RESUMO
There is an urgent need for the identification as well as clinicopathological and functional characterization of potent prognostic biomarkers and therapeutic targets in acute myeloid leukemia (AML). Using immunohistochemistry and next-generation sequencing, we investigated the protein expression as well as clinicopathological and prognostic associations of serine protease inhibitor Kazal type 2 (SPINK2) in AML and examined its potential biological functions. High SPINK2 protein expression was an independent adverse biomarker for survival and an indicator of elevated therapy resistance and relapse risk. SPINK2 expression was associated with AML with an NPM1 mutation and an intermediate risk by cytogenetics and European LeukemiaNet (ELN) 2022 criteria. Furthermore, SPINK2 expression could refine the ELN2022prognostic stratification. Functionally, an RNA sequencing analysis uncovered a potential link of SPINK2 with ferroptosis and immune response. SPINK2 regulated the expression of certain P53 targets and ferroptosis-related genes, including SLC7A11 and STEAP3, and affected cystine uptake, intracellular iron levels and sensitivity to erastin, a specific ferroptosis inducer. Furthermore, SPINK2 inhibition consistently increased the expression of ALCAM, an immune response enhancer and promoter of T-cell activity. Additionally, we identified a potential small-molecule inhibitor of SPINK2, which requires further characterization. In summary, high SPINK2 protein expression was a potent adverse prognostic marker in AML and might represent a druggable target.
Assuntos
Ferroptose , Leucemia Mieloide Aguda , Humanos , Ferroptose/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Prognóstico , Inibidores de Serina Proteinase/sangue , Inibidores de Serina Proteinase/metabolismo , Serpinas/sangue , Serpinas/metabolismoRESUMO
BACKGROUND AND AIMS: Concurrent fatty liver in hepatitis B virus (HBV)-infected patients without significant alcohol intake is a frequent and increasingly alarming problem because of the non-alcoholic fatty liver disease pandemic. The risk of HBV-related hepatocellular carcinoma (HCC) development was increased by concomitant obesity and diabetes. Direct evidence of the hepatocarcinogenic effect of fatty liver in chronic HBV remains elusive. We aimed to evaluate the risk of concurrent histologically proven fatty liver in HBV hepatocarcinogenesis. METHODS: We conducted a retrospective cohort study on a liver biopsy cohort of HBV-infected patients without significant alcohol intake to evaluate the prevalence of concurrent histologically proven fatty liver and its association with subsequent HCC development. We also examined nine polymorphisms on six non-alcoholic fatty liver disease-related candidate genes (ADIPOQ, APOC3, GCKR, LEPR, PNPLA3, and PPARG). RESULTS: Among 270 HBV-infected patients, concurrent fatty liver was found in 107 patients (39.6%) and was associated with metabolic risks, cirrhosis (P = 0.016) and PNPLA3 rs738409 CG/GG genotype (P = 0.002). At a median follow-up of 79.9 months, 11 patients (4.1%) developed HCC, and nine of them had concurrent fatty liver. By multivariable Cox analysis, concurrent fatty liver (HR 7.27, 95% confidence interval: 1.52-34.76; P = 0.013), age, cirrhosis, and APOC3 rs2854116 TC/CC genotype (HR 3.93, 95% confidence interval: 1.30-11.84; P = 0.013) were independent factors predicting HCC development. CONCLUSIONS: Concurrent fatty liver is common in HBV-infected patients and an independent risk factor potentiating HBV-associated HCC development by 7.3-fold. The risk of HBV-related HCC is increased by APOC3 gene polymorphism, and further characterization is required by its role.
Assuntos
Carcinoma Hepatocelular/etiologia , Hepatite B Crônica/complicações , Neoplasias Hepáticas/etiologia , Hepatopatia Gordurosa não Alcoólica/complicações , Adulto , Apolipoproteínas C/genética , Carcinoma Hepatocelular/epidemiologia , Estudos de Coortes , Complicações do Diabetes/complicações , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Neoplasias Hepáticas/epidemiologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/genética , Obesidade/complicações , Polimorfismo Genético , Prevalência , Estudos Retrospectivos , Risco , Fatores de RiscoRESUMO
BACKGROUND & AIMS: Vitamin D is an immunomodulator that might be involved in the pathogenesis of viral hepatitis. We investigated the effects of vitamin D deficiency on long-term outcomes of patients with chronic hepatitis B (CHB). METHODS: We performed a prospective cohort study of 426 patients with CHB (65% male; mean age, 41 ± 13 years), who were enrolled from 1997 through 2000. Serum levels of 25-hydroxycholecalciferol (25(OH)D3) were measured on study enrollment (baseline). Patients were followed for 159 ± 46 months until last clinic visit or death; approximately 33% received antiviral therapy during the follow-up period. The primary outcome was a clinical event (hepatocellular carcinoma, complications of cirrhosis, or death). RESULTS: At baseline, the patients' mean serum level of hepatitis B virus DNA was 5.0 ± 2.1 log10 IU/mL; their mean level of 25(OH)D3 was 24.3 ± 9.4 ng/mL, and 348 patients (82%) had vitamin D deficiency (<32 ng/mL). Serum levels of 25(OH)D3 did not correlate with cirrhosis or viral load. Ninety-seven patients (22.8%) developed clinical events by a mean time of 118 ± 60 months after study enrollment. Patients who developed clinical events had lower baseline serum levels of 25(OH)D3 (23.2 ± 10.4 ng/mL) than patients who did not (28.2 ± 9.3 ng/mL, P < .001). Low baseline serum 25(OH)D3 was an independent factor associated with clinical events after adjustment for sex, age, and cirrhosis. The adjusted hazard ratio of vitamin D deficiency for clinical events was 1.90 (95% confidence interval [CI], 1.06-2.43; P = .04). The 15-year cumulative incidence rate of clinical events among patients with vitamin D deficiency was 25.5% (95% CI, 23.1%-27.9%), compared with 11.1% (95% CI, 7.4%-14.8%) in patients with normal serum levels of 25(OH)D3. CONCLUSIONS: Vitamin D deficiency is common among patients with CHB and is associated with adverse clinical outcomes.
