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AIM: We aimed to develop a model for predicting in-hospital mortality of cirrhotic patients following major surgical procedures using a large sample of patients derived from a Japanese nationwide administrative database. METHODS: We enrolled 2197 cirrhotic patients who underwent elective (n = 1973) or emergency (n = 224) surgery. We analyzed the risk factors for postoperative mortality and established a scoring system for predicting postoperative mortality in cirrhotic patients using a split-sample method. RESULTS: In-hospital mortality rates following elective or emergency surgery were 4.7% and 20.5%, respectively. In multivariate analysis, patient age, Child-Pugh (CP) class, Charlson Comorbidity Index (CCI), and duration of anesthesia in elective surgery were significantly associated with in-hospital mortality. In emergency surgery, CP class and duration of anesthesia were significant factors. Based on multivariate analysis in the training set (n = 987), the Adequate Operative Treatment for Liver Cirrhosis (ADOPT-LC) score that used patient age, CP class, CCI, and duration of anesthesia to predict in-hospital mortality following elective surgery was developed. This scoring system was validated in the testing set (n = 986) and produced an area under the curve of 0.881. We also developed iOS/Android apps to calculate ADOPT-LC scores to allow easy access to the current evidence in daily clinical practice. CONCLUSION: Patient age, CP class, CCI, and duration of anesthesia were identified as important risk factors for predicting postoperative mortality in cirrhotic patients. The ADOPT-LC score effectively predicts in-hospital mortality following elective surgery and may assist decisions regarding surgical procedures in cirrhotic patients based on a quantitative risk assessment.
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AIM: To elucidate the impact of the serum ferritin level, a surrogate indicator of hepatic iron accumulation, on hepatocarcinogenesis in chronic hepatitis C patients. METHODS: Serum ferritin was measured in 487 chronic hepatitis C patients without history of hepatocellular carcinoma (HCC) after excluding patients in phlebotomy, those with overt chronic gastrointestinal bleeding and those who achieved sustained virological response before enrollment. Patients were divided into four groups (G1-G4) by quartile points of serum ferritin, with sexes separated. RESULTS: The serum ferritin level was positively correlated with total bilirubin, aspartate aminotransferase, alanine aminotransferase (ALT), γ-glutamyltransferase, hemoglobin and AFP, and inversely correlated with prothrombin activity in both sexes. A significant difference in HCC incidence was observed only in male patients; the incidence was higher in G1 (≤80 ng/mL, n = 54) and G4 (≥323 ng/mL, n = 54) compared with that of G2 (81-160 ng/mL, n = 54) and G3 (161-322 ng/mL, n = 52). The spline curve indicating the relationship between the hazard ratio and serum ferritin level took the form of a J-shape for male patients. In multivariate analysis, G1 and G4 showed higher incidence of HCC among men with a hazard ratio of 2.19 (95% confidence interval, 1.02-4.70; P = 0.045) compared with G2 and G3, together with older age, lower serum albumin and ALT above the normal upper limit. CONCLUSION: The serum ferritin level is an independent risk factor for HCC development in male patients with chronic hepatitis C when the level is extremely high or low.
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We report a case of tacrolimus vascular toxicity found on a protocol biopsy shortly after a deceased donor renal transplantation. The patient was immunologically high-risk and acute antibody-mediated rejection during post-transplant dialysis phase was suspected on the protocol biopsy. Although the patient was stable after treatment of rejection, a further examination showed a very rare but specific side-effect of tacrolimus. It is sometimes difficult to make a differential diagnosis during postoperative dialysis period among AMR, primary non-functioning, drug toxicity, infection or just prolonged recovery from the damage of a long agonal phase on the non-heart beating donor. Although the possibilities of coexistence of rejection or other causes such as infection have not been completely excluded, it is important to be aware of this unusual side effect of tacrolimus.
