China guideline for liver cancer screening (2022, Beijing) / 中华消化外科杂志

In China, the survival rate of liver cancer remains low while the mortality rate is high. Effectively reducing the burden of liver cancer is still a major challenge in the field of public health and chronic disease prevention in the Chinese population. Optimizing screening strategies for liver cancer remains a profound approach to secondary prevention worthy of continuous explora-tion. This guideline was commissioned by the Bureau of Disease Control and Prevention of the National Health Commission. The National Cancer Center of China initiated the guideline develop-ment and convened a multidisciplinary expert panel and working group. Following the World Health Organization Handbook for Guideline Development, this guideline integrated the most up-to-date evidence of liver cancer screening, China′s national conditions, and existing practical experience in liver cancer screening. Evidence-based recommendations on the target population, screening technologies, surveillance strategies, and other key points across the process of liver cancer screening and surveillance management were provided. This guideline would help to standardize the practice of liver cancer screening in China.

China guideline for liver cancer screening (2022, Beijing) / 临床肝胆病杂志

In China, the survival rate of liver cancer remains low while the mortality rate is high. Effectively reducing the burden of liver cancer is still a major challenge in the field of public health and chronic disease prevention in the Chinese population. Optimizing screening strategies for liver cancer remains a profound approach to secondary prevention worthy of continuous exploration. To address this pressing issue, the Bureau of Disease Control and Prevention of the National Health Commission commissioned this guideline. The National Cancer Center of China initiated the guideline development and convened a multidisciplinary expert panel and working groups. Following the World Health Organization Handbook for Guideline Development, this guideline integrated the most up-to-date evidence of liver cancer screening, China's national conditions, and existing practical experience in liver cancer screening. Evidence-based recommendations on the target population, screening technologies, surveillance strategies, and other key points across the process of liver cancer screening and surveillance management were provided. This guideline would help standardize the practice of liver cancer screening in China.

Induction of specific CD8+ T cells against hepatocellular carcinoma-associated neoantigens / 中华肿瘤杂志

Objective@#To predict the tumor neoantigen peptides in hepatocellular carcinoma (HCC), and examine their specific immune effects against the tumor cells without injury to normal cells.@*Methods@#The data of whole-genome sequencing and exome sequencing of HCC tumor and matched non-tumor liver tissues were analyzed to confirm the HCC-associated somatic mutations. Based on the HLA phenotype of the patients, we used NetMHC software to predict the neoantigen epitopes with high binding affinity to their MHC-I molecules. The predicted peptides with mutation sites included were synthesized. GPL10687 platform was applied to examine the gene expression difference between tumor and normal tissues of the selected genes in GSE25097, one of the GEO databases. The quantitative real-time PCR (qRT-qPCR) and immunohistochemistry were used to confirm the expressions in tumors and normal tissues of the selected genes. By using the predicted peptides, we induced the generation of antigen-specific CD8+ cytotoxic T lymphocytes (CTLs) and examined their specific effects against tumor cells.@*Results@#The mutation frequency of TP53 (tumor protein p53) was 40%, and LAMA3 (Laminin Subunit Alpha 3) was 8% in the analyzed HCC tissues. In GSE25097 database, TP53 and LAMA3 mRNA levels in tumors were 1.57±0.02 and 1.37±0.10, which were significantly increased than those in matched no-tumor tissue (0.54±0.01 and 0.36±0.01, P<0.05). The differences of expression levels of TP53 and LAMA3 in tumor and no-tumor tissues were validated by using qRT-qPCR and immunohistochemistry in 10 HCC tissues. The mRNA levels of TP53 and LAMA3 in tumors were 0.24±0.03 and 0.13±0.06, which were significantly elevated than those in matched no-tumor tissue (0.11±0.01 and 0.01±0.01, P<0.05). Among the Chinese population, HLA-A2 and HLA-A11 and HLA-A24 accounted for 70%, representing the major MHC-I molecules. The CTLs induced by predicted peptides showed cytotoxicity to the targets pulsed with mutated peptide, with no effect on the target pulsed with normal peptide and on normal cells.@*Conclusions@#TP53 and LAMA3 existed relative higher mutation frequency in HCC, and expressed higher in tumor tissues. The induced CTLs by predicted peptides derived from mutation-associated protein could specific kill the target cells without injury to normal cells.

