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Wang S, Lin X, Li Y, Xie Z, Zhang M, Liang Y, Zhu C, Dong Y, Zeng P, He X, Ju W, Chen M. Identification of a postoperative survival scoring index for adult liver transplantation. Ann Med 2025; 57:2458212. [PMID: 39903479 PMCID: PMC11795760 DOI: 10.1080/07853890.2025.2458212] [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: 04/25/2024] [Revised: 09/15/2024] [Accepted: 01/14/2025] [Indexed: 02/06/2025] Open
Abstract
BACKGROUND In addition to surgical technology, successful liver transplantation (LT) depends on perioperative management, which needs an effective prognostic index. Therefore, a simplified and sensitive postoperative index for adult LT should be developed. METHODS In total, 906 patients who underwent LT were included in this cross-sectional study. Univariate analysis was used to identify the independent risk factors for recipient survival. Multivariate logistic and stepwise regression analyses were used to construct and simplify the model design. Area under the curve (AUC) and Kaplan-Meier's (K-M) analysis demonstrated superiority of the new index. The postoperative survival score (POSS) index was further simplified via restricted cubic spline (RCS) analysis. Finally, the interpretation of the long-term mortality and subgroup analyses extended the application of the POSS index. RESULTS Finally, a total of five factors (donor sex, recipient body mass index (BMI), total bilirubin (Tbil), international normalized ratio (INR) and total operative time) were identified as independent risk parameters and included in our POSS index. The AUCs of the original and simplified POSS indices were 0.764 and 0.723, respectively. Patients with high scores had poor short-term survival. Our index also functioned well in predicting long-term mortality, and it was more effective for patients with hepatitis B cirrhosis or hepatocellular carcinoma (HCC). CONCLUSIONS We constructed a simplified and effective postoperative survival scoring index to predict short-term complications and survival in adult LT patients.
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Affiliation(s)
- Shuai Wang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Xiaohong Lin
- Department of Breast and Thyroid Surgery, Eastern Hospital of the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yefu Li
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Zhonghao Xie
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Ming Zhang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Yicheng Liang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Chuchen Zhu
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Yuqi Dong
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Ping Zeng
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Xiaoshun He
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Weiqiang Ju
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Maogen Chen
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
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Kawashima J, Akabane M, Khalil M, Woldesenbet S, Endo Y, Sahara K, Ruzzenente A, Ratti F, Marques HP, Oliveira S, Balaia J, Cauchy F, Lam V, Poultsides GA, Kitago M, Popescu I, Martel G, Gleisner A, Hugh T, Weiss M, Aucejo F, Aldrighetti L, Endo I, Pawlik TM. Model of End-Stage Liver Disease-alpha-fetoprotein-tumor burden (MELD-AFP-TBS) score to stratify prognosis after liver resection for hepatocellular carcinoma. Surgery 2025; 183:109388. [PMID: 40311416 DOI: 10.1016/j.surg.2025.109388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 03/06/2025] [Accepted: 03/31/2025] [Indexed: 05/03/2025]
Abstract
INTRODUCTION Morphologic criteria, such as the Barcelona Clinic Liver Cancer staging system often fail to accurately predict long-term survival among patients undergoing liver resection for hepatocellular carcinoma. We sought to develop a continuous risk score that incorporates established markers of tumor biology and liver function to improve the prediction of overall survival. METHODS Data from a multi-institutional database were used to identify patients who underwent curative-intent hepatectomy for hepatocellular carcinoma. A predictive score for overall survival was developed using weighted beta-coefficients from a multivariable Cox regression model. RESULTS Among 850 patients, 595 (70.0%) were assigned to the training cohort, and 255 (30.0%) to the test cohort. In the training cohort, multivariable analysis identified the Model of End-Stage Liver Disease (hazard ratio, 1.04; 95% confidence interval, 1.01-1.07), log-transformed alpha-fetoprotein (hazard ratio, 1.07; 95% confidence interval, 1.02-1.13), and tumor burden score (hazard ratio, 1.07; 95% confidence interval, 1.03-1.11) as independent predictors of worse overall survival. The Model of End-Stage Liver Disease-alpha-fetoprotein-tumor burden score, based on the Cox model, stratified patients into low-risk (n = 466, 78.3%) with a 5-year OS of 70.5% and high-risk (n = 129, 21.7%) with a 5-year OS of 47.0% (P < .001). In the test cohort, the Model of End-Stage Liver Disease-alpha-fetoprotein-tumor burden score demonstrated superior discriminative accuracy (C-index: 0.72, time-dependent area under the curve 1-year: 0.80, 3-year 0.76, 5-year 0.70) compared with the Barcelona Clinic Liver Cancer staging system (C-index: 0.53, time-dependent area under the curve 1-year: 0.61, 3-year 0.55, 5-year 0.56). An online tool was made accessible at https://jk-osu.shinyapps.io/MELD_AFP_TBS/. CONCLUSION The Model of End-Stage Liver Disease-alpha-fetoprotein-tumor burden score provides a novel, accurate tool for prognostic stratification of patients with hepatocellular carcinoma, identifying high-risk patients who may benefit from alternative treatments to improve outcomes.
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Affiliation(s)
- Jun Kawashima
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH; Department of Gastroenterological Surgery, Yokohama City University, Yokohama, Japan
| | - Miho Akabane
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH
| | - Mujtaba Khalil
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH
| | - Selamawit Woldesenbet
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH
| | - Yutaka Endo
- Department of Transplant Surgery, University of Rochester Medical Center, Rochester, NY
| | - Kota Sahara
- Department of Gastroenterological Surgery, Yokohama City University, Yokohama, Japan
| | - Andrea Ruzzenente
- Division of General and Hepatobiliary Surgery, University of Verona, Verona, Italy
| | | | - Hugo P Marques
- Department of Surgery, Curry Cabral Hospital, Lisbon, Portugal
| | - Sara Oliveira
- Department of Surgery, Curry Cabral Hospital, Lisbon, Portugal
| | - Jorge Balaia
- Department of Surgery, Curry Cabral Hospital, Lisbon, Portugal
| | - François Cauchy
- Department of HPB Surgery and Liver Transplantation, Beaujon Hospital, Clichy, France
| | - Vincent Lam
- Department of Surgery, Westmead Hospital, Westmead, New South Wales, Australia
| | | | - Minoru Kitago
- Department of Surgery, Keio University, Tokyo, Japan
| | - Irinel Popescu
- Department of Surgery, Fundeni Clinical Institute, Bucharest, Romania
| | | | - Ana Gleisner
- Department of Surgery, University of Colorado Denver, Denver, CO
| | - Tom Hugh
- Department of Surgery, The University of Sydney, Sydney, New South Wales, Australia
| | - Matthew Weiss
- Department of Surgery, Cancer Institute, Northwell Health, New Hyde Park, NY
| | - Federico Aucejo
- Department of Hepato-pancreato-biliary & Liver Transplant Surgery, Cleveland Clinic Foundation, Digestive Diseases and Surgery Institute, Cleveland, OH
| | | | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University, Yokohama, Japan
| | - Timothy M Pawlik
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH.
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Endo Y, Bekki Y, Hernandez-Alejandro R, Tomiyama K. Recent Strategies to Attenuate Hepatocellular Carcinoma Recurrence After Liver Transplantation: A Narrative Review. Cancers (Basel) 2025; 17:1650. [PMID: 40427147 PMCID: PMC12110414 DOI: 10.3390/cancers17101650] [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: 02/27/2025] [Revised: 05/03/2025] [Accepted: 05/09/2025] [Indexed: 05/29/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of liver transplant worldwide. While liver transplantation offers a survival advantage for early-stage HCC patients, post-transplant recurrence remains a significant concern, affecting up to 15% of recipients. We sought to conduct a comprehensive review related to HCC recurrence after liver transplant. Tumor-related factors such as poor differentiation, vascular invasion, and elevated tumor biomarkers like alpha-fetoprotein are key predictors of recurrence. Donor-related factors, including graft type and surgical procedures, can also influence outcomes, though their effects are less conclusive. Advancements in patient selection criteria and scoring systems, such as the Milan Criteria and RETREAT score, have improved risk stratification by incorporating tumor size, biomarkers, and response to pre-transplant treatment. Despite these measures, recurrent HCC after transplantation poses treatment challenges. Curative approaches such as resection are feasible for localized or oligometastatic recurrence and offer the best outcomes when applicable. Locoregional treatments, including ablation and transarterial chemoembolization, provide options for unresectable cases but have limited long-term efficacy. Systemic therapies, including targeted agents like sorafenib, regorafenib, and lenvatinib, have shown modest benefits in managing advanced recurrent HCC. Emerging immunotherapy approaches hold promise but face unique challenges due to the required immunosuppression in transplant recipients. Multidisciplinary evaluation remains essential for tailoring treatment plans. Future efforts should focus on refining predictive tools and exploring novel therapies to improve survival outcomes for patients with recurrent HCC after liver transplantation.
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Affiliation(s)
| | | | | | - Koji Tomiyama
- Department of Transplant Surgery, University of Rochester Medical Center, Rochester, NY 14626, USA; (Y.E.); (Y.B.); (R.H.-A.)
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Saegusa Y, Imaoka Y, Ohira M, Kobayashi T, Honmyo N, Hamaoka M, Onoe T, Takei D, Oishi K, Abe T, Nakayama T, Akabane M, Sasaki K, Ohdan H. Cluster analysis of hepatocellular carcinoma prognosis using preoperative alpha-fetoprotein and des-gamma-carboxy prothrombin levels: a multi-institutional study. J Gastrointest Surg 2025; 29:101980. [PMID: 39884550 DOI: 10.1016/j.gassur.2025.101980] [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: 12/11/2024] [Revised: 01/23/2025] [Accepted: 01/25/2025] [Indexed: 02/01/2025]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) remains the leading cause of cancer-related mortality worldwide and is characterized by high recurrence rates after curative resection. The tumor markers des-gamma-carboxy prothrombin (DCP) and alpha-fetoprotein (AFP) are crucial for HCC diagnosis and prognosis. However, their roles in the modern era of HCC epidemiology require reevaluation. METHODS This multi-institutional retrospective study analyzed 1515 patients who underwent hepatectomy for primary HCC. Patients were classified into 4 clusters using k-means analysis based on preoperative DCP and AFP levels. Clinicopathologic characteristics, overall survival (OS), and recurrence rate (RR) were evaluated using Cox proportional hazards models and area under the receiver operating characteristic curve (AUROC) comparisons. RESULTS Cluster 3 (concurrent elevations of DCP and AFP) had the poorest 5-year OS (52.8%) and the highest RR (79.3%), whereas cluster 4 (low levels of both markers) had the most favorable outcomes, with a 5-year OS rate of 71.5% and an RR of 55.7%. Cluster 1 (elevated DCP alone) was associated with larger tumors (median of 45 mm) and more frequent vascular invasion (43%) than cluster 2 (elevated AFP alone, median tumor size of 24 mm, and vascular invasion of 36%). DCP was a stronger predictor of 5-year OS in patients with preserved liver function (AUROC, 0.63), whereas AFP was more effective in stratifying RR in patients with impaired liver function (AUROC, 0.57). Non-B, non-C hepatitis (NBNC)-related HCC exhibited a distinct biomarker profile, with an elevated DCP level correlating with a higher 5-year RR (67%) than other etiologies. CONCLUSION Our study introduces tumor marker clustering as a novel analytical approach, providing a nuanced understanding of AFP and DCP's combined utility in predicting prognosis and recurrence. Our findings highlight the independent and complementary roles of these biomarkers, particularly in NBNC-related HCC and in cases with impaired liver function. AFP and DCP remain crucial tools for recurrence risk assessment, guiding personalized management strategies, such as surveillance, neoadjuvant therapies, and tailored postoperative interventions.
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Affiliation(s)
- Yoshitaka Saegusa
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yuki Imaoka
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan; Division of Abdominal Transplant, Stanford University, Stanford, CA, United States
| | - Masahiro Ohira
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan; Division of Regeneration and Medicine, Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima, Japan.
| | - Tsuyoshi Kobayashi
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Naruhiko Honmyo
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan; Department of Surgery, Hiroshima City North Medical Center Asa Citizens Hospital, Hiroshima, Japan
| | - Michinori Hamaoka
- Department of Gastroenterological, Breast and Transplant Surgery, Hiroshima Prefectural Hospital, Hiroshima, Japan
| | - Takashi Onoe
- Department of Surgery, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure City, Japan
| | - Daisuke Takei
- Department of Surgery, Onomichi General Hospital, Onomichi City, Japan
| | - Koichi Oishi
- Department of Surgery, Chugoku Rosai Hospital, Kure City, Japan
| | - Tomoyuki Abe
- Department of Surgery, National Hospital Organization, Higashihiroshima Medical Center, Higashihiroshima, Japan
| | - Toshihiro Nakayama
- Division of Abdominal Transplant, Stanford University, Stanford, CA, United States
| | - Miho Akabane
- Division of Abdominal Transplant, Stanford University, Stanford, CA, United States
| | - Kazunari Sasaki
- Division of Abdominal Transplant, Stanford University, Stanford, CA, United States
| | - Hideki Ohdan
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
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Schindler P, von Beauvais P, Hoffmann E, Morgül H, Börner N, Masthoff M, Ben Khaled N, Rennebaum F, Lange CM, Trebicka J, Ingrisch M, Köhler M, Ricke J, Pascher A, Seidensticker M, Guba M, Öcal O, Wildgruber M. Combining radiomics and imaging biomarkers with clinical variables for the prediction of HCC recurrence after liver transplantation. Liver Transpl 2025:01445473-990000000-00582. [PMID: 40100771 DOI: 10.1097/lvt.0000000000000603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Accepted: 02/14/2025] [Indexed: 03/20/2025]
Abstract
To develop and validate an integrated model that combines CT-based radiomics and imaging biomarkers with clinical variables to predict recurrence and recurrence-free survival in patients with HCC following liver transplantation (LT), this 2-center retrospective study includes 123 patients with HCC who underwent LT between 2007 and 2021. Radiomic features (RFs) were extracted from baseline CT liver tumor volume. Feature selection was performed using the Least Absolute Shrinkage and Selection Operator (LASSO) regression method with 10-fold cross-validation in the training cohort (n=48) to build a predictive radiomics signature for HCC recurrence. Combined diagnostic models were built based on the radiomics signature supplemented with imaging features beyond the Milan criteria, the AFP (alpha-fetoprotein) model, and Metroticket 2.0 before LT using multivariate logistic regression. Receiver operating characteristic analyses were performed in both internal (n=22) and external (n=53) validation cohorts, and patients were stratified into either high-risk or low-risk groups for HCC recurrence. Kaplan-Meier analysis was performed to analyze recurrence-free survival. LASSO and multivariate regression analysis revealed 4 independent predictors associated with an increased risk of HCC recurrence: radiomics signature of 5 RF, peritumoral enhancement, satellite nodules, and no bridging therapies. For the prediction of tumor recurrence, the highest AUC of the final integrated models combining clinical variables, non-radiomics imaging features, and radiomics was 0.990 and 0.900 for the internal and external validation sets, respectively, outperforming the Milan and clinical stand-alone models. In all integrated models, the high-risk groups had a shorter recurrence-free survival than the corresponding low-risk group. CT-based radiomics and imaging parameters beyond the Milan criteria representing aggressive behavior, along with the history of bridging therapies, show potential for predicting HCC recurrence after LT.