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Arteríolas/efeitos dos fármacos , Inibidores de Calcineurina/efeitos adversos , Rejeição de Enxerto/diagnóstico , Imunossupressores/efeitos adversos , Transplante de Rim/efeitos adversos , Rim/irrigação sanguínea , Tacrolimo/efeitos adversos , Doenças Vasculares/induzido quimicamente , Aloenxertos , Arteríolas/patologia , Biópsia , Diagnóstico Diferencial , Erros de Diagnóstico , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/patologia , Humanos , Imuno-Histoquímica , Masculino , Valor Preditivo dos Testes , Resultado do Tratamento , Doenças Vasculares/patologia , Adulto JovemRESUMO
AIM: Gastroesophageal variceal hemorrhage is an important complication of cirrhosis. We investigated the in-hospital mortality and its risk factors after variceal hemorrhage in a large sample population, using a nationwide Japanese database. METHODS: Data on the patients with variceal hemorrhage were collected for a total of 39 months from a nationwide administrative database covering approximately 1000 hospitals in Japan. The risk factors for fatal outcome after variceal hemorrhage were analyzed with receiver-operator curves (ROC) and univariate and multivariate logistic regression. Comorbidities were assessed with the Charlson Comorbidity Index. RESULTS: We identified 9987 patients with variceal hemorrhage from a total of 20.3 million inpatients in the database. The median age was 63 years and 68.8% were male. The overall in-hospital mortality was 16.8% (1676 cases). In univariate analysis, Child-Pugh class was the strongest predictor; the area under the ROC of Child-Pugh score for predicting in-hospital mortality was 0.802. In multivariate analysis, increased in-hospital mortality was significantly associated with male sex (vs female: odds ratio [OR] = 1.19, P = 0.01), older age, Child-Pugh class B or C (B vs A: OR = 2.80, P < 0.001; C vs A: OR = 20.1, P < 0.001) and higher Charlson Comorbidity Index (≥6 vs ≤5; OR = 1.29, P < 0.001). CONCLUSION: In spite of recent advances in the treatment of variceal hemorrhage, the in-hospital mortality remained as high as 16%. Poor liver function was the most important predictor, suggesting that liver failure after variceal hemorrhage might have been the cause of death.
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AIM: Treatment strategies for hepatocellular carcinoma (HCC) have been advanced. The aim of this study was to compare the change of the prognosis between hepatitis B-related HCC (B-HCC) and hepatitis C-related HCC (C-HCC) in the last two decades. METHODS: We enrolled 166 B-HCC patients who underwent percutaneous ablation between 1990 and 2009. Patients were divided into three groups according to the treatment time period: 1990-1995 (cohort 1, n = 19), 1996-2002 (cohort 2, n = 49) and 2003-2009 (cohort 3, n = 98). We enrolled 1219 C-HCC patients who underwent percutaneous ablation during the same period (n = 190, 413 and 616, respectively.). Interferon and nucleoside/nucleotide analog use was investigated. Prognosis was evaluated for each cohort using the Kaplan-Meier method and a multivariate Cox proportional hazard regression model. RESULTS: Two (11%), 24 (49%) and 80 (82%) B-HCC patients received nucleoside/nucleotide analogs during the follow-up period in cohorts 1-3, respectively. Among them 1, 18 and 62 patients achieved viral remission, respectively. Thirty-four (18%), 35 (8%) and 84 (14%) C-HCC patients received interferon therapy, respectively. The 5-year B-HCC (P < 0.001) survival rates were 52.6%, 61.1% and 81.6% for cohorts 1-3, respectively. However, the survival rates were 55.6%, 58.8% and 61.1% for C-HCC (P = 0.12), respectively. The B-HCC prognosis improved dramatically (P < 0.001) over time, whereas the prognosis of C-HCC improved moderately (P = 0.01). CONCLUSION: The prognosis of B-HCC has improved dramatically over time, whereas that of C-HCC has improved moderately.
