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Von Pawel J.,Asklepios Fachkliniken Munich Gauting | Harvey J.H.,Alabama Oncology | Spigel D.R.,Sarah Cannon Research Institute | Dediu M.,Institute Of Oncology Prof Dr Alexandru Trestioreanu | And 5 more authors.
Clinical Lung Cancer | Year: 2014

Background This phase II study examined the efficacy of mapatumumab in combination with paclitaxel and carboplatin in patients with non-small-cell lung cancer (NSCLC). Patients and Methods Patients with stage IIIB or stage IV advanced primary NSCLC were randomly assigned (1:1:1) to receive up to 6 courses of standard-dose paclitaxel and carboplatin or a combination of paclitaxel, carboplatin, and mapatumumab (10 mg/kg or 30 mg/kg). Primary efficacy end points were overall response rate and median progression-free survival (PFS). Secondary efficacy end points included disease control rate, overall survival (OS), time to response, and duration of response. Exploratory studies included evaluation of historical biopsy materials for TRAIL-R1 expression by immunohistochemical analysis and serum levels of M30, a marker of apoptosis, before and after the first 2 doses of mapatumumab. Safety parameters, including adverse events (AEs), laboratory tests, and immunogenicity, were assessed. Results The majority of patients had stage IV disease (79%) and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (58%); baseline characteristics were similar across treatment arms. No improvements in response or disease control rates, PFS, or OS were gained from the addition of mapatumumab. Adverse events in the mapatumumab arms were generally consistent with toxicities seen in the carboplatin and paclitaxel control arm. Levels of M30 were highly variable, and consistent patterns were not seen across treatment arms. Conclusion This study showed no clinical benefit from adding mapatumumab to carboplatin and paclitaxel in unselected patients with NSCLC. The combination was generally well tolerated. The possibility of subgroups sensitive to mapatumumab is discussed. © 2014 Elsevier Inc. All rights reserved.


PubMed | Asklepios Fachkliniken Munich Gauting and Zweigniederlassung der synlab MVZ Augsburg GmbH
Type: Journal Article | Journal: Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases | Year: 2016

QuantiFERON-TB Gold IT analyses interferon- release from CD4(+) T cells after stimulation with specific tuberculosis (TB) antigens. Its sensitivity is approximately 80% for active TB. A new test generation (QFTGplus) also analyses the response of CD8(+) T cells. We investigated both test generations in a direct head-to-head comparison in a German pulmonary hospital. Sensitivity rates for active TB were identical, no matter whether diagnosis was bacteriologically confirmed or not.


Manegold C.,University of Mannheim | Vansteenkiste J.,University Hospital Gasthuisberg | Cardenal F.,08907 LHospitalet Barcelona | Schuette W.,Krankenhaus Martha Maria Halle Dolau | And 5 more authors.
Investigational New Drugs | Year: 2013

Summary: Introduction This multicenter, open-label, phase II study was carried out to compare the efficacy and safety of cilengitide (EMD 121974), a selective inhibitor of the cell-surface integrins αVβ3 and αVβ5, with that of docetaxel in patients with advanced non-small-cell lung cancer (NSCLC). Methods Patients (n = 140) with advanced NSCLC who had failed first-line chemotherapy were randomized to cilengitide 240, 400, or 600 mg/m2 twice weekly, or docetaxel 75 mg/m2 once every 3 weeks for eight cycles. Non-progressing patients could continue cilengitide for up to 1 year. The primary endpoint was progression-free survival (PFS). No statistical tests were performed since the study was exploratory in nature and the number of patients enrolled was relatively small. Results Median PFS was 54, 63, 63, and 67 days for cilengitide 240, 400, and 600 mg/m2, and docetaxel 75 mg/m2, respectively. One-year survival rates were 13 %, 13 %, 29 %, and 27 %, respectively. The response rate (partial response only) with docetaxel was 15 %. No responses were reported in any cilengitide arm. The most frequent grade 3/4 treatment-related adverse events in the docetaxel group were leukopenia and neutropenia (experienced by 13 % of patients). Hematologic toxicity of this severity did not occur in cilengitide-treated patients. Conclusion With the highest dose of cilengitide (600 mg/m2), median PFS and 1-year survival were similar to those in patients treated with docetaxel 75 mg/m2 and there were fewer grade 3/4 treatment-related adverse events. © 2012 The Author(s).