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Affiliation(s)
| | | | - Emily Hoffmann
- Department of Radiology, University of Muenster, Muenster, Germany
| | - Haluk Morgül
- Department of General, Visceral and Transplant Surgery, University of Muenster, Muenster, Germany
| | - Nikolaus Börner
- Department of General, Visceral and Transplantation Surgery, LMU Munich, Munich, Germany
| | - Max Masthoff
- Department of Radiology, University of Muenster, Muenster, Germany
| | - Najib Ben Khaled
- Department for Internal Medicine II, LMU Munich, Munich, Germany
| | - Florian Rennebaum
- Department for Internal Medicine B, University of Muenster, Muenster, Germany
| | | | - Jonel Trebicka
- Department for Internal Medicine B, University of Muenster, Muenster, Germany
| | | | - Michael Köhler
- Department of Radiology, University of Muenster, Muenster, Germany
| | - Jens Ricke
- Department of Radiology, LMU Munich, Munich, Germany
| | - Andreas Pascher
- Department of General, Visceral and Transplant Surgery, University of Muenster, Muenster, Germany
| | | | - Markus Guba
- Department of General, Visceral and Transplantation Surgery, LMU Munich, Munich, Germany
| | - Osman Öcal
- Department of Diagnostic and Interventional Radiology, University of Heidelberg, Heidelberg, Germany
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Kojima L, Akabane M, Murray M, Fruscione M, Soma D, Snyder A, McVey J, Firl DJ, Hernandez-Alejandro R, Kubal CA, Markmann JF, Aucejo FN, Tomiyama K, Kimura S, Sasaki K. Reappraisal of tacrolimus levels after liver transplant for HCC: A multicenter study toward personalized immunosuppression regimen. Liver Transpl 2025; 31:344-354. [PMID: 39172007 DOI: 10.1097/lvt.0000000000000459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Accepted: 06/25/2024] [Indexed: 08/23/2024]
Abstract
Post-liver transplant (LT) immunosuppression is necessary to prevent rejection; however, a major consequence of this is tumor recurrence. Although recurrence is a concern after LT for patients with HCC, the oncologically optimal tacrolimus (FK) regimen is still unknown. This retrospective study included 1406 patients with HCC who underwent LT (2002-2019) at 4 US institutions using variable post-LT immunosuppression regimens. Receiver operating characteristic analyses were performed to investigate the influences of post-LT time-weighted average FK (TWA-FK) level on HCC recurrence. A competing risk analysis was employed to evaluate the prognostic influence of TWA-FK while adjusting for patient and tumor characteristics. The AUC for TWA-FK was greatest at 2 weeks (0.68), followed by 1 week (0.64) after LT. Importantly, this was consistently observed across the institutions despite immunosuppression regimen variability. In addition, the TWA-FK at 2 weeks was not associated with rejection within 6 months of LT. A competing risk regression analysis showed that TWA-FK at 2 weeks after LT is significantly associated with recurrence (HR: 1.31, 95% CI: 1.21-1.41, p < 0.001). The TWA-FK effect on recurrence varied depending on the exposure level and the individual's risk of recurrence, including vascular invasion and tumor morphology. Although previous studies have explored the influence of FK levels at 1-3 months after LT on HCC recurrence, this current study suggests that earlier time points and exposure levels must be evaluated. Each patient's oncological risk must also be considered in developing an individualized immunosuppression regimen.
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Affiliation(s)
- Lisa Kojima
- Department of Hepato-pancreato-biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA
| | - Miho Akabane
- Division of Abdominal Transplantation, Department of Surgery, Stanford University, Stanford, California, USA
| | - Matthew Murray
- Department of Surgery, Division of Abdominal Transplantation and Hepatobiliary Surgery, University of Rochester Medical Center, Rochester, New York, USA
| | - Michael Fruscione
- Transplantation Unit, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Daiki Soma
- Division of Abdominal Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Abigail Snyder
- Department of Hepato-pancreato-biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA
| | - John McVey
- Department of Hepato-pancreato-biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA
| | - Daniel J Firl
- Department of Surgery, Duke University, Durham, North Carolina, USA
| | - Roberto Hernandez-Alejandro
- Department of Surgery, Division of Abdominal Transplantation and Hepatobiliary Surgery, University of Rochester Medical Center, Rochester, New York, USA
| | - Chandrashekhar A Kubal
- Division of Abdominal Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - James F Markmann
- Transplantation Unit, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Federico N Aucejo
- Department of Hepato-pancreato-biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA
| | - Koji Tomiyama
- Department of Surgery, Division of Abdominal Transplantation and Hepatobiliary Surgery, University of Rochester Medical Center, Rochester, New York, USA
| | - Shoko Kimura
- Transplantation Unit, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Kazunari Sasaki
- Division of Abdominal Transplantation, Department of Surgery, Stanford University, Stanford, California, USA
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7
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Koh HH, Kang M, Kim DG, Park JH, Min EK, Lee JG, Kim MS, Joo DJ. Comparative Validation of Prediction Models for HCC Outcomes in Living Donor Liver Transplantation: Superiority of Tumor Markers to Imaging Study. J Gastroenterol Hepatol 2025; 40:626-634. [PMID: 39723645 DOI: 10.1111/jgh.16857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 11/22/2024] [Accepted: 12/10/2024] [Indexed: 12/28/2024]
Abstract
BACKGROUND Living donor liver transplantation (LDLT) offers timely curative treatment for unresectable hepatocellular carcinoma (HCC). This study aims to validate and compare previous prediction models for HCC outcomes in 488 LDLT recipients. METHODS For 488 patients who underwent LDLT for HCC, pretransplant imaging studies assessed by modified RECSIT criteria, tumor markers such as alpha feto-protein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA II), and explant pathology were recruited. C-index of models for the HCC outcomes was compared, followed by further investigation for the predictive performances of the best model. RESULTS We found MoRAL (11√PIVKA-II + 2√AFP) demonstrated a higher C-index for HCC recurrence than other models that included radiologically viable tumor number and/or size (MoRAL: 0.709, Milan: 0.537, UCSF: 0.575, Up-to-7: 0.572, French AFP: 0.634, Pre-MORAL: 0.637, HALT-HCC: 0.626, Metroticket2.0: 0.629) and also had the highest C-index for HCC-specific deaths (0.706). Five-year HCC recurrence was well stratified upon dividing the patients into three groups by MoRAL cutoffs (11.9% for MoRAL < 100, 29.6% for MoRAL 100-200, and 48.6% for MoRAL > 200, p < 0.001). However, patients with major vessel invasion or portal vein tumor thrombus showed similarly high HCC recurrence regardless of this grouping (p = 0.612). CONCLUSION The MoRAL, based on tumor markers, showed the best predictive performance for HCC recurrence and HCC-specific death among the validated models, except in cases with major vessel invasion or portal vein tumor thrombus.
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Affiliation(s)
- Hwa-Hee Koh
- Department of Surgery, The Research Institute for Transplantation, College of Medicine, Yonsei University, Seoul, South Korea
| | - Minyu Kang
- Department of Surgery, The Research Institute for Transplantation, College of Medicine, Yonsei University, Seoul, South Korea
| | - Deok-Gie Kim
- Department of Surgery, The Research Institute for Transplantation, College of Medicine, Yonsei University, Seoul, South Korea
| | - Jae Hyon Park
- Department of Radiology, Armed Forces Daejeon Hospital, Daejeon, South Korea
| | - Eun-Ki Min
- Department of Surgery, The Research Institute for Transplantation, College of Medicine, Yonsei University, Seoul, South Korea
| | - Jae Geun Lee
- Department of Surgery, The Research Institute for Transplantation, College of Medicine, Yonsei University, Seoul, South Korea
| | - Myoung Soo Kim
- Department of Surgery, The Research Institute for Transplantation, College of Medicine, Yonsei University, Seoul, South Korea
| | - Dong Jin Joo
- Department of Surgery, The Research Institute for Transplantation, College of Medicine, Yonsei University, Seoul, South Korea
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8
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Sangro B, Argemi J, Ronot M, Paradis V, Meyer T, Mazzaferro V, Jepsen P, Golfieri R, Galle P, Dawson L, Reig M. EASL Clinical Practice Guidelines on the management of hepatocellular carcinoma. J Hepatol 2025; 82:315-374. [PMID: 39690085 DOI: 10.1016/j.jhep.2024.08.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 08/29/2024] [Indexed: 12/19/2024]
Abstract
Liver cancer is the third leading cause of cancer-related deaths worldwide, with hepatocellular carcinoma (HCC) accounting for approximately 90% of primary liver cancers. Advances in diagnostic and therapeutic tools, along with improved understanding of their application, are transforming patient treatment. Integrating these innovations into clinical practice presents challenges and necessitates guidance. These clinical practice guidelines offer updated advice for managing patients with HCC and provide a comprehensive review of pertinent data. Key updates from the 2018 EASL guidelines include personalised surveillance based on individual risk assessment and the use of new tools, standardisation of liver imaging procedures and diagnostic criteria, use of minimally invasive surgery in complex cases together with updates on the integrated role of liver transplantation, transitions between surgical, locoregional, and systemic therapies, the role of radiation therapies, and the use of combination immunotherapies at various stages of disease. Above all, there is an absolute need for a multiparametric assessment of individual risks and benefits, considering the patient's perspective, by a multidisciplinary team encompassing various specialties.
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Agarwal A, Wehrle CJ, Satish S, Mahajan P, Kamath S, Koyfman S, Ma WW, Linganna M, Modaresi Esfeh J, Miller C, Kwon DCH, Schlegel A, Aucejo F. PET-Assessed Metabolic Tumor Volume Across the Spectrum of Solid-Organ Malignancies: A Review of the Literature. Biomedicines 2025; 13:123. [PMID: 39857707 PMCID: PMC11762135 DOI: 10.3390/biomedicines13010123] [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: 12/19/2024] [Accepted: 01/05/2025] [Indexed: 01/27/2025] Open
Abstract
Solid-organ malignancies represent a significant disease burden and remain one of the leading causes of death globally. In the past few decades, the rapid evolution of imaging modalities has shifted the paradigm towards image-based precision medicine, especially in the care of patients with solid-organ malignancies. Metabolic tumor volume (MTV) is one such semi-quantitative parameter obtained from positron emission tomography (PET) imaging with 18F-fluorodeoxyglucose (FDG) that has been shown to have significant implications in the clinical oncology setting. Across various solid tumor malignancies, including lung cancer, head and neck cancer, breast cancer, esophageal cancer, and colorectal cancer, the current literature has demonstrated an association between MTV and various clinical outcomes. MTV may be used in conjunction with several existing and established clinical parameters to help inform risk stratification and treatment strategies and predict outcomes in cancer. Optimizing such volumetric parameters is paramount for advancing efforts to advance cancer care for our patients. While such advancements are made, it is important to investigate and address the limitations of MTV, including variability in terms of measurement methods, a lack of standardized cut-off values, and the impact of inherent tumor heterogeneity. Despite these limitations, which can precipitate challenges in standardization, MTV as a prognostic factor has great potential and opens an avenue for the future integration of technology into an image-based precision medicine model of care for cancer patients. This article serves as a narrative review and explores the utility and limitations of PET-MTV in various settings of solid-organ malignancy.
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Affiliation(s)
- Anusha Agarwal
- Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, OH 44195, USA;
| | - Chase J. Wehrle
- Digestive Diseases and Surgery Institute, HPB and Transplant Surgery, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Sangeeta Satish
- Digestive Diseases and Surgery Institute, HPB and Transplant Surgery, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Paresh Mahajan
- Department of Radiology, Nuclear Medicine Section, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Suneel Kamath
- Taussig Cancer Institute, GI Oncology Section, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Shlomo Koyfman
- Taussig Cancer Institute, Head & Neck Oncology Section, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Wen Wee Ma
- Taussig Cancer Institute, GI Oncology Section, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Maureen Linganna
- Digestive Diseases and Surgery Institute, Hepatology Section, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Jamak Modaresi Esfeh
- Digestive Diseases and Surgery Institute, Hepatology Section, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Charles Miller
- Digestive Diseases and Surgery Institute, HPB and Transplant Surgery, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - David C. H. Kwon
- Digestive Diseases and Surgery Institute, HPB and Transplant Surgery, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Andrea Schlegel
- Digestive Diseases and Surgery Institute, HPB and Transplant Surgery, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Federico Aucejo
- Digestive Diseases and Surgery Institute, HPB and Transplant Surgery, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
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Piñero F, Lai Q, Costentin C, Degroote H, Schnitzbauer A, Geissler EK, Duvoux C. Validation of the R3-AFP model for risk prediction of HCC recurrence after liver transplantation in the SiLVER randomized clinical trial. Liver Transpl 2025; 31:45-57. [PMID: 39297745 DOI: 10.1097/lvt.0000000000000487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 08/27/2024] [Indexed: 10/23/2024]
Abstract
Explant-based models for assessing HCC recurrence after liver transplantation serve as the gold standard, guiding post-liver transplantation screening and immunosuppression adjustment. Incorporating alpha-fetoprotein (AFP) levels into these models, such as the novel R3-AFP score, has notably enhanced risk stratification. However, validation of these models in high-evidence data is mandatory. Therefore, the aim of the present research was to validate the R3-AFP score in a randomized clinical trial. We analyzed the intention-to-treat population from the 2-arm SiLVER trial (NCT00355862), comparing calcineurin-based ([calcineurin inhibitors]-Group A) versus mammalian target of rapamycin inhibitors-based (sirolimus-Group B) immunosuppression for post-liver transplantation HCC recurrence. Competing risk analysis estimated sub-hazard ratios, with testing of discriminant function and calibration. Overall, 508 patients from the intention-to-treat analysis were included (Group A, n = 256; Group B, n = 252). The R3-AFP score distribution was as follows: 42.6% low-risk (n = 216), 35.7% intermediate-risk (n = 181), 19.5% high-risk (n = 99), and 2.2% very-high-risk (n = 11) groups. The R3-AFP score effectively stratified HCC recurrence risk, with increasing risk for each stratum. Calibration of the R3-AFP model significantly outperformed other explant-based models (Milan, Up-to-7, and RETREAT), whereas discrimination power (0.75 [95% CI: 0.69; 0.81]) surpassed these models, except for the RETREAT model ( p = 0.49). Subgroup analysis showed lower discrimination power in the mammalian target of rapamycin group versus the calcineurin inhibitors group ( p = 0.048). In conclusion, the R3-AFP score accurately predicted HCC recurrence using high-quality evidence-based data, exhibiting reduced performance under mammalian target of rapamycin immunosuppression. This highlights the need for further research to evaluate surveillance schedules and adjuvant regimens.
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Affiliation(s)
- Federico Piñero
- Hepatology Section, Liver Transplant Unit, Hepatology, Hospital Universitario Austral, Pilar, Buenos Aires, Argentina
| | - Quirino Lai
- Department of Surgery, General Surgery and Organ Transplantation Unit, Sapienza University of Rome, Rome, Italy
| | - Charlotte Costentin
- Gastroenterology, Hepatology and GI Oncology Department, Grenoble Alpes University, Institute for Advanced Biosciences, Research Center UGA/Inserm U 1209/CNRS 5309, Digidune, Grenoble Alpes University Hospital, La Tronche, France
| | - Helena Degroote
- Department of Hepatology and Gastroenterology, Ghent University Hospital, Ghent, Belgium
| | - Andreas Schnitzbauer
- Department of Surgery, HPB and Transplant Surgery, University Hospital Frankfurt, Frankfurt, Germany
| | - Edward K Geissler
- Department of Surgery, University Hospital Regensburg, Regensburg, Germany
| | - Christophe Duvoux
- Department of Hepatology, Medical Liver Transplant Unit, Hospital Henri Mondor AP-HP, University of Paris-Est Créteil (UPEC), Créteil, France
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Liu H, Zhang W, Di M, Lee H, Shi L, Wang X, Xingyu Z, Powers CA, Sethi V, Li X, Xiao Y, Crane A, Kaltenmeier C, Alberola RB, Behari J, Duarte-Rojo A, Hughes D, Malik S, Jonassaint N, Geller D, Tohme S, Gunabushanam V, Tevar A, Cruz R, Hughes C, Dharmayan S, Ayloo S, Humar A, Molinari M. Survival benefit associated with liver transplantation for hepatocellular carcinoma based on tumor burden scores at listing. Hepatol Commun 2025; 9:e0619. [PMID: 39774957 PMCID: PMC11717502 DOI: 10.1097/hc9.0000000000000619] [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: 05/08/2024] [Accepted: 10/16/2024] [Indexed: 01/11/2025] Open
Abstract
INTRODUCTION Liver transplantation (LT) provides significant survival benefits to patients with unresectable HCC. In the United States, organ allocation policies for HCCs within the United Network for Organ Sharing criteria do not prioritize patients based on their differences in oncological characteristics. This study assessed whether transplant-associated survival benefits (TASBs) vary among patients with different tumor burden scores (TBS) measured at the time of listing. METHODS We analyzed data from adults applying for HCC MELD exception points between 2002 and 2019, with follow-up until December 2023, using the Scientific Registry of Transplant Recipients. TBS was determined based on the largest tumor diameter and number of HCCs. Patients were categorized into low (≤3), intermediate (3.1-5), and high (>5) TBS groups. TASB was measured as the difference in 5-year survival with and without LT. RESULTS This study included 36,634 LT candidates. High-TBS patients had higher waitlist dropout rates and marginally lower post-transplant survival, resulting in a significantly greater TASB. The 5-year TASB for the low, intermediate, and high TBS groups were 15.7, 22.1, and 25.0 months, respectively. The adjusted survival benefit expressed in 5-year survival differences was 21.9%, 34.5%, and 39.4% in the low, intermediate, and high TBS groups, respectively (p<0.001). CONCLUSIONS Higher TBS during listing correlates with greater LT benefits for patients with unresectable HCC within UNOS criteria. We conclude that organ allocation policies in the United States should prioritize patients with high TBS due to their increased risk of dropout and comparable post-transplant survival when compared to patients with less advanced tumors.
