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Bad Essen, Germany

King Jr. T.E.,University of California at San Francisco | Albera C.,University of Turin | Bradford W.Z.,InterMune Inc. | Costabel U.,Ruhrlandklinik | And 6 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2014

Rationale: FVC has emerged as a standard primary endpoint in clinical trials evaluating novel therapies for patients with idiopathic pulmonary fibrosis (IPF). However, it has recently been proposed that all-cause mortality or a composite comprised of all-cause mortality and all-cause nonelective hospitalization be adopted as the standard primary endpoint for IPF clinical trials. Objectives: To conduct a comprehensive evaluation of mortality in three phase 3 clinical trials and evaluate the feasibility of mortality trials in patients with IPF. Methods: The study population included 622 patients randomized to placebo in the CAPACITY studies evaluating pirfenidone (n = 347) or the INSPIRE study evaluating interferon-g1b (n = 275). The Kaplan-Meier estimate of 2-year survival was fit to the exponential distribution and used to calculate sample size requirements for a mortality study with 90% power to detect a 25% reduction in all-cause mortality with a two-sided a of 0.05. Modeling analyses were used to assess the effects of selected variables on sample size and study design. Measurements and Main Results: A total of 73 deaths occurred during the period of observation (mean duration of follow-up, 80.1 wk). The all-cause mortality rate was 6.6% at 1 year and 13.7% at 2 years. Based on the observed 2-year mortality rate, a total of 508 events would be required to detect a significant treatment benefit in a two-arm trial with 90% power to detect a 25% reduction in all-cause mortality. The estimated sample size for a trial enrolled over 3 years with a maximum follow-up period of 5 years is 2,582 patients. Conclusions: The all-cause mortality rate is relatively low in patients with IPF with mild to moderate impairment in lung function. Accordingly, the necessary size, duration, and cost of all-cause mortality trials in this population are substantial and likely prohibitive. Copyright © 2014 by the American Thoracic Society.

Drosten C.,University of Bonn | Seilmaier M.,Klinikum Schwabing | Corman V.M.,University of Bonn | Hartmann W.,Klinikum Schwabing | And 17 more authors.
The Lancet Infectious Diseases | Year: 2013

Background: The Middle East respiratory syndrome coronavirus (MERS-CoV) is an emerging virus involved in cases and case clusters of severe acute respiratory infection in the Arabian Peninsula, Tunisia, Morocco, France, Italy, Germany, and the UK. We provide a full description of a fatal case of MERS-CoV infection and associated phylogenetic analyses. Methods: We report data for a patient who was admitted to the Klinikum Schwabing (Munich, Germany) for severe acute respiratory infection. We did diagnostic RT-PCR and indirect immunofluorescence. From time of diagnosis, respiratory, faecal, and urine samples were obtained for virus quantification. We constructed a maximum likelihood tree of the five available complete MERS-CoV genomes. Findings: A 73-year-old man from Abu Dhabi, United Arab Emirates, was transferred to Klinikum Schwabing on March 19, 2013, on day 11 of illness. He had been diagnosed with multiple myeloma in 2008, and had received several lines of treatment. The patient died on day 18, due to septic shock. MERS-CoV was detected in two samples of bronchoalveolar fluid. Viral loads were highest in samples from the lower respiratory tract (up to 1·2×106 copies per mL). Maximum virus concentration in urine samples was 2691 RNA copies per mL on day 13; the virus was not present in the urine after renal failure on day 14. Stool samples obtained on days 12 and 16 contained the virus, with up to 1031 RNA copies per g (close to the lowest detection limit of the assay). One of two oronasal swabs obtained on day 16 were positive, but yielded little viral RNA (5370 copies per mL). No virus was detected in blood. The full virus genome was combined with four other available full genome sequences in a maximum likelihood phylogeny, correlating branch lengths with dates of isolation. The time of the common ancestor was halfway through 2011. Addition of novel genome data from an unlinked case treated 6 months previously in Essen, Germany, showed a clustering of viruses derived from Qatar and the United Arab Emirates. Interpretation: We have provided the first complete viral load profile in a case of MERS-CoV infection. MERS-CoV might have shedding patterns that are different from those of severe acute respiratory syndrome and so might need alternative diagnostic approaches. © 2013 Elsevier Ltd.