Chiappori A.A.,H. Lee Moffitt Cancer Center and Research Institute | Kolevska T.,Kaiser Permanente | Spigel D.R.,Sarah Cannon Research Institute | Hager S.,Cancer Care Associates of Fresno Medical Group | And 9 more authors.
Annals of Oncology | Year: 2015

Imetelstat, a novel telomerase inhibitor, failed to improve significantly median PFS and OS as maintenance therapy (±bevacizumab) in advanced NSCLC. Telomere length (TL) biomarker results were consistent with the hypothesis that telomerase inhibition is of greater benefit to patients with tumors possessing shorter telomeres; the patients with shorter TL had a trend toward longer median PFS and OS. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Moller W.,Helmholtz Center for Environmental Research | Saba G.K.,Helmholtz Center for Environmental Research | Haussinger K.,Asklepios Fachkliniken Munich Gauting | Becker S.,Ludwig Maximilians University of Munich | And 2 more authors.
Rhinology | Year: 2011

Objectives: Topical delivery of drugs to the sinuses is challenging and requires also particular administration manoeuvres from the patient. This study was conducted to investigate 1) the delivery efficiency of a pulsating aerosol (Vibrent prototype device) to the sinuses and the nose, 2) the aerosol fraction that will deposit in the lungs and 3) potential differences regarding sinus and nasal deposition ratio when comparing aerosol administration during two different administration routes. Methods: An open label deposition study in healthy volunteers was conducted using 99mTc-DTPA radiolabeled pulsating aerosols in comparison to nasal pump sprays. Deposition and retention of pulsating aerosols was assessed by gamma camera imaging during spontaneous nasal breathing and during closed soft palate administration. Results: Aerosol administration during nasal breathing vs. application with closed soft plate results in significant lung, nasal and sinus deposition. No significant differences were observed for nasal clearance. In comparison, drug delivery using nasal pump sprays resulted in non-significant sinus, 100% nasal and non-significant lung deposition. The clearance kinetics after nasal pump spray delivery was significantly accelerated. Discussion: The standard application mode of pulsation aerosols with closed soft palate results in negligible lung deposition and therefore limits drug delivery to the nasal cavity only, minimizing unwanted side effects. Administration during spontaneous nasal breathing shows only 10% lung deposition, which is tolerable during drug administration. Relevant paranasal sinus deposition is noted during both application modes and clearance kinetics remains essentially unchanged. In contrast, nasal pump sprays do not show sinus drug delivery and nasal drug residence time is shortened. Conclusion: Pulsating aerosols offer advantageous topical nasal and sinus drug delivery options.


Frankenberger M.,Helmholtz Center Munich | Eder C.,Helmholtz Center Munich | Hofer T.P.J.,Helmholtz Center Munich | Heimbeck I.,Helmholtz Center Munich | And 5 more authors.
Molecular Medicine | Year: 2011

Small sputum macrophages represent highly active cells that increase in the airways of patients with inflammatory diseases such as chronic obstructive pulmonary disease (COPD). It has been reported often that levels of cytokines, chemokines and proteases are increased in sputum supernatants of these patients. In COPD, the small sputum macrophages may contribute to these supernatant proteins and recruit additional cells via specific chemokine expression patterns. We therefore investigated the expression profile of chemokines in sputum macrophages obtained from COPD patients in comparison to cells from healthy donors and cells isolated after inhalation of lipopolysaccharide (LPS). We used the minimally invasive procedure of sputum induction and have purified macrophages with the RosetteSep technology. Using macrophage purification and flow cytometry we show that in COPD small sputum macrophages account for 85.9% ± 8.3% compared with 12.9% ± 7.1% of total macrophages in control donors. When looking at chemokine expression we found, for the small macrophages in COPD, increased transcript and protein levels for CCL2, CCL7, CCL13 and CCL22 with a more than 100-fold increase for CCL13 mRNA (P < 0.001). Looking at active smokers without COPD, there is a substantial increase of small macrophages to 60% ± 15% and, here, chemokine expression is increased as well. In a model of airway inflammation healthy volunteers inhaled 20 μg of lipopolysaccharide (LPS), which resulted in an increase of small sputum macrophages from 18% ± 19% to 64% ± 25%. The pattern of chemokine expression was, however, different with an upregulation for CCL2 and CCL7, while CCL13 was downregulated three-fold in the LPS-induced small macrophages. These data demonstrate that sputum macrophages in COPD show induction of a specific set of CCL chemokines, which is distinct from what can be induced by LPS. © 2011 The Feinstein Institute for Medical Research.


