Apatinib reduces liver cancer cell multidrug resistance by modulating NF-κB signaling pathway

Objectives:This investigation aimed to elucidate the inhibitory impact of apatinib on the multidrug resistance of liver cancer both in vivo and in vitro.Methods:To establish a Hep3B/5-Fu resistant cell line,5-Fu concentrations were gradually increased in the culture media.Hep3B/5-Fu cells drug resistance and its alleviation by apatinib were confirmed via flow cytometry and Cell Counting Kit 8(CCK8)test.Further,Nuclear factor kappa B(NF-κB)siRNA was transfected into Hep3B/5-Fu cells to assess alterations in the expression of multidrug resistance(MDR)-related genes and proteins.Nude mice were injected with Hep3B/5-Fu cells to establish subcutaneous xenograft tumors and then categorized into 8 treatment groups.The treatments included oxaliplatin,5-Fu,and apatinib.In the tumor tissues,the expression of MDRrelated genes was elucidated via qRT-PCR,immunohistochemistry,and Western blot analyses.Results:The apatinibtreated mice indicated slower tumor growth with smaller size compared to the control group.Both the in vivo and in vitro investigations revealed that the apatinib-treated groups had reduced expression of MDR genes GST-pi,LRP,MDR1,and p-p65.Conclusions:Apatinib effectively suppresses MDR in human hepatic cancer cells by modulating the expression of genes related to MDR,potentially by suppressing the NF-κB signaling pathway.

Study on the expression and prognostic relationship of MYL6B in liver cancer based on bioinformatics

BACKGROUND Primary liver cancer is a prevalent and deadly cancer type.Despite treatment advances,prognosis remains poor,with high recurrence rates.Early detection is crucial but challenging due to the disease’s insidious nature.Myosin proteins play significant roles in cancer development,influencing cell migration,invasion,and tumor suppression.MYL6B,a myosin light chain,is involved in various cellular processes and has been associated with poor prognosis in colorectal adenocarcinoma and potential as a biomarker in breast cancer.AIM To investigate the expression of MYL6B in liver hepatocellular carcinoma(LIHC)and its impact on prognosis and potential mechanisms of action using bioinformatics methods.METHODS The expression of MYL6B in pan-cancer and normal tissues was analyzed using the gene expression profiling interactive analysis 2 and tumor immune estimation resource databases.The expression level of MYL6B in LIHC tissues and its relationship with prognosis were analyzed,immunohistochemical analysis of MYL6B and its effect on immune cell infiltration,and the protein network were further studied.RESULTS MYL6B was highly expressed in diffuse large b-cell lymphoma,LIHC,pancreatic adenocarcinoma,skin cutaneous melanoma,thymoma,uterine corpus endometrial carcinoma,uterine carcinosarcoma,and lowly expressed in kidney chromophobe,acute myeloid leukemia,testicular germ cell tumors.The expression level of MYL6B was significantly different between cancer and normal tissues.It had a significant impact on both overall survival and disease-free survival.MYL6B is highly expressed in hepatocellular carcinoma and its expression level increases with cancer progression.High MYL6B expression is associated with poor prognosis in terms of overall survival and recurrence-free survival.The immunohistochemical level of MYL6B is high in hepatocellular carcinoma tissues,and MYL6B has a high level of immune infiltration inflammation.In protein network analysis,MYL6B is correlated with MYL2,MYL6,MYL9,MYLK4,MYLK2,MYL12A,MYL12B,MYH11,MYH9 and MYH10.CONCLUSION The expression level of MYL6B in LIHC was significantly higher than in normal liver tissues,and it was correlated with the degree of differentiation survival rate,and immune infiltration.MYL6B is a potential target for LIHC treatment.

Qidong: a crucible for studies on liver cancer etiology and prevention

Qidong(Jiangsu, China) has been of interest to cancer epidemiologists and biologists because, until recently, it was an endemic area for liver cancer, having amongst the highest incidence rates in the world. The establishment of the Qidong Cancer Registry together with the Qidong Liver Cancer Institute in 1972 has charted the patterns of liver cancer incidence and mortality in a stable population throughout a period of enormous economic, social, and environmental changes as well as of improvements in health care delivery. Updated incidence trends in Qidong are described. Notably, the China age-standardized incidence rate for liver cancer has dropped by over 50% in the past several decades. Molecular epidemiologic and genomic deep sequencing studies have affirmed that infection with hepatitis B virus as well as dietary exposure to aflatoxins through contamination of dietary staples such as corn, and to microcystins–blue-green algal toxins found in ditch and pond water – were likely important etiologic factors that account for the high incidence of liver cancer in this region. Public health initiatives to facilitate universal vaccination of newborns against HBV and to improve drinking water sources in this rural area, as well as economic and social mandates serendipitously facilitating dietary diversity, have led to precipitous declines in exposures to these etiologic factors, concomitantly driving substantive declines in the liver cancer incidence seen now in Qidong. In this regard, Qidong serves as a template for the global impact that a package of intervention strategies may exert on cancer burden.

