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The broad-spectrum triazole isavuconazole is used for the treatment of invasive aspergillosis and mucormycosis. Data regarding human plasma concentrations in clinical routine of the drug are rare.Plasma concentrations of isavuconazole were determined in critically ill ICU patients while considering different patients' characteristics.Retrospective analysis of isavuconazole plasma concentrations were obtained as part of routine therapeutic drug monitoring (TDM) of ICU patients with invasive aspergillosis or other fungal infections treated with isavuconazole. Plasma levels 0-4 h after last dosing were defined as peak levels (COverall, 223 isavuconazole levels of 41 patients were analysed, divided into 141 peak levels and 82 trough levels. The overall median CThis study shows that isavuconazole plasma concentrations vary in critical ill ICU patients. Significantly lower isavuconazole levels were associated with elevated BMI and higher SOFA score indicating a need of isavuconazole TDM in this specific patient population.

Peter Alter,1 Kathrin Kahnert,2 Franziska C Trudzinski,3 Robert Bals,4 Henrik Watz,5 Tim Speicher,1 Sandra Söhler,1 Stefan Andreas,6 Tobias Welte,7 Klaus F Rabe,8 Emiel FM Wouters,9 Antonia Sassmann-Schweda,10 Hubert Wirtz,11 Joachim H Ficker,12,13 Claus F Vogelmeier,1 Rudolf A Jörres14 1Department of Medicine, Pulmonary and Critical Care Medicine, Philipps University of Marburg (UMR), Germany, Member of the German Center for Lung Research (DZL), Marburg, Germany; 2Department of Internal Medicine V, University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, Germany; 3Department of Pneumology and Critical Care Medicine, Thoraxklinik, University of Heidelberg, Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; 4Department of Internal Medicine V - Pulmonology, Allergology, Intensive Care Medicine, Saarland University Hospital, Homburg, Germany; 5Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany; 6LungClinic Immenhausen and Department of Cardiology and Pneumology, University Medical Center Göttingen, Germany, Member of the German Center for Lung Research (DZL), Göttingen, Germany; 7Clinic for Pneumology, Hannover Medical School, Member of the German Center for Lung Research (DZL), Hannover, Germany; 8LungenClinic Grosshansdorf and Department of Medicine, Christian-Albrechts University, Kiel, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany; 9Department of Respiratory Medicine, Maastricht University Medical Centre, Maastricht, Netherlands and Ludwig Boltzmann Institute for Lung Health, Vienna, Austria; 10Center for Clinical Studies, Research Center Borstel, Borstel, Germany; 11Department of Internal Medicine I, Pneumology, University of Leipzig, Leipzig, Germany; 12Department of Respiratory Medicine, Allergology and Sleep Medicine, Klinikum Nuremberg, Nürnberg, Germany; 13Paracelsus Medical University Nuremberg, Nürnberg, Germany; 14Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, GermanyCorrespondence: Peter Alter, Department of Medicine, Pulmonary and Critical Care Medicine, Philipps University of Marburg (UMR), Baldingerstrasse 1, Marburg, Germany, Email Alter@uni-marburg.deBackground: Multimorbidity plays an important role in chronic obstructive pulmonary disease (COPD) but is also a feature of ageing. We estimated to what extent increases in the prevalence of multimorbidity over time are attributable to COPD progression compared to increasing patient age.Methods: Patients with COPD from the long-term COSYCONET (COPD and Systemic Consequences - Comorbidities Network) cohort with four follow-up visits were included in this analysis. At each visit, symptoms, exacerbation history, quality of life and lung function were assessed, along with the comorbidities heart failure (HF), coronary artery disease (CAD), peripheral arterial disease (PAD), hypertension, sleep apnea, diabetes mellitus, hyperlipidemia, hyperuricemia and osteoporosis. Using longitudinal logistic regression analysis, we determined what proportion of the increase in the prevalence of comorbidities could be attributed to patients’ age or to the progression of COPD over visits.Results: Of 2030 patients at baseline, 878 completed four follow-up visits (up to 4.5 years). CAD prevalence increased over time, with similar effects attributable to the 4.5-year follow-up, used as indicator of COPD progression, and to a 5-year increase in patients’ age. The prevalence of HF, diabetes, hyperlipidemia, hyperuricemia, osteoporosis and sleep apnea showed stronger contributions of COPD progression than of age; in contrast, age dominated for hypertension and PAD. There were different relationships to patients’ characteristics including BMI and sex. The results were not critically dependent on the duration of COPD prior to enrolment, or the inclusion of patients with all four follow-up visits vs those attending only at least one of them.Conclusion: Analyzing the increasing prevalence of multimorbidity in COPD over time, we separated age-independent contributions, probably reflecting intrinsic COPD-related disease progression, from age-dependent contributions. This distinction might be useful for the individual assessment of disease progression in COPD.Keywords: chronic obstructive pulmonary disease, comorbidities, multimorbidity, prognosis, disease progression

