Liver transplantation for hepatocellular carcinoma - non-cancer factors and implications for improving outcome beyond standard tumor criteria

Abstract

Liver transplantation (LT) is recognized as best treatment option in patients with early hepatocellular cancer (HCC) in underlying liver cirrhosis. Apart from tumor size and number implemented in the Milan criteria, which are current worldwide standards for patient selection, several biological tumor factors have been identified to affect cancer-specific outcome. In particular, grading and vascular tumor invasions were shown to correlate with aggressive biological tumor behavior and poor survival following LT. Identifying tumors with favorable biology is one important approach for expanding the pool of eligible liver recipients beyond the Milan burden limits. Improving the immunological state and condition for appropriate defense against circulating cancer cell attack may be another important prognostic aspect. Therefore, there is increasing interest in non-cancer factors related to the peritransplant period that may influence the oncological outcome by providing negative immunomodulatory actions. Considering and modulation of these non-HCC factors of prognosis might contribute in safely expanding the HCC LT selection criteria.

Keywords

Hepatocellular carcinoma / liver transplantation / tumor biology / non-cancer factors / outcome

References

[1] Bhardwaj N,Silva MA.Current treatment approaches to HCC with a special consideration to transplantation.J Transplant2016;2016:7926264 PMCID:PMC4931061

[2] Sapisochin G.Liver transplantation for hepatocellular carcinoma: outcomes and novel surgical approaches.Nat Rev Gastroenterol Hepatol2017;14:203-17

[3] Mazzaferro V,Doci R,Pulvirenti A,Montalto F,Morabito A.Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis.N Engl J Med1996;334:693-9

[4] McPeake JR,Zaman S,Wight DG,Calne RY.Liver transplantation for primary hepatocellular carcinoma: tumor size and number determine outcome.J Hepatol1993;18:226-34

[5] Iwatsuki S.Role of liver transplantation in the treatment of hepatocellular carcinoma.Semin Surg Oncol1993;9:337-40 PMCID:PMC2989620

[6] Mazzaferro V,Poon RT,Yao FY,Bhoori S.Liver transplantation for hepatocellular carcinoma.Ann Surg Oncol2008;15:1001-7 PMCID:PMC2266786

[7] De Giorgio M,Cohen E,Lucà MG,Pinelli D,Valsecchi MG,Colledan M,Strazzabosco M.Prediction of progression-free survival in patients presenting with hepatocellular carcinoma within the Milan criteria.Liver Transpl2010;16:503-12

[8] Hoffmann K,Hillebrand N,Ganten TM,Schmidt J,Schemmer P.Risk factors of survival after liver transplantation for HCC: a multivariate single-center analysis.Clin Transplant2011;25:E541-51

[9] Taniguchi M.Liver transplantation in the MELD era--analysis of the OPTN/UNOS registry.Clin Transpl2012;41-65

[10] Adler M,Vereerstraeten P,Lerut J,Van Vlierberghe H,Donckier V,Delwaide J,Chapelle T,Nevens F.Outcome of patients with hepatocellular carcinoma listed for liver transplantation within the Eurotransplant allocation system.Liver Transpl2008;14:526-33

[11] Ferre C,Aguilera L,Rodríguez-Santiago E,García-González M,López-Buenadicha A,Rodríguez-Gandía M,Albillos A.Current allocation policy is favorable for patients with hepatocellular carcinoma waiting for liver transplantation.Dig Liver Dis2018;pii:S1590-8658:30721

[12] Massie AB,Gentry SE,Axelrod DA,Schnitzler MA,Salvalaggio PR.MELD exceptions and rates of waiting list outcomes.Am J Transplant2011;11:2362-71 PMCID:PMC3229963

[13] Facciuto ME,Katta U,Sharma J,Sheiner P,Wolf DC.Liver transplantation for hepatocellular carcinoma: defining the impact of using extended criteria liver allografts.Transplantation2011;92:446-52

[14] Choi HJ,Na GH,You YK.Extended criteria for living donor liver transplantation in patients with advanced hepatocellular carcinoma.Transplant Proc2012;44:399-402

[15] Volk ML,Lok AS.Who decides? Living donor liver transplantation for advanced hepatocellular carcinoma.Transplantation2006;82:1136-9

[16] Yao FY,Bass NM,Ascher NL.Liver transplantation for hepatocellular carcinoma: comparison of the proposed UCSF criteria with the Milan criteria and the Pittsburgh modified TNM criteria.Liver Transpl2002;8:765-74

[17] Decaens T,Hadni-Bresson S,Gugenheim J,Bernard PH,Sulpice L,Hardwigsen J,Pageaux GP,Chazouilleres O,Duvoux C.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 Transpl2006;12:1761-9

