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Hulsmann H.J.,German Cancer Research Center | Rolff J.,Max Delbrück Center for Molecular Medicine | Rolff J.,Experimental Pharmacology and oOncology Berlin Buch GmbH | Bender C.,German Cancer Research Center | And 13 more authors.
Lung Cancer | Year: 2014

Objectives: The therapeutic scheme for non-small cell lung cancer (NSCLC) patients can be improved if adapted to the individual response. For example, 60-70% of adenocarcinoma patients show response to EGFR-tyrosine kinase inhibitors in the presence of mutated EGFR. We searched for additional target molecules involved in the action of the EGFR-tyrosine kinase inhibitor erlotinib in the absence of EGFR mutations, which might be suitable for combinatorial therapy approaches. Materials and Methods: Erlotinib-response associated proteins were investigated in patient-derived NSCLC mouse xenografts by reverse-phase protein array technology (RPPA) and Western blotting. A combinatorial treatment approach was carried out in NSCLC cell lines and H1299 mouse xenografts, and subsequently analyzed for consequences in cell growth and signal transduction. Results: AMP-activated protein kinase (AMPK) expression was increased in erlotinib responders before and after treatment. In a combinatorial approach, activation of AMPK by A-769662 and erlotinib treatment showed a synergistic effect in cell growth reduction and apoptosis activation in H1299 cells compared to the single drugs. AMPK pathway analyses revealed an effective inhibition of mTOR signaling by drug combination. In H1299 xenografts, the tumor size was significantly decreased after combinatorial treatment. Conclusion: Our results suggest that AMPK activation status affects response to erlotinib in distinct lung tumor models. © 2014 Elsevier Ireland Ltd.


Pabst S.,University of Bonn | Hammerstingl C.,University of Bonn | Grau N.,University of Bonn | Kreuz J.,University of Bonn | And 4 more authors.
Advances in Experimental Medicine and Biology | Year: 2013

Sarcoidosis is a systemic granulomatous disease with unknown etiology. Lungs and lymph nodes are commonly affected. Also, cases of pulmonary hypertension (PH) and pulmonary arterial hypertension (PAH) are described. However, the exact prevalence of PAH in patients with sarcoidosis is unclear. A 111 patients with proven sarcoidosis were recruited from January 2010 to October 2010. All patients were studied prospectively by transthoracic echocardiography (TTE) for the presence of PH. In assumed PH, a right heart catheterization (RHC) followed if there were no other reasons for PH. In 23 of the 111 patients (21%) PH was assumed in TTE. Three patients presented with severe mitral insufficiency III° and IV°, in eight patients PH was supposed to be caused by chronic heart failure or relevant diastolic dysfunction > II°, two patients declined undergoing RHC. Of the ten patients investigated with RHC, four showed a precapillary pulmonary arterial hypertension and in one patient a postcapillary hypertension was diagnosed. All four patients with precapillary PH had a radiologic stage III and IV. In three of the four patients a significantly reduced transfer factor for carbon monoxide (TLCO) <50% was found. All patients with precapillary PH had a chronic course of sarcoidosis lasting ≥13 years. This is the first study which prospectively investigated a large cohort of patients with sarcoidosis for the prevalence of PH and PAH. The prevalence of precapillary PH was found to be at least 3.6% (4/111) and therefore exceeds the prevalence of PAH in the normal population by far. A chronic and progressive lung involvement due to sarcoidosis seems to be the most evident risk factor for developing a sarcoidosis PH. © Springer Science+Business Media Dordrecht 2013.


Fischer A.,University of Kiel | Schmid B.,University of Kiel | Ellinghaus D.,University of Kiel | Nothnagel M.,University of Kiel | And 22 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2012

Rationale: Sarcoidosis is a complex inflammatory disease with a heterogeneous clinical picture. Among others, an acute and chronic clinical course can be distinguished, for which specific genetic risk factors are known. Objectives: To identify additional risk loci for sarcoidosis and its acute and chronic subforms, we analyzed imputed data from a genomewide association scan for these phenotypes. Methods: After quality control, the genome-wide association scan comprised nearly 1.3 million imputed single-nucleotide polymorphisms based on an Affymetrix 6.0 Gene Chip dataset of 564 German sarcoidosis cases, including 176 acute and 354 chronic cases and 1,575 control subjects. Measurements and Main Results:We identified chromosome 11q13.1 (rs479777) as a novel locus influencing susceptibility to sarcoidosis with genome-wide significance. The marker was significantly associated in three distinct German case-control populations and in an additional German family sample with odds ratios ranging from 0.67 to 0.77. This finding was further replicated in two independent European case-control populations from the Czech Republic (odds ratio, 0.75) and from Sweden (odds ratio, 0.79). In a meta-analysis of the included European case-control samples the marker yielded a P value of 2.68 3 10-18. The locus was previously reported to be associated with Crohn disease, psoriasis, alopecia areata, and leprosy. For sarcoidosis, fine-mapping and expression analysis suggest KCNK4, PRDX5, PCLB3, and most promising CCDC88B as candidates for the underlying risk gene in the associated region. Conclusions: This study provides striking evidence for association of chromosome 11q13.1 with sarcoidosis in Europeans, and thus identified a further genetic risk locus sharedby sarcoidosis, Crohndisease and psoriasis. Copyright © 2012 by the American Thoracic Society.