Assuntos
Hepatite B Crônica/patologia , Deficiência de Vitamina D/complicações , Adulto , Antivirais/uso terapêutico , Estudos de Coortes , Progressão da Doença , Feminino , Hepatite B Crônica/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
UNLABELLED: Alpha-fetoprotein (AFP) is the most widely used biomarker for hepatocellular carcinoma (HCC) surveillance, which is criticized as neither sensitive nor specific in active hepatitis and liver cirrhosis. The aim of this study was to determine the performance of AFP as a tumor marker for HCC in entecavir-treated patients with chronic hepatitis B (CHB). This was a retrospective-prospective cohort study of 1,531 entecavir-treated patients under regular HCC surveillance with AFP and ultrasonography. Mean age was 52 ± 12 years; 1,099 (72%) patients were male and 332 (21.7%) had clinical evidence of cirrhosis. At a mean follow-up of 51 ± 13 months, 57 (2.9%) patients developed HCC (median size: 3.3 cm). AFP fluctuated with alanine aminotransferase (ALT) and peaked at the time of starting entecavir, then gradually decreased after. AFP started to increase 6 months before the diagnosis of HCC. The receiver operator characteristic curve (AUROC) of AFP was highest at the time of HCC diagnosis (0.85; 95% confidence interval [CI]: 0.73-0.98) and remained satisfactory at 3 (0.82; 95% CI: 0.73-0.91) and 6 months (0.79; 95% CI: 0.69-0.89) before the diagnosis. Using the conventional AFP cut-off (20 µg/L) at month 0, the sensitivity and specificity to diagnose HCC were 38.6% and 98.9%, respectively. Adopting the lower cut-off value (6 µg/L) of AFP level at month 0, sensitivity was increased to 80.7%, whereas specificity was decreased to 80.4%. CONCLUSION: On-treatment AFP is a specific tumor marker for HCC in CHB patients receiving entecavir therapy. Adopting a lower cut-off value of AFP level at 6 µg/L would significantly increase the sensitivity for HCC detection.
Assuntos
Carcinoma Hepatocelular/diagnóstico , Guanina/análogos & derivados , Hepatite B Crônica/tratamento farmacológico , Neoplasias Hepáticas/diagnóstico , alfa-Fetoproteínas/metabolismo , Adulto , Idoso , Antivirais/uso terapêutico , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/virologia , Feminino , Seguimentos , Guanina/uso terapêutico , Hepatite B Crônica/epidemiologia , Hepatite B Crônica/patologia , Humanos , Incidência , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , Sensibilidade e EspecificidadeRESUMO
BACKGROUND AND AIM: Lifestyle modification is the cornerstone for the management of nonalcoholic fatty liver disease (NAFLD), and patatin-like phospholipase 3 (PNPLA3) is one of the most important genetic determinants of NAFLD. We aimed to investigate the effect of PNPLA3 gene polymorphism on the response to lifestyle modification in NAFLD patients. METHODS: This was a post-hoc analysis of a randomized controlled trial on a lifestyle modification program in community NAFLD patients. The PNPLA3 rs738409 gene polymorphism was correlated with changes in metabolic profile and intrahepatic triglyceride content (IHTG) as measured by proton magnetic resonance spectroscopy. RESULTS: One hundred and fifty-four patients were equally randomized into the intervention and control groups. The presence of G allele was associated with greater reduction in IHTG (CC: 3.7 ± 5.2%, CG: 6.5 ± 3.6%), and GG: 11.3 ± 8.8% (Spearman's correlation, 0.34; P = 0.002), body weight (P = 0.030), waist-to-hip ratio (P = 0.024), total cholesterol (P = 0.031), and low-density lipoprotein cholesterol (P = 0.009) in the intervention group. In contrast, PNPLA3 polymorphism had no impact on IHTG changes in the control group. By multivariable analysis, PNPLA3 genotype and body mass index (BMI) change were independently associated with IHTG reduction in the intervention group. Only BMI change was associated with IHTG reduction in the control group. CONCLUSION: Although the PNPLA3 rs738409 GG genotype confers a higher risk of NAFLD, these patients are more sensitive to the beneficial effects of lifestyle modification and should be encouraged to do so.
