Lungenklinik Merheim

Köln, Germany

Lungenklinik Merheim

Köln, Germany
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Kreuter M.,University of Heidelberg | Kreuter M.,Translational Lung Research Center Heidelberg | Vansteenkiste J.,Universities Hospital Leuven | Fischer J.R.,Oncology | And 16 more authors.
Annals of Oncology | Year: 2013

Background: Adjuvant chemotherapy is beneficial in non-small-cell lung cancer (NSCLC). However, balancing toxicity and efficacy mandates improvement. Patients and methods: Patients with completely resected stages IB-pT3N1 NSCLC were randomly assigned to either four cycles cisplatin (C: 50 mg/m2 day (d)1 + 8) and vinorelbine (V: 25 mg/m2 d1, 8, 15, 22) q4 weeks or four cycles cisplatin (75 mg/m2 d1) and pemetrexed (Px: 500 mg/m2 d1) q3 weeks. Primary objective was the clinical feasibility rate (no grade (G)4 neutropenia/thrombocytopenia or thrombocytopenia with bleeding, no G3/4 febrile neutropenia or nonhematological toxicity; no premature withdrawal/death). Secondary objectives were drug delivery and efficacy. Results: One hundred and thirty two patients were randomized (stages: 38% IB, 10% IIA, 47% IIB, 5% pT3pN1; histology: 43% squamous, 57% non-squamous). The feasibility rates were 95.5% (cisplatin and pemetrexed, CPx) and 75.4% (cisplatin and vinorelbine, CVb) (P = 0.001); hematological G3/4 toxic effects were 10% (CPx) and 74% (CVb) (P < 0.001), non-hematological toxic effects were comparable (33% and 31%, P = 0.798). Delivery of total mean doses was 90% of planned with CPx, but 66% (cisplatin) and 64% (vinorelbine) with CVb (P < 0.0001). The median number of cycles [treatment time (weeks)] was 4 for CPx (11.2) and 3 for CVb (9.9). Time to withdrawal from therapy differed significantly between arms favoring CPx (P<0.001). Conclusion: Adjuvant chemotherapy with CPx is safe and feasible with less toxicity and superior dose delivery compared with CVb. © The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


PubMed | Dr. Horst Schmidt Kliniken GmbH, Oncology, Lungenklinik Hemer, Pius Hospital Oldenburg and 10 more.
Type: Clinical Trial, Phase II | Journal: Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer | Year: 2016

Adjuvant chemotherapy in non-small cell lung cancer (NSCLC) improves survival but is associated with significant toxicity. The Randomized Phase II Trial on Refinement of Early-Stage NSCLC Adjuvant Chemotherapy with Cisplatin and Pemetrexed versus Cisplatin and Vinorelbine (TREAT study) was designed to test the hypothesis that a protocol with reduced toxicity might improve feasibility of postoperative delivery of adjuvant chemotherapy drugs to patients with NSCLC, thereby improving compliance and, potentially, survival.Two adjuvant regimens were evaluated for feasibility in 132 patients with NSCLC: the standard regimen of cisplatin and vinorelbine (CVb) (cisplatin 50 mg/m(2) on day 1 and day 8 and vinorelbine 25 mg/m(2) on days 1, 8, 15, and 22 every 4 weeks) and a regimen consisting of cisplatin and pemetrexed (CPx) (cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 every 3 weeks). The primary end-point analysis showing that CPx is safe and feasible with dose delivery superior to that of CVb has already been published. Here we report the 3-year follow-up results of the secondary efficacy end points-overall, relapse-free, distant metastasis-free, and local relapse-free survival-also with regard to histologic diagnosis.After a median of 39 months, no significant differences in any of the outcome parameters between CVb and CPx were observed. Also, histologic diagnosis and tumor size in stage IB did not influence survival in the CPx-treated patients. Yet, Cox regression analyses showed that overall survival at 3 years was significantly correlated with feasibility and the occurrence of dose-limiting toxicity.Although adjuvant chemotherapy with CPx is safe and characterized by less toxicity and better dose delivery than CVb, overall survival was not influenced by treatment arm in the context of this phase II trial.


