Metzger J.,Mosaiques Diagnostics GmbH |
Negm A.A.,Hannover Medical School |
Plentz R.R.,University Hospital of Tuebingen |
Weismuller T.J.,Hannover Medical School |
And 8 more authors.
Gut | Year: 2013
Background: Diagnosis and curative treatment of cholangiocarcinoma (CC) often comes too late due to the lack of reliable tumour markers especially in patients with primary sclerosing cholangitis (PSC). The authors recently introduced bile proteomic analysis for CC diagnosis. Nevertheless, bile collection depends on invasive endoscopic retrograde cholangiography. The authors therefore evaluated urine proteomic analysis for non-invasive CC diagnosis. Methods: Using capillary electrophoresis mass spectrometry the authors established a CC-specific peptide marker model based on the distribution of 42 peptides in 14 CC, 13 PSC and 14 benign biliary disorder (BBD) patients. Results: In cross-sectional validation of 123 patients, the urine peptide marker model correctly classified 35 of 42 CC patients and 64 of 81 PSC and BBD patients with an area under the curve value of 0.87 (95% CI 0.80 to 0.92, p=0.0001, 83% sensitivity, 79% specificity). Evaluation of 101 normal controls resulted in 86% specificity. All 10 patients with CC on top of PSC were correctly classified. The majority of sequence-identified peptides are fragments of interstitial collagens with some of them also detected in blood indicating their extra-renal origin. Immunostaining of liver sections for matrix metallopeptidase 1 indicated increased activity of the interstitial collagenase in liver epithelial cells of CC patients. Conclusion: The urine test differentiates CC from PSC and other BBD and may provide a new diagnostic noninvasive tool for PSC surveillance and CC detection.
Lau S.,TU Ilmenau |
Lau S.,Jena University Hospital |
Lau S.,University of Melbourne |
Flemming L.,Jena University Hospital |
And 3 more authors.
Clinical Neurophysiology | Year: 2014
Objective: Magnetoencephalography (MEG) signals had previously been hypothesized to have negligible sensitivity to skull defects. The objective is to experimentally investigate the influence of conducting skull defects on MEG and EEG signals. Methods: A miniaturized electric dipole was implanted in vivo into rabbit brains. Simultaneous recording using 64-channel EEG and 16-channel MEG was conducted, first above the intact skull and then above a skull defect. Skull defects were filled with agar gels, which had been formulated to have tissue-like homogeneous conductivities. The dipole was moved beneath the skull defects, and measurements were taken at regularly spaced points. Results: The EEG signal amplitude increased 2-10 times, whereas the MEG signal amplitude reduced by as much as 20%. The EEG signal amplitude deviated more when the source was under the edge of the defect, whereas the MEG signal amplitude deviated more when the source was central under the defect. The change in MEG field-map topography (relative difference measure, RDM*= 0.15) was geometrically related to the skull defect edge. Conclusions: MEG and EEG signals can be substantially affected by skull defects. Significance: MEG source modeling requires realistic volume conductor head models that incorporate skull defects. © 2013 International Federation of Clinical Neurophysiology.
Nagel S.,Hospital Martha Maria |
Kellner O.,Municipal Hospital |
Engel-Riedel W.,Hospital of Lung Diseases |
Guetz S.,Robert Koch Hospital |
And 3 more authors.
Clinical Lung Cancer | Year: 2011
Darbepoetin alfa, an erythropoiesis-stimulating agent (ESA), is used in cancer patients as a supportive care for anemia. For small-cell lung cancer (SCLC), several studies have shown that the administration of ESAs does not affect survival but decreases the need for blood transfusions and improves the quality of life (QOL) of patients receiving chemotherapy. The present randomized phase II study assessed the feasibility, efficacy, and safety of the administration of darbepoetin alfa to patients with SCLC receiving dose-dense (every 2 weeks) standard chemotherapy consisting of carboplatin plus etoposide, pegfilgrastim prophylactically. Seventy-four chemotherapy-naive patients with limited or extensive SCLC received combination chemotherapy for 6 cycles, and half of the patients additionally received darbepoetin to achieve a target hemoglobin concentration of 12-13 g/dL. The primary study outcome, progression-free survival, showed no difference between the 2 arms of the study. Among the secondary endpoints, objective response was similar in the presence and absence of darbepoetin (best response rates = 75.0% vs. 77.8%). Likewise, 1-year survival rates were not different between the 2 treatment arms (40.1% vs. 45.9%). There were no significant differences in grade 3/4 toxicities. As expected, the need for blood transfusions differed significantly: 19.4% of patients in the darbepoetin arm received transfusions versus 38.9% in the control arm. Analysis of European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-C30) scales at different time points showed that the darbepoetin group's QOL was significantly better for certain readouts and never significantly worse than that of the control group. Thus, the combination of darbepoetin alfa with dose-dense carboplatin plus etoposide was feasible and well tolerated. Addition of darbepoetin alfa to chemotherapy lowered the need for blood transfusions and did not affect measures of survival and objective response.
