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INTRODUCTION: There is some evidence that Bordetella pertussis (B. pertussis) can co-infect with viral respiratory infections in young infants. METHODS: B. pertussis infection was studied by culture, polymerase chain reaction (PCR), and loop-mediated isothermal amplification (LAMP) from nasopharyngeal swabs (NPSs) in 49 infants < 12 months of age, who were admitted for lower respiratory tract infections during the winter season. Seven other possible viral pathogens were documented by antigen detection or PCR in NPSs. The clinical feature of infants with mixed infection of B. pertussis and respiratory viruses were examined. RESULTS: Overall, B. pertussis infection was found in 10 (20.4%) cases, nine were less than 6 months of age and seven were unvaccinated. Viral etiology was found in 41 (84%) cases and pertussis-viral co-infection was present in eight patients, five of whom had mixed infection with respiratory syncytial virus. Only the presence of staccato coughing, cyanosis, and lymphocytosis were significantly different in B. pertussis-positive cases compared with B. pertussis-negative cases. Of the 10 pertussis cases, only the culture-positive cases showed the typical symptoms and laboratory findings of pertussis in addition to virus-associated respiratory symptoms with severe hospital course, whereas cases identified as DNA-positive lacked the characteristics of pertussis and their clinical severities were the same as B. pertussis-negative cases. CONCLUSION: In the absence of typical paroxysmal cough and lymphocytosis, we should carefully consider diagnosis of pertussis in young children hospitalized for presumed viral respiratory illness according to local epidemiological surveillance.
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Infecciones del Sistema Respiratorio , Tos Ferina , Bordetella pertussis/genética , Niño , Preescolar , Humanos , Lactante , Técnicas de Diagnóstico Molecular , Técnicas de Amplificación de Ácido Nucleico , Infecciones del Sistema Respiratorio/diagnóstico , Infecciones del Sistema Respiratorio/epidemiología , Estaciones del Año , Tos Ferina/diagnóstico , Tos Ferina/epidemiologíaRESUMEN
Combined daclatasvir (DCV)/asunaprevir (ASV) plus beclabuvir (BCV) treatment shows a high virological response for genotype 1b chronic hepatitis C patients. However, its efficacy for patients for whom previous direct-acting antiviral (DAA) therapy failed is not known. We analysed the efficacy of DCV/ASV/BCV treatment for HCV-infected mice and chronic hepatitis patients. Human hepatocyte chimaeric mice were injected with serum samples obtained from either a DAA-naïve patient or a DCV/ASV treatment failure and were then treated with DCV/ASV alone or in combination with BCV for 4 weeks. DCV/ASV treatment successfully eliminated the virus in DAA-naïve-patient HCV-infected mice. DCV/ASV treatment failure HCV-infected mice developed viral breakthrough during DCV/ASV treatment, with the emergence of NS5A-L31V/Y93H HCV resistance-associated variants (RAVs) being observed by direct sequencing. DCV/ASV/BCV treatment inhibited viral breakthrough in NS5A-L31V/Y93H-mutated HCV-infected mice, but HCV relapsed with the emergence of NS5B-P495S variants after the cessation of the treatment. The efficacy of the triple therapy was also analysed in HCV-infected patients; one DAA-naïve patient and four prior DAA treatment failures were treated with 12 weeks of DCV/ASV/BCV therapy. Sustained virological response was achieved in a DAA-naïve patient and one of the DCV/ASV treatment failures through DCV/ASV/BCV therapy; however, HCV relapse occurred in the other patients with prior DCV/ASV and/or sofosbuvir/ledipasvir treatment failures. DCV/ASV/BCV therapy seems to have limited efficacy for patients with NS5A RAVs for whom prior DAA treatment has failed.