HBV infection decreases risk of liver metastasis in patients with colorectal cancer:A cohort study

AIM:To evaluate the effect of hepatitis B virus (HBV) infection on liver metastasis of colorectal cancer.METHODS:A total of 1298 colorectal cancer patients were recruited from January 2001 to March 2005 in this study.Enzyme-linked immunosorbent assay was used to test serum HBV markers for colorectal cancer.Patients were divided into study (infection) group and control (non-infection) group.Clinical features of patients in two groups were compared.RESULTS:Liver metastasis was found in 319 out of the 1298 colorectal cancer patients.The incidence of liver metastasis was significantly lower in study group than in control group (14.2% vs 28.2%,P < 0.01).HBV infection significantly decreased the risk of liver metastasis [hazard ratio (HR):0.50,95% confidence interval (95% CI):0.38-0.66],but the incidence of extrahepatic metastasis was significantly higher in study group than in control group (31.9% vs 17.0%,P < 0.01).The HR was the lowest in chronic hepatitis B group (HR:0.29,95% CI:0.12-0.72).The number of liver metastatic lesions was significantly less in study group than in control group with a higher surgical resection rate.However,no significant difference was found in survival rate between the two groups (P=0.95).CONCLUSION:HBV infection decreases the risk of liver metastasis in patients with colorectal cancer and elevates the surgical resection rate of liver metastatic lesions.

Rethinking the Barcelona clinic liver cancer guidelines:Intermediate stage and Child-Pugh B patients are suitable for surgery?

According to Barcelona Clinic Liver Cancer recommendations,intermediate stage hepatocellular carcinomas(stage B)are excluded from liver resection and are referred to palliative treatment.Moreover,Child-Pugh B patients are not usually candidates for liver resection.However,many hepatobiliary centers in the world manage patients with intermediate stage hepatocellular carcinoma or Child-Pugh B cirrhosis with liver resection,maintaining that hepatic resection is not contraindicated in selected patients with non–early-stage hepatocellular carcinoma and without normal liver function.Several studies demonstrate that resection provides the best survival benefit for selected patients in very early/early and even in intermediate stages of Barcelona Clinic Liver Cancer classification,and this treatment gives good results in the setting of multinodular,large tumors in patients with portal hypertension and/or Child-Pugh B cirrhosis.In this review we explore this controversial topic,and we show through the literature analysis how liver resection may improve the short-and long-term survival rate of carefully selected Barcelona Clinic Liver Cancer B and Child-Pugh B hepatocellular carcinoma patients.However,other large clinical studies are needed to clarify which patients with intermediate stage hepatocellular carcinoma are most likely to benefit from liver resection.

Negative impact of hepatitis B surface seroclearance on prognosis of hepatitis B-related primary liver cancer

AIM To assess the impact of hepatitis B surface(HBs Ag) seroclearance on survival outcomes in hepatitis B-related primary liver cancer.METHODS Information from patients with hepatitis B-related liver cancer admitted in our hospital from 2008-2017 was retrieved. Cases diagnosed with HBs Ag(-) and HBc Ab(+) liver cancer were included in the HBs Ag seroclearance(SC) group. HBs Ag(+) liver cancer patients strictly matched for liver cancer stage(AJCC staging system, 8 th edition), Child-Pugh score, and first diagnosis/treatment method(surgery, ablation and TACE) were assigned to the HBsA g non-seroclearance(NSC) group. Then, clinical, pathological and survival data in both groups were assessed.RESULTS The SC and NSC groups comprised of 72 and 216 patients, respectively. Patient age(P < 0.001) and platelet count(P = 0.001) in the SC group were significantly higher than those of the NSC group. SC group patients who underwent surgery had more intrahepatic cholangiocarcinoma(ICC) and combined HCC-CC(CHC) cases than the NSC group, but no significant differences in tumor cell differentiation and history of liver cirrhosis were found between the two groups. The numbers of interventional treatments were similar in both groups(4.57 vs 5.07, P > 0.05). Overall survival was lower in the SC group than the NSC group(P = 0.019), with 1-,3-, and 5-year survival rates of 82.1% vs 85.1%, 43.2%vs 56.8%, and 27.0% vs 45.2%, respectively. Survival of patients with AJCC stage Ⅰ disease in the SC group was lower than that of the NSC group(P = 0.029).CONCLUSION Seroclearance in patients with hepatitis B-related primary liver cancer has protective effects with respect to tumorigenesis, cirrhosis, and portal hypertension but confers worse prognosis, which may be due to the frequent occurrence of highly malignant ICC and CHC.

