Liver transplantation for hepatocellular carcinoma: Outcomes and novel surgical approaches

Nature Reviews Gastroenterology and Hepatology

Volumn 14, Issue 4, 2017, Pages 203-217

  Sapisochin, Gonzalo ^a   Bruix, Jordi ^b  

^a TORONTO GENERAL HOSPITAL   (Canada)

^b UNIVERSITY OF BARCELONA   (Spain)

Author keywords

[No Author keywords available]

Indexed keywords

RAPAMYCIN; SORAFENIB; TUMOR MARKER;

CANCER ADJUVANT THERAPY; CANCER MORTALITY; CANCER PREVENTION; CANCER PROGNOSIS; CANCER SURGERY; CANCER SURVIVAL; CANCER THERAPY; HUMAN; IMMUNOSUPPRESSIVE TREATMENT; LIVER CELL CARCINOMA; LIVER TRANSPLANTATION; LIVING DONOR; MODEL FOR END STAGE LIVER DISEASE SCORE; MULTICENTER STUDY (TOPIC); ORGAN DONOR; PHASE 3 CLINICAL TRIAL (TOPIC); PREDICTOR VARIABLE; RANDOMIZED CONTROLLED TRIAL (TOPIC); RECURRENCE RISK; REVIEW; RISK FACTOR; TREATMENT OUTCOME; TUMOR RECURRENCE; CARCINOMA, HEPATOCELLULAR; LIVER NEOPLASMS; MORTALITY;

CARCINOMA, HEPATOCELLULAR; HUMANS; LIVER NEOPLASMS; LIVER TRANSPLANTATION; NEOPLASM RECURRENCE, LOCAL; TREATMENT OUTCOME;

EID: 85008330472     PISSN: 17595045     EISSN: 17595053     Source Type: Journal    
DOI: 10.1038/nrgastro.2016.193     Document Type: Review

References (277)

