Year of publication
- Medizin (38) (remove)
- High prevalence of anti-HCV antibodies in two metropolitan emergency departments in Germany: a prospective screening analysis of 28,809 patients (2012)
- Background and Aims: The prevalence of hepatitis C virus (HCV) antibodies in Germany has been estimated to be in the range of 0.4–0.63%. Screening for HCV is recommended in patients with elevated ALT levels or significant risk factors for HCV transmission only. However, 15–30% of patients report no risk factors and ALT levels can be normal in up to 20–30% of patients with chronic HCV infection. The aim of this study was to assess the HCV seroprevalence in patients visiting two tertiary care emergency departments in Berlin and Frankfurt, respectively. Methods: Between May 2008 and March 2010, a total of 28,809 consecutive patients were screened for the presence of anti-HCV antibodies. Anti-HCV positive sera were subsequently tested for HCV-RNA. Results: The overall HCV seroprevalence was 2.6% (95% CI: 2.4–2.8; 2.4% in Berlin and 3.5% in Frankfurt). HCV-RNA was detectable in 68% of anti-HCV positive cases. Thus, the prevalence of chronic HCV infection in the overall study population was 1.6% (95% CI 1.5–1.8). The most commonly reported risk factor was former/current injection drug use (IDU; 31.2%) and those with IDU as the main risk factor were significantly younger than patients without IDU (p<0.001) and the male-to-female ratio was 72% (121 vs. 46 patients; p<0.001). Finally, 18.8% of contacted HCV-RNA positive patients had not been diagnosed previously. Conclusions: The HCV seroprevalence was more than four times higher compared to current estimates and almost one fifth of contacted HCV-RNA positive patients had not been diagnosed previously.
- A genetic validation study reveals a role of vitamin D metabolism in the response to interferon-alfa-based therapy of chronic hepatitis C (2012)
- Background: To perform a comprehensive study on the relationship between vitamin D metabolism and the response to interferon-α-based therapy of chronic hepatitis C. Methodology/Principal Findings: Associations between a functionally relevant polymorphism in the gene encoding the vitamin D 1α-hydroxylase (CYP27B1-1260 rs10877012) and the response to treatment with pegylated interferon-α (PEG-IFN-α) and ribavirin were determined in 701 patients with chronic hepatitis C. In addition, associations between serum concentrations of 25-hydroxyvitamin D3 (25[OH]D3) and treatment outcome were analysed. CYP27B1-1260 rs10877012 was found to be an independent predictor of sustained virologic response (SVR) in patients with poor-response IL28B genotypes (15% difference in SVR for rs10877012 genotype AA vs. CC, p = 0.02, OR = 1.52, 95% CI = 1.061–2.188), but not in patients with favourable IL28B genotype. Patients with chronic hepatitis C showed a high prevalence of vitamin D insufficiency (25[OH]D3<20 ng/mL) during all seasons, but 25(OH)D3 serum levels were not associated with treatment outcome. Conclusions/Significance: Our study suggests a role of bioactive vitamin D (1,25[OH]2D3, calcitriol) in the response to treatment of chronic hepatitis C. However, serum concentration of the calcitriol precursor 25(OH)D3 is not a suitable predictor of treatment outcome.
- Acoustic radiation force impulse imaging for differentiation of thyroid nodules (2012)
- Background: Acoustic Radiation Force Impulse (ARFI)-Imaging is an ultrasound-based elastography method enabling quantitative measurement of tissue stiffness. The aim of the present study was to evaluate sensitivity and specificity of ARFIimaging for differentiation of thyroid nodules and to compare it to the well evaluated qualitative real-time elastography (RTE). Methods: ARFI-imaging involves the mechanical excitation of tissue using acoustic pulses to generate localized displacements resulting in shear-wave propagation which is tracked using correlation-based methods and recorded in m/s. Inclusion criteria were: nodules $5 mm, and cytological/histological assessment. All patients received conventional ultrasound, real-time elastography (RTE) and ARFI-imaging. Results: One-hundred-fifty-eight nodules in 138 patients were available for analysis. One-hundred-thirty-seven nodules were benign on cytology/histology, and twenty-one nodules were malignant. The median velocity of ARFI-imaging in the healthy thyroid tissue, as well as in benign and malignant thyroid nodules was 1.76 m/s, 1.90 m/s, and 2.69 m/s, respectively. While no significant difference in median velocity was found between healthy thyroid tissue and benign thyroid nodules, a significant difference was found between malignant thyroid nodules on the one hand and healthy thyroid tissue (p = 0.0019) or benign thyroid nodules (p = 0.0039) on the other hand. No significant difference of diagnostic accuracy for the diagnosis of malignant thyroid nodules was found between RTE and ARFI-imaging (0.74 vs. 0.69, p = 0.54). The combination of RTE with ARFI did not improve diagnostic accuracy. Conclusions: ARFI can be used as an additional tool in the diagnostic work up of thyroid nodules with high negative predictive value and comparable results to RTE.
