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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.


Nienhaus A.,University of Hamburg | Nienhaus A.,Institute for Statutory Accident Insurance and Prevention | Schablon A.,University of Hamburg | Preisser A.M.,University of Hamburg | And 3 more authors.
Journal of Occupational Medicine and Toxicology | Year: 2014

Introduction. Despite the decline of tuberculosis in the population at large, healthcare workers (HCW) are still at risk of infection. Methods. In a narrative review the TB risk in HCW and preventive measures are described, with the focus on epidemiology and Occupational Safety and Health (OSH) regulations in Germany. Results: There is an increased risk of infection not only in pneumology and laboratories with regular contact with tuberculosis patients or infectious materials. Epidemiological studies have also verified an increased risk of infection from activities that involve close contact with patients' breath (e.g. bronchoscopy, intubation) or close contact with patients in need of care in geriatric medicine or geriatric nursing. In occupational disease claim proceedings on account of tuberculosis, the burden of proof can be eased for insured persons who work in these or other comparable fields. Forgoing evidence of an index person as a source of infection has led to a doubling of the rate of cases of tuberculosis recognised as an occupational disease and has halved the duration of occupational disease claim proceedings in Germany. For several years now, it has been possible to use the new interferon-y release assays (IGRAs) to diagnose a latent tuberculosis infection (LTBI) with significantly greater validity than with the traditional tuberculin skin test (TST). However, variability of the IGRAs around the cut-off poses problems especially in serial testing of HCWs. At around 10%, LTBI prevalence in German healthcare workers is lower than had been assumed. It can make sense to treat a recent LTBI in a young healthcare worker so as to prevent progression into active tuberculosis. If the LTBI is occupational in origin, the provider of statutory accident insurance can cover the costs of preventive treatment. However, little is known about disease progression in HCWs with positive IGRA sofar. Conclusion: TB screening in HCWs will remain an important issue in the near future even in low incidence, high income countries, as active TB in HCWs is often due to workplace exposure. The IGRAs facilitate these screenings. However, variability of IGRA results in serial testing of HCWs need further investigations. © 2014 Nienhaus et al.; licensee BioMed Central Ltd.


Reinmuth N.,Member of the German Center for Lung Research | Reck M.,Airway Research Center North
Oncology Research and Treatment | Year: 2016

Immune evasion is recognized as a key strategy for cancer survival and progression. Hence, various approaches to restore antitumor immune responses are currently being investigated. In particular, agents targeting immune checkpoints, such as the cytotoxic T-lymphocyte-associated antigen-4 receptor and programmed death-1 receptor, have shown potential for improving tumor responses and survival in lung cancer patients. With the first immunomodulating agents having been approved for treatment of selected lung cancer patients, there are high expectations that treatment outcomes may be improved with the incorporation of immunotherapies into the various treatment cascades. © 2016 S. Karger GmbH, Freiburg.


Muller-Redetzky H.C.,Charite - Medical University of Berlin | Will D.,Charite - Medical University of Berlin | Hellwig K.,Charite - Medical University of Berlin | Kummer W.,Justus Liebig University | And 11 more authors.
Critical Care | Year: 2014

Introduction: Ventilator-induced lung injury (VILI) contributes to morbidity and mortality in acute respiratory distress syndrome (ARDS). Particularly pre-injured lungs are susceptible to VILI despite protective ventilation. In a previous study, the endogenous peptide adrenomedullin (AM) protected murine lungs from VILI. We hypothesized that mechanical ventilation (MV) contributes to lung injury and sepsis in pneumonia, and that AM may reduce lung injury and multiple organ failure in ventilated mice with pneumococcal pneumonia.Methods: We analyzed in mice the impact of MV in established pneumonia on lung injury, inflammation, bacterial burden, hemodynamics and extrapulmonary organ injury, and assessed the therapeutic potential of AM by starting treatment at intubation.Results: In pneumococcal pneumonia, MV increased lung permeability, and worsened lung mechanics and oxygenation failure. MV dramatically increased lung and blood cytokines but not lung leukocyte counts in pneumonia. MV induced systemic leukocytopenia and liver, gut and kidney injury in mice with pneumonia. Lung and blood bacterial burden was not affected by MV pneumonia and MV increased lung AM expression, whereas receptor activity modifying protein (RAMP) 1-3 expression was increased in pneumonia and reduced by MV. Infusion of AM protected against MV-induced lung injury (66% reduction of pulmonary permeability p < 0.01; prevention of pulmonary restriction) and against VILI-induced liver and gut injury in pneumonia (91% reduction of AST levels p < 0.05, 96% reduction of alanine aminotransaminase (ALT) levels p < 0.05, abrogation of histopathological changes and parenchymal apoptosis in liver and gut).Conclusions: MV paved the way for the progression of pneumonia towards ARDS and sepsis by aggravating lung injury and systemic hyperinflammation leading to liver, kidney and gut injury. AM may be a promising therapeutic option to protect against development of lung injury, sepsis and extrapulmonary organ injury in mechanically ventilated individuals with severe pneumonia. © 2014 Müller-Redetzky et al.; licensee BioMed Central Ltd.


Sebastian M.,University Hospital Frankfurt | Schmittel A.,Hematology Oncology | Reck M.,Member of the German Center for Lung Research
European Respiratory Review | Year: 2014

Recent advances in understanding the mechanisms of nonsmall cell lung cancer (NSCLC) has led to the development of targeted treatments, including the reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors gefitinib and erlotinib, and the irreversible ErbB family blocker afatinib. Several important activating EGFR mutations have now been identified, which correlate strongly with response to treatment with these agents. Multiple randomised controlled trials have confirmed the association between the presence of activating EGFR mutations and objective response to gefitinib, erlotinib and afatinib, thus demonstrating their superiority over platinum-based chemotherapy as first-line treatment for NSCLC patients with EGFR mutation-positive tumours, and resulting in approval of these agents for use in this setting. It can be tempting to compare outcome data across multiple clinical trials and agents; however, substantial differences in methodology between studies, including investigator versus independent assessment and differences in patient eligibility, makes such comparisons fraught with difficulty. This critical review provides an overview of the evolution of the methodology used in eight phase III trials investigating first-line targeted treatment of NSCLC, identifies key differences in methodology and reporting, and critically assesses how these differences should be taken into account when interpreting the findings from such trials. © ERS 2014.

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