Serum biomarkers and risk of hepatocellular carcinoma recurrence after liver transplantation

Table 1 Main selection criteria for liver transplantation including alpha-fetoprotein

Reference	Country	n	AFP cutoff, ng/mL	Criteria	Validated in
Yang et al[34], 2007	Korea	63	20, 200 and 1000	Tumor number, tumor size and AFP level with different cutoffs
Zheng et al[35], 2008	China	195	400	Hangzhou criteria: (1) TTD ≤ 8 or (2) TTD > 8, well or moderately differentiated and AFP < 400
Toso et al[36], 2009	SRTR database	6487	400	TTV/AFP criteria for overall survival after LT: TTV ≤ 115cm3 and AFP ≤ 400	Validated for recurrence after LT: Grat et al[37], 2013; Toso et al[38],2015.
Duvoux et al[17], 2012	France	537 (training cohort); 435 (validation cohort)	100 and 1000	AFP model: tumor number, tumor size and AFP level with different cutoffs	Varona et al[39], 2015; Notarpaolo et al[20], 2017; Piñero et al[40], 2016; Rhu et al[41], 2018
Lai et al[45], 2012	Italy	158	400	AFP-TTD criteria: TTD < 8 cm and AFP < 400
Grąt et al[42], 2014	Poland	101	100	Warsaw criteria: (I) fulfillment of Milan criteria; or (II) Up-to-7 or UCSF criteria and AFP < 100	Piñero et al[43], 2016; Grat et al[44], 2017
Kim et al[46], 2014	Korea	180	1000	Samsung criteria: Up to 7 tumors ≤ 6 cm, and AFP ≤ 1000

AFP: Alpha-fetoprotein; LT: Liver transplantation; SRTR: Scientific Registry of Transplant Recipients; TTD: Total tumor diameter; TTV: Total tumor volume; UCSF: University of California San Francisco.

Table 2 Main selection criteria for liver transplantation including des-gamma-carboxyprothrombin

Reference	Country	n	Cutoff values	Criteria	Validated in
Takada et al[61],2007	Japan	125	DCP: 400	Kyoto criteria: up to 10 tumors ≤ 5 cm and DCP ≤ 400	Fujiki et al[63], 2009; Kaido et al[64], 2013
Soejima et al[62], 2007	Japan	60	DCP: 300	Kyushu criteria: any number of tumors < 5 cm and DCP < 300	Shirabe et al[65], 2011
Todo et al[66], 2007	Japan	551	AFP:200, DCP: 100	A-P level: AFP ≤ 200 and DCP ≤ 100
Chaiteerakij et al[70], 2015	United States	127	AFP:250, DCP: 7.5
Yang et al[67], 2016	Korea	88 (training cohort); 198 (validation cohort)	AFP: 200; DCP: 200	A-P 200: AFP ≤ 200 or DCP ≤ 200
Kim et al[68], 2016	Korea	461	AFP: 150; DCP:100	--
Lee et al[69], 2016	Korea	566	AFP and DCP; continuous variables	MoRAL score: 11x√ DCP + 2x√AFP

AFP: Alpha-fetoprotein; DCP: Des-gamma-carboxyprothrombin; MoRAL: Model of recurrence after liver transplantation.

Table 3 Main studies analyzing several pre-liver transplantation systemic inflammation biomarkers and proposed scores

Reference	Country	LT type	n	Biomarkers	Time of biomarker test	Risk factors by multivariate analysis	Risk score
Yoshizumi et al[95], 2013	Japan	LDLT	104	AFP > 400, DCP > 300, NLR ≥ 4	Not specified	NLR, tumor size + number ≥ 8	No
Na et al[96], 2014	Korea	LDLT	224	AFP ≥ 100, NLR ≥ 6, CRP ≥ 1,	Day of LT	NLR ≥ 6 and AFP ≥ 100	Prognostic factor score: NLR ≥ 6 and CRP ≥ 1 (one point each)
Shindoh et al[80], 2014	Japan	LDLT	124	AFP, DCP, NLR	Day before LT, maximum and mean values within 90 d before LT	Tumor ≥ 5, MVI, mean NLR and maximum AFP and DCP before LT	Tokyo criteria, AFP > 250 and DCP > 450 (one point each)
Lai et al[78], 2014	Belgium	DDLT	146	AFP > 200, NLR > 5.4, PLR > 150	At inclusion on the waiting list, at LT,	AFP, NLR and PLR in univariate analysis	No
Parisi et al[79], 2014	UK	DDLT	150	NLR ≥ 5, PLR ≥ 150, IBI score	Day of LT	Absence of neoadjuvant therapy, beyond Milan criteria on explant	No
Harimoto et al[99], 2016	Japan	LDLT	190	DCP ≥ 300, NLR ≥ 2.66, PLR ≥ 70.4, CRP ≥ 0.27	Not specified	NLR, DCP, and tumor number ≥ 5	No
Wang et al[97], 2016	China	DDLT/LDLT	248	NLR continuous, AFP > 400	Within 1 wk before LT	NLR , AFP > 400, age, tumor number and size	Model TFS: 1.094 × tumor number (≤ 3, 0 points; > 3 (1 point) + 0.094 × maximum tumor diameter + 0.754 × AFP (≤ 400, 0 points; > 400, 1 point) + 0.085 × NLR -0.024 × age
Halazun et al[98], 2017	United States	DDLT/LDLT	339	NLR ≥ 5, AFP	NLR at day of LT; serial AFP at HCC diagnosis, before pre-LT treatment and at LT.	Tumor size and number, NLR ≥ 5, maximum pre-LT AFP, vascular invasion and poor differentiated tumors	MoRAL score: (1) pre-MoRAL: NLR ≥ 5 (6 points) + AFP > 200 (4 points) + largest tumor size > 3 cm by imaging (3 points); (2) post-MoRAL: grade IV tumors (6 points) + vascular invasion (2 points) + tumor size > 3 on pathology (3 points) + tumor number > 3 on pathology (2 points); and (3) combined score.
Fu et al[100], 2018	China	LDLT	150	NLR, PLR, MLR, SII	Within 1 wk before LT	No association	No

AFP: Alpha-fetoprotein; CRP: C-reactive protein; DCP: Des-gamma-carboxyprothrombin; DDLT: Deceased donor liver transplantation; IBI: Inflammation based index; LDLT: Living donor liver transplantation; LT: Liver transplantation; MVI: Microvascular invasion; NLR: Neutrophil-to-lymphocyte ratio; PLR: Platelet-to-lymphocyte ratio; SII: Systemic inflammation index; TFS: Tumor-free survival.