Liver transplantation for hepatocellular carcinoma: Role of inflammatory and immunological state on recurrence and prognosis

Table 1 Studies reporting the negative impact of increased neutrophil-to-lymphocyte ratio measured at transplant on the outcome of liver transplantation for hepatocellular carcinoma

Ref.	Patients (n)	Type of LT	NLR cut-off level for poor prognosis	Other factors associated with worse outcome	5-yr RFS with high vs low NLR	5-yr OS with high vs low NLR	Parameters positively correlated with increased NLR
Halazun et al[15]	150	NA	5	Tumor sizeAFP	25% vs 75%1	28% vs 64%	None
Bertuzzo et al[16]	219	DDLT	5	Microvascular invasion	6% vs 89%	14% vs 73%	Micro/macro vascular invasionTumor gradingAFPCRPOutside MC
Wang et al[17]	101	DDLT	3	Tumor numberMacrovascular invasion	28% vs 65%1	19% vs 62%	Macrovascular invasionAFPTumor sizeOutside MCOutside UCSF criteriaOutside Hangzhou criteria
Limaye et al[18]	160	NA	5	Microvascular invasion AFP	27% vs 79%	38% vs 68%	None
Motomura et al[19]	158	LDLT	4	Outside MC	30% vs 89%	57% vs 84%	Serum/peritumoral IL-17Density of peritumoral CD163CRPTacrolimus vs cyclosporine
2Yoshizumi et al[20]	104	LDLT	4	Nodule size + number ≥ 8.0	42% vs 86%	Not reported	Microvascular invasionTumor grading

¹In these studies, disease-free survival instead of recurrence-free survival rates were reported (and displayed in the present table);

²This study was performed by the same authors as the previous one[19], and included only patients with surgical and/or locoregional treatment preceding living donor liver transplantation (LDLT). Thus, the patient population is probably at least partly included in the population of the previous study from the same Institution. NLR: Neutrophil-to-lymphocyte ratio; LT: Liver transplantation; HCC: Hepatocellular carcinoma; RFS: Recurrence-free survival; OS: Overall survival; NA: Not assessable; AFP: Alpha-fetoprotein; CRP: C-reactive protein; MC: Milan criteria; DDLT: Deceased donor liver transplantation; UCSF: University of California at San Francisco.

Table 2 Studies reporting the effect of different basal immunosuppression schedules on the outcome of liver transplantation for hepatocellular carcinoma

Ref.	Evaluatedimmunosuppressor	Evaluated parameter	Patients (n)	Overall recurrence rate	Outcome parameters	Pvalue
Vivarelli et al[24]	CsA cumulative dosage 1st yr	Low dosage 1st yr vs high dosage 1st yr	39 vs 30	12.20%	5 yr RFS: 93% vs 5 yr RFS: 76%	0.0100
Kneteman et al[25]	SRL	in MC vs out MC	19 vs 21	12.50%	4 yr RFS: 81.1% vs 4 yr RFS: 76.8%	0.4800
Vivarelli et al[26]	CsA	Low exposure vs high exposure	49 vs 21	10.00%	RR: 0% vs RR: 33.3%	< 0.0010
Decaens et al[27]	CNI	CsA vs TAC	264 vs 119	31.80%	5 yr RFS: 52.5% vs 5 yr RFS: 70.8%	0.0030
Decaens et al[27]	ATG/OKT3	Not administered vs administered	356 vs 55	31.80%	5 yr RFS: 58.8% vs 5 yr RFS: 45.4%	0.0200
Vivarelli et al[7]	TAC	Low exposure vs high exposure	44 vs 16	20.00%	RR: 9.1% vs RR: 50%	0.0010
Zhou et al[28]	TAC and SRLin patients outMC	TAC vs SRL	46 vs 27	27.40%	2 yr OS: 50.9% vs 2 yr OS: 80.6%	0.0110
Zimmerman et al[29]	TAC and SRL	TAC + MMF vs TAC + SRL	52 vs 45	12.40%	5 yr RFS: 54.0% vs 5 yr RFS: 78.8%	-
Chinnakotla et al[8]	TAC and SRL	TAC + MMF vs SRL	106 vs 121	11.00%	5 yr RFS: 60% vs 5 yr RFS: 80%	0.0001
Vivarelli et al[30]	TAC and SRL	TAC vs TAC + SRL	31 vs 31	25.80%	3 yr RFS: 56% vs 3 yr RFS: 86%	0.0400
Toso et al[31]	SRL	Not administered vs administered	2382 vs 109	-	5 yr OS: 68.7% vs 5 yr OS: 83.1%	≤ 0.0500
Xing et al[32]	Basiliximab and steroids in patients in MC	TAC + MMF + basiliximab vs TAC + MMF + steroids	28 vs 36	-	5 yr OS: 88.9% vs 5 yr OS: 57.4%	0.0220
Rodríguez-Perálvarez et al[33]	CNI	Low exposure 1st mo vs high exposure 1st mo	171 vs 48	16.40%	5 yr RR: 14.7% vs 5 yr RR: 27%	0.0070

LT: Liver transplantation; HCC: Hepatocellular carcinoma; CsA: Cyclosporine A; RFS: Recurrence free survival; SRL: Sirolimus; MC: Milan criteria; RR: Recurrence rate; CNI: Calcineurin inhibitors; TAC: Tacrolimus; ATG: Anti-thymocyte globulins; OS: Overall survival; MMF: Mycophenolate mofetil.