- Baseline MELD score predicts hepatic decompensation during antiviral therapy in patients with chronic hepatitis C and advanced cirrhosis (2013)
- Background and Aims: In patients with advanced liver cirrhosis due to chronic hepatitis C virus (HCV) infection antiviral therapy with peginterferon and ribavirin is feasible in selected cases only due to potentially life-threatening side effects. However, predictive factors associated with hepatic decompensation during antiviral therapy are poorly defined. Methods: In a retrospective cohort study, 68 patients with HCV-associated liver cirrhosis (mean MELD score 9.18±2.72) were treated with peginterferon and ribavirin. Clinical events indicating hepatic decompensation (onset of ascites, hepatic encephalopathy, upper gastrointestinal bleeding, hospitalization) as well as laboratory data were recorded at baseline and during a follow up period of 72 weeks after initiation of antiviral therapy. To monitor long term sequelae of end stage liver disease an extended follow up for HCC development, transplantation and death was applied (240weeks, ±SD 136weeks). Results: Eighteen patients (26.5%) achieved a sustained virologic response. During the observational period a hepatic decompensation was observed in 36.8%. Patients with hepatic decompensation had higher MELD scores (10.84 vs. 8.23, p<0.001) and higher mean bilirubin levels (26.74 vs. 14.63 µmol/l, p<0.001), as well as lower serum albumin levels (38.2 vs. 41.1 g/l, p = 0.015), mean platelets (102.64 vs. 138.95/nl, p = 0.014) and mean leukocytes (4.02 vs. 5.68/nl, p = 0.002) at baseline as compared to those without decompensation. In the multivariate analysis the MELD score remained independently associated with hepatic decompensation (OR 1.56, 1.18–2.07; p = 0.002). When the patients were grouped according to their baseline MELD scores, hepatic decompensation occurred in 22%, 59%, and 83% of patients with MELD scores of 6–9, 10–13, and >14, respectively. Baseline MELD score was significantly associated with the risk for transplantation/death (p<0.001). Conclusions: Our data suggest that the baseline MELD score predicts the risk of hepatic decompensation during antiviral therapy and thus contributes to decision making when antiviral therapy is discussed in HCV patients with advanced liver cirrhosis.
- Differential stability of cell-free circulating microRNAs : implications for their utilization as biomarkers (2013)
- Background: MicroRNAs circulating in the blood, stabilized by complexation with proteins and/or additionally by encapsulation in lipid vesicles, are currently being evaluated as biomarkers. The consequences of their differential association with lipids/vesicles for their stability and use as biomarkers are largely unexplored and are subject of the present study. Methods: The levels of a set of selected microRNAs were determined by quantitative reverse-transcription PCR after extraction from sera or vesicle- and non-vesicle fractions prepared from sera. The stability of these microRNAs after incubation with RNase A or RNase inhibitor, an inhibitor of RNase A family enzymes was studied. Results: The levels of microRNA-1 and microRNA-122, but not those of microRNA-16, microRNA-21 and microRNA-142-3p, declined significantly during a 5-h incubation of the sera. RNase inhibitor prevented the loss of microRNAs in serum as well as the degradation of microRNA-122, a microRNA not expressed in blood cells, in whole blood. Stabilization of microRNA-122 was also achieved by hemolysis. Prolonged incubation of the sera led to enrichment of vesicle-associated relative to non-vesicle-associated microRNAs. Vesicle-associated microRNAs were more resistant to RNase A treatment than the respective microRNAs not associated with vesicles. Conclusions: Serum microRNAs showed differential stability upon prolonged incubation. RNase inhibitor might be useful to robustly preserve the pattern of cell-free circulating microRNAs. In the case of microRNAs not expressed in blood cells this can also be achieved by hemolysis. Vesicle-associated microRNAs appeared to be more stable than those not associated with vesicles, which might be useful to disclose additional biomarker properties of miRNAs.
