Genomic analyses of most solid tumors reveal a complex mutational landscape with vast inter-tumor and intratumor heterogeneities.Each histological tumor type and the tumor cells within each tumor type display striking...Genomic analyses of most solid tumors reveal a complex mutational landscape with vast inter-tumor and intratumor heterogeneities.Each histological tumor type and the tumor cells within each tumor type display striking molecular and biological variations.The molecular heterogeneity in tumors is a major obstacle for early diagnosis and effective treatment.This is especially relevant to hepatocellular carcinoma(HCC)and intrahepatic cholangiocarcinoma(iCCA)where the etiological factors elicit different molecular mechanisms to initiate carcinogenesis leading to distinct molecular subtypes and complex tumor cell communities.Such heterogeneity poses a major challenge in exploring the factors responsible for early stage hepatocarcinogenesis,development of diagnostic tools,and defining effective treatment strategies for HCC and iCCA.These obstacles emphasize the importance of developing new strategies to change the current dire situation.The establishment of patient populations with associated wellannotated biobanks and molecularly well-characterized samples are essential to define unique tumor subtypes.Moreover,understanding the molecular features of tumor cells at a single cell level might provide a better understanding of tumor cell communities and help define the key drivers responsible for tumor initiation and progression.Molecular-based technologies such as integrated genomics,transcriptomics,and metabolomics aid in a better way to distinguish tumor subtypes allowing the stratification of patients with greater homogeneity and assist in molecular re-staging.These genome-based signatures might serve to delineate the critical gatekeepers of cancer initiation and progression which further helps to identify the druggable targets by integrated genomics and to explore the functionally linked networks in HCC and iCCA.With these available backgrounds,we might effectively identify biomarkers and potential targets for early liver cancer intervention.展开更多
The estimated world prevalence of hepatitis B virus(HBV)infection is 316 million.HBV infection was identified in 1963 and nowadays is a major cause of cirrhosis and hepatocellular carcinoma(HCC)despite universal vacci...The estimated world prevalence of hepatitis B virus(HBV)infection is 316 million.HBV infection was identified in 1963 and nowadays is a major cause of cirrhosis and hepatocellular carcinoma(HCC)despite universal vaccination programs,and effective antiviral therapy.Long-term administration of nucleos(t)ide analogues(NA)has been the treatment of choice for chronic hepatitis B during the last decades.The NA has shown a good safety profile and high efficacy in controlling viral replication,improving histology,and decreasing the HCC incidence,decompensation,and mortality.However,the low probability of HBV surface antigen seroclearance made necessary an indefinite treatment.The knowledge,in recent years,about the different phases of the viral cycle,and the new insights into the role of the immune system have yielded an increase in new therapeutic approaches.Consequently,several clinical trials evaluating combinations of new drugs with different mechanisms of action are ongoing with promising results.This integrative literature review aims to assess the knowledge and major advances from the past of hepatitis B,the present of NA treatment and withdrawal,and the future perspectives with combined molecules to achieve a functional cure.展开更多
BACKGROUND Hepatitis B e antigen-negative chronic hepatitis B patients under nucleos(t)ids analogues(NAs)rarely achieve hepatitis B surface antigen(HBsAg)loss.AIM To evaluate if the addition of pegylated interferon(Pe...BACKGROUND Hepatitis B e antigen-negative chronic hepatitis B patients under nucleos(t)ids analogues(NAs)rarely achieve hepatitis B surface antigen(HBsAg)loss.AIM To evaluate if the addition of pegylated interferon(Peg-IFN)could decrease HBsAg and hepatitis B core-related antigen(HBcrAg)levels and increase HBsAg loss rate in patients under NAs therapy.METHODS Prospective,non-randomized,open-label trial evaluating the combination of Peg-IFN 180μg/week plus NAs during forty-eight weeks vs NAs in monotherapy.Hepatitis B e