Kathrin Kahnert,1 Rudolf A Jörres,2 Tanja Lucke,2 Franziska C Trudzinski,3 Pontus Mertsch,1 Christiane Bickert,1 Joachim H Ficker,4 Jürgen Behr,1 Robert Bals,5 Henrik Watz,6 Tobias Welte,7 Claus F Vogelmeier,8 Peter Alter8 On behalf of COSYCONET Study Group1Department of Medicine V, University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, Germany; 2Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, Germany; 3Department of Pneumology and Critical Care Medicine, Thoraxklinik, University of Heidelberg, Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; 4Department of Respiratory Medicine, Nürnberg General Hospital, Paracelsus Medical University, Nürnberg, Germany; 5Department of Internal Medicine V - Pulmonology, Allergology, Intensive Care Medicine, Saarland University Hospital, Homburg, Germany; 6Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany; 7Clinic for Pneumology, Hannover Medical School, Member of the German Center for Lung Research (DZL), Hannover, Germany; 8Department of Medicine, Pulmonary and Critical Care Medicine, University of Marburg (UMR), Germany, Member of the German Center for Lung Research (DZL), Marburg, GermanyCorrespondence: Kathrin KahnertDepartment of Medicine V, University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, GermanyTel +49 89 4400 52590Fax +49 89 4400 54905Email kathrin.kahnert@med.uni-muenchen.deBackground: Patients with chronic obstructive pulmonary disease (COPD) often have osteoporosis and diabetes as comorbid conditions. Anti-diabetic medication, including metformin, has protective effects on osteoporosis in experimental studies. We therefore studied whether patients with COPD receiving anti-diabetic medication had a lower osteoporosis prevalence in a large COPD cohort, COSYCONET.Methods: Assessment of osteoporosis was based on patients’ reports of physician-based diagnoses and the presence of disease-specific medication. The predictive value of physical characteristics, lung function, comorbidities, cardiovascular medication, and the use of anti-inflammatory diabetes medication, including metformin, sulfonylureas, glinides or DPP4I, was evaluated using logistic regression analysis. ClinicalTrials.gov: NCT01245933.Results: In total, 2222 patients were eligible for analysis (863 [39%] female, mean age 65 y), 515 of whom had higher symptoms and exacerbations (Global Initiative for Chronic Obstructive Lung Disease group D). Osteoporosis was present in 15.8% of the overall cohort, and in 24.1% of GOLD D patients. Regression analyses identified the following as associated with osteoporosis (p < 0.05): female sex, higher age, lower body-mass index, asthma, higher air trapping, oral steroids, and cardiovascular medication. Although oral anti-diabetic medication was overall not associated with a lower prevalence of osteoporosis (p = 0.131), anti-inflammatory anti-diabetic medication (p = 0.009) and metformin-containing therapy (p = 0.039) were. This was driven by GOLD D patients.Conclusion: In a large COPD cohort, anti-inflammatory diabetes therapy, including metformin, was associated with a lower prevalence of osteoporosis, especially in patients with higher symptoms and exacerbations. These findings suggest a protective effect of common anti-diabetic medication on osteoporosis, possibly as a result of attenuated systemic inflammation.Keywords: chronic obstructive pulmonary disease, oral corticosteroids, inhaled corticosteroids, anti-inflammatory, metformin, diabetes

Dyspnea is a leading symptom in COPD. Bronchodilators (long acting anticholinergics and long acting beta agonists) are the mainstay of medical treatment. Non pharmacological therapies like pulmonary rehabilitation, long-term oxygen therapy or lung volume reduction can help to further improve dyspnea. Nevertheless, patients with advanced disease may develop refractory dyspnea. Randomized controlled trials demonstrated that the palliative treatment with low-dose systemic opioids is an effective treatment option in these patients. A low starting dose (e. g. 1.0 mg morphine, immediate release) is recommended. Subsequent doses are titrated to achieve the lowest effective dose based on whether dyspnea relief has been achieved and whether any side effects have developed. This low-dose opioid treatment has been demonstrated to be safe for symptom reduction in severe COPD and is not associated with increased hospital admissions or deaths. Physicians should offer a trial of low-dose oral opioids to patients with refractory dyspnea that affects their daily activities and quality of life.

Background Immune checkpoint inhibitors (ICI) either alone or in combination with chemotherapy have expanded our choice of agents for the palliative treatment of non-small cell lung cancer (NSCLC) patients. Unfortunately, not all patients will experience favorable response to treatment with ICI and may even suffer from severe side effects. Therefore, prognostic and predictive markers, beyond programmed death ligand 1 (PD-L1) expression status, are of utmost importance for decision making in the palliative treatment. This review focuses on clinical, laboratory and genetic markers, most of them easily to obtain in the daily clinical practice. Results Recently, a number of prognostic and predictive factors in association to palliative ICI therapy have been described in NSCLC. Besides biometric parameters and clinical characteristics of the tumor, there are useful markers from routine blood sampling as well as innovative soluble genetic markers which can be determined before and during ICI treatment. Additionally, the level of evidence is noted. Conclusions These factors can be helpful to predict patients’ outcome and tumor response to ICI. They should be implemented prospectively in ICI based clinical trials to develop reliable algorithms for palliative NSCLC treatment.

