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Petersen I.,University Hospital Jena | Warth A.,University of Heidelberg | Warth A.,Translational Lung Research Center Heidelberg
Journal of Cancer Research and Clinical Oncology | Year: 2015

Introduction: Diagnostic methods and algorithms for the diagnosis of pulmonary neoplasms have considerably changed over the recent years. Based on large-scale molecular characterization studies and the development of targeted therapies, precise morphological, immunohistochemical, and molecular pathological tumor subtyping is now of utmost importance for evidence-based treatment decisions. Changes of diagnostic concepts initially referred to biopsies and cytology specimens but are now also transferred to resection specimens. Methods: This review is focused on recent developments in morphological and immunohistochemical subtyping of pulmonary neoplasms and concepts of tumor progression. It also provides perspectives on relevant changes of diagnostic concepts within the context of the new WHO classification. Conclusion: It becomes apparent that a three-step diagnostic concept based on morphology, immunohistochemistry, and molecular pathology is important to meet the requirements of an increasingly more complex, interdisciplinary care of lung cancer patients and to allow for reliable, clinically meaningful tumor diagnoses. © 2015 Springer-Verlag Berlin Heidelberg

Mall M.A.,Translational Lung Research Center Heidelberg | Mall M.A.,University of Heidelberg | Galietta L.J.V.,Istituto Giannina Gaslini
Journal of Cystic Fibrosis | Year: 2015

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause a characteristic defect in epithelial ion transport that plays a central role in the pathogenesis of cystic fibrosis (CF). Hence, pharmacological correction of this ion transport defect by targeting of mutant CFTR, or alternative ion channels that may compensate for CFTR dysfunction, has long been considered as an attractive approach to a causal therapy of this life-limiting disease. The recent introduction of the CFTR potentiator ivacaftor into the therapy of a subgroup of patients with specific CFTR mutations was a major milestone and enormous stimulus for seeking effective ion transport modulators for all patients with CF. In this review, we discuss recent breakthroughs and setbacks with CFTR modulators designed to rescue mutant CFTR including the common mutation F508del. Further, we examine the alternative chloride channels TMEM16A and SLC26A9, as well as the epithelial sodium channel ENaC as alternative targets in CF lung disease, which remains the major cause of morbidity and mortality in patients with CF. Finally, we will focus on the hurdles that still need to be overcome to make effective ion transport modulation therapies available for all patients with CF irrespective of their CFTR genotype. © 2015 European Cystic Fibrosis Society.

Berger M.M.,Paracelsus Medical University | Berger M.M.,University of Heidelberg | Macholz F.,Paracelsus Medical University | Mairbaurl H.,University of Heidelberg | And 2 more authors.
Journal of Applied Physiology | Year: 2015

Berger MM, Macholz F, Mairbäurl H, Bärtsch P. Remote ischemic preconditioning for prevention of high-altitude diseases: fact or fiction? J Appl Physiol 119: 1143-1151, 2015. First published June 18, 2015; doi:10.1152/japplphysiol.00156.2015.- Preconditioning refers to exposure to brief episodes of potentially adverse stimuli and protects against injury during subsequent exposures. This was first described in the heart, where episodes of ischemia/reperfusion render the myocardium resistant to subsequent ischemic injury, which is likely caused by reactive oxygen species (ROS) and proinflammatory processes. Protection of the heart was also found when preconditioning was performed in an organ different from the target, which is called remote ischemic preconditioning (RIPC). The mechanisms causing protection seem to include stimulation of nitric oxide (NO) synthase, increase in antioxidant enzymes, and downregulation of proinflammatory cytokines. These pathways are also thought to play a role in high-altitude diseases: high-altitude pulmonary edema (HAPE) is associated with decreased bioavailability of NO and increased generation of ROS, whereas mechanisms causing acute mountain sickness (AMS) and high-altitude cerebral edema (HACE) seem to involve cytotoxic effects by ROS and inflammation. Based on these apparent similarities between ischemic damage and AMS, HACE, and HAPE, it is reasonable to assume that RIPC might be protective and improve altitude tolerance. In studies addressing high-altitude/hypoxia tolerance, RIPC has been shown to decrease pulmonary arterial systolic pressure in normobaric hypoxia (13% O2) and at high altitude (4,342 m). Our own results indicate that RIPC transiently decreases the severity of AMS at 12% O2. Thus preliminary studies show some benefit, but clearly, further experiments to establish the efficacy and potential mechanism of RIPC are needed. © 2015 The American Physiological 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.

Mall M.A.,Translational Lung Research Center Heidelberg | Mall M.A.,University of Heidelberg | Boucher R.C.,University of North Carolina at Chapel Hill
European Respiratory Monograph | Year: 2014

Chronic obstructive lung disease starting in the first months of life remains the major cause of morbidity and mortality in patients with cystic fibrosis (CF). The discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene 25 years ago paved the way for investigation of the molecular and cellular basis of CF lung disease, and the generation of animal models forin vivostudies of pathogenesis. In this chapter, we focus on major advances in the understanding of the link between mutations in CFTR and the predictable development of chronic mucus obstruction, inflammation and infection of CF airways. We discuss evidence from translational studies supporting the concept that increased mucus concentration (i.e. dehydration) and reduced pH of the airway surface layer are key abnormalities underlying impaired innate defence of the CF lung. Novel therapeutic strategies targeting these defects may be successful for the prevention and treatment of CF lung disease independent of the patient's CF genotype.

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