In the past 10 years, the progress in systemic therapy for hepatocellular carcinoma (HCC) is attributed to the application of molecular target therapy and the improvement in immunotherapy. The immunosuppressive microenvironment of HCC enables HCC cells to avoid attack by the immune system, which is also an important reason for the progression of HCC. Improving immune killing of HCC and correcting immunosuppressive conditions are important strategies for immunotherapy for HCC. Tumor vaccine therapy based on HCC specific antigen, genetically engineered T lymphocytes, and basic research and bench-to-bedside translation of immune checkpoint inhibitors have significantly improved the outcome of immunotherapy. Further studies should be performed for immunotherapy combined with other antitumor therapies such as local ablation, molecular targeted therapy, and tumor vaccine therapy.

ObjectiveTo investigate the value of serum cystatin C (Cys C) in the diagnosis of early renal injury in patients with viral hepatitis. MethodsA retrospective analysis was performed for the clinical data of 270 patients with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. According to the fibrosis degree determined by FibroScan, the patients were divided into non-significant liver fibrosis group (F0-F2), significant liver fibrosis group (F2-F3), progressive liver fibrosis group (F3-F4), and liver cirrhosis group (＞F4). The four groups were compared in terms of urea nitrogen, creatinine, Cys C, and estimated glomerular filtration rate (eGFR). The t-test was used for comparison of continuous data between two groups; a one-way analysis of variance was used for comparison between multiple groups, and the least significant difference t-test was used for further comparison between two groups. A Pearson correlation analysis was used to investigate correlation. ResultsAmong the 270 patients, 200 had HBV infection and 70 had chronic HCV infection. There were significant differences in eGFR and Cys C between the four groups (F=2.714 and 3.081, P=0.032 and 0.017). Further comparison between two groups showed that the liver cirrhosis group had a significantly lower eGFR than the non-significant liver fibrosis group (99.61±6.92 ml·min-1·1.73 m-2 vs 105.32±1.86 ml·min-1·1.73 m-2, t=2.655, P=0.008); compared with the non-significant liver fibrosis group, the other three groups had significant increases in the serum level of Cys C (significant liver fibrosis group: 1.01±0.08 mg/L vs 084±0.03 mg/L, t=-2.218, P=0.028; progressive liver fibrosis group: 1.02±0.04 mg/L vs 0.84±0.03 mg/L, t=-4218, P＜0001; liver cirrhosis group: 1.07±0.05 mg/L vs 0.84±0.03 mg/L, t=-4.675, P＜0.001). For the patients with HBV or HCV infection, the patients with liver cirrhosis had a significantly higher serum level of Cys C than those without significant liver fibrosis (patients with HBV infection: 1.06±0.36 mg/L vs 0.84±0.13 mg/L, t=-3.192, P=0.003; patients with HCV infection: 1.04±022 mg/L vs 086±0.15 mg/L, t=-2.318, P=0.029). Liver stiffness measurement was positively correlated with the serum level of Cys C (r=0247, P=0.003), while there was no correlation between liver stiffness measurement and eGFR (r=-0.002, P=0.975). Conclusion Cys C can be used for the diagnosis of early renal injury in patients with viral hepatitis, and regular monitoring of Cys C level has a positive significance in the prevention and treatment of hepatorenal syndrome in such patients.

