Risk Factors for Dropout From the Liver Transplant Waiting List of Hepatocellular Carcinoma Patients Under Locoregional Treatment.

BACKGROUND: In new organ allocation policy, patients with hepatocellular carcinoma (HCC) experience a 6-month delay in being granted Model for End-Stage Liver Disease exception points. However, it may not be fair for patients at risk of early progression of HCC. METHODS: All patients who were diagnosed as United Network for Organ Sharing (UNOS) stage 1 or 2 of HCC between January 2004 and December 2012 were included. Patients who received surgical resection or liver transplant (LT) as a primary treatment and who did not receive any treatment for HCC were excluded. Patients with baseline Model for End-Stage Liver Disease score ≥22 were also excluded because they have a higher chance of receiving LT. Patients who developed extrahepatic progression within 1 year were considered as high-risk for early recurrence after LT. RESULTS: A total of 586 patients were included. Mean (SD) age was 59.9 (10.3) years and 409 patients (69.8%) were men. The cumulative incidence of estimated dropout was 8.9% at 6 months; size of the maximum nodule (≥3 cm) and nonachievement of complete response were independent factors. Extrahepatic progression developed in 16 patients (2.7%) within 1 year; size of the maximum nodule (4 cm) and alpha-fetoprotein level (>100 ng/mL) were independent predictors. CONCLUSIONS: The estimated dropout rate from the waiting list within 6 months was 8.9%. Advantage points might be needed for patients with maximum nodule size ≥3 cm or those with noncomplete response. However, in patients with maximum nodule size ≥4 cm or alpha-fetoprotein level >100 ng/mL, caution is needed.

Switching to tenofovir vs continuing entecavir for hepatitis B virus with partial virologic response to entecavir: a randomized controlled trial.

Entecavir 0.5 mg (ETV) is widely used among treatment-naïve chronic hepatitis B (CHB) patients. However, 10%-30% of patients show partial virologic response (PVR) to the drug. If the hepatitis B virus (HBV) continues to replicate, the underlying liver disease may progress. Herein, we compared the efficacy of switching to tenofovir disoproxil fumarate (TDF) with that of continuing ETV in CHB patients with PVR to ETV. This was an open-label randomized controlled trial including CHB patients who had been receiving 0.5 mg of ETV for >12 months, but who still had detectable HBV DNA levels of >60 IU/mL without known resistance to ETV. Sixty patients were enrolled and 45 qualified for the study: Twenty-two patients were randomly assigned into the TDF group and 23 into the ETV group. After 12 months of treatment, the virologic response rate (HBV DNA <20 IU/mL) was significantly higher in the TDF group than in the ETV group, as measured using per-protocol analysis (55% vs 20%; P = .022) and intention-to-treat analysis (50% vs 17.4%; P = .020). The reduction in HBV DNA was greater (-1.13 vs -0.67 log10 IU/mL; P = .024), and the mean HBV DNA level was lower (1.54 vs 2.01 log10 IU/mL; P = .011) in the TDF group than in the ETV group. In conclusion, to achieve optimal response in CHB patients with PVR to ETV, switching to TDF would be a better strategy than continuing ETV. Appropriate modification of therapy would further improve the outcome of chronic HBV infection.

Abdominal adiposity intensifies the negative effects of ambient air pollution on lung function in Korean men.

