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  • Review Article
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Liver transplantation for hepatocellular carcinoma: outcomes and novel surgical approaches

Nature Reviews Gastroenterology & Hepatology volume 14, pages 203–217 (2017)Cite this article

Subjects

Key Points

  • Liver transplantation is the best treatment option for patients with hepatocellular carcinoma (HCC), but selection of the best candidates is critical to achieving good results and not misusing a valuable resource

  • Allocation of liver grafts for patients with HCC is complicated and mainly depends on the number of patients on the waiting list and organ availability in each region

  • Surgical techniques to expand the available organ donor pool include living donor liver transplantation, donation after circulatory death and split livers

  • The outcomes for patients with HCC using these surgical techniques are good and therefore might be safely used in this context

  • Expanding the indications for liver transplantation for HCC increases the risk of tumour recurrence; this recurrence might be treated in selected cases to improve patient survival

  • Direct-acting antiviral agents for HCV will probably affect the management of patients with HCC listed for liver transplantation, but its role in this context is still undergoing active research

Abstract

Liver transplantation for hepatocellular carcinoma (HCC) is the best treatment option for patients with early-stage tumours and accounts for ∼20–40% of all liver transplantations performed at most centres worldwide. The Milan criteria are the most common criteria to select patients with HCC for transplantation but they can be seen as too restrictive. Several proposals have been made for a moderate expansion of the criteria, which result in good outcomes but with an increase in the risk of tumour recurrence. In this Review, we provide a comprehensive overview of the outcomes after liver transplantation for HCC, focusing on tumour recurrence in terms of surveillance, prevention and treatment. Additionally, novel surgical techniques have been developed to increase the available pool of organs for liver transplantation (such as living donor liver transplantation, donation after circulatory death and split livers), but the effect of these techniques on patients with HCC is still under debate. Thus, we will describe these techniques and expose the benefits and disadvantages of each surgical approach. Finally, we will comment on the limitations of the current priority policies for liver transplantation and the need to further refine them to better serve the population.

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Figure 1: Enlistment for liver transplantation using a specific priority system according to disease category.
Figure 2: Surgical techniques developed to enlarge the pool of available donor livers.
Figure 3: Sites of tumour recurrence after liver transplantation for hepatocellular carcinoma.
Figure 4: Risk factors for tumour recurrence after liver transplantation.

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References

  1. European Association For The Study Of The Liver & European Organisation For Research And Treatment Of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J. Hepatol. 56, 908–943 (2012).

  2. Bruix, J. & Sherman, M. Management of hepatocellular carcinoma: an update. Hepatology 53, 1020 (2011).

    PubMed  Google Scholar 

  3. Bruix, J. et al. Evidence-based diagnosis, staging, and treatment of patients with hepatocellular carcinoma. Gastroenterology 150, 835–853 (2016).

    PubMed  Google Scholar 

  4. Forner, A., Llovet, J. M. & Bruix, J. Hepatocellular carcinoma. Lancet 379, 1245–1255 (2012).

    PubMed  Google Scholar 

  5. de Lope, C. R., Tremosini, S., Forner, A. & Bruix, J. Management of HCC. J. Hepatol. 56 (Suppl. 1), S75–S87 (2012).

    PubMed  Google Scholar 

  6. El-Serag, H. B., Davila, J. A., Petersen, N. J. & McGlynn, K. A. The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update. Ann. Intern. Med. 139, 817–823 (2003).

    PubMed  Google Scholar 

  7. El-Serag, H. B. & Mason, A. C. Rising incidence of hepatocellular carcinoma in the United States. N. Engl. J. Med. 340, 745–750 (1999).

    CAS  PubMed  Google Scholar 

  8. El-Serag, H. B. & Kanwal, F. Epidemiology of hepatocellular carcinoma in the United States: where are we? Where do we go? Hepatology 60, 1767–1775 (2014).

    PubMed  Google Scholar 

  9. Ferlay, J. et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer 136, E359–E386 (2014).

    PubMed  Google Scholar 

  10. de Villa, V. Liver transplantation for hepatocellular carcinoma in Asia. Oncologist 12, 1321–1331 (2007).

    PubMed  Google Scholar 

  11. Kim, W. R. et al. OPTN/SRTR 2013 Annual Data Report: liver. Am. J. Transplant. 15 (Suppl. 2), 1–28 (2015).

    PubMed  Google Scholar 

  12. Adam, R. et al. Evolution of indications and results of liver transplantation in Europe. A report from the European Liver Transplant Registry (ELTR). J. Hepatol. 57, 675–688 (2012).

    PubMed  Google Scholar 

  13. Wong, R. J., Cheung, R. & Ahmed, A. Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in patients with hepatocellular carcinoma in the U.S.. Hepatology 59, 2188–2195 (2014).

    PubMed  Google Scholar 

  14. Yeh, H., Smoot, E., Schoenfeld, D. A. & Markmann, J. F. Geographic inequity in access to livers for transplantation. Transplantation 91, 479–486 (2011).

    PubMed  PubMed Central  Google Scholar 

  15. Johnson, R. J., Bradbury, L. L., Martin, K. & Neuberger, J. Organ donation and transplantation in the UK-the last decade: a report from the UK national transplant registry. Transplantation 97 (Suppl. 1), S1–S27 (2013).

    Google Scholar 

  16. Freeman, R. B. et al. Liver and intestine transplantation in the United States, 1997–2006. Am. J. Transplant. 8, 958–976 (2008).

    PubMed  Google Scholar 

  17. Northup, P. G. et al. Excess mortality on the liver transplant waiting list: unintended policy consequences and Model for End-Stage Liver Disease (MELD) inflation. Hepatology 61, 285–291 (2014).

    PubMed  Google Scholar 

  18. Roberts, J. P. Transplantation: allocation of liver transplants — a road to consensus. Nat. Rev. Gastroenterol. Hepatol. 12, 615–616 (2015).

    PubMed  Google Scholar 

  19. Bhoori, S. & Mazzaferro, V. Current challenges in liver transplantation for hepatocellular carcinoma. Best Pract. Res. Clin. Gastroenterol. 28, 867–879 (2014).

    PubMed  Google Scholar 

  20. Marsh, J. W. & Dvorchik, I. Liver organ allocation for hepatocellular carcinoma: are we sure? Liver Transpl. 9, 693–696 (2003).

    PubMed  Google Scholar 

  21. Ladner, D. P. et al. Long-term quality of life after liver donation in the adult to adult living donor liver transplantation cohort study (A2ALL). J. Hepatol. 62, 346–353 (2014).

    PubMed  PubMed Central  Google Scholar 

  22. Lee, S.-G. A complete treatment of adult living donor liver transplantation: a review of surgical technique and current challenges to expand indication of patients. Am. J. Transplant. 15, 17–38 (2014).

    PubMed  Google Scholar 

  23. Morioka, D. et al. Outcomes of adult-to-adult living donor liver transplantation: a single institution's experience with 335 consecutive cases. Ann. Surg. 245, 315–325 (2007).

    PubMed  PubMed Central  Google Scholar 

  24. Olthoff, K. M. et al. Outcomes of 385 adult-to-adult living donor liver transplant recipients: a report from the A2ALL Consortium. Ann. Surg. 242, 108 (2005).

    Google Scholar 

  25. Kootstra, G. Statement on non-heart-beating donor programs. Transplant. Proc. 27, 2965 (1995).

    CAS  PubMed  Google Scholar 

  26. Merion, R. M., Pelletier, S. J., Goodrich, N., Englesbe, M. J. & Delmonico, F. L. Donation after cardiac death as a strategy to increase deceased donor liver availability. Ann. Surg. 244, 555–562 (2006).

    PubMed  PubMed Central  Google Scholar 

  27. Casavilla, A. et al. Experience with liver and kidney allografts from non-heart-beating donors. Transplant. Proc. 27, 2898 (1995).

    CAS  PubMed  Google Scholar 

  28. Kootstra, G., Daemen, J. H. & Oomen, A. P. Categories of non-heart-beating donors. Transplant. Proc. 27, 2893–2894 (1995).

    CAS  PubMed  Google Scholar 

  29. Monbaliu, D., Pirenne, J. & Talbot, D. Liver transplantation using donation after cardiac death donors. J. Hepatol. 56, 474–485 (2011).