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AIM: Hepatocellular carcinoma (HCC) is associated with chronic inflammation derived from various origins. We investigated whether high-sensitivity C-reactive protein (hsCRP) could predict recurrence and survival after curative treatment for early stage hepatitis C virus-related HCC (C-HCC). METHODS: We enrolled 387 patients with three or fewer C-HCC nodules, none of which exceeded 3 cm, and of Child-Pugh class A or B who underwent radiofrequency ablation. We divided the patients into high and low hsCRP groups based on the optimal cut-off value for recurrence using a split-sample method and maximally selected rank statistics. Differences in recurrence and survival rates were evaluated by the Kaplan-Meier method and the log-rank test. Hazard ratios of hsCRP were adjusted with confounding factors using a multiple Cox regression model. We also assessed the correlations between hsCRP levels and clinical parameters. RESULTS: The optimal hsCRP cut-off value was 0.08 mg/dL. The cumulative recurrence rates after 5 years in the high and low hsCRP groups were 90.0% and 82.2%, respectively (P = 0.028), and the corresponding survival rates were 50.9% and 71.8%, respectively (P < 0.001). Higher hsCRP was an independent predictor for recurrence (adjusted hazard ratio [aHR], 1.32; 95% confidence interval [CI], 1.03-1.67; P = 0.026) and survival (aHR, 1.59; 95% CI, 1.14-2.22; P = 0.007). hsCRP was correlated with central obesity as well as tumor burden and liver dysfunction. CONCLUSION: Slight elevation of the hsCRP level, even within the normal range, can predict recurrence and survival after curative treatment among patients with early stage C-HCC.
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AIM: The objectives of this study was to evaluate the utility of tumor markers in hepatocellular carcinoma (HCC) surveillance based on the reliability of ultrasonography. METHODS: We analyzed 313 patients with HCC detected through a surveillance program using ultrasonography combined with three tumor markers from February 2000 to December 2010. The patients were categorized into two groups based on the triggering event: the US group (n = 281) in which a tumor was first detected using ultrasonography and the TM group (n = 32) in which elevated tumor markers led to the diagnosis of a tumor that was undetected using ultrasonography. The reliability of ultrasonography was scored on a 4-point scale based on three items (coarseness of liver parenchyma, patient obesity and liver atrophy). Additionally, patient survival was assessed using the Kaplan-Meier method and log-rank test. RESULTS: The median tumor size was 20 mm (interquartile range, 15-24). The reliability of ultrasonography was evaluated as good in 208 (66.5%), satisfactory in 80 (8.0%), poor in 21 (6.7%) and unsatisfactory in four (1.2%) patients. The proportion of patients in the TM group increased significantly according to the score, from 7.2% to 25.0% (P = 0.01). The survival rates of patients at 3 and 5 years were 83.7% and 57.2% in the US group, and 79.3% and 59.4% in the TM group, respectively (P = 0.98). CONCLUSION: Tumor markers may play a diagnostic role in patients with unreliable ultrasonography results. The survival of patients diagnosed by elevated tumor markers was not significantly different from those diagnosed by ultrasonography.
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BACKGROUND AND AIM: Various inflammatory cytokines and adipokines have been implicated in hepatitis C virus (HCV)-mediated liver disease, and interleukin-6 (IL-6) and adiponectin may play key roles. In addition, these factors may be associated with chronic hepatitis C (CHC)-induced extrahepatic manifestations. However, little data are available on the role of these factors on future outcomes of CHC patients. This study aims to evaluate the impact of serum levels of IL-6 and adiponectin on all-cause mortality, liver-related mortality, and liver-unrelated mortality. METHODS: A long-term follow-up study was conducted, consisting of 325 CHC patients, for which we previously reported positive associations between these factors (Serum levels of IL-6 and adiponectin) and hepatocellular carcinoma (HCC) development. RESULTS: During the follow-up period (mean, 13.0 year), there were 92 events consisting of 91 deaths (liver related, 72; liver unrelated, 19) and 1 liver transplantation due to liver failure. High IL-6 and adiponectin levels, defined as being higher than each median value at baseline, were associated with significantly higher incidences of not only HCC development but also all-cause mortality. Interestingly, high IL-6 was strongly associated with only liver-related mortality, whereas high-serum adiponectin was associated with not only liver-related, but also liver-unrelated mortality. Multivariate analysis identified high IL-6 as an independent risk factor for liver-related mortality and high adiponectin as an independent risk factor for liver-unrelated mortality. CONCLUSION: High serum levels of IL-6 and adiponectin were associated with higher all-cause and liver-related mortality in CHC patients. In addition, high adiponectin was associated with liver-unrelated mortality. The measurement of these factors may provide information useful for predicting future outcomes in CHC patients.