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).
3. Bruix, J., et al. Evidence-based diagnosis, staging, treatment of patients with hepatocellular carcinoma. Gastroenterology 150, 835-853 (2016).
4. Forner, A., Llovet, J. M., Bruix, J. Hepatocellular carcinoma. Lancet 379, 1245-1255 (2012).
5. de Lope, C. R., Tremosini, S., Forner, A., Bruix, J. Management of HCC. J. Hepatol. 56 (Suppl. 1), S75-S87 (2012).
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).
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).
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).
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).
10. de Villa, V. Liver transplantation for hepatocellular carcinoma in Asia. Oncologist 12, 1321-1331 (2007).
11. Kim, W. R., et al. OPTN/SRTR 2013 Annual Data Report: liver. Am. J. Transplant. 15 (Suppl. 2), 1-28 (2015).
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).
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).
14. Yeh, H., Smoot, E., Schoenfeld, D. A., Markmann, J. F. Geographic inequity in access to livers for transplantation. Transplantation 91, 479-486 (2011).
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).
16. Freeman, R. B., et al. Liver and intestine transplantation in the United States, 1997-2006. Am. J. Transplant. 8, 958-976 (2008).
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).
18. Roberts, J. P. Transplantation: allocation of liver transplants-a road to consensus. Nat. Rev. Gastroenterol. Hepatol. 12, 615-616 (2015).
19. Bhoori, S., Mazzaferro, V. Current challenges in liver transplantation for hepatocellular carcinoma. Best Pract. Res. Clin. Gastroenterol. 28, 867-879 (2014).
20. Marsh, J. W., Dvorchik, I. Liver organ allocation for hepatocellular carcinoma: are we sure Liver Transpl. 9, 693-696 (2003).
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).
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).
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).
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).
25. Kootstra, G. Statement on non-heart-beating donor programs. Transplant. Proc. 27, 2965 (1995).
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).
27. Casavilla, A., et al. Experience with liver and kidney allografts from non-heart-beating donors. Transplant. Proc. 27, 2898 (1995).
28. Kootstra, G., Daemen, J. H., Oomen, A. P. Categories of non-heart-beating donors. Transplant. Proc. 27, 2893-2894 (1995).
29. Monbaliu, D., Pirenne, J., Talbot, D. Liver transplantation using donation after cardiac death donors. J. Hepatol. 56, 474-485 (2011).
30. Beecher, H. K. After the "definition of irreversible coma". N. Engl. J. Med. 281, 1070-1071 (1969).
31. Renz, J. F., et al. Split-liver transplantation: a review. Am. J. Transplant. 3, 1323-1335 (2003).
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).
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).
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).
35. Emre, S., et al. Safe use of hepatic allografts from donors older than 70 years. Transplantation 62, 62-65 (1996).
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).
37. Lué, A., et al. How important is donor age in liver transplantation World J. Gastroenterol. 22, 4966-4976 (2016).
38. Yao, F. Y. Expanded criteria for liver transplantation in patients with hepatocellular carcinoma. Hepatol. Res. 37 (Suppl. 2), S267-S274 (2007).
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).
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).
41. Silva, M., et al. Expanded criteria for liver transplantation in patients with cirrhosis and hepatocellular carcinoma. Liver Transpl. 14, 1449-1460 (2008).
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).
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).
44. Silva, M. F., Sherman, M. Criteria for liver transplantation for HCC: what should the limits be J. Hepatol. 55, 1137-1147 (2011).
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).
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).
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).
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).
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).
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).
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).
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).
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).
54. Llovet, J. M. Expanding HCC criteria for liver transplant: the urgent need for prospective, robust data. Liver Transpl. 12, 1741-1743 (2006).
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).
56. Sugawara, Y., Tamura, S., Makuuchi, M. Living donor liver transplantation for hepatocellular carcinoma: Tokyo University series. Dig. Dis. 25, 310-312 (2007).
57. Zheng, S.-S., et al. Liver transplantation for hepatocellular carcinoma: Hangzhou experiences. Transplantation 85, 1726-1732 (2008).
58. Soejima, Y., et al. Extended indication for living donor liver transplantation in patients with hepatocellular carcinoma. Transplantation 83, 893-899 (2007).
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).
60. Duvoux, C., et al. Liver transplantation for hepatocellular carcinoma: a model including-fetoprotein improves the performance of Milan criteria. Gastroenterology 143, 986-994. e3 (2012).
61. Cillo, U., et al. Prediction of hepatocellular carcinoma biological behavior in patient selection for liver transplantation. World J. Gastroenterol. 22, 232-252 (2016).
62. Cillo, U., et al. Liver transplantation for the treatment of moderately or well-differentiated hepatocellular carcinoma. Ann. Surg. 239, 150-159 (2004).
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).
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).
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).
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).
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).
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).
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).
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).
71. Mailey, B., et al. Evaluation of absolute serum-fetoprotein levels in liver transplant for hepatocellular cancer. Arch. Surg. 146, 26-33 (2011).
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).
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).
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).
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).
76. Fox, E. J., Loeb, L. A. Cancer: one cell at a time. Nature 512, 143-144 (2014).
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).
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).
79. Yoshino, M. Growth kinetics of hepatocellular carcinoma. Jpn J. Clin. Oncol. 13, 45-52 (1983).
80. Sheu, J. C., et al. Hepatocellular carcinoma in the early stage. Radiology 155, 463-467 (1985).
81. Wald, C., et al. New OPTN/UNOS policy for liver transplant allocation: standardization of liver imaging, diagnosis, classification, reporting of hepatocellular carcinoma. Radiology 266, 376-382 (2013).
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).
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).
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).
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).
86. Mazzaferro, V. Squaring the circle of selection and allocation in liver transplantation for HCC: an adaptive approach. Hepatology 63, 1707-1717 (2016).
