RESUMO
BACKGROUND AND AIMS: The predominantly progressive, indeterminate, and predominantly regressive (P-I-R) classification extends beyond staging and provides information on dynamic changes of liver fibrosis. However, the prognostic implication of P-I-R classification is not elucidated. Therefore, in the present research, we investigated the utility of P-I-R classification in predicting the on-treatment clinical outcomes. APPROACH AND RESULTS: In an extension study on a randomized controlled trial, we originally enrolled 1000 patients with chronic hepatitis B and biopsy-proven histological significant fibrosis, and treated them for more than 7 years with entecavir-based therapy. Among the 727 patients with a second biopsy at treatment week 72, we compared P-I-R classification and Ishak score changes in 646 patients with adequate liver sections for the histological evaluation. Progressive, indeterminate, and regressive cases were observed in 70%, 17%, and 13% of patients before treatments and 20%, 14%, and 64% after 72-week treatment, respectively, which could further differentiate the histological outcomes of patients with stable Ishak scores. The 7-year cumulative incidence of HCC was 1.5% for the regressive cases, 4.3% for the indeterminate cases, and 22.8% for the progressive cases ( p <0.001). After adjusting for age, treatment regimen, platelet counts, cirrhosis, Ishak fibrosis score changes, and Laennec staging, the posttreatment progressive had a HR of 17.77 (vs. posttreatment regressive; 95% CI: 5.55-56.88) for the incidence of liver-related events (decompensation, HCC, and death/liver transplantation). CONCLUSIONS: The P-I-R classification can be a meaningful complement to the Ishak fibrosis score not only in evaluating the histological changes but also in predicting the clinical outcomes.
Assuntos
Carcinoma Hepatocelular , Hepatite B Crônica , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patologia , Antivirais/uso terapêutico , Neoplasias Hepáticas/patologia , Cirrose Hepática/patologia , Fígado/patologia , Hepatite B Crônica/complicações , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/patologia , Fibrose , Biópsia/efeitos adversosRESUMO
BACKGROUND & AIMS: Management of elderly patients with hepatocellular carcinoma (HCC) has become a major concern. Some data suggest that cryoablation improves the outcomes of elderly patients with HCC, but its efficacy and safety remain unknown. This study aimed to evaluate and compare the efficacy and safety of percutaneous cryoablation with those of radiofrequency ablation (RFA) for elderly HCC patients. METHODS: In all, 223 patients with small HCC aged ≥70 years, treatment-naïve, without metastasis were enrolled and randomized into a cryoablation group (n = 112) or a RFA (n = 111) group from July 2015 to October 2018. The primary endpoint was local tumour progression (LTP) at 3 years after treatment. The secondary endpoints including overall survival (OS), tumour-free survival (TFS), LTP and safety were analysed for these two groups after both treatments. RESULTS: LTP rates at 1-, 3- and 5-year were 12%, 17% and 20% for cryoablation and 17%, 18% and 21% for RFA respectively (P = .735). For lesions >3 cm in diameter, LTP rates at 1- and 3-year were 13% and 22% in cryoablation group and 22% and 42% respectively, in the RFA group (P = .039). The 1-, 3- and 5-year OS rates were 90, 75% and 62% for cryoablation and 90%, 68% and 63% for RFA respectively (P = .331). The 1-, 3- and 5-year TFS rates were 59%, 32% and 25% in the cryoablation and 59%, 28% and 20% in the RFA respectively (P = .309). Major complications occurred in 6 patients (5%) following cryoablation and 6 patients (6%) following RFA (P = .886). CONCLUSION: Cryoablation and RFA had similar LTP in elderly patients with small HCC and this study failed to meet the primary endpoint, although for a relatively large early-stage HCC the LTP rate after cryoablation was significantly lower than that after RFA.
Assuntos
Carcinoma Hepatocelular , Ablação por Cateter , Criocirurgia , Neoplasias Hepáticas , Idoso , Criocirurgia/efeitos adversos , Humanos , Estudos Prospectivos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Although concomitant nonalcoholic steatohepatitis (NASH) is common in chronic hepatitis B (CHB), the impact of viral factors on NASH and the outcome of CHB patients concomitant with NASH remain unclear. We aimed to investigate the outcomes of NASH in CHB patients receiving antiviral treatment. METHODS: In the post-hoc analysis of a multicenter trial, naïve CHB patients receiving 72-week entecavir treatment were enrolled. We evaluated the biochemical, viral and histopathological responses of these patients. The histopathological features of NASH were also evaluated, using paired liver biopsies at baseline and week 72. RESULTS: A total of 1000 CHB patients were finally enrolled for analysis, with 18.2% of whom fulfilling the criteria of NASH. A total of 727 patients completed entecavir antiviral treatment and received the second biopsy. Serum HBeAg loss, HBeAg seroconversion and HBV-DNA undetectable rates were similar between patients with or without NASH (P > 0.05). Among patients with NASH, the hepatic steatosis, ballooning, lobular inflammation scores and fibrosis stages all improved during follow-up (all P < 0.001), 46% (63/136) achieved NASH resolution. Patients with baseline body mass index (BMI) ≥ 23 kg/m2 (Asian criteria) [odds ratio (OR): 0.414; 95% confidence interval (95% CI): 0.190-0.899; P = 0.012] and weight gain (OR: 0.187; 95% CI: 0.050-0.693; P = 0.026) were less likely to have NASH resolution. Among patients without NASH at baseline, 22 (3.7%) developed NASH. Baseline BMI ≥ 23 kg/m2 (OR: 12.506; 95% CI: 2.813-55.606; P = 0.001) and weight gain (OR: 5.126; 95% CI: 1.674-15.694; P = 0.005) were predictors of incident NASH. CONCLUSIONS: Lower BMI and weight reduction but not virologic factors determine NASH resolution in CHB. The value of weight management in CHB patients during antiviral treatment deserves further evaluation.