Change of the peripheral blood immune pattern and its correlation with prognosis in patients with liver cancer treated by sorafenib

Objective:To study the change of the peripheral blood immune pattern and its correlation with prognosis in patients with liver cancer after treated by sorafenib.Methods:Patients with advanced liver cancer admitted in our hospital were enrolled and treated with sorafenib.After two months of the treatment,their peripheral blood was collected.The immune cell subset and cytokines level were determined by flow cytometry and luminex technology.According to the reaction expressed by patients towards sorafenib,patients were divided into the response group and the no response group.The changes of the peripheral blood immune pattern and its correlation with prognosis of patients in the two groups were compared.Results:Before and after treatment of sorafenib,there was no significant difference in the ratios of T cells,NK cells and their subtypes in peripheral blood of patients between the two groups;while after treatment the ratio of B cells and regulatory B cells(Breg) of patients in the response group was significant higher than that of the no response group(P<0.05),and the prognosis conditions of patients with decreased ratio of Breg cells were better than other patients after undergoing chemotherapy.The levels of plasma cytokines IL-6,IL-10,IL-12,IL17,FIL-3L,IFN- γ,TNF-α,MCP-1 and VEGF showed no significant differences.Conclusions:After treatment of sorafenib,the prognosis conditions of patients of advanced liver cancer with a reduced Breg ratio are better than patients with an unaltered or increased Breg ratio.The ratio of Breg in peripheral blood may be considered as early biological indicator for the prediction of the curative effects of sorafenib.

High expression levels of IKK alpha and IKK beta are necessary for the malignant properties of liver cancer

IKK-NF-kappa B signaling is regarded as an important factor in hepatocarcinogenesis and a potential target for liver cancer therapy.Therefore,in this study,we analyzed the expression of mRNAs encoding components and targets of NF-kappa B signaling including IKK alpha,IKK beta,RANK,RANKL,OPG,CyclinD3,mammary serine protease inhibitor(Maspin),CyclinD1,c-FLIP,Bcl-x1,Stat3,Cip1 and Cip2 by real-time PCR in 40 patients with liver cancer.After statistical analysis,7 indices including IKK alpha,IKK beta,RANK,Maspin,c-FLIP,Cip2 and cyclinD1 were found to show significant differences between tumor tissue and its corresponding adjacent tissue.When IKK alpha and IKK beta were downregulated in the hepatocellular carcinoma(HCC) cell lines of MHCC-97L and MHCC-97H in vitro,the numbers of BrdU positive cells were decreased in both IKK alpha and IKK beta knockdown cells.Levels of apoptosis were also investigated in IKK alpha and IKK beta knockdown cells.The growth of HCC was inhibited in the subcutaneous implantation model,and lung metastatogenesis was also significantly inhibited in the kidney capsule transplantation model.Downregulation of IKK alpha and IKK beta in HCC cultured in vitro revealed that increased Maspin,OPG and RANKL expression was associated with metastasis of HCC.These findings were associated with downregulation of Bcl-XL and c-FLIP,which may be the reason for increased apoptosis.The therapeutic effect of IKK alpha and IKK beta downregulation depends on extent of NF-kappa B inhibition and the malignant nature of the HCC.We anticipate that IKK-targeted gene therapy can be used in the treatment of HCC,a cancer that is notoriously resistant to radiation and chemotherapy.

Application of the woodchuck animal model for the treatment of hepatitis B virus-induced liver cancer

This review describes woodchucks chronically infected with the woodchuck hepatitis virus(WHV)as an animal model for hepatocarcinogenesis and treatment of primary liver cancer or hepatocellular carcinoma(HCC)induced by the hepatitis B virus(HBV).Since laboratory animal models susceptible to HBV infection are limited,woodchucks experimentally infected with WHV,a hepatitis virus closely related to HBV,are increasingly used to enhance our understanding of virus-host interactions,immune response,and liver disease progression.A correlation of severe liver pathogenesis with high-level viral replication and deficient antiviral immunity has been established,which are present during chronic infection after WHV inoculation of neonatal woodchucks for modeling vertical HBV transmission in humans.HCC in chronic carrier woodchucks develops 17 to 36 mo after neonatal WHV infection and involves liver tumors that are comparable in size,morphology,and molecular gene signature to those of HBV-infected patients.Accordingly,woodchucks with WHV-induced liver tumors have been used for the improvement of imaging and ablation techniques of human HCC.In addition,drug efficacy studies in woodchucks with chronic WHV infection have revealed that prolonged treatment with nucleos(t)ide analogs,alone or in combination with other compounds,minimizes the risk of liver disease progression to HCC.More recently,woodchucks have been utilized in the delineation of mechanisms involved in innate and adaptive immune responses against WHV during acute,self-limited and chronic infections.Therapeutic interventions based on modulating the deficient host antiviral immunity have been explored in woodchucks for inducing functional cure in HBV-infected patients and for reducing or even delaying associated liver disease sequelae,including the onset of HCC.Therefore,woodchucks with chronic WHV infection constitute a well-characterized,fully immunocompetent animal model for HBV-induced liver cancer and for preclinical evaluation of the safety and efficacy of new modalities,which are based on chemo,gene,and immune therapy,for the prevention and treatment of HCC in patients for which current treatment options are dismal.