Assuntos
Fígado Gorduroso/genética , Fígado Gorduroso/terapia , Estilo de Vida , Lipase/genética , Proteínas de Membrana/genética , Polimorfismo Genético , Adulto , Alelos , Índice de Massa Corporal , Fígado Gorduroso/metabolismo , Feminino , Humanos , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Ensaios Clínicos Controlados Aleatórios como Assunto , Triglicerídeos/metabolismoRESUMO
BACKGROUND AND AIMS: The prognostic role of noninvasive assessments of liver fibrosis has been evolving. Our aim was to investigate the prognostic value of liver stiffness measurement (LSM) with transient elastography and serum-based Hui index to predict hepatic events and deaths in chronic hepatitis B (CHB) patients. METHODS: The main prospective cohort included 1555 consecutive CHB patients referred for transient elastography examination; a subgroup of 980 patients underwent follow-up assessments at least 3 years later formed the serial cohort. Cox proportional hazard model was performed to determine the relationship of LSM, Hui index and other clinical variables with hepatic events and deaths. RESULTS: During a mean follow-up of 69 ± 9 months, 119 patients (7.6%) developed hepatic events or deaths. Hepatic event-free survival was significantly decreased with increasing stages of LSM and Hui index. The 5-year cumulative probability of hepatic event-free survival of patients of Stage 1-7 of LSM were 99.3%, 98.8%, 95.7%, 90.9%, 89.6%, 74.6%, and 50.0%, respectively; that of Stage 1 to 3 of Hui index were 98.2%, 93.1%, and 77.5%, respectively. Independent predictors of hepatic event-free survival were age, baseline LSM, and follow-up Hui index. Serum ALT and body mass index affected the accuracy of prediction by LSM. Patients remained early stages of LSM or Hui index at follow-up visit had better survival compared to those remained at late stages. CONCLUSION: Baseline and change in noninvasive parameters of liver fibrosis, LSM and Hui index, are accurate to predict hepatic event-free survival in CHB patients.
Assuntos
Técnicas de Imagem por Elasticidade/métodos , Hepatite B Crônica/complicações , Hepatite B Crônica/mortalidade , Cirrose Hepática/diagnóstico , Transaminases/sangue , Adulto , Fatores Etários , Idoso , Biomarcadores/sangue , Índice de Massa Corporal , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Cirrose Hepática/etiologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Receptores de TIE , Índice de Gravidade de DoençaRESUMO
BACKGROUND & AIMS: Little is known about the validity of hepatocellular carcinoma (HCC) risk scores derived from treatment-naïve patients with chronic hepatitis B for patients treated with entecavir. METHODS: We performed a retrospective-prospective cohort study of 1531 patients with chronic hepatitis B (age, 51 ± 12 years; 1099 male; 332 with clinical cirrhosis) who were treated with entecavir 0.5 mg daily for at least 12 months at Prince of Wales Hospital in Hong Kong from December 2005 to August 2012. The patients were assessed once every 3 to 6 months for symptoms, drug history, and adherence; blood samples were collected for biochemical analyses. We validated 3 HCC risk scores (CU-HCC, GAG-HCC, and REACH-B scores) based on data collected when patients began treatment with entecavir and 2 years later. RESULTS: After 42 ± 13 months of follow-up, 47 patients (2.9%) developed HCC. The 5-year cumulative incidence of HCC was 4.3% (95% confidence interval [CI], 3.6%-5.0%). Older age, presence of cirrhosis, and virologic remission after 24 months or more of therapy were independently associated with HCC in the entire cohort; advanced age and hypoalbuminemia were associated with HCC in patients without cirrhosis. The area under the receiver operating characteristic curves (AUCs) for baseline CU-HCC, GAG-HCC, and REACH-B scores for HCC were 0.80 (95% CI, 0.75-0.86), 0.76 (95% CI, 0.70-0.82), and 0.71 (95% CI, 0.62-0.81), respectively; the time-dependent AUCs 1 to 4 years after patients started treatment were comparable to those at baseline. The cutoff value of the baseline CU-HCC score identified patients who would develop HCC with 93.6% sensitivity and 47.8% specificity, the baseline GAG-HCC score with 55.3% sensitivity and 78.9% specificity, and the baseline REACH-B score with 95.2% sensitivity and 16.5% specificity. Compared with patients with CU-HCC scores <5 at baseline, those with CU-HCC scores that either decreased from ≥5 to <5 or remained ≥5 had a higher risk of HCC (5-year cumulative incidences, 0% vs 3.9% and 7.3%; P = .002 and P < .001, respectively). CONCLUSIONS: The CU-HCC, GAG-HCC, and REACH-B HCC risk scores accurately predict which patients with chronic hepatitis B treated with entecavir will develop HCC.