Knobloch J.,University Hospital Bergmannsheil | Feldmann M.,University Hospital Bergmannsheil | Wahl C.,University Hospital Bergmannsheil | Jungck D.,University Hospital Bergmannsheil | And 3 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2013

Bacterial infections induce exacerbations in chronic lung diseases, e.g., chronic obstructive pulmonary disease (COPD), by enhancing airway inflammation. Exacerbations are frequently associated with right heart decompensation and accelerate disease progression. Endothelin receptor antagonists (ERAs) might have therapeutic potential as pulmonary vasodilators and anti-inflammatory agents, but utility in exacerbations of chronic lung diseases is unknown. We hypothesized that cytokine releases induced by lipopolysaccharide (LPS), the major bacterial trigger of inflammation, are reduced by ERAs in pulmonary vascular smooth muscle cells (PVSMCs). Ex vivo cultivated human PVSMCs were preincubated with the endothelin-A-receptor selective inhibitor ambrisentan, with the endothelin-B-receptor selective inhibitor BQ788 [sodium (2R)-2- {[(2S)-2-({[(2R,6S)-2,6-dimethyl-1-piperidinyl]carbonyl}amino)- 4,4-dimethylpentanoyl][1-(methoxycarbonyl)-D-tryptophyl]amino} hexanoate], or with the dual blocker bosentan before stimulation with smooth LPS (S-LPS), rough LPS (Re-LPS), or a mixture of long and short forms (M-LPS). Expression of cytokines and LPS receptors (TLR4, CD14) were analyzed via enzyme-linked immunosorbent assay (ELISA) and/or quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). All LPS forms induced interleukin (IL)-6-, IL-8-, and granulocyte macrophage- colony stimulating factor (GM-CSF) release. Bosentan and BQ788 inhibited M-LPS-induced release of all cytokines and soluble CD14 (sCD14) but not TLR4 expression. Ambrisentan blocked M-LPS-induced IL-6 release but not IL-8, GM-CSF, or LPS receptors. IL-8 release induced by S-LPS, which requires CD14 to activate TLR4, was blocked by bosentan and BQ788. IL-8 release induced by Re-LPS, which does not require CD14 to activate TLR4, was insensitive to both bosentan and BQ788. In conclusion, PVSMCs contribute to inflammation in bacteriainduced exacerbations of chronic lung diseases. Inhibition of the endothelin-B receptor suppresses cytokine release induced by long/smooth LPS attributable to sCD14 downregulation. ERAs, particularly when targeting the endothelin-B receptor, might have therapeutic utility in exacerbations of chronic lung diseases. Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics.


Knobloch J.,University Hospital Bergmannsheil | Knobloch J.,University of Cologne | Lin Y.,University of Cologne | Konradi J.,University of Cologne | And 8 more authors.
American Journal of Respiratory Cell and Molecular Biology | Year: 2013

Endothelin receptor antagonists (ETRAs), authorized for pulmonary hypertension, have failed to prove their utility in chronic lung diseases with corticosteroid-resistant airway inflammation when applied at late disease stages with emphysema/fibrosis. Earlier administration might prove effective by targeting the interaction between airway inflammationandtissue remodeling.Wehypothesizedthathumanairwaysmooth muscle cells (HASMCs) participate in linking inflammation with remodeling and that associated genes become differentially suppressed by ambrisentan (A-receptor selective ETRA) and bosentan (nonselective/ dual ETRA). Inflammatory responses of ex vivo-cultivated HASMCs to TNF-α were investigated by whole-genome microarray analyses. qRTPCR and ELISA were used to test inflammatory and remodeling genes for sensitivity to bosentan and ambrisentan and to investigate differential sensitivities mechanistically. ETRA and corticosteroid effects were compared inHASMCsfrom patients with chronic obstructive pulmonary disease. TNF-α induced the expression of 18 cytokines/chemokines and five tissue remodeling genes involved in severe, corticosteroidinsensitive asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and/or pulmonary hypertension. Thirteen cytokines/chemokines, MMP13, and WISP1 were suppressed by ETRAs. Eight genes had differential sensitivity to bosentan and ambrisentan depending on the endothelin-B receptor impact on transcriptional regulation and mRNA stabilization. Chemokine (C-C motif) ligands 2 and 5, granulocyte macrophage colonystimulating factor, andMMP13hadincreased sensitivity to bosentan or bosentan/dexamethasone combination versus dexamethasone alone. Suppression of cytokine and remodeling gene expression by ETRAs was confirmed in TNF-α-activatedhumanbronchial epithelial cells. HASMCs and human bronchial epithelial cells participate in the interaction of inflammation and tissue remodeling. This interaction is targeted differentially by selective and nonselective ETRAs, which could be used in therapies of chronic lung diseases with corticosteroid-resistant airway inflammation at early disease stages to attenuate inflammation-induced airway remodeling. Copyright © 2013 by the American Thoracic Society.


