Association of preoperative antiviral treatment with incidences of post-hepatectomy liver failure in hepatitis B virus-related hepatocellular carcinoma

BACKGROUND Post-hepatectomy liver failure(PHLF)is a common consequence of radical partial hepatectomy in hepatocellular carcinoma(HCC).AIMS To investigate the relationship between preoperative antiviral therapy and PHLF,as well as assess the potential efficacy of hepatitis B virus(HBV)DNA level in predicting PHLF.METHODS A retrospective study was performed involving 1301 HCC patients with HBV who underwent radical hepatectomy.Receiver operating characteristic(ROC)analysis was used to assess the capacity of HBV DNA to predict PHLF and establish the optimal cutoff value for subsequent analyses.Logistic regression analyses were performed to assess the independent risk factors of PHLF.The increase in the area under the ROC curve,categorical net reclassification improvement(NRI),and integrated discrimination improvement(IDI)were used to quantify the efficacy of HBV DNA level for predicting PHLF.The P<0.05 was considered statistically significant.RESULTS Logistic regression analyses showed that preoperative antiviral therapy was independently associated with a reduced risk of PHLF(P<0.05).HBV DNA level with an optimal cutoff value of 269 IU/mL(P<0.001)was an independent risk factor of PHLF.All the reference models by adding the variable of HBV DNA level had an improvement in area under the curve,categorical NRI,and IDI,particularly for the fibrosis-4 model,with values of 0.729(95%CI:0.705-0.754),1.382(95%CI:1.341-1.423),and 0.112(95%CI:0.110-0.114),respectively.All the above findings were statistically significant.CONCLUSION In summary,preoperative antiviral treatment can reduce the incidence of PHLF,whereas an increased preoperative HBV DNA level has a correlative relationship with an increased susceptibility to PHLF.

Tumor characteristics of hepatocellular carcinoma after direct-acting antiviral treatment for hepatitis C: Comparative analysis with antiviral therapy-naive patients

BACKGROUND Insufficient and contradictory data are available about the relation between directacting antivirals(DAAs)and hepatocellular carcinoma(HCC)development in patients with hepatitis C virus(HCV).AIM To analyze differences in basic clinical,radiological,and laboratory characteristics in addition to tumor behavior upon HCC diagnosis between patients with and without a previous history of DAAs exposure.METHODS This multicenter case-control study included 497 patients with chronic HCVrelated HCC,allocated into one of two groups according to their history of antiviral treatment for their HCV.RESULTS Group I included 151 HCC patients with a history of DAAs,while 346 patients who had never been treated with DAAs were assigned to group II.A significant difference was observed between both groups regarding basic assessment scores(Child,MELD,and BCLC),which tended to have more advanced liver disease and HCC stage upon diagnosis in group I.However,serum albumin was significantly affected,and serumα-fetoprotein was significantly higher in group II(P<0.001).In addition,group I showed significant HCC multicentricity than group II,while the incidence of portal vein thrombosis was significantly higher in group I(P<0.001).CONCLUSION The basic clinical scores and laboratory characteristics of HCC patients are advanced in patients who are naïve to DAAs treatment;however,HCC behavior is more aggressive in DAA-treated patients.

Prevalence of hepatocarcinoma-related hepatitis B virus mutants in patients in grey zone of treatment

