tumor with 100% or 0% necrosis across regions (P = 0.9 and 0.2, respectively). Conclusions. The 2015 T2 exception policy has led to reduced geographic variability in the use of pretransplant LRT and in less frequent tumor viability on explant for recipients in previously short-waiting times.
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Yoon JH, Goo YJ, Lim CJ, Choi SK, Cho SB, Shin SS, Jun CH. Features of extrahepatic metastasis after radiofrequency ablation for hepatocellular carcinoma. World J Gastroenterol 2020; 26:4833-4845. [PMID: 32921960 PMCID: PMC7459202 DOI: 10.3748/wjg.v26.i32.4833] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 05/04/2020] [Accepted: 08/12/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Extrahepatic metastasis (EHM) of hepatocellular carcinoma (HCC) is associated with poor outcomes. However, the clinical features and risk factors of EHM of HCC after radiofrequency ablation (RFA) remain unclear.
AIM To elucidate the characteristics and risk factors of EHM after RFA for HCC.
METHODS From January 2008 to December 2017, we retrospectively enrolled 661 patients who underwent RFA as first-line treatment for HCC at 2 tertiary hospitals. The inclusion criteria were age ≥ 18 years, a diagnosis of HCC, and treatment-naivety. Abdominal computed tomography (CT) or magnetic resonance imaging (MRI) and alpha-fetoprotein measurements were routinely performed at 1 mo after RFA and followed-up at intervals of 3-6 mo. Univariate analyses were performed using the chi-squared test or Student’s t-test, and univariate and multivariate analyses were performed via logistic regression, as appropriate.
RESULTS EHM was diagnosed in 44 patients (6.7%) during a median follow-up period of 1204 days. The 10-year cumulative rate of HCC recurrence and EHM was 92.7% and 33.7%, respectively. Initial recurrence was most often intrahepatic, and the rate of extrahepatic recurrence at initial recurrence was only 1.2%. The median time to the diagnosis of EHM was 2.68 years, and 68.2% of patients developed EHM within 2 years of the first recurrence, regardless of recurrence-free survival and 75.0% of patients developed EHM within 5 years after first recurrence. EHM was mostly diagnosed via abdominal CT/MRI in 33 (75.0%) and 38 of 44 patients (86.4%) with EHM had either positive abdominal CT scan results or serum AFP level elevation. In multivariate analysis, recurrence-free survival < 2 years, ablation zone/tumor size < 2, and alpha-fetoprotein level > 400 IU/mL were associated with a high EHM risk.
CONCLUSION EHM occurs following multiple intrahepatic recurrences after RFA and combined contrast-enhanced abdominal CT and serum AFP were useful for surveillance. Patients especially with high-risk factors require close follow-up for EHM.
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Affiliation(s)
- Jae H Yoon
- Department of Gastroenterology, Chonnam National University Hospital and Medical School, Gwangju 61469, South Korea
| | - Young J Goo
- Department of Gastroenterology, Chonnam National University Hospital and Medical School, Gwangju 61469, South Korea
| | - Chae-Jun Lim
- Department of Gastroenterology, Chonnam National University Hospital and Medical School, Gwangju 61469, South Korea
| | - Sung K Choi
- Department of Gastroenterology, Chonnam National University Hospital and Medical School, Gwangju 61469, South Korea
| | - Sung B Cho
- Department of Gastroenterology, Hwasun Chonnam National University Hospital and Medical School, Hwasun 58128, South Korea
| | - Sang S Shin
- Department of Radiology, Chonnam National University Hospital and Medical School, Gwangju 61469, South Korea
| | - Chung H Jun
- Department of Internal Medicine, Mokpo Hankook Hospital, Mokpo 58643, South Korea
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Mahmud N, Hoteit MA, Goldberg DS. Risk Factors and Center-Level Variation in Hepatocellular Carcinoma Under-Staging for Liver Transplantation. Liver Transpl 2020; 26:977-988. [PMID: 32363720 PMCID: PMC7897468 DOI: 10.1002/lt.25787] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 04/13/2020] [Accepted: 04/25/2020] [Indexed: 12/20/2022]
Abstract
Liver transplantation (LT) is curative for most patients with hepatocellular carcinoma (HCC). However, 10%-15% of patients experience HCC recurrence. Patients who are reported as within Milan criteria by imaging are frequently found to be outside the criteria on explant. This under-staging of HCC worsens post-LT outcomes. However, risk factors for under-staging have not been elucidated. Furthermore, it is not known if there is regional or center-level variation in under-staging. We conducted a retrospective analysis of adult patients transplanted for HCC in the United Network for Organ Sharing (UNOS) database between 2012 and 2016. Under-staging was determined on the basis of comparing pre-LT imaging to explant findings. Kaplan-Meier methods and Cox regression were used to evaluate the impact of under-staging on HCC recurrence and post-LT survival. Mixed effects logistic regression was used to identify risk factors for under-staging and to study regional and center-level variation in adjusted analyses. A total of 5424 patients were included in the cohort, of whom 24.9% (n = 1353) were under-staged. Post-LT HCC recurrence and death were significantly associated with under-staging (each P < 0.001). In adjusted analyses, independent predictors of under-staging included age (odds ratio [OR], 1.13 per 10 years; 95% confidence interval [CI], 1.03-1.25), male sex (OR, 1.61; 95% CI, 1.36-1.89), down-staging (OR, 4.03; 95% CI, 2.65-6.11), and pre-LT alpha-fetoprotein (P < 0.001). There was also significant variation in under-staging between UNOS regions and among transplant centers, ranging from 14.8% to 38.1%. We report novel risk factors for HCC under-staging, which worsens post-LT outcomes. Significant center-level and regional variation in under-staging highlights the need for standards that achieve greater uniformity in staging.
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Affiliation(s)
- Nadim Mahmud
- Division of Gastroenterology, Hospital of the University of Pennsylvania, Philadelphia, PA,Leonard David Institute of Health Economics, University of Pennsylvania, Philadelphia, PA
| | - Maarouf A. Hoteit
- Division of Gastroenterology, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - David S. Goldberg
- Division of Digestive Health and Liver Diseases, University of Miami Miller School of Medicine, Miami, FL
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