Clinical significance of serum oxidative stress and serum uric acid levels before surgery for hepatitis B-related liver cancer

BACKGROUND The incidence and mortality of liver cancer are among the highest of all malignant tumors in China.The high recurrence rate after conventional hepatectomy is worrying.There is a lack of effective prognostic indicators for liver cancer.AIM To explore the clinical significance of preoperative serum oxidative stress and serum uric acid(UA)levels in hepatitis B-related liver cancer.METHODS The medical records of 110 hepatitis B-related liver cancer patients who under-went hepatectomy in Gansu Provincial Hospital were retrospectively analyzed.Recurrence in patients within 3 years after surgery was determined.The logistic regression model and Pearson or Spearman correlation were used to analyze the correlation between oxidative stress level and UA,and the recurrence of hepatitis B-related liver cancer.RESULTS Compared with the non-recurrence group,the levels of superoxide dismutase(SOD)and glutathione(GSH)in the recurrence group were lower and the levels of malondialdehyde(MDA)and UA were higher(all P<0.05).UA,SOD,MDA,and GSH were risk factors for postoperative recurrence in hepatitis B-related liver cancer patients(P<0.05).UA was positively correlated with MDA(r=0.395,P<0.001)and negatively correlated with GSH(r=-0.204,P=0.032).The area under the receiver operating characteristic curve(AUC)of SOD,MDA,GSH,and UA in predicting the prognosis was 0.276,0.910,0.199,and 0.784,respectively(all P<0.001).CONCLUSION The preoperative serum SOD,GSH,MDA,and UA levels had significant predictive effects on postoperative recurrence of hepatitis B-related liver cancer.

Impact of guideline adherence on the prognosis of Barcelona clinic liver cancer stage B hepatocellular carcinoma

BACKGROUND Patients with Barcelona clinic liver cancer(BCLC)stage B hepatocellular carcinoma(HCC)are considerably heterogeneous in terms of tumor burden,liver function,and performance status.To improve the poor survival outcomes of these patients,treatment approaches other than transarterial chemoembolization(TACE),which is recommended by HCC guidelines,have been adopted in realworld clinical practice.We hypothesize that this non-adherence to treatment guidelines,particularly with respect to the use of liver resection,improves survival in patients with stage B HCC.AIM To assess guideline adherence in South Korean patients with stage B HCC and study its impact on survival.METHODS A retrospective analysis was conducted using data from 2008 to 2016 obtained from the Korea Central Cancer Registry.Patients with stage B HCC were categorized into three treatment groups,guideline-adherent,upward,and downward,based on HCC guidelines recommended by the Asian Pacific Association for the Study of the Liver(APASL),the European Association for the Study of the Liver(EASL),and the American Association for the Study of Liver Diseases(AASLD).The primary outcome was HCC-related deaths;tumor recurrence served as the secondary outcome.Survival among the groups was compared using the Kaplan-Meier method and the log-rank test.Predictors of survival outcomes were identified using multivariable Cox regression analysis.RESULTS In South Korea, over the study period from 2008 to 2016, a notable trend was observed in adherence to HCCguidelines. Adherence to the EASL guidelines started relatively high, ranging from 77% to 80% between 2008 and2012, but it gradually declined to 58.8% to 71.6% from 2013 to 2016. Adherence to the AASLD guidelines began at71.7% to 75.9% from 2008 to 2010, and then it fluctuated between 49.2% and 73.8% from 2011 to 2016. In contrast,adherence to the APASL guidelines remained consistently high, staying within the range of 90.14% to 94.5%throughout the entire study period. Upward treatment, for example with liver resection, liver transplantation, orradiofrequency ablation, significantly improved the survival of patients with BCLC stage B HCC compared to thatof patients treated in adherence to the guidelines (for patients analyzed according to the 2000 EASL guidelines, the5-year survival rates were 63.4% vs 27.2%, P < 0.001), although results varied depending on the guidelines.Progression-free survival rates were also significantly improved upon the use of upward treatments in certaingroups. Patients receiving upward treatments were typically < 70 years old, had platelet counts > 105/μL, andserum albumin levels ≥ 3.5 g/dL.CONCLUSIONAdherence to guidelines significantly influences survival in South Korean stage B HCC patients. Curativetreatments outperform TACE, but liver resection should be selected with caution due to disease heterogeneity.