An analysis of the annual expenditure per liver cancer patient in China: from the perspective of the whole disease course / 中华健康管理学杂志

Objective To estimate the mean annual expenditure of patients with prevalent liver cancer in China on the perspective of the natural progression of the disease and to provide baseline information for liver cancer?related disease burden estimation and evaluation of prevention strategies. Methods A multicenter survey on liver cancer was conducted between 2012 and 2014 in 13 sites where the cancer screening program was conducted in Urban China, by face?to?face interviews with hospitalized patients. Data on basic information, clinical diagnosis and treatment, direct medical expenditure, and direct non?medical expenditure were collected. By?year expenditure and number of visits from the first visit to the end of the survey were analyzed. The trend for the two indicators in each year was analyzed. The subgroup analysis of factors such as sex and age was conducted. All the expenditure data were discounted to the year 2014 and presented in Chinese yuan. The statistical analysis was performed using the SAS 9.4 software. Results A total of 2 222 patients with liver cancer, with a mean age of 55.7±11.2 years, were included. Men accounted for 79.2% (1 759 cases) of the patients, women accounted for 20.8% (463 cases) of the patients, and 75.6% (1 679 cases) of the cases were from cancer hospitals. Stage Ⅰ cases only accounted for 14.1% (299 cases) of all the cases, and most cases were stageⅢorⅣ(62.6%, 1 325 cases). Of the cases, 64.4% (1 430 cases) had pathological information, and 83.6%(1 195 cases) were pathologically hepatocellular carcinoma. The sample sizes for the first 3 years from the first visit were 2 222, 149, and 57, respectively (by?year sample sizes thereafter were<50). The annual total medical expenditures for the first 3 years were 49 091 yuan (95% confidence interval [CI]: 47 376-50 806), 30 506 yuan (95% CI: 26 462-34 549), and 32 100 yuan (95% CI: 25 917-38 283) (P<0.001). The corresponding number of visits were 1.9, 1.6, and 1.5 (P<0.001). The trend for each province was consistent with the overall trend, while the down trend from years 1 to 2 varied among provinces, ranging from 1.4 (Zhejiang province) to 5.6 times (Henan province). For the trend in the first 3 years, differences were found in subgroups such as region (P<0.001) and treatment (P<0.05), instead of sex, age, stage, and other subgroups. Conclusions For liver cancer patients in China, the annual expenditure for the first year in the whole disease course was 1.6 times higher than that for the second year, which varied among provinces. However, information on annual expenditure for the later course of liver cancer is still limited.

Primary prevention model of liver cancer in rural China / 中华肿瘤杂志

Hepatocellular carcinoma (HCC) is the major histological type of primary liver cancer (PLC), and the etiology is relative clear. Chronic infection of hepatitis B virus (HBV) plays dominant roles, and high exposure to aflatoxins is an important co-factor. Qidong was one of the endemic area with high PLC incidence in rural China. The results from a series of etiological intervention studies on PLC in this area indicated that 1) the protective efficacy of neonatal HBV vaccination against PLC development under the age of 30 was 84% (95% CI 23%-97%); 2) the relative risk of liver cancer incidence decreased at least 4 folds in young adults aged <35 years with reducing aflatoxin exposures and cleaning drinking water. The prevention of HBV infection and the supplies of clean water and safe food with limited aflatoxins demonstrated as an effective primary prevention model of liver cancer in rural China.

Trend analysis of age of diagnosis for liver cancer in cancer registry areas of China, 2000-2014 / 中华预防医学杂志

Objective@#To investigate trends of mean age of diagnosis for liver cancer during 2000 to 2014, which may provide basic information for making feasible cancer prevention strategies.@*Methods@#Based on the continuous cancer incidence data from 22 cancer registries of China between 1 January 2000 and 31 December 2014, the incidence by birth-cohort (year of birth between 1925 and 1994) and age specific incidence rates were calculated. The incidence of different age groups were also calculated. World Segi's population was used for age standardization. The liner regression model was applied to analyze the changing trend of mean age of diagnosis.@*Results@#In 2014, the incidence rate for population with 80 years older and above was 108.21 per 100 000, whereas the rate for population at 30-39 years old was 5.09 per 100 000. But the mean age of diagnosis for liver cancer showed an increasing trend from 2000 to 2014. For male, it had increased from 58.80 to 62.35 (t=18.70, P<0.001) . For female, it had increased from 64.02 to 68.99 (t=20.50, P<0.001) . After age standardization, the mean age of diagnosis still showed increasing trend. Meanwhile, the proportion of liver cancer in people above 70 years old was 25.05% in 2014, which was higher than that in 2000 (22.49%).@*Conclusion@#The mean age of liver cancer incidence was increasing during 2000-2014.