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Benzazepinas/uso terapéutico , Farmacorresistencia Viral , Hepatitis C/tratamiento farmacológico , Imidazoles/uso terapéutico , Indoles/uso terapéutico , Isoquinolinas/uso terapéutico , Sulfonamidas/uso terapéutico , Animales , Antivirales/administración & dosificación , Antivirales/uso terapéutico , Benzazepinas/administración & dosificación , Biomarcadores , Carbamatos , Combinación de Medicamentos , Quimioterapia Combinada , Genotipo , Hepacivirus/efectos de los fármacos , Hepatitis C/virología , Humanos , Imidazoles/administración & dosificación , Indoles/administración & dosificación , Isoquinolinas/administración & dosificación , Ratones , Inhibidores de Proteasas/administración & dosificación , Inhibidores de Proteasas/uso terapéutico , Pirrolidinas , Sulfonamidas/administración & dosificación , Insuficiencia del Tratamiento , Valina/análogos & derivados , Proteínas no Estructurales Virales/antagonistas & inhibidores , Proteínas no Estructurales Virales/genética , ViremiaRESUMEN
Nucleot(s)ide analogues and peginterferon (PEG-IFN) treatment are the only approved therapies for chronic hepatitis B virus (HBV) infection. However, complete eradication of the virus, as indicated by persistent loss of hepatitis B surface antigen (HBsAg), is rare among treated patients. This is due to long-term persistence of the HBV genome in infected hepatocytes in the form of covalently closed circular DNA (cccDNA). In this study, we investigated whether administration of a large dose of a nucleoside analogue in combination with PEG-IFN can achieve long-term loss of HBsAg in human hepatocyte chimeric mice. Mice were treated with a high dose of entecavir and/or PEG-IFN for 6 weeks. High-dose combination therapy with both drugs resulted in persistently negative HBV DNA in serum. Although small amounts of HBV DNA and cccDNA (0.1 and 0.01 copy/cell, respectively) remained in the mouse livers, some of the mice remained persistently negative for serum HBV DNA at 13 weeks after cessation of the therapy. Serum HBsAg and hepatitis B core-related antigen (HBcrAg) continued to decrease and eventually became negative at 12 weeks after cessation of the therapy. Analysis of the HBV genome in treated mice showed accumulation of G-to-A hypermutation and CpG III island methylation. Persistent loss of serum HBV DNA and loss of HBV markers by high-dose entecavir and PEG-IFN combination treatment in chimeric mice suggests that control of HBV can be achieved even in the absence of a cellular immune response.
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Antivirales/uso terapéutico , ADN Circular/sangre , ADN Viral/sangre , Guanina/análogos & derivados , Antígenos de Superficie de la Hepatitis B/sangre , Virus de la Hepatitis B/efectos de los fármacos , Hepatitis B Crónica/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Polietilenglicoles/uso terapéutico , Animales , Metilación de ADN/genética , Quimioterapia Combinada , Guanina/uso terapéutico , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/inmunología , Hepatocitos/virología , Humanos , Inmunidad Celular/inmunología , Hígado/virología , Ratones , Proteínas Recombinantes/uso terapéuticoRESUMEN
Although nucleot(s)ide analogues and pegylated interferon alpha 2a (PEG-IFN-α2a) can suppress hepatitis B virus (HBV) replication, it is difficult to achieve complete HBV elimination from hepatocytes. A novel site-specific pegylated recombinant human IFN-ß (TRK-560) was recently developed. In the present study, we evaluated the antiviral effects of TRK-560 on HBV replication in vitro and in vivo. In vitro and in vivo HBV replication models were treated with antivirals including TRK-560, and changes in HBV markers were evaluated. To analyze antiviral mechanisms, cDNA microarray analysis and an enzyme-linked immunoassay (ELISA) were performed. TRK-560 significantly suppressed the production of intracellular HBV replication intermediates and extracellular HBV surface antigen (HBsAg) (P < 0.001 and P < 0.001, respectively), and the antiviral effects of TRK-560 were enhanced in combination with nucleot(s)ide analogues, such as entecavir and tenofovir disoproxil fumarate. The reduction in HBV DNA levels by TRK-560 treatment was significantly higher than that by PEG-IFN-α2a treatment both in vitro and in vivo (P = 0.004 and P = 0.046, respectively), and intracellular HBV covalently closed circular DNA (cccDNA) reduction by TRK-560 treatment was also significantly higher than that by PEG-IFN-α2a treatment in vivo (P = 0.0495). cDNA microarrays and ELISA for CXCL10 production revealed significant differences between TRK-560 and PEG-IFN-α2a in the induction potency of interferon-stimulated genes. TRK-560 shows a stronger antiviral potency via higher induction of interferon-stimulated genes and stronger stimulation of immune cell chemotaxis than PEG-IFN-α2a. As HBsAg loss and HBV cccDNA eradication are important clinical goals, these results suggest a potential role for TRK-560 in the development of more effective treatment for chronic hepatitis B infection.