Assuntos
Hepatite B Crônica , Hepatopatia Gordurosa não Alcoólica , Antivirais/efeitos adversos , DNA Viral , Antígenos E da Hepatite B , Vírus da Hepatite B/genética , Hepatite B Crônica/complicações , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/tratamento farmacológico , Humanos , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Prognóstico , Resultado do Tratamento , Aumento de PesoRESUMO
UNLABELLED: Radiofrequency ablation (RFA) is considered a curative treatment option for hepatocellular carcinoma (HCC). Growing data have demonstrated that cryoablation represents a safe and effective alternative therapy for HCC, but no randomized controlled trial (RCT) has been reported to compare cryoablation with RFA in HCC treatment. The present study was a multicenter RCT aimed to compare the outcomes of percutaneous cryoablation with RFA for the treatment of HCC. In all, 360 patients with Child-Pugh class A or B cirrhosis and one or two HCC lesions ≤ 4 cm, treatment-naïve, without metastasis were randomly assigned to cryoablation (n = 180) or RFA (n = 180). The primary endpoints were local tumor progression at 3 years after treatment and safety. Local tumor progression rates at 1, 2, and 3 years were 3%, 7%, and 7% for cryoablation and 9%, 11%, and 11% for RFA, respectively (P = 0.043). For lesions >3 cm in diameter, the local tumor progression rate was significantly lower in the cryoablation group versus the RFA group (7.7% versus 18.2%, P = 0.041). The 1-, 3-, and 5-year overall survival rates were 97%, 67%, and 40% for cryoablation and 97%, 66%, and 38% for RFA, respectively (P = 0.747). The 1-, 3-, and 5-year tumor-free survival rates were 89%, 54%, and 35% in the cryoablation group and 84%, 50%, and 34% in the RFA group, respectively (P = 0.628). Multivariate analyses demonstrated that Child-Pugh class B and distant intrahepatic recurrence were significant negative predictors for overall survival. Major complications occurred in seven patients (3.9%) following cryoablation and in six patients (3.3%) following RFA (P = 0.776). CONCLUSION: Cryoablation resulted in a significantly lower local tumor progression than RFA, although both cryoablation and RFA were equally safe and effective, with similar 5-year survival rates.
Assuntos
Carcinoma Hepatocelular/cirurgia , Ablação por Cateter , Criocirurgia , Neoplasias Hepáticas/cirurgia , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Criocirurgia/métodos , Feminino , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Taxa de SobrevidaRESUMO
BACKGROUND: Epigenetic alterations are well documented in hepatocarcinogenesis. However, hypomethylation of long interspersed nuclear element 1(LINE-1) promoter and its relationship with clinicopathological features in hepatocellular carcinoma(HCC) remain unknown. METHODS: The bisulfite-specific PCR and DNA sequencing analysis was performed to assess the methylation status of LINE-1 promoter in a pilot cohort of 71 patients with HCC. Additionally,methylation levels of two hot CpG sites of LINE-1 promoter, site 7 and 18 were measured by real-time PCR and compared with clinicopathological parameters in a cohort of 172 HCC. All the patients included were in BCLC stage A or B. RESULTS: Most patients with HCC (87.3%) showed hypomethylation of LINE-1 promoter compared with HBV-related cirrhosis and normal controls (P < 0.001). The HCC patients with LINE-1 promoter hypomethylation had a median tumour-free survival (TFS) and overall survival (OS)post-resection of 22.0 (95% CI: 13.330.7) months and 35.0 (95% CI: 24.046.1) months, respectively, compared with 40 months and ~60 months for those with LINE-1 promoter hypermethylation (P < 0.05). Multivariate analyses showed that the hypomethylation level at CpG site 7 and 18 of LINE-1 promoter, along with tumour size and tumour differentiation, was independently associated with both TFS and OS for patients with HCC after resection. CONCLUSION: Promoter hypomethylation of LINE-1, especially at the CpG site 7 and 18, was associated with a poor prognosis in HCC.
Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/cirurgia , Metilação de DNA , Hepatectomia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/cirurgia , Elementos Nucleotídeos Longos e Dispersos/genética , Regiões Promotoras Genéticas , Adolescente , Adulto , Idoso , Sequência de Bases , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Diferenciação Celular , Distribuição de Qui-Quadrado , Ilhas de CpG , Intervalo Livre de Doença , Epigênese Genética , Feminino , Hepatectomia/efeitos adversos , Hepatectomia/mortalidade , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Análise Multivariada , Modelos de Riscos Proporcionais , Estudos Prospectivos , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Risco , Análise de Sequência de DNA , Fatores de Tempo , Resultado do Tratamento , Carga Tumoral , Adulto JovemRESUMO
INTRODUCTION: Liver fibrosis results from chronic liver injury and inflammation, often leading to cirrhosis, liver failure, portal hypertension, and hepatocellular carcinoma. Progress has been made in understanding the molecular mechanisms underlying hepatic fibrosis; however, translating this knowledge into effective therapies for disease regression remains a challenge, with considerably few interventions having entered clinical validation. The roles of exosomes during fibrogenesis and their potential as a therapeutic approach for reversing fibrosis have gained significant interest. This study aimed to investigate the association between microRNAs (miRNAs) derived from serum exosomes and liver fibrosis and to evaluate the effect of serum exosomes on fibrogenesis and fibrosis reversal, while identifying the underlying mechanism. METHODS: Using serum samples collected from healthy adults and paired histologic patients with advanced fibrosis or cirrhosis, we extracted human serum exosomes by ultrahigh-speed centrifugation. Transcriptomic analysis was conducted to identify dysregulated exosome-derived miRNAs. Liver fibrosis-related molecules were determined by qRT-PCR, Western blot, Masson staining, and immunohistochemical staining. In addition, we analyzed the importance of serum exosome-derived miRNA expression levels in 42 patients with advanced fibrosis or cirrhosis. RESULTS: Exosome-derived miR-193a-5p and miR-381-3p were associated with fibrogenesis, as determined by transcriptomic screening. Compared with healthy control group, the high expression of serum exosome-derived miR-193a-5p and miR-381-3 in chronic hepatitis B (n = 42) was closely associated with advanced liver fibrosis and cirrhosis. In vitro , exosome-derived miRNA-193a-5p and miR-381-3p upregulated the expression of α-smooth muscle actin, collagen 1a1, and tissue inhibitors of metalloproteinase 1 in the human hepatic stellate cell line at both mRNA and protein levels. DISCUSSION: Serum exosome-derived miR-193a-5p and miR-381-3p regulated the adenosine 5'-monophosphate-activated protein kinase/transforming growth factor beta/Smad2/3 signaling pathway and promoted fibrogenesis.
Assuntos
Exossomos , MicroRNAs , Adulto , Humanos , Proteínas Quinases/metabolismo , Proteínas Quinases/farmacologia , Exossomos/genética , Exossomos/metabolismo , Exossomos/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Transdução de Sinais , Cirrose Hepática/patologia , Fator de Crescimento Transformador beta/metabolismo , Adenosina/metabolismo , Adenosina/farmacologiaRESUMO
BACKGROUND: Cryoablation is one of the local therapies for hepatocellular carcinoma (HCC), but its safety and effect has not been studied in patients with Child class A or B and Barcelona Clinic Liver Cancer (BCLC) stage C HCC. Metastasis-associated in colon cancer-1 (MACC1) overexpression has been associated with poor prognosis of HCC, but its predictive value to post-cryoablation outcomes remains unknown in patients with BCLC stage C HCC. METHODS: This study assessed the safety and outcomes of cryoablation measured by time to progression (TTP) and overall survival (OS), and predictive value of MACC1 mRNA and protein overexpression in tumorous tissue to post-cryoablation outcomes in 120 advanced HCC patients with child-pugh class A or B by quantitative polymerase chain reaction and immunohistochemical staining. The potenial correlation of MACC1 and c-Met expression to tumor cell proliferation and apoptosis was also analyzed. RESULTS: The cryoablation in patients with advanced unresectable HCC resulted in a median TTP and OS of 5.5 (4.2- 6.7) months and 10.5 (9.0-12.0) months, respectively and no significant complications, comparable to the historical report for RFA therapy. The MACC1 mRNA and nuclear protein expression was significantly increased in tumorous tissues in these patients than that in normal liver tissue controls. Higher expression of MACC1 mRNA and nuclear protein in tumorous tissues in these patients was associated with shorter post cryoablation median TTP and OS than that with lower MACC1 expression. CONCLUSIONS: Cryoablation is a safe and effective therapeutic option for patients with advanced HCC and Child-pugh class A or B cirrhosis; and a higher intratumoral expression of MACC1 or nuclear translocation predicts poor outcomes of cryotherapy in these patients.