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Adiponectina/sangue , Hepatite C Crônica/sangue , Hepatite C Crônica/mortalidade , Interleucina-6/sangue , Idoso , Biomarcadores/sangue , Carbolinas , Causas de Morte , Feminino , Seguimentos , Previsões , Hepatite C Crônica/complicações , Hepatite C Crônica/epidemiologia , Humanos , Hepatopatias/sangue , Hepatopatias/epidemiologia , Hepatopatias/etiologia , Hepatopatias/mortalidade , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Fatores de Risco , Fatores de TempoRESUMO
Using desensitization protocol, we performed a secondary donor specific antibody (DSA) positive and ABO incompatible kidney transplantation. One-hour biopsy showed no C4d deposition. The protocol biopsy after 2 weeks showed diffuse C4d deposition with peritubulitis. After 12 weeks, however, the protocol biopsy showed disappearance of tubulitis in spite of remaining C4d deposition. The recipient was in stable condition with excellent graft function despite high titer of the DSA. Monitoring of protocol biopsy is critical while antibody titer and the interpretation of the histological findings correlating with clinical markers must be considered.
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Sistema ABO de Grupos Sanguíneos/imunologia , Incompatibilidade de Grupos Sanguíneos/imunologia , Histocompatibilidade , Isoanticorpos/sangue , Transplante de Rim/efeitos adversos , Rim/imunologia , Aloenxertos , Biópsia , Incompatibilidade de Grupos Sanguíneos/terapia , Complemento C4b/análise , Dessensibilização Imunológica/métodos , Humanos , Imunossupressores/uso terapêutico , Rim/patologia , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/análise , Reoperação , Fatores de Tempo , Resultado do TratamentoRESUMO
Serum mitochondrial creatine kinase (MtCK) activity was reportedly increased in cirrhotic patients although less prominent than that in hepatocellular carcinoma (HCC) patients. To elucidate the clinical significance of serum MtCK activity in chronic liver disease, 171 chronic hepatitis C patients were enrolled. Serum MtCK activity in study subjects was correlated with serum albumin, platelet counts, liver stiffness values and serum aspartate and alanine aminotransferase. In mouse fibrotic liver induced by bile duct ligation, ubiquitous MtCK mRNA and protein expressions were significantly enhanced and its immunoreactivity was increased, predominantly in hepatocytes. During the mean follow-up period of 2.7 years, HCC developed in 21 patients, in whom serum MtCK activity was significantly higher than that in patients without HCC development. Multivariate Cox regression analysis revealed that higher serum MtCK activity was a risk for HCC development. A cutoff value of MtCK for the prediction of HCC development was determined as 9.0 U/L on receiver operating characteristics analysis, where area under receiver operating characteristics curve was 0.754, with a sensitivity of 61.9%, a specificity of 92.8% and a high negative predictive value of 94.2%. Cumulative incidence of HCC was significantly higher in patients with serum MtCK activity of >9.0 U/L compared to those with serum MtCK activity of ≤ 9.0 U/L even in patients with elevated liver stiffness value, >15 kPa. In conclusion, serum MtCK activity may be increased correlatively with the stage of liver fibrosis and hepatocellular damage. Increased serum MtCK activity is an independent risk for hepatocarcinogenesis in chronic hepatitis C patients.