Gesierich W.,Asklepios Fachkliniken Munich Gauting
Medical Laser Application | Year: 2010

Lasers are valuable tools in pulmonary medicine. Endobronchial photoresection with the Nd:YAG laser is well-established in interventional bronchoscopy. Photodynamic therapy (PDT), which uses monochromatic laser light to activate photosensitizers, has several proven and experimental indications in pulmonary medicine. Lasers serve as the light source in autofluorescence bronchoscopy (AFB), which has aided pulmonologists for nearly two decades in the early diagnosis of lung cancer. They also feature in fibered confocal fluorescence microscopy (FCFM), which promises to extend endoscopic visibility in clinical medicine to the cellular level. This paper is a review of these laser applications and their clinical results. © 2009 Elsevier GmbH. All rights reserved.


Management of respiratory allergies comprises prevention of exposure to allergens, pharmacologic treatment with controllers and relievers and specific immunotherapy (SIT). Omalizumab is an immunomodulating agent the use of which is confined to asthma which cannot otherwise be treated. Avoiding exposure to tobacco smoke is easily implemented and effective. Controlling airway inflammation primarily by inhaled glucocorticosteroids is of high significance and is already to be applied at step 2 in a 5-step treatment. In managing allergic rhinitis topical glucocorticosteroids are likewise of high significance. The SIT as a causal approach is proven in either form of application in treatment of rhinitis but the efficacy in asthma is still limited. Concerning sublingual immunotherapy (SLIT) in treatment of asthma a conclusive appraisal is not yet permitted. © Springer-Verlag Berlin Heidelberg 2012.


Staab-Weijnitz C.A.,Helmholtz Center Munich | Fernandez I.E.,Helmholtz Center Munich | Knuppel L.,Helmholtz Center Munich | Maul J.,Helmholtz Center Munich | And 11 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2015

Rationale: Increased abundance and stiffness of the extracellular matrix, in particular collagens, is a hallmark of idiopathic pulmonary fibrosis (IPF). FK506-binding protein 10 (FKBP10) is a collagen chaperone, mutations of which have been indicated in the reduction of extracellular matrix stiffness (e.g., in osteogenesis imperfecta). Objectives: To assess the expression and function of FKBP10 in IPF. Methods: We assessed FKBP10 expression in bleomycin-induced lung fibrosis (using quantitative reverse transcriptase-polymerase chain reaction, Western blot, and immunofluorescence), analyzed microarray data from 99 patients with IPF and 43 control subjects from a U.S. cohort, and performed Western blot analysis from 6 patients with IPF and 5 control subjects from a German cohort. Subcellular localization of FKBP10 was assessed by immunofluorescent stainings. The expression and function of FKBP10, as well as its regulation by endoplasmic reticulum stress or transforming growth factor-β1, was analyzed by small interfering RNA-mediated loss-of-function experiments, quantitative reverse transcriptase-polymerase chain reaction, Western blot, and quantification of secreted collagens in the lung and in primary human lung fibroblasts (phLF). Effects on collagen secretion were compared with those of the drugs nintedanib and pirfenidone, recently approved for IPF. Measurements and Main Results: FKBP10 expression was up-regulated in bleomycin-induced lung fibrosis and IPF. Immunofluorescent stainings demonstrated localization to interstitial (myo)fibroblasts and CD68+ macrophages. Transforming growth factor-β1, but not endoplasmic reticulum stress, induced FKBP10 expression in phLF. The small interfering RNA-mediated knockdown of FKBP10 attenuated expression of profibrotic mediators and effectors, including collagens I and V and α-smooth muscle actin, on the transcript and protein level. Importantly, loss of FKBP10 expression significantly suppressed collagen secretion by phLF. Conclusions: FKBP10 might be a novel drug target for IPF. Copyright © 2015 by the American Thoracic Society.


The prevalence of allergies has increased worldwide in the last decades but the prevalence as well as the dynamics of the increase vary in different countries and regions without obvious conclusive reasons. In some countries including Germany a plateau has been reached. Allergies pose a challenge for clinicians but early diagnosis can reduce subsequent damage. Diagnostic procedures are clearly structured and are based on a valid and comprehensive medical history. Suspected sensitization can be confirmed or excluded by the results of skin tests. Serological screening completes the diagnostic procedure and in rare cases this is the only tool for in vitro diagnostics. The gold standard is the respiratory challenge test; however, this test must be performed under specified conditions. Based on a clear diagnosis, measures including prevention and medical treatment can be derived. © Springer-Verlag 2012.

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