Carvedilol to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension stratified by liver stiffness: study protocol for a randomied, double-blind, placebo-controlled, multicentre trial in China.

INTRODUCTION: Patients with clinically significant portal hypertension (CSPH) are recommended to be treated with non-selective beta-blockers (ie, carvedilol) to prevent the first hepatic decompensation event by the renewing Baveno VII consensus. CSPH is defined by hepatic venous pressure gradient (HVPG)≥10 mm Hg; however, the HVPG measurement is not widely adopted due to its invasiveness. Liver stiffness (LS)≥25 kPa can be used as a surrogate of HVPG≥10 mm Hg to rule in CSPH with 90% of the positive predicting value in majority aetiologies of patients. A compelling argument is existing for using LS≥25 kPa to diagnose CSPH and then to initiate carvedilol in patients with compensated cirrhosis, and about 5%-6% of patients under this diagnosis criteria may not be benefited from carvedilol and are at risk of lower heart rate and mean arterial pressure. Randomised controlled trial on the use of carvedilol to prevent liver decompensation in CSPH diagnosed by LS remains to elucidate. Therefore, we aimed to investigate if compensated cirrhosis patients with LS≥25 kPa may benefit from carvedilol therapy. METHODS AND ANALYSIS: This study is a randomised, double-blind, placebo-controlled, multicentre trial. We will randomly assign 446 adult compensated cirrhosis patients with LS≥25 kPa and without any previous decompensated event and without high-risk gastro-oesophageal varices. Patients are randomly divided into two groups, with 223 subjects in group A and 223 subjects in group B. Group A is a carvedilol intervention group, while group B is a placebo group. All patients in both groups will receive aetiology therapies and are followed up at an interval of 6 months. The 3-year incidences of decompensated events of cirrhosis-related and liver-related death are the primary outcome. The secondary outcomes include development of each complication of portal hypertension individually (ascites, variceal bleeding or overt hepatic encephalopathy), development of spontaneous bacterial peritonitis and other bacterial infections, development of new varices, growth of small varices to large varices, delta changes in LS and spleen stiffness, change in hepatic dysfunction assessed by Child-Pugh and model for end-stage liver disease score, change in platelet count, development of hepatocellular carcinoma, development of portal vein thrombosis and adverse events with a 3-year follow-up. A predefined interim analysis will be performed to ensure that the calculation is reasonable. ETHICS AND DISSEMINATION: The study protocol has been approved by the ethics committees of the Sixth People's Hospital of Shenyang (2023-05-003-01) and independent ethics committee for clinical research of Zhongda Hospital, affiliated to Southeast University (2023ZDSYLL433-P01). The results from this trial will be submitted for publication in peer-reviewed journals and will be presented at international conferences. TRIAL REGISTRATION NUMBER: ChiCTR2300073864.

Risk factors of liver abscess and biloma formation after drug-eluting bead transarterial chemoembolization for unresectable intrahepatic cholangiocarcinoma.

BACKGROUND AND STUDY AIMS: Drug-eluting bead transarterial chemoembolization (DEB-TACE) causes serious complications, including liver abscess and biloma formation. This study aimed to investigate the frequency and risk factors of liver abscess and biloma formation after dug-eluting bead transarterial chemoembolization for unresectable intrahepatic cholangiocarcinoma (ICC). PATIENTS AND METHODS: 152 unresectable ICC patients received 241 DEB-TACE procedures from February 2018 to November 2022 were studied retrospectively. Patients were evaluated for the presence of liver abscess and biloma formation after DEB-TACE. The medical records, including baseline demographic data, preoperative imaging data, DEB-TACE details, and postoperative management, were reviewed to search for risk factors of liver abscess and biloma formation. RESULTS: Liver abscesses developed in 11 cases, with an incidence rate of 7.2 % (11/152) per patient and 4.6 % (11/241) per procedure. In the 11 patients with abscesses, the incidence of biloma formation was 36.4 % (n = 4). The binary logistic regression analysis showed that diabetes mellitus (OR 7.967, 95 % CI 1.491-42.571, p = 0.015), bilioenterostomy or biliary stent implantation (OR 18.716, 95 % CI 1.006-348.049, p = 0.049) and grade 1 arterial occlusion (OR 9.712, 95 % CI 1.054-89.484, p = 0.045) were independent risk factors for liver abscess and biloma formation. CONCLUSION: Liver abscesses and biloma formation induced by DEB-TACE are associated with various factors. Diabetes mellitus, bilioenterostomy or biliary stent implantation, and grade 1 artery occlusion were all associated with liver abscess and biloma formation after DEB-TACE for unresectable ICC. In patients with these risk factors, the DEB-TACE procedure should be finely designed and manipulated with more caution.

Therapeutic efficacy of TACE 125I seed implantation and its combination with intra-tumor injection of cisplatin for the treatment of hepatocellular carcinoma.

BACKGROUND: This study aimed to compare the therapeutic efficacy of transcatheter arterial chemoembolization (TACE) combined with either 125I seed implantation or 125I seed implantation and intra-tumor injection of cisplatin in treating hepatocellular carcinoma (HCC). METHODS: A total of 100 patients with HCC were analyzed. The control group (n = 50) received TACE combined with 125I seed implantation therapy. The therapy group (n = 50) was treated with an intra-tumor injection of cisplatin along with TACE and 125I seed implantation therapy. After treatment, routine blood, liver and kidney function, tumor volume, T lymphocyte subset count (CD3, CD4, and CD8), implanted metastases, and survival were studied. RESULTS: The tumor volume decreased by 27.4% on average in the control group, and by 38.6% in the therapy group. Alpha fetoprotein (AFP) level decreased in all cases, and it was significantly lower in the therapy group than in the control group. Remote metastasis was observed in both groups (7 in the control group and 3 in the therapy group). No significant difference in routine blood, liver and kidney function, and T-lymphocyte subset counts were found between the two groups. Eight patients died of metastases in the control group and 2 in the therapy group at 1-year follow-up (P < 0.05). CONCLUSION: TACE combined with either 125I seed implantation or 125I seed implantation and intra-tumor injection of cisplatin was effective for the treatment of HCC. Of the 2 combination therapies, TACE combined with 125I seed implantation and intra-tumor injection of cisplatin was more effective for the treatment of HCC.