Vacca G.,Robert Koch Hospital |
Randerath W.J.,Witten/Herdecke University |
Gillissen A.,General Hospital
Respiratory Research | Year: 2011
Study objectives: Neutrophil influx into the airways is an important mechanism in the pathophysiology of the inflammatory process in the airways of patients with chronic obstructive pulmonary disease (COPD). Previously it was shown that anticholinergic drugs reduce the release of non-neuronal paracrine mediators, which modulate inflammation in the airways. On this basis, we investigated the ability of the long-acting anticholinergic tiotropium bromide to inhibit a) alveolar macrophage (AM)-mediated chemotaxis of neutrophils, and b) cellular release of reactive oxygen species (ROS). Method: AM and neutrophils were collected from 71 COPD patients. Nanomolar concentrations of tiotropium bromide were tested in AM cultured up to 20 h with LPS (1 μg/ml). AM supernatant was tested for TNFα, IL8, IL6, LTB4, GM-CSF, MIPα/β and ROS. It was further used in a 96-well chemotaxis chamber to stimulate the migration of fluorescence labelled neutrophils. Control stimulants consisted of acetylcholine (ACh), carbachol, muscarine or oxotremorine and in part PMA (phorbol myristate acetate, 0.1 μg/ml). Potential contribution of M1-3-receptors was ascertained by a) analysis of mRNA transcription by RT-PCR, and b) co-incubation with selective M-receptor inhibitors. Results: Supernatant from AM stimulated with LPS induced neutrophilic migration which could be reduced by tiotropium in a dose dependent manner: 22.1 ± 10.2 (3 nM), 26.5 ± 18,4 (30 nM), and 37.8 ± 24.0 (300 nM, p < 0.001 compared to non-LPS activated AM). Concomitantly TNFα release of stimulated AM dropped by 19.2 ± 7.2% of control (p = 0.001). Tiotropium bromide did not affect cellular IL8, IL6, LTB4, GM-CSF and MIPα/β release in this setting. Tiotropium (30 nM) reduced ROS release of LPS stimulated AM by 36.1 ± 15.2% (p = 0.002) and in carbachol stimulated AM by 46.2 ± 30.2 (p < 0.001). M3R gene expression dominated over M2R and M1R. Chemotaxis inhibitory effect of tiotropium bromide was mainly driven by M3R inhibition. Conclusion: Our data confirm that inhibiting muscarinic cholinergic receptors with tiotropium bromide reduces TNFα mediated chemotactic properties and ROS release of human AM, and thus may contribute to lessen cellular inflammation. © 2011 Vacca et al; licensee BioMed Central Ltd.
Sipeky C.,University of Pécs |
Weber A.,University of Miskolc |
Szabo M.,Robert Koch Hospital |
Melegh B.I.,University of Pécs |
And 4 more authors.
Molecular Biology Reports | Year: 2013
The purpose of our study was to characterise the CYP2C19*2 and CYP2C19*3 alleles in healthy Roma and Hungarian populations. DNA of 500 Roma and 370 Hungarian subjects were genotyped for CYP2C19*2 (G681A, rs4244285) and CYP2C19*3 (G636A, rs4986893) by PCR-RFLP assay and direct sequencing. Significant differences were found comparing the Roma and Hungarian populations in CYP2C19 681 GG (63.6 vs. 75.9 %), GA (31.8 vs. 23.0 %), AA (4.6 vs. 1.1 %), GA+AA (36.4 vs. 24.1 %) and A allele frequencies (0.205 vs. 0.125) (p < 0.004). Striking differences were found between Roma and Hungarian samples in CYP2C19*1 (79.5 vs. 87.4 %) and CYP2C19*2 (20.5 vs. 12.6 %) alleles, respectively (p < 0.001). None of the subjects was found to carry the CYP2C19*3 allele. Frequencies of the intermedier metabolizer phenotype defined by the*1/*2 genotype (0.318 vs. 0.230, p < 0.005) and poor metabolizer predicted by the*2/*2 genotype (0.046 vs. 0.011, p < 0.005) was significantly higher in Roma than in Hungarians, respectively. Genotype distribution of the Roma population was similar to those of the population of North India, however, a major difference was found in the frequency of the CYP2C19*2 allele, which is likely a result of admixture with European lineages. In conclusion, the frequencies of the CYP2C19 alleles, genotypes and corresponding extensive, intermediate and poor metabolizer phenotypes studied here in the Hungarian population are similar to those of other European Caucasian populations, but display clear differences when compared to the Roma population. © 2013 Springer Science+Business Media Dordrecht.
PubMed | Robert Koch Hospital, End und Dickdarmzentrum Hanover edh and MHH
Type: Journal Article | Journal: Anticancer research | Year: 2016
To assess the clinical value of squamous cell carcinoma antigen (SCCAg) in anal cancer for chemoradiotherapy (CRT) patients.In 24 patients with SCC of the anus, SCCAg was determined before CRT and at every follow-up visit.16/24 (66.7%) had normal SCCAg and 11/16 (68.8%) achieved complete remission (CR), while 7/8 (87.5%) with elevated SCCAg achieved CR. In two patients, elevated SCCAg was observed after radiotherapy. One was false-positive and one was true-positive leading to diagnosis of metachronous recurrent and metastatic disease after interim CR.SCCAg was inappropriate to predict the clinical outcome but can provide additional information on the regular follow-up examinations to detect a relapse.