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Antivirales/farmacología , Antígenos de Superficie de la Hepatitis B/metabolismo , Virus de la Hepatitis B/efectos de los fármacos , Hepatitis B Crónica/tratamiento farmacológico , Interferón-alfa/farmacología , Polietilenglicoles/farmacología , Animales , Línea Celular Tumoral , Quimiocina CXCL10/biosíntesis , ADN Circular/metabolismo , ADN Viral/metabolismo , Células Hep G2 , Humanos , Ratones , Ratones SCID , Ratones Transgénicos , Proteínas Recombinantes/farmacología , Resultado del Tratamiento , Carga Viral/efectos de los fármacos , Replicación Viral/efectos de los fármacosRESUMEN
Urokinase-type plasminogen activator/severe combined immunodeficiency (uPA/SCID) mice transplanted with human hepatocytes are permissive for hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. However, one of the problems affecting uPA transgenic mice is the expansion of mouse hepatocyte colonies due to homologous recombination of the uPA gene. In this study, we attempted to infect HBV and HCV in humanized cDNA-uPA/SCID mice, a novel uPA transgenic mouse model designed to overcome this disadvantage. Three hundred and eighty-six uPA/SCID and 493 cDNA-uPA/SCID mice were transplanted with human hepatocytes and then injected with either HBV- or HCV-positive human serum samples or HBV-transfected cell culture medium. Twelve weeks after human hepatocyte transplantation, the mouse serum concentration of human albumin, which is correlated with the degree of repopulation by human hepatocytes, was significantly higher in cDNA-uPA/SCID mice compared with uPA/SCID mice. HBV-infected cDNA-uPA/SCID mice showed significantly greater and more persistent viraemia, and similar virological effects by entecavir treatment were achieved in both systems. HCV-infected cDNA-uPA/SCID mice developed more frequent and significantly higher viraemia compared with uPA/SCID mice. The present study using a large number of mice showed that cDNA-uPA/SCID mice transplanted with human hepatocytes developed high and long-term persistent viraemia following HBV and HCV infection, and a higher survival rate was observed in cDNA-uPA/SCID compared with uPA/SCID mice. These mice may be a useful animal model for the study of HBV and HCV virology and the analysis of the effect of antiviral drugs.
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Modelos Animales de Enfermedad , Hepatitis B/virología , Hepatitis C/virología , Activador de Plasminógeno de Tipo Uroquinasa/genética , Animales , Hepatocitos/virología , Humanos , Ratones , Ratones SCID , Ratones Transgénicos , Activador de Plasminógeno de Tipo Uroquinasa/metabolismo , ViremiaRESUMEN
Combination of sofosbuvir plus ledipasvir therapy has been expected to enhance sustained virological response (SVR) rates in hepatitis C virus (HCV) genotype 1 chronic infected patients. We analyzed the emergence of drug resistance-associated variants (RAVs) in treatment failure and changes in lipid profiles in sofosbuvir/ledipasvir-treated patients. A total of 176 patients with chronic HCV genotype 1 infection without decompensated liver cirrhosis were treated with sofosbuvir/ledipasvir for 12 weeks. NS5A and NS5B RAVs were determined by either Invader assay or direct sequencing. Serum lipid-related markers were measured at the start of treatment and at week 4 in patients who received sofosbuvir/ledipasvir and ombitasvir/paritaprevir/ritonavir therapies. SVR was achieved in 94.9% (167 out of 176) of patients. SVR12 rate was 97.1% for patietns with low frequncy (<25%) of baseline NS5A RAVs, but 82.8% for patients with high frequency (>75%) of NS5A RAVs. In multivariate regression analysis, higher albumin (odds ratio [OR] = 0.020 for presence; P = 0.007), and NS5A-L31/Y93 RAVs with a population frequency <75% (OR = 29.860 for presence; P = 0.023) were identified as significant independent predictors for SVR12. NS5A-Y93H substitutions were detected in all nine treatment failures at HCV relapse, and three out of six patients with NS5A inhibitor-naïve patients achieved additional NS5A RAVs. Serum low-density lipoprotein cholesterol and apolipoprotein B levels were significantly elevated at week 4 in sofosbuvir/ledipasvir-treated patients. These elevations were greater than in ombitasvir/paritaprevir/ritonavir-treated patients. In conclusion, NS5A multi-RAVs are likely to develop in patients who fail to respond to sofosbuvir/ledipasvir therapy. Inhibition of HCV replication with sofosbuvir might affect lipid metabolism.