Assuntos
Carcinoma Hepatocelular/terapia , Criocirurgia , Neoplasias Hepáticas/terapia , Metástase Neoplásica , RNA Mensageiro/genética , Fatores de Transcrição/metabolismo , Adulto , Idoso , Sequência de Bases , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Primers do DNA , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transativadores , Fatores de Transcrição/genética , Resultado do TratamentoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Obesity is closely related to diabetes. Jatrorrhizine (JAT) from Rhizoma Coptidis (RC) can reduce blood glucose and lipid levels. However, the molecular mechanisms for JAT's anti-obesity effect are still not clear. AIM OF THE STUDY: To explore the effect of JAT in the treatment of obesity and the underlying molecular mechanisms. MATERIALS AND METHODS: db/db mice were used as a typical obese animal model in current study. The anti-obesity effects of five alkaloids from RC were compared by feeding the mice for 8 weeks with a dosage of 105 mg/kg while the dose-dependent study (35 mg/kg and 105 mg/kg) of JAT on obese mice was conducted in another 8-week-long animal experiment. Meanwhile, RNA-seq analysis, in vitro experiments, and western blotting were utilized to predict and confirm the potential pathway that JAT participated in improving obesity. RESULTS: The experimental results demonstrated that five RC alkaloids caused different degrees of weight loss in db/db obese mice. Among them, JAT showed the best effect. It could significantly reduce the body weight, blood lipid levels, and epididymal fat weight of db/db mice. H&E and Oil red O staining results showed that it could also dramatically improve liver lipid metabolism. The results from RNA-seq suggested that JAT had significantly altered 207 DEGs for the treatment of obesity, among which IRS1 changed the most. Next, GO and KEGG analysis enriched four major lipid metabolism-related pathways: biosynthesis of unsaturated fatty acids, PI3K-AKT signaling pathway, metabolic pathways, and fatty acid elongation. Finally, in vitro experiments and western blotting proved that JAT regulated the expression of IRS1/PI3K/AKT pathway-related proteins in a dose-dependent manner to address obesity. CONCLUSIONS: In conclusion, JAT from RC has an effect on treating obesity, and its anti-obesity effect may be exerted via the IRS1/PI3K/AKT signaling pathway.
Assuntos
Alcaloides , Antineoplásicos , Medicamentos de Ervas Chinesas , Animais , Berberina/análogos & derivados , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Lipídeos , Camundongos , Camundongos Obesos , Obesidade/tratamento farmacológico , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-aktRESUMO
BACKGROUND: Although transjugular intrahepatic portosystemic shunt (TIPS) is recommended for secondary prophylaxis of variceal bleeding if standard therapy fails and for patients with high risk of recurrent bleeding, no guidelines for the treatment of symptomatic portal hypertension in HCC patients are available. This study aimed to compare the efficacy and safety of TIPS with endoscopic + ß-blocker for prevention of the rebleeding in such patients. METHODS: 106 consecutive advanced HCC patients receiving tyrosine kinase inhibitor (TKI) who had been treated with vasoactive drugs plus endoscopic therapy for variceal bleeding were randomly assigned to receive either TIPS (n = 52) or endoscopic + ß-blocker therapy (n = 54) for the prevention of rebleeding. The primary endpoint was variceal rebleeding after randomization. RESULTS: During a median follow-up of 16 months, rebleeding occurred in 14 patients in the endoscopic + ß-blocker group and 3 patients in the TIPS group (p < 0.001). Forty-nine patients died (38 in endoscopic + ß-blocker group and 11 in TIPS group, p < 0.001). The 6-, 12-, and 18-month overall survival rates were 95, 81, and 73% for TIPS group and 35, 21, and 15% for endoscopic + ß-blocker group, respectively (p < 0.001). Eight patients in endoscopic + ß-blocker group received TIPS as rescue therapy, but two died. TKIs was discontinued in 32 patients, including 24 in the endoscopic + ß-blocker group and 8 in the TIPS group (p < 0.001). No significant differences were observed between the two groups with respect to serious adverse events. CONCLUSIONS: In advanced HCC patients receiving TKIs and presented with variceal bleeding, the use of TIPS was associated with significant reduction in rebleeding, improved a higher adherence to TKIs therapy, and prolonged survival.
Assuntos
Carcinoma Hepatocelular , Varizes Esofágicas e Gástricas , Neoplasias Hepáticas , Derivação Portossistêmica Transjugular Intra-Hepática , Humanos , Varizes Esofágicas e Gástricas/complicações , Varizes Esofágicas e Gástricas/terapia , Derivação Portossistêmica Transjugular Intra-Hepática/métodos , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/tratamento farmacológico , Projetos Piloto , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/prevenção & controle , Terapia de Alvo Molecular , Cirrose Hepática/etiologia , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Antagonistas Adrenérgicos beta/uso terapêutico , Resultado do Tratamento , RecidivaRESUMO
OBJECTIVES: Investigate the clinical efficacy of cryotherapy ablation treatment for advanced hepatocellular carcinoma. analyse the predictive factors of cryotherapy ablation treatment. METHODS: There were 190 cases of hepatitis B-related HCC patients with advanced HCC from 2005 to 2008 in our hospital. By using clinical cohort method, they included cryoablation group (147 cases) and control group (43 cases), The median survival time and time to disease progression were compared. Evaluate clinical significance of age, gender, location of portal vein tumor thrombus, HBeAg, tumor histological grade, Child-Pugh classification, end-stage liver disease (MELD) score, advanced liver cancer prediction system (ALCPS) score and the Eastern Cooperative Oncology Group performance status (ECOG PS) score for predicting the efficacy of cryoablation. Group rates were compared with the x2 test, survival analysis by using Kaplan-Meier method, survival rates were compared by Log-rank analysis; multiple factor survival analysis by using Cox regression model. RESULTS: Median survival time of cryoablation group and Control group was 7.5 (4.2 to 14.6) months and 3.2 (1.2 to 8.6) months, median TTP was 3.5 (2.5 to 4.5) months and 1.5 (1.0 to 3.5 months), the differences were statistically significant ( P less than 0.05 ). Median OS and TTP of advanced HCC patients who had Well-differentiated tumor, Child-pugh A-class and low score of MELD score, ALCPS score, ECOG PS score were significantly longer than the poorly differentiate, Child-Pugh B-class and the high those scores ( P less than 0.05). ECOG PS ( P less than 0.05, 95% CI 1.074 to 2.143) and ALCPS (P less than 0.05, 95% CI 1.005 to 2.121) were independent predictors for OS of advanced HCC. CONCLUSION: Cryoablation treatment can prolong median OS and TTP of advanced HCC; ECOG PS and ALCPS are important predictors for survival time of advanced HCC.