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Carcinoma Hepatocelular/sangue , Creatina Quinase Mitocondrial/sangue , Hepatite C Crônica/sangue , Neoplasias Hepáticas/sangue , Idoso , Animais , Carcinoma Hepatocelular/complicações , Feminino , Fibrose , Hepatite C Crônica/complicações , Hepatócitos/citologia , Humanos , Fígado/patologia , Neoplasias Hepáticas/complicações , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Contagem de Plaquetas , Modelos de Riscos Proporcionais , Curva ROC , Risco , Sensibilidade e Especificidade , Albumina Sérica/metabolismoRESUMO
We previously reported the increased serum mitochondrial creatine kinase (MtCK) activity in patients with hepatocellular carcinoma (HCC), mostly due to the increase in ubiquitous MtCK (uMtCK), and high uMtCK mRNA expression in HCC cell lines. We explored the mechanism(s) and the relevance of high uMtCK expression in HCC. In hepatitis C virus core gene transgenic mice, known to lose mitochondrial integrity in liver and subsequently develop HCC, uMtCK mRNA and protein levels were increased in HCC tissues but not in non-tumorous liver tissues. Transient overexpression of ankyrin repeat and suppressor of cytokine signaling box protein 9 (ASB9) reduced uMtCK protein levels in HCC cells, suggesting that increased uMtCK levels in HCC cells may be caused by increased gene expression and decreased protein degradation due to reduced ASB9 expression. The reduction of uMtCK expression by siRNA led to increased cell death, and reduced proliferation, migration and invasion in HCC cell lines. Then, consecutive 105 HCC patients, who underwent radiofrequency ablation with curative intent, were enrolled to analyze their prognosis. The patients with serum MtCK activity >19.4 U/L prior to the treatment had significantly shorter survival time than those with serum MtCK activity ≤ 19.4 U/L, where higher serum MtCK activity was retained as an independent risk for HCC-related death on multivariate analysis. In conclusion, high uMtCK expression in HCC may be caused by hepatocarcinogenesis per se but not by loss of mitochondrial integrity, of which ASB9 could be a negative regulator, and associated with highly malignant potential to suggest a poor prognosis.
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Carcinoma Hepatocelular/enzimologia , Creatina Quinase Mitocondrial/metabolismo , Neoplasias Hepáticas/enzimologia , Animais , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Feminino , Humanos , Immunoblotting , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Prognóstico , RNA Interferente Pequeno , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Supressoras da Sinalização de Citocina/metabolismo , TransfecçãoRESUMO
UNLABELLED: MicroRNAs (miRNAs) are small RNAs that regulate the expression of specific target genes. While deregulated miRNA expression levels have been detected in many tumors, whether miRNA functional impairment is also involved in carcinogenesis remains unknown. We investigated whether deregulation of miRNA machinery components and subsequent functional impairment of miRNAs are involved in hepatocarcinogenesis. Among miRNA-containing ribonucleoprotein complex components, reduced expression of DDX20 was frequently observed in human hepatocellular carcinomas, in which enhanced nuclear factor-κB (NF-κB) activity is believed to be closely linked to carcinogenesis. Because DDX20 normally suppresses NF-κB activity by preferentially regulating the function of the NF-κB-suppressing miRNA-140, we hypothesized that impairment of miRNA-140 function may be involved in hepatocarcinogenesis. DNA methyltransferase 1 (Dnmt1) was identified as a direct target of miRNA-140, and increased Dnmt1 expression in DDX20-deficient cells hypermethylated the promoters of metallothionein genes, resulting in decreased metallothionein expression leading to enhanced NF-κB activity. MiRNA-140-knockout mice were prone to hepatocarcinogenesis and had a phenotype similar to that of DDX20 deficiency, suggesting that miRNA-140 plays a central role in DDX20 deficiency-related pathogenesis. CONCLUSION: These results indicate that miRNA-140 acts as a liver tumor suppressor, and that impairment of miRNA-140 function due to a deficiency of DDX20, a miRNA machinery component, could lead to hepatocarcinogenesis.