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Antivirales/uso terapéutico , Bencimidazoles/uso terapéutico , Farmacorresistencia Viral Múltiple/genética , Fluorenos/uso terapéutico , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/tratamiento farmacológico , Lípidos/sangre , Uridina Monofosfato/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Anilidas/uso terapéutico , Carbamatos/uso terapéutico , Ciclopropanos , Quimioterapia Combinada , Femenino , Variación Genética , Hepacivirus/genética , Hepatitis C Crónica/virología , Humanos , Lactamas Macrocíclicas , Compuestos Macrocíclicos/uso terapéutico , Masculino , Persona de Mediana Edad , Mutación , Prolina/análogos & derivados , Ritonavir/uso terapéutico , Sofosbuvir , Sulfonamidas , Respuesta Virológica Sostenida , Insuficiencia del Tratamiento , Uridina Monofosfato/uso terapéutico , Valina , Adulto JovenRESUMEN
BACKGROUND: Although treatment-emergent NS3/4A protease inhibitor (PI)-resistant variants typically decrease in frequency after cessation of PI therapy in patients with chronic hepatitis C virus (HCV) infection, HCV susceptibility to PIs in patients who have not responded to previous PI therapy has not been addressed. METHODS: Patients with chronic HCV genotype 1 infection were treated either with simeprevir plus interferon or with daclatasvir plus asunaprevir. Frequencies of drug-resistant mutations among patients with treatment failure were analyzed by deep sequencing. Human hepatocyte chimeric mice were injected with serum samples obtained from either treatment-naive patients or nonresponders to treatment with daclatasvir plus asunaprevir and then were treated with simeprevir and sofosbuvir. RESULTS: Virological response to daclatasvir plus asunaprevir treatment was significantly lower in patients with simeprevir treatment failure as compared to those without previous treatment. Deep-sequencing analysis showed that the frequency of PI treatment-emergent NS3-D168 mutations gradually decreased and were completely replaced by wild-type genes after cessation of therapy. However, mice injected with serum obtained from a patient with PI treatment failure rapidly developed NS3-D168 mutations at significantly higher frequencies following either simeprevir or sofosbuvir treatment. CONCLUSIONS: The virological response to daclatasvir plus asunaprevir treatment was low in patients with simeprevir treatment failure. PI resistance remains even after disappearance of mutant strains by deep sequencing.
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Antivirales/uso terapéutico , Farmacorresistencia Viral , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/virología , Inhibidores de Proteasas/uso terapéutico , Animales , Carbamatos , Hepacivirus/aislamiento & purificación , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Imidazoles/uso terapéutico , Interferones/uso terapéutico , Isoquinolinas/uso terapéutico , Ratones SCID , Pirrolidinas , Simeprevir/uso terapéutico , Sulfonamidas/uso terapéutico , Insuficiencia del Tratamiento , Valina/análogos & derivadosRESUMEN
AIM: A genome-wide association study revealed that the single nucleotide polymorphism (SNP) rs738409 in the patatin-like phospholipase 3 gene (PNPLA3) was strongly associated with non-alcoholic fatty liver disease (NAFLD). Recent pilot studies investigated the effects of dipeptidyl peptidase-4 inhibitors on liver function and glucose metabolism in NAFLD with type 2 diabetes mellitus (DM). We herein evaluated the efficacy of alogliptin in NAFLD patients with type 2 DM as well as the relationship between genotypes at rs738409 in PNPLA3 and treatment efficacy. METHODS: Forty-one biopsy-proven NAFLD patients with type 2 DM treated with 25 mg/day alogliptin were retrospectively enrolled. SNP rs738409 in PNPLA3 was present in all patients. Clinical data were measured before and after the treatment. RESULTS: Average hemoglobin A1c (HbA1c) levels mostly remained unchanged. Moreover, significant changes were not noted in the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) during the follow-up period. A positive correlation was observed between improvements in HbA1c (ΔHbA1c) levels and changes in AST (ΔAST) and ALT (ΔALT) levels (r = 0.325 and 0.439, respectively). Patients with the risk allele (G-allele) showed more positive correlation between ΔHbA1c and changes in transaminase. Furthermore, improvements in the levels of total cholesterol, triglycerides and hyaluronic acid were significantly greater in G-allele patients in the weight loss group. CONCLUSION: The treatment of NAFLD with type 2 DM with alogliptin contributed to the amelioration of NAFLD. Our results suggested that differences in the PNPLA3 risk allele affected the therapeutic effects of this treatment.
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Recently, treatments for chronic hepatitis C virus (HCV) infection have been drastically improved by the development of direct-acting antiviral agents. In September 2014, dual oral therapy using daclatasvir (DCV) and asunaprevir (ASV) was approved for the treatment of chronic HCV infection in Japan. We treated a patient with HCV-related liver cirrhosis with severe leg edema due to chronic renal dysfunction using this dual oral therapy. Although serum alanine aminotransferase increased rapidly during the first week of treatment, the antiviral therapy was able to continue, and liver function recovered spontaneously. After 1 month of treatment, serum HCV RNA became continuously undetectable, and serum albumin level gradually increased. Throughout the therapy, serum creatinine level nearly normalized, and leg edema gradually improved. These improvements continued after the combination therapy was completed. HCV RNA remained undetectable following the end of therapy, and sustained virological response at 12 weeks was achieved. It has been reported that chronic HCV infection is associated with renal dysfunction and that HCV eradication can improve it. DCV and ASV combination therapy is safe for patients who have renal dysfunction and may be a suitable therapy for chronic hepatitis C patients with renal dysfunction.