[18] Mazzaferro V,Miceli R,Schiavo M,Camerini T,Schwartz ME,Adam R,Salizzoni M,Forner A,Cillo U,Troisi R,Gerunda GE,Belghiti J,Gugenheim J,Van Hoek B.Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis.Lancet Oncol2009;10:35-43

[19] Ecker BL,Forde KA,Reddy KR,Siegelman ES,Ben-Josef E,Abt PL,Olthoff KM.Patterns of discordance between pretransplant imaging stage of hepatocellular carcinoma and posttransplant pathologic stage: a contemporary appraisal of the Milan criteria.Transplantation2018;102:648-55

[20] Shah SA,McGilvray ID,Cleary SP,Greig PD.Accuracy of staging as a predictor for recurrence after liver transplantation for hepatocellular carcinoma.Transplantation2006;81:1633-9

[21] Pecchi A,De Santis M,Nosseir S,Di Benedetto F.Post-transplantation hepatocellular carcinoma recurrence: patterns and relation between vascularity and differentiation degree.World J Hepatol2015;7:276-84 PMCID:PMC4342610

[22] Li WX,Gao PJ,Zhu JY.Histological differentiation predicts post-liver transplantation survival time.Clin Res Hepatol Gastroenterol.2014;38:201-8

[23] Zhang X,Shen F.Significance of presence of microvascular invasion in specimens obtained after surgical treatment of hepatocellular carcinoma.J Gastroenterol Hepatol2018;33:347-54

[24] Grąt M,Patkowski W,Krasnodębski M,Lewandowski Z,Grąt K,Ligocka J.Limitations of predicting microvascular invasion in patients with hepatocellular cancer prior to liver transplantation.Sci Rep2017;7:39881 PMCID:PMC5216407

[25] Chandarana H,Hajdu CH,Babb JS.Microvascular invasion in hepatocellular carcinoma: is it predictable with pretransplant MRI?.AJR Am J Roentgenol2011;196:1083-9

[26] Pawlik TM,Anders RA,Maley W.Preoperative assessment of hepatocellular carcinoma tumor grade using needle biopsy: implications for transplant eligibility.Ann Surg2007;245:435-42 PMCID:PMC1877015

[27] Lee HW,Lee SG,Joh JW,Kim SI,Kim DS,Suh KS.Patient selection by tumor markers in liver transplantation for advanced hepatocellular carcinoma.Liver Transpl2018;

[28] Viveiros A,Finkenstedt A.Hepatocellular carcinoma: when is liver transplantation oncologically futile?.Transl Gastroenterol Hepatol2017;2:63 PMCID:PMC5539399

[29] El-Fattah MA.Hepatocellular carcinoma biology predicts survival outcome after liver transplantation in the USA.Indian J Gastroenterol2017;36:117-25

[30] Sapisochin G,Laurence JM,Barbas A,Cleary SP,Cattral MS,Selzner M,Selzner N,Greig PD.The extended Toronto criteria for liver transplantation in patients with hepatocellular carcinoma: a prospective validation study.Hepatology2016;64:2077-88

[31] Andreou A,Guel S,Sauer IM,Pascher A,Seehofer D.Tumor DNA index and α-fetoprotein level define outcome following liver transplantation for advanced hepatocellular carcinoma.Eur Surg Res2015;55:302-18

[32] Kim SH,Kim WJ,Kwon JH,Cho HD,Chung YK.Preoperative prognostic values of α-fetoprotein (AFP) and protein induced by Vitamin K absence or antagonist-II (PIVKA-II) in patients with hepatocellular carcinoma for living donor liver transplantation.Hepatobiliary Surg Nutr2016;5:461-9 PMCID:PMC5218910

[33] Chaiteerakij R,Addissie BD,Harmsen WS,Peters BE,Ward MM,Moser CD,Umeda N,Harnois DM,Yamada H,Algeciras-Schimnich A,Therneau TM.Combinations of biomarkers and Milan criteria for predicting hepatocellular carcinoma recurrence after liver transplantation.Liver Transpl2015;21:599-606 PMCID:PMC4490162

[34] Cescon M,Ercolani G,Odaldi F.Liver transplantation for hepatocellular carcinoma: role of inflammatory and immunological state on recurrence and prognosis.World J Gastroenterol2013;19:9174-82 PMCID:PMC3882391

[35] Hsu CC,Wang CC,Yong CC,Liu YW,Lee WF,Chan YC,Eng HL.Combination of FDG-PET and UCSF criteria for predicting HCC recurrence after living donor liver transplantation.Transplantation2016;100:1925-32