BACKGROUND Antiviral treatment of patients with chronic hepatitis B(CHB)in the grey zone of treatment comands risk management in order to optimize the health outcome.In this sense,the identification of HBV mutants related with an increased risk of hepatocellular carcinoma(HCC)could be useful to identify subpopulations with potential indication of antiviral treatment.AIM To analyze the prevalence/persistence of hepatitis B virus(HBV)preS and basal core promoter(BCP)/precore/core variants associated to HCC development in CHB patients in the grey zone.METHODS Work was designed as a longitudinal retrospective study,including 106 plasma samples from 31 patients with CHB in the grey zone of treatment:Hepatitis B e antigen negative,HBV-DNA levels between 12-20000 IU/mL,normal or discordant transaminase levels during follow up and mild/moderate necroinflammatory activity in liver biopsy or Fibroscan(up to 9.5 kPa).Serum HBVDNA was tested using the Abbott Real Time HBV Assay and the BCP/precore/core and the hepatitis B surface antigen(HBsAg)coding regions were analyzed in positive samples by PCR/bulk-sequencing to identify the HCCrelated HBV mutants.RESULTS High-risk HCC related mutants were detected in 24(77%)patients:19(61%)in the BCP/precore/core,and 7(23%)in the HBsAg coding region(2 preS1 and 5 preS2 deletions).The prevalence of preS deletions was genotype-dependent:3/5(60%)patients with preS2 deletions and 1/2 with preS1 deletions were infected with the HBV-E genotype.Since HBV-E was the most prevalent in sub-Saharan patients,a correlation between preS deletions and ethnicity was also found:6/8(75%)sub-Saharan vs 1/19(5%)Caucasian patients had preS deletions(P=0.00016).Remarkably,this correlation was maintained in those patients infected with HBV-A,a minor genotype in sub-Saharan patients:2/2 patients infected with HBV-A from West Africa vs 0/6 of Caucasian origin had preS deletions.The HCC related variants were the major strains and persisted over time(up to 48 mo).Patients with preS deletions had a significant higher prevalence of F2 fibrosis stage than the negatives(57%vs 10%,P=0.0078).CONCLUSION HBV genetic analysis of selected populations,like sub-Saharans infected with HBV-E/A genotypes,will allow identification of subpopulations with risk of HCC development due to accumulation of high-risk HBV variants,thus commanding their increased clinical surveillance.

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.

Then and now: The progress in hepatitis B treatment over the past 20 years

The ultimate goals of treating chronic hepatitis B(CHB)is prevention of hepatocellular carcinoma(HCC)and hepatic decompensation.Since the advent of effective antiviral drugs that appeared during the past two decades,considerable advances have been made not only in controlling hepatitis B virus(HBV)infection,but also in preventing and reducing the incidence of liver cirrhosis and HCC.Furthermore,several recent studies have suggested the possibility of reducing the incidence of recurrent or new HCC in patients even after they have developed HCC.Currently,six medications are available for HBV treatment including,interferon and five nucleoside/nucleotide analogues.In this review,we will examine the antiviral drugs and the progresses that have been made with antiviral treatments in the field of CHB.

Hepatitis C virus:Virology,diagnosis and treatment

More than twenty years of study has provided a better understanding of hepatitis C virus(HCV) life cycle,including the general properties of viral RNA and proteins. This effort facilitates the development of sensitive diagnostic tools and effective antiviraltreatments. At present,serologic screening test is recommended to perform on individuals in the high risk groups and nucleic acid tests are recommended to confirm the active HCV infections. Quantization and genotyping of HCV RNAs are important to determine the optimal duration of anti-viral therapy and predict the likelihood of response. In the early 2000 s,pegylated interferon plus ribavirin became the standard antiHCV treatment. However,this therapy is not ideal. To 2014,boceprevir,telaprevir,simeprevir,sofosbuvir and Harvoni are approved by Food and Drug Administration for the treat of HCV infections. It is likely that the new all-oral,interferon-free,pan-genotyping anti-HCV therapy will be available within the next few years. Majority of HCV infections will be cured by these antiviral treatments. However,not all patients are expected to be cured due to viral resistance and the high cost of antiviral treatments. Thus,an efficient prophylactic vaccine will be the next challenge in the fight against HCV infection.

Efficacy of hepatic arterial infusion chemotherapy and its combination strategies for advanced hepatocellular carcinoma:A network meta-analysis