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AIM: Polymorphisms in the ITPA gene influence anemia during peg-interferon (PEG-IFN) and ribavirin (RBV) therapy, but their effects during triple therapy with simeprevir, PEG-IFN, and RBV are not sufficiently known. METHODS: We analyzed 212 patients with genotype 1 chronic hepatitis C, who were treated with simeprevir plus PEG-IFN/RBV triple therapy, and assessed the effect of the ITPA polymorphism on hemoglobin levels and RBV dose reduction. ITPA (rs1127354) and IFNL4 (ss469415590) polymorphisms were genotyped using the Invader assay. A stepwise multivariate regression analysis was carried out to identify factors associated with outcome of the therapy. RESULTS: Reduction of hemoglobin levels was similar between patients treated with simeprevir plus PEG-IFN/RBV and those treated with PEG-IFN/RBV therapy. In simeprevir plus PEG-IFN/RBV-treated patients, decreases in hemoglobin levels were faster and greater, and the cumulative proportion of patients with ribavirin dose reduction was significantly greater in ITPA genotype CC patients than in CA/AA patients. The total dose of simeprevir and PEG-IFN was similar between ITPA genotype CC and CA/AA patients. In contrast, the total dose of RBV was lower in patients with the CC genotype. Multivariate analysis showed that the IFNL4 TT/TT genotype, but not the ITPA SNP genotype, treatment history (treatment-naive or relapse during prior treatment), and treatment completion were significantly associated with outcome of therapy. CONCLUSION: ITPA polymorphism influences hemoglobin levels and incidence of RVB dose reduction during simeprevir triple therapy, indicating the importance of monitoring anemia during treatment, particularly for ITPA genotype CC patients.
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BACKGROUND: We assessed the risk factors for the development of hepatocellular carcinoma (HCC) following successful eradication of hepatitis C virus (HCV) with interferon (IFN) therapy in a long-term, large-scale cohort study. METHODS: We reviewed 1094 consecutive patients with HCV who achieved sustained virological response (SVR) following IFN therapy between January 1995 and September 2013. RESULTS: During the observation period (median 50 months: range 13-224), 36 (3%) of 1094 patients developed HCC after SVR. The median period from SVR to diagnosis of HCC was 37 months (range 17-141), and the cumulative rates of HCC at 5, 10, and 15 years were 4%, 6%, and 12%, respectively. Multivariate analysis identified old age (≥60 years, HR, 3.1: 95%CI, 1.3-6.6: P = 0.009), male sex (HR, 12.0: 95%CI, 2.8-50.0: P < 0.0001), advanced fibrosis stage (F3/4, HR, 3.2: 95%CI, 1.6-7.2: P < 0.0001), and alpha-fetoprotein ≥10 ng/mL at 1 year after SVR (HR, 7.8: 95%CI, 2.9-16.8: P < 0.0001) as significant and independent risk factors for post-SVR HCC. CONCLUSIONS: Older age and male sex (host factors), advanced fibrosis stage (pre-IFN treatment factor), and higher alpha-fetoprotein values (post-treatment factor) were significantly associated with HCC development after HCV eradication.
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Antivirales/uso terapéutico , Carcinoma Hepatocelular/virología , Hepatitis C/tratamiento farmacológico , Interferones/uso terapéutico , Neoplasias Hepáticas/virología , Respuesta Virológica Sostenida , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/diagnóstico , Distribución de Chi-Cuadrado , Niño , Femenino , Hepatitis C/complicaciones , Hepatitis C/diagnóstico , Humanos , Estimación de Kaplan-Meier , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/virología , Pruebas de Función Hepática , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/diagnóstico , Masculino , Persona de Mediana Edad , Análisis Multivariante , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Factores Sexuales , Factores de Tiempo , Resultado del Tratamiento , Regulación hacia Arriba , Adulto Joven , alfa-Fetoproteínas/análisisRESUMEN
BACKGROUND & AIMS: Single nucleotide polymorphisms within the interferon lambda 4 (IFNL4) locus are strongly associated with spontaneous clearance of hepatitis C virus (HCV) infection and early viral response to interferon therapy. Interaction between host genotype and amino acid substitutions might also influence the risk of antiviral resistance in interferon-free direct acting antiviral (DAA) therapies. METHODS: The relationship between IFNL4 genotype and HCV substitutions was analyzed in 929 patients with chronic HCV genotype 1b infection. Ultra-deep sequencing and quasispecies reconstruction was performed on the N-terminal region of NS5A in 57 patients. RESULTS: IFNL4 genotype was strongly associated with HCV NS5A Y93 and core protein substitutions, and the number and diversity of predicted quasispecies was marginally greater in IFNL4 TT/TT patients compared to TT/ΔG, ΔG/ΔG patients. RNA secondary structure prediction of the NS5A region suggests that variable sites are more likely to occupy unpaired, high entropy positions. CONCLUSIONS: HCV infection is proposed to induce a more efficient antiviral response in individuals with the IFNL4 TT/TT genotype that results either in viral clearance or selection for viral adaptations. The association between IFNL4 TT/TT genotype and Y93 substitutions may impact the risk of antiviral resistance in NS5A inhibitors in DAA therapy.
