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Ichida et al. Hepatoma Res 2020;6:54 I http://dx.doi.org/10.20517/2394-5079.2020.59 Page 9 of 11
[15]
model was developed in Korea, i.e., the MoRAL score, using only serum levels of AFP and DCP , which
was shown to be more effective than the Milan criteria in predicting recurrence after LT. While DCP is
criticized for not being a routine laboratory test in the West and for its dependence on vitamin K status and
warfarin administration in clinical settings, reports from Asia as well as the present study warrant further
study on the DCP in predicting HCC recurrence after LT.

NLR and PLR are indicators of inflammatory status previously reported as prognostic markers for the
recurrence of various cancers, including HCC [16,17] . As the usefulness of NLR has been presented in
both DDLT and LDLT settings [40,41] , NLR is incorporated in some prognostic models [14,42] . Although the
usefulness of PLR has also been reported since 2012, supporting evidence is still limited [40,41] . NLR and
PLR were not as useful as AFP, AFP-L3, and DCP in predicting HCC recurrence after LT in the present
study [Figure 2, Table 2, Supplementary Figure 2]. One of the drawbacks of these inflammatory markers
may be the inconstant nature of neutrophil, platelet, and lymphocyte counts. This is more so in cirrhotic
patients who suffer from portal hypertension, splenomegaly, and consequently, pancytopenia. As for other
biomarkers, we could not evaluate the usefulness of FDG-PET, one of the promising biomarkers reported
previously [18,19] , because FDG-PET was not routinely performed at our institute.

Our analysis has several weaknesses related to its retrospective design and the limited number of patients
included. Both the present and the national cohorts used in the establishment of the 5-5-500 criteria
were based on the long time-course with a considerable number of cases from nearly 20 years ago. As
the developments and advances in imaging modalities, anti-viral treatments, and immunosuppression
regimens might have changed practice in the management of LT considerably over the last two decades,
it seems mandatory to validate the criteria in the recent cohort or in the prospective study. Although the
[43]
usefulness of tumor downstaging before LT has been reported recently , unfortunately there was no case
of intentional downstaging in the present cohort. In Japan, where the indication of LT for HCC is restricted
to those with decompensated cirrhosis by the national insurance system, HCC patients with compensated
cirrhosis are usually recommended for locoregional treatments and will be referred for LT when they
develop decompensated cirrhosis not amenable to locoregional treatments. The downstaging strategy for
those beyond the selection criteria and the expansion of the indication criteria are two opposite ways to
expand the indication of LT for candidates, which should be compared and discussed in future studies.

In conclusion, the present study suggests that both the 5-5-500 criteria and the Japanese DEC are
appropriate for patients with HCC in LDLT. AFP, including AFP-L3, was demonstrated to be a reliable
biomarker and could reasonably be incorporated into the expanded selection criteria. Further validation
with more recent cases and a prospective study is warranted.

DECLARATIONS
Authors’ contributions
Conception and design: Ichida A, Akamatsu N
Provision of study materials or patients: Ichida A
Collection and assembly of data: Ichida A, Akamatsu N
Data analysis and interpretation: Ichida A, Akamatsu N
Manuscript writing: Ichida A, Akamatsu N, Hasegawa K
Final approval of manuscript: Ichida A, Akamatsu N, Hasegawa K

Availability of data and materials
The data used in the present study were submitted to the journal.