Primary prevention by hepatitis B vaccine on liver cancer in high incidence area of China / 中华预防医学杂志

Objective@#Incidence of primary liver cancer (PLC) in China is mostly related to chronic infection of hepatitis B virus (HBV). Qidong was one of the endemic areas with high incidence of PLC in China before 2000. We conducted a series of studies regarding on PLC etiological prevention during the past decades to develop better primary prevention strategies for PLC.@*Methods@#Qidong Hepatitis B Intervention Study was conducted in 1983-1990. A total of 41 182 newborns were randomly assigned to vaccination group and 40 211 (97.64%) of them completed the three-dose, 5 µg-plasma-derived hepatitis B (HB) vaccination series at age 0, 1, 6 month. Among them, 28 988 participants received one-dose 10 µg recombinant HB booster vaccination at age 10-14 years. A total of 41 730 newborns were randomly assigned to the control group. When they were at age 10-14 years, 23 368 participants received the catch-up vaccination with three-dose, 10 µg-recombinant HB vaccine. Two cross-sectional HBV serology surveys were conducted in 1996-2000 and 2008-2012. Information on PLC incidence and mortality of chronic liver diseases were collected through cancer registry and vital statistics until December 31, 2016. Cox proportional hazard models were employed to compute hazard ratio (HR) of PLC and other liver diseases for the participants with neonatal HB vaccination or catch-up vaccination, and the protective efficacy was also calculated.@*Results@#During serologic survey in 1996-2000, a total of 22 689 participants in vaccination group and 12 395 participants in control group donated blood samples. The HBsAg seropositive rates in the vaccination group was 2.16% (491/22 689), which is significantly lower than that of control group (9.08%, 1 126/12 395) (χ2=896.61, P<0.001). During serologic survey in 2008-2012, a total of 17 386 participants in vaccination group and 18 060 participants in control group donated blood samples. The HBsAg seropositive rates in the vaccination group was 1.83% (319/17 386), which is still significantly lower than that of control group (6.77%,1 222/18 060) (χ2=518.05, P<0.001). By December 31, 2016, 4 cases of PLC in the vaccination group and 17 cases of PLC were identified in the vaccination and control group, respectively. The estimated efficacy of neonatal HB vaccination on HBsAg seroprevalence in childhood (at age 10-11 years), early adulthood (at age 19-28 years) and incidence rate of PLC at age below 33 years was 79% (95%CI: 76%-81%), 74% (95%CI: 71%-78%) and 79% (95%CI: 36%-93%), respectively. The estimated efficacy of three-dose, 10 µg-recombinant HB catch-up vaccination in early adulthood is 21% (95%CI: 11%-30%), which is significantly lower than that of neonatal HB vaccination.@*Conclusion@#HB vaccination to neonates/infants is crucial against chronic HBV infection in childhood through young adulthood, and subsequently reduced the risk of PLC in young adults.

Long-term efficacy of neonatal hepatitis B vaccination against chronic hepatitis B virus infection and chronic liver disease: a cross-sectional study based on Qidong Hepatitis B Intervention Study / 中华流行病学杂志