    PubMed  Google Scholar 

  30. Beecher, H. K. After the “definition of irreversible coma”. N. Engl. J. Med. 281, 1070–1071 (1969).

    CAS  PubMed  Google Scholar 

  31. Renz, J. F. et al. Split-liver transplantation: a review. Am. J. Transplant. 3, 1323–1335 (2003).

    PubMed  Google Scholar 

  32. Vagefi, P. A., Parekh, J., Ascher, N. L., Roberts, J. P. & Freise, C. E. Outcomes with split liver transplantation in 106 recipients: the University of California, San Francisco, experience from 1993 to 2010. Arch. Surg. 146, 1052–1059 (2011).

    PubMed  Google Scholar 

  33. Pichlmayr, R., Ringe, B., Gubernatis, G., Hauss, J. & Bunzendahl, H. [Transplantation of a donor liver to 2 recipients (splitting transplantation)—a new method in the further development of segmental liver transplantation]. Langenbecks Arch. Chir. 373, 127–130 (in German) (1988).

    CAS  PubMed  Google Scholar 

  34. Vagefi, P. A., Parekh, J., Ascher, N. L., Roberts, J. P. & Freise, C. E. Ex vivo split-liver transplantation: the true right/left split. HPB (Oxford) 16, 267–274 (2013).

    Google Scholar 

  35. Emre, S. et al. Safe use of hepatic allografts from donors older than 70 years. Transplantation 62, 62–65 (1996).

    CAS  PubMed  Google Scholar 

  36. McCormack, L., Dutkowski, P., El-Badry, A. M. & Clavien, P.-A. Liver transplantation using fatty livers: always feasible? J. Hepatol. 54, 1055–1062 (2010).

    PubMed  Google Scholar 

  37. Lué, A. et al. How important is donor age in liver transplantation? World J. Gastroenterol. 22, 4966–4976 (2016).

    PubMed  PubMed Central  Google Scholar 

  38. Yao, F. Y. Expanded criteria for liver transplantation in patients with hepatocellular carcinoma. Hepatol. Res. 37 (Suppl. 2), S267–S274 (2007).

    PubMed  Google Scholar 

  39. Yao, F. Y. et al. Liver transplantation for hepatocellular carcinoma: validation of the UCSF-expanded criteria based on preoperative imaging. Am. J. Transplant. 7, 2587–2596 (2007).

    CAS  PubMed  Google Scholar 

  40. Herrero, J. I. et al. Influence of tumor characteristics on the outcome of liver transplantation among patients with liver cirrhosis and hepatocellular carcinoma. Liver Transpl. 7, 631–636 (2001).

    CAS  PubMed  Google Scholar 

  41. Silva, M. et al. Expanded criteria for liver transplantation in patients with cirrhosis and hepatocellular carcinoma. Liver Transpl. 14, 1449–1460 (2008).

    PubMed  Google Scholar 

  42. Lee, S.-G. et al. Expanded indication criteria of living donor liver transplantation for hepatocellular carcinoma at one large-volume center. Liver Transpl. 14, 935–945 (2008).

    PubMed  Google Scholar 

  43. Sapisochin, G. et al. The extended Toronto criteria for liver transplantation in patients with hepatocellular carcinoma: a prospective validation study. Hepatology 64, 2077–2088 (2016).

    PubMed  Google Scholar 

  44. Silva, M. F. & Sherman, M. Criteria for liver transplantation for HCC: what should the limits be? J. Hepatol. 55, 1137–1147 (2011).

    PubMed  Google Scholar 

  45. Onaca, N., Davis, G. L., Goldstein, R. M., Jennings, L. W. & Klintmalm, G. B. Expanded criteria for liver transplantation in patients with hepatocellular carcinoma: a report from the International Registry of Hepatic Tumors in Liver Transplantation. Liver Transpl. 13, 391–399 (2007).

    PubMed  Google Scholar 

  46. Hong, G. et al. Alpha-fetoprotein and 18F-FDG positron emission tomography predict tumor recurrence better than Milan criteria in living donor liver transplantation. J. Hepatol. 64, 852–859 (2015).

    PubMed  Google Scholar 

  47. Toso, C. et al. Total tumor volume and alpha-fetoprotein for selection of transplant candidates with hepatocellular carcinoma: a prospective validation. Hepatology 62, 158–165 (2015).

    CAS  PubMed  Google Scholar 

  48. Sapisochin, G. et al. Benefit of treating hepatocellular carcinoma recurrence after liver transplantation and analysis of prognostic factors for survival in a large Euro-American series. Ann. Surg. Oncol. 22, 2286–2294 (2014).

    PubMed  Google Scholar 

  49. Mazzaferro, V. et al. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncol. 10, 35–43 (2008).

    PubMed  Google Scholar 

  50. Mazzaferro, V. et al. Milan criteria in liver transplantation for hepatocellular carcinoma: an evidence-based analysis of 15 years of experience. Liver Transpl. 17 (Suppl. 2), S44–S57 (2011).

    PubMed  Google Scholar 

  51. Mazzaferro, V. et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N. Engl. J. Med. 334, 693–699 (1996).

    CAS  PubMed  Google Scholar 

  52. Decaens, T. et al. Impact of UCSF criteria according to pre- and post-OLT tumor features: analysis of 479 patients listed for HCC with a short waiting time. Liver Transpl. 12, 1761–1769 (2006).

    PubMed  Google Scholar 

  53. Roayaie, S. et al. Long-term results with multimodal adjuvant therapy and liver transplantation for the treatment of hepatocellular carcinomas larger than 5 centimeters. Ann. Surg. 235, 533–539 (2002).

    PubMed  PubMed Central  Google Scholar 

  54. Llovet, J. M. Expanding HCC criteria for liver transplant: the urgent need for prospective, robust data. Liver Transpl. 12, 1741–1743 (2006).

    PubMed  Google Scholar 

  55. Kaido, T. et al. Usefulness of the Kyoto criteria as expanded selection criteria for liver transplantation for hepatocellular carcinoma. Surgery 154, 1053–1060 (2013).

    PubMed  Google Scholar 

  56. Sugawara, Y., Tamura, S. & Makuuchi, M. Living donor liver transplantation for hepatocellular carcinoma: Tokyo University series. Dig. Dis. 25, 310–312 (2007).

    PubMed  Google Scholar 

  57. Zheng, S.-S. et al. Liver transplantation for hepatocellular carcinoma: Hangzhou experiences. Transplantation 85, 1726–1732 (2008).

    CAS  PubMed  Google Scholar 

  58. Soejima, Y. et al. Extended indication for living donor liver transplantation in patients with hepatocellular carcinoma. Transplantation 83, 893–899 (2007).

    PubMed  Google Scholar 

  59. Mehta, N. & Yao, F. Y. Moving past 'one size (and number) fits all' in the selection of candidates with hepatocellular carcinoma for liver transplantation. Liver Transpl. 19, 1055–1058 (2013).

    PubMed  Google Scholar 

  60. Duvoux, C. et al. Liver transplantation for hepatocellular carcinoma: a model including α-fetoprotein improves the performance of Milan criteria. Gastroenterology 143, 986–994.e3 (2012).

    CAS  PubMed  Google Scholar 

  61. Cillo, U. et al. Prediction of hepatocellular carcinoma biological behavior in patient selection for liver transplantation. World J. Gastroenterol. 22, 232–252 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Cillo, U. et al. Liver transplantation for the treatment of moderately or well-differentiated hepatocellular carcinoma. Ann. Surg. 239, 150–159 (2004).

    PubMed  PubMed Central  Google Scholar 

  63. Lai, Q. et al. A novel prognostic index in patients with hepatocellular cancer waiting for liver transplantation: Time-Radiological-response-Alpha-fetoprotein-INflammation (TRAIN) score. Ann. Surg. 264, 787–796 (2016).

    PubMed  Google Scholar 

  64. Toso, C. et al. Toward a better liver graft allocation that accounts for candidates with and without hepatocellular carcinoma. Am. J. Transplant. 14, 2221–2227 (2014).

    CAS  PubMed  Google Scholar 

  65. Berry, K. & Ioannou, G. N. Serum alpha-fetoprotein level independently predicts posttransplant survival in patients with hepatocellular carcinoma. Liver Transpl. 19, 634–645 (2013).

    PubMed  Google Scholar 

  66. Liebman, H. A. et al. Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma. N. Engl. J. Med. 310, 1427–1431 (1984).