ObjectiveTo investigate the clinical features of patients with failure or recurrence after treatment with PEG-IFN combined with ribavirin (PR regimen) in the real world and the clinical effect of different direct-acting antiviral agent (DAA) regimens in such patients. MethodsA retrospective analysis was performed for the clinical data of 106 patients with chronic hepatitis C or hepatitis C-related compensated liver cirrhosis who attended the outpatient service or were hospitalized in The First Peoples’ s Hospital of Lanzhou from March 2014 to January 2018, and these patients experienced failure or recurrence after the treatment with the standard PR regimen. There were 54 male and 52 female patients. According to the response to PR treatment, the patients were divided into failure group with 13 patients, recurrence group with 51 patients, and sustained virologic response group with 42 patients. All patients underwent IL-28B rs12979860/rs8099917 detection, baseline biochemical examination, Cobas HCV RNA test, and viral genotyping, and these results were compared between groups. The clinical outcomes of patients with failure or recurrence after PR treatment were observed after the treatment with different DAA regimens. The chi-square test was used for comparison of categorical data between groups; a one-way analysis of variance was used for comparison between multiple groups. ResultsThe failure group and the recurrence group had a significantly higher age than the sustained virologic response group (F=14.05, P＜0.001). Among the patients in the failure group, 86.4% had viral genotype 1b, while among those in the recurrence group, 72.5% had viral genotype 2a, and there was a significant difference between the three groups (χ2=17269, P=0.002). Among the patients in the failure group, 92.3% had a baseline HCV RNA level of ≥106 IU/L, and the failure group had a significantly higher proportion of such patients than the recurrence group and the sustained virologic response group (χ2=10.407, P=0.005). There were no significant differences in sex and liver cirrhosis between the three groups (all P＞0.05). Among the patients with primary treatment failure, 100% patients had the non-protective genotype of IL-28B rs12979860 CT/TT, and 92.3% had the non-protective genotype of IL-28B rs8099917 TG/GG; among the patients with recurrence, 84.3% patients had the non-protective genotype of IL-28B rs12979860 CT/TT, and 86.3% had the non-protective genotype of IL-28B rs8099917 TG/GG; among the patients in the sustained virologic response group, 85.7% gad genotype CC at IL-28B rs12979860 and 88.1% had genotype TT at IL-28B rs8099917. There were significant differences in the constituent ratios of rs12979860 and rs8099917 gene polymorphisms between the three groups (χ2=57.263 and 59.651, both P＜0.001). The patients with failure or recurrence after PR treatment achieved a sustained virologic response rate of 100% after the treatment with three different DAA regimens based on sofosbuvir. ConclusionViral genotype and non-protective genotypes at IL-28B rs12979860 and rs8099917 are influencing factors for failure and recurrence after PR treatment. The three different DAA regimens based on sofosbuvir achieves a sustained virologic response rate of 100% and has good safety in patients with failure or recurrence after PR treatment, which is not affected by the factors including IL-28B single nucleotide polymorphism and viral replication level in the host.

ObjectiveTo investigate the differences in the plasma levels of angiotensin II (Ang II) and angiotensin (1-7) ［Ang(1-7)］ in different stages among patients with chronic hepatitis B (CHB) liver fibrosis and their significance in the pathogenesis of liver fibrosis. MethodsA prospective study was performed. A total of 86 patients with hepatitis B virus (HBV) infection who attended our hospital from March 2017 to March 2019 were enrolled and divided into CHB group (group A) with 25 patients, compensated hepatitis B cirrhosis group (group B) with 31 patients, and decompensated hepatitis B cirrhosis group (group C) with 30 patients. The double-antibody sandwich method was used to measure the plasma levels of Ang II and Ang(1-7), and FibroTouch scan was used for liver stiffness measurement (LSM). A one-way analysis of variance was used for comparison of continuous data between multiple groups, and the least significant difference t-test was used for further comparison between two groups; the chi-square test was used for comparison of categorical data between groups. A binary linear correlation analysis was used to investigate the correlation of the plasma levels of Ang II and Ang(1-7) with LSM; a Spearman rank correlation analysis was used to investigate the correlation of the plasma levels of Ang II and Ang(1-7) with the progression of CHB liver fibrosis; a logistic regression analysis was used to evaluate the value