Schuler M.,University of Duisburg - Essen | Fischer J.R.,Klinik Lowenstein | Grohe C.,Evangelische. Lungenklinik | Gutz S.,Evangelisches Diakonissenkrankenhaus | And 5 more authors.
Oncologist | Year: 2014

Background: Afatinib, an irreversible ErbB family blocker, demonstrated superiority to chemotherapy as first-line treatment in patients with EGFR-mutated non-small cell lung cancer (NSCLC). Afatinib is also active in patients progressing on EGFR tyrosine kinase inhibitors (EGFR-TKIs). We report the results of a large cohort of NSCLC patients receiving afatinib within a compassionate-use program (CUP). Patients and Methods: Patients with advanced NSCLC progressing after one line or more of chemotherapy and one line or more of EGFR-TKI treatment with either an EGFR mutation or documented clinical benefit were enrolled. Data collection was not monitored or verified by central review. The intention of this CUP was to provide controlled preregistration access to afatinib for patients with life-threatening diseases and no other treatment option. Results: From May 2010 to October 2013, 573 patients (65% female; median age: 64 years [range: 28–89 years]) were enrolled, with strong participation of community oncologists. Comorbidities were allowed, including second malignancies in 11% of patients. EGFR mutation status was available in 391 patients (72%), and 83% tested mutation positive. Median time to treatment failure (TTF) of 541 patients treated with afatinib was 3.7 months (range: 0.0 to >29.0 months). Median TTF was 4.0 and 2.7 months in patients with adenocarcinomas and squamous cell carcinomas, respectively, and 4.6 months in patients with EGFR-mutated NSCLC. Adverse events were generally manageable. Conclusion: Afatinib was able to be given in a real-world setting to heavily pretreated patients with EGFR-mutated or EGFR-TKI-sensitive NSCLC. Acknowledging the constraints of data collection in a CUP, afatinib appears to be safe and to confer some clinical benefit in this population. ©AlphaMed Press 2014.


Hammer S.,Bayer AG | Sommer A.,Bayer AG | Fichtner I.,Max Delbrück Center for Molecular Medicine | Fichtner I.,Experimental Pharmacology and Oncology GmbH | And 7 more authors.
Clinical Cancer Research | Year: 2010

Purpose: Characterization of new anticancer drugs in a few xenograft models derived from established human cancer cell lines frequently results in the discrepancy between preclinical and clinical results. To take the heterogeneity of tumors into consideration more thoroughly, we describe here a preclinical approach that may allow a more rational clinical development of new anticancer drugs. Experimental Design: We tested Sagopilone, an optimized fully synthetic epothilone, in 22 well-characterized patient-derived non-small cell lung cancer models and correlated results with mutational and genome-wide gene expression analysis. Results: Response analysis according to clinical trial criteria revealed that Sagopilone induced overall responses in 64% of the xenograft models (14 of 22), with 3 models showing stable disease and 11 models showing partial response. A comparison with response rates for established drugs showed the strong efficacy of Sagopilone in non-small cell lung cancer. In gene expression analyses, Sagopilone induced tubulin isoforms in all tumor samples, but genes related to mitotic arrest only in responder models. Moreover, tumors with high expression of genes involved in cell adhesion/angiogenesis as well as of wild-type TP53 were more likely to be resistant to Sagopilone therapy. As suggested by these findings, Sagopilone was combined with Bevacizumab and Sorafenib, drugs targeting vascular endothelial growth factor signaling, in Sagopilone-resistant models and, indeed, antitumor activity could be restored. Conclusion: Analyses provided here show how preclinical studies can provide hypotheses for the identification of patients who more likely will benefit from new drugs as well as a rationale for combination therapies to be tested in clinical trials. ©2010 AACR.