EXPERIMENTAL PRIMARY LIVER CANCER IN TREE SHREWS EXPOSED TO HUMAN HEPATITIS B VIRUS AND AFLATOXIN B_(1)

On the basis of the successful establishment of an animal model in tree shrews experimentally in fected with human hepatitis B virus (HHBV), a study on the hepatocarcinogenic effects of HHBV and aflatoxin B1 (AFB1) by using this animal model was conducted through a lifelong experiment. Among 41 tree shrews exposed to AFB1, 17 were experimentally infected by HHBV and 24 were uninfected. After 158 weeks, significant difference of primary liver cancer (PLC) incidence was present between the HHBV infected (52.94%) and uninfected (12.5%) groups (p<0.05). No difference was found between these two groups in the amount of AFB4 ingestion. Moreover, 1/9 of the tree shrews infected only by HHBV but not exposed to AFB4 developed PLC. No PLC was found in 6 tree shrews that had neither been infected with HHBV nor been exposed to AFB4. These results suggest the possible etiologic relationship between HHBV infection and PLC, as well as the synergetic effects of HHBV and AFB4 during PLC development.

Correlation analysis of TCM syndrome types with T lymphocytes and biochemical indices in patients with HBV-related primary liver cancer

Objective:To investigate the correlation between T lymphocytes and biochemical indices in patients with Primary liver cancer(PLC)associated with hepatitis B virus(HBV)and TCM syndrome differentiation.Methods:263 HBV-related PLC patients who were admitted to the First Affiliated Hospital of Henan University of Traditional Chinese Medicine from January 2018 to December 2019 were retrospectively collected.There were 127 cases of liver depression and spleen deficiency syndrome(48.3%),48 cases of spleen deficiency and dampness syndrome(18.3%),31 cases of liver and gallbladder dampness and heat syndrome(11.8%),35 cases of liver and blood stasis syndrome(13.3%),and 22 cases of liver and kidney Yin deficiency syndrome(8.4%).The general data,T cell subsets,oncology and virology indicators,oncology characteristics,biochemical indicators and other data were counted.Epidata and Excel were used to collect and summarize the data,and SPSS26.0 software was used for statistical analysis.Results:There was no significant difference in gender and age distribution among the five syndrome types(χ^(2)=5.462,F=1.979,ALL P>0.05).The differences among T lymphocyte count(χ^(2)=57.785,P<0.001),CD4(+)T cell count(χ^(2)=47.103,P<0.001)and CD8(+)T lymphocyte count(F=12.760,P<0.001)were statistically significant.The T lymphocyte count,CD4(+)T lymphocyte count and CD8(+)T lymphocyte explicit count in patients with liver and kidney Yin deficiency syndrome were significantly lower than those in the other four syndrome types.AFP(χ^(2)=89.986,P<0.001),CEA(χ^(2)=95.501,P<0.001),CA199(χ^(2)=30.044,P<0.001)of the five syndrome types increased successively from the syndrome of liver depression and spleen deficiency to the syndrome of liver and kidney Yin deficiency,and the difference was statistically significant.There were statistically significant differences in the inner diameter of main portal vein,portal vein cancer thrombin and extrahepatic metastasis among the five syndrome types(ALL P<0.001).The main symptoms of portal vein cancer thrombin and extrahepatic metastasis were liver-gallbladder dampness-heat syndrome and liver-blood stasis syndrome.The differences among PLT(χ^(2)=39.234,P<0.001),Alb(χ^(2)=75.171,P<0.001),TBil(χ^(2)=51.140,P<0.001),AST(χ^(2)=55.881,P<0.001),PT(χ^(2)=21.515,P<0.001)were statistically significant.PLT and Alb decreased successively from the syndrome of liver depression and spleen deficiency to the syndrome of liver and kidney Yin deficiency.PLT and Alb of the syndrome of liver depression and spleen deficiency were significantly higher than those of the other four groups,and TBil and AST of the syndrome of liver and gallbladder dampness and heat were significantly higher than those of the other four groups.PT of liver and kidney Yin deficiency was significantly higher than that of the other four groups.The lymphocyte count,CD4(+) lymphocyte count and CD8(+) lymphocyte count were negatively correlated with AFP,PT and TBil(ALL P<0.05),and positively correlated with PLT(P<0.05).T lymphocyte count was positively correlated with AIb(P<0.05).Conclusion:This study found that patients with liver depression and spleen deficiency syndrome have better cellular immune function,liver function and prognosis.Patients with liver and kidney Yin deficiency have lower cellular immunity,worse liver function,and worse prognosis.Portal vein carcinoma embolus and extrahepatic metastasis were mainly characterized by dampness and heat of liver and gallbladder and blood stasis of liver.Patients with lower lymphocyte counts have poorer blood clotting,worse the liver reserve,and the higher the risk of further cancer.