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Affiliation(s)
- Hao Liu
- Division of Transplant, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Wei Zhang
- Department of Mathematics and Statistics, the University of Arkansas at Little Rock, Little Rock, Arkansas, USA
| | - Mengyang Di
- Division of Hematology-Oncology, University of Washington, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Hang Lee
- Biostatistics Center, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Liuhua Shi
- Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA
| | - Xixi Wang
- Department of Mathematics and Statistics, the University of Arkansas at Little Rock, Little Rock, Arkansas, USA
| | - Zhang Xingyu
- Division of Transplant, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
- Department of Biostatistics, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Colin A. Powers
- Division of Transplant, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Vrishketan Sethi
- Division of Transplant, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Xingjie Li
- Division of Transplant Surgery, Department of Surgery, Mayo Clinic Arizona, Phoenix, Arizona, USA
| | - Yao Xiao
- Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Andrew Crane
- Division of Transplant, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Christof Kaltenmeier
- Division of Transplant, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Ramon Bataller Alberola
- Liver Unit, Hospital Clinic, Barcelona, Spain
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Jaideep Behari
- Division of Gastroenterology, Department of Medicine, Hepatology, and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Andres Duarte-Rojo
- Department of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Dempsey Hughes
- Department of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Shahid Malik
- Division of Gastroenterology, Department of Medicine, Hepatology, and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Naudia Jonassaint
- Division of Gastroenterology, Department of Medicine, Hepatology, and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - David Geller
- Division of Transplant, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Samer Tohme
- Division of Transplant, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Vikraman Gunabushanam
- Division of Transplant, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Amit Tevar
- Division of Transplant, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Ruy Cruz
- Division of Transplant, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Christopher Hughes
- Division of Transplant, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Stalin Dharmayan
- Division of Transplant, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Subhashini Ayloo
- Division of Transplant, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
- Department of Surgery, Brown University, Providence, Rhode Island, USA
| | - Abhinav Humar
- Division of Transplant, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Michele Molinari
- Division of Transplant, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
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Pantea R, Bednarsch J, Schmitz S, Meister P, Heise D, Ulmer F, Neumann UP, Lang SA. The assessment of impaired liver function and prognosis in hepatocellular carcinoma. Expert Rev Gastroenterol Hepatol 2024; 18:779-794. [PMID: 39688572 DOI: 10.1080/17474124.2024.2442573] [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: 10/16/2024] [Revised: 12/05/2024] [Accepted: 12/11/2024] [Indexed: 12/18/2024]
Abstract
INTRODUCTION The impairment of liver function strongly limits the therapeutic options for hepatocellular carcinoma (HCC), and the assessment of liver function is key to finding the appropriate therapy for patients suffering from this disease. Furthermore, preexisting liver dysfunction has a negative impact on the prognosis of patients in addition to the malignant potential of HCC. Hence, defining the optimal treatment of patients with HCC requires a comprehensive examination with liver function being a crucial part of it. AREAS COVERED This review will provide an overview of the currently existing methods for evaluating the liver function in patients with HCC. Assessment of liver function includes scoring systems but also functional and technical methods. In addition, the role of these tests in different treatment facilities such as liver resection, transplantation, interventional and systemic therapy is summarized. EXPERT OPINION A comprehensive pretherapeutic assessment of the liver function includes laboratory-based scoring systems, as well as imaging- and non-imaging-based functional tests. Combining diverse parameters can help to improve the safety and efficacy of HCC therapy particularly in patients with compromised liver function. Future research should focus on optimizing pretherapeutic assessment recommendations for each therapy.
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Affiliation(s)
- Roxana Pantea
- Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany
| | - Jan Bednarsch
- Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany
| | - Sophia Schmitz
- Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany
| | - Phil Meister
- Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany
| | - Daniel Heise
- Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany
| | - Florian Ulmer
- Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany
| | - Ulf Peter Neumann
- Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany
| | - Sven Arke Lang
- Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany
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Schmauch B, Elsoukkary SS, Moro A, Raj R, Wehrle CJ, Sasaki K, Calderaro J, Sin-Chan P, Aucejo F, Roberts DE. Combining a deep learning model with clinical data better predicts hepatocellular carcinoma behavior following surgery. J Pathol Inform 2024; 15:100360. [PMID: 38292073 PMCID: PMC10825615 DOI: 10.1016/j.jpi.2023.100360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 12/10/2023] [Accepted: 12/23/2023] [Indexed: 02/01/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is among the most common cancers worldwide, and tumor recurrence following liver resection or transplantation is one of the highest contributors to mortality in HCC patients after surgery. Using artificial intelligence (AI), we developed an interdisciplinary model to predict HCC recurrence and patient survival following surgery. We collected whole-slide H&E images, clinical variables, and follow-up data from 300 patients with HCC who underwent transplant and 169 patients who underwent resection at the Cleveland Clinic. A deep learning model was trained to predict recurrence-free survival (RFS) and disease-specific survival (DSS) from the H&E-stained slides. Repeated cross-validation splits were used to compute robust C-index estimates, and the results were compared to those obtained by fitting a Cox proportional hazard model using only clinical variables. While the deep learning model alone was predictive of recurrence and survival among patients in both cohorts, integrating the clinical and histologic models significantly increased the C-index in each cohort. In every subgroup analyzed, we found that a combined clinical and deep learning model better predicted post-surgical outcome in HCC patients compared to either approach independently.
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Affiliation(s)
| | - Sarah S. Elsoukkary
- Owkin Lab, Owkin, Inc., New York, NY, USA
- Department of Pathology, Cleveland Clinic, Cleveland, OH, USA
| | - Amika Moro
- Department of Surgery, Cleveland Clinic, Cleveland, OH, USA
| | - Roma Raj
- Department of Surgery, Cleveland Clinic, Cleveland, OH, USA
| | | | - Kazunari Sasaki
- Department of Surgery, Stanford University, Palo Alto, CA, USA
| | - Julien Calderaro
- Department of Pathology, Henri Mondor University Hospital, Créteil, France
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14
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Wehrle CJ, Kusakabe J, Akabane M, Maspero M, Zervos B, Modaresi Esfeh J, Whitsett Linganna M, Imaoka Y, Khalil M, Pita A, Kim J, Diago-Uso T, Fujiki M, Eghtesad B, Quintini C, Kwon CD, Pinna A, Aucejo F, Miller C, Mazzaferro V, Schlegel A, Sasaki K, Hashimoto K. Expanding Selection Criteria in Deceased Donor Liver Transplantation for Hepatocellular Carcinoma: Long-term Follow-up of a National Registry and 2 Transplant Centers. Transplantation 2024; 108:2386-2395. [PMID: 38831488 DOI: 10.1097/tp.0000000000005097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/05/2024]
Abstract
BACKGROUND This study compares selection criteria for liver transplant (LT) for hepatocellular carcinoma (HCC) for inclusivity and predictive ability to identify the most permissive criteria that maintain patient outcomes. METHODS The Scientific Registry of Transplant Recipients (SRTR) database was queried for deceased donor LT's for HCC (2003-2020) with 3-y follow-up; these data were compared with a 2-center experience. Milan, University of California, San Francisco (UCSF), 5-5-500, Up-to-seven (U7), HALT-HCC, and Metroticket 2.0 scores were calculated. RESULTS Nationally, 26 409 patients were included, and 547 at the 2 institutions. Median SRTR-follow-up was 6.8 y (interquartile range 3.9-10.1). Three criteria allowed the expansion of candidacy versus Milan: UCSF (7.7%, n = 1898), Metroticket 2.0 (4.2%, n = 1037), and U7 (3.5%, n = 828). The absolute difference in 3-y overall survival (OS) between scores was 1.5%. HALT-HCC (area under the curve [AUC] = 0.559, 0.551-0.567) best predicted 3-y OS although AUC was notably similar between criteria (0.506 < AUC < 0.527, Mila n = 0.513, UCSF = 0.506, 5-5-500 = 0.522, U7 = 0.511, HALT-HCC = 0.559, and Metroticket 2.0 = 0.520), as was Harrall's c-statistic (0.507 < c-statistic < 0.532). All scores predicted survival to P < 0.001 on competing risk analysis. Median follow-up in our enterprise was 9.8 y (interquartile range 7.1-13.3). U7 (13.0%, n = 58), UCSF (11.1%, n = 50), HALT-HCC (6.4%, n = 29), and Metroticket 2.0 (6.3%, n = 28) allowed candidate expansion. HALT-HCC (AUC = 0.768, 0.713-0.823) and Metroticket 2.0 (AUC = 0.739, 0.677-0.801) were the most predictive of recurrence. All scores predicted recurrence and survival to P < 0.001 using competing risk analysis. CONCLUSIONS Less restrictive criteria such as Metroticket 2.0, UCSF, or U7 allow broader application of transplants for HCC without sacrificing outcomes. Thus, the criteria for Model for End-stage Liver Disease-exception points for HCC should be expanded to allow more patients to receive life-saving transplantation.
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Affiliation(s)
- Chase J Wehrle
- Department of Surgery, Transplantation Center, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH
| | - Jiro Kusakabe
- Department of Surgery, Transplantation Center, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH
| | - Miho Akabane
- Department of Surgery, Stanford University Hospital, Palo Alto, CA
| | - Marianna Maspero
- General Surgery and Liver Transplantation Unit, IRCCS Istituto Tumori, Milan, Italy
| | - Bobby Zervos
- Department of Liver Transplantation, Cleveland Clinic Weston Hospital, Weston, FL
| | | | | | - Yuki Imaoka
- Department of Surgery, Stanford University Hospital, Palo Alto, CA
| | - Mazhar Khalil
- Department of Surgery, Transplantation Center, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH
| | - Alejandro Pita
- Department of Surgery, Transplantation Center, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH
| | - Jaekeun Kim
- Department of Surgery, Transplantation Center, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH
| | - Teresa Diago-Uso
- Department of Surgery, Digestive Disease Institute, Transplantation Center, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Masato Fujiki
- Department of Surgery, Transplantation Center, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH
| | - Bijan Eghtesad
- Department of Surgery, Transplantation Center, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH
| | - Cristiano Quintini
- Department of Surgery, Digestive Disease Institute, Transplantation Center, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Choon David Kwon
- Department of Surgery, Transplantation Center, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH
| | - Antonio Pinna
- Department of Liver Transplantation, Cleveland Clinic Weston Hospital, Weston, FL
| | - Federico Aucejo
- Department of Surgery, Transplantation Center, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH
| | - Charles Miller
- Department of Surgery, Transplantation Center, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH
| | - Vincenzo Mazzaferro
- General Surgery and Liver Transplantation Unit, IRCCS Istituto Tumori, Milan, Italy
| | - Andrea Schlegel
- Department of Surgery, Transplantation Center, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
| | - Kazunari Sasaki
- Department of Surgery, Stanford University Hospital, Palo Alto, CA
| | - Koji Hashimoto
- Department of Surgery, Transplantation Center, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH
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15
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Imaoka Y, Ohira M, Kobayashi T, Honmyo N, Hamaoka M, Onoe T, Takei D, Oishi K, Abe T, Nakayama T, Akabane M, Sasaki K, Ohdan H, Hiroshima Surgical Study Group of Clinical Oncology (HiSCO). Evaluation of prognostic efficacy of liver immune status index in predicting postoperative outcomes in hepatocellular carcinoma patients: A multi-institutional retrospective study. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2024; 31:798-808. [PMID: 39313837 PMCID: PMC11589398 DOI: 10.1002/jhbp.12070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/25/2024]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) ranks third in cancer-related deaths globally. Despite treatment advances, high post-hepatectomy recurrence rates (RR), especially with liver fibrosis and hepatitis C virus infection, remain challenging. Key prognostic factors include vascular invasion and perioperative blood loss, impacting extrahepatic recurrence. Natural killer (NK) cells are crucial in countering circulating tumor cells through TRAIL-mediated pathways. The aim of this study was to validate the liver immune status index (LISI) as a predictive tool for liver NK cell antitumor efficiency, particularly in HCC patients with vascular invasion. METHODS A retrospective analysis of 1337 primary HCC hepatectomies was conducted by the Hiroshima Surgical Study Group of Clinical Oncology (HiSCO). Clinicodemographic data were extracted from electronic medical records. Prognostic indices (FIB-4, ALBI, ALICE, GNRI, APRI, and LISI) were evaluated using area under the receiver operating characteristic curve values. Survival analyses employed Kaplan-Meier estimations and log-rank tests. RESULTS LISI significantly correlated with other prognostic markers and stratified patients into risk groups with distinct overall survival (OS) and RR. It showed superior predictive performance for 2-year OS and RR, especially in patients with vascular invasion. Over longer periods, APRI and FIB-4 index reliabilities improved. The HISCO-HCC score, combining LISI, tumor burden score, and alpha-fetoprotein levels, enhanced prognostic accuracy. CONCLUSION LISI outperformed existing models, particularly in HCC with vascular invasion. The HISCO-HCC score offers improved prognostic precision, guiding immunotherapeutic strategies and individualized patient care in HCC.
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Affiliation(s)
- Yuki Imaoka
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
- Division of Abdominal TransplantStanford UniversityStanfordCaliforniaUSA
| | - Masahiro Ohira
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
- Division of Regeneration and Medicine, Medical Center for Translational and Clinical ResearchHiroshima University HospitalHiroshimaJapan
| | - Tsuyoshi Kobayashi
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
| | - Naruhiko Honmyo
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
- Department of SurgeryHiroshima City North Medical Center Asa Citizens HospitalHiroshimaJapan
| | - Michinori Hamaoka
- Department of GastroenterologicalBreast and Transplant Surgery Hiroshima Prefectural HospitalHiroshimaJapan
| | - Takashi Onoe
- Department of SurgeryNational Hospital Organization Kure Medical Center and Chugoku Cancer CenterKureJapan
| | - Daisuke Takei
- Department of SurgeryOnomichi General HospitalOnomichiJapan
| | - Koichi Oishi
- Department of SurgeryChugoku Rosai HospitalKureJapan
| | - Tomoyuki Abe
- Department of SurgeryNational Hospital Organization Higashi Hiroshima Medical CenterHigashihiroshimaJapan
| | - Toshihiro Nakayama
- Division of Abdominal TransplantStanford UniversityStanfordCaliforniaUSA
| | - Miho Akabane
- Division of Abdominal TransplantStanford UniversityStanfordCaliforniaUSA
| | - Kazunari Sasaki
- Division of Abdominal TransplantStanford UniversityStanfordCaliforniaUSA
| | - Hideki Ohdan
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
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Akabane M, McVey JC, Firl DJ, Kwong AJ, Melcher ML, Kim WR, Sasaki K. Continuous Risk Score Predicts Waitlist and Post-transplant Outcomes in Hepatocellular Carcinoma Despite Exception Changes. Clin Gastroenterol Hepatol 2024; 22:2044-2052.e4. [PMID: 38908731 DOI: 10.1016/j.cgh.2024.05.046] [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: 04/25/2024] [Accepted: 05/27/2024] [Indexed: 06/24/2024]
Abstract
BACKGROUND & AIMS Continuous risk-stratification of candidates and urgency-based prioritization have been utilized for liver transplantation (LT) in patients with non-hepatocellular carcinoma (HCC) in the United States. Instead, for patients with HCC, a dichotomous criterion with exception points is still used. This study evaluated the utility of the hazard associated with LT for HCC (HALT-HCC), an oncological continuous risk score, to stratify waitlist dropout and post-LT outcomes. METHODS A competing risk model was developed and validated using the UNOS database (2012-2021) through multiple policy changes. The primary outcome was to assess the discrimination ability of waitlist dropouts and LT outcomes. The study focused on the HALT-HCC score, compared with other HCC risk scores. RESULTS Among 23,858 candidates, 14,646 (59.9%) underwent LT and 5196 (21.8%) dropped out of the waitlist. Higher HALT-HCC scores correlated with increased dropout incidence and lower predicted 5-year overall survival after LT. HALT-HCC demonstrated the highest area under the curve (AUC) values for predicting dropout at various intervals post-listing (0.68 at 6 months, 0.66 at 1 year), with excellent calibration (R2 = 0.95 at 6 months, 0.88 at 1 year). Its accuracy remained stable across policy periods and locoregional therapy applications. CONCLUSIONS This study highlights the predictive capability of the continuous oncological risk score to forecast waitlist dropout and post-LT outcomes in patients with HCC, independent of policy changes. The study advocates integrating continuous scoring systems like HALT-HCC in liver allocation decisions, balancing urgency, organ utility, and survival benefit.
