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Objective: To study the surgical safety and efficacy of preoperative neoadjuvant therapy with immune checkpoint inhibitors combined with anti-angiogenic drugs in patients with China liver cancer staging(CNLC)-Ⅱb and Ⅲa resectable hepatocellular carcinoma. Methods: The data of 129 patients with Ⅱb and Ⅲa hepatocellular carcinoma who underwent surgery at the First Affiliated Hospital of Nanjing Medical University from January 2018 to December 2020 were analyzed. All patients were divided into two groups: the neoadjuvant therapy group( n =14,13 males and 1 female,aged (55.4±12.6)years(range:34 to 75 years)) received immune combined targeted therapy before surgery,immune checkpoint inhibitor camrelizumab was administered intravenously at a dose of 200 mg each time,every 2 weeks for 3 cycles,anti-angiogenesis drug apatinib was taken orally and continuously with a dose of 250 mg for 3 weeks and the conventional surgery group( n =115,103 males and 12 females,aged (55.8±12.0)years(range:21 to 83 years)) did not receive antitumor systemic therapy before surgery. There were 3 patients with CNLC-Ⅱb,11 with CNLC-Ⅲa in the neoadjuvant group;28 patients with CNLC-Ⅱb,87 with CNLC-Ⅲa in the conventional group. Student's t test or rank-sum test was used to compare the differences between two groups for quantitative data, Fisher's exact probability method was used to compare the differences of proportions between two groups, and Log-rank test was used to compare survival differences between two groups. Results: The 1-year recurrence rate in the neoadjuvant group was 42.9%,and the 1-year recurrence rate in the conventional group was 64.0%,with a statistically significant difference between the two groups(χ²=3.850, P =0.050);The 1-year survival rate in the neoadjuvant group was 100% and that in the conventional group was 74.2%,with a statistically significant difference between the two groups(χ²=5.170, P =0.023). According to the stratified analysis of the number of tumors,for single tumor,the 1-year recurrence rate in the neoadjuvant group was 25.0%,and that in the conventional surgery group was 71.0%,and the difference between the two groups was statistically significant(χ²=5.280, P =0.022). For multiple tumors, the 1-year recurrence rate in the neoadjuvant group was 66.7%,and the 1-year recurrence rate in the conventional surgery group was 58.9%,with no significant difference between the two groups(χ²=0.110, P =0.736). The operative time,intraoperative blood loss,and postoperative hospital stay in the neoadjuvant group were similar to those in the conventional group,and their differences were not statistically significant. Conclusions: Immune checkpoint inhibitors combined with anti-angiogenic targeted drugs as a neoadjuvant therapy for resectable hepatocellular carcinoma can reduce the 1-year recurrence rate and improve the 1-year survival rate,especially for those with solitary tumor. Limited by the sample size of the neoadjuvant group,the safety of immune combined targeted therapy before surgery cannot be observed more comprehensively,and further studies will be explored.

Objective: To summarize the experience of surgical treatment of primary liver cancer. Methods: The clinical data of 10 966 surgically managed cases with primary liver cancer, from January 1986 to December 2019 at Hepatobiliary Center, the First Affiliated Hospital of Nanjing Medical University, were retrospectively analyzed. The life table method was used to calculate the survival rate and postoperative recurrence rate. Log-rank test was used to compare the survival process of different groups, and the Cox regression model was used for multivariate analysis. In addition, 2 884 cases of hepatocellular carcinoma(HCC) with more detailed follow-up data from 2009 to 2019 were selected for survival analysis. Among 2 549 patients treated with hepatectomy, there were 2 107 males and 442 females, with an age of (56.6±11.1) years (range: 20 to 86 years). Among 335 