of Ang II, Ang(1-7), and LSM in predicting hepatitis B cirrhosis. ResultsWith the progression of liver fibrosis from group A to group C, there was a significant increase in course of disease (5.2±1.3 years vs 7.8±1.6 years vs 10.1±1.5 years, F=4.266, P=0.002), a significant reduction in the proportion of patients receiving antiviral therapy (76.00% vs 64.52% vs 53.33%, χ２=5.544, P＜0.001), significant increases in Ang II (51.01±868 pg/ml vs 74.38±10.05 pg/ml vs 102.78±13.22 pg/ml, F=520.260, P<0.001), Ang II/Ang(1-7) ratio (1.06±0.41 vs 232±023 vs 5.82±1.24, F=18.860, P＜0.001), and LSM (6.85±1.26 kPa vs 18.25±3.22 kPa vs 26.84±7.57 kPa, F=93.260, P＜0001), and a significant reduction in Ang(1-7) (45.93±10.24 pg/ml vs 31.52±9.62 pg/ml vs 16.55±9.48 pg/ml, F=209.860, P＜0001). Ang II and Ang II/Ang(1-7) ratio were positively correlated with LSM (r=0.623 and 0.813, both P＜0.01), while Ang(1-7) was negatively correlated with LSM (r=-0.677, P＜0.01). Ang II, Ang II/Ang(1-7) ratio, and LSM gradually increased with the progression of liver fibrosis (r=0639, 0.886, and 0.712, all P＜0.01), while Ang(1-7) was negatively correlated with the progression of liver fibrosis (r=-0.653, P＜0.01). Ang II/Ang(1-7) ratio and LSM had an early warning effect for liver cirrhosis in patients with HBV infection (odds ratio=1884 and 2.015, both P＜0.01). ConclusionIn patients with HBV infection, there are gradual increases in Ang II and Ang II/Ang(1-7) ratio and a gradual reduction in Ang(1-7) with the aggravation of liver fibrosis. Dynamic monitoring of the plasma levels of Ang II and Ang(1-7) can provide a reference for real-time assessment of liver fibrosis and decision-making in clinical diagnosis and treatment.

ObjectiveTo investigate the value of the four serum liver fibrosis markers, i.e., procollagen Ⅲ (PCⅢ), type Ⅳ collagen (C-Ⅳ), hyaluronic acid (HA), and laminin (LN), in the diagnosis of liver fibrosis. MethodsA retrospective analysis was performed for the clinical data of 155 patients with liver cirrhosis, 42 patients with liver cirrhosis and primary hepatic carcinoma (PHC), and 150 patients with chronic hepatitis who were admitted to The First Affiliated Hospital of Southwest Medical University from April 2018 to April 2019, and 73 healthy individuals who underwent physical examination were also enrolled. The serum levels of the above four markers were measured for all subjects and were compared between groups. The receiver operating characteristic (ROC) curve was plotted to compare the diagnostic efficiency of these four markers. The t-test was used for normally distributed continuous data between two groups; the Kruskal-Wallis H rank sum test was used for comparison of non-normally distributed continuous data between multiple groups, and the Wilcoxon rank-sum test was used for further comparison between two groups. The chi-square test was used for comparison of categorical data between groups. ResultsThe patients with liver cirrhosis and the patients with liver cirrhosis and PHC had significantly higher serum levels and positive rates of the four markers than the patients with chronic hepatitis and the healthy subjects (all P＜0.05). while there were no significant differences in the levels and positive rates of PCⅢ, C-Ⅳ, and HA between the patients with liver cirrhosis and the patients with liver cirrhosis and PHC (all P＞0.05). Although the patients with liver cirrhosis and PHC had a significantly higher serum level of LN than those with liver cirrhosis (P＜0.05), there was no significant difference in the positive rate of LN between the two groups (P＞0.05). The patients with alcoholic cirrhosis had significantly higher serum levels of PCⅢ and C-Ⅳ than those with viral cirrhosis, viral-alcoholic cirrhosis, or autoimmune cirrhosis (all P＜0.05), the patients with autoimmune cirrhosis, alcoholic cirrhosis, or viral-alcoholic cirrhosis had a significantly higher serum level of HA than those with viral cirrhosis (all P＜0.05), and the patients with viral-alcoholic cirrhosis, viral cirrhosis, or alcoholic cirrhosis had a significantly higher serum level of LN than those autoimmune(all P＜0.05). The patients with chronic hepatitis of different etiologies had significantly lower serum levels and positive rates of these four markers than those with liver cirrhosis (all P＜0.05), and the patients with severe viral hepatitis had significantly higher positive rates of the four markers than the other patients (all P＜0.05). PCⅢ, C-IV, HA, LN, and the combination of these four markers had an area under the ROC curve of 0.836, 0.832, 0895, 0.808, and 0.901, respectively, in the diagnosis of liver cirrhosis. HA had a significantly larger area under the ROC curve than PCⅢ, C-Ⅳ, and LN (all P＜0.05), while there was no significant difference between HA and the combination of these four markers (P＞0.05). ConclusionHA has a high diagnostic efficiency in liver fibrosis.