Assuntos
Carcinoma Hepatocelular/epidemiologia , Guanina/análogos & derivados , Hepatite B Crônica/tratamento farmacológico , Neoplasias Hepáticas/epidemiologia , Medição de Risco/métodos , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Carcinoma Hepatocelular/etiologia , Intervalos de Confiança , DNA Viral/análise , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Guanina/administração & dosagem , Guanina/efeitos adversos , Vírus da Hepatite B/genética , Hepatite B Crônica/complicações , Hepatite B Crônica/virologia , Hong Kong/epidemiologia , Humanos , Neoplasias Hepáticas/etiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reprodutibilidade dos Testes , Estudos Retrospectivos , Fatores de RiscoRESUMO
UNLABELLED: Entecavir is a potent antiviral agent with high genetic barrier to resistance, hence it is currently recommended as first-line antiviral therapy for chronic hepatitis B (CHB). The aim of this study was to investigate the efficacy of entecavir on clinical outcomes and deaths. It was a retrospective-prospective cohort study based on two cohorts of patients. The entecavir cohort included consecutive CHB patients who had received entecavir 0.5 mg/day for at least 12 months. The historical control cohort included untreated patients recruited since 1997 who underwent routine clinical care. The primary outcome was the 5-year cumulative probability of hepatic events, defined as any cirrhotic complications, hepatocellular carcinoma (HCC), and/or liver-related mortality. A total of 1,446 entecavir-treated patients (72% men; age, 51 ± 12 years; follow-up, 36 ± 13 months) and 424 treatment-naïve patients (65% men; age, 41 ± 13 years; follow-up, 114 ± 31 months) were studied. Overall, there was no difference in hepatic events between the entecavir and control cohorts. Among patients with liver cirrhosis (482 entecavir-treated, 69 treatment-naïve), entecavir-treated patients had reduced risks of all clinical outcomes when compared with treatment-naïve patients with cirrhosis after adjusted for model for end-stage liver disease score: hepatic events (hazard ratio [HR], 0.51; 95% confidence interval [CI], 0.34-0.78; P = 0.002), HCC (HR, 0.55; 95% CI, 0.31-0.99; P = 0.049), liver-related mortality (HR, 0.26; 95% CI, 0.13-0.55; P < 0.001), and all-cause mortality (HR, 0.34; 95% CI, 0.18-0.62; P < 0.001). Entecavir-treated patients with cirrhosis who failed to achieve undetectable hepatitis B virus DNA (105/482 [22%]) had comparable risk of hepatic events as the untreated patients. CONCLUSION: Entecavir therapy reduces the risks of hepatic events, HCC, liver-related and all-cause mortality of CHB patients with liver cirrhosis in 5 years, particularly among those who had maintained viral suppression.
Assuntos
Antivirais/uso terapêutico , Guanina/análogos & derivados , Hepatite B Crônica/tratamento farmacológico , Cirrose Hepática/virologia , Adulto , Idoso , Carcinoma Hepatocelular/prevenção & controle , DNA Viral/sangue , Feminino , Guanina/uso terapêutico , Hepatite B Crônica/complicações , Hepatite B Crônica/mortalidade , Hepatite B Crônica/virologia , Humanos , Neoplasias Hepáticas/prevenção & controle , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos RetrospectivosRESUMO
BACKGROUND AND AIMS: The European Association for the Study of the Liver (EASL) defines the inactive hepatitis B virus (HBV) carrier state based on HBV DNA and alanine aminotransferase (ALT) levels. This study aimed to evaluate the risk of disease progression in such patients. METHODS: Three hundred sixty-one patients negative for hepatitis B e antigen (HBeAg) with HBV DNA levels < 20,000 IU/mL and normal ALT and without advanced fibrosis at baseline underwent liver stiffness measurement (LSM) by transient elastography between 2006 and 2008 and again between 2010 and 2012. Liver fibrosis progression was defined as an increase in LSM by 30% or more at the second assessment to levels suggestive of advanced fibrosis. RESULTS: At baseline, the mean age was 48 ± 11 years and 51% were males; ALT level was 28 ± 11 IU/L, HBV DNA level was 2.7 ± 1.0 log10 IU/mL, and LSM was 5.4 ± 1.5 kPa. After an interval of 44 ± 7 months, liver fibrosis progression was observed in 10 (2.8%) patients, and 49 (13.6%) started antiviral therapy. Gender, age, and levels of ALT, HBV DNA, and HBsAg were shown not to be associated with liver fibrosis progression. Among 244 patients with baseline HBV DNA < 2000 IU/mL, 2.9% had liver fibrosis progression, 8.2% started antiviral therapy, and 4.1% had HBV DNA ≥ 20,000 IU/mL during follow-up. Corresponding figures in 117 patients with baseline HBV DNA levels of 2000-20,000 IU/mL were 2.6%, 24.8%, and 7.7%, respectively (P = 1.0, < 0.001 and = 0.21 respectively). CONCLUSIONS: Liver fibrosis progression within 3-4 years is rare in HBeAg-negative patients with HBV DNA <20,000 IU/mL and normal ALT, but a significant proportion of patients develop treatment indications during follow-up. The study supports the EASL's definition of inactive carriers and its recommendation of regular monitoring.