    CAS  PubMed  Google Scholar 

  67. Vibert, E. et al. Progression of alphafetoprotein before liver transplantation for hepatocellular carcinoma in cirrhotic patients: a critical factor. Am. J. Transplant. 10, 129–137 (2010).

    CAS  PubMed  Google Scholar 

  68. Shindoh, J. et al. Evaluation methods for pretransplant oncologic markers and their prognostic impacts in patient undergoing living donor liver transplantation for hepatocellular carcinoma. Transpl. Int. 27, 391–398 (2014).

    CAS  PubMed  Google Scholar 

  69. Hameed, B., Mehta, N., Sapisochin, G., Roberts, J. P. & Yao, F. Y. Alpha-fetoprotein level >1000 ng/mL as an exclusion criterion for liver transplantation in patients with hepatocellular carcinoma meeting the Milan criteria. Liver Transpl. 20, 945–951 (2014).

    PubMed  PubMed Central  Google Scholar 

  70. Merani, S. et al. The impact of waiting list alpha-fetoprotein changes on the outcome of liver transplant for hepatocellular carcinoma. J. Hepatol. 55, 814–819 (2011).

    CAS  PubMed  Google Scholar 

  71. Mailey, B. et al. Evaluation of absolute serum α-fetoprotein levels in liver transplant for hepatocellular cancer. Arch. Surg. 146, 26–33 (2011).

    PubMed  Google Scholar 

  72. Fujiki, M. et al. Significance of des-gamma-carboxy prothrombin in selection criteria for living donor liver transplantation for hepatocellular carcinoma. Am. J. Transplant. 9, 2362–2371 (2009).

    CAS  PubMed  Google Scholar 

  73. Taketomi, A. et al. Impact of des-gamma-carboxy prothrombin and tumor size on the recurrence of hepatocellular carcinoma after living donor liver transplantation. Transplantation 87, 531–537 (2009).

    PubMed  Google Scholar 

  74. Miltiadous, O. et al. Progenitor cell markers predict outcome of patients with hepatocellular carcinoma beyond Milan criteria undergoing liver transplantation. J. Hepatol. 63, 1368–1377 (2015).

    PubMed  Google Scholar 

  75. Fuks, D. et al. Preoperative tumour biopsy does not affect the oncologic course of patients with transplantable HCC. J. Hepatol. 61, 589–593 (2014).

    PubMed  Google Scholar 

  76. Fox, E. J. & Loeb, L. A. Cancer: one cell at a time. Nature 512, 143–144 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Barbara, L. et al. Natural history of small untreated hepatocellular carcinoma in cirrhosis: a multivariate analysis of prognostic factors of tumor growth rate and patient survival. Hepatology 16, 132–137 (1992).

    CAS  PubMed  Google Scholar 

  78. Ebara, M. et al. Natural history of minute hepatocellular carcinoma smaller than three centimeters complicating cirrhosis. A study in 22 patients. Gastroenterology 90, 289–298 (1986).

    CAS  PubMed  Google Scholar 

  79. Yoshino, M. Growth kinetics of hepatocellular carcinoma. Jpn J. Clin. Oncol. 13, 45–52 (1983).

    CAS  PubMed  Google Scholar 

  80. Sheu, J. C. et al. Hepatocellular carcinoma in the early stage. Radiology 155, 463–467 (1985).

    CAS  PubMed  Google Scholar 

  81. Wald, C. et al. New OPTN/UNOS policy for liver transplant allocation: standardization of liver imaging, diagnosis, classification, and reporting of hepatocellular carcinoma. Radiology 266, 376–382 (2013).

    PubMed  Google Scholar 

  82. Feng, K. et al. A randomized controlled trial of radiofrequency ablation and surgical resection in the treatment of small hepatocellular carcinoma. J. Hepatol. 57, 794–802 (2012).

    PubMed  Google Scholar 

  83. Livraghi, T. et al. Sustained complete response and complications rates after radiofrequency ablation of very early hepatocellular carcinoma in cirrhosis: is resection still the treatment of choice? Hepatology 47, 82–89 (2007).

    Google Scholar 

  84. Romagnoli, R., Mazzaferro, V. & Bruix, J. Surgical resection for hepatocellular carcinoma: moving from what can be done to what is worth doing. Hepatology 62, 340–342 (2015).

    PubMed  Google Scholar 

  85. Cho, Y. K., Kim, J. K., Kim, W. T. & Chung, J. W. Hepatic resection versus radiofrequency ablation for very early stage hepatocellular carcinoma: a Markov model analysis. Hepatology 51, 1284–1290 (2010).

    PubMed  Google Scholar 

  86. Mazzaferro, V. Squaring the circle of selection and allocation in liver transplantation for HCC: an adaptive approach. Hepatology 63, 1707–1717 (2016).

    PubMed  Google Scholar 

  87. Cillo, U. et al. A multistep, consensus-based approach to organ allocation in liver transplantation: toward a “blended principle model”. Am. J. Transplant. 15, 2552–2561 (2015).

    CAS  PubMed  Google Scholar 

  88. Yao, F. Y. & Fidelman, N. Reassessing the boundaries of liver transplantation for hepatocellular carcinoma: where do we stand with tumor down-staging? Hepatology 63, 1014–1025 (2015).

    PubMed  Google Scholar 

  89. Neuberger, J. & James, O. Guidelines for selection of patients for liver transplantation in the era of donor-organ shortage. Lancet 354, 1636–1639 (1999).

    CAS  PubMed  Google Scholar 

  90. Ringe, B., Wittekind, C., Bechstein, W. O., Bunzendahl, H. & Pichlmayr, R. The role of liver transplantation in hepatobiliary malignancy. A retrospective analysis of 95 patients with particular regard to tumor stage and recurrence. Ann. Surg. 209, 88–98 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. O'Grady, J. G., Polson, R. J., Rolles, K., Calne, R. Y. & Williams, R. Liver transplantation for malignant disease. Results in 93 consecutive patients. Ann. Surg. 207, 373–379 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Iwatsuki, S., Gordon, R. D., Shaw, B. W. & Starzl, T. E. Role of liver transplantation in cancer therapy. Liver Transpl. 202, 401–407 (1985).

    CAS  Google Scholar 

  93. Bismuth, H., Majno, P. E. & Adam, R. Liver transplantation for hepatocellular carcinoma. Semin. Liver Dis. 19, 311–322 (1999).

    CAS  PubMed  Google Scholar 

  94. Bruix, J., Fuster, J. & Llovet, J. M. Liver transplantation for hepatocellular carcinoma: Foucault pendulum versus evidence-based decision. Liver Transpl. 9, 700–702 (2003).

    PubMed  Google Scholar 

  95. Navasa, M. & Bruix, J. Multifaceted perspective of the waiting list for liver transplantation: the value of pharmacokinetic models. Hepatology 51, 12–15 (2009).

    Google Scholar 

  96. Clavien, P.-A. et al. Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report. Lancet Oncol. 13, e11–e22 (2011).

    PubMed  PubMed Central  Google Scholar 

  97. Volk, M. L., Vijan, S. & Marrero, J. A. A novel model measuring the harm of transplanting hepatocellular carcinoma exceeding Milan criteria. Am. J. Transplant. 8, 839–846 (2008).

    CAS  PubMed  Google Scholar 

  98. Vitale, A. et al. Barcelona Clinic Liver Cancer staging and transplant survival benefit for patients with hepatocellular carcinoma: a multicentre, cohort study. Lancet Oncol. 12, 654–662 (2011).

    PubMed  Google Scholar 

  99. Mazzaferro, V. Living donor liver transplantation for hepatocellular carcinoma exceeding conventional criteria: questions, answers and demands for a common language. Liver Transpl. 12, 896–898 (2006).

    PubMed  Google Scholar 

  100. Grant, D. et al. Should the liver transplant criteria for hepatocellular carcinoma be different for deceased donation and living donation? Liver Transpl. 17 (Suppl. 2), S133–S138 (2011).

    PubMed  Google Scholar 

  101. Abecassis, M. M. et al. Complications of living donor hepatic lobectomy — a comprehensive report. Am. J. Transplant. 12, 1208–1217 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Cheah, Y. L., Simpson, M. A., Pomposelli, J. J. & Pomfret, E. A. Incidence of death and potentially life-threatening near-miss events in living donor hepatic lobectomy: a world-wide survey. Liver Transpl. 19, 499–506 (2012).

