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Reinmuth N.,Member of the German Center for Lung Research | Meyer A.,Kliniken Maria Hilf | Hartwigsen D.,Malteser Krankenhaus St. Franziskus | Schaeper C.,Universitaetsklinikum | And 6 more authors.
Lung Cancer | Year: 2014

Objectives: Adding nitroglycerin to the combination of vinorelbine plus cisplatin has been reported to improve the overall survival (OS) of Asian patients with stage IIIB/IV non-small cell lung cancer (NSCLC) probably due to better drug delivery based on changed vascular tonus. The main objective of our study was to evaluate the effect of adding nitroglycerin to vinorelbine and cisplatin in a Caucasian population. Methods: 66 chemonaïve patients with stage IIIB/IV NSCLC received oral vinorelbine (first cycle 60mg/m2, subsequent cycles: 80mg/m2 in the absence of any hematological toxicity ≥grade 3 in cycle 1) once daily on days 1 and 8 of each cycle and cisplatin (80mg/m2 i.v.) on day 1 of each cycle (q3w). Nitroglycerin (arm A, n=34) or placebo patches (arm B, n=32) were administered once daily from day -3 to day 2 of each cycle and were removed about 12h after administration. One nitroglycerin patch contained 25mg nitroglycerin. Results: Median age was 62.5 (33-82) years. In the overall population (n= 66), the objective response rate (ORR) was 27.3% (all PR; 95%CI: 17.0-39.6), with a disease control rate (DCR) of 57.6% (95%CI: 44.8-69.7), a median time to progression (TTP) of 4.8 months (n= 58; 95%CI: 3.4-5.9) and a median overall survival (OS) of 11.5 months (95%CI: 7.9-13.6). ORR and DCR were numerically higher in arm A than in arm B (35.3% vs. 18.8% and 61.8% vs. 53.1%, respectively), whereas TTP and OS were comparable. The main hematological and non-hematological toxicities grade ≥3 were moderate with no significant differences between the two treatment arms. Conclusions: Overall, oral vinorelbine plus cisplatin showed a high level of efficacy and adequate tolerability in first line treatment of NSCLC. Despite the low sample size per group the results seem to confirm the previous results reported in Asian patients. © 2014 Elsevier Ireland Ltd.


Legendre C.M.,University of Paris Descartes | Licht C.,Hospital for Sick Children | Muus P.,Radboud University Nijmegen | Greenbaum L.A.,Children's Healthcare Of Atlanta | And 29 more authors.
New England Journal of Medicine | Year: 2013

BACKGROUND: Atypical hemolytic-uremic syndrome is a genetic, life-threatening, chronic disease of complement-mediated thrombotic microangiopathy. Plasma exchange or infusion may transiently maintain normal levels of hematologic measures but does not treat the underlying systemic disease. METHODS: We conducted two prospective phase 2 trials in which patients with atypical hemolytic-uremic syndrome who were 12 years of age or older received eculizumab for 26 weeks and during long-term extension phases. Patients with low platelet counts and renal damage (in trial 1) and those with renal damage but no decrease in the platelet count of more than 25% for at least 8 weeks during plasma exchange or infusion (in trial 2) were recruited. The primary end points included a change in the platelet count (in trial 1) and thrombotic microangiopathy event-free status (no decrease in the platelet count of >25%, no plasma exchange or infusion, and no initiation of dialysis) (in trial 2). RESULTS: A total of 37 patients (17 in trial 1 and 20 in trial 2) received eculizumab for a median of 64 and 62 weeks, respectively. Eculizumab resulted in increases in the platelet count; in trial 1, the mean increase in the count from baseline to week 26 was 73x109 per liter (P<0.001). In trial 2, 80% of the patients had thrombotic microangiopathy event-free status. Eculizumab was associated with significant improvement in all secondary end points, with continuous, time-dependent increases in the estimated glomerular filtration rate (GFR). In trial 1, dialysis was discontinued in 4 of 5 patients. Earlier intervention with eculizumab was associated with significantly greater improvement in the estimated GFR. Eculizumab was also associated with improvement in health-related quality of life. No cumulative toxicity of therapy or serious infection-related adverse events, including meningococcal infections, were observed through the extension period. CONCLUSIONS: Eculizumab inhibited complement-mediated thrombotic microangiopathy and was associated with significant time-dependent improvement in renal function in patients with atypical hemolytic-uremic syndrome. (Funded by Alexion Pharmaceuticals; C08- 002 ClinicalTrials.gov numbers, NCT00844545 [adults] and NCT00844844 [adolescents]; C08-003 ClinicalTrials.gov numbers, NCT00838513 [adults] and NCT00844428 [adolescents]). Copyright © 2013 Massachusetts Medical Society.


