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Calderon Novoa et al. Hepatoma Res 2023;9:33 https://dx.doi.org/10.20517/2394-5079.2023.36 Page 7 of 11

were transplanted. Neoadjuvant protocol for these patients consisted of first-line gemcitabine in
combination with cisplatin, with optional locoregional therapy, mainly comprising SRBT. In order to be
included in the protocol and listed, patients required a 6-month period of disease stability with neoadjuvant
protocol. These patients presented with an 83% OS at 5 years and a 50% RFS, with no recurrences after the
first year. This is the second of the prospective series of patients with a preoperative diagnosis of iCCA, and
shows excellent results for a select few patients, using disease stability and treatment response as a surrogate
for tumor biology. Follow-up with 36 patients enrolled on the waiting list using the same adjuvant protocol
[67]
was published by this team in 2022 . Of these patients, 18 were eventually transplanted, with tumor size
mean values of 10.4 cm, and multifocality present in 56% of transplanted patients. OS continued to show
good results in this cohort, with rates of 100%, 71% and 57% at 1, 3 and 5 years respectively. 38% of LT
patients recurred, with a median time to recurrence of 11 months. Another interesting information about
this paper is that out of the 37 listed patients, 5 were resected after downstaging with NAT. Upon specimen
analysis, one patient was found to have a complete pathological response. This protocol requires further
investigation and external validation with robust data and eventually a randomized trial in order to confirm
the findings. It would seem that neoadjuvant systemic therapy can potentially negate the effect of tumor
burden, as this prospective series had comparable results to the very-early series by Sapisochin et al., while
presenting locally unresectable tumors with a mean size of 10 cm. Better refined prospective protocols with
locoregional therapies are necessary in order to determine their real impact on iCCA [48,49] . It is the authors’
opinion that although tumor size may be one factor that contributes to worse outcomes, a correct
assessment of patients with iCCA as candidates for LT must focus not only on size but on other key factors
such as lymph node invasion and response to neoadjuvant therapies. Disease stability or conversion towards
resectable disease may be clear indicators for favorable outcomes and should prompt multidisciplinary
teams to consider such patients for LT, as shown by the Houston Methodist’s results with large locally
advanced iCCA. Given the molecular similarities between iCCA and hCCA and other bile tract cancers, and
the success of Gemcitabine-based regimes as shown by Lunsford , Macmillan and S-1 adjuvant therapy
[66]
[67]
[68]
by Nakachi et al. , we believe that tumor burden may serve initially as a cutoff value for neoadjuvant
therapy, rather than a contraindication for LT. Patients with “very early” iCCA should be enlisted without
the use of NAT, while patients with larger tumors could potentially benefit from Gemcitabine-based
regimes and possibly local therapies, such as SRBT, and show evidence of stable disease before enlisting.

Follow-up after Liver Transplantation
As mentioned, recurrence rates after LT remain high. Following LR, recurrence location is most frequently
intrahepatic, with over 60% of patients having intrahepatic recurrence either at the surgical margin or
satellite nodules. This shows the effect of the pathological liver on the course of the disease, and the
potential benefits of LT. Less than 15% of patients will have extra hepatic recurrence alone . The time to
[69]
recurrence varies depending on the recurrence pattern: intrahepatic margin recurrence as well as
extrahepatic recurrence alone tend to be very early recurrences (6 months), possibly explained by either
suboptimal surgery or unrecognized metastases at the time of resection. Non-marginal intrahepatic
recurrences tend to happen slowly during the first two years of LR [70,71] . Given these typical patterns of
recurrence, follow-up should be kept in an exhaustive manner for the 2-3 years, with gradual spacing out
following this peak in recurrence. There are multiple known risk factors for recurrence after LR, such as
tumor size, amount of lesions and vascular invasion [72,73] , and preoperative CA 19.9 values, which may serve
as a biological surrogate for disease burden [74,75] . In the last years, there have been several studies that have
developed different tools in order to identify patients at higher risk of recurrence following a curative intent
LR. Preoperative neutrophil-to-lymphocyte ratio, a very popular and easily obtainable parameter, has been
[76]
found to have independent prognostic value for early recurrence (< 1 year) in resected iCCA . Several
groups are beginning to explore the applicability of AI and machine learning models to assist in predicting
recurrence [77-79] . Machine learning radionics has been found to accurately predict recurrence using