Olsson K.M.,Hannover Medical School |
Delcroix M.,University Hospitals of Leuven |
Ghofrani H.A.,Justus Liebig University |
Tiede H.,Justus Liebig University |
And 24 more authors.
Circulation | Year: 2014
BACKGROUND-: For almost 30 years, anticoagulation has been recommended for patients with idiopathic pulmonary arterial hypertension (IPAH). Supporting evidence, however, is limited, and it is unclear whether this recommendation is still justified in the modern management era and whether it should be extended to patients with other forms of pulmonary arterial hypertension (PAH). METHODS AND RESULTS-: We analyzed data from Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA), an ongoing European pulmonary hypertension registry. Survival rates of patients with IPAH and other forms of PAH were compared by the use of anticoagulation. The sample consisted of 1283 consecutively enrolled patients with newly diagnosed PAH. Anticoagulation was used in 66% of 800 patients with IPAH and in 43% of 483 patients with other forms of PAH. In patients with IPAH, there was a significantly better 3-year survival (P=0.006) in patients on anticoagulation compared with patients who never received anticoagulation, albeit the patients in the anticoagulation group had more severe disease at baseline. The survival difference at 3 years remained statistically significant (P=0.017) in a matched-pair analysis of n=336 IPAH patients. The beneficial effect of anticoagulation on survival of IPAH patients was confirmed by Cox multivariable regression analysis (hazard ratio, 0.79; 95% confidence interval, 0.66-0.94). In contrast, the use of anticoagulants was not associated with a survival benefit in patients with other forms of PAH. CONCLUSIONS-: The present data suggest that the use of anticoagulation is associated with a survival benefit in patients with IPAH, supporting current treatment recommendations. The evidence remains inconclusive for other forms of PAH. CLINICAL TRIAL REGISTRATION-: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01347216. © 2013 American Heart Association, Inc.
Brahmer J.,Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins |
Reckamp K.L.,City of Hope Comprehensive Cancer Center |
Baas P.,Netherlands Cancer Institute |
Crino L.,University of Perugia |
And 21 more authors.
New England Journal of Medicine | Year: 2015
BACKGROUND Patients with advanced squamous-cell non-small-cell lung cancer (NSCLC) who have disease progression during or after first-line chemotherapy have limited treatment options. This randomized, open-label, international, phase 3 study evaluated the efficacy and safety of nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody, as compared with docetaxel in this patient population. METHODS We randomly assigned 272 patients to receive nivolumab, at a dose of 3 mg per kilogram of body weight every 2 weeks, or docetaxel, at a dose of 75 mg per square meter of body-surface area every 3 weeks. The primary end point was overall survival. RESULTS The median overall survival was 9.2 months (95% confidence interval [CI], 7.3 to 13.3) with nivolumab versus 6.0 months (95% CI, 5.1 to 7.3) with docetaxel. The risk of death was 41% lower with nivolumab than with docetaxel (hazard ratio, 0.59; 95% CI, 0.44 to 0.79; P<0.001). At 1 year, the overall survival rate was 42% (95% CI, 34 to 50) with nivolumab versus 24% (95% CI, 17 to 31) with docetaxel. The response rate was 20% with nivolumab versus 9% with docetaxel (P = 0.008). The median progression-free survival was 3.5 months with nivolumab versus 2.8 months with docetaxel (hazard ratio for death or disease progression, 0.62; 95% CI, 0.47 to 0.81; P<0.001). The expression of the PD-1 ligand (PD-L1) was neither prognostic nor predictive of benefit. Treatment-related adverse events of grade 3 or 4 were reported in 7% of the patients in the nivolumab group as compared with 55% of those in the docetaxel group. CONCLUSIONS Among patients with advanced, previously treated squamous-cell NSCLC, overall survival, response rate, and progression-free survival were significantly better with nivolumab than with docetaxel, regardless of PD-L1 expression level. Copyright © 2015 Massachusetts Medical Society.