PubMed | HELIOS Kliniken, German Society of Orthopaedics and Orthopaedic Surgery DGOOC, Research Institute of the Local Health Care Funds WIdO, Kreisklinik Jugenheim and 4 more.
Type: Journal Article | Journal: The Journal of bone and joint surgery. American volume | Year: 2016

Improvements in implant design and surgical technique of unicondylar knee arthroplasty have led to reduced revision rates, but patient selection seems to be crucial for success of such arthroplasties. The purpose of the present study was to analyze the 5-year implant survival rate of unicondylar knee replacements in Germany and to identify patient factors associated with an increased risk of revision, including >30 comorbid conditions.Using nationwide billing data of the largest German health-care insurance for inpatient hospital treatment, we identified patients who underwent unicondylar knee arthroplasty between 2006 and 2012. Kaplan-Meier survival curves with revision as the end point and log-rank tests were used to evaluate 5-year implant survival. A multivariable Cox regression model was used to determine factors associated with revision. The risk factors of age, sex, diagnosis, comorbidities, type of implant fixation, and hospital volume were analyzed. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated.During the study period, a total of 20,946 unicondylar knee arthroplasties were included. The number of unicondylar knee arthroplasties per year increased during the study period from 2,527 in 2006 to 4,036 in 2012. The median patient age was 64 years (interquartile range, 56 to 72 years), and 60.4% of patients were female. During the time evaluated, the 1-year revision rate decreased from 14.3% in 2006 to 8.7% in 2011. The 5-year survival rate was 87.8% (95% CI, 87.3% to 88.3%). Significant risk factors (p < 0.05) for unicondylar knee arthroplasty revision were younger age (the HR was 2.93 [95% CI, 2.48 to 3.46] for patient age of <55 years, 1.86 [95% CI, 1.58 to 2.19] for 55 to 64 years, and 1.52 [95% CI, 1.29 to 1.79] for 65 to 74 years; patient age of >74 years was used as the reference); female sex (HR, 1.18 [95% CI, 1.07 to 1.29]); complicated diabetes (HR, 1.47 [95% CI, 1.03 to 2.12]); depression (HR, 1.29 [95% CI, 1.06 to 1.57]); obesity, defined as a body mass index of 30 kg/mApart from known risk factors, this study showed a significant negative influence of obesity, depression, and complicated diabetes on the 5-year unicondylar knee replacement survival rate. Surgical indications and preoperative patient counseling should consider these findings.Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.


Huber M.B.,University of Rochester | Nagarajan M.B.,University of Rochester | Leinsinger G.,Ludwig Maximilians University of Munich | Eibel R.,Helios Kliniken | And 3 more authors.
Medical Physics | Year: 2011

Purpose: Topological texture features were compared in their ability to classify "honeycombing," a morphological pattern that is considered indicative for the presence of fibrotic interstitial lung disease in high-resolution computed tomography (HRCT) images. Methods: For 14 patients with known occurrence of honeycombing, a stack of 70 axial, lung kernel reconstructed images was acquired from HRCT chest exams. A set of 964 regions of interest of both healthy and pathological (356) lung tissue was identified by an experienced radiologist. Texture features were extracted using statistical features (Stat), six properties calculated from gray-level co-occurrence matrices (GLCMs), Minkowski dimensions (MDs), and three Minkowski functionals (MFs) (e.g., MF.Euler). A naïve Bayes (NB) and k -nearest-neighbor (k -NN) classifier, a multilayer radial basis functions network (RBFN), and a support vector machine with a radial basis function (SVMrbf) kernel were optimized in a tenfold cross-validation for each texture vector, and the classification accuracy was calculated on independent test sets as a quantitative measure of automated tissue characterization. A Wilcoxon signed-rank test was used to compare two accuracy distributions and the significance thresholds were adjusted for multiple comparisons by the Bonferroni correction. Results: The best classification results were obtained by the MF features, which performed significantly better than all the standard Stat, GLCM, and MD features (p<0.001) for both classifiers. The highest accuracies were found for MF.Euler (93.6%, 94.9%, 94.2%, and 95.0% for NB, k -NN, RBFN, and SVMrbf, respectively). The best groups of standard texture features were a Stat and GLCM ("homogeneity") feature set (up to 91.8%). Conclusions: The results indicate that advanced topological texture features derived from MFs can provide superior classification performance in computer-assisted diagnosis of fibrotic interstitial lung disease patterns when compared to standard texture analysis methods. © 2011 American Association of Physicists in Medicine.