Assuntos
Hepatite B Crônica/complicações , Cirrose Hepática/virologia , Adulto , Alanina Transaminase/sangue , Antivirais/uso terapêutico , Portador Sadio/tratamento farmacológico , Portador Sadio/virologia , DNA Viral/sangue , Progressão da Doença , Técnicas de Imagem por Elasticidade/métodos , Feminino , Seguimentos , Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B/genética , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/diagnóstico por imagem , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/virologia , Humanos , Cirrose Hepática/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Fatores de Risco , Carga ViralRESUMO
BACKGROUND AND AIM: Chronic hepatitis B patients in immune-reactive hepatitis B e antigen (HBeAg)-positive phase may have more rapid progression than those in immune-tolerant phase. We aimed to evaluate the risk of liver fibrosis progression in HBeAg-positive patients at different phases. METHODS: Two hundred forty-seven HBeAg-positive patients without advanced fibrosis at baseline underwent liver stiffness measurement (LSM) by transient elastography in 2006-2008 and again in 2010-2012. Liver fibrosis progression was defined as increase in LSM by 30% or more to levels suggestive of advanced fibrosis at the second assessment. RESULTS: At baseline, the mean age was 38 ± 11 years, 58% were males, alanine aminotransferase (ALT) was 65 ± 52 IU/L, hepatitis B virus DNA was 4.2 ± 1.2 log IU/mL, and LSM was 6.3 ± 2.1 kPa. At an interval of 42 ± 6 months, 13 patients (5.2%) developed liver fibrosis progression, and 106 patients (42.9%) required antiviral therapy. None of the clinical parameters (e.g., gender, age, ALT, hepatitis B virus DNA, hepatitis B surface antigen level, etc.) was associated with liver fibrosis progression. Among 74 and 137 patients in immune-tolerant and immune-reactive phase, 4.1% and 6.6% had liver fibrosis progression, and 12.2% and 67.2% received antiviral therapy respectively (P = 0.45 and P < 0.001). Immune-tolerant patients with low-normal (< 0.5× upper limit of normal) or high-normal ALT (0.5-1× upper limit of normal) also had similar risk of liver fibrosis progression (5.7% vs. 2.6%; P = 0.49). CONCLUSIONS: Liver fibrosis progression is uncommon in HBeAg-positive patients. Patients in immune-reactive phase treated with antiviral therapy did not have increased risk of liver fibrosis progression.
Assuntos
Técnicas de Imagem por Elasticidade/métodos , Antígenos E da Hepatite B/imunologia , Vírus da Hepatite B/imunologia , Hepatite B Crônica/complicações , Hepatite B Crônica/virologia , Cirrose Hepática/diagnóstico , Cirrose Hepática/etiologia , Adulto , Antivirais/uso terapêutico , Estudos de Coortes , Progressão da Doença , Feminino , Seguimentos , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/imunologia , Humanos , Incidência , Cirrose Hepática/epidemiologia , Cirrose Hepática/prevenção & controle , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de RiscoRESUMO
Pediatric acute myeloid leukemia (AML) is an uncommon but aggressive hematological malignancy. The poor outcome is attributed to inadequate prognostic classification and limited treatment options. A thorough understanding on the genetic basis of pediatric AML is important for the development of effective approaches to improve outcomes. Here, by comprehensively profiling fusion genes as well as mutations and copy number changes of 141 myeloid-related genes in 147 pediatric AML patients with subsequent variant functional characterization, we unveil complex mutational patterns of biological relevance and disease mechanisms including MYC deregulation. Also, our findings highlight TP53 alterations as strong adverse prognostic markers in pediatric AML and suggest the core spindle checkpoint kinase BUB1B as a selective dependency in this aggressive subgroup. Collectively, our present study provides detailed genomic characterization revealing not only complexities and mechanistic insights into pediatric AML but also significant risk stratification and therapeutic strategies to tackle the disease.
Assuntos
Leucemia Mieloide Aguda , Criança , Humanos , Prognóstico , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Mutação , GenômicaRESUMO
BACKGROUND & AIMS: The diagnosis of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) is limited by the need for liver biopsy. We aimed at testing the accuracy of cytokeratin-18 fragment (CK-18), adipocyte fatty acid binding protein (AFABP) and fibroblast growth factor 21 (FGF21) for the diagnosis of NAFLD and NASH. METHODS: 146 patients with biopsy-proven NAFLD and 74 age- and gender-matched healthy controls were included. Serum CK-18, AFABP and FGF21 levels were determined by enzyme-linked immunosorbent assay. RESULTS: Serum CK-18, AFABP, and FGF21 increased in a stepwise fashion in control subjects (median 103 U/L, 15.4 ng/ml, and 104 pg/ml), patients with non-NASH NAFLD (263 U/L, 18.9 ng/ml, and 249 pg/ml) and NASH (418 U/L, 19.4 ng/ml, and 354 pg/ml) (p<0.001, 0.060, and 0.016, respectively). The area under receiver-operating characteristics curve to diagnose NAFLD and NASH was 0.91 and 0.70 for CK-18, 0.66 and 0.59 for AFABP, and 0.84 and 0.62 for FGF21. At cut-offs of 203 and 670 U/L, CK-18 had 71% negative predictive value (NPV) and 77% positive predictive value (PPV) to exclude and diagnose NASH. A 2-step approach measuring CK-18 followed by FGF21 further improved the NPV to 74% and PPV to 82%. In a validation cohort of 51 patients with paired liver biopsies, the NPV and PPV of the 2-step approach were 67% and 78%, respectively. CONCLUSIONS: CK-18 is the most accurate biomarker for NAFLD and NASH. A two-step approach using CK-18 and FGF21 further improves the accuracy in diagnosing NASH.