Assuntos
Carcinoma Hepatocelular/cirurgia , Criocirurgia , Neoplasias Hepáticas/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Several studies have demonstrated that chronic hepatitis delta virus (HDV) infection is associated with a worsening of hepatitis B virus (HBV) infection and increased risk of hepatocellular carcinoma (HCC). However, there is limited data on the role of HDV in the oncogenesis of HCC. This study is aimed at assessing the potential mechanisms of HDV-associated hepatocarcinogenesis, especially to screen and identify key genes and pathways possibly involved in the pathogenesis of HCC. We selected three microarray datasets: GSE55092 contains 39 cancer specimens and 81 paracancer specimens from 11 HBV-associated HCC patients, GSE98383 contains 11 cancer specimens and 24 paracancer specimens from 5 HDV-associated HCC patients, and 371 HCC patients with the RNA-sequencing data combined with their clinical data from the Cancer Genome Atlas (TCGA). Afterwards, 948 differentially expressed genes (DEGs) closely related to HDV-associated HCC were obtained using the R package and filtering with a Venn diagram. We then performed gene ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis to determine the biological processes (BP), cellular component (CC), molecular function (MF), and KEGG signaling pathways most enriched for DEGs. Additionally, we performed Weighted Gene Coexpression Network Analysis (WGCNA) and protein-to-protein interaction (PPI) network construction with 948 DEGs, from which one module was identified by WGCNA and three modules were identified by the PPI network. Subsequently, we validated the expression of 52 hub genes from the PPI network with an independent set of HCC dataset stored in the Gene Expression Profiling Interactive Analysis (GEPIA) database. Finally, seven potential key genes were identified by intersecting with key modules from WGCNA, including 3 reported genes, namely, CDCA5, CENPH, and MCM7, and 4 novel genes, namely, CDC6, CDC45, CDCA8, and MCM4, which are associated with nucleoplasm, cell cycle, DNA replication, and mitotic cell cycle. The CDCA8 and stage of HCC were the independent factors associated with overall survival of HDV-associated HCC. All the related findings of these genes can help gain a better understanding of the role of HDV in the underlying mechanism of HCC carcinogenesis.
Assuntos
Carcinoma Hepatocelular/genética , Hepatite B/genética , Neoplasias Hepáticas/genética , Proteínas de Neoplasias/genética , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Biologia Computacional , Mineração de Dados/estatística & dados numéricos , Regulação Neoplásica da Expressão Gênica/genética , Hepatite B/complicações , Hepatite B/patologia , Vírus Delta da Hepatite/genética , Vírus Delta da Hepatite/patogenicidade , Humanos , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Análise em Microsséries/estatística & dados numéricos , Mapas de Interação de Proteínas/genéticaRESUMO
BACKGROUND: HBeAg-positive chronic infection is a unique phase of chronic hepatitis B virus (HBV) infection. Current guidelines advise against starting antiviral treatment for HBeAg-positive chronic hepatitis B virus (HBV) infection patients, some data suggest treating such patients may reduce the risk of hepatocellular carcinoma. We aimed to explore whether these patients can have evident histological liver injury (EHLI), and develop a non-invasive model for identifying EHLI in such patients. METHOD: We assessed whether HBeAg-positive chronic HBV infection patients can have EHLI defined by Ishak fibrosis stage ≥3 and/or histologic activity index ≥ 9 in a prospective multicenter study. Logistic and Lasso regression was used to select the optimal predictors. We used Akaike information criterion, discrimination improvement, net reclassification improvement to develop and validate models predicting EHLI risk in training cohort and two external validation cohorts. FINDINGS: Of these 336 patients met the inclusion criteria, 181(54%) were HBeAg-positive chronic HBV infection, of whom 60 patients (33%) had EHLI, the proportion of significant fibrosis was higher than that of significant inflammation (33% vs. 8%, P < 0.001). Age, liver stiffness measurement, ALT, alkaline phosphatase, and albumin were identified as independent predictors for EHLI and used to develop a nomogram that have been demonstrated having a good performance in predicting EHLI with AUROCs of 0.92(95%CI: 0.86-0.99) in the training cohort (n = 233) and 0.90(95%CI: 0.84-0.95) in validation cohort 1(n = 103), significant correcting current guidelines recommendations overestimating insignificant or significant histological disease. After 72-weeks entecavir treatment for HBeAg-positive chronic HBV infection patients with EHLI identified by nomogram, histological improvement occurred in 40 of 49(82%), 38(78%) had fibrosis reversal, and 35(73%) no longer had EHLI. INTERPRETATION: In HBeAg-positive chronic HBV infection patients, 33% has EHLI. The nomogram developed in this study can accurately identify HBeAg-positive chronic HBV infection patients with EHLI, and that responded very well to antiviral therapy. FUNDING: This study was funded by the State Key Projects Specialized on Infectious Disease, Chinese Ministry of science and technology (2013ZX10005002; 2018ZX10725506), National Natural Science Foundation of China (81970525) and Beijing Key Research Project of Special Clinical Application (Z151100004015221).