Differential expression and significance of 5-hydroxymethylcytosine modification in hepatitis B virus carriers and patients with liver cirrhosis and liver cancer

BACKGROUND The relationship between hepatitis B surface antigen(HBsAg)-positive carrier status and liver cancer has been extensively studied.However,the epigenetic changes that occur during progression from HBsAg-positive carrier status or cirrhosis to liver cancer are unknown.The epigenetic modification of DNA hydroxymethylation is critical in tumor development.Further,5-hydroxymethylcytosine(5hmC)is an important base for DNA demethylation and epigenetic regulation.It is also involved in the assembly of chromosomes and the regulation of gene expression.However,the mechanism of action of 5hmC in HBsAgpositive carriers or patients with cirrhosis who develop liver cancer has not been fully elucidated.AIM To investigate the possible epigenetic mechanism of HBsAg-positive carriers and hepatocellular carcinoma(HCC)progression from cirrhosis.METHODS Forty HBsAg-positive carriers,forty patients with liver cirrhosis,and forty patients with liver cancer admitted to the First People's Hospital of Yongkang between March 2020 and November 2021 were selected as participants.Free DNA was extracted using a cf-DNA kit.cfDNA was extracted by 5hmC DNA sequencing for principal component analysis,the expression profiles of the three groups of samples were detected,and the differentially expressed genes(DEGs)modified by hydroxymethylation were screened.Bioinformatic analysis was used to enrich DEGs,such as in biological pathways.RESULTS A total of 16455 hydroxymethylated genes were identified.Sequencing results showed that 32 genes had significant 5hmC modification differences between HBsAg carriers and liver cancer patients,of which 30 were upregulated and 2 downregulated in patients with HCC compared with HBsAg-positive carriers.Significant 5hmC modification differences between liver cirrhosis and liver cancer patients were identified in 20 genes,of which 17 were upregulated and 3 were downregulated in patients with HCC compared with those with cirrhosis.These genes may have potential loci that are undiscovered or unelucidated,which contribute to the development and progression of liver cancer.Analysis of gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes showed that the major signaling pathways involved in the differential genes were biliary secretion and insulin secretion.The analysis of protein interactions showed that the important genes in the protein-protein interaction network were phosphoenolpyruvate carboxykinase and solute carrier family 2.CONCLUSION The occurrence and development of liver cancer involves multiple genes and pathways,which may be potential targets for preventing hepatitis B carriers from developing liver cancer.

Barcelona Clinic Liver Cancer Classification and Treatment of Hepatocellular Carcinoma in a Côte d’Ivoire University Hospital

Context/Objectives: Hepatocellular carcinoma occurs mainly and increasingly in developing countries, where the prognosis is particularly poor. The Barcelona Clinic Liver Cancer classification is used to guide the treatment of hepatocellular carcinoma. The aim of this retrospective study was to describe the Barcelona Clinic Liver Cancer classification and the treatment of hepatocellular carcinoma in a University Hospital in Côte d’Ivoire. Methods: Patients with hepatocellular carcinoma hospitalized in the hepato-gastroenterology unit of the University Hospital of Yopougon from 01 January 2012 to 30 June 2017 were included. The diagnosis of hepatocellular carcinoma was based on the presence of hepatic nodules on the abdominal ultrasound scan, typical images with the helical scanner associated or not with an increase of the α-fetoprotein higher than 200 ng/ml or with histology. Demographic, clinical, biological and radiological data were determined at the time of diagnosis. Patients were classified according to the Barcelona Clinic Liver Cancer classification. Their treatment was specified. Results: There were 258 patients whose median age was 48.1 years. Viral hepatitis B virus was the primary cause of hepatocellular carcinoma in 64.7% of cases. The severity of the underlying cirrhosis was Child-Pugh A in 12.1%, B in 63.6% and C in 24.3% of cases. The median size of the tumor was 63 mm. The α-fetoprotein level was higher than 200 mg/ml in 56.03% of cases. The Eastern Cooperative Oncology Group (ECOG)/World Health Organization (WHO) system was ≥2 in 82.9%. The Barcelona Clinic Liver Cancer classification was A in 1.3%, B in 0%, C in 55.2% and D in 43.5% of patients. There was no transplantation or hepatic resection. Very few patients (1.9%) received radio-frequency curative therapy. The treatment was predominantly symptomatic in 97.8% of patients. During hospitalization 43.7% of patients died. Conclusion: Hepatocellular carcinoma occurs on a liver with severe cirrhosis at a late stage. This does not allow cure treatment and explains a high mortality rate during hospitalization. Hepatitis B virus is the main risk factor and immunization at birth will reduce the incidence of this cancer in Africa.