BACKGROUND: Some studies have provided the possibility that adipose tissue may mediate air pollution-induced lung dysfunction. Studies using quantified fat mass data are needed to understand the biological mechanisms between adipocyte and air pollution in lung function. We aimed to investigate whether abdominal adiposity measured by computed tomography (CT) modifies the effects of air pollution on lung function in Korean men. METHODS: A total of 1876 men who visited one of two health checkup centers were recruited for this study. Adiposity traits such as visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and total adipose tissue (TAT) areas were measured by CT. We used the annual mean concentrations of ambient air pollutants including nitrogen dioxide (NO2) and particulate matter with an aerodynamic diameter ⩽10 µm (PM10). RESULTS: Interquartile range (IQR) increase in annual mean concentration of NO2 was significantly associated with a 2.5% lower forced expiratory volume in 1 s (FEV1) and 2.9% lower forced vital capacity (FVC) (both P<0.05). The decrease in lung function was more strongly associated with adiposity traits than with body mass index. In a stratified analysis of adiposity, compared with subjects with low-VAT area (VAT⩽200 cm2), those with high-VAT area (VAT>200 cm2) showed a rapid decrease in FEV1 with each IQR increase in PM10 (ß=-0.0812; 95% confidence interval (CI) =-0.1590, -0.0035) and NO2 (ß=-0.0979; 95% CI=-0.1611, -0.0346). In the high-VAT group, each IQR increase in NO2 content was significantly associated with a 10.6% decrease (ß=-0.1056; 95% CI=-0.1770, -0.0343) in FVC. SAT and TAT areas showed similar patterns. CONCLUSIONS: We report the first finding that abdominal adiposity intensifies the inverse relationship between air pollution and lung function.

Intracellular annexin A2 regulates NF-κB signaling by binding to the p50 subunit: implications for gemcitabine resistance in pancreatic cancer.

Annexin A2 (ANXA2) expression is highly upregulated in many types of cancer. Although cell surface localization of ANXA2 has been reported to have a critical role in the progression and metastasis of a variety of tumors, including pancreatic cancer, the biological role of intracellular ANXA2 is not fully understood. Herein the role of intracellular ANXA2 was investigated in a pancreatic cancer cell line. We first determined whether ANXA2 is involved in NF-κB signaling pathways. ANXA2 bound to the p50 subunit of NF-κB in a calcium-independent manner, and the ANXA2-p50 complex translocated into the nucleus. Furthermore, ANXA2 increased the transcriptional activity of NF-κB in both the resting and activated states and upregulated the transcription of several target genes downstream of NF-κB, including that encoding interleukin (IL)-6, which contributes to anti-apoptotic signaling. In Mia-Paca2 cells, we determined the effects of wild-type ANXA2 and an ANXA2 mutant, Y23A, which suppresses the cell surface localization, on upregulation of NF-κB transcriptional activity and secretion of IL-6. Both wild-type and Y23A ANXA2 induced anti-apoptotic effects in response to treatment with tumor necrosis factor-α or gemcitabine. Based on these results, we suggest that ANXA2 mediates resistance to gemcitabine by directly increasing the activity of NF-κB. Collectively, these data may provide additional information about the biological role of ANXA2 in pancreatic cancer and suggest that ANXA2 is a potential biomarker for the drug resistance phenotype and a candidate therapeutic target for the treatment of pancreatic cancer.

Curcumin decreases oleic acid-induced lipid accumulation via AMPK phosphorylation in hepatocarcinoma cells.

BACKGROUND AND OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) is one of the most common metabolic syndromes and is characterized by the accumulation of hepatic triglycerides (TG), which result from an imbalance between uptake, synthesis, export, and oxidation of fatty acids. Curcumin is a polyphenol derived from the herbal remedy and dietary spice turmeric, was found to prevent obesity and diabetes in mouse models. However, a hypolipidemic effect of curcumin in oleic acid- induced hepatocarcinoma cells has not been reported. In this study, we examined the effect of curcumin on reducing lipid accumulation in hepatic cells. MATERIALS AND METHODS: Hepatocytes were treated with oleic acid (OA) containing with or without curcumin to observe the lipid accumulation by Oil Red O stain. We also tested the effects of curcumin on triglycerides (TG) and total cholesterol (TC) in HepG2 cells. Western blot and reverse transcription polymerase chain reaction (RT-PCR) was used to measure sterol regulatory element binding proteins-1 (SREBP-1), fatty acid synthase (FAS), peroxisome proliferator-activated receptor (PPAR)-α, and adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) expression. RESULTS: Curcumin suppressed OA-induced lipid accumulation and TG and TC levels. Also, curcumin decreased hepatic lipogenesis such as SREBP-1, and FAS. Besides, we also found out the antioxidative effect of curcumin by increasing the expression of PPARα. Curcumin increased AMPK phosphorylation in hepatocytes. CONCLUSIONS: These results indicated that curcumin has the same ability to activate AMPK and then reduce SREBP-1, and FAS expression, finally leading to inhibit hepatic lipogenesis and hepatic antioxidative ability. In this report, we found curcumin exerted a regulatory effect on lipid accumulation by decreasing lipogenesis in hepatocyte. Therefore, curcumin extract may be active in the prevention of fatty liver.