Zusammenfassung Hintergrund Die Standardtherapie einer obstruktiven Schlafapnoe (OSA) ist die nächtliche positive Überdruckbeatmung (PAP). Sie ist in der Regel nebenwirkungsarm und stellt eine Langzeittherapie dar. Doch nicht jeder Patient toleriert oder akzeptiert die Therapie oder möchte sie fortführen. Andere müssen sie aus objektiven Gründen beenden. Fragestellung Klare Begrifflichkeiten für eine Nicht-Anwendung der PAP-Therapie sind bisher nicht in den Leitlinien definiert. Ziel dieses Beitrags ist es, einheitliche Definitionen einzuführen, die eine Vorlage für klinisches Handeln und wissenschaftliche Ansätze sein können. Material und Methode Ein Expertengremium hat sich intensiv mit der Literatur, Definitionen und Hintergrundinformationen hinsichtlich des Themas befasst. Es wurden verschiedene Möglichkeiten der PAP-Nicht-Nutzung bzw. der Beendigung der Therapie betrachtet und dementsprechend Kategorien und Definitionen zusammengestellt. Ergebnisse Dies sind die vom Expertengremium vorgeschlagenen Kategorien für eine PAP-Nichtbenutzung: PAP-Inakzeptanz, PAP-Unverträglichkeit, PAP-Intoleranz, PAP-Versagen und PAP-Abbruch. Diskussion Diese Kategorien inklusive Definition können die Grundlage für ein einheitliches Management bei Patienten/Patientinnen mit obstruktiver Schlafapnoe (OSA) sein, die auf eine PAP-Therapie eingestellt werden bzw. wurden.

Lung cancer is most common in older patients; despite this, older patients are historically under-represented in clinical studies. Here we present data from GIDEON, a study undertaken in Germany in patients with epidermal growth factor receptor mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC) receiving first-line afatinib. GIDEON enrolled a high proportion of patients aged ≥70 years, providing an opportunity to study afatinib use in older patients.In GIDEON (NCT02047903), a prospective non-interventional study, patients with EGFRm + NSCLC received first-line afatinib in routine clinical practice until disease progression, death or intolerable adverse events. Key objectives were twelve-month progression-free survival (PFS) rate and objective response rate (ORR). Overall survival (OS) and safety were also assessed. This post hoc analysis explores outcomes of patients grouped by age (≥70 and 70 years).In the 152 patients enrolled in GIDEON (69.7% female, 64.5%/22.4%/13.2% with Del19/L858R/other exon 18-21 mutations, 33.6% with brain metastases), the median age was 67 years (range 38-89) and 43.4% were aged ≥70 years. In the ≥70 years age group and the70 years age group, twelve-month PFS rate was 58.9% and 43.9%, median PFS was 17.2 months and 10.6 months, ORR was 72.0% and 76.5%, twelve-month OS rate was 79.1% and 79.2%, 24-month OS rate was 52.0% and 61.7%, and median OS was 30.4 months and 27.4 months, respectively. In the ≥70 years age group and the70 years age group, grade ≥ 3 adverse drug reactions (ADRs) were observed in 34.8% and 40.7% of patients, respectively; the most common were diarrhea (13.6% and 14.0%), acneiform dermatitis (7.6% and 7.0%), stomatitis (1.5% and 4.7%) and maculopapular rash (1.5% and 4.7%).Patients with EGFRm + NSCLC aged ≥70 years showed clinical benefit from first-line afatinib with no unexpected safety signals, supporting the use of afatinib in this setting.

IntroductionSpecialized biopsychosocial care concepts are necessary to overcome the dualism between physical and psychosocial treatment in acute care hospitals. For patients with complex and chronic comorbid physical and mental health problems, neither standardized psychiatric/psychosomatic nor somatic care units alone are appropriate to their needs. The “Nuremberg Integrated Psychosomatic Acute Unit” (NIPA) has been developed to integrate treatment of both, psychosocial and physical impairments, in an acute somatic care setting.MethodNIPA has been established in inpatient internal medical wards for respiratory medicine, oncology and gastroenterology. One to two patients per ward are regularly enrolled in the NIPA treatment while remaining in the same inpatient bed after completion of the somatic care. In a naturalistic study design, we evaluated treatment effects by assessment of symptom load at admission and at discharge using the Patient Health Questionnaire (PHQ) and the Generalized Anxiety Disorder Scale-7 (GAD-7). Furthermore, we assessed the severity of morbidity using diagnosis data during treatment. At discharge, we measured satisfaction with treatment through the Patient Satisfaction Questionnaire (ZUF-8).ResultsData from 41 NIPA patients were analyzed (18–87 years, 76% female). Seventy-eight percent suffered from at least moderate depression and 49% from anxiety disorders. Other diagnoses were somatoform pain disorder, somatoform autonomic dysfunction, eating disorder and posttraumatic stress disorder. Hypertension, chronic lung diseases and musculoskeletal disorders as well as chronic oncological and cardiac diseases were the most common somatic comorbidities. Treatment resulted in a significant reduction of depressive mood (admission: M = 10.9, SD = 6.1, discharge: M = 7.6, SD = 5.3, d = 0.58, p = 0.001), anxiety (admission: M = 10.6, SD = 4.9, discharge: M = 7.3, SD = 4.1, d = 0.65, p< 0.001) and stress (admission: M = 6.0, SD = 3.6, discharge: M = 4.1, SD = 2.5, d = 0.70, p< 0.001). Somatic symptom burden was reduced by NIPA treatment (admission: M = 10.9, SD = 5.8, discharge: M = 9.6, SD = 5.5, d = 0.30), albeit not statistically significant (p = 0.073) ZUF-8 revealed that 89% reported large or full satisfaction and 11% partial dissatisfaction with treatment.DiscussionNIPA acute care is bridging the gap for patients in need of psychosocial treatment with complex somatic comorbidity. Further long-term evaluation will show whether psychosocial NIPA care is able to reduce the course of physical illness and hospital costs by preventing hospitalization and short-term inpatient re-admissions.