    Google Scholar 

  103. Barr, M. L. et al. A report of the Vancouver Forum on the care of the live organ donor: lung, liver, pancreas, and intestine data and medical guidelines. Transplantation 81, 1373–1385 (2006).

    PubMed  Google Scholar 

  104. Sapisochin, G. et al. Right lobe living-donor hepatectomy — the Toronto approach, tips and tricks. Hepatobiliary Surg. Nutr. 5, 118–126 (2016).

    PubMed  PubMed Central  Google Scholar 

  105. Rössler, F. et al. Defining benchmarks for major liver surgery: a multicenter analysis of 5202 living liver donors. Ann. Surg. 264, 492–500 (2016).

    PubMed  Google Scholar 

  106. Levy, G. A., Selzner, N. & Grant, D. R. Fostering liver living donor liver transplantation. Curr. Opin. Organ Transplant. 21, 224–230 (2016).

    PubMed  Google Scholar 

  107. Kulik, L. & Abecassis, M. Living donor liver transplantation for hepatocellular carcinoma. Gastroenterology 127, S277–S282 (2004).

    PubMed  Google Scholar 

  108. Pang, T. C. & Lam, V. W. Surgical management of hepatocellular carcinoma. World J. Hepatol. 7, 245–252 (2015).

    PubMed  PubMed Central  Google Scholar 

  109. Lo, C. M. et al. Living donor versus deceased donor liver transplantation for early irresectable hepatocellular carcinoma. Br. J. Surg. 94, 78–86 (2006).

    Google Scholar 

  110. Lee, H. W. & Suh, K.-S. Expansion of the criteria for living donor liver transplantation for hepatocellular carcinoma. Curr. Opin. Organ Transplant. 21, 231–237 (2016).

    PubMed  Google Scholar 

  111. Wiesner, R. et al. Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology 124, 91–96 (2003).

    PubMed  Google Scholar 

  112. Malinchoc, M. et al. A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts. Hepatology 31, 864–871 (2000).

    CAS  PubMed  Google Scholar 

  113. Lamas, D. & Rosenbaum, L. Very complicated math — reconfiguring organ allocation. N. Engl. J. Med. 371, 2447–2450 (2014).

    PubMed  Google Scholar 

  114. Washburn, K., Edwards, E., Harper, A. & Freeman, R. Hepatocellular carcinoma patients are advantaged in the current liver transplant allocation system. Am. J. Transplant. 10, 1643–1648 (2010).

    CAS  PubMed  Google Scholar 

  115. Aloia, T. A., Adam, R., Samuel, D., Azoulay, D. & Castaing, D. A decision analysis model identifies the interval of efficacy for transarterial chemoembolization (TACE) in cirrhotic patients with hepatocellular carcinoma awaiting liver transplantation. J. Gastrointest. Surg. 11, 1328–1332 (2007).

    PubMed  Google Scholar 

  116. Yao, F. Y. et al. A follow-up analysis of the pattern and predictors of dropout from the waiting list for liver transplantation in patients with hepatocellular carcinoma: implications for the current organ allocation policy. Liver Transpl. 9, 684–692 (2003).

    PubMed  Google Scholar 

  117. Lencioni, R., Mornex, F., Girard, N., Poon, R. T. & Cherqui, D. Is the treatment of hepatocellular carcinoma on the waiting list necessary? Liver Transpl. 17 (Suppl. 2), S98–S108 (2011).

    PubMed  Google Scholar 

  118. Llovet, J. M., Fuster, J. & Bruix, J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology 30, 1434–1440 (1999).

    CAS  PubMed  Google Scholar 

  119. Llovet, J. M. et al. Cost effectiveness of adjuvant therapy for hepatocellular carcinoma during the waiting list for liver transplantation. Gut 50, 123–128 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Bruix, J. & Sherman, M. Management of hepatocellular carcinoma. Hepatology 42, 1208–1236 (2005).

    PubMed  Google Scholar 

  121. Ferrer-Fàbrega, J. et al. Prospective validation of ab initio liver transplantation in hepatocellular carcinoma upon detection of risk factors for recurrence after resection. Hepatology 63, 839–849 (2016).

    PubMed  Google Scholar 

  122. Cherqui, D. et al. Liver resection for transplantable hepatocellular carcinoma: long-term survival and role of secondary liver transplantation. Ann. Surg. 250, 738–746 (2009).

    PubMed  Google Scholar 

  123. Salem, R., Mazzaferro, V. & Sangro, B. Yttrium 90 radioembolization for the treatment of hepatocellular carcinoma: biological lessons, current challenges, and clinical perspectives. Hepatology 58, 2188–2197 (2013).

    CAS  PubMed  Google Scholar 

  124. Majno, P. E. et al. Influence of preoperative transarterial lipiodol chemoembolization on resection and transplantation for hepatocellular carcinoma in patients with cirrhosis. Ann. Surg. 226, 688 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Otto, G. et al. Response to transarterial chemoembolization as a biological selection criterion for liver transplantation in hepatocellular carcinoma. Liver Transpl. 12, 1260–1267 (2006).

    PubMed  Google Scholar 

  126. Lu, D. S. K. et al. Radiofrequency ablation of hepatocellular carcinoma: treatment success as defined by histologic examination of the explanted liver. Radiology 234, 954–960 (2005).

    PubMed  Google Scholar 

  127. Mazzaferro, V. et al. Radiofrequency ablation of small hepatocellular carcinoma in cirrhotic patients awaiting liver transplantation: a prospective study. Ann. Surg. 240, 900–909 (2004).

    PubMed  PubMed Central  Google Scholar 

  128. Sandroussi, C. et al. Radiotherapy as a bridge to liver transplantation for hepatocellular carcinoma. Transpl. Int. 23, 299–306 (2009).

    PubMed  Google Scholar 

  129. O'Connor, J. K., Trotter, J., Davis, G. L., Dempster, J. & Goldstein, R. M. Long-term outcomes of stereotactic body radiation therapy in the treatment of hepatocellular cancer as a bridge to transplantation. Liver Transpl. 18, 949–954 (2012).

    PubMed  Google Scholar 

  130. Porrett, P. M. et al. Lack of benefit of pre-transplant locoregional hepatic therapy for hepatocellular cancer in the current MELD era. Liver Transpl. 12, 665–673 (2006).

    PubMed  Google Scholar 

  131. Cucchetti, A. et al. Priority of candidates with hepatocellular carcinoma awaiting liver transplantation can be reduced after successful bridge therapy. Liver Transpl. 17, 1344–1354 (2011).

    PubMed  Google Scholar 

  132. Allard, M.-A. et al. Does pathological response after transarterial chemoembolization for hepatocellular carcinoma in cirrhotic patients with cirrhosis predict outcome after liver resection or transplantation? J. Hepatol. 63, 83–92 (2015).

    PubMed  Google Scholar 

  133. Agopian, V. G. et al. Complete pathologic response to pretransplant locoregional therapy for hepatocellular carcinoma defines cancer cure after liver transplantation: analysis of 501 consecutively treated patients. Ann. Surg. 262, 536 (2015).

    PubMed  Google Scholar 

  134. Cescon, M., Cucchetti, A., Ravaioli, M. & Pinna, A. D. Hepatocellular carcinoma locoregional therapies for patients in the waiting list. Impact on transplantability and recurrence rate. J. Hepatol. 58, 609–618 (2012).

    PubMed  Google Scholar 

  135. Lo, C.-M. Deceased donation in Asia: challenges and opportunities. Liver Transpl. 18 (Suppl. 2), S5–S7 (2012).

    PubMed  Google Scholar 

  136. Park, G.-C., Song, G.-W., Moon, D.-B. & Lee, S.-G. A review of current status of living donor liver transplantation. Hepatobiliary Surg. Nutr. 5, 107–117 (2016).

    PubMed  PubMed Central  Google Scholar 

  137. Vakili, K. et al. Living donor liver transplantation for hepatocellular carcinoma: increased recurrence but improved survival. Liver Transpl. 15, 1861–1866 (2009).

