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Aim: Liver fibrosis, heralding the potential progression to cirrhosis and hepatocellular carcinoma (HCC), compromises patient survival and augments post-hepatectomy recurrence. This study examined the detrimental effects of liver fibrosis on the antitumor functions of liver natural killer (NK) cells and the interleukin-33 (IL-33) signaling pathway., Methods: Our investigation, anchored in both human physiologies using living and deceased donor livers and the carbon tetrachloride (CCl 4 )-induced mouse fibrosis model, aimed to show a troubling interface between liver fibrosis and weakened hepatic immunity., Results: The Fibrosis-4 (FIB-4) index emerged as a salient, non-invasive prognostic marker, and its elevation correlated with reduced survival and heightened recurrence after HCC surgery even after propensity matching (n = 385). We established a strong correlation between liver fibrosis and liver NK cell dysfunction by developing a method for extracting liver NK cells from the liver graft perfusate. Furthermore, liver fibrosis ostensibly disrupted chemokines and promoted IL-33 expression, impeding liver NK cell antitumor activities, as evidenced in mouse models. Intriguingly, our results implicated IL-33 in diminishing the antitumor responses of NK cells. This interrelation, consistent across both mouse and human studies, coincides with clinical data suggesting that liver fibrosis predisposes patients to an increased risk of HCC recurrence., Conclusion: Our study revealed a critical relationship between liver fibrosis and compromised tumor immunity, emphasizing the potential interference of IL-33 with NK cell function. These insights advocate for advanced immunostimulatory therapies targeting cytokines, such as IL-33, aiming to bolster the hepatic immune response against HCC in the context of liver fibrosis., (© 2024 The Author(s). Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Hepatology.)

Aim: Living-donor liver transplantation (LDLT) is a highly effective life-saving procedure; however, it requires substantial medical resources, and the cost-effectiveness of LDLT versus conservative management (CM) for adult patients with end-stage liver disease (ESLD) remains unclear in Japan., Methods: We performed a cost-effectiveness analysis using the Diagnostic Procedure Combination (DPC) data from the nationwide database of the DPC research group. We selected adult patients (18 years or older) who were admitted or discharged between 2010 and 2021 with a diagnosis of ESLD with Child-Pugh class C or B. A decision tree and Markov model were constructed, and all event probabilities were computed in 3-month cycles over a 10-year period. The willingness-to-pay per quality-adjusted life-year (QALY) was set at 5 million Japanese yen (JPY) (49,801 US dollars [USD]) from the perspective of the public health-care payer., Results: After propensity score matching, we identified 1297 and 111,849 patients in the LDLT and CM groups, respectively. The incremental cost-effectiveness ratio for LDLT versus CM for Child-Pugh classes C and B was 2.08 million JPY/QALY (20,708 USD/QALY) and 5.24 million JPY/QALY (52,153 USD/QALY), respectively. The cost-effectiveness acceptability curves showed the probabilities of being below the willingness-to-pay of 49,801 USD/QALY as 95.4% in class C and 48.5% in class B. Tornado diagrams revealed all variables in class C were below 49,801 USD/QALY while their ranges included or exceeded 49,801 USD/QALY in class B., Conclusions: Living-donor liver transplantation for adult patients with Child-Pugh class C was cost-effective compared with CM, whereas LDLT versus CM for class B patients was not cost-effective in Japan., (© 2023 Japan Society of Hepatology.)

Aim: Six-month recipient mortality after adult-to-adult living-donor liver transplantation (LDLT) remains high. Early and accurate prediction of recipient outcome and continuous monitoring of recipient severity after surgery are both essential for guiding appropriate care. This study was designed to identify early post-transplant parameters associated with 6-month mortality, and thereby to construct a discriminatory prognostic index (PI)., Methods: We retrospectively analyzed 400 consecutive primary adult-to-adult LDLTs in our center (2006-2017). Perioperative variables were comprehensively analyzed for their accuracy in predicting recipient mortality by comparing the area under the receiver operating characteristic (AUROC) of each factor., Results: The AUROCs of preoperative predictive factors, for example, Model for End-stage Liver Disease (MELD) score and donor age, were 0.56 and 0.64, respectively, whereas those of post-transplant platelet count (PLT), total bilirubin (T-BIL), and prothrombin time - international normalized ratio (INR) on postoperative day (POD)-7-14 were 0.71/0.84, 0.68/0.82, and 0.71/0.78, respectively. Logistic regression analysis provided a formula: PI POD-14  = 3.39 + 0.12 × PLT POD-14  - 0.09 × T-BIL POD-14  - 1.23 × INR POD-14 , indicating a high AUROC of 0.87. Recipient 6-month survival with PI POD-14  < 2.38 (n = 173) was 71.7%, whereas that with PI POD-14  ≥ 2.38 (n = 222) was 97.7% (P < 0.001). The AUROCs of PI POD-7 were as high as 0.8 in the subgroups with younger donors (<50 years of age), right lobe grafts, ABO-identical/compatible combinations, or low MELD score (<20), indicating usefulness of PI to identify unexpectedly complicated cases within the first week., Conclusions: A novel, post-transplant survival estimator, PI, accurately predicts recipient 6-month mortality within 1-2 weeks after adult LDLT. Daily monitoring of PI could facilitate early interventions including retransplantation in critically ill patients., (© 2020 The Authors. Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Hepatology.)