Assuntos
Fígado Gorduroso/diagnóstico , Fatores de Crescimento de Fibroblastos/sangue , Queratina-18/sangue , Adulto , Biomarcadores/sangue , Proteínas de Ligação a Ácido Graxo/sangue , Fígado Gorduroso/sangue , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não AlcoólicaRESUMO
BACKGROUND & AIMS: In animal studies, expression of hepatitis B virus (HBV) proteins causes hepatic steatosis. We aimed to study the prevalence of fatty liver in people with and without HBV infection in the general population. METHODS: We performed a cross-sectional population study in Hong Kong Chinese. Intrahepatic triglyceride content (IHTG) was measured by proton-magnetic resonance spectroscopy. RESULTS: One thousand and thirteen subjects (91 HBV patients and 922 controls) were recruited. The median IHTG was 1.3% (0.2-33.3) in HBV patients and 2.1% (0-44.2) in controls (p <0.001). Excluding subjects with significant alcohol consumption, the prevalence of nonalcoholic fatty liver disease was 13.5% (95% confidence interval [CI] 6.4%, 20.6%) in HBV patients and 28.3% (95% CI 25.3%, 31.2%) in controls (p=0.003). The fatty liver prevalence differed in HBV patients and controls aged 40-59 years but was similar in those aged 60 years or above. After adjusting for demographic and metabolic factors, HBV infection remained an independent factor associated with lower risk of fatty liver (adjusted odds ratio 0.42; 95% CI 0.20, 0.88; p=0.022). HBV patients also had a lower prevalence of metabolic syndrome (11.0% vs. 20.2%; p=0.034), but the difference was mainly attributed to lower triglyceride levels. Among HBV patients, viral genotypes, HBV DNA level and hepatitis B e antigen status were not associated with fatty liver. CONCLUSIONS: HBV infection is associated with a lower prevalence of fatty liver, hypertriglyceridemia and metabolic syndrome. Viral replication may affect lipid metabolism and this warrants further studies.
Assuntos
Fígado Gorduroso/etnologia , Fígado Gorduroso/metabolismo , Hepatite B Crônica/epidemiologia , Hepatite B Crônica/metabolismo , Adolescente , Adulto , Idoso , Estudos Transversais , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Hong Kong/epidemiologia , Humanos , Hipertrigliceridemia/epidemiologia , Hipertrigliceridemia/metabolismo , Metabolismo dos Lipídeos/fisiologia , Masculino , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/metabolismo , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND: Antiviral drugs against hepatitis B virus are limited by the emergence of drug resistance. AIMS: We aimed to study the impact of drug resistance testing on treatment decisions. METHODS: In part 1 of this study, consecutive patients with chronic hepatitis B who had antiviral drug resistance testing were studied. Part 2 was a two-step questionnaire survey including ten characteristic case scenarios. Hepatologists were asked about their treatment decisions before and after the knowledge of drug resistance results. RESULTS: Fifty-one patients underwent drug resistance testing, most of whom were on lamivudine, adefovir dipivoxil or entecavir monotherapy. Thirty-four (67%) patients had drug-resistant mutants detected, 4 (8%) had low viral load, and 13 (25%) harboured wild-type virus. Twenty-nine of 34 (85%) patients harbouring drug-resistant mutants and 9 of 17 (53%) patients with no mutants detected changed their drug regimens (P = 0.038). In part 2, 18 hepatologists completed all two questionnaires. Overall, treatment decision was modified in 52% of cases upon receiving the drug resistance testing results. The detection of rtA181V/I resulted in decision changes in most hepatologists, with the preferred treatment switching from tenofovir to entecavir. When no mutants were detected in partial responders to entecavir monotherapy, most hepatologists chose to increase the dose of entecavir. CONCLUSIONS: Drug-resistant mutations are detected in around two-thirds of chronic hepatitis B patients undergoing drug resistance testing. Drug resistance testing alters management in over half of the cases, and should be considered in all patients with virological breakthrough and suboptimal virological suppression.