[36] Kornberg A,Tannapfel A,Krause B,Gottschild D.Patients with non-[18 F]fludeoxyglucose-avid advanced hepatocellular carcinoma on clinical staging may achieve long-term recurrence-free survival after liver transplantation.Liver Transpl2012;18:53-61

[37] Chapman WC,Vachharajani N,Saad N,Wellen J,Khan AS.Liver transplantation for advanced hepatocellular carcinoma after downstaging without up-front stage restrictions.J Am Coll Surg2017;224:610-21

[38] Agopian VG,McWilliams J,Markovic D,Kaldas FM,Yersiz H,Busuttil RW.Complete pathologic response to pretransplant locoregional therapy for hepatocellular carcinoma defines cancer cure after liver transplantation: analysis of 501 consecutively treated patients.Ann Surg2015;262:536-45

[39] Fernandes JV,Jatobá CA,de Azevedo JW.The role of the mediators of inflammation in cancer development.Pathol Oncol Res2015;21:527-34

[40] Horiguchi H,Hawkins RB,Stortz JA,Weiss BP,Bihorac A,Mohr AM,Tsujimoto H,Moore FA,Efron PA.Innate immunity in the persistent inflammation, immunosuppression, and catabolism syndrome and its implications for therapy.Front Immunol2018;9:595 PMCID:PMC5893931

[41] Yu LX,Wang HY.Role of nonresolving inflammation in hepatocellular carcinoma development and progression.NPJ Precis Oncol2018;2:6 PMCID:PMC5871907

[42] Ringelhan M,O'Connor T,Heikenwalder M.The immunology of hepatocellular carcinoma.Nat Immunol2018;19:222-32

[43] Ghouri YA,Rowe JH.Review of hepatocellular carcinoma: epidemiology, etiology, and carcinogenesis.J Carcinog2017;16:1 PMCID:PMC5490340

[44] Toso C,Majno P.Liver transplantation for hepatocellular carcinoma: five steps to prevent recurrence.Am J Transplant2011;11:2031-5

[45] Shirabe K,Kimura K,Ikeda T,Yoshizumi T,Aishima S.New scoring system for prediction of microvascular invasion in patients with hepatocellular carcinoma.Liver Int2014;34:937-41

[46] Sun C,Deng Z,Feng Q,Yuan R,Mao Y,Wu L.The diagnostic value of assays for circulating tumor cells in hepatocellular carcinoma: a meta-analysis.Medicine (Baltimore)2017;96:e7513 PMCID:PMC5521903

[47] Noor MT.Immune dysfunction in cirrhosis.J Clin Transl Hepatol2017;5:50-8 PMCID:PMC5411357

[48] Wang Q,Blank S,Kadri H,Manizate F,Labow DM,Hiotis SP.Impact of liver fibrosis on prognosis following liver resection for hepatitis B-associated hepatocellular carcinoma.Br J Cancer2013;109:573-81 PMCID:PMC3738114

[49] Sasaki K,Margonis GA,Andreatos N,Hashimoto M.Effect of background liver cirrhosis on outcomes of hepatectomy for hepatocellular carcinoma.JAMA Surg2017;152:e165059

[50] Ioannou GN,Carithers RLJr.Liver transplantation for hepatocellular carcinoma: impact of the MELD allocation system and predictors of survival.Gastroenterology2008;134:1342-51

[51] Halazun K, Przybyszewski E, Verna E, Samstein B, Fox A, Brown R, Emond J. The influence of rising Lab MELD on vascular invasion in HCC. Available from: https://atcmeetingabstracts.com/abstract/the-influence-of-rising-lab-meld-on-vascular-invasion-in-hcc/. [Last accessed on 26 Sep 2018]

[52] Macdonald B,Harper AM,Yao FY.Liver transplantation for hepatocellular carcinoma: analysis of factors predicting outcome in 1074 patients in OPTN Region 5.Clin Transplant2015;29:506-12 PMCID:PMC4797941

[53] Komorowski AL,Julka KD,Lin CC,Chen CL.AFP role in predicting recurrence of hepatocellular carcinoma after living donor liver transplantation in HCV patients.Neoplasma2018;65:455-60

[54] Foerster F,Darstein F,Marquardt JU,Weinmann A,Hoppe-Lotichius M,Kloeckner R,Schattenberg JM,Düber C,Lang H,Zimmermann T.Recipient liver function before liver transplantation influences post-transplantation survival in patients with HCC.Eur J Intern Med2018;55:57-65

[55] Faitot F,Pittau G,Adam R,Cunha AS,Cherqui D,Vibert E.Impact of clinically evident portal hypertension on the course of hepatocellular carcinoma in patients listed for liver transplantation.Hepatology2015;62:179-87