    PubMed  Google Scholar 

  138. Fisher, R. A. et al. Hepatocellular carcinoma recurrence and death following living and deceased donor liver transplantation. Am. J. Transplant. 7, 1601–1608 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Kulik, L. M. et al. Outcomes of living and deceased donor liver transplant recipients with hepatocellular carcinoma: results of the A2ALL cohort. Am. J. Transplant. 12, 2997–3007 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Bhangui, P. et al. Intention-to-treat analysis of liver transplantation for hepatocellular carcinoma: living versus deceased donor transplantation. Hepatology 53, 1570–1579 (2011).

    PubMed  Google Scholar 

  141. Ninomiya, M. et al. Comparative study of living and deceased donor liver transplantation as a treatment for hepatocellular carcinoma. J. Am. Coll. Surg. 220, 297–304.e3 (2014).

    PubMed  Google Scholar 

  142. Xiao, G.-Q., Song, J.-L., Shen, S., Yang, J.-Y. & Yan, L.-N. Living donor liver transplantation does not increase tumor recurrence of hepatocellular carcinoma compared to deceased donor transplantation. World J. Gastroenterol. 20, 10953–10959 (2014).

    PubMed  PubMed Central  Google Scholar 

  143. Liang, W. et al. Living donor liver transplantation versus deceased donor liver transplantation for hepatocellular carcinoma: a meta-analysis. Liver Transpl. 18, 1226–1236 (2012).

    PubMed  Google Scholar 

  144. Wan, P. et al. Living-donor or deceased-donor liver transplantation for hepatic carcinoma: a case-matched comparison. World J. Gastroenterol. 20, 4393–4400 (2014).

    PubMed  PubMed Central  Google Scholar 

  145. Grant, R. C. et al. Living versus deceased donor liver transplantation for hepatocellular carcinoma: a systematic review and meta-analysis. Clin. Transplant. 27, 140–147 (2012).

    PubMed  Google Scholar 

  146. Shirabe, K. et al. Comparative evaluation of expanded criteria for patients with hepatocellular carcinoma beyond the Milan criteria undergoing living-related donor liver transplantation. Clin. Transplant. 25, E491–E498 (2011).

    PubMed  Google Scholar 

  147. Song, G.-W. & Lee, S.-G. Living donor liver transplantation. Curr. Opin. Organ Transplant. 19, 217–222 (2014).

    CAS  PubMed  Google Scholar 

  148. Akamatsu, N., Sugawara, Y. & Kokudo, N. Living donor liver transplantation for patients with hepatocellular carcinoma. Liver Cancer 3, 108–118 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Kim, J. M. et al. Expanded criteria for liver transplantation in patients with hepatocellular carcinoma. Transplant. Proc. 46, 726–729 (2014).

    CAS  PubMed  Google Scholar 

  150. Cucchetti, A. et al. Tumor doubling time predicts recurrence after surgery and describes the histological pattern of hepatocellular carcinoma on cirrhosis. J. Hepatol. 43, 310–316 (2005).

    PubMed  Google Scholar 

  151. Heimbach, J. K. et al. Delayed hepatocellular carcinoma model for end-stage liver disease exception score improves disparity in access to liver transplant in the United States. Hepatology 61, 1643–1650 (2015).

    PubMed  Google Scholar 

  152. Chen, W.-T., Fernandes, M. L., Lin, C.-C. & Lin, S.-M. Delay in treatment of early-stage hepatocellular carcinoma using radiofrequency ablation may impact survival of cirrhotic patients in a surveillance program. J. Surg. Oncol. 103, 133–139 (2010).

    PubMed  Google Scholar 

  153. Ghobrial, R. M. et al. Donor morbidity after living donation for liver transplantation. Gastroenterology 135, 468–476 (2008).

    PubMed  Google Scholar 

  154. Kim, P. T. W. & Testa, G. Living donor liver transplantation in the USA. Hepatobiliary Surg. Nutr. 5, 133–140 (2016).

    PubMed  PubMed Central  Google Scholar 

  155. Mangus, R. S. et al. Use of the piggyback hepatectomy technique in liver transplant recipients with hepatocellular carcinoma. Transplantation 85, 1496–1499 (2008).

    PubMed  Google Scholar 

  156. Busuttil, R. W. & Tanaka, K. The utility of marginal donors in liver transplantation. Liver Transpl. 9, 651–663 (2003).

    PubMed  Google Scholar 

  157. Fondevila, C. A bridge too far: we have not overstepped the line for extended deceased donors. Liver Transpl. 20 (Suppl. 2), S9–S13 (2014).

    PubMed  Google Scholar 

  158. Bowring, M. G. et al. Changes in utilization and discard of hepatitis C-infected donor livers in the recent era. Am. J. Transplant. http://dx.doi.org/10.1111/ajt.13976 (2016).

  159. Coilly, A. & Samuel, D. Pros and cons: usage of organs from donors infected with hepatitis C virus — revision in the direct-acting antiviral era. J. Hepatol. 64, 226–231 (2015).

    PubMed  Google Scholar 

  160. Sotiropoulos, G. C. et al. Liver transplantation for hepatocellular carcinoma in cirrhosis within the Eurotransplant area: an additional option with “livers that nobody wants”. Transplantation 80, 897–902 (2005).

    PubMed  Google Scholar 

  161. Schaubel, D. E., Sima, C. S., Goodrich, N. P., Feng, S. & Merion, R. M. The survival benefit of deceased donor liver transplantation as a function of candidate disease severity and donor quality. Am. J. Transplant. 8, 419–425 (2008).

    CAS  PubMed  Google Scholar 

  162. Selck, F. W., Grossman, E. B., Ratner, L. E. & Renz, J. F. Utilization, outcomes, and retransplantation of liver allografts from donation after cardiac death: implications for further expansion of the deceased-donor pool. Ann. Surg. 248, 599–607 (2008).

    PubMed  Google Scholar 

  163. de la Rosa, G., Fondevila, C. & Navasa, M. Liver transplantation in Spain. Liver Transpl. 22, 1259–1264 (2016).

    PubMed  Google Scholar 

  164. Callaghan, C. J. et al. Outcomes of transplantation of livers from donation after circulatory death donors in the UK: a cohort study. BMJ Open 3, e003287 (2013).

    PubMed  PubMed Central  Google Scholar 

  165. Fondevila, C. et al. Liver transplant using donors after unexpected cardiac death: novel preservation protocol and acceptance criteria. Am. J. Transplant. 7, 1849–1855 (2007).

    CAS  PubMed  Google Scholar 

  166. Man, K. et al. Ischemia-reperfusion of small liver remnant promotes liver tumor growth and metastases — activation of cell invasion and migration pathways. Liver Transpl. 13, 1669–1677 (2007).

    PubMed  Google Scholar 

  167. van der Bilt, J. D. W. et al. Ischemia/reperfusion accelerates the outgrowth of hepatic micrometastases in a highly standardized murine model. Hepatology 42, 165–175 (2005).

    CAS  PubMed  Google Scholar 

  168. Croome, K. P. et al. Inferior survival in liver transplant recipients with hepatocellular carcinoma receiving donation after cardiac death liver allografts. Liver Transpl. 19, 1214–1223 (2013).

    PubMed  Google Scholar 

  169. Croome, K. P. et al. The use of donation after cardiac death allografts does not increase recurrence of hepatocellular carcinoma. Am. J. Transplant. 15, 2704–2711 (2015).

    CAS  PubMed  Google Scholar 

  170. Khorsandi, S. E. et al. Does donation after cardiac death utilization adversely effect hepatocellular cancer survival? Transplantation 100, 1916–1924 (2016).

    PubMed  Google Scholar 

  171. Mathur, A. K. et al. Donation after cardiac death liver transplantation: predictors of outcome. Am. J. Transplant. 10, 2512–2519 (2010).

    CAS  PubMed  Google Scholar 

  172. Seal, J. B. et al. Thrombolytic protocol minimizes ischemic-type biliary complications in liver transplantation from donation after circulatory death donors. Liver Transpl. 21, 321–328 (2014).

    Google Scholar 

  173. Selzner, M. et al. Normothermic ex vivo liver perfusion using steen solution as perfusate for human liver transplantation — first North American results. Liver Transpl. 22, 1501–1508 (2016).

    PubMed  Google Scholar 

  174. Ravikumar, R. et al. Liver transplantation after ex vivo normothermic machine preservation: a phase 1 (first-in-man) clinical trial. Am. J. Transplant. 16, 1779–1787 (2016).