Kabitz H.-J.,University Hospital Freiburg | Bremer H.-C.,Schwarzwald Baar Klinikum Donaueschingen | Schwoerer A.,University Hospital Freiburg | Sonntag F.,University Hospital Freiburg | And 6 more authors.
Lung | Year: 2014

Purpose: Increased dyspnea and reduced exercise capacity in pulmonary arterial hypertension (PAH) can be partly attributed to impaired respiratory muscle function. This prospective study was designed to assess the impact of exercise and respiratory training on respiratory muscle strength and 6-min walking distance (6MWD) in PAH patients. Methods: Patients with invasively confirmed PAH underwent 3 weeks of in-hospital exercise and respiratory training, which was continued at home for another 12 weeks. Medication remained constant during the study period. Blinded observers assessed efficacy parameters at baseline (I) and after 3 (II) and 15 weeks (III). Respiratory muscle function was assessed by twitch mouth pressure (TwPmo) during nonvolitional supramaximal magnetic phrenic nerve stimulation. Results: Seven PAH patients (4 women; mean pulmonary artery pressure 45 ± 11 mmHg, median WHO functional class 3.1 ± 0.4, idiopathic/associated PAH n = 5/2) were included. The training program was feasible and well tolerated by all patients with excellent compliance. TwPmo was I: 0.86 ± 0.37 kPa, II: 1.04 ± 0.29 kPa, and III: 1.27 ± 0.44 kPa, respectively. 6MWD was I: 417 ± 51 m, II: 509 ± 39 m, and III: 498 ± 39 m, respectively. Both TwPmo (+0.41 ± 0.34 kPa, +56 ± 39 %) and 6MWD (+81 ± 30 m, +20 ± 9 %) increased significantly in the period between baseline and the final assessment (pairwise comparison: p = 0.012/<0.001; RM-ANOVA considering I, II, III: p = 0.037/<0.001). Conclusions: Exercise and respiratory training as an adjunct to medical therapy may be effective in patients with PAH to improve respiratory muscle strength and exercise capacity. Future, randomized, controlled trials should be carried out to further investigate these findings. © 2013 Springer Science+Business Media.


Background: Inhalation therapy is well recognized as a cornerstone treatment of airway diseases. In daily practice, however, high failure rates of inhalation technique are evident, which substantially attenuates the treatment success. Methods: In 2011 the German Airway League has initiated the production of video screens for correct inhalation aimed at providing an efficient and globally available platform for information. All devices regularly used have been filmed and published via internet and DVD; thereby, video screens, spoken text passages, and visual insertion of information have been combined. Here, all important steps of inhalation therapy like preparation, performance, and termination have been covered. Results: Video screens of 20 different devices lasting between 1:42 and 3:11 min:sec have been produced between July 2011 and January 2013 and published on the YouTube channel of the German Airway League with more than 70.000 clicks so far (27. February 2013). Conclusions: Pragmatic, internet-based video screens on the correct inhalation therapy are available and are cost-free. Further studies aimed at evaluating the benefits of these screens are necessary.© Georg Thieme Verlag KG Stuttgart.New York.


Walterspacher S.,University Hospital Freiburg | Walker D.J.,University Hospital Freiburg | Kabitz H.-J.,University Hospital Freiburg | Windisch W.,Lungenklinik Merheim | Dreher M.,University Hospital Freiburg
COPD: Journal of Chronic Obstructive Pulmonary Disease | Year: 2013

Stair climbing is associated with dynamic pulmonary hyperinflation and the development of severe dyspnea in patients with chronic obstructive pulmonary disease (COPD). This study aimed to assess whether (i) continuous positive airway pressure (CPAP) applied during stair climbing prevents dynamic hyperinflation and thereby reduces exercise-induced dyspnea in oxygen-dependent COPD-patients, and (ii) the CPAP-device and oxygen tank can be carried in a hip belt. In a randomised cross-over design, oxygen-dependent COPD patients performed two stair-climbing tests (44 steps): with supplemental oxygen only, then with the addition of CPAP (7 mbar). The oxygen tank and CPAP-device were carried in a hip belt during both trials. Eighteen COPD patients were included in the study. Although all patients could tolerate stair climbing with oxygen alone, 4 patients were unable to perform stair climbing while using CPAP. Fourteen COPD patients (mean FEV1 36 ± 14% pred.) completed the trial and were analyzed. The mean flow rate of supplemental oxygen was 3 ± 2 l/min during stair climbing. Lung hyperinflation, deoxygenation, hypoventilation, blood lactate production, dyspnea and the time needed to manage stair climbing were not improved by the application of CPAP (all p > 0.05). However, in comparison to climbing with oxygen alone, limb discomfort was reduced when oxygen was supplemented with CPAP (p = 0.008). In conclusion, very severe COPD patients are able to carry supporting devices such as oxygen tanks or CPAP-devices in a hip belt during stair climbing. However, the application of CPAP in addition to supplemental oxygen during stair climbing prevents neither exercise-induced dynamic hyperinflation, nor dyspnea. © 2013 Informa Healthcare USA, Inc.