[56] Lai JC,Strasburg D.Performance-based measures associate with frailty in patients with end-stage liver disease.Transplantation2016;100:2656-60 PMCID:PMC5118057

[57] Lai JC,Terrault NA,Hayssen H.Frailty predicts waitlist mortality in liver transplant candidates.Am J Transplant2014;14:1870-9 PMCID:PMC4107151

[58] Chang SF.Systematic literature review and meta-analysis of the Association of Sarcopenia with Mortality.Worldviews Evid Based Nurs2016;13:153-62

[59] Laube R,Park L,Vidot H,Strasser SI,Liu K.Frailty in advanced liver disease.Liver Int.2018;

[60] Ebadi M.Insights on clinical relevance of sarcopenia in patients with cirrhosis and sepsis.Liver Int2018;38:786-8

[61] Kahn J,Homfeld N,Kniepeiss D.Both sarcopenia and frailty determine suitability of patients for liver transplantation-a systematic review and meta-analysis of the literature.Clin Transplant2018;32:e13226

[62] Chae MS,Jung JY,Chung HS,Lee J,Hong SH.Perioperative loss of psoas muscle is associated with patient survival in living donor liver transplantation.Liver Transpl2018;24:623-33

[63] Kaido T,Uemoto S.Sarcopenia plays a crucial role in liver transplantation.Hepatobiliary Surg Nutr2017;6:434-6 PMCID:PMC5756760

[64] Wilson D,Sapey E.Frailty and sarcopenia: the potential role of an aged immune system.Ageing Res Rev2017;36:1-10

[65] Brzeszczyńska J,McGregor R,Degen S,Johns N,Schols A,Roubenoff R,Fearon KCH,Jacobi C.Alterations in the in vitro and in vivo regulation of muscle regeneration in healthy ageing and the influence of sarcopenia.J Cachexia Sarcopenia Muscle2018;9:93-105 PMCID:PMC5803613

[66] Angulo J,Rodríguez-Ma-as L.Frailty and sarcopenia as the basis for the phenotypic manifestation of chronic diseases in older adults.Mol Aspects Med2016;50:1-32

[67] Pistilli EE,Alway SE.Interleukin-15 responses to aging and unloading-induced skeletal muscle atrophy.Am J Physiol Cell Physiol2007;292:1298-304

[68] Fujiwara N,Kudo Y,Taguri M,Nakagomi R,Nakatsuka T,Sato M,Enooku K,Asaoka Y,Ohtomo K,Koike K.Sarcopenia, intramuscular fat deposition, and visceral adiposity independently predict the outcomes of hepatocellular carcinoma.J Hepatol2015;63:131-40

[69] Shirai H,Hamaguchi Y,Okumura S,Yagi S,Taura K,Uemoto S.Preoperative low muscle mass and low muscle quality negatively impact on pulmonary function in patients undergoing hepatectomy for hepatocellular carcinoma.Liver Cancer2018;7:76-89

[70] Yabusaki N,Yamada S,Sugimoto H,Nakayama G,Fujiwara M.Adverse impact of low skeletal muscle index on the prognosis of hepatocellular carcinoma after hepatic resection.Int J Surg2016;30:136-42

[71] Voron T,Pietrasz D,Laurent A,Salloum C,Azoulay D.Sarcopenia impacts on short- and long-term results of hepatectomy for hepatocellular carcinoma.Ann Surg2015;261:1173-83

[72] Itoh S,Kimura K,Harimoto N,Uchiyama H,Nishie A.Effect of sarcopenic obesity on outcomes of living-donor liver transplantation for hepatocellular carcinoma.Anticancer Res2016;36:3029-34

[73] Kim YR,Han S,Kim S,Jeong WK,Gwak MS.Sarcopenia as a predictor of post-transplant tumor recurrence after living donor liver transplantation for hepatocellular carcinoma beyond the Milan criteria.Sci Rep2018;8:7157 PMCID:PMC5940915

[74] Sharma P,Yu J,Derstine BA,Wang SC.Bone mineral density predicts posttransplant survival among hepatocellular carcinoma liver transplant recipients.Liver Transpl2016;22:1092-8 PMCID:PMC4961525

[75] Chang KV,Wu WT,Hsu CT.Association between loss of skeletal muscle mass and mortality and tumor recurrence in hepatocellular carcinoma: a systematic review and meta-analysis.Liver Cancer2018;7:90-103

[76] Kamo N,Hamaguchi Y,Okumura S,Shirai H,Okajima H.Impact of enteral nutrition with an immunomodulating diet enriched with hydrolyzed whey peptide on infection after liver transplantation.World J Surg2018;