92031例癌症患者HBV血清标志物特征分析

目的了解癌症患者乙型肝炎病毒(hepatitis B virus,HBV)的感染状态和感染特点。方法回顾性分析2017年7月26日至2023年9月18日于广西医科大学附属肿瘤医院确诊的92031例癌症患者的HBV血清标志物检测结果,以肝癌、非肝癌进行分组,比较未感染(全阴或Anti-HBs阳性)、感染(除外Anti-HBs任何一项阳性)、隐性感染(occult hepatitis B virus infection,OBI;HBsAg阴性、血清或肝组织HBV DNA阳性)的占比。结果92031例癌症患者的HBV总感染率为73.75%(67876/92031),其中肝癌患者的HBV总感染率为97.65%(8922/9137),非肝癌患者的HBV总感染率为71.12%(58954/82894),肝癌组的普通感染率和OBI率均显著高于非肝癌组(均P<0.001)。肝癌组HBV血清标志物中HBsAg、HBeAg、Anti-HBe、Anti-HBc的阳性率明显高于非肝癌组(均P<0.001),但Anti-HBs的阳性率低于非肝癌组(P<0.001)。肝癌组和非肝癌组分别有20种和27种血清标志物组合模式,其中14种模式构成比在两组间差异有统计学意义(均P<0.001);两组均有7种OBI血清组合模式,其中5种模式构成比在两组间的差异有统计学意义(均P<0.05)。结论癌症患者HBV感染状态和血清学组合模式复杂,区分肝癌与非肝癌进行HBV感染统计更利于癌症患者的HBV感染评估。

Direct antiviral agents in hepatitis C virus related liver disease:Don’t count the chickens before they’re hatched

Since molecules with direct-acting antiviral(DAA)became available,the landscape of the treatment of hepatitis C virus(HCV)infection has completely changed.The new drugs are extremely effective in eradicating infection,and treatment is very well tolerated with a duration of 8-12 wk.This review aims to report the outstanding clinical benefits of DAA and to highlight their critical disadvantages,identifying some clinically relevant hot topics.First,do the rates of virological response remain as high when patients with more advanced cirrhosis are considered?Large studies have shown slightly lower but still satisfactory rates of response in these patients.Nevertheless,modified schedules with an extended treatment duration and use of ribavirin may be necessary.Second,does the treatment of HCV infection affect the risk of occurrence and recurrence of liver cancer?Incidence is reduced after viral eradication but remains high enough to warrant periodic surveillance for an early diagnosis.In contrast,the risk of recurrence seems to be unaffected by viral clearance;however,DAA treatment improves survival because of the reduced risk of progression of liver disease.Third,can HCV treatment also have favorable effects on major comorbidities?HCV eradication is associated with a reduced incidence of diabetes,an improvement in glycemic control and a decreased risk of cardiovascular events;nevertheless,a risk of hypoglycemia during DAA treatment has been reported.Finally,is it safe to treat patients with HCV/hepatitis B virus(HBV)coinfection?In this setting,HCV is usually the main driver of viral activity,while HBV replication is suppressed.Because various studies have described HBV reactivation after HCV clearance,a baseline evaluation for HBV coinfection and a specific follow-up is mandatory.

乙型肝炎相关性肝癌患者T淋巴细胞、白介素-28B及高尔基体蛋白73的表达及临床意义

目的:分析乙型肝炎相关性肝癌患者T淋巴细胞、白介素-28B (IL-28B)及高尔基体蛋白73 (GP73)的表达及临床意义。方法:选取2018年10月—2021年10月商丘市第一人民医院收治的119例乙型肝炎相关性肝癌患者作为观察组,选取同期体检的112例健康人群作为对照组。比较两组研究对象血清IL-28B、GP73及T淋巴细胞水平,分析IL-28B、GP73、T淋巴细胞与病理特征及预后的关系。结果:观察组血清IL-28B、GP73及CD8^(+)表达水平均高于对照组,CD3^(+)、CD4^(+)及CD4^(+)/CD8^(+)均低于对照组,差异有统计学意义(t=148.380、13.155、9.827、9.939、16.367、11.453,P<0.05)。不同年龄、性别、肿瘤直径的乙型肝炎病毒(HBV)相关性肝癌患者血清中IL-28B、GP73水平比较,差异无统计学意义(P>0.05)。有淋巴结转移、TNM分期Ⅲ~Ⅳ期、低分化、有血管浸润者血清中IL-28B、GP73水平高于无淋巴结转移、TNM分期Ⅰ~Ⅱ期、中/高分化、无血管浸润者,差异有统计学意义(P<0.05)。HBV相关性肝癌患者血清中CD3^(+)、CD4^(+)、CD8^(+)在不同年龄、性别、肿瘤直径中比较,差异无统计学意义(P>0.05),CD3^(+)、CD4^(+)、CD8^(+)水平在不同淋巴结转移情况、TNM分期、分化程度及血管浸润中比较,差异无统计学意义(P>0.05)。死亡者血清GP73、IL-28B水平均高于生存者,CD4^(+)/CD8^(+)指标低于生存者,差异有统计学意义(t=16.629、2.082、9.267,P<0.05)。结论:乙型肝炎相关性肝癌患者血清IL-28B、GP73及CD8^(+)表达水平明显升高,CD3^(+)、CD4^(+)及CD4^(+)/CD8^(+)指标下降,IL-28B、GP73及CD4^(+)/CD8^(+)水平与相关病理特征、预后具有密切的联系。