patients treated with liver transplantation, there were 292 males and 43 females, with an age of (51.0±9.7) years (range: 21 to 73 years). The outcomes of hepatectomy versus liver transplantation, anatomic versus non-anatomic hepatectomy were compared, respectively. Results: Of the 10 966 patients with primary liver cancer, 10 331 patients underwent hepatectomy and 635 patients underwent liver transplantation. Patients with liver resection were categorized into three groups: 1986－1995(712 cases), 1996－2008(3 988 cases), 2009‒2019(5 631 cases). The 5-year overall survival rate was 32.9% in the first group(1986－1995). The 5-year overall survival rate of resected primary liver cancer was 51.7% in the third group(2009-2019), among which the 5-year overal survival rates of hepatocellular carcinoma, intrahepatic cholangiocarcinoma and mixed liver cancer were 57.4%, 26.6% and 50.6%, respectively. Further analysis was performed on 2 549 HCC patients with primary hepatectomy. The 1-, 3-, 5-, and 10-year overall survival rates were 88.1%, 71.9%, 60.0%, and 41.0%, respectively, and the perioperative mortality rate was 1.0%. Two hundred and forty-seven HCC patients underwent primary liver transplantation, with 1-, 3-, 5-, and 10-year overall survival rates of 84.0%, 64.8%, 61.9%, and 57.6%, respectively. Eighty-eight HCC patients underwent salvage liver transplantation, with the 1-, 3-, 5-, and 10-year overall survival rates of 86.8%, 65.2%, 52.5%, and 52.5%, respectively. There was no significant difference in survival rates between the two groups with liver transplantation ( P >0.05). Comparing the overall survival rates and recurrence rates of primary hepatectomy (2 549 cases) with primary liver transplantation (247 cases), the 1-, 3-, 5-, and 10-year overall survival rates in patients within Milan criteria treated with hepatectomy and transplantation were 96.3%, 87.1%, 76.9%, 54.7%, and 95.4%, 79.4%, 77.4%, 71.7%, respectively ( P =0.754). The 1-, 3-, 5-year recurrence rates were 16.3%, 35.9%, 47.6% and 8.1%, 11.7%, 13.9%, respectively( P <0.01). The 1-, 3-, 5-, 10-year overall survival rates in patients with no large vessels invasion beyond the Milan criteria treated with liver resection and transplantation were 87.2%, 65.9%, 53.0%, 33.0% and 87.6%, 71.8%, 71.8%, 69.3%, respectively( P =0.003); the 1-, 3-, 5-year recurrence rate were 39.2%, 57.8%, 69.7% and 29.7%, 36.7%, 36.7%, respectively ( P <0.01). The 1-, 3-, 5-, and 10-year overall survival rates in patients with large vessels invasion treated with liver resection and transplantation were 62.1%, 36.1%, 22.2%, 15.0% and 62.9%, 31.8%,19.9%, 0, respectively ( P =0.387); the 1-, 3-, 5-year recurrence rates were 61.5%, 74.7%, 80.8% and 59.7%, 82.9%, 87.2%, respectively( P =0.909). Independent prognostic factors for both overall survival and recurrence-free survival rates of HCC patients treated with liver resection included gender, neoadjuvant therapy, symptoms, AST, intraoperative or postoperative blood transfusion, tumor number, tumor size, cirrhosis, macrovascular invasion, microvascular invasion, and pathological differentiation. Propensity score matching analysis of 443 pairs further showed that there was no significant difference in overall survival rate between anatomical liver resection and non-anatomical liver resection( P =0.895), but the recurrence rate of non-anatomical liver resection was higher than that of anatomical liver resection( P =0.035). Conclusions: In the past decade, the overall survival rate of HCC undergoing surgical treatment is significantly higher than before. For HCC patients with good liver function reservation, surgical resection can be performed first, and salvage liver transplantation can be performed after recurrence. The effect of salvage liver transplantation is comparable to that of primary liver transplantation. As for the choice of liver resection approaches, non-anatomical resection can reserve more liver tissue and can be selected as long as the negative margin is guaranteed.