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Affiliation(s)
- Miho Akabane
- Division of Abdominal Transplant, Department of Surgery, Stanford University Medical Center, Stanford, California
| | - John C McVey
- Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Daniel J Firl
- Department of Surgery, Duke University Hospital, Durham, North Carolina
| | - Allison J Kwong
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford, California
| | - Marc L Melcher
- Division of Abdominal Transplant, Department of Surgery, Stanford University Medical Center, Stanford, California
| | - W Ray Kim
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford, California
| | - Kazunari Sasaki
- Division of Abdominal Transplant, Department of Surgery, Stanford University Medical Center, Stanford, California.
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Akabane M, Esquivel CO, Kim WR, Sasaki K. The Future Frontier of Liver Transplantation Exploring Young Donor Allocation Strategies for HCC Recipients. Transplant Direct 2024; 10:e1657. [PMID: 38881743 PMCID: PMC11177833 DOI: 10.1097/txd.0000000000001657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 02/21/2024] [Accepted: 02/23/2024] [Indexed: 06/18/2024] Open
Abstract
Background The role of donor age in liver transplantation (LT) outcomes for hepatocellular carcinoma (HCC) is controversial. Given the significant risk of HCC recurrence post-LT, optimizing donor/recipient matching is crucial. This study reassesses the impact of young donors on LT outcomes in patients with HCC. Methods A retrospective review of 11 704 LT cases from the United Network for Organ Sharing database (2012-2021) was conducted. The study focused on the effect of donor age on recurrence-free survival, using hazard associated with LT for HCC (HALT-HCC) and Metroticket 2.0 scores to evaluate post-LT survival in patients with HCC. Results Of 4706 cases with young donors, 11.0% had HCC recurrence or death within 2 y, and 18.3% within 5 y. These outcomes were comparable with those of non-young donors. A significant correlation between donor age and post-LT recurrence or mortality (P = 0.04) was observed, which became statistically insignificant after tumor-related adjustments (P = 0.32). The Kaplan-Meier curve showed that recipients with lower HALT-HCC scores (<9) and Metroticket 2.0 scores (<2.2) significantly benefited from young donors, unlike those exceeding these score thresholds. Cox regression analysis showed that donor age significantly influenced outcomes in recipients below certain score thresholds but was less impactful for higher scores. Conclusions Young donors are particularly beneficial for LT recipients with less aggressive HCC, as indicated by their HALT-HCC and Metroticket 2.0 scores. These findings suggest strategically allocating young donors to recipients with less aggressive tumor profiles, which could foster more efficient use of the scarce donor supply and potentially enhance post-LT outcomes.
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Affiliation(s)
- Miho Akabane
- Division of Abdominal Transplant, Department of Surgery, Stanford University Medical Center, Stanford, CA
| | - Carlos O Esquivel
- Division of Abdominal Transplant, Department of Surgery, Stanford University Medical Center, Stanford, CA
| | - W Ray Kim
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford, CA
| | - Kazunari Sasaki
- Division of Abdominal Transplant, Department of Surgery, Stanford University Medical Center, Stanford, CA
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Okumura K, Dhand A, Hanna K, Misawa R, Sogawa H, Veillette G, Nishida S. Indications and outcomes of liver transplantation for liver tumors in the United States. SURGERY IN PRACTICE AND SCIENCE 2024; 17:100245. [PMID: 39845637 PMCID: PMC11749412 DOI: 10.1016/j.sipas.2024.100245] [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: 08/31/2023] [Revised: 04/01/2024] [Accepted: 04/01/2024] [Indexed: 01/24/2025] Open
Abstract
Background While hepatocellular carcinoma (HCC) remains the leading cause of liver transplant (LT) for liver tumors, indications have broadened over the years. Data regarding patient characteristics and outcomes of LT for liver tumors are limited. Methods From Jan-2002 to March-2022, 14,406 LT recipients for various liver tumors were identified in United Network for Organ Sharing database. Overall post-transplant survival analysis was performed with Kaplan-Meier method and multivariable Cox proportional-hazards model. Results During the study period, indications for LT for various hepatic tumors were HCC (88.5 %), benign tumors (5.1 %), cholangiocarcinoma (3.9 %), angiosarcoma (0.7 %), bile duct cancer (0.7 %), secondary tumors (0.5 %) and others (0.7 %). Compared to non-HCC, LT recipients for HCC were older (median age 61 vs 54 years, P < 0.001), more often male (77% vs 48 %, P < 0.001), more often Hispanic (16% vs 8.0 %), had higher BMI (28.2 vs 25.3, P < 0.001) and higher prevalence of Hepatitis C (53% vs 3.9 %, P < 0.001). Donor characteristics across various groups were similar. One-year survival in LT recipients of HCC was higher (HCC: 91.7% vs. non-HCC: 90.3 %) with adjusted Hazard Ratio (aHR) of 0.87; 95 % CI 0.77-0.99, P = 0.033 in a multivariable Cox regression analysis. Compared to HCC, survival outcomes were worse in cholangiocarcinoma (aHR 1.70; 95 %CI 1.43-2.01, P < 0.001), bile duct cancer (aHR 3.03; 95 %CI 2.12-4.33, P < 0.001), secondary tumors including colon cancer and neuroendocrine tumors (aHR 1.88; 95 % CI 1.24-2.85, P = 0.003), with best survival in patients with benign tumors (aHR 0.57; 95 %CI 0.46-0.70, P < 0.001). Conclusions LT is performed for various liver tumors with variable outcomes among these primary indications.
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Affiliation(s)
- Kenji Okumura
- Department of Surgery, Westchester Medical Center and New York Medical College, Valhalla, NY, USA
| | - Abhay Dhand
- Department of Surgery, Westchester Medical Center and New York Medical College, Valhalla, NY, USA
| | - Kamil Hanna
- Department of Surgery, Westchester Medical Center and New York Medical College, Valhalla, NY, USA
| | - Ryosuke Misawa
- Department of Surgery, Westchester Medical Center and New York Medical College, Valhalla, NY, USA
| | - Hiroshi Sogawa
- Department of Surgery, Westchester Medical Center and New York Medical College, Valhalla, NY, USA
| | - Gregory Veillette
- Department of Surgery, Westchester Medical Center and New York Medical College, Valhalla, NY, USA
| | - Seigo Nishida
- Department of Surgery, Westchester Medical Center and New York Medical College, Valhalla, NY, USA
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Liu L, Qin S, Lin K, Xu Q, Yang Y, Cai J, Zeng Y, Yuan S, Xiang B, Lau WY, Zhou W. Development and comprehensive validation of a predictive prognosis model for very early HCC recurrence within one year after curative resection: a multicenter cohort study. Int J Surg 2024; 110:3401-3411. [PMID: 38626419 PMCID: PMC11175792 DOI: 10.1097/js9.0000000000001467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Accepted: 03/31/2024] [Indexed: 04/18/2024]
Abstract
BACKGROUND The high incidence of early recurrence after liver resection (LR) for hepatocellular carcinoma (HCC) is the main obstacle in achieving good long-term survival outcomes. The aim of the present study is to develop a prognostic model in predicting the risk of very early (1-year) recurrence. MATERIAL AND METHODS Consecutive patients who underwent LR for HCC with curative intent at multicenters in China were enrolled in this study. The VERM-pre (the Preoperative Very Early Recurrence Model of HCC) with good performance was derived and validated by internal and external cohorts retrospectively and by another two-center cohort prospectively. RESULTS Seven thousand four hundred one patients were enrolled and divided randomly into three cohorts. Eight variables (tumor diameter, tumor number, macrovascular invasion, satellite nodule, alpha-fetoprotein, level of HBV-DNA, γ-GT, and prothrombin time) were identified as independent risk factors for recurrence-free survival on univariate and multivariate analyses. The VERM-pre model was developed which showed a high capacity of discrimination (C-index: 0.722; AUROC at 1-year: 0.722)) and was validated comprehensively by the internal, external, and prospective cohorts, retrospectively. Calibration plots showed satisfactory fitting of probability of early HCC recurrence in the cohorts. Three risk strata were derived to have significantly different recurrence-free survival rates (low-risk: 80.4-85.4%; intermediate-risk: 59.7-64.8%; high-risk: 32.6-42.6%). In the prospective validation cohort, the swimming plot illustrated consistent outcomes with the beginning predictive score. CONCLUSION The VERM-pre model accurately predicted the 1-year recurrence rates of HCC after LR with curative intent. The model was retrospectively and prospectively validated and then developed as the online tool.
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Affiliation(s)
- Lei Liu
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital
| | - Shangdong Qin
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning
| | - Kongying Lin
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou
| | - Qingguo Xu
- Organ Transplantation Center, The Institute of Transplantation Science, The Affiliated Hospital of Qingdao University
| | - Yuan Yang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital
| | - Jinzhen Cai
- Organ Transplantation Center, The Institute of Transplantation Science, The Affiliated Hospital of Qingdao University
| | - Yongyi Zeng
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou
| | - Shengxian Yuan
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital
| | - Bangde Xiang
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning
| | - Wan Yee Lau
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital
- Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR
| | - Weiping Zhou
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital
- Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education
- Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai, People’s Republic of China
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20
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Fares S, Wehrle CJ, Hong H, Sun K, Jiao C, Zhang M, Gross A, Allkushi E, Uysal M, Kamath S, Ma WW, Modaresi Esfeh J, Linganna MW, Khalil M, Pita A, Kim J, Walsh RM, Miller C, Hashimoto K, Schlegel A, Kwon DCH, Aucejo F. Emerging and Clinically Accepted Biomarkers for Hepatocellular Carcinoma. Cancers (Basel) 2024; 16:1453. [PMID: 38672535 PMCID: PMC11047909 DOI: 10.3390/cancers16081453] [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: 02/21/2024] [Revised: 04/03/2024] [Accepted: 04/08/2024] [Indexed: 04/28/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death and the sixth most diagnosed malignancy worldwide. Serum alpha-fetoprotein (AFP) is the traditional, ubiquitous biomarker for HCC. However, there has been an increasing call for the use of multiple biomarkers to optimize care for these patients. AFP, AFP-L3, and prothrombin induced by vitamin K absence II (DCP) have described clinical utility for HCC, but unfortunately, they also have well established and significant limitations. Circulating tumor DNA (ctDNA), genomic glycosylation, and even totally non-invasive salivary metabolomics and/or micro-RNAS demonstrate great promise for early detection and long-term surveillance, but still require large-scale prospective validation to definitively validate their clinical validity. This review aims to provide an update on clinically available and emerging biomarkers for HCC, focusing on their respective clinical strengths and weaknesses.
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Affiliation(s)
- Sami Fares
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Chase J. Wehrle
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Hanna Hong
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Keyue Sun
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Chunbao Jiao
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Mingyi Zhang
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Abby Gross
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Erlind Allkushi
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Melis Uysal
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Suneel Kamath
- Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.K.); (W.W.M.)
| | - Wen Wee Ma
- Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.K.); (W.W.M.)
| | - Jamak Modaresi Esfeh
- Department of Gastroenterology, Hepatology, and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (J.M.E.); (M.W.L.)
| | - Maureen Whitsett Linganna
- Department of Gastroenterology, Hepatology, and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (J.M.E.); (M.W.L.)
| | - Mazhar Khalil
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Alejandro Pita
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Jaekeun Kim
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - R. Matthew Walsh
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Charles Miller
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Koji Hashimoto
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Andrea Schlegel
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - David Choon Hyuck Kwon
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Federico Aucejo
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
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Battistella S, Grasso M, Catanzaro E, D’Arcangelo F, Corrà G, Germani G, Senzolo M, Zanetto A, Ferrarese A, Gambato M, Burra P, Russo FP. Evolution of Liver Transplantation Indications: Expanding Horizons. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:412. [PMID: 38541138 PMCID: PMC10972065 DOI: 10.3390/medicina60030412] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 02/22/2024] [Accepted: 02/26/2024] [Indexed: 01/03/2025]
Abstract
Liver transplantation (LT) has significantly transformed the prognosis of patients with end-stage liver disease and hepatocellular carcinoma (HCC). The traditional epidemiology of liver diseases has undergone a remarkable shift in indications for LT, marked by a decline in viral hepatitis and an increase in metabolic dysfunction-associated steatotic liver disease (MASLD), along with expanded indications for HCC. Recent advancements in surgical techniques, organ preservation and post-transplant patients' management have opened new possibilities for LT. Conditions that were historically considered absolute contraindications have emerged as potential new indications, demonstrating promising results in terms of patient survival. While these expanding indications provide newfound hope, the ethical dilemma of organ scarcity persists. Addressing this requires careful consideration and international collaboration to ensure equitable access to LT. Multidisciplinary approaches and ongoing research efforts are crucial to navigate the evolving landscape of LT. This review aims to offer a current overview of the primary emerging indications for LT, focusing on acute-on-chronic liver failure (ACLF), acute alcoholic hepatitis (AH), intrahepatic and perihilar cholangiocarcinoma (i- and p-CCA), colorectal liver metastasis (CRLM), and neuroendocrine tumor (NET) liver metastases.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Francesco Paolo Russo
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, 35128 Padua, Italy; (S.B.); (E.C.); (F.D.); (G.C.); (G.G.); (M.S.); (A.Z.); (A.F.); (M.G.); (P.B.)
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22
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Liu H, Sethi V, Li X, Xiao Y, Humar A. Liver Transplantation for Hepatocellular Carcinoma: A Narrative Review and A Glimpse into The Future. Semin Liver Dis 2024; 44:79-98. [PMID: 38211621 DOI: 10.1055/a-2242-7543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2024]
Abstract
Liver transplantation (LT) is a highly effective treatment for carefully selected patients with hepatocellular carcinoma (HCC). In this review, we explored the development of LT selection criteria and organ allocation policies, comparing original data to underscore their historical progression into the intricate task of quantitatively estimating pre- and post-LT survivals. We emphasized the role of biomarkers such as serum alpha-fetoprotein, Des-gamma-carboxy-prothrombin, circulating tumor cells, and circulating tumor DNA in predicting patient outcomes. Additionally, we examined the transplant-associated survival benefits and the difficulties in accurately calculating these benefits. We also reviewed recent advancements in targeted therapy and checkpoint inhibitors for advanced, inoperable HCC and projected their integration into LT for HCC. We further discussed the growing use of living donor liver transplants in the United States and compared its outcomes with those of deceased donor liver transplants. Furthermore, we examined the progress in machine perfusion techniques, which have shown potential in improving patient outcomes and enlarging the donor pool. These advancements present opportunities to enhance LT patient survivals, refine selection criteria, establish new priority metrics, develop innovative bridging and downstaging strategies, and formulate redesigned LT strategies for HCC treatments.