[77] Duarte-Rojo A,Monta-o-Loza AJ,Ferrando A.Exercise and physical activity for patients with end-stage liver disease: Improving functional status and sarcopenia while on the transplant waiting list.Liver Transpl2018;24:122-39

[78] Nagai S,Kazimi M,Moonka D.Peritransplant lymphopenia is a novel prognostic factor in recurrence of hepatocellular carcinoma after liver transplantation.Transplantation2014;97:694-701

[79] Zhai Y,Hong JC,Kupiec-Weglinski JW.Ischaemia-reperfusion injury in liver transplantation--from bench to bedside.Nat Rev Gastroenterol Hepatol2013;10:79-89 PMCID:PMC3577927

[80] Wang S,Wang X,Dai B,Ma HC,Shi XL.PARP-1 promotes tumor recurrence after warm ischemic liver graft transplantation via neutrophil recruitment and polarization.Oncotarget2017;8:88918-33

[81] Li CX,Shao Y,Li XC,Liu XB,Qi X,Liu J,Yang XX,Lam YF,Lo CM.CXCL10/CXCR3 signaling mobilized-regulatory T cells promote liver tumor recurrence after transplantation.J Hepatol2016;65:944-52

[82] Li CX,Lo CM.The impact of liver graft injury on cancer recurrence posttransplantation.Transplantation2017;101:2665-70

[83] Grąt M,Wronka KM,Lewandowski Z,Krawczyk P,Patkowski W.Ischemia-reperfusion injury and the risk of hepatocellular carcinoma recurrence after deceased donor liver transplantation.Sci Rep2018;8:8935 PMCID:PMC5997656

[84] Kornberg A,Kornberg J,Thrum K.Extended ischemia times promote risk of HCC recurrence in liver transplant patients.Dig Dis Sci2015;60:2832-9

[85] Nagai S,Facciuto M,Abouljoud MS,Florman SS.Ischemia time impacts recurrence of hepatocellular carcinoma after liver transplantation.Hepatology2015;61:895-904

[86] Grąt M,Lewandowski Z,Zieniewicz K,Krawczyk M.The impact of surgical technique on the results of liver transplantation in patients with hepatocellular carcinoma.Ann Transplant2013;18:448-59

[87] Orci LA,Majno PE,Oldani G,Mentha G.Donor characteristics and risk of hepatocellular carcinoma recurrence after liver transplantation.Br J Surg2015;102:1250-7

[88] Vodkin I.Extended criteria donors in liver transplantation.Clin Liver Dis2017;21:289-301

[89] Nemes B,Polak WG,Hara T,Baimakhanov Z,Eguchi S.Extended-criteria donors in liver transplantation part II: reviewing the impact of extended-criteriadonors on the complications and outcomes of liver transplantation.Expert Rev Gastroenterol Hepatol2016;10:841-59

[90] Vinaixa C,Berenguer M.Fat and liver transplantation: clinical implications.Transpl Int2018;31:828-37

[91] Tashiro H,Mikuriya Y.Ischemia–reperfusion injury in patients with fatty liver and the clinical impact of steatotic liver on hepatic surgery.Surg Today2014;44:1611-25

[92] Orci LA,Oldani G,De Vito C,Rubbia-Brandt L,Morel P.Effect of ischaemic preconditioning on recurrence of hepatocellular carcinoma in an experimental model of liver steatosis.Br J Surg2016;103:417-26

[93] Teng da H,Zheng H,Sun LY,Liu YH,Shen ZY.Effect of steatosis donor liver transplantation on hepatocellular carcinoma recurrence: experience at a single institution.Hepatogastroenterology2012;59:858-62

[94] Lué A,Baptista P,Araiz JJ,Serrano MT.How important is donor age in liver transplantation?.World J Gastroenterol2016;22:4966-76 PMCID:PMC4886372

[95] Sharma P,Hussain H,Fontana RJ,Merion RM.Incidence and risk factors of hepatocellular carcinoma recurrence after liver transplantation in the MELD era.Dig Dis Sci2012;57:806-12 PMCID:PMC3288660

[96] Vagefi PA,Yao FY.Potential role of the donor in hepatocellular carcinoma recurrence after liver transplantation.Liver Transpl2015;21:187-94 PMCID:PMC4308564

[97] Ghinolfi D,Pezzati D,Rreka E.Use of elderly donors in liver transplantation: a paired-match analysis at a single center.Ann Surg2018;268:325-31

[98] Pinheiro RS,Nacif LS,Arantes RM,Martino RB,Andraus W.Living donor liver transplantation for hepatocellular cancer: an (almost) exclusive Eastern procedure?.Transl Gastroenterol Hepatol2017;2:68 PMCID:PMC5590014