BACKGROUND With the rapid progress of systematic therapy for hepatocellular carcinoma(HCC),therapeutic strategies combining hepatic arterial infusion chemotherapy(HAIC)with systematic therapy arised increasing concentrations.However,there have been no systematic review comparing HAIC and its combination strategies in the first-line treatment for advanced HCC.AIM To investigate the efficacy and safety of HAIC and its combination therapies for advanced HCC.METHODS A network meta-analysis was performed by including 9 randomized controlled trails and 35 cohort studies to carry out our study.The outcomes of interest comprised overall survival(OS),progression-free survival(PFS),tumor response and adverse events.Hazard ratios(HR)and odds ratios(OR)with a 95% confidence interval(CI)were calculated and agents were ranked based on their ranking probability.RESULTS HAIC outperformed Sorafenib(HR=0.55,95%CI:0.42-0.72;HR=0.51,95%CI:0.33-0.78;OR=2.86,95%CI:1.37-5.98;OR=5.45,95%CI:3.57-8.30;OR=7.15,95%CI:4.06-12.58;OR=2.89,95%CI:1.99-4.19;OR=0.48,95%CI:0.25-0.92,respectively)and transarterial chemoembolization(TACE)(HR=0.50,95%CI:0.33-0.75;HR=0.62,95%CI:0.39-0.98;OR=3.08,95%CI:1.36-6.98;OR=2.07,95%CI:1.54-2.80;OR=3.16,95%CI:1.71-5.85;OR=2.67,95%CI:1.59-4.50;OR=0.16,95%CI:0.05-0.54,respectively)in terms of efficacy and safety.HAIC+lenvatinib+ablation,HAIC+ablation,HAIC+anti-programmed cell death 1(PD-1),and HAIC+radiotherapy had the higher likelihood of providing better OS and PFS outcomes compared to HAIC alone.HAIC+TACE+S-1,HAIC+lenvatinib,HAIC+PD-1,HAIC+TACE,and HAIC+sorafenib had the higher likelihood of providing better partial response and objective response rate outcomes compared to HAIC.HAIC+PD-1,HAIC+TACE+S-1 and HAIC+TACE had the higher likelihood of providing better complete response and disease control rate outcomes compared to HAIC alone.CONCLUSION HAIC proved more effective and safer than sorafenib and TACE.Furthermore,combined with other interventions,HAIC showed improved efficacy over HAIC monotherapy according to the treatment ranking analysis.

Treatment strategies for advanced hepatocellular carcinoma:Sorafenib vs hepatic arterial infusion chemotherapy

Sorafenib is used worldwide as a first-line standardsystemic agent for advanced hepatocellular carcinoma(HCC) on the basis of the results of two large-scale Phase Ⅲ trials. Conversely,hepatic arterial infusion chemotherapy(HAIC) is one of the most recommended treatments in Japan. Although there have been no randomized controlled trials comparing sorafenib with HAIC,several retrospective analyses have shown no significant differences in survival between the two therapies. Outcomes are favorable for HCC patients exhibiting macroscopic vascular invasion when treated with HAIC rather than sorafenib,whereas in HCC patients exhibiting extrahepatic spread or resistance to transcatheter arterial chemoembolization,good outcomes are achieved by treatment with sorafenib rather than HAIC. Additionally,sorafenib is generally used to treat patients with Child-Pugh A,while HAIC is indicated for those with either Child-Pugh A or B. Based on these findings,we reviewed treatment strategies for advanced HCC. We propose that sorafenib might be used as a first-line treatment for advanced HCC patients without macroscopic vascular invasion or Child-Pugh A,while HAIC is recommended for those with macroscopic vascular invasion or Child-Pugh A or B. Additional research is required to determine the best second-line treatment for HAIC non-responders with Child-Pugh B through future clinical trials.

Adjuvant treatment strategy after curative resection for hepatocellular carcinoma

Hepatic resection represents the first-line treatment for patients with resectable hepatocellular carcinoma(HCC).However,the 5-year recurrence rates of HCC after surgery have been reported to range from 50%to 70%.In this review,we evaluated the available evidence for the efficiency of adjuvant treatments to prevent HCC recurrence after curative liver resection.Antiviral therapy has potential advantages in terms of reducing the recurrence rate and improving the overall survival(OS)and/or disease-free survival of patients with hepatitisrelated HCC.Postoperative adjuvant transarterial chemoembolization can significantly reduce the intrahepatic recurrence rate and improve OS,especially for patients with a high risk of recurrence.The efficacy of molecular targeted drugs as an adjuvant therapy deserves further study.Adjuvant adoptive immunotherapy can significantly improve the clinical prognosis in the early stage.Randomized controlled trial(RCT)studies evaluating adjuvant immune checkpoint inhibitors are ongoing,and the results are highly expected.Adjuvant hepatic artery infusion chemotherapy might be beneficial in patients with vascular invasion.Huaier granule,a traditional Chinese medicine,has been proved to be effective in prolonging the recurrence-free survival and reducing extrahepatic recurrence.The efficiency of other adjuvant treatments needs to be further confirmed by large RCT studies.