Assuntos
Antígenos E da Hepatite B/imunologia , Hepatite B Crônica/complicações , Cirrose Hepática/epidemiologia , Nomogramas , Adulto , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Antivirais/uso terapêutico , Biomarcadores/sangue , Feminino , Guanina/análogos & derivados , Guanina/uso terapêutico , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/imunologia , Humanos , Fígado/patologia , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-IdadeRESUMO
MicroRNA-153 (miR-153) is considered to be a tumor regulator. Silencing of miR-153 expression induced apoptosis in breast cancer cells. Data on mechanism suggest that up-regulation of miR- 153 level promotes cell proliferation via the down regulation of the expression of PTEN or FOXO1, which attenuates the proliferation of cancerous cells. This study aims to identify the effect of miR-153 on the activity of chemotherapeutic and targeted agents in HCC cells and to investigate the mechanisms involved. MTT, soft agar, trans-well and flow cytometry assays were performed to examine whether miR-153 down-regulated the activity of the chemotherapeutic and targeted drugs, Sorafenib, Etoposide and Paclitaxel in HCC cells. The rate of proliferation inhibition, relative survival rates and IC50 values of each drug were calculated. Western blot and luciferase assays were performed to assess whether miR-153 modulates the expression of important genes related to cell proliferation, apoptosis or survival. Results showed that miR-153 attenuated the effect of Etoposide, Paclitaxel and Sorafenib on HepG2 cells; the IC50 value increased from 0.25±0.01µmol/L to 1.02±0.14µmol/L, 0.05±0.01µmol/L to 0.14±0.02µmol/L and from 1.09±0.15µmol/L to 5.18±0.99µmol/L, respectively. In addition, miR-153 also reduced the effect of these drugs on MHCC- 97H, MHCC-97 L and L-02 cells; and it also reduced the effects of Sorafenib, Etoposide and Paclitaxel on anchor-independent growth of HepG2 cells. Over-expression of miR-153 down-regulated the activity of Etoposide and Paclitaxel on cell cycle arrest of HepG2 cells and the effect of Sorafenib on the invasion and migration of HepG2 cells. Furthermore, overexpression of miR-153 also enhanced the growth of HepG2, MHCC-97H, MHCC-97 L and L-02 cells. Mechanisms data showed that overexpression of miR-153 down regulated the activity of luciferase reporters, p15-Luc and p21-Luc; and enhanced the protein level of pro-survival or anti-apoptosis proteins Survivin and BCL-2. These results show that overexpression of miR-153 protects HepG2 cells against the effects of these drugs via multiple mechanisms, and miR-153 may be a novel target for HCC in future diagnostic and therapeutic interventions.
Assuntos
Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , MicroRNAs/genética , Inibidores de Proteínas Quinases/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Etoposídeo/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Terapia de Alvo Molecular/métodos , Niacinamida/análogos & derivados , Niacinamida/farmacologia , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Paclitaxel/farmacologia , Compostos de Fenilureia/farmacologia , SorafenibeRESUMO
The incidence, risk factors, and clinical features of hepatocellular carcinoma (HCC) in primary biliary cirrhosis (PBC) have been a long-standing subject of interest. We took advantage of a large cohort of 1865 well-defined Chinese patients with PBC for whom follow-up was conducted for up to 20 years to study the incidence of HCC. Our goal was to address the incidence and prevalence of HCC in PBC and the risk factors, including hepatitis B virus (HBV) infection, and finally to compare the tumor characteristics of PBC-related HCC, including size, location, mortality, and long-term outcomes, to that of HBV-related HCC. In this cohort, HCC occurred in 70 of 1865 PBC patients with a prevalence of 3.75 % and an incidence of 0.66 cases per 100 patient-years. The 5- and 10-year cumulative incidences were 2.6 % (95 % confidence interval (CI) 1.8-3.4) and 8.9 % (95 % CI 5.5-12.3), respectively. Age >54 years (odds ratio [OR] = 5.5, 95 % CI 3.0-10.1, p = 0.001), male sex (OR = 2.2, 95 % CI 1.2-4.0, p = 0.001), co-existence of diabetes mellitus (DM) (OR = 3.1, 95 % CI 1.6-6.2, p = 0.002), and previous HBV infection (OR = 6.6, 95 % CI 3.7-11.9, p = 0.001) were independently associated with the development of HCC. The tumor size, number, location, and 5-year survival were not significantly different in PBC-related HCC compared to HBV-related HCC. Alpha-fetoprotein was elevated in only 20 % of the cases with PBC-related HCC. Although HCC was uncommon, occurring in fewer than 5 % of patients, the risk is significantly increased by age, sex, DM, and past HBV infection.