[99] Cho Y,Lee DH,Yu SJ,Lee KW,Yoon JH.Comparison of treatment outcome between living donor liver transplantation and sorafenib for patients with hepatocellular carcinoma beyond the Milan criteria.Oncotarget2017;8:47555-64 PMCID:PMC5564586

[100] Chan SC.Section 2.Small-for-size liver graft and hepatocellular carcinoma recurrence. Transplantation2014;S7-10

[101] Llovet JM,Rimola J,Colmenero J,Fondevila C,Fuster J,Bruix J.Pilot study of living donor liver transplantation for patients with hepatocellular carcinoma exceeding Milan criteria (Barcelona Clinic Liver Cancer extended criteria).Liver Transpl2018;24:369-79

[102] Liang W,Ling X,Ju W,Shang Y,Guo Z.Living donor liver transplantation versus deceased donor liver transplantation for hepatocellular carcinoma: a meta-analysis.Liver Transpl2012;18:1226-36

[103] Grant RC,Dixon PR,Grant DR.Living vs.deceased donor liver transplantation for hepatocellular carcinoma: a systematic review and meta-analysis. Clin Transplant2013;27:140-7

[104] Kim SH,Kim WJ,Kwon JH,Cho HD,Chung YK.Preoperative prognostic values of α-fetoprotein (AFP) and protein induced by Vitamin K absence or antagonist-II (PIVKA-II) in patients with hepatocellular carcinoma for living donor liver transplantation.Hepatobiliary Surg Nutr2016;5:461-9 PMCID:PMC5218910

[105] Hu Z,Zhou J,Li Z,Wu J,Zheng S.Smaller grafts do not imply early recurrence in recipients transplanted for hepatocellular carcinoma: a Chinese experience.Sci Rep2016;6:26487 PMCID:PMC4880903

[106] Lee EC,Shim JR.Small-for-size grafts increase recurrence of hepatocellular carcinoma in liver transplantation beyond milan criteria.Liver Transpl2018;24:35-43

[107] Eren EA,Beal E,Whitson B.Donations after circulatory death in liver transplant.Exp Clin Transplant2016;14:463-70 PMCID:PMC5461820

[108] Sutherland AI.Challenges and advances in optimizing liver allografts from donation after circulatory deathdonors.J Nat Sci Biol Med2016;7:10-5 PMCID:PMC4780154

[109] Croome KP,Chandok N,Marotta P.Inferior survival in liver transplant recipients with hepatocellular carcinoma receiving donation aftercardiac death liver allografts.Liver Transpl19:1214-23

[110] Croome KP,Burns JM,Paz D,Perry DK,Taner CB.The use of donation after cardiac death allografts does not increase recurrence of hepatocellular carcinoma.Am J Transplant2015;15:2704-11

[111] Khorsandi SE,Cortes M,Quaglia A,Heneghan M,Agarwal K,Vilca-Melendez H,Srinivasan P,Rela M.Does donation after cardiac death utilization adversely affect hepatocellular cancer survival?.Transplantation2016;100:1916-24

[112] Orci LA,Oldani G,De Vito C,Rubbia-Brandt L,Morel P.Effect of ischaemic preconditioning on recurrence of hepatocellular carcinoma in an experimental model of liver steatosis.Br J Surg2016;103:417-26

[113] Orci LA,Delaune V,Oldani G,Rossetti C,Morel P.Effects of the gut-liver axis on ischaemia-mediated hepatocellular carcinoma recurrence in the mouse liver.J Hepatol2018;68:978-85

[114] Kornberg A,Kornberg J,Thrum K.Treating ischaemia-reperfusion injury with prostaglandin E1 reduces the risk of early hepatocellular carcinoma recurrence following liver transplantation.Aliment Pharmacol Ther2015;42:1101-10

[115] Goldaracena N,Selzner M.Normothermic and subnormothermic ex-vivo liver perfusion in liver transplantation.Curr Opin Organ Transplant2016;21:315-21

[116] Allard MA,Imai K,Lopez A,Lemoine A,Cherqui D,Vibert E.Suitability of livers for transplantation when treated by normothermic machine perfusion.Clin Transplant2018;32:e13256

[117] Quillin RC.Hypothermic machine perfusion in liver transplantation.Liver Transpl2018;24:276-81

[118] He X,Zhao Q,Wang D,Yang L,Tang Y,Huang S,Zhu Z,Zhu Y,Xiong W,Liao B,Ma Y,Huang W,Guan X,Huang J.The first case of ischemia-free organ transplantation in humans: a proof of concept.Am J Transplant2018;18:737-44