Advances in immunotherapy for hepatitis B virus associated hepatocellular carcinoma patients

Hepatitis B virus(HBV)infection plays an important role in the occurrence and development of hepatocellular carcinoma(HCC),and the rate of HBV infection in liver cancer patients in China is as high as 92.05%.Due to long-term exposure to chronic antigens from the gut,the liver needs to maintain a certain level of immune tolerance,both to avoid severe inflammation caused by non-pathogenic antigens and to maintain the possibility of rapid and violent responses to infection and tumors.Therefore,HBV infection interacts with the tumor microenvironment(TME)through a highly complex and intertwined signaling pathway,which results in a special TME in HCC.Due to changes in the TME,tumor cells can evade immune surveillance by inhibiting tumor-specific T cell function through cytotoxic T-lymphocy-associated protein-4(CTLA-4)and programmed cell death 1(PD-1)/programmed cell death ligand 1(PD-L1).Interferons,as a class of immune factors with strong biological activity,can improve the TME of HBV-HCC through various pathways.In recent years,the systematic treatment of HCC has gradually come out of the dilemma.In addition to the continuous emergence of new multi-target anti-vascular tyrosine kinase inhibitor drugs,immune checkpoint inhibitors have opened up a new avenue for the systematic treatment of HCC.At present,immunotherapy based on PD-1/L1 inhibitors has gradually become a new direction of systematic treatment for HCC,and the disease charac-teristics of patients included in global clinical studies are different from those of Chinese patients.Therefore,whether a group of HCC patients with HBV background and poor prognosis in China can also benefit from immunotherapy is an issue of wide concern.This review aims to elucidate the advances of immuno-therapy for HBV related HCC patients with regard to:(1)Immunotherapy based on interferons;(2)Immunotherapy based on PD-1/L1 inhibitors;(3)Immunotherapy based on CTLA4 inhibitors;(4)Adoptive cell transfer;(5)Combination immunotherapy strategy;and(6)Shortcomings of immunotherapy.

Hepatic resection vs percutaneous radiofrequency ablation of hepatocellular carcinoma abutting right diaphragm

BACKGROUND It is usually difficult to adequately conduct percutaneous ultrasound-guided radiofrequency(RF) ablation for hepatocellular carcinomas(HCCs) abutting the diaphragm. Our hypothesis was that the subphrenic location of HCC could have an effect on the long-term therapeutic outcomes after hepatic resection and RF ablation.AIM To compare the long-term therapeutic outcomes of hepatic resection and percutaneous RF ablation for HCCs abutting the diaphragm.METHODS A total of 143 Child-Pugh class A patients who had undergone hepatic resection(n = 80) or percutaneous ultrasound-guided RF ablation(n = 63) for an HCC(≤ 3 cm) abutting the right diaphragm were included. Cumulative local tumor progression(LTP), cumulative intrahepatic distant recurrence(IDR), disease-free survival(DFS), and overall survival(OS) rates were estimated. Prognostic factors for DFS and OS were analyzed. Complications were evaluated.RESULTS The cumulative IDR rate, DFS rate, and OS rate for the hepatic resection group and RF ablation group at 5 years were "35.9% vs 65.8%", "64.1% vs 18.3%", and"88.4% vs 68.7%", respectively. Hepatic resection was an independent prognostic factor for DFS(P ≤ 0.001; hazard ratio, 0.352; 95%CI: 0.205, 0.605; with RF ablation as the reference category); however, treatment modality was not an independent prognostic factor for OS. The LTP rate was 46.6% at 5 years for the RF ablation group. The major complication rate was not significantly different between the groups(P = 0.630). The rate of occurrence of peritoneal seeding was higher in the RF ablation group(1.3% vs 9.5%, P = 0.044).CONCLUSION Although OS was not significantly different between patients who had gone hepatic resection or percutaneous RF ablation for HCCs abutting the diaphragm,DFS was better in the hepatic resection group.

Efficacy of 5-Fluorouracil and High-Concentration Cisplatin Suspended in Lipiodol by Short-Term Hepatic Arterial Infusion Chemotherapy for Advanced Hepatocellular Carcinoma with Portal Vein Tumor Thrombosis