antigen-negative non-cirrhotic chronic hepatitis B patients of a tertiary hospital,under NAs therapy for at least 2 years and with undetectable viral load,were eligible.Patients with hepatitis C virus,hepatitis D virus or human immunodeficiency virus co-infection and liver transplanted patients were excluded.HBsAg and HBcrAg levels(log10 U/mL)were measured at baseline and during ninety-six weeks.HBsAg loss rate was evaluated in both groups.Adverse events were recorded in both groups.The kinetic of HBsAg for each treatment group was evaluated from baseline to weeks 24 and 48 by the slope of the HBsAg decline(log10 IU/mL/week)using a linear regression model.RESULTS Sixty-five patients were enrolled,61%receiving tenofovir and 33%entecavir.Thirty-six(55%)were included in Peg-IFN-NA group and 29(44%)in NA group.After matching by age and treatment duration,baseline HBsAg levels were comparable between groups(3.1 vs 3.2)(P=0.25).HBsAg levels at weeks 24,48 and 96 declined in Peg-IFN-NA group(-0.26,-0.40 and-0.44)and remained stable in NA group(-0.10,-0.10 and-0.10)(P<0.05).The slope of HBsAg decline in Peg-IFN-NA group(-0.02)was higher than in NA group(-0.00)(P=0.015).HBcrAg levels did not change.Eight(22%)patients discontinued Peg-IFN due to adverse events.The HBsAg loss was achieved in 3(8.3%)patients of the Peg-IFN-NA group and 0(0%)of the NA group.CONCLUSION The addition of Peg-IFN to NAs caused a greater and faster decrease of HBsAg levels compared to NA therapy.Side effects of Peg-IFN can limit its use in clinical practice.展开更多
Objective:Patients with hepatocellular carcinoma(HCC)suffer from a poor survival rate and a high incidence of postoperative recurrence.γδT cells are known to detect and react to chronic inflammation,which is intimat...Objective:Patients with hepatocellular carcinoma(HCC)suffer from a poor survival rate and a high incidence of postoperative recurrence.γδT cells are known to detect and react to chronic inflammation,which is intimately associated with cancer development,progression and metastasis.展开更多
Objective:Cancer metabolite profiling(or cancer metabolomics),the global view of the biochemical end products of cellular processes,is a promising approach to identify biomarkers and tumor subgroups,and to understand ...Objective:Cancer metabolite profiling(or cancer metabolomics),the global view of the biochemical end products of cellular processes,is a promising approach to identify biomarkers and tumor subgroups,and to understand the biological mechanisms underlying cancer development and progression.展开更多
Objective:Hepatocellular carcinoma(HCC)is among the deadliest cancers in Thailand.The Thailand Initiative in Genomics and Expression Research for Liver Cancer(TIGER-LC)cohort was established to discover molecular mark...Objective:Hepatocellular carcinoma(HCC)is among the deadliest cancers in Thailand.The Thailand Initiative in Genomics and Expression Research for Liver Cancer(TIGER-LC)cohort was established to discover molecular markers that can be used for early detection and diagnosis and to understand possible molecular mechanisms underlying the disease.展开更多
Background:It has been found that the efficacy of lamivudine(LAM)therapy can be improved by preceding administration with a short course of corticosteroid that induces a flare of the disease upon its withdrawal.Becaus...Background:It has been found that the efficacy of lamivudine(LAM)therapy can be improved by preceding administration with a short course of corticosteroid that induces a flare of the disease upon its withdrawal.Because of the side effects of corticosteroid,we tested the effect of a short course of interferon(IFN)as the primer instead of prednisolone,which was followed by LAM when the hepatitis flare occurred.The incidence of LAM resistance mutations and the effect of core promoter and precore mutations on the durability of the responses were also studied.Methods:Patients treated with interferon(IFN)-LAM therapy(n = 73)were compared to those treated with IFN alone(n = 117).The IFN-LAM group received IFN-α6 MU/day,t.i.w.for a 3-month period.LAM(10mg/day during 1 year)was started when IFN withdrawal hepatitis occurred during 2-10 months after stopping IFN.The LAM-resistant,core promoter,and precore mutations were examined by sequencing.Results:(1)The IFN-LAM group developed exacerbated hepatitis following IFN withdrawal in 63 patients before starting LAM therapy.The seroconversion(SC)rate was significantly higher in the IFN-LAM group than in the IFN-alone group(61%vs 26%,P = 0.0001).