Knipel V.,Lungenklinik Merheim | Windisch W.,Lungenklinik Merheim | Bayarassou A.H.,Lungenklinik Merheim
Pneumologe | Year: 2012

Diseases of the respiratory system increase with advancing age and contribute substantially to worldwide morbidity and mortality. With respect to the number of deaths pulmonary diseases constitute the third most frequent cause of death following cardiovascular diseases and neoplasms. Lower respiratory tract infections, chronic obstructive pulmonary disease, lung cancer and tuberculosis are among the top ten causes of death worldwide and asthma is globally one of the most common chronic diseases. Despite improved medical diagnostics and therapy the prevalence and morbidity have increased in recent years. Due to increased life expectation and declining morbidity the age structure of the German population will change in the coming years with the growing group of people aged 60 years or older. While diseases, such as chronic obstructive pulmonary disease, lung cancer and pneumonia predominantly affect older people, asthma and tuberculosis occur in all age groups. Worldwide, an increase in the prevalence of lung diseases is expected for the future. The healthcare costs increase disproportionally with advancing age, therefore, the demographic transition will have a decisive impact on the healthcare system. © Springer-Verlag 2012.


Wolter A.,Lungenklinik Merheim | Ludwig C.,Lungenklinik Merheim | Beckers F.,Lungenklinik Merheim | Stoelben E.,Lungenklinik Merheim
Pneumologie | Year: 2012

Background: Complications located at the tracheostoma often occur in combination with nosocomial infections. We posed the question: how is the surgical result in tracheal resections influenced by bacterial contamination with multiresistant germs? Patients and Methods: Between 2005 and 2009 we performed a primary end-to-end-resection of the trachea after tracheotomy in 30 patients. The demographic basic data, the diagnostic data on tracheal stenosis after decanullation and type of tracheotomy were documented. Preoperatively all patients underwent a flexible bronchoscopy with bronchial lavage. All patients received an antibiotic inhalation therapy postoperatively. Results: 16 patients presented a status post-permanent tracheotomy (PT), in 14 cases after percutaneous dilatative tracheotomy (PDT). In 64% of all cases the preoperative bronchial lavage was positive for bacterial contamination. The major pathogen was with 23% a multiresistant Pseudomonas aeruginosa (MR). In three cases long-term-complications occurred, all of which were bacterially contaminated. Conclusion: After long-term intubation a bacterial contamination is very common and presents a negative predictor for the outcome of primary tracheal end-to-end resections. A prophylactic postoperative antibiotic therapy can improve the short- and long-term results. © Georg Thieme Verlag KG Stuttgart - New York.


Knobloch J.,University of Cologne | Sibbing B.,University of Cologne | Jungck D.,University of Cologne | Lin Y.,University of Cologne | And 4 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2010

Chronic obstructive pulmonary disease (COPD) therapy is complicated by corticosteroid resistance of the interleukin 8 (IL-8)-dependent and granulocyte macrophage-colony stimulating factor (GM-CSF)-dependent chronic airway inflammation, for whose establishment human airway smooth muscle cells (HASMCs) might be crucial. It is unclear whether the release of inflammatory mediators from HASMCs is modulated by cigarette smoking and is refractory to corticosteroids in COPD. Resveratrol, an antiaging drug with protective effects against lung cancer, might be an alternative to corticosteroids in COPD therapy. Vascular endothelial growth factor (VEGF) might offer protection from developing emphysema. We tested the following hypotheses for HASMCs: 1) smoking with or without airway obstruction modulates IL-8, GM-CSF, and VEGF release; and 2) corticosteroids, but not resveratrol, fail to inhibit cytokine release in COPD. Cytokine release from HASMCs exposed to tumor necrosis factor α (TNFα), dexamethasone, and/or resveratrol was measured via enzyme-linked immunosorbent assay and compared between nonsmokers (NS), smokers without COPD (S), and smokers with COPD (all n = 10). In response to TNFα, IL-8 release was increased, but GM-CSF and VEGF release was decreased in S and COPD compared with NS. Dexamethasone and resveratrol inhibited concentration-dependently TNFα-induced IL-8, GM-CSF, and VEGF release. For IL-8 and GM-CSF efficiency of dexamethasone was NS > S > COPD. That of resveratrol was NS=S=COPD for IL-8 and NS= S < COPD for GM-CSF. For VEGF the efficiency of dexamethasone was NS = S = COPD, and that of resveratrol was NS = S > COPD. All resveratrol effects were partially based on p38 mitogen-activated protein kinase blockade. In conclusion, smoking modulates cytokine release from HASMCs. Corticosteroid refractoriness of HASMCs in COPD is cytokine-dependent. Resveratrol might be superior to corticosteroids in COPD therapy, because it more efficiently reduces the release of inflammatory mediators and has limited effects on VEGF in COPD. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics.

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