Mertens M.,Friedrich LoeZer Institute | Hofmann J.,University Hospital Charite | Petraityte-Burneikiene R.,Vilnius University | Ziller M.,Friedrich LoeZer Institute | And 8 more authors.
Medical Microbiology and Immunology | Year: 2011

Highly endemic and outbreak regions for human hantavirus infections are located in the southern, southeastern, and western parts of Germany. The dominant hantavirus is the bank vole transmitted Puumala virus (PUUV). In the eastern part of Germany, previous investigations revealed Tula virus (TULV) and Dobrava-Belgrade virus (DOBV) infections in the respective rodent reservoirs. Here, we describe a seroprevalence study in forestry workers from Brandenburg, eastern Germany, using IgG ELISA and immunoblot tests based on recombinant TULV, DOBV, and PUUV antigens. Out of the 563 sera tested, 499 from male and 64 from female workers, we found 41 out of the 499 (8.2%) sera from men (mean age 47 years) and 10 out of 64 (15.6%) from the women (mean age 48 years) anti-hantavirus-positive. The majority of the 51 seropositive samples reacted exclusively in the TULV (n = 22) and DOBV tests (n = 17). Focus reduction neutralization assay investigations on selected sera conWrmed the presence of TULV-and DOBV-speciWc antibodies in the forestry workers. These investigations demonstrated a potential health threat for forestry workers and also the average population in non-endemic geographical regions where TULV and DOBV are circulating in the corresponding reservoir hosts. The infections in this region might be frequently overlooked due to their unspeciWc and mild symptoms. © Springer-Verlag 2011.


Chen Y.,Chinese People's Liberation Army | Chen Y.,Mario Negri Institute for Pharmacological Research | Schieppati A.,Ospedali Riuniti di Bergamo | Cai G.,Chinese People's Liberation Army | And 5 more authors.
Clinical Journal of the American Society of Nephrology | Year: 2013

Background and objectives The efficacy and safety of immunosuppression for idiopathic membranous nephropathy (IMN) with nephrotic syndrome are still controversial. A systematic review and meta-analysis of randomized controlled trials (RCTs) was performed. Design, setting, participants, & measurements The Cochrane Library, PUBMED, EMBASE, Chinese Database, and Clinical Trial Registries (June 2012) were searched to identify RCTs investigating the effect of immunosuppression on adults with IMN and nephrotic syndrome. Results This review was an update (36 RCTs, 1762 participants) of the 2004 version (18 RCTs, 1025 participants). Immunosuppression significantly reduced all-cause mortality or ESRD (15 RCTs, 791 participants; risk ratio, 0.58 [95% confidence interval, 0.36-0.95]; P=0.03). However, the result was not consistent when prespecified subgroup analyses were undertaken. Immunosuppression increased complete or partial remission (CR + PR) (16 RCTs, 864 participants; 1.31 [1.01-1.70]; P=0.04) but resulted in more withdrawals or hospitalizations (16 RCTs, 880 participants; 5.35 [2.19-13.02]; P=0.002). Corticosteroids combined with alkylating agents significantly reduced all-cause mortality or ESRD (8 RCTs, 448 participants; 0.44 [0.26-0.75]; P=0.002) and increased CR + PR (7 RCTs, 422 participants; 1.46 [1.13-1.89]; P=0.004) but led to more adverse events (4 RCTs, 303 participants; 4.20 [1.15-15.32]; P=0.03). Cyclophosphamide was safer than chlorambucil (3 RCTs, 147 participants; 0.48 [0.26-0.90]; P=0.02). Cyclosporine and mycophenolate mofetil failed to show superiority over alkylating agents. Tacrolimus and adrenocorticotropic hormone significantly reduced proteinuria. Conclusions Alkylating agents plus corticosteroids had long-term and short-term benefits for adult IMN, but resulted in more withdrawals or hospitalizations. © 2013 by the American Society of Nephrology.


Schleife H.,Helios Kliniken | Sachtleben C.,Helios Kliniken | Finck Barboza C.,University of Los Andes, Colombia | Singer S.,University of Leipzig | Hinz A.,University of Leipzig
Breast Cancer | Year: 2014

Background: The aim of the study was to determine the predictors of health-related quality of life in ambulatory breast cancer patients. Methods: A total of 107 breast cancer outpatients were tested with the Hospital Anxiety and Depression Scale (HADS) and the quality of life instrument EORTC QLQ-C30. Furthermore, the degree of social support and shared decision making (SDM) were assessed. Results: In nearly all domains of EORTC QLQ-C30 the patients reported worse mean scores than the general population in a clinically significant range, especially in the symptom scales. Therapy-related factors and the degree of SDM contributed only marginally to quality of life. Social support, however, proved to be predictive of better mental health and better quality of life in many domains. Conclusion: Irrespective of the therapy, the social network of the patients should be activated to help the patients to cope with the disease. However, the findings do not support the idea that enhanced SDM would have beneficial effects on mental health. © 2012 The Japanese Breast Cancer Society.