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Hepatitis C/tratamiento farmacológico , Interleucinas/genética , Proteínas no Estructurales Virales/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Farmacorresistencia Viral , Femenino , Sitios Genéticos , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , ARN Viral/químicaRESUMEN
OBJECTIVE: Non-simple nodules in hepatocellular carcinoma (HCC) correlate with poor prognosis. Therefore, we examined the diagnostic ability of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) and contrast-enhanced ultrasound (CEUS) for diagnosing the macroscopic classification of small HCCs. METHODS: A total of 85 surgically resected nodules (≤30 mm) were analyzed. HCCs were pathologically classified as simple nodular (SN) and non-SN. By evaluating hepatobiliary phase (HBP) of EOB-MRI and Kupffer phase of CEUS, the diagnostic abilities of both modalities to correctly distinguish between SN and non-SN were compared. RESULTS: Forty-six nodules were diagnosed as SN and the remaining 39 nodules as non-SN. The area under the ROC curve (AUROCs, 95% confidence interval) for the diagnosis of non-SN were EOB-MRI, 0.786 (0.682-0.890): CEUS, 0.784 (0.679-0.889), in combination, 0.876 (0.792-0.959). The sensitivity, specificity, and accuracy were 64.1%, 95.7%, and 81.2% in EOB-MRI, 56.4%, 97.8%, and 78.8% in CEUS, and 84.6%, 95.7%, and 90.6% in combination, respectively. High diagnostic ability was obtained when diagnosed in both modalities combined. The sensitivity was especially statistically significant compared to CEUS. CONCLUSION: Combined diagnosis by EOB-MRI and CEUS can provide high-quality imaging assessment for determining non-SN in small HCCs. KEY POINTS: ⢠Non-SN has a higher frequency of MVI and intrahepatic metastasis than SN. ⢠Macroscopic classification is useful to choose the treatment strategy for small HCCs. ⢠Diagnostic ability for macroscopic findings of EOB-MRI and CEUS were statistically equal. ⢠The diagnosis of macroscopic findings by individual modality has limitations. ⢠Combined diagnosis of EOB-MRI and CEUS provides high diagnostic ability.
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Carcinoma Hepatocelular/diagnóstico , Medios de Contraste , Gadolinio DTPA , Neoplasias Hepáticas/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/diagnóstico por imagen , Métodos Epidemiológicos , Femenino , Humanos , Neoplasias Hepáticas/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Imagen Multimodal/métodos , UltrasonografíaRESUMEN
AIM: The main causes of mortality from non-alcoholic fatty liver disease (NAFLD) are cardiovascular disease (CVD) and malignancy. Eicosapentaenoic acid (EPA)/arachidonic acid (AA) ratio is known to be associated with CVD. However, a possible link between EPA/AA ratio and NAFLD is not well known. In this study, we investigated EPA/AA ratio in Japanese patients with NAFLD. METHODS: Two hundred and fifty-four patients with biopsy-proven NAFLD were retrospectively enrolled. Serum EPA/AA ratios were examined for each generation (<35, 35-44, 45-54, 55-64, ≥65 years), and the differences of EPA/AA ratios were evaluated based on steatotic grades and fibrotic stages. RESULTS: EPA/AA ratio in NAFLD patients was decreased compared to that reported in age-matched healthy controls. EPA/AA ratio, body mass index, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and steatotic grades in younger NAFLD patients were significantly worse than those in older NAFLD patients. Fasting glucose, hemoglobin A1c and fibrotic stages in older NAFLD patients were significantly higher than those in younger NAFLD patients. No relation was found between EPA/AA ratio and histological findings. CONCLUSION: EPA/AA ratio was lower in NAFLD, especially in younger NAFLD patients. Considering the high mortality from CVD in NAFLD patients, low EPA/AA ratio in young age may influence the increased prevalence of CVD in their older age. EPA/AA ratio is suggested to be a possible link between NAFLD and CVD, and would become a useful marker for CVD in NAFLD.