Anti-inflammatory effects of Hylomecon hylomeconoides in RAW 264.7 cells.

BACKGROUND AND OBJECTIVES: Papaveraceae serve as a rich source of various alkaloids which have anti-inflammatory effect. MATERIALS AND METHODS: In this study, we investigated the effect of Hylomecon hylomeconoides ethanol extract (HHE) on lipopolysaccharide (LPS)-induced NO and interleukin-6 (IL-6) production in RAW 264.7 cells. RESULTS: HHE inhibited LPS-induced NO and IL-6 production. Moreover, HHE suppressed the phosphorylation of ERK1/2 and p38 in LPS-induced RAW 264.7 in a dose-dependent manner. Furthermore, major constituents, dihydrosanguinarine and 6-methoxydihydrosanguinarine, of the chloroform-soluble extract were analyzed. CONCLUSIONS: Taken together, the results of this study indicate that the anti-inflammatory effects of HHE may occur via the inhibition of NO and IL-6 expression through the down-regulation of MAP kinase (ERK1/2, p38) phosphorylation in RAW 264.7 cells.

The effect of the respiratory cycle on liver stiffness values as measured by transient elastography.

The findings of several studies suggest that liver stiffness values can be affected by the degree of intrahepatic congestion respiration influence intrahepatic blood volume and may affect liver stiffness. We evaluated the influence of respiration on liver stiffness. Transient elastography (TE) was performed at the end of inspiration and at the end of expiration in patients with chronic liver disease. The median values obtained during the inspiration set and during the expiration set were defined as inspiratory and expiratory liver stiffness, respectively. A total of 123 patients with chronic liver disease were enrolled (mean age 49years; 64.2% men). Liver cirrhosis coexisted in 29 patients (23.6%). Expiratory liver stiffness was significantly higher than inspiratory liver stiffness (8.7 vs 7.9kPa, P=0.001), while the expiratory interquartile range/median ratio (IQR ratio) did not differ from the inspiratory IQR ratio. Expiratory liver stiffness was significantly higher than inspiratory liver stiffness in 49 (39.8%) patients (HE group), expiratory liver stiffness was significantly lower than inspiratory stiffness in 15 (12.2%) patients, and there was no difference in 59 (48.0%) patients. Liver cirrhosis was more frequent in those who had a lower liver stiffness reading in expiration, and only the absence of liver cirrhosis was significantly associated with a higher reading in expiration in multivariate analysis. In conclusion, liver stiffness was significantly elevated during expiration especially in patients without liver cirrhosis. The effect of respiration should be kept in mind during TE readings.

Virologic and biochemical responses to clevudine in patients with chronic HBV infection-associated cirrhosis: data at week 48.