Background: Since advanced hepatocellular carcinoma (HCC) is potentially fatal, and patients’ quality of life (QOL) often deteriorates during their treatment, improving the prognosis and QOL of patients given chemotherapy is very important. In addition, cost-effective treatments are highly desirable when chemotherapy must be given repeatedly. The aim of this study was to evaluate the efficacy and usefulness of 5-fluorouracil (5-FU) and high-concentration cisplatin by short-term hepatic arterial infusion chemotherapy (3-day FPL) in advanced HCC patients. Methods: Thirty patients with unresectable advanced HCC were enrolled. The patients underwent hepatic arterial infusion chemotherapy via the implanted port system with 5-FU on days 1 - 3 and a fine-powder formulation of cisplatin in suspended pre-warmed lipiodol on day 2 every 4 to 10 weeks. Tumor response was assessed one month later with CT. Results: All patients had evidence of portal vein invasion (Vp2-4). Four patients achieved a complete response (CR), 8 patients achieved a partial response (PR), and 7 patients had stable disease (SD). The median progression-free survival (PFS) and overall survival (OS) were 198 days and 452 days, respectively. The OS was significantly longer in the successful disease control group (CR, PR, and SD) than in the progressive disease group (P < 0.005). Conclusions: Three-day FPL was effective and tolerable in advanced HCC patients due to its shorter time of administration than conventional FP therapy. Therefore, repetitive 3-day FPL appears useful and contributes to improving the prognosis and QOL of patients with advanced HCC. In addition, this protocol is a cost-effective treatment.

Hepatocellular carcinoma and hepatitis C virus infection in Latin America: epidemiology, diagnosis and treatment

Hepatocellular carcinoma(HCC)is the most common cancer associated with chronic liver disease and cirrhosis.The most common cause of HCC is chronic hepatitis C virus infection and many studies in Europe,Asia and North America have focused on its etiology,epidemiology,diagnostic tools,and therapeutic options.However,little is known about these issues in Latin America.The aim of this review is to address these aspects of HCC in Latin America.The main risk factors associated with developing HCC in this region are:age,concomitant cirrhosis,hepatitis C infection,obesity and hereditary disease such as hemochromatosis.On the other hand,screening tests and diagnostic methods of HCC are mostly serum alpha fetoprotein quantification,liver ultrasound,computed tomography,magnetic resonance,and histopathology.Novel diagnostic methods include gut microbiota analysis and the use of nanotechnology and they continue to be tested.Finally,according to the Barcelona Clinic Liver Cancer,curative treatments used in HCC patients are mainly liver resection,liver transplantation,and local ablation,each with advantages and disadvantages.In conclusion,clear strategies are urgently needed to understand the extent of HCC and related problems in this part of the world.This review provides greater knowledge of HCC for the proper design of preventive programs by taking into consideration specific characteristics of our population.Also,this review allows for an understanding of individualizing treatments according to the patient’s needs.

Epidemiology,therapy and outcome of hepatocellular carcinoma between 2010 and 2019 in Piedmont,Italy

BACKGROUND Hepatocellular carcinoma(HCC)is the most common primary liver malignancy and the second leading cause of cancer deaths worldwide.It is often diagnosed at an advanced stage and therefore its prognosis remains poor with a low 5-year survival rate.HCC patients have increasingly complex and constantly changing characteristics,thus up-to-date and comprehensive data are fundamental.AIM To analyze the epidemiology and main clinical characteristics of HCC patients in a referral center hospital in the northwest of Italy between 2010 and 2019.METHODS In this retrospective study,we analyzed the clinical data of all consecutive patients with a new diagnosis of HCC recorded at"Santa Croce e Carle"Hospital in Cuneo(Italy)between 1 January 2010 and 31 December 2019.To highlight possible changes in HCC patterns over the 10-year period,we split the population into two 5-year groups,according to the diagnosis period(2010-2014 and 2015-2019).RESULTS Of the 328 HCC patients who were included(M/F 255/73;mean age 68.9±11.3 years),154 in the first period,and 174 in the second.Hepatitis C virus infection was the most common HCC risk factor(41%,135 patients).The alcoholic etiology rate was 18%,the hepatitis B virus infection etiology was 5%,and the non-viral/non-alcoholic etiology rate was 22%.The Child-Pugh score distribution of the patients was:class A 75%,class B 21%and class C 4%.The average Mayo end-stage liver disease score was 10.6±3.7.A total of 55 patients(17%)were affected by portal vein thrombosis and 158(48%)by portal hypertension.The average nodule size of the HCC was 4.6±3.1 cm.A total of 204 patients(63%)had more than one nodule<3,and 92%(305 patients)had a non-metastatic stage of the disease.The Barcelona Clinic Liver Cancer(BCLC)staging distribution of all patients was:4%very early,32%early,23%intermediate,34%advanced,and 7%terminal.Average survival rate was 1.6±0.3 years.Only 20%of the patients underwent treatment.Age,presence of ascites,BCLC stage and therapy were predictors of a better prognosis(P<0.01).A comparison of the two 5-year groups revealed a statistically significant difference only in global etiology(P<0.05)and alpha-fetoprotein(AFP)levels(P<0.01).CONCLUSION In this study analyzing patients with a new diagnosis of HCC between 2010-2019,hepatitis C virus infection was the most common etiology.Most patients presented with an advanced stage disease and a poor prognosis.When comparing the two 5-year groups,we observed a statistically significant difference only in global etiology(P<0.05)and AFP levels(P<0.01).