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A 50-year-old male patient was admitted to the hospital for persistent high fever and back pain. He was diagnosed with hepatocellular carcinoma (HCC), bone marrow metastasis and disseminated intravascular coagulation (DIC). Despite the diagnosis and treatment, the general condition deteriorated rapidly and he died of cerebral hemorrhage associated with generalized bleeding tendency. Autopsy showed multiple HCC in the liver and systemic metastasis including bone marrow. The case describes a rare complication of HCC with disseminated carcinomatosis of the bone marrow (DCBM) complicated with DIC, with rapid deterioration and death. This is the first case of DCBM from HCC. Physicians need to be aware of DCBM in patients with HCC.
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AIM: To assess the efficacy and safety of the anticoagulant drug, danaparoid sodium, in the treatment of portal vein thrombosis (PVT) in patients with liver cirrhosis. METHODS: A consecutive 26 cirrhotic patients with PVT were enrolled in this retrospective cohort study. The etiologies of cirrhosis were hepatitis B virus-related, hepatitis C virus-related, alcoholic and cryptogenic in five, 14, three and four patients, respectively. Child-Pugh grade A, B and C was noted in 13, eight and five patients, respectively. Patients were treated with 2 weeks' administration of danaparoid sodium followed by the evaluation of PVT reduction and adverse events. RESULTS: All patients experienced reduction of PVT through the treatment. The median volume of PVT before and after treatment was 2.40 cm(3) (range, 0.18-16.63) and 0.37 cm(3) (range, 0-5.74), respectively. The median reduction rate of PVT volume was 77.3% (range, 18-100%). According to the reduction rate, complete reduction (CR), partial reduction (PR, ≥50%) and stable disease (SD, <50%) were observed in four (15%), 16 (62%) and six patients (23%), respectively. The median volume of PVT before treatment was significantly different between CR + PR and SD (2.09 vs 4.35 cm(3) , P = 0.045). No severe adverse events such as bleeding symptoms (e.g. gastrointestinal bleeding and cerebral hemorrhage) and thrombocytopenia were encountered. CONCLUSION: Danaparoid sodium for the treatment of PVT in patients with liver cirrhosis was safe and effective. Therefore, anticoagulation therapy with danaparoid sodium could have potential as one of the treatment options in PVT accompanied by cirrhosis.
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AIM: To evaluate the response, survival and safety on 3-D conformal radiotherapy (3D-CRT) for major portal vein tumor thrombosis (PVTT) combined with hepatic arterial infusion chemotherapy (HAIC) for advanced hepatocellular carcinoma (HCC). METHODS: In this retrospective study, 83 advanced HCC patients treated with HAIC who met the following criteria were enrolled: (i) PVTT of the main trunk or first branch of the portal vein; (ii) no extrahepatic metastasis; (iii) Child-Pugh score of 5-7; (iv) performance status of 0 or 1; and (v) no history of sorafenib treatment. The response, overall survival (OS), time to treatment failure (TTF), post-progression survival (PPS) and safety were compared between HAIC combined with 3D-CRT for PVTT (RT group, n = 41) and HAIC alone (non-RT group, n = 42). RESULTS: The objective response of PVTT was significantly higher in the RT group (56.1%) than in the non-RT group (33.3%), while that of intrahepatic tumor and OS were not significantly different between groups. Median OS, TTF and PPS were significantly longer in the RT group than in the non-RT group (8.6 and 5.0 months, 5.0 and 2.7 months, and 5.3 and 1.5 months, respectively) among intrahepatic tumor non-responders to HAIC, whereas those were not significantly different between groups among intrahepatic tumor responders to HAIC. By multivariate analysis, the combination of 3D-CRT with HAIC was an independent contributing factor for OS (hazard ratio, 3.2; 95% confidence interval, 1.692-6.021; P < 0.001) among intrahepatic HCC non-responders to HAIC. CONCLUSION: 3D-CRT for PVTT combined with HAIC could provide survival benefit to non-responder to HAIC.