ObjectiveTo investigate the risk factors for death within 30 days in patients with liver cirrhosis and bacterial ascites, and to establish a predictive model of death within 30 days. MethodsA retrospective analysis was performed for the clinical data of 86 patients with liver cirrhosis and bacterial ascites who were admitted to Beijing Ditan Hospital, Capital Medical University, from January 2012 to April 2018. The patients were followed up for 30 days, and according to their prognosis, they were divided into survival group with 73 patients and death group with 13 patients. The t-test was used for comparison of normally distributed continuous data between groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between groups; the chi-square test was used for comparison of categorical data between groups. A logistic regression analysis was used to investigate the influencing factors for death within 30 days in patients with liver cirrhosis and bacterial ascites, and a predictive model was established based on these influencing factors. The area under the receiver operating characteristic curve was used to evaluate the predictive value of each independent influencing factor and the predictive model. ResultsThe multivariate logistic regression analysis showed that there were significant differences between the survival group and the death group in ascites albumin (odds ratio ［OR］=0.615, 95% confidence interval ［CI］: 0.424-0.893, P=0.011), neutrophil-to-lymphocyte ratio (NLR) (OR=1.170, 95%CI: 1.011-1.354, P=0.035), and Model for End-Stage Liver Disease (MELD) score (OR=1.341, 95% CI: 1.111-1.618, P=0.002). A scoring model was established based on the results of the multivariate analysis to predict death within 30 days in patients with liver cirrhosis and bacterial ascites, and based on this model, the patients were divided into high-risk group with death within 30 days (score ≥2 points) and low-risk group with death within 30 days (score ＜2 points). There was a significant difference in mortality rate with 30 days between the two groups (60.0% vs 5.6%, P＜0.001). ConclusionAscites albumin ≤3.5 g/L, NLR ≥6.5, and MELD score ≥20 are independent risk factors for death within 30 days in patients with liver cirrhosis and bacterial ascites. The predictive model established on this basis can effectively evaluate the population at high risk of death within 30 days.

ObjectiveTo investigate the influence of alcohol consumption on liver function and prognosis in alcoholic cirrhotic patients. MethodsA total of 211 alcoholic cirrhotic patients with gastroesophageal variceal bleeding who underwent endoscopic treatment in Beijing Ditan Hospital, Capital Medical University, from September to December, 2018 were enrolled, and among these patients, there were 208 male and 3 female patients, with a mean follow-up time of 45 months (range 2-110 months). The association of alcohol consumption with liver parameters was analyzed. According to the presence or absence of gastroesophageal variceal rebleeding, the patients were divided into early rebleeding group, delayed rebleeding group, and non-rebleeding group, and the three groups were compared in terms of liver parameters and alcohol consumption. The t-test was used for comparison of normally distributed continuous data between groups, and the Wilcoxon rank-sum test was used for comparison of non-normally distributed continuous data between groups; the chi-square test was used for comparison of categorical data between groups. The Spearman rank correlation test was used for correlation analysis. ResultsDuration of drinking was correlated with creatinine (r=0.142, P=0.039) and direct bilirubin (DBil) (r=-0.137, P=0.047), and daily alcohol consumption was correlated with DBil (r=0.144, P=0.037) and prealbumin (r=-0.190, P=0.009), while there was no correlation between total alcohol consumption and indicators for liver injury. There were significant differences between the early rebleeding group and the delayed rebleeding group in white blood cell count (WBC) (t=-2.355, P=0.020), neutrophils (t′=-2.602, P=0.010), hemoglobin (t=2.247, P=0.026), mean corpuscular volume (t=-2.073, P=0.040), alanine aminotransferase (Z=-1.985, P=0047), international normalized ratio (Z=-2.397, P=0.017), spleen thickness (Z=-2.542, P=0.011), Child-Pugh score (t′=-2.364, P=0.020), and Child-Pugh grade (Z=-2.485, P=0.013). The non-rebleeding group had significantly lower WBC (Z=-2.276, P=0.017) and neutrophils (Z=-2.375, P=0.018) than the rebleeding group, and the early and delayed rebleeding groups had a significantly shorter duration of drinking than the non-rebleeding group (Z=-2.522, P=0.012). The logistic regression analysis showed that neutrophils was a risk factor for variceal rebleeding (odds ratio=1.152, 95% confidence interval: 1.017-1.300, P=0026). ConclusionNo dose-response relationship is found between alcohol consumption and liver injury in this study, and alcohol consumption may not have a marked effect on variceal rebleeding.