    CAS  PubMed  Google Scholar 

  175. Mergental, H. et al. Transplantation of declined liver allografts following normothermic ex-situ evaluation. Am. J. Transplant. 16, 3235–3245 (2016).

    CAS  PubMed  Google Scholar 

  176. Barbas, A. S., Goldaracena, N., Dib, M. J. & Selzner, M. Ex-vivo liver perfusion for organ preservation: recent advances in the field. Transplant. Rev. (Orlando) 30, 154–160 (2016).

    CAS  Google Scholar 

  177. Marroquin, C. E. et al. Transplantation of hepatitis C-positive livers in hepatitis C-positive patients is equivalent to transplanting hepatitis C-negative livers. Liver Transpl. 7, 762–768 (2001).

    CAS  PubMed  Google Scholar 

  178. Saab, S. et al. Hepatitis C positive grafts may be used in orthotopic liver transplantation: a matched analysis. Am. J. Transplant. 3, 1167–1172 (2003).

    PubMed  Google Scholar 

  179. Belli, L. S. et al. Delisting of liver transplant candidates with chronic hepatitis C after viral eradication: a European study. J. Hepatol. 65, 524–531 (2016).

    PubMed  Google Scholar 

  180. Reig, M. et al. Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy. J. Hepatol. 65, 719–726 (2016).

    CAS  PubMed  Google Scholar 

  181. Heinrich, S., Jochum, W., Graf, R. & Clavien, P.-A. Portal vein ligation and partial hepatectomy differentially influence growth of intrahepatic metastasis and liver regeneration in mice. J. Hepatol. 45, 35–42 (2006).

    PubMed  Google Scholar 

  182. Shi, J.-H., Huitfeldt, H. S., Suo, Z.-H. & Line, P.-D. Growth of hepatocellular carcinoma in the regenerating liver. Liver Transpl. 17, 866–874 (2011).

    PubMed  Google Scholar 

  183. Hashimoto, K. et al. Split liver transplantation using Hemiliver graft in the MELD era: a single center experience in the United States. Am. J. Transplant. 14, 2072–2080 (2014).

    CAS  PubMed  Google Scholar 

  184. Liu, H., Li, R., Fu, J., He, Q. & Li, J. Technical skills required in split liver transplantation. Ann. Transplant. 21, 408–415 (2016).

    PubMed  Google Scholar 

  185. Dalal, A. R. Split liver transplantation: what's unique? World J. Transplant. 5, 89–94 (2015).

    PubMed  PubMed Central  Google Scholar 

  186. Toso, C., Asthana, S., Bigam, D. L., Shapiro, A. M. J. & Kneteman, N. M. Reassessing selection criteria prior to liver transplantation for hepatocellular carcinoma utilizing the Scientific Registry of Transplant Recipients database. Hepatology 49, 832–838 (2009).

    PubMed  Google Scholar 

  187. Sotiropoulos, G. C. et al. Meta-analysis of tumor recurrence after liver transplantation for hepatocellular carcinoma based on 1,198 cases. Eur. J. Med. Res. 12, 527–534 (2007).

    PubMed  Google Scholar 

  188. Bodzin, A. S. et al. Predicting mortality in patients developing recurrent hepatocellular carcinoma after liver transplantation: impact of treatment modality and recurrence characteristics. Ann. Surg. http://dx.doi.org/10.1097/SLA.0000000000001894 (2016).

  189. Valdivieso, A. et al. Management of hepatocellular carcinoma recurrence after liver transplantation. Transplant. Proc. 42, 660–662 (2010).

    CAS  PubMed  Google Scholar 

  190. Kornberg, A. et al. Long-term survival after recurrent hepatocellular carcinoma in liver transplant patients: clinical patterns and outcome variables. Eur. J. Surg. Oncol. 36, 275–280 (2009).

    PubMed  Google Scholar 

  191. Toso, C., Mentha, G. & Majno, P. Liver transplantation for hepatocellular carcinoma: five steps to prevent recurrence. Am. J. Transplant. 11, 2031–2035 (2011).

    CAS  PubMed  Google Scholar 

  192. Orci, L. A. et al. Donor characteristics and risk of hepatocellular carcinoma recurrence after liver transplantation. Br. J. Surg. 102, 1250–1257 (2015).

    CAS  PubMed  Google Scholar 

  193. Vagefi, P. A., Dodge, J. L., Yao, F. Y. & Roberts, J. P. Potential role of the donor in hepatocellular carcinoma recurrence after liver transplantation. Liver Transpl. 21, 187–194 (2014).

    Google Scholar 

  194. Sharma, P. et al. Incidence and risk factors of hepatocellular carcinoma recurrence after liver transplantation in the MELD era. Dig. Dis. Sci. 57, 806–812 (2011).

    PubMed  PubMed Central  Google Scholar 

  195. Nagai, S. et al. Ischemia time impacts recurrence of hepatocellular carcinoma after liver transplantation. Hepatology 61, 895–904 (2015).

    CAS  PubMed  Google Scholar 

  196. Ku, Y. et al. Stimulation of haematogenous liver metastases by ischaemia-reperfusion in rats. Eur. J. Surg. 165, 801–807 (1999).

    CAS  PubMed  Google Scholar 

  197. Harris, A. L. Hypoxia — a key regulatory factor in tumour growth. Nat. Rev. Cancer 2, 38–47 (2002).

    CAS  PubMed  Google Scholar 

  198. Orci, L. A. et al. Effect of ischaemic preconditioning on recurrence of hepatocellular carcinoma in an experimental model of liver steatosis. Br. J. Surg. 103, 417–426 (2016).

    CAS  PubMed  Google Scholar 

  199. Gu, X.-Q., Zheng, W.-P., Teng, D.-H., Sun, J.-S. & Zheng, H. Impact of non-oncological factors on tumor recurrence after liver transplantation in hepatocellular carcinoma patients. World J. Gastroenterol. 22, 2749–2759 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. Sotiropoulos, G. C. et al. Liver transplantation for hepatocellular carcinoma: University Hospital Essen experience and metaanalysis of prognostic factors. J. Am. Coll. Surg. 205, 661–675 (2007).

    PubMed  Google Scholar 

  201. Poté, N. et al. Performance of PIVKA-II for early hepatocellular carcinoma diagnosis and prediction of microvascular invasion. J. Hepatol. 62, 848–854 (2014).

    PubMed  Google Scholar 

  202. Cescon, M. et al. Liver transplantation for hepatocellular carcinoma: role of inflammatory and immunological state on recurrence and prognosis. World J. Gastroenterol. 19, 9174–9182 (2014).

    Google Scholar 

  203. Halazun, K. J. et al. Negative impact of neutrophil-lymphocyte ratio on outcome after liver transplantation for hepatocellular carcinoma. Ann. Surg. 250, 141–151 (2009).

    PubMed  Google Scholar 

  204. Sapisochin, G., Yao, F. Y. & Roberts, J. P. Do preoperative inflammatory markers impact on outcome after liver transplantation for hepatocellular carcinoma? Ann. Surg. 254, 383 (2011).

    PubMed  Google Scholar 

  205. Agopian, V. G. et al. A novel prognostic nomogram accurately predicts hepatocellular carcinoma recurrence after liver transplantation: analysis of 865 consecutive liver transplant recipients. J. Am. Coll. Surg. 220, 416–427 (2014).

    PubMed  Google Scholar 

  206. Halazun, K. J. et al. Recurrence after liver transplantation for hepatocellular carcinoma: a new MORAL to the story. Ann. Surg. http://dx.doi.org/10.1097/SLA.0000000000001966 (2016).

  207. Lee, J.-H. et al. Serum tumor markers provide refined prognostication in selecting liver transplantation candidate for hepatocellular carcinoma patients beyond the Milan criteria. Ann. Surg. 263, 842–850 (2016).

    PubMed  Google Scholar 

  208. Lee, S. D., Kim, S. H., Kim, S.-K., Kim, Y.-K. & Park, S.-J. Clinical impact of 18F-fluorodeoxyglucose positron emission tomography/computed tomography in living donor liver transplantation for advanced hepatocellular carcinoma. Transplantation 99, 2142–2149 (2015).

    CAS  PubMed  Google Scholar 

  209. Kornberg, A. et al. Patients with non-[18F]fludeoxyglucose-avid advanced hepatocellular carcinoma on clinical staging may achieve long-term recurrence-free survival after liver transplantation. Liver Transpl. 18, 53–61 (2011).