[119] Amisaki M,Tokuyasu N,Honjo S.Prognostic value of postoperative complication for early recurrence after curative resection of hepatocellular carcinoma.Hepatobiliary Pancreat Dis Int2018;17:323-9

[120] Pravisani R,Isola M,Lorenzin D,Risaliti A.Impact of surgical complications on the risk of hepatocellular carcinoma recurrence after hepatic resection.Updates Surg2018;70:57-66

[121] Khandoga A,Schoenberg M,Frenes K,Trumm C,Guba M,Rentsch M.Differential significance of early surgical complications for acute and long-term recurrence-free survival following surgical resection of hepatocellular carcinoma: do comorbidities play a role?.Eur J Gastroenterol Hepatol2017;29:1045-53

[122] Dai WC,Sin SL,Cheung TT,Lo CM.Impact of intraoperative blood transfusion on long-term outcomes of liver transplantation for hepatocellular carcinoma.ANZ J Surg2018;88:E418-23

[123] Elsabbagh AM,Hawksworth J,Williams C,Kroemer A,Smith C,Fishbein TM.Impact of early reoperation on graft survival after liver transplantation: univariate and multivariate analysis.Clin Transplant2018;32:e13228

[124] Pandey CK,Kajal K,Tandon M,Karna ST.Intraoperative blood loss in orthotopic liver transplantation: the predictive factors.World J Gastrointest Surg2015;7:86-93 PMCID:PMC4478560

[125] Teng F,Tao YF,Wang ZX,Shi XM.Criteria-specific long-term survival prediction model for hepatocellular carcinoma patients after liver transplantation.World J Gastroenterol2014;20:10900-7 PMCID:PMC4138469

[126] Liu B,Fu H,Shi XM,Gao XG,Fu ZR.Excessive intraoperative blood loss independently predicts recurrence of hepatocellular carcinoma after liver transplantation.BMC Gastroenterol2015;15:138 PMCID:PMC4608055

[127] Kornberg A,Kornberg J,Mueller K,Thrum K.Prognostic impact of intraoperative blood loss in liver transplant patients with advanced hepatocellular carcinoma.Anticancer Res2016;36:5355-64

[128] You DD,Seo CH,Yoo YK.Prognostic factors after curative resection hepatocellular carcinoma and the surgeon's role.Ann Surg Treat Res2017;93:252-9 PMCID:PMC5694716

[129] Katz SC,Liau KH,Ruo L,Fong Y,Blumgart LH.Operative blood loss independently predicts recurrence and survival after resection of hepatocellular carcinoma.Ann Surg2009;249:617-23

[130] Elemary M,Stakiw J,Sabry W.Transfusion challenges in hematology oncology and hematopoietic stem cell transplant - literature review and local experience.Transfus Apher Sci2017;56:317-21

[131] Iqbal N,Sundaram V,Burnouf T,Goubran H.Red blood cell transfusion and outcome in cancer.Transfus Apher Sci2017;56:287-90

[132] Liu L,Jiang S,Liu J,Zhou Y,Zhang Y.Perioperative allogenenic blood transfusion is associated with worse clinical outcomes for hepatocellular carcinoma: a meta-analysis.PLoS One2013;8:e64261 PMCID:PMC3669337

[133] Seehofer D,Denecke T,Andreoua A,Pratschke J.Blood transfusions and tumor biopsy may increase HCC recurrence rates after liver transplantation.J Transplant2017;

[134] Han S,Ko JS,Yang JD,Lee SK.Safety of the use of blood salvage and autotransfusion during liver transplantation for hepatocellular carcinoma.Ann Surg2016;264:339-43

[135] Zhai B.Controversy over the use of intraoperative blood salvage autotransfusion during liver transplantation for hepatocellular carcinoma patients.World J. Gastroenterol2013;19:3371-4 PMCID:PMC3683674

[136] Lerut J,Foguenne M.Hepatocellular cancer and recurrence after liver transplantation: what about the impact of immunosuppression?.Transl Gastroenterol Hepatol2017;2:80 PMCID:PMC5676205

[137] Khorsandi SE.Optimization of immunosuppressive medication upon liver transplantation against HCC recurrence.Transl Gastroenterol Hepatol2016;1:25 PMCID:PMC5244705

[138] Suthanthiran M,Maluccio M,Luan FL.Post-transplantation malignancy: a cell autonomous mechanism with implications for therapy.Trans Am Clin Climatol Assoc2009;120:369-88 PMCID:PMC2744527

[139] Zhu H,Tan C,Dai Z,Fan J.Tacrolimus promotes hepatocellular carcinoma and enhances CXCR4/SDF 1α expression in vivo.Mol Med Rep2014;10:585-92 PMCID:PMC4094770