<p><b>OBJECTIVE</b>To evaluate the long-term protection efficacy of neonatal hepatitis B vaccination on chronic hepatitis B (CHB) and liver fibrosis and cirrhosis in adults.</p><p><b>METHODS</b>From January to October, 2013, a cross-sectional study was conducted among the participants from Qidong Hepatitis B Intervention Study (QHBIS), who were selected through stratified random sampling. The detections of serum alanine aminotransferase (ALT), HBsAg, anti-HBs, anti-HBc, HBeAg, and anti-HBe were conducted and ultrasonography on liver, gallbladder and spleen was performed for them. The positive rates of each serologic markers, the prevalence of active CHB and liver fibrosis and cirrhosis were calculated, the gender specific differences between vaccination group and control group were compared with Chi-square test.</p><p><b>RESULTS</b>A total of 4 421 participants aged (25.59±1.84) years in vaccination group and 3 880 participants aged (26.61±2.24) years in control group were surveyed. The positive rates of HBsAg, anti-HBs, anti-HBc, HBeAg and anti-HBe were 2.38%, 37.73%, 3.78%, 0.57% and 2.15% in vaccination group, and 9.02%, 29.41%, 16.83%, 2.73% and 8.87% in control group, respectively, the differences between two groups were statistically significant (all P<0.05). The prevalence of active CHB and liver fibrosis and cirrhosis were 0.45% and 0.16% in vaccination group, 1.29% and 0.39% in control group, the differences between two groups were statistically significant (P<0.05). The active CHB prevalence was lower in females than in males in both vaccination group and control group (P<0.05). The liver fibrosis and cirrhosis prevalence was lower in females than in males in control group (P<0.05); whereas, no statistical significant difference in liver fibrosis & cirrhosis prevalence between males and females was found in vaccination group (P>0.05).</p><p><b>CONCLUSIONS</b>Protection conferred by neonatal hepatitis B vaccination could last to marrying age. The gender specific difference in protection efficacy needs further study.</p>

Burden of cancer in China: data on disability-adjusted life years / 中华预防医学杂志

Disability-adjusted life years (DALYs) has been increasingly used to estimate burden of disease worldwide. By giving a particular attention to DALYs, the objectives of the study were to review various data sources and to conduct an extended estimation on the burden of cancer in China. Based on the publications released by the GLOBOCAN 2008 program and the Global Burden of Disease 2010 (GBD 2010) program, we reviewed the methodological information and gathered DALY data associated with burden of cancer in China, and then we extracted and summarized the data and conducted an extended analysis. From a methodological perspective, both of the programs applied the utility weights mainly from populations other than China. The data from GLOBOCAN 2008 suggests that liver cancer has replaced lung cancer and became the leading cancer in males in China when using DALY rather than mortality rate as the indicator (6.3 million and 5.4 million DALYs, respectively); although the ranking is different, data from the GBD 2010 project shows DALYs caused by liver cancer is comparable to that associated with lung cancer (7.9 million and 8.0 million, respectively). The years lived with disability (YLDs) comprised 26% and 12% of the total DALYs associated with breast cancer and colorectal cancer in China. Both projects suggest that liver cancer might have become or is becoming the leading contributor to males' DALYs in China. There are indications that, along with economic development, YLD will play a more important role in estimation of burden of cancer in China; it suggests that China should consider introducing DALY into the estimation system as early as possible. It also suggests that research on quality of life and utility associated with the major cancers in China need to be systematically conducted to facilitate more accurate DALY estimation.