Wormanns D.,Evangelische Lungenklinik | Hamer O.W.,University of Regensburg
RoFo Fortschritte auf dem Gebiet der Rontgenstrahlen und der Bildgebenden Verfahren | Year: 2015

The Fleischner Society has published several recommendations for terms for thoracic imaging. The most recent glossary was released in 2008. One glossary in German language was published in 1996. This review provides an updated German glossary of terms for thoracic imaging. It closely adheres to the Fleischner Society terminology. In some instances adaptions to the usage of German language were necessary, as well as some additions of terms which were later defined or redefined. These deviations are summarized in a revision report. Key Points: • The Fleischner Society has published a revised version of her glossary of terms for thoracic imaging in 2008. This paper presents a German adaption of this glossary. • Some terms not contained in the original version have been added. • The general use of the presented terminology in radiological reports is recommended. © Georg Thieme Verlag KG Stuttgart New York.


Boehm O.,University of Bonn | Knuefermann P.,University of Bonn | Plueck J.,University of Bonn | Schwederski M.,University of Bonn | And 11 more authors.
Journal of Inflammation (United Kingdom) | Year: 2013

Background: Bacteria such as Staphylococcus aureus induce myocardial dysfunction in vivo. To rectify conflicting evidence about the role of TLR2 signaling and cardiac dysfunction, we hypothesized that the specific TLR2 agonist purified lipoteichoic acid (LTA) from S. aureus contributes to cardiac dysfunction in vitro and in vivo. Methods. Wildtype (WT-) and TLR2-deficient (TLR2-D) mice were challenged with LTA and in comparison with equivalent doses of lipopolysaccharide (LPS) and CpG-oligodeoxynucleotide (CpG-ODN). TLR2-expression, NFκB as well as cytokine response were determined. Sarcomere shortening of isolated cardiomyocytes was analyzed in vitro and cardiac function in vivo after stimulation with LTA. Results: LTA induced up-regulation of TLR2 mRNA, activation of NFκB and cytokine expression within 2-6 h in WT-, but not in TLR2-D hearts. Cytokines were also elevated in the serum. LPS and CpG-ODN induced a more severe cardiac inflammation. In vitro incubation of cardiomyocytes with LTA reduced sarcomere shortening via NO at stimulation frequencies ≤ 8 Hz only in WT cells. However, hemodynamic parameters in vivo were not affected by LTA challenge. Conclusions: LTA induced cardiac inflammation was relatively weak and sarcomere shortening was reduced only below physiological heart rates. This may explain the apparent contradiction between the in vivo and in vitro LTA effects. © 2013 Boehm et al.;licensee BioMed Central Ltd.


PubMed | Evangelische Lungenklinik and University of Regensburg
Type: Journal Article | Journal: RoFo : Fortschritte auf dem Gebiete der Rontgenstrahlen und der Nuklearmedizin | Year: 2015

The Fleischner Society has published several recommendations for terms for thoracic imaging. The most recent glossary was released in 2008. One glossary in German language was published in 1996. This review provides an updated German glossary of terms for thoracic imaging. It closely adheres to the Fleischner Society terminology. In some instances adaptions to the usage of German language were necessary, as well as some additions of terms which were later defined or redefined. These deviations are summarized in a revision report.The Fleischner Society has published a revised version of her glossary of terms for thoracic imaging in 2008. This paper presents a German adaption of this glossary. Some terms not contained in the original version have been added. The general use of the presented terminology in radiological reports is recommended.


PubMed | University of Bonn, Germany; Experimental Pharmacology & Oncology Berlin Buch GmbH, Max Planck Institute for Molecular Genetics, Max Delbrück Center for Molecular Medicine and 3 more.
Type: Journal Article | Journal: Lung cancer (Amsterdam, Netherlands) | Year: 2014

The therapeutic scheme for non-small cell lung cancer (NSCLC) patients can be improved if adapted to the individual response. For example, 60-70% of adenocarcinoma patients show response to EGFR-tyrosine kinase inhibitors in the presence of mutated EGFR. We searched for additional target molecules involved in the action of the EGFR-tyrosine kinase inhibitor erlotinib in the absence of EGFR mutations, which might be suitable for combinatorial therapy approaches.Erlotinib-response associated proteins were investigated in patient-derived NSCLC mouse xenografts by reverse-phase protein array technology (RPPA) and Western blotting. A combinatorial treatment approach was carried out in NSCLC cell lines and H1299 mouse xenografts, and subsequently analyzed for consequences in cell growth and signal transduction.AMP-activated protein kinase (AMPK) expression was increased in erlotinib responders before and after treatment. In a combinatorial approach, activation of AMPK by A-769662 and erlotinib treatment showed a synergistic effect in cell growth reduction and apoptosis activation in H1299 cells compared to the single drugs. AMPK pathway analyses revealed an effective inhibition of mTOR signaling by drug combination. In H1299 xenografts, the tumor size was significantly decreased after combinatorial treatment.Our results suggest that AMPK activation status affects response to erlotinib in distinct lung tumor models.

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