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Affiliation(s)
- Hao Liu
- Department of Surgery, Starzl Transplant Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Vrishketan Sethi
- Department of Surgery, Starzl Transplant Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Xingjie Li
- Division of Transplant Surgery, Department of Surgery, Mayo Clinic Arizona, Phoenix, Arizona
| | - Yao Xiao
- Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Abhinav Humar
- Department of Surgery, Starzl Transplant Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
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23
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Loosen SH, Leyh C, Neumann UP, Bock H, Weigel C, Luedde T, Roderburg C. Liver transplantation meets gastrointestinal cancer. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2024; 62:62-72. [PMID: 38195110 DOI: 10.1055/a-2226-0123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2024]
Abstract
Liver transplantation (LT) has emerged as a standard of care for patients with end-stage liver disease, providing a life-saving intervention for patients with severely compromised liver function in both the acute and chronic setting. While LT has also become a routine procedure for early-stage hepatocellular carcinoma (HCC), offering a potential cure by treating both the tumor and the underlying liver disease, its relevance in the context of other malignancies such as cholangiocellular carcinoma (CCA), combined hepatocellular-cholangiocarcinoma (cHCC-CCA) or liver metastases is still the subject of intense debate and no definite recommendations have yet been established. This review summarizes the current therapeutic standards in the context of LT for gastrointestinal malignancies and provides a reflection and outlook on current scientific and clinical developments.
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Affiliation(s)
- Sven H Loosen
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany
| | - Catherine Leyh
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany
| | - Ulf Peter Neumann
- Department of General, Visceral and Transplantation Surgery, University Hospital RWTH Aachen, Aachen, Germany
- Department of Surgery and Transplantation, University Hospital Essen, Essen, Germany
| | - Hans Bock
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany
| | - Christian Weigel
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Tom Luedde
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany
| | - Christoph Roderburg
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany
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24
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Yilma M, Mehta N. Optimal Liver Transplantation Criteria for Hepatocellular Carcinoma. Surg Oncol Clin N Am 2024; 33:133-142. [PMID: 37945139 DOI: 10.1016/j.soc.2023.06.011] [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: 11/12/2023]
Abstract
Liver transplantation continues to be the optimal treatment for hepatocellular carcinoma (HCC). Given the limited organ supply, patient selection for liver transplant must carefully balance tumor progression with risk of recurrence posttransplant. There are several pretransplant selection criteria that incorporate biomarkers as well as imaging modality to risk-stratify patients as we continue to look for the optimal transplant cutoff for patients with HCC, which should be transplant-center specific, and account for organ availability and dynamic response to locoregional therapy.
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Affiliation(s)
- Mignote Yilma
- Department of Surgery, University of California San Francisco, 513 Parnassus Avenue, S-321, San Francisco, CA 94143, USA; National Clinician Scholars Program, University of California San Francisco, 513 Parnassus Avenue, S-321, San Francisco, CA 94143, USA. https://twitter.com/mignoteyilmaMD
| | - Neil Mehta
- Department of Medicine, University of California San Francisco, Connie Frank Transplant Center, 400 Parnassus Avenue 7th Floor, San Francisco, CA 94143, USA.
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25
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Ferrarese A, Bucci M, Zanetto A, Senzolo M, Germani G, Gambato M, Russo FP, Burra P. Prognostic models in end stage liver disease. Best Pract Res Clin Gastroenterol 2023; 67:101866. [PMID: 38103926 DOI: 10.1016/j.bpg.2023.101866] [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: 07/30/2023] [Revised: 08/13/2023] [Accepted: 08/18/2023] [Indexed: 12/19/2023]
Abstract
Cirrhosis is a major cause of death worldwide, and is associated with significant health care costs. Even if milestones have been recently reached in understanding and managing end-stage liver disease (ESLD), the disease course remains somewhat difficult to prognosticate. These difficulties have already been acknowledged already in the past, when scores instead of single parameters have been proposed as valuable tools for short-term prognosis. These standard scores, like Child Turcotte Pugh (CTP) and model for end-stage liver disease (MELD) score, relying on biochemical and clinical parameters, are still widely used in clinical practice to predict short- and medium-term prognosis. The MELD score, which remains an accurate, easy-to-use, objective predictive score, has received significant modifications over time, in order to improve its performance especially in the liver transplant (LT) setting, where it is widely used as prioritization tool. Although many attempts to improve prognostic accuracy have failed because of lack of replicability or poor benefit with the comparator (often the MELD score or its variants), few scores have been recently proposed and validated especially for subgroups of patients with ESLD, as those with acute-on-chronic liver failure. Artificial intelligence will probably help hepatologists in the near future to fill the current gaps in predicting disease course and long-term prognosis of such patients.
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Affiliation(s)
- A Ferrarese
- Gastroenterology and Multivisceral Transplant Unit, Padua University Hospital, 2, Giustiniani Street, 35122, Padua, Italy
| | - M Bucci
- Gastroenterology and Multivisceral Transplant Unit, Padua University Hospital, 2, Giustiniani Street, 35122, Padua, Italy
| | - A Zanetto
- Gastroenterology and Multivisceral Transplant Unit, Padua University Hospital, 2, Giustiniani Street, 35122, Padua, Italy
| | - M Senzolo
- Gastroenterology and Multivisceral Transplant Unit, Padua University Hospital, 2, Giustiniani Street, 35122, Padua, Italy
| | - G Germani
- Gastroenterology and Multivisceral Transplant Unit, Padua University Hospital, 2, Giustiniani Street, 35122, Padua, Italy
| | - M Gambato
- Gastroenterology and Multivisceral Transplant Unit, Padua University Hospital, 2, Giustiniani Street, 35122, Padua, Italy
| | - F P Russo
- Gastroenterology and Multivisceral Transplant Unit, Padua University Hospital, 2, Giustiniani Street, 35122, Padua, Italy
| | - P Burra
- Gastroenterology and Multivisceral Transplant Unit, Padua University Hospital, 2, Giustiniani Street, 35122, Padua, Italy.
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26
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Kim DG, Yim SH, Min EK, Choi MC, Joo DJ, Kim MS, Lee JG. Cumulative exposure to tacrolimus during early period after liver transplantation does not affect the recurrence of hepatocellular carcinoma. Sci Rep 2023; 13:20236. [PMID: 37981643 PMCID: PMC10658176 DOI: 10.1038/s41598-023-46803-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 11/05/2023] [Indexed: 11/21/2023] Open
Abstract
The clinical effects of tacrolimus (TAC) exposure on hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) remain unclear. In this retrospective single centric study, 512 patients who underwent LT for HCC were divided into four groups according to cumulative exposure to tacrolimus (CET) during 3 months after LT: conventional (n = 218), aggressive minimization (n = 32), minimization (n = 161), and high exposure (n = 101). Impact of CET on HCC recurrence and death were analyzed. Compared with the conventional group, the other three CET groups showed a similar risk of HCC recurrence. The aggressive minimization group showed a higher risk [hazard ratio (HR) 5.64, P < 0.001] and the high exposure group showed a marginal risk (HR 1.67, P = 0.081) of overall death compared to the conventional group. CET during 3 months was not associated with HCC recurrence in the matched cohort and various subgroups. TAC minimization is not effective to prevent HCC recurrence but could result in higher mortality in LT recipients.
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Affiliation(s)
- Deok-Gie Kim
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea
| | - Seung Hyuk Yim
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea
| | - Eun-Ki Min
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea
| | - Mun Chae Choi
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea
| | - Dong Jin Joo
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea
| | - Myoung Soo Kim
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea
| | - Jae Geun Lee
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea.
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27
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Kim DG, Yim SH, Min EK, Choi MC, Kim MS, Joo DJ, Lee JG. Effect of statins on the recurrence of hepatocellular carcinoma after liver transplantation: An illusion revealed by exposure density sampling. Liver Int 2023; 43:2017-2025. [PMID: 37365992 DOI: 10.1111/liv.15653] [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: 03/06/2023] [Revised: 05/09/2023] [Accepted: 06/11/2023] [Indexed: 06/28/2023]
Abstract
BACKGROUND Statins have been reported to reduce overall death and hepatocellular carcinoma (HCC) recurrence in liver transplantation (LT) recipients. However, previous retrospective studies have significant flaws in immortal time bias. METHODS Using data from 658 patients who received LT for HCC, we matched 140 statin users with statin nonusers in a 1:2 ratio at the time of the first statin administration after LT using the exposure density sampling (EDS). The propensity score, calculated using baseline variables (including explant pathology), was used for EDS to equilibrate both groups. HCC recurrence and overall death were compared after adjusting for information at the time of sampling. RESULTS Among statin users, the median time to statin start was 219 (IQR 98-570) days, and intensity of statins was mainly moderate (87.1%). Statin users and nonusers sampled using EDS showed well-balanced baseline characteristics, including detailed tumour pathology, and similar HCC recurrence with cumulative incidences of 11.3% and 11.8% at 5 years, respectively (p = .861). In multivariate Cox models (HR 1.04, p = .918) and subgroup analyses, statins did not affect HCC recurrence. Conversely, statin users showed a significantly lower risk of overall death than nonusers (HR 0.28, p < .001). There was no difference in the type and intensity of statin usage between statin users who experienced HCC recurrence and those who did not. CONCLUSION Upon controlling immortal time bias by EDS, statins did not affect HCC recurrence but reduced mortality after LT. Statin usage is encouraged for survival benefits but not for preventing HCC recurrence in LT recipients.
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Affiliation(s)
- Deok-Gie Kim
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, South Korea
| | - Seung Hyuk Yim
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, South Korea
| | - Eun-Ki Min
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, South Korea
| | - Mun Chae Choi
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, South Korea
| | - Myoung Soo Kim
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, South Korea
| | - Dong Jin Joo
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, South Korea
| | - Jae Geun Lee
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, South Korea
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28
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Cuadrado A, Fortea JI, Rodríguez-Lope C, Puente Á, Fernández-Vilchez V, Echavarria VJ, Castillo Suescun FJ, Fernández R, Echeverri JA, Achalandabaso M, Toledo E, Pellón R, Rodríguez Sanjuan JC, Crespo J, Fábrega E. Risk of Recurrence of Hepatocarcinoma after Liver Transplantation: Performance of Recurrence Predictive Models in a Cohort of Transplant Patients. J Clin Med 2023; 12:5457. [PMID: 37685524 PMCID: PMC10488177 DOI: 10.3390/jcm12175457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 08/09/2023] [Accepted: 08/20/2023] [Indexed: 09/10/2023] Open
Abstract
Liver transplantation (LT) is a curative treatment for early-stage hepatocellular carcinoma (HCC) unsuitable for surgical resection. However, tumor recurrence (TR) rates range from 8% to 20% despite strict selection criteria. The validation of new prognostic tools, such as pre-MORAL or RETREAT risks, is necessary to improve recurrence prediction. A retrospective study was conducted at Marqués de Valdecilla University Hospital in Cantabria, Spain, between 2010 and 2019 to determine the rate of TR in LT patients and identify associated factors. Patients with liver-kidney transplantation, re-transplantation, HIV infection, survival less than 90 days, or incidental HCC were excluded. Data on demographic, liver disease-related, LT, and tumor-related variables, as well as follow-up records, including TR and death, were collected. TR was analyzed using the Log-Rank test, and a multivariate Cox regression analysis was performed. The study was approved by the IRB of Cantabria. TR occurred in 13.6% of LT patients (95% CI = 7.3-23.9), primarily as extrahepatic recurrence (67%) within the first 5 years (75%). Increased TR was significantly associated with higher Body Mass Index (BMI) (HR = 1.3 [95% CI = 1.1-1.5]), vascular micro-invasion (HR = 8.8 [1.6-48.0]), and medium (HR = 20.4 [3.0-140.4]) and high pre-MORAL risk (HR = 30.2 [1.6-568.6]). TR also showed a significant correlation with increased mortality. Conclusions: LT for HCC results in a 13.6% rate of tumor recurrence. Factors such as BMI, vascular micro-invasion, and medium/high pre-MORAL risk are strongly associated with TR following LT.
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Affiliation(s)
- Antonio Cuadrado
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla University Hospital, 39011 Santander, Spain
| | - José Ignacio Fortea
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla University Hospital, 39011 Santander, Spain
| | - Carlos Rodríguez-Lope
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla University Hospital, 39011 Santander, Spain
| | - Ángela Puente
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla University Hospital, 39011 Santander, Spain
| | - Vanesa Fernández-Vilchez
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla University Hospital, 39011 Santander, Spain
| | - Victor Jose Echavarria
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla University Hospital, 39011 Santander, Spain
| | | | - Roberto Fernández
- General Surgery Service, Marqués de Valdecilla University Hospital, 39008 Santander, Spain
| | - Juan Andrés Echeverri
- General Surgery Service, Marqués de Valdecilla University Hospital, 39008 Santander, Spain
| | - Mar Achalandabaso
- General Surgery Service, Marqués de Valdecilla University Hospital, 39008 Santander, Spain
| | - Enrique Toledo
- General Surgery Service, Marqués de Valdecilla University Hospital, 39008 Santander, Spain
| | - Raúl Pellón
- Radiology Service, Marqués de Valdecilla University Hospital, 39008 Santander, Spain
| | | | - Javier Crespo
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla University Hospital, 39011 Santander, Spain
| | - Emilio Fábrega
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla University Hospital, 39011 Santander, Spain
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Liang Y, Wang Z, Peng Y, Dai Z, Lai C, Qiu Y, Yao Y, Shi Y, Shang J, Huang X. Development of ensemble learning models for prognosis of hepatocellular carcinoma patients underwent postoperative adjuvant transarterial chemoembolization. Front Oncol 2023; 13:1169102. [PMID: 37305570 PMCID: PMC10254793 DOI: 10.3389/fonc.2023.1169102] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Accepted: 05/09/2023] [Indexed: 06/13/2023] Open
Abstract
Background Postoperative adjuvant transarterial chemoembolization (PA-TACE) has been increasing widely used to improve the prognosis of hepatocellular carcinoma (HCC) patients. However, clinical outcomes vary from patient to patient, which calls for individualized prognostic prediction and early management. Methods A total of 274 HCC patients who underwent PA-TACE were enrolled in this study. The prediction performance of five machine learning models was compared and the prognostic variables of postoperative outcomes were identified. Results Compared with other machine learning models, the risk prediction model based on ensemble learning strategies, including Boosting, Bagging, and Stacking algorithms, presented better prediction performance for overall mortality and HCC recurrence. Moreover, the results showed that the Stacking algorithm had relatively low time consumption, good discriminative ability, and the best prediction performance. In addition, according to time-dependent ROC analysis, the ensemble learning strategies were found to perform well in predicting both OS and RFS for the patients. Our study also found that BCLC Stage, hsCRP/ALB and frequency of PA-TACE were relatively important variables in both overall mortality and recurrence, while MVI contributed more to the recurrence of the patients. Conclusion Among the five machine learning models, the ensemble learning strategies, especially the Stacking algorithm, could better predict the prognosis of HCC patients following PA-TACE. Machine learning models could also help clinicians identify the important prognostic factors that are clinically useful in individualized patient monitoring and management.