BACKGROUND: The aim of this study was to determine whether mRNA expressions and dynamic changes of immune-related genes before and after starting first-line treatment with the PD-1 inhibitor pembrolizumab in patients with NSCLC were of predictive value. METHODS: CD3, CD8, PD-1, PD-L1 and CTLA-4 mRNA expression levels were measured from peripheral blood before and after three weeks of treatment with the PD-1 inhibitor. Univariate and multivariate analyses were performed retrospectively. Response, progression-free survival (PFS) and overall survival (OS) were determined. RESULTS: In univariate analysis an increase of CD3 and CD8 mRNA expression after the first cycle of pembrolizumab were each associated with improved PFS and OS. In contrast, patients with no change or with a decrease in CD3 and CD8 mRNA expression showed significantly worse outcome. CD8 mRNA increase remained an independent predictive factor for PFS and OS in the multivariate analysis with p values of 0.011 and 0.006, respectively. CONCLUSIONS: An increase of CD8 mRNA expression predicts favorable outcome after first line monotherapy with pembrolizumab, while no change or decrease might serve as an indicator of poor outcome and might give cause for early treatment escalation for instance by addition of chemotherapy or additional ICI treatment, e.g., against CTLA-4.

Introduction: Dose reductions in chemotherapy occur frequently due to various reasons. The ubiquitous opinion is that dose reductions favor a negative outcome. However, there are only few studies that investigate this opinion in respect to lung cancer patients. The aim of this retrospective single-center study is to identify the most common predictors of dose reductions in NSCLC IIIB patients and to evaluate the effects thereof. Methods: The study includes 132 NSCLC IIIB patients treated between 2008 and 2017. Predictors of dose reductions were evaluated using uni- and multivariate methods and survival statistics were analyzed using Kaplan-Meier and logrank method. Results: 48% of the patients (n = 63) experienced dose reductions. Male gender (p = 0.029), age (p = 0.042), comorbidities (CCI) (p = 0.00) and palliative intent (p = 0.021) were identified as predictors of initial dose reductions. Initial dose reductions were independent of ECOG status and initial laboratory values. Dose reductions later in chemotherapy were linked to hematologic toxicities. 59% of patients with leukopenia and 33% of patients with bi- / pancytopenia had chemotherapeutic doses reduced consecutively. The was no sigificant difference in overall survival (OS) and progress-free survival (PFS) between patients with and without dose reduction. Patients with reduced doses had an OS of 18.86 (± 18.65) vs. 17.51 (± 16.61) months, p = 0.593 and a PFS of 15.03 (± 18.14) vs. 12.71 (± 17.60) months, p = 0.340. Conclusion: This study supports the view that hematotoxicities are considered the most serious side effects. Contrary to expectations, a reduction in chemotherapy dosage did not seem to be associated with a worse prognosis. Maybe a dose reduction can improve the side effect profile and compliance.

Background: Lung cancer is a leading cause of cancer-related death in Germany and worldwide. Non-small cell lung cancer (NSCLC) comprises ~80% of lung cancer diagnoses; in White patients, around 10% of NSCLC cases are epidermal growth factor receptor mutation-positive ( EGFRm+). Head-to-head clinical trials have demonstrated superior efficacy with second-/third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) versus first-generation EGFR TKIs in EGFRm+ NSCLC. Data from routine clinical practice are necessary to confirm that clinical trial findings are transferable to real-world populations. Methods: In NCT02047903, a prospective non-interventional study in Germany, patients with EGFRm+ NSCLC received first-line afatinib until disease progression or intolerable adverse events. Key objectives were progression-free survival (PFS) rate at 12 months, objective response rate (ORR) and overall survival (OS). Safety/tolerability was also assessed. Results: Of 152 patients, 106 (69.7%) were female, 20 (13.1%) patients had an uncommon EGFR mutation and 51 patients (33.6%) had brain metastases. A starting dose of Conclusion: The results support clinical trial data for afatinib in routine clinical practice, including in patients generally excluded from clinical trials. Outcomes were positive in patients with uncommon EGFR mutations and in those with brain metastases. Treatment benefit was also seen in patients receiving a

Background Adherence to COPD medication is often considered to be lower than in other chronic diseases. In view of the frequent comorbidities of COPD, the economic impact of nonadherence and the potential for adverse effects, a direct comparison between the adherence to respiratory and nonrespiratory medication in the same patients seems of particular interest. Objectives We aimed to investigate the intake of respiratory and nonrespiratory medication in the same patients with COPD and frequent comorbidities. Method Within the COPD cohort COSYCONET, we contacted 1042 patients, mailing them a list with all medication regarding all their diseases, asking for regular, irregular and non-intake. Results Valid responses were obtained in 707 patients covering a wide spectrum of drugs. Intake of LABA, LAMA or ICS was regular in 91.9% of patients, even higher for cardiovascular and antidiabetes medication but lower for hyperlipidemia and depression/anxiety medication. Regular intake of respiratory medication did not depend on GOLD groups A-D or grades 1-4, was highest in patients with concomitant cardiovascular disorders and was lowest for concomitant asthma. It was slightly larger for LAMA and LABA administered via combined compared to single inhalers, and lower when similar compounds were prescribed twice. Most differences did not reach statistical significance owing to the overall high adherence. Conclusion Our results indicate a high adherence to respiratory medication in participants of a COPD cohort, especially in those with cardiovascular comorbidities. Compared to the lower adherence reported in the literature for COPD patients, our observations still suggest some room for improvement, possibly through disease management programs.