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BACKGROUND AND AIM: To assess the early response and outcome of hepatic arterial infusion chemotherapy (HAIC) in patients with advanced hepatocellular carcinoma (HCC). METHODS: One hundred sixty-five HCC patients treated with HAIC were reviewed retrospectively. The early response to one course of HAIC treatment was evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) and changes in α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP). RESULTS: The median survival time (MST) for all patients was 9.5 months. The early imaging response by RECIST was assessed as partial response (PR), stable disease (SD), and progressive disease (PD) in 32 (19.3%), 86 (52.1%), and 47 (28.4%) patients, respectively. Survival correlated with early imaging response (MST in PR, 20.6; SD, 11.4; PD, 5.0 months; P < 0.0001). The MST was also significantly different in patients with AFP ratio of ≤ 1 or > 1 and DCP ratio of ≤ 1 or > 1 (worst MST, 6.5 months in patients with AFP ratio of > 1 and DCP ratio of > 1). Among patients with SD early imaging response, patients with AFP ratio of > 1 and DCP ratio of > 1 had significantly poorer survival than others (MST 7.4 vs. 12.6 months, P = 0.014). The decrease in AFP and DCP in the early stage treatment with HAIC were identified as significant and independent factors associated with survival of not only all patients, but also patients with SD early imaging response. CONCLUSION: The use of the combination of RECIST and tumor marker ratio could be useful for assessment of the early response to HAIC and prognosis of patients with advanced HCC.
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Antineoplásicos/administración & dosificación , Biomarcadores de Tumor/sangre , Biomarcadores/sangre , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/tratamiento farmacológico , Precursores de Proteínas/sangre , alfa-Fetoproteínas/análisis , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/mortalidad , Femenino , Arteria Hepática , Humanos , Infusiones Intraarteriales , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Protrombina , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: The prevalence of non-B or non-C hepatocellular carcinoma (NBNC-HCC) has been increasing all over the world. Advanced glycation end products (AGE) play a role in the pathogenesis of alcoholic liver injury or nonalcoholic steatohepatitis (NASH). METHODS: We examined here whether serum levels of AGE were elevated in NBNC-HCC patients compared with NASH subjects without HCC and investigated which anthropometric and clinical variables were independent determinants of AGE. RESULTS: Ninety NBNC-HCC, 56 NASH, and 27 control subjects underwent a complete history and physical examination, determination of blood chemistries, including AGE levels. Serum levels of AGE were significantly higher in NBNC-HCC patients compared with NASH and control subjects [9.1 ± 2.7, 5.2 ± 1.7, 3.5 ± 1.2 (U/ml), respectively, P < 0.05]. Univariate analysis showed that AGE levels were associated with male (P < 0.05), age (P < 0.01), aspartate aminotransferase (P < 0.05), γ-glutamyl transpeptidase (GGT) (P < 0.01), HDL-cholesterol (inversely, P < 0.01), fasting plasma glucose (P < 0.01), and HbA1c (P < 0.05). By the use of multiple stepwise regression analysis, age, GGT, and HDL-cholesterol (inversely) remained significant and were independently related to AGE levels (R(2) = 0.406). CONCLUSION: The present results suggest that AGE might be involved in the pathogenesis of NBNC-HCC, thereby being a biomarker that could discriminate NBNC-HCC from NASH.
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Biomarcadores de Tumor/sangre , Carcinoma Hepatocelular/diagnóstico , Productos Finales de Glicación Avanzada/sangre , Neoplasias Hepáticas/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Anciano , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/etiología , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/etiología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , PronósticoRESUMEN
AIM: The purpose of this study was to assess the clinical outcome and identify prognostic factors following treatment of patients with advanced hepatocellular carcinoma (HCC) and extrahepatic metastasis with sorafenib. METHODS: Sixty-one HCC patients with extrahepatic metastasis who were treated with sorafenib were enrolled in this retrospective cohort study. RESULTS: The median survival time (MST) of all patients was 11 months. The median time to radiological progression was 4.2 months. The response rates (complete response [CR] + partial response [PR]) by Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST were 3.0% and 8.0%, respectively, while the disease control rates (CR + PR + stable disease) were 49% and 49%, respectively. Multivariate analysis identified T factor (intrahepatic tumor stage, T 0-2), response to disease control and des-γ-carboxy prothrombin (<2600 mAU/mL) as significant and independent determinants of survival. Intrahepatic tumor stage before treatment allows stratification of prognosis of patients treated with sorafenib. Four T0 patients remained alive. The MST of patients with T1 (n = 6), T2 (n = 10), T3 (n = 23) and T4 (n = 18) of intrahepatic tumor stage was 20, 23, 7 and 5 months, respectively. Among the progressive disease group, patients with T0-2 intrahepatic tumor stage had better prognosis than patients with T3-4. CONCLUSION: In HCC patients with extrahepatic metastasis who are treated with sorafenib, intrahepatic tumor stage was a significant and independent prognostic factor.