Page 119 - Read Online

Kornberg et al. Hepatoma Res 2018;4:60 I http://dx.doi.org/10.20517/2394-5079.2018.86 Page 11 of 19

[127]
We have recently studied the impact of IOBL with a cut-off value of 1500 mL in 111 LT patients with HCC .
Post-LT RFS rates at 3 and 5 years were 91.9% and 91.9% in the low, but only 43.9% and 37.1% in the high IOBL
subset (P < 0.001). Along with PET-status, tumor grading and AFP level, IOBL was identified as an independent
predictor of cancer-specific survival. Furthermore, IOBL correlated independently with cancer relapse in
[127]
unfavourable tumor phenotypes, such as Milan Out and PET+ tumors, but not in low-risk HCC .
Enhanced spread of occult cancer cells, aggravation of I/R injury to the graft and induction of pro-
inflammatory and immunosuppressive mechanisms are currently discussed as underlying cancerogenic
mechanisms [125-129] . Apart from that, IOBL increases the need of red blood cell transfusion, which in turn
enhances the oncological risk by induction of pro-inflammatory and immunosuppressive mechanisms [130,131] .
In a meta-analysis including 5635 cases, allogeneic blood transfusion was shown to significantly increase the
[132]
[78]
risk of HCC recurrence at 1, 3, and 5 years following liver resection . Nagai et al. identified red blood
cell transfusion as a strong univariate factor, but it had no independent prognostic significance on post-LT
[133]
HCC relapse. In a retrospective analysis including 336 LT patients, Seehofer et al. identified red blood cell
transfusion as an independent promoter of HCC recurrence, along with vascular tumor invasion. The negative
prognostic impact of blood transfusion was particularly evident in patients with vascular invasion. We have
recently identified application of > 3 red blood cell units as significant and independent prognostic factor in
[127]
patients with Milan Out HCC and patients with PET-positive tumors .

Whether the observed oncological risks are related to IOBL or rather to transfusion remains still unclear. In
any case, limiting the risk of intraoperative bleeding and, thereby, need of red blood cell transfusion seems to
be critical for improving post-LT cancer-specific outcome, particularly in patients with unfavourable tumor
stages [Table 6]. As has been shown by several recent studies, intraoperative blood salvage and autologous
re-transfusion do not increase the oncological risk and should increasingly be considered, in order to avoid
allogeneic transfusion [134,135] .

Post-transplant immunosuppression
Post-transplant immunosuppressive treatment is recognized as a major risk factor for HCC recurrence
following LT. In an immunocompetent patient, the innate immune system is able to recognize and destroy
CTC. But in the transplant setting, postoperatively high immunosuppressive doses are administered in order
to achieve liver graft acceptance, which depresses the natural anti-cancer properties of the immunological
defence. Apart from development of de-novo cancers, this may lead to acceleration of metastatic spread,
implantation and growth of circulating tumor tissue in HCC patients [136,137] .

Despite a large number of studies on this topic, the most optimal immunosuppressive concept for HCC LT
patients has not yet been defined. This may be due to the fact that the vast majority of trials are of retrospective
character with significant differences regarding patients’ selection criteria, transplant procedure, applied
immunosuppressive protocols and post-LT surveillance program. The major conclusions that can be drawn
from current available data are the following: (1) early post-LT reduced exposure to calcineurin inhibitor (CNI)
is an important factor of improved tumor-specific outcome post-LT [Table 7]. The CNIs cyclosporine and
tacrolimus are still the main immunosuppressants used in the setting of LT. Apart from immunoregulatory
properties, CNIs are also able to render oncogogenes to promote tumor cell aggressiveness and invasiveness,
growth and metastasis [138,139] . As shown by an Italian group, early post-LT dose reduction of CNIs has a
favourable effect on cancer-specific outcome [140,141] . In a large 2 European center study including 219 HCC
[141]
patients, Rodríguez-Perálvarez et al. reported that higher exposure to CNI (mean tacrolimus trough level >
10 ng/dL or cyclosporine trough concentrations > 300 ng/dL) within the first months post-LT enhanced the risk
of HCC relapse (27.7% vs. 14.7% at 5 years; P = 0.007). Early post-LT reduced CNI exposure was identified as an