Management of centrally located hepatocellular carcinoma:Update 2016

Centrally located hepatocellular carcinoma(HCC)is sited in the central part of the liver and adjacent to main hepatic vascular structures.This special location is associated with an increase in the difficulty of surgery,aggregation of the recurrence disease,and greater challenge in disease management.This review summarizes the evolution of our understanding for centrally located HCC and discusses the development of treatment strategies,surgical approaches and recurrence prevention methods.To improve patient survival,a multi-disciplinary modality is greatly needed throughout the whole treatment period.

Direct-acting antivirals for hepatitis C virus-infected patients with hepatocellular carcinoma

BACKGROUND Hepatocellular carcinoma(HCC)in hepatitis C virus(HCV)-infected patients has a high risk of recurrence.Although eradication of HCV is expected to reduce this risk,the risk in patients with a history of HCC may be high after treatment with direct-acting antivirals(DAAs).AIM To determine the risk factors for HCC recurrence in patients with HCV and a history of HCC.METHODS The risk of HCC recurrence in patients with a history of HCC and/or of HCC occurrence in patients without a history of HCC after DAA therapy was retrospectively analyzed in 311 HCV patients treated at our institution and several neighboring hospitals.The frequency and predictors of HCC recurrence/occurrence after DAA treatment were included in these analyses.The clinical course of HCC before and after DAA treatment was also evaluated.RESULTS HCV patients with a history of HCC were older and had greater progression of liver fibrosis and diabetes than patients without a history of HCC.Median recurrence-free survival(RFS)was 1092 d in patients with a history of HCC,and post-DAA HCC recurrence/occurrence was observed in 29 patients(53.7%)with and 5(1.9%)without a history of HCC over 6 years(P<0.001).RFS in patients with a history of HCC did not differ significantly before and after DAA treatment.The frequency of HCC recurrence/occurrence in patients with a history of HCC was lower after than before DAA treatment.Multivariate analysis showed that the incidence rate of HCC recurrence/occurrence before DAA treatment was the only independent predictor of HCC recurrence/occurrence after DAA treatment.Liver function was well preserved and clinical course was good in patients with HCC recurrence/occurrence after DAA therapy.CONCLUSION DAA therapy in patients infected with HCV is also effective in patients with a history of HCC.Curative treatment for HCC is desirable before DAA therapy.The frequency of HCC recurrence/occurrence before DAA therapy was associated with a significantly increased risk of HCC recurrence after DAA therapy.Careful observation after DAA therapy is required in patients with a history of HCC.

Hepatocellular carcinoma prevention:A worldwide emergence between the opulence of developed countries and the economic constraints of developing nations

Hepatocellular carcinoma (HCC) is the fifth most common neoplasm, the major cause of death in patients with liver cirrhosis, and the third most common cause of cancer-related death in the world. The geographic distribution of HCC varies significantly and 80% of cases occur in developing countries (Far East and South Asia) where the prevalence of viral hepatitis is higher. The treatment of HCC is difficult because most patients are diagnosed when the tumour is in an advanced stage and is not amenable to potential curative therapy, thus prevention is the key to reducing HCC and its related morbidity and mortality. HCC is unique among cancers, occurring mostly in patients with a known risk factor. Ninety percent of HCCs develop in the context of chronic liver diseases and mainly in patients with cirrhosis. Viral hepatitis is the most common cause of HCC worldwide, followed by alcoholic liver disease (ALD) and other causes such as non-alcoholic fatty liver disease (NAFLD), genetic haemocromatosis (GH) and primary biliary cirrhosis in an advanced stage (Ⅲ- Ⅴ). In certain areas of the People’s Republic of China, exposure to aflatoxin and HBV infection are thought to be responsible for the extraordinary high risk of HCC. Substantial progresses in the prevention of virusl-related hepatitis (screening of blood units, use of disposable sanitary tools, HBV vaccination) have been achieved in developed countries, but in the same areas, alcohol- and dysmetabolism-related HCCs are emerging problems which require specific interventions in terms of public health measures. In developing countries, economic constraints limit the development of any program for the prevention of viral hepatitis transmission (including health education campaigns, healthcare politics, primary prevention and the improvement of hygienic and sanitary conditions). When viral liver disease is established, only a minority of patients are treated worldwide and benefit a possible preventive effect of medical treatment onHCC development. Thus the real contribution of medical treatment to HCC prevention in patients with chronic viral hepatitis is small. Great efforts are needed to identify more effective medical measures for primary and secondary prevention of HCC.