解整合素-金属蛋白酶10及肝细胞配体B2在乙肝-肝纤维化-肝癌患者中的表达

目的探讨解整合素-金属蛋白酶10(ADAM10)、肝细胞配体B2(Ephrin-B2)在“肝炎-肝纤维化-肝癌”轴中的表达以及二者与肝纤维化之间的相关性。方法选取400例HBV感染患者为研究对象,以病情的严重程度分为肝纤维化组(200例)、肝细胞癌组(200例),将肝纤维化组进一步分为以下4个亚组:乙型肝炎组(56例)、轻度纤维化组(87例)、中度纤维化组(34例)、肝硬化组(23例),另外选取200例健康体检患者为健康对照组,对比组间血清ADAM10、Ephrin-B2、肝功能指标、肝纤维化指标;免疫组化检测健康肝组织、乙肝不同分级肝纤维化肝组织、肝癌组织间ADAM10与Ephrin-B2表达。采用t检验进行单因素分析,二元logistic进行多因素分析,皮尔逊相关性检测相关性,受试者工作特征(ROC)曲线进行诊断价值分析。结果ADAM10、Ephrin-B2、天冬氨酸氨基转移酶(AST)、丙氨酸氨基转移酶(ALT)、凝血酶原时间(PT)、白蛋白(ALB)、层粘连蛋白(LN)、Ⅳ型胶原(Ⅳ-C)、透明质酸(HA)、Ⅲ型前胶原(PC-Ⅲ)水平在乙型肝炎组、轻度肝纤维化组、中度肝纤维化组、肝硬化、肝细胞癌组依次升高,且均显著高于健康对照组(P<0.05),免疫组化检测显示ADAM10、Ephrin-B2二者阳性表达在乙肝肝纤维化组织与肝癌组织中显著高于健康肝组织,且随着乙肝肝纤维化的进展Ephrin-B2、ADAM10表达显著升高。ADAM10高表达组和Ephrin-B2高表达组AST、ALT、PT、ALB、LN、Ⅳ-C、HA、PC-Ⅲ显著高于ADAM10低表达组和Ephri-B2低表达组(P<0.05)。患者血清ADAM10与Ephrin-B2呈显著正相关(P<0.05),ADAM10、Ephrin-B与血清AST、ALT、PT、ALB、LN、Ⅳ-C、HA、PC-Ⅲ以及肝纤维化分期呈显著正相关(P<0.05)。ADAM10、Ephrin-B2、AST、ALT、PT、ALB、LN、Ⅳ-C、HA、PC-Ⅲ为HBV感染患者患“肝炎-肝纤维化-肝癌”轴进展的影响因素。ADAM10诊断肝纤维化、肝细胞癌曲线下面积(AUC)分别为0.680、0.713,敏感度为0.821、0.794,特异度为0.577、0.639;Ephrin-B2诊断肝纤维化、肝细胞癌AUC为0.663、0.730,敏感度为0.757、0.834,特异度为0.651、0.693。结论ADAM10、Ephrin-B2与“肝炎-肝纤维化-肝癌”轴进展呈递增表达关系,ADAM10、Ephrin-B2可能在HBV感染患者肝纤维化和肝细胞癌发生和发展进程中发挥了重要作用,ADAM10、Ephrin-B2有希望成为“肝炎-肝纤维化-肝癌”轴疾病诊断和病情监测的重要血清标记物。

免疫检查点抑制剂治疗HBV相关肝癌的临床特征及病毒再激活分析

目的 探讨接受免疫检查点抑制剂(ICIs)治疗的乙型病毒性肝炎(HBV)感染肝癌患者的临床特征、HBV再激活及其肝脏毒性。方法 回顾性收集57例肝癌患者为研究对象,根据HBsAg阳性与否分为非HBV感染肝癌组(n=10)与HBV感染肝癌组(n=47)。结果 2组患者在性别、年龄、ICIs类别、是否联合治疗、肝硬化基础、肝内转移、高血压、冠心病、吸烟及饮酒史、起始甲胎蛋白(AFP)值等各方面比较差异无统计学意义(P>0.05)。ICIs种类、肝脏基础病史、基线凝血酶原时间(PT)和国际化标准比值(INR)比较差异有统计学意义(P<0.05)。41例(71.9%)患者出现全级别免疫性肝损伤(IMH),4例(7.02%)患者在ICIs治疗期间出现HBV再激活,发生的中位时间为6个月,这4例患者均接受抗病毒治疗,其中3例患者接受恩替卡韦治疗,1例患者接受替诺福韦酯类药物治疗。结论 接受ICIs治疗的HBV相关肝癌患者可发生HBV再激活,继发性导致肝损伤。接受ICIs治疗的HBV感染患者应常规进行预防性抗病毒治疗,并规律监测HBV-DNA。