(2)The LAM resistance mutation rate was 31%at 1 year after initiating LAM therapy.(3)In a stepwise discriminant-function analysis,decreased level of HBeAg determined at 4 weeks after LAM administration and increased level of HBeAb before the start of LAM administration contributed significantly on seroconversion to anti-HBe(P = 0.0073 and 0.004,respectively).(4)The reappearance rate of HBeAg within 6 months after the therapy(relapse)was 33%in the IFN-LAM group and 10%in the IFN-alone group.The prevalence of core promoter and precore mutations did not change before and after the therapy,nor did these mutations correlate with the relapse after stopping IFN-LAM therapy.Conclusions:(1)Our findings suggest that early reduction of infected hepatocytes expressed by HBeAg by LAM may contribute to a high SC rate of IFN-LAM therapy.(2)The emergence of LAM-resistant mutations was similar to the previously reported rate,and neither core promoter nor precore mutations correlated with relapse of seroconverters after IFN-LAM withdrawal.展开更多
文摘Genomic analyses of most solid tumors reveal a complex mutational landscape with vast inter-tumor and intratumor heterogeneities.Each histological tumor type and the tumor cells within each tumor type display striking molecular and biological variations.The molecular heterogeneity in tumors is a major obstacle for early diagnosis and effective treatment.This is especially relevant to hepatocellular carcinoma(HCC)and intrahepatic cholangiocarcinoma(iCCA)where the etiological factors elicit different molecular mechanisms to initiate carcinogenesis leading to distinct molecular subtypes and complex tumor cell communities.Such heterogeneity poses a major challenge in exploring the factors responsible for early stage hepatocarcinogenesis,development of diagnostic tools,and defining effective treatment strategies for HCC and iCCA.These obstacles emphasize the importance of developing new strategies to change the current dire situation.The establishment of patient populations with associated wellannotated biobanks and molecularly well-characterized samples are essential to define unique tumor subtypes.Moreover,understanding the molecular features of tumor cells at a single cell level might provide a better understanding of tumor cell communities and help define the key drivers responsible for tumor initiation and progression.Molecular-based technologies such as integrated genomics,transcriptomics,and metabolomics aid in a better way to distinguish tumor subtypes allowing the stratification of patients with greater homogeneity and assist in molecular re-staging.These genome-based signatures might serve to delineate the critical gatekeepers of cancer initiation and progression which further helps to identify the druggable targets by integrated genomics and to explore the functionally linked networks in HCC and iCCA.With these available backgrounds,we might effectively identify biomarkers and potential targets for early liver cancer intervention.
文摘The estimated world prevalence of hepatitis B virus(HBV)infection is 316 million.HBV infection was identified in 1963 and nowadays is a major cause of cirrhosis and hepatocellular carcinoma(HCC)despite universal vaccination programs,and effective antiviral therapy.Long-term administration of nucleos(t)ide analogues(NA)has been the treatment of choice for chronic hepatitis B during the last decades.The NA has shown a good safety profile and high efficacy in controlling viral replication,improving histology,and decreasing the HCC incidence,decompensation,and mortality.However,the low probability of HBV surface antigen seroclearance made necessary an indefinite treatment.The knowledge,in recent years,about the different phases of the viral cycle,and the new insights into the role of the immune system have yielded an increase in new therapeutic approaches.Consequently,several clinical trials evaluating combinations of new drugs with different mechanisms of action are ongoing with promising results.This integrative literature review aims to assess the knowledge and major advances from the past of hepatitis B,the present of NA treatment and withdrawal,and the future perspectives with combined molecules to achieve a functional cure.