Assuntos
Antivirais/uso terapêutico , Farmacorresistência Viral/genética , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Mutação/genética , Adenina/análogos & derivados , Adenina/uso terapêutico , Adulto , DNA Viral/sangue , Coleta de Dados , Tomada de Decisões , Feminino , Guanina/análogos & derivados , Guanina/uso terapêutico , Hepatite B Crônica/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Organofosfonatos/uso terapêutico , Estudos Retrospectivos , Inquéritos e Questionários , Tenofovir , Resultado do Tratamento , Carga ViralRESUMO
BACKGROUND: We studied whether quantification of serum HBsAg and HBV DNA levels could predict spontaneous HBsAg clearance in patients with negative hepatitis B e antigen (HBeAg). METHODS: Serum HBsAg and HBV DNA levels were measured at baseline among a longitudinal cohort of 103 HBeAg-negative patients recruited since 1997. RESULTS: Twelve (12%) patients developed HBsAg seroclearance after 88 ± 26 months (range, 21-139) of follow-up. At baseline, the serum HBsAg level among patients who cleared HBsAg (1.30 ± 1.27 log IU/mL) was significantly lower than those who did not clear HBsAg (2.96 ± 0.84 log IU/mL; P < .001). The area under receiver operating characteristics (ROC) curve for serum HBsAg to predict HBsAg seroclearance was 0.90 (95% confidence interval [CI], 0.83-0.97; P < .001). Nine (75%) of 12 patients who had HBsAg seroclearance versus 8 (9%) of 91 who remained HBsAg-positive had serum HBsAg ≤100 IU/mL at the baseline (P < .001). An HBsAg cutoff of ≤100 IU/mL had 75% sensitivity and 91% specificity to predict HBsAg seroclearance. Baseline serum HBV DNA could not predict HBsAg seroclearance; the area under ROC curve was 0.64 (95% CI, 0.46-0.81; P = .13). CONCLUSIONS: Single-point serum HBsAg level can predict the chance of HBsAg seroclearance in chronic hepatitis B patients with negative HBeAg.
Assuntos
DNA Viral/sangue , Antígenos de Superfície da Hepatite B/sangue , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/imunologia , Alanina Transaminase/sangue , Carcinoma Hepatocelular/etiologia , Seguimentos , Hepatite B Crônica/complicações , Hepatite B Crônica/virologia , Humanos , Neoplasias Hepáticas/etiologia , Estudos LongitudinaisRESUMO
Prefibrotic primary myelofibrosis (Pre-PMF) has been classified as a separate entity of myeloproliferative neoplasms (MPNs). Pre-PMF is clinically heterogeneous but a specific prognostic model is lacking. Gene mutations have emerged as useful tools for stratification of myelofibrosis patients. However, there have been limited studies comprehensively investigating the mutational spectrum and its clinicopathological significance in pre-PMF subjects. In this study, we addressed these issues by profiling the mutation status of 141 genes in 172 Chinese MPN patients including 72 pre-PMF cases. Our findings corroborated the clinical/molecular distinctiveness of pre-PMF and suggested a refined risk classification strategy for this entity.
RESUMO
Acute promyelocytic leukemia (APL) is a specific subtype of acute myeloid leukemia (AML) characterized by block of differentiation at the promyelocytic stage and the presence of PML-RARA fusion. In rare instances, RARA is fused with other partners in variant APL. More infrequently, non-RARA genes are rearranged in AML patients resembling APL. However, the underlying disease pathogenesis in these atypical cases is largely unknown. Here, we report the identification and characterization of a NUP98- JADE2 fusion in a pediatric AML patient showing APL-like morphology and immunophenotype. Mechanistically, we showed that NUP98-JADE2 could impair all-trans retinoic acid (ATRA)-mediated transcriptional control and myeloid differentiation. Intriguingly, NUP98-JADE2 was found to alter the subcellular distribution of wild-type JADE2, whose down-regulation similarly led to attenuated ATRA-induced responses and myeloid activation, suggesting that NUP98-JADE2 may mediate JADE2 inhibition. To our knowledge, this is the first report of a NUP98-non-RAR rearrangement identified in an AML patient mimicking APL. Our findings suggest JADE2 as a novel myeloid player involved in retinoic acid-induced differentiation. Despite lacking a rearranged RARA, our findings implicate that altered retinoic acid signaling by JADE2 disruption may underlie the APL-like features in our case, corroborating the importance of this signaling in APL pathogenesis.