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Affiliation(s)
- Yuxin Liang
- Liver Transplantation Center and Hepatobiliary and Pancreatic Surgery, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Department of Hepatobiliary-Pancreatic Surgery, Cell Transplantation Center, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Zirui Wang
- School of Computer Science and Engineering, University of Electronic Science and Technology of China, Chengdu, China
| | - Yujiao Peng
- Liver Transplantation Center and Hepatobiliary and Pancreatic Surgery, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Zonglin Dai
- Liver Transplantation Center and Hepatobiliary and Pancreatic Surgery, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Department of Hepatobiliary-Pancreatic Surgery, Cell Transplantation Center, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Chunyou Lai
- Liver Transplantation Center and Hepatobiliary and Pancreatic Surgery, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Department of Hepatobiliary-Pancreatic Surgery, Cell Transplantation Center, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Yuqin Qiu
- Liver Transplantation Center and Hepatobiliary and Pancreatic Surgery, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yutong Yao
- Liver Transplantation Center and Hepatobiliary and Pancreatic Surgery, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Department of Hepatobiliary-Pancreatic Surgery, Cell Transplantation Center, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Ying Shi
- Liver Transplantation Center and Hepatobiliary and Pancreatic Surgery, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Department of Hepatobiliary-Pancreatic Surgery, Cell Transplantation Center, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Jin Shang
- Liver Transplantation Center and Hepatobiliary and Pancreatic Surgery, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Department of Hepatobiliary-Pancreatic Surgery, Cell Transplantation Center, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Xiaolun Huang
- Liver Transplantation Center and Hepatobiliary and Pancreatic Surgery, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Department of Hepatobiliary-Pancreatic Surgery, Cell Transplantation Center, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
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30
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Li WF, Liu YW, Wang CC, Yong CC, Lin CC, Yen YH. Radiographic tumor burden score is useful for stratifying the overall survival of hepatocellular carcinoma patients undergoing resection at different Barcelona Clinic Liver Cancer stages. Langenbecks Arch Surg 2023; 408:169. [PMID: 37121930 DOI: 10.1007/s00423-023-02869-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 03/24/2023] [Indexed: 05/02/2023]
Abstract
PURPOSE The Barcelona Clinic Liver Cancer (BCLC) staging system has been recommended for prognostic prediction. However, prognosis is variable at different BCLC stages. We aimed to evaluate whether the radiographic tumor burden score (TBS) could be used to stratify prognosis in different BCLC stages. METHODS Hepatocellular carcinoma (HCC) patients undergoing liver resection (LR) at BCLC-0, -A, or -B stage in our institution in 2007-2018 were divided into derivation and validation cohorts. Overall survival (OS) was analyzed according to the TBS and BCLC stage. TBS cutoff values for OS were determined with X-tile. RESULTS Of the 749 patients in the derivation cohort, 138 (18.4%) had BCLC-0, 542 (72.3%) BCLC-A, and 69 (9.2%) BCLC-B HCC; 76 (10.1%) had a high TBS (> 7.9), 477 (63.7%) a medium TBS (2.6-7.9), and 196 (26.2%) a low TBS (< 2.6). OS worsened progressively with increasing TBS in the cohort (p < 0.001) and in BCLC-A (p = 0.04) and BCLC-B (p = 0.002) stages. Multivariate analysis showed that the TBS was associated with OS of patients with BCLC-A (medium vs. low TBS: hazard ratio [HR] = 2.390, 95% CI = 1.024-5.581, p = 0.04; high vs. low TBS: HR = 3.885, 95% CI = 1.443-10.456, p = 0.007) and BCLC-B (high vs. medium TBS: HR = 2.542, 95% CI = 1.077-6.002, p = 0.033) HCC. The TBS could also be used to stratify the OS of patients in the validation cohort (p < 0.001). CONCLUSION The TBS could be used to stratify the OS of the entire cohort and BCLC stages A and B of HCC patients undergoing LR.
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Affiliation(s)
- Wei-Feng Li
- Liver Transplantation Center and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, 123 Ta Pei Road, Kaohsiung, Taiwan
| | - Yueh-Wei Liu
- Liver Transplantation Center and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, 123 Ta Pei Road, Kaohsiung, Taiwan
| | - Chih-Chi Wang
- Liver Transplantation Center and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, 123 Ta Pei Road, Kaohsiung, Taiwan.
| | - Chee-Chien Yong
- Liver Transplantation Center and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, 123 Ta Pei Road, Kaohsiung, Taiwan
| | - Chih-Che Lin
- Liver Transplantation Center and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, 123 Ta Pei Road, Kaohsiung, Taiwan
| | - Yi-Hao Yen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan.
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Nishio T, Ito T, Hata K, Taura K, Hatano E. Current status of liver transplantation for non-B non-C liver cirrhosis and hepatocellular carcinoma. Ann Gastroenterol Surg 2023; 7:42-52. [PMID: 36643372 PMCID: PMC9831911 DOI: 10.1002/ags3.12612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Accepted: 08/05/2022] [Indexed: 01/18/2023] Open
Abstract
Recently, non-B non-C chronic liver diseases, including alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), have markedly increased worldwide. Liver transplantation (LT) is an effective curative therapy for hepatocellular carcinoma (HCC) as well as decompensated liver cirrhosis. In Japan, where the source of liver grafts is strongly dependent on living donors, efforts have been made to unify the indications for eligibility of HCC patients for LT, leading to the development of 5-5-500 criteria. Along with the expansion of eligibility for LT, the current changing trends in underlying liver diseases of LT recipients, which are related to the rising tide of non-B non-C cirrhosis and HCC, are highlighting the importance of peri-transplant management of patients with various comorbidities. The post-LT prognosis of patients with ALD is significantly affected by de novo malignancies and metabolic syndrome-related complications as well as posttransplant alcohol relapse. NAFLD/NASH patients often suffer from obesity, type 2 diabetes mellitus, and other metabolic syndrome-related disorders, and nonneoplastic factors such as cardiovascular events and recurrence of NAFLD/NASH have a significant impact on post-LT outcomes. Patient management in the peri-transplant period as well as risk assessment for LT are key to improving post-LT outcomes in the era of a growing number of cases of LT for non-B non-C liver diseases.
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Affiliation(s)
- Takahiro Nishio
- Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Takashi Ito
- Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Koichiro Hata
- Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Kojiro Taura
- Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Etsuro Hatano
- Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
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Sehjal J, Sharples LD, Keogh RH, Walker K, Prachalias A, Heaton N, Ivanics T, van der Meulen J, Wallace D. Time-varying Comparison of All-cause Mortality After Liver Transplantation Between Recipients With and Without Hepatocellular Carcinoma: A Population-based Cohort Study Using the United Kingdom Liver Transplant Registry. Transplantation 2022; 106:e464-e475. [PMID: 36017919 PMCID: PMC9592162 DOI: 10.1097/tp.0000000000004282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Accurately identifying time-varying differences in the hazard of all-cause mortality after liver transplantation (LT) between recipients with and without hepatocellular carcinoma (HCC) may inform patient selection and organ allocation policies as well as post-LT surveillance protocols. METHODS A UK population-based study was carried out using 9586 LT recipients. The time-varying association between HCC and post-LT all-cause mortality was estimated using an adjusted flexible parametric model (FPM) and expressed as hazard ratios (HRs). Differences in this association by transplant year were then investigated. Non-cancer-specific mortality was compared between HCC and non-HCC recipients using an adjusted subdistribution hazard model. RESULTS The HR comparing HCC recipients with non-HCC recipients was below one immediately after LT (1-mo HR = 0.76; 95% confidence interval [CI], 0.59-0.99; P = 0.044). The HR then increased sharply to a maximum at 1.3 y (HR = 2.07; 95% CI, 1.70-2.52; P < 0.001) before decreasing. The hazard of death was significantly higher in HCC recipients than in non-HCC recipients between 4 mo and 7.4 y post-LT. There were no notable differences in the association between HCC and the post-LT hazard of death by transplant year. The estimated non-cancer-specific subdistribution HR for HCC was 0.93 (95% CI, 0.80-1.09; P = 0.390) and not found to vary over time. CONCLUSIONS FPMs can provide a more precise comparison of post-LT hazards of mortality between HCC and non-HCC patients. The results provide further evidence that some HCC patients have extra-hepatic spread at the time of LT, which has implications for optimal post-LT surveillance protocols.
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Affiliation(s)
- Jyoti Sehjal
- Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, United Kingdom
| | - Linda D. Sharples
- Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, United Kingdom
| | - Ruth H. Keogh
- Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, United Kingdom
| | - Kate Walker
- Department of Health Services Research and Policy, London School of Hygiene and Tropical Medicine, London, United Kingdom
| | - Andreas Prachalias
- Institute of Liver Studies, King’s College Hospital NHS Foundation Trust, London, United Kingdom
| | - Nigel Heaton
- Institute of Liver Studies, King’s College Hospital NHS Foundation Trust, London, United Kingdom
| | - Tommy Ivanics
- Division of General Surgery, Multi-organ Transplant Program, University Health Network, University of Toronto, Toronto, ON, Canada
- Department of Surgery, Henry Ford Hospital, Detroit, MI
- Department of Surgical Sciences, Akademiska Sjukhuset, Uppsala University, Uppsala, Sweden
| | - Jan van der Meulen
- Department of Health Services Research and Policy, London School of Hygiene and Tropical Medicine, London, United Kingdom
| | - David Wallace
- Department of Health Services Research and Policy, London School of Hygiene and Tropical Medicine, London, United Kingdom
- Institute of Liver Studies, King’s College Hospital NHS Foundation Trust, London, United Kingdom
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33
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Okumura K, Sogawa H, Samson D, Butler J, Veillette G, John D, Diflo T, Bodin R, Wolf DC, Latifi R, Nishida S. Improving Liver Transplant Outcomes for Hepatitis C Virus Hepatocellular Carcinoma in the Direct-Acting Antiviral Therapy Era. Transplant Proc 2022; 54:1834-1838. [PMID: 35933231 DOI: 10.1016/j.transproceed.2022.03.070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Revised: 01/27/2022] [Accepted: 03/07/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND Direct-acting antiviral (DAA) therapy has transformed the outcomes of liver transplant (LT) with hepatitis C virus (HCV). This study aimed to analyze the effects of DAA treatment for HCV-associated hepatocellular carcinoma (HCC) in LT. METHODS We included patients confirmed with HCC on explant, analyzed data from United Network for Organ Sharing, and defined the pre-DAA era (2012-2013) and DAA era (2014-2016). RESULTS HCV-associated HCC cases totaled 4778 (62%) during the study period. In the DAA era, the median recipient age was older and the median days on the waiting list were longer. For the donor, median age, body mass index, and the rate of HCV significantly increased in the DAA era. In pathology, the median largest tumor size was significantly higher; however, the rate of completed tumor necrosis was significant higher in the DAA era. The 3-year graft/patient survival had significantly improved in the DAA era. In multivariable analysis, the DAA era (hazard ratio, 0.79; 95% confidence interval, 0.68-0.91) had significantly affected the 3-year graft survival. CONCLUSIONS DAA has a significant beneficial effect on LT. In the DAA era, graft survival for HCV-associated HCC has been significantly improving.
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Affiliation(s)
- Kenji Okumura
- Department of Surgery, Westchester Medical Center/New York Medical College, Valhalla, New York
| | - Hiroshi Sogawa
- Department of Surgery, Westchester Medical Center/New York Medical College, Valhalla, New York
| | - David Samson
- Department of Surgery, Westchester Medical Center/New York Medical College, Valhalla, New York
| | - Jonathan Butler
- Department of Surgery, Westchester Medical Center/New York Medical College, Valhalla, New York
| | - Gregory Veillette
- Department of Surgery, Westchester Medical Center/New York Medical College, Valhalla, New York
| | - Devon John
- Department of Surgery, Westchester Medical Center/New York Medical College, Valhalla, New York
| | - Thomas Diflo
- Department of Surgery, Westchester Medical Center/New York Medical College, Valhalla, New York
| | - Roxana Bodin
- Department of Surgery, Westchester Medical Center/New York Medical College, Valhalla, New York
| | - David C Wolf
- Department of Surgery, Westchester Medical Center/New York Medical College, Valhalla, New York
| | - Rifat Latifi
- Department of Surgery, Westchester Medical Center/New York Medical College, Valhalla, New York
| | - Seigo Nishida
- Department of Surgery, Westchester Medical Center/New York Medical College, Valhalla, New York.
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34
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Lai Q, Lesari S, Lerut JP. The impact of biological features for a better prediction of posttransplant hepatocellular cancer recurrence. Curr Opin Organ Transplant 2022; 27:305-311. [PMID: 36354256 DOI: 10.1097/mot.0000000000000955] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
PURPOSE OF REVIEW Morphological criteria (i.e., Milan Criteria) have been considered for a long time to be the best tool for selecting patients with hepatocellular cancer (HCC) waiting for liver transplantation (LT). In the last ten years, a refinement of the selection criteria has been observed, with the introduction of biological tumor characteristics enabling to enlarge the number of potential transplant candidates and to select LT candidates with a lower risk of posttransplant recurrence. RECENT FINDINGS Several biological tumor aspects have been explored and validated in international cohorts to expand the ability to predict patients at high risk for recurrence. Alpha-fetoprotein, radiological response to locoregional treatments, and other more recently proposed markers have been principally explored. Moreover, more complex statistical approaches (i.e., deep learning) have been advocated to explore the nonlinear intercorrelations between the investigated features. SUMMARY The addition of biological aspects to morphology has improved the ability to discriminate among high- and low-risk patients for recurrence. New prognostic algorithms based on the more sophisticated artificial intelligence approach are further improving the capability to select LT candidates with HCC.
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Affiliation(s)
- Quirino Lai
- General Surgery and Organ Transplantation Unit, Department of General and Specialistic Surgery 'Paride Stefanini', Sapienza University of Rome, AOU Policlinico Umberto I of Rome, Rome
| | - Samuele Lesari
- Kidney Transplantation Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Jan P Lerut
- Institute for Experimental and Clinical Research (IREC), Universite catholique Louvain (UCL), Brussels, Belgium
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35
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Salehi O, Vega EA, Kutlu OC, Lunsford K, Freeman R, Ladin K, Alarcon SV, Kazakova V, Conrad C. Poorly differentiated hepatocellular carcinoma: resection is equivalent to transplantation in patients with low liver fibrosis. HPB (Oxford) 2022; 24:1100-1109. [PMID: 34969618 DOI: 10.1016/j.hpb.2021.12.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 11/28/2021] [Accepted: 12/08/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Organ allocation criteria for liver transplantation focus on tumor size and multifocality while tumor differentiation and existing liver damage are omitted. This study analyzes the impact of hepatocellular carcinoma (HCC) grade and liver fibrosis comparing resection (SX) to transplantation (LT). METHODS The National Cancer Database was queried between 2004 and 2016 for solitary HCC meeting Milan criteria undergoing SX vs LT. Two groups were created: low fibrosis (LF) vs high fibrosis (HF) and stratified by grade. Cox multivariable regression models, Kaplan-Meier survival analyses and log-rank tests were performed. RESULTS 1515 patients were identified; 780 had LT and 735 had SX. Median overall survival (mOS) was 39.7 months; LT mOS was 47.9 months vs SX mOS of 34.9 months (P < .001). Multivariate analysis revealed SX, no chemotherapy, longer hospital stays, and age to be associated with worse survival. However, while transplantation conferred survival benefit for well-moderately differentiated tumors, SX vs LT did not impact survival for poorly differentiated HCC in LF patients, independent of tumor size. DISCUSSION HCC differentiation and liver fibrosis, but not size, synergistically determine efficacy of SX vs LT. Therefore, current HCC transplantation criteria should incorporate tumor grade or liver fibrosis for optimal organ allocation.
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Affiliation(s)
- Omid Salehi
- Department of Surgery, St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA, USA
| | - Eduardo A Vega
- Department of Surgery, St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA, USA
| | - Onur C Kutlu
- Department of Surgery, University of Miami Health System, Miller School of Medicine, Miami, FL, USA
| | - Keri Lunsford
- Department of Surgery, Division of Transplant and Hepatobiliary Surgery, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Richard Freeman
- Department of Surgery, St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA, USA
| | - Keren Ladin
- Department of Occupational Therapy and Community Health, Tufts University, Boston, MA, USA
| | - Sylvia V Alarcon
- Department of Medical Oncology, Dana-Farber Cancer Institute at St. Elizabeth's Medical Center, Harvard Medical School, Boston, MA, USA
| | - Vera Kazakova
- Department of Medical Oncology, Dana-Farber Cancer Institute at St. Elizabeth's Medical Center, Harvard Medical School, Boston, MA, USA
| | - Claudius Conrad
- Department of Surgery, St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA, USA.
