Perioperative impact of liver cirrhosis on robotic liver resection for hepatocellular carcinoma: a retrospective cohort study.

BACKGROUND: The safety and efficacy of robotic liver resection (RLR) for patients with hepatocellular carcinoma (HCC) have been reported worldwide. However, the exact role of RLR in HCC patients with liver cirrhosis is not sufficiently determined. METHODS: We conducted a retrospective study on consecutive patients with cirrhosis or non-cirrhosis who received RLR for HCC from 2018 to 2023. Data on patients' demographics and perioperative outcomes were collected and analyzed. Propensity score matching (PSM) analysis was performed. Multivariate logistic regression analysis was performed to determine the risk factors of prolonged postoperative length of stay (LOS) and morbidity. RESULTS: Of the 571 patients included, 364 (64%) had cirrhosis. Among the cirrhotic patients, 48 (13%) were classified as Child-Pugh B. After PSM, the cirrhosis and non-cirrhosis group (n = 183) had similar operative time, estimated blood loss, postoperative blood transfusion, LOS, overall morbidity (p > 0.05). In addition, the intraoperative and postoperative outcomes were similar between the two groups in the subgroup analyses of patients with tumor size ≥ 5 cm, major hepatectomy, and high/expert IWATE difficulty grade. However, patients with Child-Pugh B cirrhosis had longer LOS and more overall morbidity than that of Child-Pugh A. Child-Pugh B cirrhosis, ASA score > 2, longer operative time, and multiple tumors were risk factors of prolonged LOS or morbidity in patients with cirrhosis. CONCLUSION: The presence of Child-Pugh A cirrhosis didn't significantly influence the difficulty and perioperative outcomes of RLR for selected patients with HCC. However, even in high-volume center, Child-Pugh B cirrhosis was a risk factor for poor postoperative outcomes.

Enhanced NK cell activation via eEF2K-mediated potentiation of the cGAS-STING pathway in hepatocellular carcinoma.

BACKGROUND: Liver cancer, particularly hepatocellular carcinoma (HCC), is characterized by a high mortality rate, attributed primarily to the establishment of an immunosuppressive microenvironment. Within this context, we aimed to elucidate the pivotal role of eukaryotic elongation factor 2 kinase (eEF2K) in orchestrating the infiltration and activation of natural killer (NK) cells within the HCC tumor microenvironment. By shedding light on the immunomodulatory mechanisms at play, our findings should clarify HCC pathogenesis and help identify potential therapeutic intervention venues. METHODS: We performed a comprehensive bioinformatics analysis to determine the functions of eEF2K in the context of HCC. We initially used paired tumor and adjacent normal tissue samples from patients with HCC to measure eEF2K expression and its correlation with prognosis. Subsequently, we enrolled a cohort of patients with HCC undergoing immunotherapy to examine the ability of eEF2K to predict treatment efficacy. To delve deeper into the mechanistic aspects, we established an eEF2K-knockout cell line using CRISPR/Cas9 gene editing. This step was crucial for verifying activation of the cGAS-STING pathway and the subsequent secretion of cytokines. To further elucidate the role of eEF2K in NK cell function, we applied siRNA-based techniques to effectively suppress eEF2K expression in vitro. For in vivo validation, we developed a tumor-bearing mouse model that enabled us to compare the infiltration and activation of NK cells within the tumor microenvironment following various treatment strategies. RESULTS: We detected elevated eEF2K expression within HCC tissues, and this was correlated with an unfavorable prognosis (30.84 vs. 20.99 months, P = 0.033). In addition, co-culturing eEF2K-knockout HepG2 cells with dendritic cells led to activation of the cGAS-STING pathway and a subsequent increase in the secretion of IL-2 and CXCL9. Moreover, inhibiting eEF2K resulted in notable NK cell proliferation along with apoptosis reduction. Remarkably, after combining NH125 and PD-1 treatments, we found a significant increase in NK cell infiltration within HCC tumors in our murine model. Our flow cytometry analysis revealed reduced NKG2A expression and elevated NKG2D expression and secretion of granzyme B, TNF-α, and IFN-γ in NK cells. Immunohistochemical examination confirmed no evidence of damage to vital organs in the mice treated with the combination therapy. Additionally, we noted higher levels of glutathione peroxidase and lipid peroxidation in the peripheral blood serum of the treated mice. CONCLUSION: Targeted eEF2K blockade may result in cGAS-STING pathway activation, leading to enhanced infiltration and activity of NK cells within HCC tumors. The synergistic effect achieved by combining an eEF2K inhibitor with PD-1 antibody therapy represents a novel and promising approach for the treatment of HCC.