Assuntos
Leucemia Mieloide Aguda , Leucemia Promielocítica Aguda , Criança , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/patologia , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Receptores do Ácido Retinoico/genética , TretinoínaRESUMO
BACKGROUND & AIMS: Severe acute exacerbation of chronic hepatitis B is a unique clinical presentation with significant morbidity and mortality. Lamivudine was used in most previous studies, but the drug was limited by the development of resistance. Our objective is to study the safety and efficacy of entecavir in patients with severe acute exacerbation. METHODS: Consecutive patients with severe acute exacerbation of chronic hepatitis B were recruited from 1998 to 2009. All patients had serum alanine aminotransferase and bilirubin increased beyond 10 and 3 times the upper limit of normal, respectively. The primary endpoint was overall mortality at week 48. Virological and biochemical responses were also studied. RESULTS: Thirty-six patients and 117 patients were treated with entecavir and lamivudine, respectively. By week 48, 7 (19%) patients in the entecavir group and 5 (4%) patients in the lamivudine group died (adjusted hazard ratio 5.1, 95% confidence interval 1.5-17.2, p=0.010). Similarly, the entecavir group had higher liver-related mortality (adjusted hazard ratio 4.0, 95% confidence interval 1.0-15.7, p=0.044). Despite a lower prevalence of cirrhosis, more patients in the entecavir group developed prolonged jaundice, hepatic encephalopathy, and ascites. Entecavir resulted in more rapid and complete viral suppression, with 71% of patients achieving undetectable hepatitis B virus (HBV) DNA at week 48, compared to 40% in the lamivudine group (p=0.007). However, rapid HBV DNA reduction at week 4 was associated with prolonged jaundice. CONCLUSIONS: Entecavir treatment is associated with increased short-term mortality in patients with severe acute exacerbation of chronic hepatitis B but achieves better virological response in the long run.
Assuntos
Antivirais/efeitos adversos , Guanina/análogos & derivados , Hepatite B Crônica/tratamento farmacológico , Adulto , Idoso , Alanina Transaminase/sangue , DNA Viral/sangue , Feminino , Guanina/efeitos adversos , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/complicações , Hepatite B Crônica/mortalidade , Hepatite B Crônica/virologia , Humanos , Lamivudina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Ativação ViralRESUMO
UNLABELLED: Serum hepatitis B surface antigen (HBsAg) quantification has been suggested to reflect the concentration of covalently closed circular DNA in the liver. We aimed to investigate the HBsAg levels at different stages of chronic hepatitis B and the changes in HBsAg level during the natural progression of disease. One hundred seventeen untreated patients with chronic hepatitis B were studied with longitudinal follow-up for 99 ± 16 months. HBsAg quantification was performed at the first visit, the last visit, and three visits at each quartile during the follow-up. At the first visit, HBsAg level was higher among patients who were hepatitis B e antigen (HBeAg)-positive (N = 49) than those who were HBeAg-negative (N = 68) (4.01 ± 0.91 log IU/mL versus 2.73 ± 1.25 log IU/mL, P < 0.001). HBsAg level was persistently high at approximately 5 log IU/mL among patients in the immune tolerance phase (N = 7). The HBsAg levels among patients with HBeAg-positive active disease (N = 25) or sustained HBeAg seroconversion (N = 17) were comparable at approximately 3-4 log IU/mL. The HBsAg levels among patients who were HBeAg-negative tended to be higher among patients with active (N = 46) than those with inactive disease (N = 22). The median HBsAg levels decreased in HBeAg-negative patients with active and inactive disease by 0.041 log IU/mL/year and 0.043 log IU/mL/year, respectively. Twenty-two (17%) patients had HBsAg reduction >1 log IU/mL at the last visit; most of them showed reduced hepatitis B virus DNA, and eight had HBsAg loss. CONCLUSION: HBsAg remained stable in HBeAg-positive patients and tended to reduce slowly in HBeAg-negative patients. Reduction of HBsAg for >1 log IU/mL could reflect improved immune control.
Assuntos
Antígenos de Superfície da Hepatite B/sangue , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/imunologia , Adolescente , Adulto , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-IdadeRESUMO
UNLABELLED: Approximately 30%-40% of patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B treated with peginterferon and/or lamivudine achieve HBeAg seroconversion 6 months after the end of treatment. The durability and long-term effect of treatment are unknown. In this study, 85 HBeAg-positive patients who received peginterferon alfa-2b 1.5 microg/kg/week for 32 weeks and lamivudine 100 mg/day for 52 or 104 weeks were prospectively followed for 6.1 +/- 1.7 years posttreatment. Twenty-five (29%) patients had virologic response (HBeAg seroconversion and HBV DNA <10,000 copies/mL) at 5 years. The rate of HBeAg seroconversion rose progressively from 37% at the end of treatment to 60% at 5 years. Twenty-seven (32%) and 11 (13%) patients had undetectable HBV DNA (<100 copies/mL) at the end of peginterferon treatment and at 5 years, respectively. Two (2.4%) patients achieved hepatitis B surface antigen (HBsAg) seroclearance at 2.6 and 84 months posttreatment. Among virologic responders at the end of treatment, 82% and 57% and sustained HBeAg seroconversion and virologic response at 5 years. End-of-treatment serum quantitative HBsAg was significantly lower in patients with sustained virologic response at 5 years (median 1,431 IU/mL versus 2,689 IU/mL [P = 0.041]). At the last follow-up, the liver stiffness measurement by transient elastography was 5.8 +/- 2.7 kPa. Only two patients had liver stiffness suggestive of advanced fibrosis. Week 16 HBV DNA, end-of-treatment HBeAg seroconversion, and undetectable HBV DNA were independent factors associated with virologic response at 5 years. The duration of concomitant lamivudine treatment had no impact on any long-term response. CONCLUSION: Peginterferon has high durability in HBeAg-positive chronic hepatitis B patients with end-of-treatment virologic response.