Relationship between CCL20/CCR6/Th17 axis and vascular invasion and metastasis in patients with primary hepatocellular carcinoma / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To investigate the role of CCL20/CCR6/Th17 axis in vascular invasion and metastasis of primary hepatocellular carcinoma (HCC).</p><p><b>METHODS</b>Expression levels of CCL20 mRNA in the normal human liver cell line L-02, and human hepatocellular carcinoma cell lines Hep3B, Huh7 and HepG2 were quantified by using SYBR green real time PCR. CCL20 secretions from these cell lines were quantified by using ELISA. The chemotactic effect of HCC cell line Hep3B on human peripheral blood mononuclear cells was determined by using transwell chemotaxis assay. Pre-therapy serum levels of IL-1α, IL-1β, IL-6, IL-8, IL-10, IL-17, IL-23, IFN-γ, TNF-α and CCL20 in 93 patients with HCC were measured by using 9-plex array and ELISA. All the patients were chronic hepatitis B virus associated HCC, and 51 cases were those with vascular invasion and metastasis (metastasis group) and 42 cases were not (non-metastasis group). CCL20 and CCR6 mRNA expressions in the HCC and tumor-adjacent tissues were determined by using SYBR Green real time PCR in 41 patients, among them, 20 cases were from the group of patients with metastasis and 21 cases were from the group of patients without metastasis. The CCL20 expression was further determined by immunohistochemistry.</p><p><b>RESULTS</b>The HCC cell lines expressed and secreted higher amount of CCL20, which effectively recruited CCR6(+) T cells. Pre-therapy serum levels of CCL20 in 93 HCC patients were (38.2 ± 28.4)pg/ml, significantly increased than those with benign hepatic hemangiomas [(7.8 ± 17.8)pg/ml, P < 0.01]. In addition, the serum levels of CCL20 were positively correlated with the tumor diameters in HCC patients (r = 0.32, P = 0.0018). CCL20 was dominantly expressed in the cytoplasm in HCC cells, and it was also expressed by some infiltrating immune cells. The mRNA expression levels of CCL20 of the tumor tissues were significantly higher than that in the tumor-adjacent tissues (P < 0.05). Multivariate logistic regression analysis showed that serum levels of IL-17 and CCL20 were independent risk factors of metastasis in HCC patients (P < 0.05 for both). CCL20 mRNA showed no statistically significant differences between patients with metastasis and without metastasis in both tumor tissues and tumor-adjacent tissues (P > 0.05 for both). But the patients with metastasis showed significantly higher expressions of CCR6 both in their tumor [5.75 (1.79, 19.13)]and tumor-adjacent tissues [7.99 (4.49, 19.54)] than those with non-metastasis [1.69 (0.76, 2.87) and 3.58 (1.84, 4.32), P < 0.05 for both].</p><p><b>CONCLUSION</b>CCL20/CCR6/Th17 axis may promote vascular invasion and metastasis hepatocellular carcinoma.</p>

Chronic colitis induced by irritant dextran sodium sulphate promote hepatoma development in mice / 中国比较医学杂志

Objective To investigate the effect of gut bacteria under chronic colitis on the progression of hepatoma in mice.Methods 22 hepatitis B virus (HBV) -transgenic mice ( male, 8 weeks) were randomly divided into two groups, one group (n =10) was fed the drinking water containing 2% dextran sodium sulphate(DSS)to induce chronic colitis and the control group(n =12)was fed with normal drinking water.In order to investigate the effect of gut microbes, 7 male HBV-transgenic mice(8 weeks, with no detectable hepatoma under microscopy) were cohoused with 4 mice with hepatoma for 16 weeks.Results No significant liver cell damage was observed in the group of the mice fed with 2% DSS-containing drinking water.By the 22 -week old,9 of the 10 mice(90.0%) fed with 2% DSS-containing drinking water, 2 of the 12 mice(16.7%) fed with normal drinking had hepatoma.Both the hepatoma incidence and the tumor numbers in the group of mice fed with DSS-containing water were significantly higher than that in the controls (P =0.002 and P =0.028respetively).Compared to controls, the bacteria family Prevotella (P =0.022) and Anaeroplasma (P =0.014) reduced significantly in the mice with induced chronic colitis.All the mice (n =7) cohoused with the mice with hepatoma had the liver tumor developed at 24 -week-old.Conclusion Alterations of gut bacteria under chronic colitis may promote the development of liver cancer.

Characteristics of dendritic cells derived from different monocyte subtypes and their functions in tumor immunotherapy / 中国肿瘤生物治疗杂志

Dendritic cells (DCs) have different subtypes with distinct phenotypes and biological functions. Meloyiod dendritic cell subtype is one of the most important DCs subtypes. Recent studies have revealed that human monocytes were composed of CD14++CD16-and CD14+CD16+ subtypes,and mouse monocytes consisted of CD115+Ly6Chigh and CD115+Ly6Clow/-subtypes. Different monocyte subsets differentiate into different dendritic cells subsets with distinct phenotypes and induce different types of immune responses in vivo or in vitro. Under steady state,mouse CD115+Ly6Clow monocyte subtype is an important precursor of dendritic cells in peripheral organs and tissues,but in inflammatory response,CD115+Ly6Chigh monocyte subtype is the main precursor of dendritic cells in peripheral lymphoid organs. CD115+Ly6Chigh monocyte derived dendritic cells can directly present antigens that acquired in peripheral tissues after differentiating into dendritic cells,and transfer their MHC-Ⅰ/peptide complex to residential dendritic cells as well. The cooperation and interaction of dendritic cells from different sources enable the immune system to respond to different stimuli properly.