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).
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).
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).
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).
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).
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).
93. Bismuth, H., Majno, P. E., Adam, R. Liver transplantation for hepatocellular carcinoma. Semin. Liver Dis. 19, 311-322 (1999).
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).
95. Navasa, M., Bruix, J. Multifaceted perspective of the waiting list for liver transplantation: the value of pharmacokinetic models. Hepatology 51, 12-15 (2009).
96. Clavien, P.-A., et al. Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report. Lancet Oncol. 13, e11-e22 (2011).
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).
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).
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).
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).
101. Abecassis, M. M., et al. Complications of living donor hepatic lobectomy-a comprehensive report. Am. J. Transplant. 12, 1208-1217 (2012).
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).
103. Barr, M. L., et al. A report of the Vancouver Forum on the care of the live organ donor: lung, liver, pancreas, intestine data and medical guidelines. Transplantation 81, 1373-1385 (2006).
104. Sapisochin, G., et al. Right lobe living-donor hepatectomy-the Toronto approach, tips and tricks. Hepatobiliary Surg. Nutr. 5, 118-126 (2016).
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).
106. Levy, G. A., Selzner, N., Grant, D. R. Fostering liver living donor liver transplantation. Curr. Opin. Organ Transplant. 21, 224-230 (2016).
107. Kulik, L., Abecassis, M. Living donor liver transplantation for hepatocellular carcinoma. Gastroenterology 127, S277-S282 (2004).
108. Pang, T. C., Lam, V. W. Surgical management of hepatocellular carcinoma. World J. Hepatol. 7, 245-252 (2015).
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).
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).
111. Wiesner, R., et al. Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology 124, 91-96 (2003).
112. Malinchoc, M., et al. A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts. Hepatology 31, 864-871 (2000).
113. Lamas, D., Rosenbaum, L. Very complicated math-reconfiguring organ allocation. N. Engl. J. Med. 371, 2447-2450 (2014).
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).
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).
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).
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).
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).
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).
120. Bruix, J., Sherman, M. Management of hepatocellular carcinoma. Hepatology 42, 1208-1236 (2005).
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).
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).
123. Salem, R., Mazzaferro, V., Sangro, B. Yttrium 90 radioembolization for the treatment of hepatocellular carcinoma: biological lessons, current challenges, clinical perspectives. Hepatology 58, 2188-2197 (2013).
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).
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).
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).
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).
128. Sandroussi, C., et al. Radiotherapy as a bridge to liver transplantation for hepatocellular carcinoma. Transpl. Int. 23, 299-306 (2009).
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).
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).
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).
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).
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).
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).
135. Lo, C.-M. Deceased donation in Asia: challenges and opportunities. Liver Transpl. 18 (Suppl. 2), S5-S7 (2012).
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).
137. Vakili, K., et al. Living donor liver transplantation for hepatocellular carcinoma: increased recurrence but improved survival. Liver Transpl. 15, 1861-1866 (2009).
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).
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).
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).
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).
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).
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).
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).
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).
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).
147. Song, G.-W., Lee, S.-G. Living donor liver transplantation. Curr. Opin. Organ Transplant. 19, 217-222 (2014).
148. Akamatsu, N., Sugawara, Y., Kokudo, N. Living donor liver transplantation for patients with hepatocellular carcinoma. Liver Cancer 3, 108-118 (2014).
149. Kim, J. M., et al. Expanded criteria for liver transplantation in patients with hepatocellular carcinoma. Transplant. Proc. 46, 726-729 (2014).
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).
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).
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).
153. Ghobrial, R. M., et al. Donor morbidity after living donation for liver transplantation. Gastroenterology 135, 468-476 (2008).
154. Kim, P. T. W., Testa, G. Living donor liver transplantation in the USA. Hepatobiliary Surg. Nutr. 5, 133-140 (2016).
155. Mangus, R. S., et al. Use of the piggyback hepatectomy technique in liver transplant recipients with hepatocellular carcinoma. Transplantation 85, 1496-1499 (2008).
156. Busuttil, R. W., Tanaka, K. The utility of marginal donors in liver transplantation. Liver Transpl. 9, 651-663 (2003).
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).
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).
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).
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).
162. Selck, F. W., Grossman, E. B., Ratner, L. E., Renz, J. F. Utilization, outcomes, retransplantation of liver allografts from donation after cardiac death: implications for further expansion of the deceased-donor pool. Ann. Surg. 248, 599-607 (2008).
163. de la Rosa, G., Fondevila, C., Navasa, M. Liver transplantation in Spain. Liver Transpl. 22, 1259-1264 (2016).
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).
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).
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).
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).
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).
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).
170. Khorsandi, S. E., et al. Does donation after cardiac death utilization adversely effect hepatocellular cancer survival Transplantation 100, 1916-1924 (2016).
171. Mathur, A. K., et al. Donation after cardiac death liver transplantation: predictors of outcome. Am. J. Transplant. 10, 2512-2519 (2010).
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).
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).
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).
175. Mergental, H., et al. Transplantation of declined liver allografts following normothermic ex-situ evaluation. Am. J. Transplant. 16, 3235-3245 (2016).