AATD deficiency; Diagnosis; Europe Deficiència d'AATD; Diagnosi; Europa Deficiencia de AATD; Diagnóstico; Europa Despite recent improvements, α1-antitrypsin deficiency (AATD) remains a rarely diagnosed and treated condition. To assess the variability of AATD diagnosis/treatment in Europe, and to evaluate clinicians' views on methods to optimise management, specialist AATD clinicians were invited to complete a web-based survey. Surveys were completed by 15 physicians from 14 centres in 13 European countries. All respondents perceived the AATD diagnosis rate to be low in their country; 77% of physicians believed that ∼15% of cases were diagnosed. Low awareness was perceived as the greatest barrier to diagnosis. Spirometry was considered more practical than quantitative computed tomography (QCT) for monitoring AATD patients in clinical practice; QCT was considered more useful in trials. AAT therapy provision was reported to be highly variable: France and Germany were reported to treat the highest proportion (∼60%) of diagnosed patients, in contrast to the UK and Hungary, where virtually no patients receive AAT therapy. Most clinicians supported self-administration and extended dosing intervals to improve convenience of AAT therapy. This survey indicates that AATD diagnosis and management are highly heterogeneous in Europe; European cooperation is essential to generate data to support access to AAT therapy. Improving convenience of AAT therapy is an ongoing objective.

Der derzeitige Standard in Deutschland ist, dass die PAP-Therapie im Schlaflabor unter polysomnographischer Überwachung eingeleitet wird. Anschließend werdennach ungefähr 6 Wochen eine ambulante klinische Kontrolle, eventuell zusätzlich mit einer ambulanten Polygraphie sowie weitere jährliche Kontrollen empfohlen (1). Des Weiteren gibt es die Möglichkeit, die PAP-Therapie durch Analyse der im Gerät gespeicherten Daten zu verfolgen und gegebenenfalls zu optimieren. Je nach Gerätehersteller werden im Therapiegerät verschiedene Therapiedaten gespeichert (Anwendungsdauer, Anwendungsmuster, residuelle Atmungsstörungen gesamt/differenziert, Leckagen, Befeuchteranwendung, Druckverlauf), wobei keine einheitliche Validierung für einige dieser Informationen vorliegt.

Recent evidence supports the use of pulse wave analysis during sleep for assessing functional aspects of the cardiovascular system. The current study compared the influence of pulse wave and sleep study-derived parameters on cardiovascular risk assessment. In a multi-centric study design, 358 sleep apnea patients (age 55 ± 13 years, 64% male, body mass index 30 ± 6 kg m-2 , apnea-hypopnea index 13 [5-26] events per hr) underwent a standard overnight sleep recording. A novel cardiac risk index was computed based on pulse wave signals derived from pulse oximetry, reflecting vascular stiffness, cardiac variability, vascular autonomic tone and nocturnal hypoxia. Cardiovascular risk was determined using the ESC/ESH cardiovascular risk matrix, and categorized to high/low added cardiovascular risk. Comparisons between cardiac risk index and sleep parameters were performed for cardiovascular risk prediction. Apnea-hypopnea index, oxygen desaturation index and cardiac risk index were associated with high cardiovascular risk after adjustment for confounders (p = .002, .001

Background Chemotherapy plus immune-checkpoint inhibitor (CTx+ICI) therapy has become the preferred 1st line treatment in patients with metastatic NSCLC without oncogenic driven mutations. However, the optimal subsequent 2nd line treatment is not defined and several alternatives exist. The purpose of this analysis was to evaluate the efficacy of 2nd line docetaxel plus ramucirumab (D+R) initiated after failure of 1st line CTx+ICI. Methods Retrospective data were collected during routine care from German thoracic oncology centers. Only patients who had received at least one course of 2nd line D+R were included. ORR, PFS, OS and numbers of courses of D+R were investigated with PFS after initiation of D+R being the primary endpoint. Results Seventy-seven patients met the inclusion criteria. 2nd line treatment with D+R achieved an ORR and DCR of 32.5% and 62.4%, respectively. Median PFS for 2nd line therapy was 3.9 months with a DOR of 6.4 months. Median OS of 15.5 and 7.5 months were observed from the start of 1st line therapy and 2nd line treatment, respectively. No unexpected toxicities occurred. Presence of KRAS mutations was associated with significantly worse median PFS to D+R (2.8 vs. 4.5 months in wild-type cases; P=0.021) and was an independent predictor of inferior PFS in multivariate analysis. Conclusions D+R is an effective and safe 2nd line treatment after failure of 1st line CTx+ICI irrespective of NSCLC histology. However, patients with a KRAS mutation did not benefit from D+R in terms of PFS and will require further investigations.