Assuntos
Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/etiologia , Cirrose Hepática Biliar/complicações , Cirrose Hepática Biliar/epidemiologia , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/etiologia , Adulto , Idoso , Carcinoma Hepatocelular/diagnóstico , Feminino , Seguimentos , Humanos , Incidência , Cirrose Hepática Biliar/diagnóstico , Neoplasias Hepáticas/diagnóstico , Masculino , Pessoa de Meia-Idade , Mortalidade , Estudos Retrospectivos , Fatores de Risco , Carga TumoralRESUMO
BACKGROUND: Accumulating evidences have suggested that percutaneous cryoablation could be a valuable alternative ablation therapy for HCC but there has been no large cohort-based analysis on its long-term outcomes. METHODS: A series of 866 patients with Child-Pugh class A-B cirrhosis and HCC within Milan criteria who underwent percutaneous cryoablation was long-term followed. The safety, efficacy, 5-year survival, and prognostic factors of percutaneous cryoablation in the treatment of HCC were analyzed. RESULTS: A total of 1197 HCC lesions were ablated with 1401 cryoablation sessions. Complete response (CR) was achieved in 1163 (97.2%) lesions and 832 (96.1%) patients with 34 (2.8%) major complications, but no treatment-related mortality. After a median of 30.9 months follow-up, 502 (60.3%) patients who achieved CR developed different types of recurrence. The cumulative local tumor recurrence rate was 24.2% at 5-years. Multiple tumor lesions, tumor size > 3 cm, and repeated ablation of same lesion were independent risk factors associated with local recurrence. The 5-year overall survival (OS) rates were 59.5%. Age < 36 years, HCC family history, baseline hepatitis B virus DNA >106 copies/ml, and three HCC lesions were independently and significantly negative predictors to the post-cryoablation OS. CONCLUSIONS: Percutaneous cryoablation is an effective therapy for patients with HCC within Milan criteria, with comparable efficacy, safety and long-term survival to the reported outcomes of radiofrequency ablation.
Assuntos
Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Criocirurgia/métodos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Criocirurgia/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Prognóstico , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
Cryoablation is a less prevalent percutaneous ablative therapy for hepatocellular carcinoma (HCC), and current evidence about its usefulness is limited. We report our experience in treating 1595 HCC cases with percutaneous cryoablation to give a comprehensive profile about the effectiveness, safety and long-term outcome of this therapy. From January 2003 to December 2013, 1595 patients with 2313 HCC nodules were ablated with 2958 cryoablation sessions in our center. Complete ablation was achieved in 1294 patients for 1893 nodules with a mean diameter of 3.4 ± 2.2 cm. The complete ablation rate was 81.2%, 99.4%, 94.4%, and 45.6% in all tumors, tumors < 3 cm, tumors < 5 cm, and tumors > 5 cm, respectively. Major complications were observed after 80 (3.4%) of the 2958 cryoablations and minor complications were observed after 330 cryoablations with no treatment-related deaths. After a median follow-up of 33.4 months, 937 patients developed different types of recurrence. The 5- and 10-year overall survival was 25.7% and 9.2%, respectively. Cryoablation showed reliable safety and efficacy and should be considered as a promising technique, particularly when a large zone of ablation is required.
Assuntos
Carcinoma Hepatocelular , Ablação por Cateter/métodos , Crioterapia/métodos , Neoplasias Hepáticas , Recidiva Local de Neoplasia , Complicações Pós-Operatórias/diagnóstico , Adulto , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , China/epidemiologia , Feminino , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Carga TumoralRESUMO
Sorafenib may prolong survival in patients with advanced hepatocellular carcinoma (HCC), but with limited efficacy. The present study aimed to prospectively investigate the efficacy and analyze the prognostic factors for survival in sorafenib-treated patients with advanced HCC. The baseline characteristics and clinical outcomes of 110 patients with advanced hepatitis B virus-related HCC treated with sorafenib with/without local therapy (transarterial chemoembolization with/without cryoablation) at a single liver cancer center were recorded. Predictors of progression-free survival (PFS) and overall survival (OS) were determined by multivariate analysis. A total of 14 (12.7%) patients achieved complete response (CR), 16 (14.5%) achieved partial response (PR) and 40 (36.4%) achieved stable disease (SD) lasting longer than 8 weeks. The median OS and PFS for the whole cohort were 10.5 [95% confidence interval (CI), 8.7-12.3] and 5.0 months (95% CI, 3.7-6.3), respectively. Sorafenib in combination with local therapy was an independent predictor for longer PFS, whereas Eastern Cooperative Group (ECOG) performance status (PS) and Child-Pugh class were associated with reduced PFS. Local therapy was associated with longer OS while ECOG PS and α-fetoprotein were associated with reduced OS. In a subset of patients with radiological progressive disease, a significant difference was found in OS between patients who continued taking sorafenib and those who discontinued therapy (11 vs. 7.5 months, P<0.001). In conclusion, sorafenib in combination with local therapy (transarterial chemoembolization with/without cryoablation) was independently associated with longer OS and PFS in advanced HCC patients. Poor ECOG PS was associated with shorter OS and PFS and is thus a marker of poor outcomes in sorafenib-treated HCC patients.