- SEMS vs cSEMS in duodenal and small bowel obstruction: High risk of migration in the covered stent group (2013)
- AIM: To compare clinical success and complications of uncovered self-expanding metal stents (SEMS) vs covered SEMS (cSEMS) in obstruction of the small bowel. METHODS: Technical success, complications and outcome of endoscopic SEMS or cSEMS placement in tumor related obstruction of the duodenum or jejunum were retrospectively assessed. The primary end points were rates of stent migration and overgrowth. Secondary end points were the effect of concomitant biliary drainage on migration rate and overall survival. The data was analyzed according to the Strengthening the Reporting of Observational Studies in Epidemiology guidelines. RESULTS: Thirty-two SEMS were implanted in 20 patients. In all patients, endoscopic stent implantation was successful. Stent migration was observed in 9 of 16 cSEMS (56%) in comparison to 0/16 SEMS (0%) implantations (P = 0.002). Stent overgrowth did not significantly differ between the two stent types (SEMS: 3/16, 19%; cSEMS: 2/16, 13%). One cSEMS dislodged and had to be recovered from the jejunum by way of laparotomy. Time until migration between SEMS and cSEMS in patients with and without concomitant biliary stents did not significantly differ (HR = 1.530, 95%CI 0.731-6.306; P = 0.556). The mean follow-up was 57 ± 71 d (range: 1-275 d). CONCLUSION: SEMS and cSEMS placement is safe in small bowel tumor obstruction. However, cSEMS is accompanied with a high rate of migration in comparison to uncovered SEMS.
- Interobserver agreement of Thyroid Imaging Reporting and Data System (TIRADS) and strain elastography for the assessment of thyroid nodules (2013)
- Background: Thyroid Imaging Reporting and Data System (TIRADS) was developed to improve patient management and cost-effectiveness by avoiding unnecessary fine needle aspiration biopsy (FNAB) in patients with thyroid nodules. However, its clinical use is still very limited. Strain elastography (SE) enables the determination of tissue elasticity and has shown promising results for the differentiation of thyroid nodules. Methods: The aim of the present study was to evaluate the interobserver agreement (IA) of TIRADS developed by Horvath et al. and SE. Three blinded observers independently scored stored images of TIRADS and SE in 114 thyroid nodules (114 patients). Cytology and/or histology was available for all benign (n = 99) and histology for all malignant nodules (n = 15). Results: The IA between the 3 observers was only fair for TIRADS categories 2–5 (Coheńs kappa = 0.27,p = 0.000001) and TIRADS categories 2/3 versus 4/5 (ck = 0.25,p = 0.0020). The IA was substantial for SE scores 1–4 (ck = 0.66,p<0.000001) and very good for SE scores 1/2 versus 3/4 (ck = 0.81,p<0.000001). 92–100% of patients with TIRADS-2 had benign lesions, while 28–42% with TIRADS-5 had malignant cytology/histology. The negative-predictive-value (NPV) was 92–100% for TIRADS using TIRADS-categories 4&5 and 96–98% for SE using score ES-3&4 for the diagnosis of malignancy, respectively. However, only 11–42% of nodules were in TIRADS-categories 2&3, as compared to 58–60% with ES-1&2. Conclusions: IA of TIRADS developed by Horvath et al. is only fair. TIRADS and SE have high NPV for excluding malignancy in the diagnostic work-up of thyroid nodules.
- Reduced migration of MLH1 deficient colon cancer cells depends on SPTAN1 (2014)
- Introduction: Defects in the DNA mismatch repair (MMR) protein MLH1 are frequently observed in sporadic and hereditary colorectal cancers (CRC). Affected tumors generate much less metastatic potential than the MLH1 proficient forms. Although MLH1 has been shown to be not only involved in postreplicative MMR but also in several MMR independent processes like cytoskeletal organization, the connection between MLH1 and metastasis remains unclear. We recently identified non-erythroid spectrin αII (SPTAN1), a scaffolding protein involved in cell adhesion and motility, to interact with MLH1. In the current study, the interaction of MLH1 and SPTAN1 and its potential consequences for CRC metastasis was evaluated. Methods: Nine cancer cell lines as well as fresh and paraffin embedded colon cancer tissue from 12 patients were used in gene expression studies of SPTAN1 and MLH1. Co-expression of SPTAN1 and MLH1 was analyzed by siRNA knock down of MLH1 in HeLa, HEK293, MLH1 positive HCT116, SW480 and LoVo cells. Effects on cellular motility were determined in MLH1 deficient HCT116 and MLH1 deficient HEK293T compared to their MLH1 proficient sister cells, respectively. Results: MLH1 deficiency is clearly associated with SPTAN1 reduction. Moreover, siRNA knock down of MLH1 decreased the mRNA level of SPTAN1 in HeLa, HEK293 as well as in MLH1 positive HCT116 cells, which indicates a co-expression of SPTAN1 by MLH1. In addition, cellular motility of MLH1 deficient HCT116 and MLH1 deficient HEK293T cells was impaired compared to the MLH1 proficient sister clones. Consequently, overexpression of SPTAN1 increased migration of MLH1 deficient cells while knock down of SPTAN1 decreased cellular mobility of MLH1 proficient cells, indicating SPTAN1-dependent migration ability. Conclusions: These data suggest that SPTAN1 levels decreased in concordance with MLH1 reduction and impaired cellular mobility in MLH1 deficient colon cancer cells. Therefore, aggressiveness of MLH1-positive CRC might be related to SPTAN1.