Methods We did a multicentre, double-blind, randomised, placebo-controlled, parallel phase 2b trial (RELIEF) in 17 centres with expertise in ILD in Germany. Eligible participants were patients aged 18?80 years with progressive fibrotic ILD due to four diagnoses: collagen or vascular diseases (ie, connective tissue disease-associated ILDs), fibrotic non-specific interstitial pneumonia, chronic hypersensitivity pneumonitis, or asbestos-induced lung fibrosis. Other eligibility criteria included a forced vital capacity (FVC) of 40?90% predicted, a diffusing capacity of the lung for carbon monoxide of 10?90% predicted, and an annual decline of FVC of at least 5% predicted despite conventional therapy, based on at least three measurements within 6?24 months before enrolment. Patients who had received any previous antifibrotic therapy were excluded. We randomly assigned patients (1:1) to either oral pirfenidone (267 mg three times per day in week 1, 534 mg three times per day in week 2, and 801 mg three times per day thereafter) or matched placebo, added to their ongoing medication. Randomisation was done centrally using permuted block randomisation with varying block sizes stratified by the four diagnostic groups. Patients, investigators, statisticians, monitors, and the study coordinator were masked to treatment assignment until database closure. The placebocontrolled study period was 48 weeks (including up-titration). The primary endpoint was absolute change in percentage of predicted FVC (FVC % predicted) from baseline to week 48 in the intention-to-treat population, with imputation of missing data by the smallest sum of squared differences and attribution of deceased patients to the lowest rank in a rank ANCOVA model. Additionally, we did linear mixed-model repeated measures slope analyses of FVC % predicted longitudinal data over the course of the study as a prespecified sensitivity analysis and post-hoc sensitivity analyses of the primary endpoint in the intention-to-treat population using imputation methods of last observation carried forward [LOCF] and a regression-based multiple imputation procedure. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered with EudraCT 2014-000861-32;Background Pirfenidone has been shown to slow disease progression in patients with idiopathic pulmonary fibrosis (IPF). However, there are few treatment options for progressive fibrotic interstitial lung diseases (ILDs)) other than IPF. In view of the pathomechanistic and clinical similarities between IPF and other progressive fibrotic ILDs, we aimed to assess the efficacy and safety of pirfenidone in patients with four non-IPF progressive fibrotic ILDs. Methods We did a multicentre, double-blind, randomised, placebo-controlled, parallel phase 2b trial (RELIEF) in 17 centres with expertise in ILD in Germany. Eligible participants were patients aged 18-80 years with progressive fibrotic ILD due to four diagnoses: collagen or vascular diseases (ie, connective tissue disease-associated ILDs), fibrotic non-specific interstitial pneumonia, chronic hypersensitivity pneumonitis, or asbestos-induced lung fibrosis. Other eligibility criteria included a forced vital capacity (FVC) of 40-90% predicted, a diffusing capacity of the lung for carbon monoxide of 10-90% predicted, and an annual decline of FVC of at least 5% predicted despite conventional therapy, based on at least three measurements within 6-24 months before enrolment. Patients who had received any previous antifibrotic therapy were excluded. We randomly assigned patients (1:1) to either oral pirfenidone (267 mg three times per day in week 1, 534 mg three times per day in week 2, and 801 mg three times per day thereafter) or matched placebo, added to their ongoing medication. Randomisation was done centrally using permuted block randomisation with varying block sizes stratified by the four diagnostic groups. Patients, investigators, statisticians, monitors, and the study coordinator were masked to treatment assignment until database closure. The placebo controlled study period was 48 weeks (including up-titration). The primary endpoint was absolute change in percentage of predicted FVC (FVC % predicted) from baseline to week 48 in the intention-to-treat population, with imputation of missing data by the smallest sum of squared differences and attribution of deceased patients to the lowest rank in a rank ANCOVA model. Additionally, we did linear mixed-model repeated measures slope analyses of FVC % predicted longitudinal data over the course of the study as a prespecified sensitivity analysis and post-hoc sensitivity analyses of the primary endpoint in the intention-to-treat population using imputation methods of last observation carried forward [LOCF] and a regression-based multiple imputation procedure. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered with EudraCT 2014-000861-32; DRKS00009822 and is no longer recruiting. Findings Between April 5, 2016, and Oct 4, 2018, we randomly assigned 127 patients to treatment: 64 to pirfenidone, 63 to placebo. After 127 patients had been randomised, the study was prematurely terminated on the basis of an interim analysis for futility triggered by slow recruitment. After 48 weeks and in the overall population of 127 patients, rank ANCOVA with diagnostic group included as a factor showed a significantly lower decline in FVC % predicted in the pirfenidone group compared with placebo (p=0.043); the result was similar when the model was stratified by diagnostic group (p=0.042). A significant treatment effect was also observed when applying the LOCF and multiple imputation methods to analyses of the primary endpoint.The median difference (Hodges-Lehmann estimate) between pirfenidone and placebo groups for the primary endpoint was 1.69 FVC % predicted (95% CI -0.65 to 4.03). In the linear mixed-model repeated measures slope analysis of FVC % predicted, the estimated difference between treatment and placebo groups from baseline to week 48 was 3.53 FVC % predicted (95% CI 0.21 to 6.86) with imputation of deaths as prespecified, or 2.79 FVC % predicted (95% CI 0.03 to 5.54) without imputation. One death (non-respiratory) occurred in the pirfenidone group (2%) and five deaths (three of which were respiratory) occurred in the placebo group (8%). The most frequent serious adverse events in both groups were infections and infestations (five [8%] in the pirfenidone group, ten [16%] in the placebo group); general disorders including disease worsening (two [3%] in the pirfenidone group, seven [11%] in the placebo group); and cardiac disorders (one ([2%] in the pirfenidone group, 5 [8%] in the placebo group). Adverse events (grade 3-4) of nausea (two patients on pirfenidone, two on placebo), dyspnoea (one patient on pirfenidone, one on placebo), and diarrhoea (one patient on pirfenidone) were also observed. Interpretation In view of the premature study termination, results should be interpreted with care. Nevertheless, our data suggest that in patients with fibrotic ILDs other than IPF who deteriorate despite conventional therapy, adding pirfenidone to existing treatment might attenuate disease progression as measured by decline in FVC. Funding German Center for Lung Research, Roche Pharma.