    Google Scholar 

  210. Kornberg, A. et al. 18F-FDG-uptake of hepatocellular carcinoma on PET predicts microvascular tumor invasion in liver transplant patients. Am. J. Transplant. 9, 592–600 (2009).

    CAS  PubMed  Google Scholar 

  211. Yang, S. H. et al. The role of 18F-FDG-PET imaging for the selection of liver transplantation candidates among hepatocellular carcinoma patients. Liver Transpl. 12, 1655–1660 (2006).

    PubMed  Google Scholar 

  212. Tamura, S. et al. Impact of histological grade of hepatocellular carcinoma on the outcome of liver transplantation. Arch. Surg. 136, 25 (2001).

    CAS  PubMed  Google Scholar 

  213. Llovet, J. M. et al. Liver transplantation for small hepatocellular carcinoma: the tumor-node-metastasis classification does not have prognostic power. Hepatology 27, 1572–1577 (1998).

    CAS  PubMed  Google Scholar 

  214. Iwatsuki, S. et al. Liver transplantation for hepatocellular carcinoma: a proposal of a prognostic scoring system. J. Am. Coll. Surg. 191, 389–394 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  215. Jonas, S. et al. Vascular invasion and histopathologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis. Hepatology 33, 1080–1086 (2001).

    CAS  PubMed  Google Scholar 

  216. Margarit, C. et al. Liver transplantation for malignant diseases: selection and pattern of recurrence. World J. Surg. 26, 257–263 (2001).

    PubMed  Google Scholar 

  217. Hemming, A. W. et al. Liver transplantation for hepatocellular carcinoma. Ann. Surg. 233, 652–659 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  218. Marsh, J. W. et al. The prediction of risk of recurrence and time to recurrence of hepatocellular carcinoma after orthotopic liver transplantation: a pilot study. Hepatology 26, 444–450 (1997).

    CAS  PubMed  Google Scholar 

  219. DuBay, D. et al. Liver transplantation for advanced hepatocellular carcinoma using poor tumor differentiation on biopsy as an exclusion criterion. Ann. Surg. 253, 166–172 (2011).

    PubMed  Google Scholar 

  220. Reddy, K. R. et al. Ledipasvir and sofosbuvir in patients with genotype 1 hepatitis C virus infection and compensated cirrhosis: an integrated safety and efficacy analysis. Hepatology 62, 79–86 (2015).

    CAS  PubMed  Google Scholar 

  221. Lawitz, E. et al. Efficacy and safety of ombitasvir, paritaprevir, and ritonavir in an open-label study of patients with genotype 1b chronic hepatitis C virus infection with and without cirrhosis. Gastroenterology 149, 971–980.e1 (2015).

    CAS  PubMed  Google Scholar 

  222. Poordad, F. et al. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N. Engl. J. Med. 370, 1973–1982 (2014).

    PubMed  Google Scholar 

  223. Chen, T. & Terrault, N. A. Perspectives on treating hepatitis C infection in the liver transplantation setting. Curr. Opin. Organ Transplant. 21, 111–119 (2016).

    PubMed  Google Scholar 

  224. Berenguer, M. et al. Natural history of clinically compensated hepatitis C virus-related graft cirrhosis after liver transplantation. Hepatology 32, 852–858 (2000).

    CAS  PubMed  Google Scholar 

  225. Sánchez-Fueyo, A. et al. Impact of the recurrence of hepatitis C virus infection after liver transplantation on the long-term viability of the graft. Transplantation 73, 56–63 (2002).

    PubMed  Google Scholar 

  226. Ballardini, G. et al. Timing of reinfection and mechanisms of hepatocellular damage in transplanted hepatitis C virus-reinfected liver. Liver Transpl. 8, 10–20 (2002).

    PubMed  Google Scholar 

  227. Yang, J. D. et al. Direct acting antiviral therapy and tumor recurrence after liver transplantation for hepatitis C-associated hepatocellular carcinoma. J. Hepatol. 65, 859–860 (2016).

    PubMed  Google Scholar 

  228. Conti, F. et al. Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals. J. Hepatol. 65, 727–733 (2016).

    CAS  PubMed  Google Scholar 

  229. The ANRS collaborative study group on hepatocellular carcinoma (ANRS CO22 HEPATHER, CO12 CirVir and CO23 CUPILT cohorts). Lack of evidence of an effect of direct-acting antivirals on the recurrence of hepatocellular carcinoma: data from three ANRS cohorts. J. Hepatol. 65, 734–740 (2016).

  230. Renzulli, M. et al. Imaging features of microvascular invasion in hepatocellular carcinoma developed in HCV-related cirrhosis after direct-acting antiviral therapy [abstract 440]. Hepatology 64:S1, 223A (2016).

    Google Scholar 

  231. Romano, A. et al. Incidence and pattern of 'de novo' hepatocellular carcinoma in HCV patients treated with oral DAAs [abstract 19]. Hepatology 64:S1, 10A (2016).

    Google Scholar 

  232. Nault, J.-C. & Colombo, M. Hepatocellular carcinoma and direct acting antiviral treatments: controversy after the revolution. J. Hepatol. 65, 663–665 (2016).

    PubMed  Google Scholar 

  233. National Comprehensive Cancer Network. NCCN Guidelines. NCCN https://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf (2016)

  234. Roberts, J. P. Tumor surveillance — what can and should be done? Screening for recurrence of hepatocellular carcinoma after liver transplantation. Liver Transpl. 11, S45–S46 (2005).

    Google Scholar 

  235. Roayaie, S. et al. Recurrence of hepatocellular carcinoma after liver transplant: patterns and prognosis. Liver Transpl. 10, 534–540 (2004).

    PubMed  Google Scholar 

  236. Davis, E. et al. Treatment of recurrent hepatocellular carcinoma after liver transplantation. Liver Transpl. 17 (Suppl. 2), S162–S166 (2011).

    PubMed  Google Scholar 

  237. Welker, M.-W., Bechstein, W.-O., Zeuzem, S. & Trojan, J. Recurrent hepatocellular carcinoma after liver transplantation — an emerging clinical challenge. Transpl. Int. 26, 109–118 (2012).

    PubMed  Google Scholar 

  238. Regalia, E. et al. Pattern and management of recurrent hepatocellular carcinoma after liver transplantation. J. Hepatobiliary Pancreat. Surg. 5, 29–34 (1998).

    CAS  PubMed  Google Scholar 

  239. Cho, Y. K. A comparison of surgical resection and radiofrequency ablation for the treatment of single small hepatocellular carcinoma ≤2 cm. Hepatology 59, 1653 (2014).

    PubMed  Google Scholar 

  240. Bernal, E. et al. Adjuvant chemotherapy for prevention of recurrence of invasive hepatocellular carcinoma after orthotopic liver transplantation. Transplant. Proc. 38, 2495–2498 (2006).

    CAS  PubMed  Google Scholar 

  241. Bassanello, M. et al. Adjuvant chemotherapy for transplanted hepatocellular carcinoma patients: impact on survival or HCV recurrence timing. Transplant. Proc. 35, 2991–2994 (2003).

    CAS  PubMed  Google Scholar 

  242. Olthoff, K. M. et al. Adjuvant chemotherapy improves survival after liver transplantation for hepatocellular carcinoma. Ann. Surg. 221, 734 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  243. Söderdahl, G. et al. A prospective, randomized, multi-centre trial of systemic adjuvant chemotherapy versus no additional treatment in liver transplantation for hepatocellular carcinoma. Transpl. Int. 19, 288–294 (2006).

    PubMed  Google Scholar 

  244. Llovet, J. M. et al. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359, 378–390 (2008).

    CAS  PubMed  Google Scholar 

  245. Cheng, A.-L. et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 10, 25–34 (2008).

    PubMed  Google Scholar 

  246. Huang, L. et al. Efficacy of sorafenib after liver transplantation in patients with primary hepatic carcinoma exceeding the Milan criteria: a preliminary study. Onco Targets Ther. 5, 457–462 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  247. Saab, S., McTigue, M., Finn, R. S. & Busuttil, R. W. Sorafenib as adjuvant therapy for high-risk hepatocellular carcinoma in liver transplant recipients: feasibility and efficacy. Exp. Clin. Transplant. 8, 307–313 (2010).