Groschel A.,Luisenhospital |
Warth A.,Universitatsklinikum Heidelberg |
Reinmuth N.,Lungenclinic Grosshansdorf
Pneumologie | Year: 2013
The anaplastic lymphoma kinase (ALK) can act as a key oncogenic driver after activation by means of processes such as gene rearrangement. In approximately 5 % of patients with advanced non-small cell lung cancer (NSCLC), an oncogenic fusion gene of echinoderm microtubule-associated protein-like 4 (EML4) and ALK has been detected using fluorescence in situ hybridisation (FISH). Moreover, various methods including immunohistochemistry and PCR-based assays can be used for analysing ALK expression. Clinical data have been generated for crizotinib, a small molecule inhibitor of the ALK receptor tyrosine kinase, demonstrating a substantial improvement of objective response rate and prolonged progression-free survival (PFS) compared to standard chemotherapy in pretreated NSCLC patients harbouring EML4-ALK fusion genes. In the current review, recent data on the detection and inhibition of ALK in advanced NSCLC are summarised. © Georg Thieme Verlag KG Stuttgart · New York.
Cagnoni E.F.,University of Sao Paulo |
Ferreira D.S.,University of Sao Paulo |
Ferraz Da Silva L.F.,University of Sao Paulo |
Nicoletti Carvalho Petry A.L.,University of Sao Paulo |
And 5 more authors.
Journal of Allergy and Clinical Immunology | Year: 2015
Background Immune responses in asthmatic patients involve coordinated cellular responses in the airways and lymph nodes (LNs). However, no studies have described the composition of different cell populations in the bronchopulmonary LNs of asthmatic patients. Objective We sought to investigate the expression of dendritic cells (DCs) and costimulatory molecules, B cells, T cells, TH2-related cytokines, eosinophils, and vascular cell adhesion molecule in the bronchopulmonary LNs and large airways of asthmatic patients. Methods Using histochemistry, immunohistochemistry, and image analysis, we investigated the expression of Factor XIIIa+, CD1a+, CD83+, and CD207+ DCs; CD4+ and CD8+ T cells; CD20+ B cells; CD23+ (FcεRII) cells; IL-4; IL-5; eosinophils, and vascular cell adhesion molecule 1 in the large airways and bronchopulmonary LNs of 11 nonsmokers who died from an asthma exacerbation (fatal asthma [FA]) in comparison with 8 nonasthmatic control subjects. In selected cases of FA, we analyzed the coexpression of HLA-DR, CD40, and CD80 in lung and LN eosinophils. Results The LNs of asthmatic patients exhibited increased density of eosinophils. No other cells were expressed differently in the LNs of patients with FA. The large airways of patients with FA had increased expression of eosinophils in all layers and increased expression of Factor XIIIa+ cells, CD4+ and CD8+ T cells, CD20+ B cells, and CD23+ cells in the outer layer. There was colocalization of HLA-DR, CD40, and CD80 in the eosinophils at both sites. Conclusions FA is associated with the increased presence of eosinophils in the LNs and large airways, which express HLA-DR and costimulatory molecules. The expression of Factor XIIIa+ monocyte-derived DCs, CD4+ and CD8+ T cells, CD20+ B cells, and CD23+ cells was increased in the large airways without a corresponding increase in the expression of these cells in the bronchopulmonary LNs. These findings support the concept that eosinophils might act as antigen-presenting cells in patients with FA. © 2015 American Academy of Allergy, Asthma & Immunology.
Jager J.,TU Braunschweig |
Marwitz S.,Research Center Borstel |
Marwitz S.,Airway Research Center North |
Tiefenau J.,TU Braunschweig |
And 8 more authors.