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36
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Degroote H, Geerts A, Verhelst X, Van Vlierberghe H. Different Models to Predict the Risk of Recurrent Hepatocellular Carcinoma in the Setting of Liver Transplantation. Cancers (Basel) 2022; 14:cancers14122973. [PMID: 35740638 PMCID: PMC9221160 DOI: 10.3390/cancers14122973] [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: 05/17/2022] [Accepted: 06/14/2022] [Indexed: 11/17/2022] Open
Abstract
Simple Summary Liver transplantation is considered the first-choice curative therapy for hepatocellular carcinoma in the early phase of the disease, when surgical resection is not possible. Even when implementing restrictive criteria to select patients for liver transplantation, there is a risk of recurrence in the transplanted liver, influencing the long-term outcome and prognosis. As it is challenging to predict the individual risk of recurrence, there is a need for validated and predictive scoring systems to use to stratify patients before and/or after liver transplantation. Most of the proposed scorings include biological markers for tumour behavior, in addition to the number and size of tumoral nodules. In this review, we discuss different published models to assess the risk of recurrent hepatocellular carcinoma after transplantation. Our aim is to refine clinical decisions about prioritization and listing for liver transplantation, to better inform patients and provide an appropriate surveillance strategy to influence their prognosis. Abstract Liver transplantation is the preferred therapeutic option for non-resectable hepatocellular carcinoma in early-stage disease. Taking into account the limited number of donor organs, liver transplantation is restricted to candidates with long-term outcomes comparable to benign indications on the waiting list. Introducing the morphometric Milan criteria as the gold standard for transplant eligibility reduced the recurrence rate. Even with strict patient selection, there is a risk of recurrence of between 8 and 20% in the transplanted liver, and this is of even greater importance when using more expanded criteria and downstaging protocols. Currently, it remains challenging to predict the risk of recurrence and the related prognosis for individual patients. In this review, the recurrence-risk-assessment scores proposed in the literature are discussed. Currently there is no consensus on the optimal model or the implications of risk stratification in clinical practice. The most recent scorings include additional biological markers for tumour behavior, such as alfa-foetoprotein, and the response to locoregional therapies, in addition to the number and diameter of tumoral nodules. The refinement of the prediction of recurrence is important to better inform patients, guide decisions about prioritization and listing and implement individualized surveillance strategies. In the future, this might also provide indications for tailored immunosuppressive therapy or inclusion in trials for adjuvant treatment.
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37
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Wang J, Chen Z, Wang L, Feng S, Qiu Q, Chen D, Li N, Xiao Y. A new model based inflammatory index and tumor burden score (TBS) to predict the recurrence of hepatocellular carcinoma (HCC) after liver resection. Sci Rep 2022; 12:8670. [PMID: 35606395 PMCID: PMC9126887 DOI: 10.1038/s41598-022-12518-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 05/04/2022] [Indexed: 02/08/2023] Open
Abstract
To establish a model based on inflammation index and tumor burden score (TBS) to predict recurrence of hepatocellular carcinoma (HCC) after liver resection. A retrospective study was performed on 217 patients who diagnosed HCC underwent liver resection at Xiangya Hospital Central South University from June 1, 2017 to June 1, 2019. According to the receiver operating characteristic (ROC) curve, the optimal cut-off value of inflammatory index and the TBS was determined by the Youden index. Prediction performance was compared by the area under the receiver operating characteristic curve (AUC). Cox regression analysis was used to determine the risk factors for the recurrence of HCC after liver resection. According to the independent risk factors of the patients, a prediction model for HCC was established based on inflammation index and tumor burden score (TBS).The prediction performance of the model was compared with single index (TBS group and NLR group) and traditional HCC stage models (TNM stage and BCLC stage). MLR = 0.39, NLR = 2.63, PLR = 134, SII = 428 and TBS = 8.06 are the optimal cut-off values. AUC of SII, PLR, NLR, MLR and TBS were 0.643, 0.642, 0.642, 0.618 and 0.724respectively. MVI (P = 0.005), satellite nodule (P = 0.017), BCLC B-C stage (P = 0.013), NLR > 2.63 (P = 0.013), TBS > 8.06 (P = 0.017) are independent risk factors for the recurrence of HCC after liver resection. According to this study, the optimal inflammatory index NLR combined with TBS was obtained. The AUC of NLR-TBS model was 0.762, not only better than NLR group (AUC = 0.630) and TBS group (AUC = 0.671), also better than traditional BCLC (AUC = 0.620) and TNM (AUC = 0.587) stage models. Interestingly, we found that NLR and TBS should be good prognostic factor for recurrence of HCC after liver resection. The NLR-TBS model based the best inflammatory index (NLR) and TBS have a better prediction performance and the prediction performance of NLR-TBS model not only better than NLR group and TBS group, but better than BCLC and TNM stage models.
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Affiliation(s)
- Jianhua Wang
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Zeguo Chen
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Liheng Wang
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Sijia Feng
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Qixuan Qiu
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Dongdong Chen
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Nianfeng Li
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China.
| | - Yao Xiao
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China.
- International Joint Research Center of Minimally Invasive Endoscopic Technology Equipment and Standards, Changsha, 410008, China.
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38
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Seehofer D, Petrowsky H, Schneeberger S, Vibert E, Ricke J, Sapisochin G, Nault JC, Berg T. Patient Selection for Downstaging of Hepatocellular Carcinoma Prior to Liver Transplantation—Adjusting the Odds? Transpl Int 2022; 35:10333. [PMID: 35529597 PMCID: PMC9069348 DOI: 10.3389/ti.2022.10333] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 02/22/2022] [Indexed: 11/30/2022]
Abstract
Background and Aims: Morphometric features such as the Milan criteria serve as standard criteria for liver transplantation (LT) in patients with hepatocellular carcinoma (HCC). Since it has been recognized that these criteria are too restrictive and do not adequately display the tumor biology, additional selection parameters are emerging. Methods: Concise review of the current literature on patient selection for downstaging and LT for HCC outside the Milan criteria. Results: The major task in patients outside the Milan criteria is the need for higher granularity with patient selection, since the benefit through LT is not uniform. The recent literature clearly shows that beneath tumor size and number, additional selection parameters are useful in the process of patient selection for and during downstaging. For initial patient selection, the alpha fetoprotein (AFP) level adds additional information to the size and number of HCC nodules concerning the chance of successful downstaging and LT. This effect is quantifiable using newer selection tools like the WE (West-Eastern) downstaging criteria or the Metroticket 2.0 criteria. Also an initial PET-scan and/or tumor biopsy can be helpful, especially in the high risk group of patients outside the University of California San Francisco (UCSF) criteria. After this entry selection, the clinical course during downstaging procedures concerning the tumor and the AFP response is of paramount importance and serves as an additional final selection tool. Conclusion: Selection criteria for liver transplantation in HCC patients are becoming more and more sophisticated, but are still imperfect. The implementation of molecular knowledge will hopefully support a more specific risk prediction for HCC patients in the future, but do not provide a profound basis for clinical decision-making at present.
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Affiliation(s)
- Daniel Seehofer
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital, Leipzig, Germany
- *Correspondence: Daniel Seehofer,
| | - Henrik Petrowsky
- Swiss HPB and Transplantation Center, Department of Surgery and Transplantation, University Hospital Zürich, Zurich, Switzerland
| | - Stefan Schneeberger
- Department of Visceral, Transplantation and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Eric Vibert
- Centre Hépato-Biliaire, Hôpital Paul Brousse, Villejuif, France
| | - Jens Ricke
- Department of Radiology, LMU Munich, Munich, Germany
| | - Gonzalo Sapisochin
- Ajmera Transplant Program and HPB Surgical Oncology, Department of Surgery, Toronto General Hospital, University of Toronto, Toronto, ON, Canada
| | - Jean-Charles Nault
- Service d’Hépatologie, Hôpital Avicenne, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Université Paris Nord, Paris, France
- INSERM UMR 1138 Functional Genomics of Solid Tumors Laboratory, Paris, France
| | - Thomas Berg
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
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39
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Ivanics T, Nelson W, Patel MS, Claasen MPAW, Lau L, Gorgen A, Abreu P, Goldenberg A, Erdman L, Sapisochin G. The Toronto Postliver Transplantation Hepatocellular Carcinoma Recurrence Calculator: A Machine Learning Approach. Liver Transpl 2022; 28:593-602. [PMID: 34626159 DOI: 10.1002/lt.26332] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 09/13/2021] [Accepted: 09/23/2021] [Indexed: 01/02/2023]
Abstract
Liver transplantation (LT) listing criteria for hepatocellular carcinoma (HCC) remain controversial. To optimize the utility of limited donor organs, this study aims to leverage machine learning to develop an accurate posttransplantation HCC recurrence prediction calculator. Patients with HCC listed for LT from 2000 to 2016 were identified, with 739 patients who underwent LT used for modeling. Data included serial imaging, alpha-fetoprotein (AFP), locoregional therapies, treatment response, and posttransplantation outcomes. We compared the CoxNet (regularized Cox regression), survival random forest, survival support vector machine, and DeepSurv machine learning algorithms via the mean cross-validated concordance index. We validated the selected CoxNet model by comparing it with other currently available recurrence risk algorithms on a held-out test set (AFP, Model of Recurrence After Liver Transplant [MORAL], and Hazard Associated with liver Transplantation for Hepatocellular Carcinoma [HALT-HCC score]). The developed CoxNet-based recurrence prediction model showed a satisfying overall concordance score of 0.75 (95% confidence interval [CI], 0.64-0.84). In comparison, the recalibrated risk algorithms' concordance scores were as follows: AFP score 0.64 (outperformed by the CoxNet model, 1-sided 95% CI, >0.01; P = 0.04) and MORAL score 0.64 (outperformed by the CoxNet model 1-sided 95% CI, >0.02; P = 0.03). The recalibrated HALT-HCC score performed well with a concordance of 0.72 (95% CI, 0.63-0.81) and was not significantly outperformed (1-sided 95% CI, ≥0.05; P = 0.29). Developing a comprehensive posttransplantation HCC recurrence risk calculator using machine learning is feasible and can yield higher accuracy than other available risk scores. Further research is needed to confirm the utility of machine learning in this setting.
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Affiliation(s)
- Tommy Ivanics
- Multi-Organ Transplant Program, Division of General Surgery, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada.,Department of Surgery, Henry Ford Hospital, Detroit, MI.,Department of Surgical Sciences, Uppsala University, Akademiska Sjukhuset, Uppsala, Sweden
| | - Walter Nelson
- Centre for Data Science and Digital Health, Hamilton Health Sciences, Hamilton, ON, Canada.,Department of Statistical Sciences, University of Toronto, Toronto, ON, Canada
| | - Madhukar S Patel
- Division of Surgical Transplantation, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX
| | - Marco P A W Claasen
- Multi-Organ Transplant Program, Division of General Surgery, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada.,Department of Surgery, Erasmus MC, University Medical Center Rotterdam, the Netherlands
| | - Lawrence Lau
- Multi-Organ Transplant Program, Division of General Surgery, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Andre Gorgen
- Multi-Organ Transplant Program, Division of General Surgery, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Phillipe Abreu
- Multi-Organ Transplant Program, Division of General Surgery, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Anna Goldenberg
- Centre for Computational Medicine, SickKids Research Institute, University of Toronto, Toronto, ON, Canada
| | - Lauren Erdman
- Centre for Computational Medicine, SickKids Research Institute, University of Toronto, Toronto, ON, Canada.,Center for Computational Medicine, SickKids Research Institute, Toronto, ON, Canada
| | - Gonzalo Sapisochin
- Multi-Organ Transplant Program, Division of General Surgery, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada.,Abdominal Transplant & HPB Surgical Oncology, Toronto General Hospital, University of Toronto, Toronto, ON, Canada
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40
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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: 26] [Impact Index Per Article: 8.7] [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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41
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Role of Pretransplant Treatments for Patients with Hepatocellular Carcinoma Waiting for Liver Transplantation. Cancers (Basel) 2022; 14:cancers14020396. [PMID: 35053558 PMCID: PMC8773674 DOI: 10.3390/cancers14020396] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 01/09/2022] [Accepted: 01/12/2022] [Indexed: 02/01/2023] Open
Abstract
Simple Summary Hepatocellular carcinoma (HCC) is the fifth most common cancer in men worldwide and the second leading cause of cancer death. Liver transplantation (LT) is one of the treatment options for patients with HCC. Recently, there have been many reports of the usefulness of locoregional therapy, such as transarterial chemoembolization and radiofrequency ablation, for HCC as pretreatment before LT. In Western countries, locoregional therapy is used to bridge until transplantation to prevent drop-outs from the waiting list or for downstaging to treat patients with advanced HCC who initially exceed the criteria for LT. With the progress of locoregional therapy, new reports on the effects of bridging and downstaging locoregional therapy as pretransplant treatment are increasing in number. Abstract Recently, there have been many reports of the usefulness of locoregional therapy such as transarterial chemoembolization and radiofrequency ablation for hepatocellular carcinoma (HCC) as pretreatment before liver transplantation (LT). Locoregional therapy is performed with curative intent in Japan, where living donor LT constitutes the majority of LT due to the critical shortage of deceased donors. However, in Western countries, where deceased donor LT is the main procedure, LT is indicated for early-stage HCC regardless of liver functional reserve, and locoregional therapy is used for bridging until transplantation to prevent drop-outs from the waiting list or for downstaging to treat patients with advanced HCC who initially exceed the criteria for LT. There are many reports of the effect of bridging and downstaging locoregional therapy before LT, and its indications and efficacy are becoming clear. Responses to locoregional therapy, such as changes in tumor markers, the avidity of FDG-PET, etc., are considered useful for successful bridging and downstaging. In this review, the effects of bridging and downstaging locoregional therapy as a pretransplant treatment on the results of transplantation are clarified, focusing on recent reports.
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Hu X, Chen R, Wei Q, Xu X. The Landscape Of Alpha Fetoprotein In Hepatocellular Carcinoma: Where Are We? Int J Biol Sci 2022; 18:536-551. [PMID: 35002508 PMCID: PMC8741863 DOI: 10.7150/ijbs.64537] [Citation(s) in RCA: 117] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Accepted: 10/15/2021] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and has been acknowledged as a leading cause of death among cirrhosis patients. Difficulties in early diagnosis and heterogeneity are obstacles to effective treatment, especially for advanced HCC. Liver transplantation (LT) is considered the best therapy for HCC. Although many biomarkers are being proposed, alpha-fetoprotein (AFP), which was identified over 60 years ago, remains the most utilized. Recently, much hope has been placed in the immunogenicity of AFP to develop novel therapies, such as AFP vaccines and AFP-specific adoptive T-cell transfer (ACT). This review summarizes the performance of AFP as a biomarker for HCC diagnosis and prognosis, as well as its correlation with molecular classes. In addition, the role of AFP in LT is also described. Finally, we highlight the mechanism and application prospects of two immune therapies (AFP vaccine and ACT) for HCC. In general, our review points out the prevalence of AFP in HCC, accompanied by some controversies and novel directions for future research.