- Promoter methylation of MLH1, PMS2, MSH2 and p16 is a phenomenon of advanced-stage HCCs (2014)
- Epigenetic silencing of tumour suppressor genes has been observed in various cancers. Looking at hepatocellular carcinoma (HCC) specific protein silencing was previously demonstrated to be associated with the Hepatitis C virus (HCV). However, the proposed HCV dependent promoter methylation of DNA mismatch repair (MMR) genes and thereby enhanced progression of hepatocarcinogenesis has been the subject of controversial discussion. We investigated promoter methylation pattern of the MMR genes MLH1, MSH2 and PMS2 as well as the cyclin-dependent kinase inhibitor 2A gene (p16) in 61 well characterized patients with HCCs associated with HCV, Hepatitis B virus infection or alcoholic liver disease. DNA was isolated from formalin-fixed, paraffin-embedded tumour and non-tumour adjacent tissue and analysed by methylation-specific PCR. Moreover, microsatellite analysis was performed in tissues showing methylation in MMR gene promoters. Our data demonstrated that promoter methylation of MLH1, MSH2, PMS2 and p16 is present among all considered HCCs. Hereby, promoter silencing was detectable more frequently in advanced-stage HCCs than in low-stage ones. However, there was no significant correlation between aberrant DNA methylation of MMR genes or p16 and HCV infection in related HCC specimens. In summary, we show that promoter methylation of essential MMR genes and p16 is detectable in HCCs most dominantly in pT3 stage tumour cases. Since loss of MMR proteins was previously described to be not only responsible for tumour development but also for chemotherapy resistance, the knowledge of mechanisms jointly responsible for HCC progression might enable significant improvement of individual HCC therapy in the future.
- Vitamin D levels vary during antiviral treatment but are unable to predict treatment outcome in HCV genotype 1 infected patients (2014)
- Background: Different parameters have been determined for prediction of treatment outcome in hepatitis c virus genotype 1 infected patients undergoing pegylated interferon, ribavirin combination therapy. Results on the importance of vitamin D levels are conflicting. In the present study, a comprehensive analysis of vitamin D levels before and during therapy together with single nucleotide polymorphisms involved in vitamin D metabolism in the context of other known treatment predictors has been performed. Methods: In a well characterized prospective cohort of 398 genotype 1 infected patients treated with pegylated interferon-α and ribavirin for 24–72 weeks (INDIV-2 study) 25-OH-vitamin D levels and different single nucleotide polymorphisms were analyzed together with known biochemical parameters for a correlation with virologic treatment outcome. Results: Fluctuations of more than 5 (10) ng/ml in 25-OH-vitamin D-levels have been observed in 66 (39) % of patients during the course of antiviral therapy and neither pretreatment nor under treatment 25-OH-vitamin D-levels were associated with treatment outcome. The DHCR7-TT-polymorphism within the 7-dehydrocholesterol-reductase showed a significant association (P = 0.031) to sustained viral response in univariate analysis. Among numerous further parameters analyzed we found that age (OR = 1.028, CI = 1.002–1.056, P = 0.035), cholesterol (OR = 0.983, CI = 0.975–0.991, P<0.001), ferritin (OR = 1.002, CI = 1.000–1.004, P = 0.033), gGT (OR = 1.467, CI = 1.073–2.006, P = 0.016) and IL28B-genotype (OR = 2.442, CI = 1.271–4.695, P = 0.007) constituted the strongest predictors of treatment response. Conclusions: While 25-OH-vitamin D-levels levels show considerable variations during the long-lasting course of antiviral therapy they do not show any significant association to treatment outcome in genotype 1 infected patients.