Brangewitz M.,Hannover Medical School |
Voigtlander T.,Hannover Medical School |
Helfritz F.A.,Hannover Medical School |
Lankisch T.O.,Hannover Medical School |
And 6 more authors.
Endoscopy | Year: 2013
Background and study aim: Placement of covered self-expanding metal or plastic stents (SEMS or SEPS) is an established method for managing intrathoracic leaks. Recently, endoscopic vacuum-assisted closure (EVAC) has been described as a new effective treatment option. Our aim was to compare stent placement with EVAC for nonsurgical closure of intrathoracic anastomotic leaks. Patients and methods: In a retrospective analysis we were able to identify 39 patients who were treated with SEMS or SEPS and 32 patients who were treated with EVAC for intrathoracic leakage. In addition to successful fistula closure, we analyzed hospital mortality, number of endoscopic interventions, incidence of stenoses, and duration of hospitalization. Results: In a multivariate analysis, successful wound closure was independently associated with EVAC therapy (hazard ratio 2.997, 95 % confidence interval [95 %CI] 1.568 - 5.729; P = 0.001). The overall closure rate was significantly higher in the EVAC group (84.4 %) compared with the SEMS/SEPS group (53.8 %). No difference was found for hospitalization and hospital mortality. We found significantly more strictures in the stent group (28.2 % vs. 9.4 % with EVAC, P < 0,05). Conclusions: EVAC is an effective endoscopic treatment option for intrathoracic leaks and showed higher effectiveness than stent placement in our cohort. © Georg Thieme Verlag KG Stuttgart · New York.
Wedemeyer J.,Hannover Medical School |
Wedemeyer J.,Robert Koch Hospital |
Kubicka S.,Hannover Medical School |
Lankisch T.O.,Hannover Medical School |
And 5 more authors.
Gastrointestinal Endoscopy | Year: 2012
Background: Endoscopic transluminal débridement of infected pancreatic necrosis has been proved to be an important alternative to surgical débridement. Recently, endoscopic vacuum-assisted closure (EVAC) has been described as a new effective treatment option in upper intestinal anastomotic leaks. Objective: To test whether the EVAC can be applied to transgastrically accessible infected cavities. Design: Single-center case study. Setting: Academic medical center. Patients: Two patients with necrotizing pancreatitis. Main Outcome Measurement: Successful closure of leak. Results: We successfully applied EVAC to treat transgastrically accessible necrotic cavities. Limitations: Small case number. Conclusions: EVAC might be an important additional endoscopic treatment option for infected pancreatic necrosis, especially if established endoscopic treatment options fail. © 2012 American Society for Gastrointestinal Endoscopy.
Mehrtens S.,Robert Koch Hospital |
Reboll M.R.,Hannover Medical School
Methods in Molecular Biology | Year: 2014
The dicistronic luciferase reporter gene system is the most common method to isolate and characterize internal ribosome entry sites (IRES). It is based on the expression of a dicistronic RNA comprising two independent reporter genes in 3' and 5'cistrons, and the putative IRES inserted into intercistronic region. The most convenient aspect of using Renilla and firefly luciferase genes is that both gene products can be detected in a single assay using Dual-Luciferase® Reporter Assay System from Promega. The Renilla luciferase coding sequence is often inserted into the 5'cistron and serves as internal control. It is translated cap dependently, as it is close to the cap structure at the 5' end. The 3'cistron located far downstream to the cap structure can only be translated by a cap-independent mechanism when the intercistronic sequence is capable of ribosome binding and re-initiation of translation. Expression level of the 3'cistron is usually normalized to the expression of 5'cistron to estimate the relative IRES activity of intercistronic sequences. © Springer Science+Business Media New York 2014.
A randomised multi-centre phase-II trial to assess the effect of dose splitting of carboplatin (CARBO) in comparison to a single application of carboplatin in a gemcitabine (GEM)/carboplatin regime for stage IIIB and IV non small cell lung cancer (NSCLC)
PubMed | Robert Koch Hospital
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2016
7130 Background: Gem/Carbo is an active regime in the treatment of stage IIIB and IV NSCLC without relevant non hematological toxicity. The main hematological toxicity is thrombocytopenia. The aim of the study is the reduction of thrombocytopenia in the Gem/Carbo regime by splitting the dose of carbo.A multi-centre randomised phase II trial in NSCLC comparing Gem (1250 mg/m160 pts were randomised between 05/03 and 08/04. Pretreatment characteristics were well balanced between the two groups; median age 62.4 years, WHO PS 0-1 81%, stage IV 78% of pts. Preliminary data are available; response rate and stable disease rate were 45%/36% in arm A and 38%/46% in arm B respectively. WHO grade 3/4 thrombocytopenia is significantly reduced in arm B (Chi-square p = 0.026).Preliminary data show a reduction of severe thrombocytopenia in arm B (splitted dose). Data on primary and secondary endpoints will be available for presentation at the ASCO meeting. No significant financial relationships to disclose.