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Carcinoma Hepatocelular/metabolismo , Proteína DEAD-box 20/metabolismo , DNA (Citosina-5-)-Metiltransferases/metabolismo , Neoplasias Hepáticas/metabolismo , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Animais , Linhagem Celular Tumoral , DNA (Citosina-5-)-Metiltransferase 1 , Células Hep G2 , Humanos , Metalotioneína/metabolismo , Camundongos , Camundongos Knockout , Proteínas Supressoras de Tumor/metabolismoRESUMO
BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) cause a high frequency of mucosal injuries in the small intestine. However, no reliable intervention, other than cessation of NSAIDs, has been established. OBJECTIVE: To evaluate whether irsogladine maleate reduces these injuries while continuing NSAID therapy. DESIGN: Prospective, interventional, endoscopist-blinded, randomized, controlled trial (RCT). SETTING: University hospital. PATIENTS: Patients regularly taking conventional NSAIDs for more than 4 weeks. INTERVENTIONS: We initially examined small-intestinal mucosal injuries by capsule endoscopy (CE) and screened participants for the RCT. In the RCT, patients with any mucosal injury were randomly assigned to the irsogladine group (4 mg/day) or the control group. MAIN OUTCOME MEASUREMENTS: The primary endpoint was the rate of mucosal injury improvement after 4 weeks of treatment monitored with a second CE. RESULTS: Sixty-one patients were evaluated with the first CE. Small intestine mucosal injuries were found in 41 patients (67.2%) and erosive or ulcerative lesions in 21 patients (34.4%). The injury prevalence was not different with gastroprotective drug treatment. Of 41 patients enrolled, 39 (19 patients in the irsogladine group and 20 in the control group) completed the study. The improvement rate was significantly higher in the irsogladine group (16/19 patients; 84.2%) than in the control group (9/20 patients; 45.0%; P = .02). LIMITATIONS: Asymptomatic lesions, single-institution data, and single-blind setting. CONCLUSION: Irsogladine maleate was effective for reducing NSAID-induced small-intestinal mucosal injury. (University Hospital Medical Information Network Clinical Trials Registry number UMIN000001507.).
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Anti-Inflamatórios não Esteroides/efeitos adversos , Antiulcerosos/uso terapêutico , Mucosa Intestinal/patologia , Intestino Delgado/patologia , Úlcera Péptica/tratamento farmacológico , Triazinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Endoscopia por Cápsula , Feminino , Humanos , Mucosa Intestinal/efeitos dos fármacos , Intestino Delgado/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Úlcera Péptica/induzido quimicamente , Estudos Prospectivos , Método Simples-Cego , Resultado do TratamentoRESUMO
AIM: Spontaneous clearance of serum hepatitis C virus (HCV) RNA in chronic HCV carriers is assumed to be rare especially after development of hepatocellular carcinoma (HCC). We analyzed patients with chronic hepatitis C who spontaneously resolved serum HCV RNA after the treatment for HCC. METHODS: A database search was performed to identify patients with HCC in whom serum HCV RNA was positive before the treatment for HCC and became negative during the clinical course. Those who received interferon therapy were excluded. RESULTS: A total of 1145 patients with HCC who had not received interferon therapy were positive for HCV RNA before the treatment. Among them, five patients (M/F = 4/1) spontaneously resolved viremia during the clinical course, with the incidence rate of at least 0.11%/person-year (95% confidence interval: 0.05%-0.26%). The mean age at the time of negative test for HCV RNA was 77 (range: 52-84). Three and two were infected with HCV genotype 1 and 2, respectively. The mean initial viral load was 9.0 K IU/mL (range: 1.6-31.6). The alanine aminotransferase level decreased to within the normal range in all patients after the clearance of serum HCV RNA. Fibrosis grade of background liver, evaluated according to METAVIR classification, was F1 in 1, F2 in 1, F4 in 2, and unknown in 1. All patients survived more than 7 years after the initial treatment for HCC. CONCLUSION: Spontaneous clearance of serum HCV RNA after HCC development possibly occurs even in elderly patients. The prognosis was good probably due to improved inflammation in the liver.