Objective: To investigate the association between miR-146a single nucleotide polymorphism and genetic susceptibility to hepatocellular carcinoma (HCC). Methods: PubMed, Web of Science, Cochrane Library, Wanfang Data, and Google Scholar were searched for case-control studies on the association between miR-146a single nucleotide polymorphism and genetic susceptibility to HCC published up to October, 2016 in Chinese or English. The Q-statistics test was used to evaluate the heterogeneity of these articles. Results: A total of 18 articles with 5 610 cases and 7 531 controls were included for the meta-analysis. There was no significant association between miR-146a single nucleotide polymorphism and genetic susceptibility to HCC. The odds ratio ( OR ), 95% confidence interval (95% CI ), and P values for the five genetic models were as follows: the allele model C/G ( OR = 0.99, 95% CI 0.88-1.06, P = 0.440); the heterozygous model CG/GG ( OR = 0.99, 95% CI 0.90-1.10, P = 0.898); the homozygous model CC/GG ( OR = 0.91, 95% CI 0.75-1.10, P = 0.314); the dominant model CC+CG/GG ( OR = 0.97, 95% CI 0.79-1.19, P = 0.759); the recessive model CG+GG/CC ( OR = 1.05, 95% CI 0.94-1.18, P = 0.405). A subgroup analysis of race, source of control population, and Hardy-Weinberg equilibrium were performed in these five genetic models, and miR-146a single nucleotide polymorphism increased the susceptibility to HCC only in the control population-based subgroups of the recessive model CG+GG/CC ( OR = 1.20, 95% CI 1.02-1.40, P = 0.024). There was no association between miR-146a rs2910164 polymorphism and susceptibility to HCC in all the other subgroups. A stratified analysis of HBV infection revealed that miR-146a rs2910164 polymorphism increased the risk of HBV-positive HCC ( OR = 1.26, 95% CI 1.10-1.49, P = 0.001). Conclusion: There is no significant association between miR-146a rs2910164 polymorphism and the risk of HCC, but miR-146a rs2910164 polymorphism may increase the risk of HBV-positive HCC.

Hepatocellular carcinoma is one of the most common malignant tumors worldwide; it is estimated that there were 782,000 new cases in 2012. MicroRNAs (miRNAs) play an important role in carcinogenesis by regulating oncogenes and tumor suppressors. We investigated the role of miR-146a, miR-196a2, and miR-499 polymorphisms in the risk of hepatocellular carcinoma in a Chinese population. Hepatocellular carcinoma patients (175) and healthy controls (302) were recruited between April 2013 and March 2015. Genotype analysis of miR-146a, miR-196a2, and miR-499 polymorphisms was carried out by polymerase chain reaction-restriction fragment length polymorphism. There was a significant difference between the genotype distribution of miR-196a2 in hepatocellular carcinoma patients and controls (X 2 = 17.23, P < 0.001). CG and GG miR-146a genotypes significantly elevated the risk of hepatocellular carcinoma compared with the CC genotype, with adjusted ORs (95%CI) of 3.05 (1.07-8.70) and 4.96 (1.64-14.97), respectively. In the recessive model, the CG + GG genotype had a 3.75-fold risk of hepatocellular carcinoma compared with the CC genotype, with an adjusted OR (95%CI) of 3.75 (1.39-10.11). However, no significant association was observed between miR-196a2 and miR-499 variants and risk of hepatocellular carcinoma in the co-dominant, dominant, and recessive models. The miR-146a polymorphism is a G to C substitution that causes a mismatch in the stem-loop of miRNA, which influences how the expression and transcriptional regulation of miRNA affects its target genes. Our study revealed that the GG and CG genotypes of miR-146a increased the risk of hepatocellular carcinoma in the Chinese population., Competing Interests: The authors declare no conflict of interest.

We produced monoclonal antibodies (MAbs) against acidic isoferritin (AIF) of primary hepatic carcinoma (PHC) and human placental tissues. Competitive enzyme-linked immunosorbent assay (ELISA) revealed that each MAb bound to different antigenic determinants of AIF, but there is the same epitope between PHC AIF and placental AIF. Sandwich-type ELISA was developed to measure the concentration of serum AIF in the patients with PHC, chronic hepatitis, and cirrhosis. In most of cases of PHC, serum AIF levels were found to be significantly elevated, but were in low levels in almost all of the patients with chronic hepatitis and cirrhosis. On the other hand, we have studied the expression of AIF in liver tissue. Immunohistochemical study using MAb4c9 specific for PHC AIF and MAb7a9 specific for placental AIF has shown that AIF positive staining rates of hepatocytes with liver tissues of PHC, nonmalignant live diseases and normal control were 81.6, 6.7, 0%, and 73.7, 10, 0%, respectively. We also studied the p53 protein expression in those liver tissues (47.4, 0, 0% in PHC, nonmalignant liver diseases and normal liver, respectively). Our data indicated that there was significant correlation between AIF and p53 expression in liver tissues of PHC. Taken together, the results suggested that AIF is probably synthesized and secreted by the tumor cells of PHC and its production may reflect carcinogenesis of hepatocytes. Anti-PHC AIF MAb was clearly superior in diagnosis of PHC to antiplacental AIF MAb, and has potential application of immunotherapy.