Infection and Immunity | Year: 2014
Histological and clinical investigations describe late stages of Legionnaires' disease but cannot characterize early events of human infection. Cellular or rodent infection models lack the complexity of tissue or have nonhuman backgrounds. Therefore, we developed and applied a novel model for Legionella pneumophila infection comprising living human lung tissue. We stimulated lung explants with L. pneumophila strains and outer membrane vesicles (OMVs) to analyze tissue damage, bacterial replication, and localization as well as the transcriptional response of infected tissue. Interestingly, we found that extracellular adhesion of L. pneumophila to the entire alveolar lining precedes bacterial invasion and replication in recruited macrophages. In contrast, OMVs predominantly bound to alveolar macrophages. Specific damage to septa and epithelia increased over 48 h and was stronger in wild-type-infected and OMV-treated samples than in samples infected with the replication-deficient, type IVB secretiondeficient DotA- strain. Transcriptome analysis of lung tissue explants revealed a differential regulation of 2,499 genes after infection. The transcriptional response included the upregulation of uteroglobin and the downregulation of the macrophage receptor with collagenous structure (MARCO). Immunohistochemistry confirmed the downregulation of MARCO at sites of pathogen-induced tissue destruction. Neither host factor has ever been described in the context of L. pneumophila infections. This work demonstrates that the tissue explant model reproduces realistic features of Legionnaires' disease and reveals new functions for bacterial OMVs during infection. Our model allows us to characterize early steps of human infection which otherwise are not feasible for investigations. © 2014, American Society for Microbiology.
Schneider A.,TU Munich |
Faderl B.,TU Munich |
Schwarzbach J.,TU Munich |
Welker L.,Lungenclinic Grosshansdorf |
And 2 more authors.
Respiratory Medicine | Year: 2014
Objectives: To compare the prognostic value of FENO with bronchoprovocation testing when the clinical course within the first year after assessment was taken into account; to compare the prognostic values with respect to eosinophilic versus non-eosinophilic inflammatory pattern. Methods: Cross-sectional diagnostic study with a delayed-type reference standard in 393 patients attending a private practice of pneumologists with complaints suspicious of obstructive airway disease. Index test: FENO measurement. Reference standard: ratio FEV1/VC or airway resistance assessed by body plethysmography, with additional bronchoprovocation or bronchodilator testing, as well as spontaneous sputum (smear slides). This was combined with a follow-up evaluation by a structured interview after 12 months. Results: 302 (76.8%) patients were reached for follow-up. Regarding asthma diagnosis, the area under the curve (AUC) for FENO was 0.603 (95%CI 0.528-0.677) for the whole group. With eosinophilic asthma as target, AUC increased (0.819 (95%CI 0.703-0.934)) and exceeded that of bronchoprovocation (0.711 (95%CI 0.584-0.874)). FENO showed no diagnostic value in non-eosinophilic asthma. In patients reporting wheezing and allergic rhinitis at the initial assessment, its positive predictive value was 90.9% (95%CI 62.3%-98.4) at a cut-off of 45 ppb, and 100% (95%CI 56.6-100%) at 81 ppb. Conclusions: FENO bears limited information when measured non-specifically in primary care, but is useful for diagnosing eosinophilic asthma. If sputum is not available, information on wheezing and rhinitis can narrow down the range of patients in whom FENO is informative. Moreover, the evaluation of the clinical value of FENO benefits from taking into account follow-up data to confirm the diagnosis. © 2013 Elsevier Ltd. All rights reserved.
Reinmuth N.,LungenClinic Grosshansdorf |
Reinmuth N.,Airway Research Center North |
Heigener D.,LungenClinic Grosshansdorf |
Heigener D.,Airway Research Center North |
And 2 more authors.