[140] Vivarelli M,Piscaglia F,Bolondi L,Pinna AD.Analysis of risk factors for tumor recurrence after liver transplantation for hepatocellular carcinoma: key role of immunosuppression.Liver Transpl2005;11:497-503

[141] Vivarelli M,La Barba G,Del Gaudio M,Grazi GL.Liver transplantation for hepatocellular carcinoma under calcineurin inhibitors: reassessment of risk factors for tumor recurrence.Ann Surg2008;248:857-62

[142] Rodríguez-Perálvarez M,Naveas MC,García-Caparrós C,Poyato-González A,Montero-álvarez JL,Thorburn D,De la Mata M.Reduced exposure to calcineurin inhibitors early after liver transplantation prevents recurrence of hepatocellular carcinoma.J Hepatol2013;59:1193-9

[143] Zaza G,Caletti C,Stallone G.mTOR inhibition role in cellular mechanisms.Transplantation2018;102:S3-16

[144] de Fijter JW.Cancer and mTOR inhibitors in transplant recipients.Transplantation2017;101:45-55

[145] Duvoux C.mTOR inhibitor therapy: does it prevent HCC recurrence after liver transplantation?.Transplant Rev (Orlando)2015;29:168-74

[146] Yanik EL,Gustafson SK,Israni AK,Engels EA.Effects of maintenance immunosuppression with sirolimus after liver transplant for hepatocellular carcinoma.Liver Transpl2016;22:627-34 PMCID:PMC4846564

[147] Ferreiro AO,López FS,Diaz SP.Everolimus-based immunosuppression in patients with hepatocellular carcinoma at high risk of recurrence after liver transplantation: a case series.Transplant Proc2014;46:3496-501

[148] Vivarelli M,Cucchetti A,Zanello M,Bianchi G,Gaudio MD,Cescon M,Pinna AD.Sirolimus in liver transplant recipients: a large single-center experience.Transplant Proc2010;42:2579-84

[149] Liang W,Ling X,Kong Y,Guo Z.Sirolimus-based immunosuppression in liver transplantation for hepatocellular carcinoma: a meta-analysis.Liver Transpl2012;18:62-9

[150] Menon KV,Heaton ND.Meta-analysis: recurrence and survival following the use of sirolimus in liver transplantation for hepatocellular carcinoma.Aliment Pharmacol Ther2013;37:411-9

[151] Cholongitas E,Rodríguez-Castro KI.Mammalian target of rapamycin inhibitors are associated with lower rates of hepatocellular carcinoma recurrence after liver transplantation: a systematic review.Transpl Int2014;27:1039-49

[152] Zhang ZH,Li P,Pan B.Sirolimus in liver transplant recipients with hepatocellular carcinoma: an updated meta-analysis.J Invest Surg2018;20:1-10

[153] Geissler EK,Zülke C,Proneth A,Burra P,Rentsch M,Schmidt J,Heise M,Cillo U,Adam R,Bachellier P,Rostaing L,Rizell M,Hidalgo E,Wolters H,Roy A,Schlitt A,Graeb C,Valente U,Jamieson N,Colledan M,Becker T,Chazouillères O,Pageaux GP,Soliman T,Pirenne J,Pratschke J,Hauss J,Strasser S,Troisi RI,Lerut J,Klein CG,Mirza DF,Mazzaferro V,Schlitt HJ.Sirolimus use in liver transplant recipients with hepatocellular carcinoma: a randomized, multicenter, open-label phase 3 trial.Transplantation2016;100:116-25 PMCID:PMC4683033

[154] Angelico R,Manzia TM.Using a weaning immunosuppression protocol in liver transplantation recipients with hepatocellular carcinoma: a compromise between the risk of recurrence and the risk of rejection?.Transl Gastroenterol Hepatol2017;2:74 PMCID:PMC5639004

[155] Todo S,Goto R,Nagatsu A,Watanabe M,Suzuki T,Kamiyama T,Sugita J,Bashuda H,Demetris AJ.A pilot study of operational tolerance with a regulatory T-cell-based cell therapy in living donor liver transplantation.Hepatology2016;64:632-43

[156] de la Garza RG,Merino J,D'Avola D,Delgado JA,I-arrairaegui M,Sola JJ,Quiroga J.Trial of complete weaning from immunosuppression for liver transplant recipients: factors predictive of tolerance.Liver Transpl2013;19:937-44

[157] Manzia TM,Baiocchi L,Ciano P,Angelico M,Tisone G.The tor vergata weaning of immunosuppression protocols in stable hepatitis C virus liver transplant patients: the 10-year follow-up.Transpl Int2013;26:259-66