ObjectiveTo investigate the effect of Hic-5 gene knockout on NF-κB/p65 expression and liver fibrosis. MethodsTen wild-type male C57BL/6 mice were randomly divided into wild-type control group (WT-Control group with 5 mice) and wild-type experimental group (WT-CCl4 group with 5 mice), and ten male C57BL/6 mice with Hic-5 gene knockout were randomly divided into Hic-5 knockout control group (Hic-5 KO-Control group with 5 mice) and Hic-5 knockout experimental group (Hic-5 KO-CCl4 group with 5 mice). The serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured. Picrosirius red staining was used to observe collagen deposition in liver tissue. Immunohistochemistry was used to measure the expression of alpha-smooth muscle actin (α-SMA) and p65 protein, and real-time quantitative PCR was used to measure the mRNA expression of α-SMA, collagen 1, and p65 in liver tissue. The primary hepatic stellate cells of mice were isolated and stimulated with different concentrations of TGF-β1, and then real-time quantitative PCR was used to measure the mRNA expression of α-SMA, collagen 1, and p65 in primary hepatic stellate cells. A one-way analysis of variance was used for comparison of continuous data between multiple groups, and the least significant difference t-test was used for further comparison between two groups. ResultsPicrosirius red staining showed that compared with the WT-CCl4 group, the Hic-5 KO-CCl4 group had a significant reduction in collagen fibers in liver tissue (P＜0.001). Measurement of serum ALT and AST showed that there were significant differences in ALT and AST between the WT-Control group, the WT-CCl4 group, the Hic-5 KO-Control group, and the Hic-5 KO-CCl4 group (F=22.85 and 25.15, both P＜0.001), and the Hic-5 KO-CCl4 group had significantly lower serum levels of ALT and AST than the WT-CCl4 group (both P＜0.05). Immunohistochemistry showed that there were significant differences in the expression levels of α-SMA and p65 protein in liver tissue between the WT-Control group, the WT-CCl4 group, the Hic-5 KO-Control group, and the Hic-5 KO-CCl4 group (F=207.10 and 98.16, both P＜0.001), and the Hic-5 KO-CCl4 group had significantly lower expression of α-SMA and p65 protein in liver tissue than the WT-CCl4 group (both P＜0.01). The results of real-time quantitative PCR showed that there were significant differences in the relative mRNA expression of α-SMA, collagen 1, and p65 in liver tissue between the WT-Control group, the WT-CCl4 group, the Hic-5 KO-Control group, and the Hic-5 KO-CCl4 group (F=41.62, 13.93, and 98.16, all P＜0.001), and the Hic-5 KO-CCl4 group had significantly lower relative mRNA expression of α-SMA, collagen 1, and p65 in liver tissue than the WT-CCl4 group (all P＜0.05). After the primary hepatic stellate cells were stimulated by TGF-β1 at concentrations of 0, 5, and 10 ng/ml, there were significant differences in the relative mRNA expression of α-SMA, collagen 1, and p65 between the WT 0 ng/ml group, the WT 5 ng/ml group, the WT 10 ng/ml group, the KO 0 ng/ml group, the KO 5 ng/ml group, and the KO 10 ng/ml group (F=53.9, 75.82, and 52.41, all P＜0.001), and the Hic-5 KO group had significantly lower relative mRNA expression of α-SMA, collagen 1, and p65 than the WT group (all P＜0.01). ConclusionHic-5 knockout inhibits NF-κB/p65 expression and hepatic stellate cell activation and alleviates CCl4-induced liver fibrosis.