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AIM: The PNPLA3 rs738409 C>G polymorphism (encoding for I148M) has recently been identified as a susceptibility factor for steatosis-mediated liver damage. We evaluated the influence of this polymorphism on hepatocarcinogenesis in patients with chronic hepatitis C (CHC) virus infection. METHODS: We genotyped the rs738409 single nucleotide polymorphism in 358 hepatitis C-associated hepatocellular carcinoma (HCC) patients and correlated the age at onset of HCC and the interval between hepatitis C virus (HCV) infection and the development of HCC in patients with each genotype. RESULTS: The frequencies of CC, CG and GG genotypes were 27.9% (100/358), 49.2% (176/358) and 22.9% (82/358), respectively, and were in Hardy-Weinberg equilibrium. The median age at onset of HCC for the GG genotype was significantly younger compared to for non-GG genotypes (67.81 vs 69.87 years, P < 0.001), and the median interval between HCV infection and the development of HCC was significantly shorter in patients with the GG genotype (39.96 vs 40.85 years, P = 0.008). PNPLA3 GG genotype was also associated with a higher aspartate aminotransferase level (69.5 vs 59.0 IU/L, P = 0.02), lower prothrombin time (73.0% vs 78.0%, P = 0.008) and a higher prevalence of histological steatosis (40.0% vs. 22.2%, P = 0.01) at the time of HCC onset. CONCLUSION: The PNPLA3 genotype GG may be associated with accelerated hepatocarcinogenesis in CHC patients through increased steatosis in the liver.
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Mitogen-activated protein kinase (MAPK) pathways regulate multiple cellular functions and are highly active in many types of human cancers. Apoptosis signal-regulating kinase 1 (ASK1) is an upstream MAPK involved in apoptosis, inflammation, and carcinogenesis. This study investigated the role of ASK1 in the development of gastric cancer. In human gastric cancer specimens, we observed increased ASK1 expression, compared to nontumor epithelium. Using a chemically induced murine gastric tumorigenesis model, we observed increased tumor ASK1 expression, and ASK1 knockout mice had both fewer and smaller tumors than wild-type (WT) mice. ASK1 siRNA inhibited cell proliferation through the accumulation of cells in G1 phase of the cell cycle, and reduced cyclin D1 expression in gastric cancer cells, whereas these effects were uncommon in other cancer cells. ASK1 overexpression induced the transcription of cyclin D1, through AP-1 activation, and ASK1 levels were regulated by cyclin D1, via the Rb-E2F pathway. Exogenous ASK1 induced cyclin D1 expression, followed by elevated expression of endogenous ASK1. These results indicate an autoregulatory mechanism of ASK1 in the development of gastric cancer. Targeting this positive feedback loop, ASK1 may present a potential therapeutic target for the treatment of advanced gastric cancer.
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Apoptose , Ciclina D1/metabolismo , Regulação Neoplásica da Expressão Gênica , MAP Quinase Quinase Quinase 5/metabolismo , Neoplasias Gástricas/metabolismo , Animais , Ciclo Celular , Linhagem Celular Tumoral , Modelos Animais de Doenças , Fatores de Transcrição E2F/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transdução de SinaisRESUMO
OBJECTIVE: To evaluate the heat effects of radiofrequency ablation (RFA) on normal bone by mechanical testing, MRI, and histology. MATERIALS AND METHODS: The institutional animal care and use committee approved the animal study. Thirty-two adult Japanese white rabbits were included in our study. Bone biopsy needles were inserted from the distal end of the right (RFA side) and the left (control side) femurs using a fluoroscopic guide. A 17-gauge internally cooled RFA electrode with a 2-cm active tip was inserted through the needle to the right femur, and RFA was performed for 12 min using a 200-W generator. Animals were divided into four groups and 8 animals from each group were euthanized on day 1, day 7, day 30, and day 60 after RFA. MRI was performed prior to euthanasia. Three-point bending test was performed to measure flexural strength. Student's t test was used to evaluate for significant differences between RFA and control side for each group. Femurs underwent histological examination by hematoxylin and eosin staining after the bending test. RESULTS: MRI showed a high-intensity rim around the bone on T2WI. Three-point bending test showed no statistically significant differences (P < 0.05) between the RFA and the control side in any of the groups. Histologically, osteocytes of cortical bone showed cell death, but the lamellar structure was preserved in all groups and bone remodeling was observed. CONCLUSION: Heat by RFA did not change normal bone strength within 2 months, despite the heat effects in the cortical bone and cell death.