Clevudine shows high rates of virologic and biochemical responses in patients with chronic hepatitis B. However, the efficacy and safety of clevudine in patients with cirrhosis are unknown. The aims of this study were to evaluate the safety and to assess the virologic and the biochemical responses to clevudine in patients with cirrhosis with chronic hepatitis B virus (HBV) infection. We reviewed data from treatment-naïve patients with chronic hepatitis B with and without cirrhosis who started clevudine between April 2007 and March 2008 (n = 52, hepatitis B without cirrhosis n = 21 and chronic hepatitis B with cirrhosis n = 31) at Korea University Ansan/Guro Hospital. All of the patients were treated for more than 48 weeks. The mean age was older in the patients with cirrhosis. Baseline HBV DNA levels were 6.9 and 7.78 log copies/mL (P = 0.042), and alanine aminotransferase (ALT) levels were 104.9 and 147.4 IU/L (P = 0.204), for those with and without cirrhosis, respectively. Virologic response (HBV DNA <1000 copies/mL) (87.1%vs 71.4%, P = 0.24) and biochemical response (83.9%vs 80.9%, P = 0.99) at week 48 were not significantly different between the two groups. Early virologic response at week 12 was even higher in the patients with cirrhosis (61.3%vs 28.6%, P = 0.026). Neither ALT flare nor newly onset hepatic decompensation was found in the patients with cirrhosis, whereas ALT flare was transiently observed in 14.3% of the chronic hepatitis group. In conclusion, although clevudine may produce a transient elevation of ALT during the early treatment period, such findings were not observed in patients with cirrhosis and the virologic and biochemical responses of the groups were comparable.

Diagnosis of Pierce's disease using biomarkers specific to Xylella fastidiosa rRNA and Vitis vinifera gene expression.

Pierce's disease (PD), caused by Xylella fastidiosa, represents one of the most damaging diseases of cultivated grape. Management of PD in the vineyard often relies on the removal of infected individuals, which otherwise serve as a source of inoculum for nearby healthy vines. Effective implementation of such control measures requires early diagnosis, which is complicated by the fact that infected vines often harbor high titers of the pathogen in advance of visual symptom development. Here, we report a biomarker system that simultaneously monitors Xylella-induced plant transcripts as well as Xylella ribosomal (r)RNA. Plant biomarker genes were derived from a combination of in silico analysis of grape expressed sequence tags and validation by means of reverse-transcriptase polymerase chain reaction (RT-PCR). Four genes upregulated upon PD infection were individually multiplexed with an X. fastidiosa marker rRNA and scored using either real-time RT-PCR or gel-based conventional RT-PCR techniques. The system was sufficiently sensitive to detect both host gene transcript and pathogen rRNA in asymptomatic infected plants. Moreover, these plant biomarker genes were not induced by water deficit, which is a component of PD development. Such biomarker genes could have utility for disease control by aiding early detection and as a screening tool in breeding programs.

Factors that affect the diagnostic accuracy of liver fibrosis measurement by Fibroscan in patients with chronic hepatitis B.

BACKGROUND: Interquartile range/median value (IQR/M) of liver stiffness measurement (LSM) is a factor in chronic hepatitis C (CHC) leading to over estimation of fibrosis by Fibroscan. AIM: To investigate factors that affect the accuracy of LSM in chronic hepatitis B (CHB). METHODS: One hundred and ninety-nine patients were enrolled. Only procedures yielding > or =10 valid measurements were considered reliable. Liver fibrosis was evaluated using the Batts and Ludwig system. Liver biopsy (LB) specimens <15 mm were considered ineligible. RESULTS: The mean age (142 men and 57 women) was 40.1 years. A significant discordance (discordance of at least two stages between LB and LSM) was identified in 38 (19.1%) and 47 (23.6%) patients respectively, according to Marcellin et al. and Chan et al.'s cutoff values. In multivariate analyses, BMI and fibrosis stage (F0-2 vs. F3-4) were identified as independent predictors for significant discordance (P = 0.040; hazard ratio [HR], 1.126; 95% confidence interval [CI], 1.005-1.261 and P = 0.036; HR, 0.450; 95% CI, 0.213-0.949 respectively) with Marcellin et al.'s cutoffs, whereas fibrosis stage was the only independent predictor (P = 0.004; HR, 0.300; 95% CI, 0.131-0.685) with Chan's cutoffs. CONCLUSIONS: Success rate and IQR/M were not predictive factors of the accuracy for diagnosing liver fibrosis by Fibroscan in CHB. Fibrosis stage (F0-2) was the only factor to predict significant discordance between LB and LSM.