ObjectiveTo investigate the efficacy and safety of microsphere transarterial chemoembolization (TACE) combined with radiotherapy in the treatment of patients with unresectable liver cancer. MethodsA total of 68 patients with unresectable liver cancer were enrolled in Shantou central hospital from January 2016 to October 2018, among whom there were 65 male and 3 female patients, with a median age of 55 years (range 36-75 years). These patients were randomly divided into microsphere TACE group with 34 patients and microsphere TACE combined with radiotherapy group (combined group with 34 patients). The two groups were compared in terms of short-term response rate, progression-free survival (PFS) rate, overall survival (OS) rate, and adverse events to evaluate safety. The chi-square test was used for comparison of categorical data between groups, and the Kaplan-Meier method and the log-rank test were used for comparison of PFS and OS rates. ResultsUp to the last follow-up on April 30, 2019, all patients completed treatment as planned and the median follow-up time was 15.2 months. A total of 25 deaths were observed. The objective response rate was 50.0% in the microsphere TACE group and 76.5% in the combined group, and the combined group had a significantly better short-term response than the microsphere TACE group (χ2=7.995, P=0046). For the microsphere TACE group, the 6-, 12-, 18-, and 24-month OS and PFS rates were 94.1%/76.5%, 69.0%/47.1%, 51.3%/23.9%, and 30.9%/9.6%, respectively, and for the combined group, the 6-, 12-, 18-, and 24-month OS and PFS rates were 100%/93.7%, 87.8%/81.1%, 75.1%/52.9%, and 58.2%/44.1%, respectively; the combined group had significantly better PFS and OS time than the microsphere TACE group (χ2=9.027 and 4.288, P=0.002 7 and 0.038). There was a low incidence rate of adverse events in the two groups, and no treatment-related death was observed. ConclusionCompared with microsphere TACE alone, microsphere TACE combined with radiotherapy significantly improves short-term response and long-term survival in patients with unresectable liver cancer and thus provides a more effective and safer treatment for such patients.

ObjectiveTo investigate the clinical effect and adverse events of Jinlong capsules combined with Western medicine treatment in the treatment of advanced primary liver cancer. MethodsPubMed, The Cochrane library, CNKI, Wanfang Data, CBM, and VIP were searched for randomized controlled trials (RCTs) on Jinlong capsules combined with Western medicine treatment in the treatment of advanced primary liver cancer published up to May 2019. The patients treated with Jinlong capsules combined with Western medicine treatment were enrolled as intervention group, and those treated with Western medicine treatment alone were enrolled as control group. Data extraction and quality assessment were performed, and RevMan 5.3 was used to perform the Meta-analysis with a fixed or random effects model. ResultsA total of 26 RCTs were included, with a total of 2318 patients (1175 patients in the intervention group and 1143 patients in the control group). The results of the Meta-analysis showed that compared with Western medicine treatment alone, Jinlong capsules combined with Western medicine treatment had significant increases in response rate (relative risk ［RR］=1.36, 95% confidence interval ［CI］: 125-1.49, P＜0.001), 1-year survival rate (RR=1.29, 95%CI: 1.14-1.47, P＜0.001), Karnofsky Performance Scale score (RR=137, 95%CI: 1.19-1.59, P＜0.001), peripheral blood CD3+ T lymphocytes (mean difference ［MD］=11.18, 95%CI: 268-1968, P=0.01), CD4+ T lymphocytes (MD=6.43, 95%CI: 3.82-9.05, P＜0.001), and CD4+/CD8+ ratio (MD=0.31, 95%CI: 026-0.36, P＜0.001), as well as significant reductions in rate of progression (RR=0.41, 95%CI: 0.29-0.57, P＜0001), rate of leucopenia (RR=0.65, 95%CI: 0.57-0.75, P＜0.001), incidence rate of gastrointestinal reactions (RR=0.72, 95%CI: 059-088, P=0.001), and peripheral blood CD8+ T lymphocytes (MD=-4.68, 95% CI: -5.84 to -3.51, P＜0001). ConclusionJinlong capsules combined with Western medicine treatment has a marked clinical effect in the treatment of advanced primary liver cancer with few adverse events and thus holds promise for clinical application.