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Ablação por Cateter/métodos , Fêmur/fisiopatologia , Fêmur/cirurgia , Animais , Módulo de Elasticidade , Fêmur/patologia , Temperatura Alta , Imageamento por Ressonância Magnética , Coelhos , Estresse Mecânico , Resistência à Tração/fisiologiaRESUMO
To avoid retention of the capsule used in capsule endoscopy (CE), the patency capsule (PC), a self-disintegrating sham capsule, is administered prior to CE in patients suspected of small intestinal stenosis. If the PC is excreted intact within 30 hours of ingestion, the patient can undergo CE without retention. However, if the PC is not excreted within 30 hours, its location must be confirmed as in either the small intestine or the colon because of the potential for small intestinal stenosis in the former case. It is often difficult to confirm the location of the PC by abdominal radiograph. We report the case of one patient who did not excrete the PC within 30 hours and for whom it was difficult to distinguish whether the PC was in the small intestine or the colon on abdominal series. Abdominal sonography revealed the PC in the colon and subsequent CE was performed without complication.
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Endoscopia por Cápsula/instrumentação , Colo/diagnóstico por imagem , Corpos Estranhos/diagnóstico por imagem , Idoso , Humanos , Masculino , UltrassonografiaRESUMO
While inhibition of microRNA122 (miR122) function in vivo results in reduced serum cholesterol and fatty acid levels, the molecular mechanisms underlying the link between miR122 function and lipid metabolism remains unclear. Because the expression of SREBP1, a central transcription factor involved in lipid metabolism, is known to be increased by suppressor of cytokine signaling 3 (SOCS3) expression, and because we previously found that SOCS3 expression is regulated by miR122, in this study, we examined the correlation between miR122 status and the expression levels of SOCS3 and SREBP1. SREBP1 expression decreased when SOCS3 expression was reduced by miR122 silencing in vitro. Conversely, SREBP1 expression in miR122-silenced cells was restored by enforced expression of SOCS3. Such correlations were observed in human liver tissues with different miR122 expression levels. These signaling links may explain one of the molecular mechanisms linking inhibition of miR122 function or decreased expression of miR122 to decreased fatty acid and cholesterol levels, in the inhibition of miR122 function, or in pathological status in chronic liver diseases.
Assuntos
Hepatócitos/metabolismo , MicroRNAs/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Regulação para Baixo/fisiologia , Regulação da Expressão Gênica/fisiologia , Inativação Gênica/fisiologia , Humanos , Transdução de Sinais/fisiologia , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Supressão Genética/fisiologia , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/genéticaRESUMO
OBJECTIVES: The combination of computed tomography with hepatic arteriography and arterial portography (CTHA/CTAP) can detect additional hepatocellular carcinoma (HCC) nodules undetected by conventional dynamic CT. METHODS: In this single-center, randomized, open-label, controlled trial, we randomly assigned 280 patients who were diagnosed as having HCC by conventional dynamic CT, and eligible for radiofrequency ablation (RFA), to undergo CTHA/CTAP before treatment, or to the control group. Newly detected HCC nodules by CTHA/CTAP were intended to be ablated completely. The primary end point was recurrence-free survival and the key secondary end point was overall survival. The analysis was conducted on an intention-to-treat basis. Those with nonablated nodules were treated as for recurrence. RESULTS: A total of 75 nodules were newly diagnosed as HCC by CTHA/CTAP in 45 patients. Three patients (one in the CTHA/CTAP group and two in the control group) who refused treatment were excluded from all analyses. The cumulative recurrence-free survival rates at 1, 2, and 3 years were 60.1, 29.0, and 18.9% in the CTHA/CTAP group and 52.2, 29.7, and 23.1% in the control group, respectively (P=0.66 by log-rank test; hazard ratio, 0.94 for CTHA/CTAP vs. control; 95% confidence interval (CI), 0.73-1.22). The cumulative overall survival rates at 3 and 5 years were 79.7 and 56.4% in the CTHA/CTAP group and 86.8 and 60.1% in the control group, respectively (P=0.50; hazard ratio, 1.15, 95% CI, 0.77-1.71). CONCLUSIONS: CTHA/CTAP may detect recurrent lesions earlier. However, CTHA/CTAP before RFA did not improve cumulative recurrence-free survival or overall survival.