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Page 8 of 11 Ichida et al. Hepatoma Res 2020;6:54 I http://dx.doi.org/10.20517/2394-5079.2020.59
[1]
Mazzaferro et al. . In line with this recommendation, the 5-5-500 criteria was established with the intent
to enable the maximal enrollment of candidates while securing a 5-year recurrence rate below 10% and a
[24]
5-year survival rate over 70% based on a retrospective data analysis of the Japanese nationwide survey .
Because the exclusion of patients within the Milan but beyond the 5-5-500 criteria seems not socially
acceptable nor rationale, and considering the worldwide prevalence and acceptance of the Milan criteria,
the Japanese DEC, Milan + 5-5-500, was adopted as the new indication criteria now in Japan.

In the present study, the 5-year recurrence and survival rate in patients meeting the 5-5-500 criteria and
the Japanese DEC were superior to those socially accepted as mentioned above [Figure 1]. In addition,
the number of LDLT candidates increased considerably using these criteria [Supplementary Figure 1 and
Supplementary Table 1]. The outcomes of survival and recurrence were similar to our previous national
[24]
report though the increase of LDLT candidates was a bit modest in the present study. Univariate analysis
revealed that both beyond the 5-5-500 criteria and beyond the Japanese DEC were significant predictors
of recurrence [Table 2]. Meanwhile, the recurrence rate was higher in patients beyond the Japanese DEC
[Supplementary Figure 1 and Supplementary Table 1]. On the basis of these findings, we consider that the
Japanese DEC are the appropriate selection criteria to maximize the number of LDLT candidates while
securing acceptable outcomes. The major concern is that the recurrence rate was considerably high (42.9%)
in patients within the Milan but beyond the 5-5-500 criteria in the present study [Supplementary Table 1].
The exclusion of patients within the Milan criteria, however, seems not socially acceptable at present. In
addition, when the Japanese DEC was adopted, the 5-year recurrence and survival rate still fell within the
target as a whole.

Amongst five biomarkers, AFP seems to be the most reliable marker with the highest AUC value [Figure 2].
The usefulness of AFP in predicting recurrence after LT has been investigated by many researchers [12-14,30-32] ,
and AFP is incorporated in some selection [7,10,12,33] and prognostic models [12-14] . The AFP model, developed
by the Liver Transplantation French Study Group, combines serum AFP level, tumor size, and tumor
[12]
number . Another famous prognostic model is the RETREAT score, which incorporated microvascular
invasion, tumor diameter, and tumor number other than the AFP value as prognostic variables . Another
[13]
prognostic model, the TRAIN score, incorporated the AFP slope, which was defined as [(final-AFP)-
[14]
(initial-AFP)]/time . The cut-off value of AFP differs from study to study, ranging from 15 ng/mL to
1000 ng/mL [7,10,12,13,30-33] . The AFP cut-off value of 60 ng/mL, used in the present study, is relatively low
compared with those used in other studies, however, the cut-off value was shown to be useful in predicting
recurrence [Supplementary Figure 2]. The present results as well as the previous reports justifiy the use of
pretransplant AFP values in the expanded indication criteria of LT for HCC patients.

[20]
AFP-L3, a reliable marker for the diagnosis of HCC , proved to be a promising marker for recurrence
after LT since the specificity of AFP-L3 was the highest [Figure 2] and patient recurrence rate curves
[34]
were well stratified using AFP-L3 [Supplementary Figure 2]. However, there has been little study
investigating the usefulness of AFP-L3 in predicting HCC recurrence after LT. Highly sensitive AFP-L3
became available around 2010 in Japan, which enabled the measurement of AFP-L3 even in patients with
total AFP levels below 20 ng/mL [20,35-37] . Highly sensitive AFP-L3 is reported to be 5-10 times more sensitive
[37]
than conventional AFP-L3 . Along with these studies in non-transplant HCC patients, the present results
warrant further investigation and validation for the usefulness and efficacy of AFP-L3 in predicting HCC
recurrence after LT.

The AUC value of DCP was the 3rd highest [Figure 2] and multivariate analysis revealed that DCP is
one of the independent risk factors for recurrence [Table 2] in this cohort. Though DCP has not been
commonly used in the west , some argued that DCP is more predictive than AFP [8,39] , and indeed, DCP is
[38]
[6,8]
incorporated in the extended indication criteria of LT at two major centers in Japan . A new prognostic