Rationale: The long-term safety and effectiveness of bronchoscopic lung volume reduction with Zephyr endobronchial valves in subjects with severe homogeneous emphysema with little to no collateral ventilation beyond 3 months have yet to be established. Methods: Ninety-three subjects were randomized to either bronchoscopic lung volume reduction with Zephyr valves or standard of care (SoC) (1:1). Zephyr valve subjects were assessed at 3, 6, and 12 months. SoC subjects were assessed at 3 and 6 months; they were then offered crossover to Zephyr valve treatment. Results: The mean group difference (Zephyr valve – SoC) for change in FEV1 from baseline to 6 months was 16.3 ± 22.1% (mean ± SD; p < 0.001). Secondary outcomes showed the mean between-group difference for the six-minute walk distance of +28.3 ± 55.3 m (p = 0.016); St. George’s Respiratory Questionnaire, −7.51 ± 9.56 points (p < 0.001); modified Medical Research Council, −0.42 ± 0.81 points (p = 0.019); BODE index, −0.85 ± 1.39 points (p = 0.006); and residual volume of −430 ± 830 mL (p = 0.011) in favor of the Zephyr valve group. At 6 months, there were significantly more responders based on the minimal clinically important difference for these same measures in the Zephyr valve versus the SoC group. The clinical benefits were persistent at 12 months. The percentage of subjects with respiratory serious adverse events was higher in the Zephyr valve group compared to SoC during the first 30 days post-procedure but not statistically different for the Zephyr valve and SoC groups from 31 days to 6 months, and stable in the Zephyr valve group out to 12 months. There were 2 deaths in the SoC group in the 31-day to 6-month period and none in the Zephyr valve group out to 12 months. Conclusions: Bronchoscopic lung volume reduction with Zephyr valves in subjects with severe homogeneous emphysema and little to no collateral ventilation provides clinically meaningful change from baseline in lung function, quality of life, exercise capacity, dyspnea, and the BODE index at 6 months, with benefits maintained out to 12 months.

Purpose To investigate contrast dynamics and artifacts associated with different breathing maneuvers during pulmonary computed tomography angiography (pCTA) in a prospective randomized clinical trial. Method Three different breathing maneuvers (inspiration, expiration, Mueller) were randomly assigned to 146 patients receiving pCTA for suspected pulmonary embolism (PE). Contrast enhancement of central and peripheral arteries and imaging quality of lung parenchyma were compared and analyzed. Results were compared by using the analysis of variances (ANOVA) and Kruskal-Wallis-Test. Results Mean enhancement in the pulmonary trunk was highest during breath-hold in inspiration (293 HU, range 195–460 HU) compared to Mueller (259 HU, range 136–429 HU, p = 0022) and expiration (267 HU, range 115–376 HU). This was similar for the right pulmonary artery (inspiration 289 HU, range 173–454 HU; Mueller 250 HU, range 119–378 HU; p = 0.007; expiration 257 HU, range 114–366 HU; p = 0.032) and left pulmonary artery (inspiration 280.3 HU, range 170–462 HU; Mueller 245 HU, range 111–371 HU; p = 0.016; expiration 252 HU, range 110–371 HU). Delineation of peripheral arteries was significantly better in inspiration vs Mueller (p = 0.006) and expiration (p = 0.049). Assessment of the lung parenchyma was significantly better in inspiration vs Mueller (p = 0.013) or expiration (p Conclusions Resting inspiratory position achieved the highest enhancement levels in central and peripheral pulmonary arteries and best image quality of the pulmonary parenchyma in comparison to other breathing maneuvers. It is necessary to train the maneuver prior to the examination in order to avoid deep inspiration with the risk of suboptimal opacification of the pulmonary arteries.