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).
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).
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).
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).
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).
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).
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).
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).
184. Liu, H., Li, R., Fu, J., He, Q., Li, J. Technical skills required in split liver transplantation. Ann. Transplant. 21, 408-415 (2016).
185. Dalal, A. R. Split liver transplantation: what's unique World J. Transplant. 5, 89-94 (2015).
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).
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).
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).
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).
191. Toso, C., Mentha, G., Majno, P. Liver transplantation for hepatocellular carcinoma: five steps to prevent recurrence. Am. J. Transplant. 11, 2031-2035 (2011).
192. Orci, L. A., et al. Donor characteristics and risk of hepatocellular carcinoma recurrence after liver transplantation. Br. J. Surg. 102, 1250-1257 (2015).
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).
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).
195. Nagai, S., et al. Ischemia time impacts recurrence of hepatocellular carcinoma after liver transplantation. Hepatology 61, 895-904 (2015).
196. Ku, Y., et al. Stimulation of haematogenous liver metastases by ischaemia-reperfusion in rats. Eur. J. Surg. 165, 801-807 (1999).
197. Harris, A. L. Hypoxia-a key regulatory factor in tumour growth. Nat. Rev. Cancer 2, 38-47 (2002).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
212. Tamura, S., et al. Impact of histological grade of hepatocellular carcinoma on the outcome of liver transplantation. Arch. Surg. 136, 25 (2001).
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).
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).
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).
216. Margarit, C., et al. Liver transplantation for malignant diseases: selection and pattern of recurrence. World J. Surg. 26, 257-263 (2001).
217. Hemming, A. W., et al. Liver transplantation for hepatocellular carcinoma. Ann. Surg. 233, 652-659 (2001).
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).
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).
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).
221. Lawitz, E., et al. Efficacy and safety of ombitasvir, paritaprevir, 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).
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).
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).
224. Berenguer, M., et al. Natural history of clinically compensated hepatitis C virus-related graft cirrhosis after liver transplantation. Hepatology 32, 852-858 (2000).
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).
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).
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).
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).
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).
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).
232. Nault, J.-C., Colombo, M. Hepatocellular carcinoma and direct acting antiviral treatments: controversy after the revolution. J. Hepatol. 65, 663-665 (2016).
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).
235. Roayaie, S., et al. Recurrence of hepatocellular carcinoma after liver transplant: patterns and prognosis. Liver Transpl. 10, 534-540 (2004).
236. Davis, E., et al. Treatment of recurrent hepatocellular carcinoma after liver transplantation. Liver Transpl. 17 (Suppl. 2), S162-S166 (2011).
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).
238. Regalia, E., et al. Pattern and management of recurrent hepatocellular carcinoma after liver transplantation. J. Hepatobiliary Pancreat. Surg. 5, 29-34 (1998).
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).
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).
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).
242. Olthoff, K. M., et al. Adjuvant chemotherapy improves survival after liver transplantation for hepatocellular carcinoma. Ann. Surg. 221, 734 (1995).
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).
244. Llovet, J. M., et al. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359, 378-390 (2008).
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).
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).
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).
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).
249. Hojo, M., et al. Cyclosporine induces cancer progression by a cell-autonomous mechanism. Nature 397, 530-534 (1999).
250. Maluccio, M., et al. Tacrolimus enhances transforming growth factor-beta1 expression and promotes tumor progression. Transplantation 76, 597-602 (2003).
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).
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).
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).
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).
255. Rodríguez-Perálvarez, M., De la Mata, M., Burroughs, A. K. Liver transplantation: immunosuppression and oncology. Curr. Opin. Organ Transplant. 19, 253-260 (2014).
256. Villanueva, A., et al. Pivotal role of mTOR signaling in hepatocellular carcinoma. Gastroenterology 135, 1972-1983 (2008).
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).
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).
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).
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).
261. Zimmerman, M. A., et al. Sirolimus-based immunosuppression following liver transplantation for hepatocellular carcinoma. Liver Transpl. 14, 633-638 (2008).
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).
263. Liang, W., et al. Sirolimus-based immunosuppression in liver transplantation for hepatocellular carcinoma: a meta-analysis. Liver Transpl. 18, 62-69 (2011).
264. Yanik, E. L., et al. Effects of maintenance immunosuppression with sirolimus after liver transplant for hepatocellular carcinoma. Liver Transpl. 22, 627-634 (2016).
265. Bilbao, I., et al. Multiple indications for everolimus after liver transplantation in current clinical practice. World J. Transplant. 4, 122-132 (2014).
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).
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).
268. US National Library of Medicine. ClinicalTrials. gov https://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).
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).
271. Ong, J. P., Younossi, Z. M. Epidemiology and natural history of NAFLD and NASH. Clin. Liver Dis. 11, 1-16 (2007).
272. Yopp, A. C., Choti, M. A. Non-alcoholic steatohepatitis-related hepatocellular carcinoma: a growing epidemic Dig. Dis. 33, 642-647 (2015).
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).
274. Hoshida, Y., et al. Gene-expression signature of vascular invasion in hepatocellular carcinoma. J. Hepatol. 55, 1325-1331 (2011).
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).
276. Schulze, K., Nault, J.-C., Villanueva, A. Genetic profiling of hepatocellular carcinoma using next-generation sequencing. J. Hepatol. 65, 1031-1042 (2016).
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).