RESUMO
PURPOSE: To evaluate the efficacy and safety of ultrasound (US)-guided percutaneous argon-helium cryoablation for hepatocellular carcinoma (HCC) and determine appropriate indications. METHODS: We reviewed outcomes of 300 HCC patients who underwent US-guided percutaneous cryoablation. RESULTS: Overall, 223 tumors (mean diameter 7.2 ± 2.8 cm) in 165 patients were incompletely ablated, while 185 tumors (mean diameter 5.6 ± 0.8 cm, P = 0.0001 vs. incomplete ablation) in 135 patients were completely ablated. Nineteen patients (6.3%) developed serious complications while in hospital, including cryoshock syndrome in six patients, hepatic bleeding in five, stress-induced gastric bleeding in four, liver abscess in one and intestinal fistulas in one. Two patients died because of liver failure. The median follow-up was 36.7 months (range 6-63 months). The local tumor recurrence rate was 31%, and was related to tumor size (P = 0.029) and tumor location (P = 0.037). The mean survival duration of patients with early, intermediate and advanced HCC (Barcelona Clinic Liver Cancer staging system) was 45.7 ± 3.8, 28.4 ± 1.2 and 17.7 ± 0.6 months, respectively. CONCLUSIONS: US-guided percutaneous cryoablation is a relatively safe and effective therapy for selected HCC patients.
Assuntos
Argônio/uso terapêutico , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/cirurgia , Criocirurgia/métodos , Hélio/uso terapêutico , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/cirurgia , Adulto , Idoso , Carcinoma Hepatocelular/mortalidade , China/epidemiologia , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Estudos Retrospectivos , Taxa de Sobrevida/tendências , UltrassonografiaRESUMO
We assessed the safety and efficacy of sorafenib with cryotherapy (cryoRx) in advanced hepatocellular carcinoma (HCC). One hundred four HCC patients were enrolled, who met the following criteria: (i) Barcelona Clinic Liver Cancer stage C; (ii) HCC without distant metastasis; (iii) the presence of portal vein thrombosis (PVT); (iv) Child-Pugh class A or B; and (v) life expectancy of at least 12 weeks. The patients were randomly divided into sorafenib-cryoRx and sorafenib (control) groups. Primary endpoint was time to progression (TTP); secondary endpoints included overall survival (OS) and tolerability. Microvessel density (MVD) was assessed by CD34-immunostaining. After a median 10.5 (4-26) months follow-up, the data showed that median TTP was 9.5 (8.4-13.5) months in combinatorial therapy group vs. 5.3 (3.8-6.9) months in sorafenib group (P = 0.02). The median OS was 12.5 (95 % CI 10.6-16.4) months in combination therapy group vs. 8.6 (7.3-10.4) months in sorafenib group (P = 0.01). Low MVD patients in combination therapy exhibited significantly longer median TTP and OS than controls. High MVD was predictive of poor responses to sorafenib. CryoRx did not increase frequency/degree of sorafenib-related adverse events. Therefore, it was concluded that the addition of cryoRx significantly improved clinical outcomes of Sorafenib therapy in advanced HCC with acceptable tolerance and similar safety profiles as previously reported.
Assuntos
Antineoplásicos/uso terapêutico , Benzenossulfonatos/uso terapêutico , Carcinoma Hepatocelular/terapia , Crioterapia , Neoplasias Hepáticas/terapia , Piridinas/uso terapêutico , Antineoplásicos/efeitos adversos , Benzenossulfonatos/efeitos adversos , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Terapia Combinada , Crioterapia/efeitos adversos , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Microvasos/patologia , Estadiamento de Neoplasias , Niacinamida/análogos & derivados , Compostos de Fenilureia , Piridinas/efeitos adversos , Sorafenibe , Resultado do TratamentoRESUMO
Sorafenib may prolong survival in patients with advanced hepatocellular carcinoma (HCC), but with limited efficacy. The present study aimed to assess the safety and efficacy of sorafenib combined with cryotherapy (cryoRx) for the treatment of advanced HCC. A total of 104 patients met the following criteria: advanced HCC without distant metastasis, presence of portal vein thrombosis, Child-Pugh class A or B and life expectancy of at least 12 weeks. All patients were randomly assigned to sorafenib and cryoRx (n=52) or sorafenib-alone (n=52) treatment groups. The primary end-point of the study was overall survival (OS). The secondary end-points included time to progression (TTP) and tolerability. Microvessel density (MVD) was assessed following immunostaining for CD34. In a median of 10.5 (4-26) months follow-up, the median OS was 12.5 months (95% CI 10.6-16.4) in the combination therapy vs. 8.6 months (7.3-10.4) in the sorafenib-alone (P=0.01) group. The median TTP was 9.5 months (8.4-13.5) in the combination therapy vs. 5.3 months (3.8-6.9) in the sorafenib alone (P=0.02) group. CryoRx was an independent factor associated with improved clinical outcomes of sorafenib for the treatment of advanced HCC. Patients with low intratumoral MVD receiving the combination therapy exhibited a significantly longer median TTP and OS compared to those receiving sorafenib. High intratumoral MVD was an independent predictor of poor responses to sorafenib for advanced HCC. Compared with previous reports of sorafenib-related adverse drug reactions (ADRs), cryoRx did not further increase the frequency and degree of sorafenib-related ADRs. In conclusion, compared to sorafenib alone, the addition of cryoRx to sorafenib significantly improves the clinical outcomes of sorafenib for the treatment of advanced HCC with acceptable tolerance and similar safety profiles as previously reported. High intratumoral MVD is predictive of poor responses to sorafenib in advanced HCC patients.