Langhans B.,University of Bonn | Kramer B.,University of Bonn | Louis M.,University of Bonn | Nischalke H.D.,University of Bonn | And 9 more authors.
Journal of Hepatology | Year: 2013

Background & Aims Regulatory CD4+ T cells (Tregs) are considered to affect outcomes of HCV infection, because they increase in number during chronic hepatitis C and can suppress T-cell functions. Methods Using microarray analysis, in situ immunofluorescence, ELISA, and flowcytometry, we characterised functional differentiation and localisation of adaptive Tregs in patients with chronic hepatitis C. Results We found substantial upregulation of IL-8 in Foxp3+CD4+ Tregs from chronic hepatitis C. Activated GARP-positive IL-8+ Tregs were particularly enriched in livers of patients with chronic hepatitis C in close proximity to areas of fibrosis and their numbers were correlated with the stage of fibrosis. Moreover, Tregs induced upregulation of profibrogenic markers TIMP1, MMP2, TGF-beta1, alpha-SMA, collagen, and CCL2 in primary human hepatic stellate cells (HSC). HSC activation, but not Treg suppressor function, was blocked by adding a neutralizing IL-8 antibody. Conclusions Our studies identified Foxp3 +CD4+ Tregs as an additional intrahepatic source of IL-8 in chronic hepatitis C acting on HSC. Thus, Foxp3+CD4+ Tregs in chronic hepatitis C have acquired differentiation as regulators of fibrogenesis in addition to suppressing local immune responses. © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.


Wedekind D.,University of Gottingen | Broocks A.,Helios Kliniken | Weiss N.,University of Gottingen | Engel K.,University of Gottingen | And 2 more authors.
World Journal of Biological Psychiatry | Year: 2010

Objectives. Regular aerobic exercise (running) has been shown to be superior to a pill placebo in the treatment of panic disorder. Combined drug and exercise treatment has not been investigated in randomized controlled studies to date. Methods. This is a randomized, 10-week, controlled, parallel group, pilot study. A total of 75 outpatients with panic disorder with or without agoraphobia (DSM-IV and ICD-10) received either (1) exercise plus paroxetine 40 mg/day (n=21), (2) relaxation plus paroxetine (n=17), (3) exercise plus pill placebo (n=20), or (4) relaxation plus pill placebo (n=17). Changes in the Panic and Agoraphobia Scale (P&A), and the Clinical Global Impression Scale (CGI) underwent repeated measure analysis. Results. Effects sizes were large for all groups (d1.533.87), however not significantly different. Paroxetine-treated patients were significantly more improved than placebo-treated patients. On the CGI, patients in the exercise groups (plus paroxetine or placebo) had a trend toward better improvement compared to relaxation (P0.06). Response and remission rates were higher in the paroxetine compared to pill placebo groups. Conclusions. While paroxetine was superior to placebo, aerobic exercise did not differ from relaxation training in most efficacy measures. © 2010 Informa Healthcare.


Von Minckwitz G.,German Breast Group | Loibl S.,German Breast Group | Maisch A.,German Breast Group | Untch M.,Helios Kliniken
Breast | Year: 2011

Aims: To review the recent literature on neoadjuvant treatment of breast cancer with respect to insights that might be used for better using systemic treatment in early breast cancer. Results: Much more insight was gained during recent years on how to use information on pathologic complete response (pCR). pCR appears to be a valid surrogate for long-term survival mainly in triple-negative and HER2-positive disease. Patient with breast cancer of these subtypes can be relieved from poor prognosis if they achieve a pCR after neoadjuvant treatment. It can even be speculated that the extent of local and post-surgical systemic treatment can be further reduced. Patients without pCR show a high risk of early recurrence and are at high need for new treatment options. These advantages lead to the recommendation that use of neoadjuvant treatment should not be indicated by tumor size but far more by tumor subtype. As pCR appears to be more sensitive to detect treatment effects than disease-free survival, the neoadjuvant approach identifies easier promising treatments and can even discriminate optimal approaches for biologically defined subgroups. A recent meta-analysis examining pattern of neoadjuvant chemotherapy suggests that luminal-B type tumors require longer duration of treatment, triple-negative tumors require dose-intensified anthracycline-taxane-based treatment of only short duration, and HER2-positive tumors require longer duration (if hormone-receptor positive) and an optimal dose of taxanes. As biomarkers can be easily assessed on tumor tissue before, during, and after treatment, there is increasing data available on markers that e.g. potentially predict resistance to anti-HER2 treatment, predict response to anti-angiogenic drugs as well as efficacy of PARP inhibitors. Validation of these candidate markers remains a challenging task, as patients cohort are usually small and finding studies are compromised by multiple testing. Conclusion: With the acquired new knowledge from neoadjuvant studies will help to individualize treatment based on biological behavior of breast cancer subtypes. © 2011 Elsevier Ltd.

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