Risk for hepatocellular carcinoma in the course of chronic hepatitis B virus infection and the protective effect of therapy with nucleos(t)ide analogues

Hepatocellular carcinoma(HCC) is a major health problem worldwide, representing one of the leading causes of death. Chronic hepatitis B virus(HBV) infection(CHB) is the most important etiologic factor of this tumor, accounting for the development of more than50% of the cases in the world. Primary prevention ofHCC is possible by hepatitis B vaccination conferring protection from HBV infection. However, according to the World Health Organization Hepatitis B Fact sheet N° 204(update of July 2014) globally there exists a large pool of > 240 million people chronically infected with HBV who are at risk for development of HCC. These individuals represent a target population for secondary prevention both of cirrhosis and of HCC. Since ongoing HBV replication in CHB is linked with the progression of the underlying liver disease to cirrhosis as well as with the development of HCC, effective antiviral treatment in CHB has also been evaluated in terms of secondary prevention of HCC. Currently, most patients with active CHB are subjected to long term treatment with the first line nucleos(t)ide analogues entecavir and tenofovir. These compounds are of high antiviral potency and have a high barrier to HBV resistance compared to lamivudine, adefovir dipivoxil and even telbivudine. Many studies have shown that patients under antiviral treatment, especially those in virological remission, develop less frequently HCC compared to the untreated ones. However, the risk for development of HCC cannot be eliminated. Therefore, surveillance for the development of HCC of patients with chronic hepatitis B must be lifelong or until a time in the future when new treatments will be able to completely eradicate HBV from the liver particularly in the early stages of CHB infection. In this context, the aim of this review is to outline the magnitude of the risk for development of HCC among patients with CHB, in the various phases of the infection and in relation to virus, host and environmental factors as evaluated in the world literature. Moreover, the benefits of antiviral treatment of CHB with nucleos/tide analogs, which have changed the natural history of the disease and have reduced but not eliminated the risk of HCC are also reviewed.

Clinical applications of squamous cell carcinoma antigenimmunoglobulins M to monitor chronic hepatitis C

Hepatitis C virus(HCV) is the main cause of chronic liver disease and cirrhosis in Western countries. Over time, the majority of cirrhotic patients develop hepatocellular carcinoma(HCC), one of the most common fatal cancers worldwide- fourth for incidence rate. A high public health priority need is the development of biomarkers to screen for liver disease progression and for early diagnosis of HCC development, particularly in the high risk population represented by HCV-positive patients with cirrhosis. Several studies have shown that serological determination of a novel biomarker, squamous cell carcinoma antigen-immunoglobulins M(SCCA-Ig M), might be useful to identify patients with progressive liver disease. In the initial part of this review we summarize the main clinical studies that have investigated this new circulating biomarker on HCV-infected patients, providing evidence that in chronic hepatitis C SCCA-Ig M may be used to monitor progression of liver disease, and also to assess the virological response to antiviral treatment. In the last part of this review we address other, not less important, clinical applications of this biomarker in hepatology.

Aberrant expression of alternative isoforms of transcription factors in hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is one of the most prevalent malignancies worldwide and the second leading cause of death among all cancer types. Deregulation of the networks of tissue-specific transcription factors(TFs) observed in HCC leads to profound changes in the hepatic transcriptional program that facilitates tumor progression. In addition, recent reports suggest that substantial aberrations in the production of TF isoforms occur in HCC. In vitro experiments have identified distinct isoform-specific regulatory functions and related biological effects of liver-specific TFs that are implicated in carcinogenesis, which may be relevant for tumor progression and clinical outcome. This study reviews available data on the expression of isoforms of liver-specific and ubiquitous TFs in the liver and HCC and their effects, including HNF4α, C/EBPs, p73 and TCF7 L2, and indicates that assessment of the ratio of isoforms and targeting specific TF variants may be beneficial for the prognosis and treatment of HCC.