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Affiliation(s)
- Xin Hu
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.,Zhejiang University Cancer Center, Hangzhou, 310058, China.,Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China
| | - Ronggao Chen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China
| | - Qiang Wei
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Xiao Xu
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.,Zhejiang University Cancer Center, Hangzhou, 310058, China.,Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China.,Institute of Organ Transplantation, Zhejiang University, Hangzhou, 310003, China
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Zhang L, Yang Z, Zhang S, Zhou K, Zhang W, Ling S, Sun R, Tang H, Wen X, Feng X, Song P, Xu X, Xie H, Zheng S. Polyploidy Spectrum Correlates with Immunophenotype and Shapes Hepatocellular Carcinoma Recurrence Following Liver Transplantation. J Inflamm Res 2022; 15:217-233. [PMID: 35046696 PMCID: PMC8760994 DOI: 10.2147/jir.s345681] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 12/16/2021] [Indexed: 12/12/2022] Open
Affiliation(s)
- Liang Zhang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Zhejiang, 310003, People’s Republic of China
| | - Zhentao Yang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Zhejiang, 310003, People’s Republic of China
| | - Shiyu Zhang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Zhejiang, 310003, People’s Republic of China
| | - Ke Zhou
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Zhejiang, 310003, People’s Republic of China
| | - Wu Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital, Hangzhou, Zhejiang, 310004, People’s Republic of China
| | - Sunbin Ling
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Zhejiang, 310003, People’s Republic of China
| | - Ruiqi Sun
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Zhejiang, 310003, People’s Republic of China
| | - Hong Tang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Zhejiang, 310003, People’s Republic of China
| | - Xue Wen
- Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People’s Republic of China
| | - Xiaowen Feng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Zhejiang, 310003, People’s Republic of China
| | - Penghong Song
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Zhejiang, 310003, People’s Republic of China
| | - Xiao Xu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Zhejiang, 310003, People’s Republic of China
| | - Haiyang Xie
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Zhejiang, 310003, People’s Republic of China
- Correspondence: Haiyang Xie; Shusen Zheng School of Medicine, Zhejiang University, 79# Qingchun Road, Hangzhou, Zhejiang, 310000, People’s Republic of ChinaTel/Fax +86 571 87236570; +86 571 87236466 Email ;
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Zhejiang, 310003, People’s Republic of China
- Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital, Hangzhou, Zhejiang, 310004, People’s Republic of China
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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: 72] [Impact Index Per Article: 18.0] [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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Orci LA, Combescure C, Fink M, Oldani G, Compagnon P, Andres A, Berney T, Toso C. Predicting recurrence of hepatocellular carcinoma after liver transplantation using a novel model that incorporates tumor and donor-related factors. Transpl Int 2021; 34:2875-2886. [PMID: 34784081 DOI: 10.1111/tri.14161] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 08/31/2021] [Accepted: 09/03/2021] [Indexed: 01/11/2023]
Abstract
Evidence suggests that liver graft quality impacts on posttransplant recurrence of hepatocellular carcinoma (HCC). As of today, selection criteria only use variables related to tumor characteristics. Within the Scientific Registry of Transplant Recipients, we identified patients with HCC who underwent liver transplantation between 2004 and 2016 (development cohort, n = 10 887). Based on tumor recurrence rates, we fitted a competing-risk regression incorporating tumor- and donor-related factors, and we developed a prognostic score. Results were validated both internally and externally in the Australia and New Zealand Liver Transplant Registry. Total tumor diameter (subhazard ratio [sub-HR] 1.52 [1.28-1.81]), alpha-feto protein (sub-HR 1.27 [1.23-1.32], recipient male gender (sub-HR 1.43 [1.18-1.74]), elevated donor body mass index (sub-HR 1.26 [1.01-1.58]), and shared graft allocation policy (sub-HR 1.20 [1.01-1.43]) were independently associated with tumor recurrence. We next developed the Darlica score (sub-HR 2.72 [2.41-3.08] P < 0.001) that allows identifying risky combinations between a given donor and a given recipient. Results were validated internally (n = 3 629) and externally in the Australia and New Zealand Liver Transplant Registry (n = 370). The current score is based on variables that are readily available at the time of graft offer. It allows identifying hazardous donor-recipient combinations in terms of risk of tumor recurrence and overall survival.
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Affiliation(s)
- Lorenzo A Orci
- Division of Abdominal and Transplantation Surgery, Department of Surgery, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland.,Faculty of Medicine, Hepato-pancreato-biliary Centre, Geneva University Hospitals, Geneva, Switzerland
| | | | - Michael Fink
- Department of Surgery, Austin Health, Medicine Dentistry and Health Sciences, The University of Melbourne, Melbourne, Victoria, Australia
| | - Graziano Oldani
- Division of Abdominal and Transplantation Surgery, Department of Surgery, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland.,Faculty of Medicine, Hepato-pancreato-biliary Centre, Geneva University Hospitals, Geneva, Switzerland
| | - Philippe Compagnon
- Division of Abdominal and Transplantation Surgery, Department of Surgery, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland.,Faculty of Medicine, Hepato-pancreato-biliary Centre, Geneva University Hospitals, Geneva, Switzerland
| | - Axel Andres
- Division of Abdominal and Transplantation Surgery, Department of Surgery, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland.,Faculty of Medicine, Hepato-pancreato-biliary Centre, Geneva University Hospitals, Geneva, Switzerland
| | - Thierry Berney
- Division of Abdominal and Transplantation Surgery, Department of Surgery, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland.,Faculty of Medicine, Hepato-pancreato-biliary Centre, Geneva University Hospitals, Geneva, Switzerland
| | - Christian Toso
- Division of Abdominal and Transplantation Surgery, Department of Surgery, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland.,Faculty of Medicine, Hepato-pancreato-biliary Centre, Geneva University Hospitals, Geneva, Switzerland
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Pelizzaro F, Gambato M, Gringeri E, Vitale A, Cillo U, Farinati F, Burra P, Russo FP. Management of Hepatocellular Carcinoma Recurrence after Liver Transplantation. Cancers (Basel) 2021; 13:4882. [PMID: 34638365 PMCID: PMC8508053 DOI: 10.3390/cancers13194882] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 09/19/2021] [Accepted: 09/24/2021] [Indexed: 02/06/2023] Open
Abstract
Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT), occurring in 10-15% of cases, is a major concern. A lot of work has been done in order to refine the selection of LT candidates with HCC and to improve the outcome of patients with recurrence. Despite this, the prognosis of these patients remains poor, partly due to the several areas of uncertainty in their management. Even if surveillance for HCC recurrence is crucial for early detection, there is currently no evidence to support a specific and cost-effective post-LT surveillance strategy. Concerning preventive measures, consensus on the best immunosuppressive drugs has not been reached and not enough data to support adjuvant therapy are present. Several therapeutic approaches (surgical, locoregional and systemic treatments) are available in case of recurrence, but there are still few data in the post-LT setting. Moreover, the use of immune checkpoint inhibitors is controversial in transplant recipients considered the risk of rejection. In this paper, the available evidence on the management of HCC recurrence after LT is comprehensively reviewed, considering pre- and post-transplant risk stratification, post-transplant surveillance, preventive strategies and treatment options.
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Affiliation(s)
- Filippo Pelizzaro
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (F.P.); (M.G.); (F.F.); (P.B.)
| | - Martina Gambato
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (F.P.); (M.G.); (F.F.); (P.B.)
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy
| | - Enrico Gringeri
- Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (E.G.); (A.V.); (U.C.)
| | - Alessandro Vitale
- Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (E.G.); (A.V.); (U.C.)
| | - Umberto Cillo
- Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (E.G.); (A.V.); (U.C.)
| | - Fabio Farinati
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (F.P.); (M.G.); (F.F.); (P.B.)
| | - Patrizia Burra
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (F.P.); (M.G.); (F.F.); (P.B.)
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy
| | - Francesco Paolo Russo
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (F.P.); (M.G.); (F.F.); (P.B.)
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy
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Claasen MPAW, Ivanics T, Gravely A, Sapisochin G. Prognostic risk scores for liver transplantation: game changers or statistical artworks? Hepatobiliary Surg Nutr 2021; 10:553-557. [PMID: 34430542 DOI: 10.21037/hbsn-21-258] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 07/18/2021] [Indexed: 12/12/2022]
Affiliation(s)
- Marco P A W Claasen
- Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada.,Department of Surgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Tommy Ivanics
- Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada.,Department of Surgery, Henry Ford Hospital, Detroit, MI, USA.,Department of Surgical Sciences, Akademiska Sjukhuset, Uppsala University, Uppsala, Sweden
| | - Annabel Gravely
- Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada
| | - Gonzalo Sapisochin
- Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada.,Division of General Surgery, University Health Network, Toronto, ON, Canada
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Lang SA, Bednarsch J, Czigany Z, Joechle K, Kroh A, Amygdalos I, Strnad P, Bruns T, Heise D, Ulmer F, Neumann UP. Liver transplantation in malignant disease. World J Clin Oncol 2021; 12:623-645. [PMID: 34513597 PMCID: PMC8394155 DOI: 10.5306/wjco.v12.i8.623] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 06/15/2021] [Accepted: 07/23/2021] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation for malignant disease has gained increasing attention as part of transplant oncology. Following the implementation of the Milan criteria, hepatocellular carcinoma (HCC) was the first generally accepted indication for transplantation in patients with cancer. Subsequently, more liberal criteria for HCC have been developed, and research on this topic is still ongoing. The evident success of liver transplantation for HCC has led to the attempt to extend its indication to other malignancies. Regarding perihilar cholangiocarcinoma, more and more evidence supports the use of liver transplantation, especially after neoadjuvant therapy. In addition, some data also show a benefit for selected patients with very early stage intrahepatic cholangiocarcinoma. Hepatic epithelioid hemangioendothelioma is a very rare but nonetheless established indication for liver transplantation in primary liver cancer. In contrast, patients with hepatic angiosarcoma are currently not considered to be optimal candidates. In secondary liver tumors, neuroendocrine cancer liver metastases are an accepted but comparability rare indication for liver transplantation. Recently, some evidence has been published supporting the use of liver transplantation even for colorectal liver metastases. This review summarizes the current evidence for liver transplantation for primary and secondary liver cancer.
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Affiliation(s)
- Sven Arke Lang
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Jan Bednarsch
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Zoltan Czigany
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Katharina Joechle
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Andreas Kroh
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Iakovos Amygdalos
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Pavel Strnad
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Tony Bruns
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Daniel Heise
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Florian Ulmer
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Ulf Peter Neumann
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
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Goldberg D, Mantero A, Newcomb C, Delgado C, Forde KA, Kaplan DE, John B, Nuchovich N, Dominguez B, Emanuel E, Reese PP. Predicting survival after liver transplantation in patients with hepatocellular carcinoma using the LiTES-HCC score. J Hepatol 2021; 74:1398-1406. [PMID: 33453328 PMCID: PMC8137533 DOI: 10.1016/j.jhep.2020.12.021] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 11/24/2020] [Accepted: 12/18/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Liver transplant priority in the US and Europe follows the 'sickest-first' principle. However, for patients with hepatocellular carcinoma (HCC), priority is based on binary tumor criteria to expedite transplant for patients with 'acceptable' post-transplant outcomes. Newer risk scores developed to overcome limitations of these binary criteria are insufficient to be used for waitlist priority as they focus solely on HCC-related pre-transplant variables. We sought to develop a risk score to predict post-transplant survival for patients using HCC- and non-HCC-related variables. METHODS We performed a retrospective cohort study using national registry data on adult deceased-donor liver transplant (DDLT) recipients with HCC from 2/27/02-12/31/18. We fit Cox regression models focused on 5- and 10-year survival to estimate beta coefficients for a risk score using manual variable selection. We then calculated absolute predicted survival time and compared it to available risk scores. RESULTS Among 6,502 adult DDLT recipients with HCC, 11 variables were selected in the final model. The AUCs at 5- and 10-years were: 0.62, 95% CI 0.57-0.67 and 0.65, 95% CI 0.58-0.72, which was not statistically significantly different to the Metroticket and HALT-HCC scores. The LiTES-HCC score was able to discriminate patients based on post-transplant survival among those meeting Milan and UCSF criteria. CONCLUSION We developed and validated a risk score to predict post-transplant survival for patients with HCC. By including HCC- and non-HCC-related variables (e.g., age, chronic kidney disease), this score could allow transplant professionals to prioritize patients with HCC in terms of predicted survival. In the future, this score could be integrated into survival benefit-based models to lead to meaningful improvements in life-years at the population level. LAY SUMMARY We created a risk score to predict how long patients with liver cancer will live if they get a liver transplant. In the future, this could be used to decide which waitlisted patients should get the next transplant.
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Affiliation(s)
- David Goldberg
- Division of Digestive Health and Liver Diseases, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.
| | - Alejandro Mantero
- Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL
| | - Craig Newcomb
- Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
| | - Cindy Delgado
- Division of Digestive Health and Liver Diseases, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL
| | - Kimberly A. Forde
- Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA,Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
| | - David E. Kaplan
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA,Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA
| | - Binu John
- Bruce Carter VA Medica Center, Miami, FL
| | - Nadine Nuchovich
- Division of Digestive Health and Liver Diseases, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL
| | - Barbara Dominguez
- Division of Digestive Health and Liver Diseases, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL
| | - Ezekiel Emanuel
- Department of Medical Ethics and Health Policy, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
| | - Peter P. Reese
- Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA,Renal-Electrolye and Hypertension Division, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
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Vitale A, Scolari F, Bertacco A, Gringeri E, D’Amico F, Bassi D, D’Amico FE, Angeli P, Burra P, Lai Q, Cillo U. Sustained Complete Response after Biological Downstaging in Patients with Hepatocellular Carcinoma: XXL-Like Prioritization for Liver Transplantation or "Wait and See" Strategy? Cancers (Basel) 2021; 13:2406. [PMID: 34067521 PMCID: PMC8156031 DOI: 10.3390/cancers13102406] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 04/22/2021] [Accepted: 05/12/2021] [Indexed: 12/12/2022] Open
Abstract
The XXL trial represents the first prospective validation of "biological downstaging" in liver transplantation (LT) for hepatocellular carcinoma. The aim of this study was to compare the Padua downstaging protocol to the XXL protocol in terms of downstaging failure rates and patient outcome. A total of 191 patients undergoing aggressive surgical downstaging and potentially eligible for LT from 2012 to 2018 at our center were retrospectively selected according to XXL trial criteria. Unlike the XXL trial, patients with a complete response to downstaging did not receive any prioritization for LT. Downstaging failure was defined as stable progressive disease or post-treatment mortality. The statistical method of "matching-adjusted indirect comparison" was used to match the study group to the XXL population. Downstaging failure rate was considerably lower in the study group than in the XXL trial (12% vs. 32%, d value = |0.683|). The survival curves of our LT group (n = 68) overlapped with those of the LT-XXL group (p = 0.846). Survival curves of non-LT candidates with a sustained complete response (n = 64) were similar to those of transplanted patients (p = 0.281). Our study represents a validation of the current Padua and Italian policies of denying rapid prioritization to patients with complete response to downstaging. Such a policy seems to spare organs without worsening patient outcome.
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Affiliation(s)
- Alessandro Vitale
- Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgical, Oncological, and Gastroenterological Sciences, Padua University Hospital, 35128 Padova, Italy; (A.B.); (E.G.); (F.D.); (D.B.); (F.E.D.); (U.C.)
| | - Federica Scolari
- Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgical, Oncological, and Gastroenterological Sciences, Padua University Hospital, 35128 Padova, Italy; (A.B.); (E.G.); (F.D.); (D.B.); (F.E.D.); (U.C.)
| | - Alessandra Bertacco
- Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgical, Oncological, and Gastroenterological Sciences, Padua University Hospital, 35128 Padova, Italy; (A.B.); (E.G.); (F.D.); (D.B.); (F.E.D.); (U.C.)
| | - Enrico Gringeri
- Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgical, Oncological, and Gastroenterological Sciences, Padua University Hospital, 35128 Padova, Italy; (A.B.); (E.G.); (F.D.); (D.B.); (F.E.D.); (U.C.)
| | - Francesco D’Amico
- Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgical, Oncological, and Gastroenterological Sciences, Padua University Hospital, 35128 Padova, Italy; (A.B.); (E.G.); (F.D.); (D.B.); (F.E.D.); (U.C.)
| | - Domenico Bassi
- Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgical, Oncological, and Gastroenterological Sciences, Padua University Hospital, 35128 Padova, Italy; (A.B.); (E.G.); (F.D.); (D.B.); (F.E.D.); (U.C.)
| | - Francesco Enrico D’Amico
- Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgical, Oncological, and Gastroenterological Sciences, Padua University Hospital, 35128 Padova, Italy; (A.B.); (E.G.); (F.D.); (D.B.); (F.E.D.); (U.C.)
| | - Paolo Angeli
- Unit of Internal Medicine and Hepatology, Padua University Hospital, 35128 Padova, Italy;
| | - Patrizia Burra
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, 35128 Padova, Italy;
| | - Quirino Lai
- Liver Transplantation Program, Sapienza University, 00185 Rome, Italy;
| | - Umberto Cillo
- Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgical, Oncological, and Gastroenterological Sciences, Padua University Hospital, 35128 Padova, Italy; (A.B.); (E.G.); (F.D.); (D.B.); (F.E.D.); (U.C.)
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