    PubMed  Google Scholar 

  248. Bruix, J. et al. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 16, 1344–1354 (2015).

    CAS  PubMed  Google Scholar 

  249. Hojo, M. et al. Cyclosporine induces cancer progression by a cell-autonomous mechanism. Nature 397, 530–534 (1999).

    CAS  PubMed  Google Scholar 

  250. Maluccio, M. et al. Tacrolimus enhances transforming growth factor-beta1 expression and promotes tumor progression. Transplantation 76, 597–602 (2003).

    CAS  PubMed  Google Scholar 

  251. Yokoyama, I., Carr, B., Saitsu, H., Iwatsuki, S. & Starzl, T. E. Accelerated growth rates of recurrent hepatocellular carcinoma after liver transplantation. Cancer 68, 2095–2100 (1991).

    CAS  PubMed  Google Scholar 

  252. Rodríguez-Perálvarez, M. et al. Reduced exposure to calcineurin inhibitors early after liver transplantation prevents recurrence of hepatocellular carcinoma. J. Hepatol. 59, 1193–1199 (2013).

    PubMed  Google Scholar 

  253. Vivarelli, M. et al. Analysis of risk factors for tumor recurrence after liver transplantation for hepatocellular carcinoma: key role of immunosuppression. Liver Transpl. 11, 497–503 (2005).

    PubMed  Google Scholar 

  254. Vivarelli, M. et al. Liver transplantation for hepatocellular carcinoma under calcineurin inhibitors: reassessment of risk factors for tumor recurrence. Ann. Surg. 248, 857–862 (2008).

    PubMed  Google Scholar 

  255. Rodríguez-Perálvarez, M., De la Mata, M. & Burroughs, A. K. Liver transplantation: immunosuppression and oncology. Curr. Opin. Organ Transplant. 19, 253–260 (2014).

    PubMed  PubMed Central  Google Scholar 

  256. Villanueva, A. et al. Pivotal role of mTOR signaling in hepatocellular carcinoma. Gastroenterology 135, 1972–1983 (2008).

    CAS  PubMed  Google Scholar 

  257. Gaumann, A., Schlitt, H. J. & Geissler, E. K. Immunosuppression and tumor development in organ transplant recipients: the emerging dualistic role of rapamycin. Transpl. Int. 21, 207–217 (2007).

    PubMed  Google Scholar 

  258. Piguet, A.-C. et al. Inhibition of mTOR in combination with doxorubicin in an experimental model of hepatocellular carcinoma. J. Hepatol. 49, 78–87 (2008).

    CAS  PubMed  Google Scholar 

  259. Menon, K. V., Hakeem, A. R. & Heaton, N. D. Meta-analysis: recurrence and survival following the use of sirolimus in liver transplantation for hepatocellular carcinoma. Aliment. Pharmacol. Ther. 37, 411–419 (2012).

    PubMed  Google Scholar 

  260. Toso, C., Merani, S., Bigam, D. L., Shapiro, A. M. J. & Kneteman, N. M. Sirolimus-based immunosuppression is associated with increased survival after liver transplantation for hepatocellular carcinoma. Hepatology 51, 1237–1243 (2010).

    CAS  PubMed  Google Scholar 

  261. Zimmerman, M. A. et al. Sirolimus-based immunosuppression following liver transplantation for hepatocellular carcinoma. Liver Transpl. 14, 633–638 (2008).

    PubMed  Google Scholar 

  262. Vivarelli, M. et al. Effect of different immunosuppressive schedules on recurrence-free survival after liver transplantation for hepatocellular carcinoma. Transplantation 89, 227–231 (2010).

    CAS  PubMed  Google Scholar 

  263. Liang, W. et al. Sirolimus-based immunosuppression in liver transplantation for hepatocellular carcinoma: a meta-analysis. Liver Transpl. 18, 62–69 (2011).

    Google Scholar 

  264. Yanik, E. L. et al. Effects of maintenance immunosuppression with sirolimus after liver transplant for hepatocellular carcinoma. Liver Transpl. 22, 627–634 (2016).

    PubMed  PubMed Central  Google Scholar 

  265. Bilbao, I. et al. Multiple indications for everolimus after liver transplantation in current clinical practice. World J. Transplant. 4, 122–132 (2014).

    PubMed  PubMed Central  Google Scholar 

  266. Geissler, E. K. et al. Sirolimus use in liver transplant recipients with hepatocellular carcinoma: a randomized, multicenter, open-label phase 3 trial. Transplantation 100, 116–125 (2015).

    PubMed Central  Google Scholar 

  267. Mehta, N., Roberts, J. P. & Yao, F. Y. Lack of benefits of mammalian target of rapamycin inhibitor in patients transplanted for hepatocellular carcinoma: is this the end of the story? Liver Transpl. 22, 582–584 (2016).

    PubMed  Google Scholar 

  268. US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/results?term=NCT02081755&Search=Search (2016).

  269. Deuffic-Burban, S. et al. Impact of emerging hepatitis C virus treatments on future needs for liver transplantation in France: a modelling approach. Dig. Liver Dis. 46, 157–163 (2013).

    PubMed  Google Scholar 

  270. Williams, C. D. et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology 140, 124–131 (2010).

    PubMed  Google Scholar 

  271. Ong, J. P. & Younossi, Z. M. Epidemiology and natural history of NAFLD and NASH. Clin. Liver Dis. 11, 1–16 (2007).

    PubMed  Google Scholar 

  272. Yopp, A. C. & Choti, M. A. Non-alcoholic steatohepatitis-related hepatocellular carcinoma: a growing epidemic? Dig. Dis. 33, 642–647 (2015).

    PubMed  Google Scholar 

  273. Reddy, S. K. et al. Outcomes of curative treatment for hepatocellular cancer in nonalcoholic steatohepatitis versus hepatitis C and alcoholic liver disease. Hepatology 55, 1809–1819 (2012).

    PubMed  Google Scholar 

  274. Hoshida, Y. et al. Gene-expression signature of vascular invasion in hepatocellular carcinoma. J. Hepatol. 55, 1325–1331 (2011).

    PubMed  PubMed Central  Google Scholar 

  275. Llovet, J. M., Villanueva, A., Lachenmayer, A. & Finn, R. S. Advances in targeted therapies for hepatocellular carcinoma in the genomic era. Nat. Rev. Clin. Oncol. 12, 436 (2015).

    PubMed  Google Scholar 

  276. Schulze, K., Nault, J.-C. & Villanueva, A. Genetic profiling of hepatocellular carcinoma using next-generation sequencing. J. Hepatol. 65, 1031–1042 (2016).

    CAS  PubMed  Google Scholar 

  277. Ogle, L. F. et al. Imagestream detection and characterisation of circulating tumour cells — a liquid biopsy for hepatocellular carcinoma? J. Hepatol. 65, 305–313 (2016).

    CAS  PubMed  Google Scholar 

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Acknowledgements

CIBERehd is funded by the Instituto de Salud Carlos III. The authors are grateful to Albert Fung from the Toronto Video Atlas of Surgery, Canada, for help in drafting the figures.

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Authors and Affiliations

  1. Department of Surgery, University Health Network, Toronto General Hospital, University of Toronto, 585 University Avenue, 11-PMB-184, Toronto, M5G2N2, Ontario, Canada

    Gonzalo Sapisochin

  2. Barcelona Clinic Liver Cancer group, Liver Unit, Hospital Clinic, University of Barcelona, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Villaroel 170, Barcelona, 08036, Spain

    Jordi Bruix

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  1. Gonzalo Sapisochin
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Both authors contributed equally to all aspects of this manuscript.

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Correspondence to Gonzalo Sapisochin or Jordi Bruix.

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Competing interests

G.S. has received a research grant support from Bayer. J.B. received grant support from Asociación Española Contra el Cáncer (PI044031), Bayer, Instituto de Salud Carlos III (PI14/00962), Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement (2014 SGR 605) and WCR (AICR) 16–0026. J.B. has consulted for Abbvie, Arqule, Bayer, BMS, Boehringer, BTG, Gilead, Ingelheim, Kowa, Novartis, Onxeo, OSI, Roche and Terumo.

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Sapisochin, G., Bruix, J. Liver transplantation for hepatocellular carcinoma: outcomes and novel surgical approaches. Nat Rev Gastroenterol Hepatol 14, 203–217 (2017). https://doi.org/10.1038/nrgastro.2016.193

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