Current Opinion in Oncology | Year: 2015
PURPOSE OF REVIEW: The fact that growth and spread of tumours are dependent on angiogenesis has led to the investigation of the role of antiangiogenic agents in the therapeutic strategies for thoracic tumours such as nonsmall cell lung cancer (NSCLC). This review summarizes and evaluates the recent developments in this field. RECENT FINDINGS: Bevacizumab, an antivascular endothelial growth factor antibody, has been approved for the treatment of patients with advanced NSCLC of nonsquamous histology in combination with a platinum-containing chemotherapy. Like in other cancer entities, the antiangiogenic concept in NSCLC comprises maintenance therapy with the antiangiogenic compound until disease progression. Moreover, over the last years, new antiangiogenic agents have been tested in clinical trials in NSCLC patients. Recent trials have demonstrated the efficacy of antiangiogenic agents in combination with docetaxel in the second-line setting. SUMMARY: These studies - together with experiences from other cancer entities - have revived the field of antiangiogenic treatment in lung cancer. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Bahmer T.,LungenClinic Grosshansdorf |
Rabe K.F.,LungenClinic Grosshansdorf
Pneumologe | Year: 2016
Bronchial asthma is a heterogeneous disease characterized by chronic airway inflammation. Different phenotypes can be distinguished based on the underlying type of inflammatory reaction (i.e. TH2 vs. non-TH2 cells), which is particularly important for patients with severe therapy refractive asthma, as new therapeutic strategies are directly targeted against TH2-associated cytokines. Besides symptom control, successful asthma therapy also requires avoidance of exacerbations and fixed airflow limitation as well as the control of pharmacological side effects; therefore, early treatment with low-dose inhaled corticosteroid therapy (ICS) is required, if necessary in combination with a long-acting beta-2 agonist (LABA), preferably as fixed ICS/LABA combination. Before intensifying ICS therapy various factors, such as the inhalation technique have to be checked. Following increased dosage, controlled approaches to reduce ICS dosage again should not be forgotten in order to minimize drug side effects. © 2016 Springer-Verlag Berlin Heidelberg
Heigener D.F.,LungenClinic Grosshansdorf |
Reck M.,LungenClinic Grosshansdorf
Recent Results in Cancer Research | Year: 2014
Crizotinib is an ATP-competitive small-molecule inhibitor of the receptor tyrosine kinases (RTK) c-Met, anaplastic lymphoma kinase (ALK), and ROS1. There is convincing clinical evidence for the effectiveness in non-small-cell lung cancer (NSCLC) harboring EML4-ALK rearrangements resulting in constitutional activation of the ALK-RTK. The drug is approved for this entity, which represents no more than 3–5 % of all NSCLC. However, in this population, impressive response rates are generated. The same seems to be true for ROS-1 rearrangements; however, these only occur in approximately 1 % of all NSCLC. The role in c-Met altered cancers needs to be determined. Toxicities include visual impairment, nausea, peripheral edema, QT-prolongation, and liver enzyme elevation. Also, the occurrence of renal cysts is reported. Fluorescence in situ hybridization (FISH) detecting the ALK rearrangement has to be performed on tumor tissue to predict crizotinib efficacy. The role of immunohistochemistry in this setting needs to be determined. It has high concordance with FISH results when strongly positive or completely negative. The high efficacy of crizotinib in ALK- and ROS-positive lung cancer as new molecular targets beside the epidermal growth factor receptor (EGFR) underscores the importance of molecular typing in NSCLC. © Springer-Verlag Berlin Heidelberg 2014.
Kugler C.,LungenClinic Grosshansdorf |
Stanzel F.,Lung Clinic Hemer
Thoracic Surgery Clinics | Year: 2014
Tracheomalacia is excessive collapsibility of the trachea, typically during expiration. Congenital forms are associated with severe symptoms. Milder forms often present after the neonatal period. Adult malacia is mostly associated with chronic obstructive pulmonary disease. Functional bronchoscopy is still not standardized. Dynamic airway CT is a promising tool for noninvasive diagnosis. Bronchoscopy and stent insertion lead to significant improvement, but with a high complication rate. Surgical lateropexia, tracheal resection, and surgical external stabilization are options. Tracheoplasty seems to be the best choice for selected cases of adult malacia. The most commonly performed surgery in children is aortopexy. © 2014 Elsevier Inc.