Du Bois R.M.,Imperial College London | Albera C.,University of Turin | Bradford W.Z.,InterMune Inc. | Costabel U.,Ruhrlandklinik | And 6 more authors.
European Respiratory Journal | Year: 2014

6-min walk distance (6MWD) has recently been shown to be associated with the risk of mortality in patients with idiopathic pulmonary fibrosis (IPF); however, the independent contribution of 6MWD to the prediction of mortality risk has not been evaluated in a large, well-defined population of patients with IPF. A Cox proportional hazards model was used to characterise the relationship between risk factors of interest and all-cause mortality in IPF patients who completed a week 24 study visit in a clinical trial evaluating interferon γ-1b (n=748). Risk factors of interest included the independent predictors of mortality in the previously published clinical prediction model together with 6MWD and 24-week change in 6MWD. Baseline 6MWD <250 m was associated with a two-fold increase in the risk of mortality (hazard ratio 2.12, 95% CI 1.15-3.92) and a 24-week decline in 6MWD >50 m was associated with a nearly three-fold increase in mortality risk (hazard ratio 2.73; 95% CI 1.60-4.66). Inclusion of 6MWD data improved model discrimination compared with the original model (C-statistic 0.80 (95% CI 0.76-0.85) versus 0.75 (0.71-0.79)). Both 6MWD and change in 6MWD are independent predictors of mortality in patients with IPF. The addition of 6MWD to the clinical prediction model improves model discrimination compared with the original model. Copyright © ERS 2014.

Weder W.,University of Zurich | Collaud S.,University of Zurich | Eberhardt W.E.E.,University of Duisburg - Essen | Hillinger S.,University of Zurich | And 3 more authors.
Journal of Thoracic and Cardiovascular Surgery | Year: 2010

Objective: The mortality of pneumonectomy after chemotherapy or chemoradiotherapy for locally advanced non-small-cell lung cancer is reported to be as high as 26%. We retrospectively reviewed the medical records of patients undergoing these procedures in 2 specialized thoracic centers to determine the outcome. Methods: Retrospective analyses were performed of all patients who underwent pneumonectomy after neoadjuvant chemotherapy or chemoradiotherapy for locally advanced non-small-cell lung cancer from 1998 to 2007. Presurgical treatment consisted of 3-4 platin-based doublets alone in 20% of patients or combined with radiotherapy (45Gy) to the tumor and mediastinum in 80% of patients. Results: Of 827 patients who underwent neoadjuvant therapy, 176 pneumonectomies were performed, including 138 (78%) extended resections. Post-induction pathologic stages were 0 in 36 patients (21%), I in 33 patients (19%), II in 38 patients (21%), III in 57 patients (32%), and IV in 12 patients (7%). Three patients died of pulmonary embolism, 2 patients of respiratory failure, and 1 patient of cardiac failure, resulting in a 90 postoperative day mortality rate of 3%; 23 major complications occurred in 22 patients (13%). For the overall population, 3-year survival was 43% and 5-year survival was 38%. Conclusion: Pneumonectomy after neoadjuvant therapy for non-small-cell lung cancer can be performed with a perioperative mortality rate of 3%. Thus, the need of a pneumonectomy for complete resection alone should not be a reason to exclude patients from a potentially curative procedure if done in an experienced center. The 5-year survival of 38%, which can be achieved, justifies extended surgery within a multimodality concept for selected patients with locally advanced non-small-cell lung cancer. © 2010.

Welter S.,Ruhrlandklinik | Cheufou D.,Ruhrlandklinik | Sommerwerck U.,Ruhrlandklinik | Maletzki F.,Medservice | Stamatis G.,Ruhrlandklinik
Chest | Year: 2012

Background: Pulmonary metastasectomy with lung-sparing local excisions is a widely accepted method of treating stage IV malignancies in selected cases. The ability to predict postoperative lung function is an unresolved issue, especially when multiple wedge resections are planned. To help develop a method to predict postoperative lung function after wedge resections, we present this prospective observational study. Methods: A total of 77 patients who underwent one or more wedge resections to remove lung metastases completed the study protocol. Spirometry results, diffusion capacity of lung for carbon monoxide (DLCO), and blood gases and potential confounding factors were measured prior to, immediately following, and 3 months after the procedure and were analyzed. Results: Seventy-seven patients with a median age of 61.3 years underwent up to 22 wedge resections. The mean lung function losses were FVC (-7.5%), total lung capacity (TLC) (-7.9%), FEV1(-9.2%), and D LCO (-8.8%), and all were statistically significant (P < .001). The lung function losses also differed significantly between those having a single and those with more than eight wedge resections. Using regression analysis, we found that for every additional wedge resection, there was a reduction in FVC of 30 mL (0.7%), in TLC of 44 mL (0.65%), and in FEV 1 of 23 mL (0.58%). Conclusions: Metastasectomy by wedge resection significantly reduces lung function parameters. As a benchmark, we can predict a 0.6% decrease in spirometry values and DLCO for every additional wedge resection, and a decrease of approximately 5% that may be attributed to thoracotomy. © 2012 American College of Chest Physicians.

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