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Objective:To evaluate the efficacy and safety of transhepatic arterial chemoembolization (TACE) combined with tyrosine kinase inhibitors (TKI) and programmed death-1 (PD-1) inhibitors in the treatment of patients with initially unresectable hepatocellular carcinoma.Methods:The clinical data of 42 patients with initially unresectable hepatocellular carcinoma who were admitted to the Department of Hepatobiliary and Pancreatic Surgery of the First Affiliated Hospital of Zhengzhou University from January 2020 to December 2022 were included. There were 31 males and 11 females, with a median age of 56 years old (range, 45-72 years old). All patients received TACE+ TKI+ PD-1 inhibitor combined treatment. The systemic treatment cycles were calculated by the regimen of immunotherapy. The timing of local treatment depends on tumor size, blood supply and treatment response. Patients were followed up through hospitalization, outpatient visits and telephone review. The Kaplan-Meier curves were obtained for survival analysis.Results:The dosing cycle to achieve optimal imaging response in the patients was 4 (3, 7) [ M( Q1, Q3)], with a systemic treatment time of 141 (65, 194) d [ M( Q1, Q3)] and 2 (1, 3) times [ M( Q1, Q3)] of local treatments. All patients were evaluated by modified response evaluation criteria in solid tumors criteria after treatment, including nine patients with complete response (CR), 21 with partial response, eight with stable disease, and four with progressive disease. Objective response rate and disease control rate were 71.4% (30/42) and 90.5% (38/42), respectively. Treatment-related adverse reactions occurred in 85.7% (36/42) of patients and grade Ⅲ or Ⅳ adverse reactions occurred in 16.7% (7/42). There was no level Ⅳ adverse reactions. All adverse reactions were controlled after dose reduction and symptomatic treatment. Thirteen patients (31.0%, 13/42) redeemed resectable after treatment and underwent radical surgery. Seven patients had pathological CR after surgery. In two patients, the pathological residual cancer tissue was less than 10%. The cumulative overall survival rates of the 42 patients at 6 months, 1 year, 1.5 years after treatment were 100%, 91.7%, and 65.0%, respectively. The postoperative 1-year survival rate of patients undergoing surgery after successful conversion was 83.3%. Conclusion:This study preliminarily showed the safety and efficacy of TACE, TKI, and PD-1 inhibitor combined therapy in patients with initially unresectable hepatocellular carcinoma.
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Objective To investigate the effect and its molecular mechanism of phosphoglycerate mutase 5 (PGAM5) mediated pyroptosis on liver ischemia-reperfusion injury (IRI). Methods C57 mouse models of liver IRI were established and randomly divided into the 6 h reperfusion (6 h group) and 12 h reperfusion (12 h group), and sham operation group (sham group) was established too, 10 rats in each group. The effect of IRI on the parameters in the liver tissues and serum samples was evaluated. The expression levels of PGAM5 and cysteinyl aspartate specific proteinase (Caspase)-1 in the liver tissues during IRI were quantitatively detected. The IRI models of liver cells were established (IRI group). The IRI models of liver cells were established after pretreatment with Caspase-1 inhibitor Z-YVAD-FMK (inhibitor group). The untreated AML12 cells were allocated into the control group. The effect of inhibiting Caspase-1 activity on pyroptosis was analyzed. AML12 cells were transfected with PGAM5 small interfering ribonucleic acid (siRNA) (siRNA group) and siRNA-negative control (siRNA-NC) (siRNA-NC group) by liposome 3000, and then IRI models of liver cells were established. The untreated AML12 cells were assigned into the control group. The effect of PGAM5 mediated pyroptosis on IRI of liver cells was assessed. Results In the 6 h and 12 h groups, partial liver cell edema, hepatic sinusoid narrowing, central vein congestion and occasional spot necrosis were observed in the mouse liver tissues, and these changes in the 12 h group were more aggravated than those in the 6 h group. The serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the 6 h and 12 h groups were higher than those in the sham group, and the values in the 12 h group were higher than those in the 6 h group. The levels of tumor necrosis factor (TNF)-α and interleukin (IL)-1β were increased in the 6 h and 12 h groups, and the values in the 12 h group were lower than those in the 6 h group. The relative expression levels of IL-1β messenger ribonucleic acid (mRNA) in the mouse liver tissues in the 6 h and 12 h groups were up-regulated, and the value in the 12 h group was lower than that in the 6 h group. The cell apoptosis rates in the liver tissues were significantly increased in the 6 h and 12 h groups, and the value in the 12 h group was remarkably lower than that in the 6 h group (P < 0.01-0.05). Compared with the sham group, the relative expression levels of PGAM5 mRNA and protein in the mouse liver tissues in the 6 h and 12 h groups were significantly up-regulated, and the values in the 12 h group were significantly higher than those in the 6 h group (P < 0.01-0.05). The protein expression levels of PGAM5 and Caspase-1 in the liver tissues were up-regulated in the 6 h and 12 h groups. Compared with the control group, the relative expression levels of NOD-like receptor protein 3 (NLRP3), cleaved Caspase-1 and Gasdermin D (GSDMD) proteins were up-regulated and the fluorescence intensity of GSDMD was increased in the IRI group. Compared with the IRI group, the relative expression levels of NLRP3, cleaved Caspase-1 and GSDMD proteins were significantly down-regulated and the fluorescence intensity of GSDMD was considerably decreased in the inhibitor group (P < 0.01-0.05). Compared with the control group, the cell survival rate was significantly decreased, and the relative expression levels of PGAM5, NLRP3, cleaved Caspase-1 and GSDMD proteins were significantly up-regulated in the siRNA-NC group (P < 0.01-0.05). Compared with the siRNA-NC group, the cell survival rate was remarkably increased, whereas the relative expression levels of PGAM5, NLRP3, cleaved Caspase-1 and GSDMD proteins were significantly down-regulated in the siRNA group (P < 0.01-0.05). Conclusions PGAM5 may aggravate the liver IRI in mouse models probably by mediating pyroptosis via PGAM5/Caspase-1/GSDMD signaling pathway and aggravating liver cell injury.
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Objective A classification for hepatic venous outflow obstruction after piggyback liver transplantation (PBLT) and its clinical significance.Methods We conducted a retrospective study on 248 patients who underwent liver transplantation from May 2000 to August 2006.The aims were to elucidate the causes and treatment of postoperative venous outflow obstruction.Results Venous outflow obstruction occurred in 38 patients after transplantation.Among those,2 (5.26％) had superior hepatic inferior vena cava (IVC) stenosis,13 (34,21％) had the hepatic vein anastomosis twisted at an angle,7 (18.42％) had IVC stenosis at the posthepatic segment,and 16 (42.10％) had outflow obstruction at the hepatic veins.In these 38 patients,34 underwent PBLT,2 underwent APBLT,and 2 COLT.Most patients with hepatic venous outflow obstruction improved with surgical treatment and interventional therapy.Conclusions Hepatic vein outflow obstruction was associated with the technique of hepatic vein anastomosis,the type of cavocaval anastomosis and graft size mismatch between the donor and the recipient.Performing piggyback liver transplantation according to the classification of hepatic vein and appropriate treatments could improve the prognosis of venous outflow obstruction in clinical practice.
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Marginal liver donor,a way to expand the liver pool,has been maximized in the unique position due to the shortage of donors.But the definition of marginal donor liver varies from center to center and the standard is very complex.With the enhancement of organ perfusion solution,preservation methods and surgical techniques,the edge donor criteria are also gradually expanding.What decision should we make,facing such clinical controversies.This paper makes a review on the marginal liver donor in the donation after citizen deceased,so as to improve its clinical application.