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Page 6 of 19 Kornberg et al. Hepatoma Res 2018;4:60 I http://dx.doi.org/10.20517/2394-5079.2018.86

Table 3. Impact of cold and warm ischemia times on HCC recurrence following LT
Reference n Impact on tumor-specific outcome post-LT Impact on tumor-specific outcome in
unfavorable HCC phenotype
Nagai et al. [85] 391 Cumulative incidence of HCC recurrence was significantly higher in CIT > 10 h (HR = 2.6; 95%CI 1.23-5.49; P = 0.01)
CIT > vs. < 10 h (P = 0.015), and for WIT > vs. < 50 min (P = 0.036). and WIT > 50 min (HR = 3.23; 95%CI 1.24-
CIT (HR = 1.9; 95%CI 1.06-3.04; P = 0.03) and WIT (HR = 2.84, 8.38; P = 0.01) correlated independently with
95%CI 1.44-4.85; P = 0.003) were both identified as independent HCC recurrence in patients with vascular tumor
predictors of HCC relapse invasion but not in those without
Kornberg et al. [84] 103 Apart from PET+ status, AFP > 400 ng/dL and beyond MC HCC, In Milan In patients, HCC recurrence rate was
WIT > 50 min was identified as an independent and significant 0% in limited but 42.2% in extended WIT (P =
promoter of post-LT HCC relapse (HR = 52.5; 95%CI 6.0–458.1; 0.001). In the Milan Out subset, 10 of 13 patients
P < 0.001). RFS rates at 1 and 3 years post-LT were 97.2% and with WIT > 50 min (76.9%), but only 6 of 27
92.8% in WIT ≤ 50 min, and 61.4% and 42.0% in WIT > 50 min, patients with WIT ≤ 50 min (22.2%) developed
respectively (P < 0.001) HCC relapse (P = 0.001). WIT was identified as
the only independent and significant risk factor in
patients with PET+ tumors (OR 15.5; 95%CI 3.0-
101.5; P < 0.001)
Grat et al. [85] 90 Apart from beyond MC tumors, pre-LT AFP level and male In MC In patients, RFS rates at 3 years post-
donor sex, CO-LT (HR = 5.88; 95%CI 1.86-18.58; P = 0.003) LT were 100% and 66.7% following PB-LT CO-
and prolonged total ischemia time (HR = 1.48; 95%CI 1.06-2.07; LT (P = 0.003). Corresponding data in MC Out
P = 0.02) were identified as independent predictors of tumor patients were 77.8% and 48.9% (P = 0.031),
recurrence respectively
Orci et al. [86] 9724 Warm ischemia time > 19 min was independently associated with
HCC recurrence (HR = 4.26; 95%CI 1.20-15.1; P = 0.025)
AFP: alpha fetoprotein; CI: confidence interval; CIT: cold ischemia time; CO-LT: conventional liver transplantation; HCC: hepatocellular carcinoma;
HR: hazard ratio; MC: Milan criteria; OR: odds ratio; PB-LT: piggy back liver transplantation; PET: positron emission tomography; RFS: recurrence-
free survival; WIT: warm ischemia time

Transfer of these insights to the clinical transplant setting is still hampered by lack of clear standards of hepatic
I/R injury measurement [83,84] . However, there is convincing evidence that duration of cold (CIT) and warm
ischemia times (WIT), which are the major triggers of I/R damage to the liver graft, correlate with risk of HCC
recurrence post-LT [Table 3].

[85]
In a series of 391 LT patients with HCC, Nagai et al. reported that CIT > 10 h and WIT > 50 min were
independent and significant predictors of overall and early post-LT HCC recurrence. In addition, both
correlated independently with risk of tumor recurrence in patients with but not in those without vascular
tumor infiltration.

Our transplant group was able to confirm the prognostic importance of ischemia time in a subset of 103 LT
[84]
patients with HCC . Both CIT (468 vs. 375.5 min; P = 0.001) and WIT (58.4 vs. 45.7 min; P = 0.001) were
significantly longer in patients with compared to those without HCC relapse. Apart from PET+ status, AFP >
400 ng/dL and beyond MC tumors, WIT > 50 min was identified as an independent and significant promoter
[84]
of post-LT HCC relapse . RFS rates at 1 and 3 years post-LT were 97.2% and 92.8% in WIT ≤ 50 min, and
61.4% and 42.0% in WIT > 50 min, respectively (P < 0.001). In addition, WIT was able to further stratify the
oncological risk in unfavorable HCC phenotype, such as PET+ tumors [Table 3].

[86]
Another interesting approach by Grat et al. has focused on outcome differences between piggy back (PB)
and conventional (Co) LT procedures for HCC. Among others, shorter duration of anhepatic phase and
WIT were reported to be major outcome advantages of PB-LT (without clamping and replacement of the
inferior caval vein) in comparison to CO-LT (including clamping and replacement of the inferior caval vein).
In their series of 90 patients, RFS rates at 1, 2 and 3 years post-LT were 97.0%, 92.2%, and 89.4% for PB-LT,
but only 75.6%, 56.0%, and 56.0% for CO-LT, respectively (P = 0.0006). Apart from beyond MC tumors, pre-
LT AFP level and male donor sex, CO-LT and prolonged total ischemia time were identified as independent
predictors of tumor recurrence. In addition, RFS rates were significantly different in MC In and MC Out
patients when being stratified according to transplant procedure [Table 3].