Insufficient radiofrequency ablation promotes epithelial-mesenchymal transition mediated by interleukin-6/signal transducer and activator of transcription 3/Snail pathway in the H22 cells.

CONTEXT: Radiofrequency ablation (RFA), an established and minimally invasive therapy for hepatocellular carcinoma, has become an important treatment strategy. However, tumor aggressiveness remains a common problem. The epithelial-mesenchymal transition (EMT) is thought to play an important role in this process. DESIGN AND AIMS: Due to limited sample volumes harvested from patients, we established a heat-treated cell line and a mouse model to investigate the mechanisms of incomplete ablation in EMT. MATERIALS AND METHODS: We heat-treated H22 and HepG2 cells using a water bath to determine a suitable temperature for incomplete RFA. Male BALB/c mice were orthotopically transplanted with H22 cells and then subjected to incomplete ablation. Changes in the EMT biomarkers were detected by real-time polymerase chain reaction, western blotting, and immunofluorescence. STATISTICAL ANALYSIS: The experimental results are expressed as means ± standard deviations. RESULTS: Incomplete RFA promoted EMT, downregulated E-cadherin, upregulated vimentin and Snail, and enhanced the phosphorylation of signal transducer and activator of transcription 3 (STAT3) both in vivo and in vitro. Moreover, interleukin (IL)-6 secretion increased after heat treatment in the H22 cells. AG490, an IL-6 inhibitor, inhibited the occurrence of EMT. CONCLUSIONS: Insufficient ablation performed at low temperature successfully induces EMT and promotes tumor aggressiveness, which is mediated by the IL-6/STAT3/Snail pathway in both cell and mouse models.

Computed tomography-guided iodine-125 brachytherapy for unresectable hepatocellular carcinoma.

PURPOSE: This study aimed to retrospectively assess the outcome of interstitial iodine-125 brachytherapy for unresectable hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Between February 2013 and March 2019, 57 patients with 108 unresectable HCC lesions treated with computed tomography (CT)-guided iodine-125 seed brachytherapy were retrospectively analyzed. The primary endpoint was overall survival (OS). The secondary endpoints included local tumor control and progression-free survival (PFS). Potential factors associated with OS were assessed. RESULTS: The mean follow-up duration was 24.3 ± 15.6 months (median, 20.5 months; range, 3.9-66.8 months). The median OS time was 23.6 months (95% confidence interval [CI], 18.4-28.8 months). The 1-, 2-, and 3-year actuarial OS rates were 80.0%, 46.1%, and 24.3%, respectively. The median PFS time was 12 months (95% CI, 9.9-14.5 months). The 1- and 2-year actuarial PFS rates were 50% and 20.1%, respectively. Local progression was noted in 11 (11.3%) of 108 lesions with mean local control time of 20.5 ± 8.8 months. The 1- and 2-year local control rates were 96.5% and 88.8%, respectively. Barcelona clinic liver cancer stage and Child-Pugh score were independent risk factors affecting the prognosis (hazard ratio [HR] = 0.330 [95% CI, 0.128-0.853] and HR = 0.303 [95% CI, 0.151-0.610], respectively). Hepatic artery pseudoaneurysm was found in 1 (1.8%) patient with lesion located in the porta hepatis. No other major complications developed during follow-up. CONCLUSION: CT-guided iodine-125 brachytherapy may be an effective and safe alternative with promising survival and increased local control rate in unresectable HCC treatment.

[Effect of rapamycin in inducing naïve murine effector T cell convert to regulatory T cell].

OBJECTIVE: To study the effect of rapamycin in inducing naïve murine effector T cell (Teff) convert to regulatory T cell (Treg) in vitro. METHODS: The forkhead box protein 3 (FoxP3) negative Teff were isolated and purified from the spleen and lymph node of C57 BL/6 murines aged 6-8 weeks, then Teff were cultured in three groups with mature dendritic cells (mDC), B cells, and plate coated Anti-CD3. In addition, the control wells and the test wells were prepared in each group, rapamycin were not added in the control wells but added in the test wells with concentrations of 1, 10, 50, and 100 nmol/L. Percentages of FoxP3 positive Treg were examined by flow cytometry after 4 days in Anti-CD3 group and after 6 days in the other two groups. RESULTS: As shown by the flow cytometry, the percentages of FoxP3 positive Treg were as follows in three group: in the mDC group, it was 0.01% in the control well and 0.39%, 0.47%, 0.34%, and 0.26% in test wells; in B cell group, it was 0.01% in the control wells and 5.56%, 5.89%, 7.15%, and 4.72% in the test wells; in Anti-CD3 group, it was 0.93% in the control wells and 1.35%, 1.07%, 1.02%, and 1.19% in test wells. No significant difference was found between the test wells and control wells in the mDC group and Anti-CD3 group; however, the percentages of FoxP3 positive Treg was significantly different between the test wells and control wells in the B cell group (P < 0.01). CONCLUSION: When B cell is acted as the antigen-presenting cell, rapamycin can effectively induce Teff convert to Treg in vitro.