文摘BACKGROUND Hepatitis B e antigen-negative chronic hepatitis B patients under nucleos(t)ids analogues(NAs)rarely achieve hepatitis B surface antigen(HBsAg)loss.AIM To evaluate if the addition of pegylated interferon(Peg-IFN)could decrease HBsAg and hepatitis B core-related antigen(HBcrAg)levels and increase HBsAg loss rate in patients under NAs therapy.METHODS Prospective,non-randomized,open-label trial evaluating the combination of Peg-IFN 180μg/week plus NAs during forty-eight weeks vs NAs in monotherapy.Hepatitis B e antigen-negative non-cirrhotic chronic hepatitis B patients of a tertiary hospital,under NAs therapy for at least 2 years and with undetectable viral load,were eligible.Patients with hepatitis C virus,hepatitis D virus or human immunodeficiency virus co-infection and liver transplanted patients were excluded.HBsAg and HBcrAg levels(log10 U/mL)were measured at baseline and during ninety-six weeks.HBsAg loss rate was evaluated in both groups.Adverse events were recorded in both groups.The kinetic of HBsAg for each treatment group was evaluated from baseline to weeks 24 and 48 by the slope of the HBsAg decline(log10 IU/mL/week)using a linear regression model.RESULTS Sixty-five patients were enrolled,61%receiving tenofovir and 33%entecavir.Thirty-six(55%)were included in Peg-IFN-NA group and 29(44%)in NA group.After matching by age and treatment duration,baseline HBsAg levels were comparable between groups(3.1 vs 3.2)(P=0.25).HBsAg levels at weeks 24,48 and 96 declined in Peg-IFN-NA group(-0.26,-0.40 and-0.44)and remained stable in NA group(-0.10,-0.10 and-0.10)(P<0.05).The slope of HBsAg decline in Peg-IFN-NA group(-0.02)was higher than in NA group(-0.00)(P=0.015).HBcrAg levels did not change.Eight(22%)patients discontinued Peg-IFN due to adverse events.The HBsAg loss was achieved in 3(8.3%)patients of the Peg-IFN-NA group and 0(0%)of the NA group.CONCLUSION The addition of Peg-IFN to NAs caused a greater and faster decrease of HBsAg levels compared to NA therapy.Side effects of Peg-IFN can limit its use in clinical practice.
文摘Objective:Patients with hepatocellular carcinoma(HCC)suffer from a poor survival rate and a high incidence of postoperative recurrence.γδT cells are known to detect and react to chronic inflammation,which is intimately associated with cancer development,progression and metastasis.
文摘Objective:Cancer metabolite profiling(or cancer metabolomics),the global view of the biochemical end products of cellular processes,is a promising approach to identify biomarkers and tumor subgroups,and to understand the biological mechanisms underlying cancer development and progression.
文摘Objective:Hepatocellular carcinoma(HCC)is among the deadliest cancers in Thailand.The Thailand Initiative in Genomics and Expression Research for Liver Cancer(TIGER-LC)cohort was established to discover molecular markers that can be used for early detection and diagnosis and to understand possible molecular mechanisms underlying the disease.
文摘Background:It has been found that the efficacy of lamivudine(LAM)therapy can be improved by preceding administration with a short course of corticosteroid that induces a flare of the disease upon its withdrawal.Because of the side effects of corticosteroid,we tested the effect of a short course of interferon(IFN)as the primer instead of prednisolone,which was followed by LAM when the hepatitis flare occurred.The incidence of LAM resistance mutations and the effect of core promoter and precore mutations on the durability of the responses were also studied.Methods:Patients treated with interferon(IFN)-LAM therapy(n = 73)were compared to those treated with IFN alone(n = 117).The IFN-LAM group received IFN-α6 MU/day,t.i.w.for a 3-month period.LAM(10mg/day during 1 year)was started when IFN withdrawal hepatitis occurred during 2-10 months after stopping IFN.The LAM-resistant,core promoter,and precore mutations were examined by sequencing.Results:(1)The IFN-LAM group developed exacerbated hepatitis following IFN withdrawal in 63 patients before starting LAM therapy.The seroconversion(SC)rate was significantly higher in the IFN-LAM group than in the IFN-alone group(61%vs 26%,P = 0.0001).(2)The LAM resistance mutation rate was 31%at 1 year after initiating LAM therapy.(3)In a stepwise discriminant-function analysis,decreased level of HBeAg determined at 4 weeks after LAM administration and increased level of HBeAb before the start of LAM administration contributed significantly on seroconversion to anti-HBe(P = 0.0073 and 0.004,respectively).(4)The reappearance rate of HBeAg within 6 months after the therapy(relapse)was 33%in the IFN-LAM group and 10%in the IFN-alone group.The prevalence of core promoter and precore mutations did not change before and after the therapy,nor did these mutations correlate with the relapse after stopping IFN-LAM therapy.Conclusions:(1)Our findings suggest that early reduction of infected hepatocytes expressed by HBeAg by LAM may contribute to a high SC rate of IFN-LAM therapy.(2)The emergence of LAM-resistant mutations was similar to the previously reported rate,and neither core promoter nor precore mutations correlated with relapse of seroconverters after IFN-LAM withdrawal.