Lung cancer is a leading cause of cancer-related death in Germany and worldwide. Non-small cell lung cancer (NSCLC) comprises ~80% of lung cancer diagnoses; in White patients, around 10% of NSCLC cases are epidermal growth factor receptor mutation-positive (In NCT02047903, a prospective non-interventional study in Germany, patients withOf 152 patients, 106 (69.7%) were female, 20 (13.1%) patients had an uncommonThe results support clinical trial data for afatinib in routine clinical practice, including in patients generally excluded from clinical trials. Outcomes were positive in patients with uncommon

IntroductionEarly discharge of patients with acute low-risk pulmonary embolism requires validation by prospective trials with clinical and quality-of-life outcomes.MethodsThe multinational Home Treatment of Patients with Low-Risk Pulmonary Embolism with the Oral Factor Xa Inhibitor Rivaroxaban (HoT-PE) single-arm management trial investigated early discharge followed by ambulatory treatment with rivaroxaban. The study was stopped for efficacy after the positive results of the predefined interim analysis at 50% of the planned population. The present analysis includes the entire trial population (576 patients). In addition to 3-month recurrence (primary outcome) and 1-year overall mortality, we analysed self-reported disease-specific (Pulmonary Embolism Quality of Life (PEmb-QoL) questionnaire) and generic (five-level five-dimension EuroQoL (EQ-5D-5L) scale) quality of life as well as treatment satisfaction (Anti-Clot Treatment Scale (ACTS)) after pulmonary embolism.ResultsThe primary efficacy outcome occurred in three (0.5%, one-sided upper 95% CI 1.3%) patients. The 1-year mortality was 2.4%. The mean±sdPEmb-QoL decreased from 28.9±20.6% at 3 weeks to 19.9±15.4% at 3 months, a mean change (improvement) of −9.1% (pConclusionsOur results further support early discharge and ambulatory oral anticoagulation for selected patients with low-risk pulmonary embolism. Targeted strategies may be necessary to further improve quality of life in specific patient subgroups.

The COPD Assessment Test (CAT) is in widespread use for the evaluation of patients with chronic obstructive pulmonary disease (COPD). We assessed whether the CAT items carry additional information beyond the sum score regarding COPD characteristics including emphysema. Patients of GOLD grades 1 to 4 from the COPD cohort COSYCONET (German COPD and Systemic Consequences - Comorbidities Network) with complete CAT data were included (n = 2270), of whom 493 had chest CT evaluated for the presence of emphysema. Comorbidities and lung function were assessed following standardised procedures. Cross-sectional data analysis was based on multiple regression analysis of the single CAT items against a panel of comorbidities, lung function, or CT characteristics (qualitative score, 15th percentile of mean lung density), with age, BMI and gender as covariates. This was supported by exploratory factor analysis. Regarding the relationship to comorbidities and emphysema, there were marked differences between CAT items, especially items 1 and 2 versus 3 to 8. This grouping was basically confirmed by factor analysis. Items 4 and 5, and to a lower degree 1, 2 and 6, appeared to be informative regarding the presence of emphysema, whereas the total score was not or less informative. Regarding comorbidities, similar findings as for the total CAT score were obtained for the modified Medical Research Council scale (mMRC) which was also informative regarding emphysema. Our findings suggest that the usefulness of the CAT can be increased if evaluated on the basis of single items which may be indicating the presence of comorbidities and emphysema.

Background: Biomarkers for predicting response to immune checkpoint inhibitors (ICI) are scarce and often lack external validation. This study provides a comprehensive investigation of pretreatment C-reactive protein (CRP) levels as well as its longitudinal trajectories as a marker of treatment response and disease outcome in patients with advanced non-small cell lung cancer (NSCLC) undergoing immunotherapy with anti PD-1 or anti PD-L1 agents. Methods: We performed a retrospective bi-center study to assess the association between baseline CRP levels and anti PD-(L)1 treatment outcomes in the discovery cohort (n = 90), confirm these findings in an external validation cohort (n = 101) and explore the longitudinal evolution of CRP during anti PD-(L)1 treatment and the potential impact of dynamic CRP changes on treatment response and disease outcome in the discovery cohort. Joint models were implemented to evaluate the association of longitudinal CRP trajectories and progression risk. Primary treatment outcomes were progression-free survival (PFS) and overall survival (OS), while the objective response rate (ORR) was a secondary outcome, respectively. Results: In the discovery cohort, elevated pretreatment CRP levels emerged as independent predictors of worse PFS (HR per doubling of baseline CRP = 1.37, 95% CI: 1.16&ndash, 1.63, p &lt, 0.0001), worse OS (HR per doubling of baseline CRP = 1.42, 95% CI: 1.18&ndash, 1.71, p &lt, 0.0001) and a lower ORR ((odds ratio (OR) of ORR per doubling of baseline CRP = 0.68, 95% CI: 0.51&ndash, 0.92, p = 0.013)). In the validation cohort, pretreatment CRP could be fully confirmed as a predictor of PFS and OS, but not ORR. Elevated trajectories of CRP during anti PD-(L)1 treatment (adjusted HR per 10 mg/L increase in CRP = 1.22, 95% CI: 1.15&ndash, 1.30, p &lt, 0.0001), as well as a faster increases of CRP over time (HR per 10 mg/L/month faster increase in CRP levels = 13.26, 95% CI: 1.14&ndash, 154.54, p = 0.039) were strong predictors of an elevated progression risk, whereas an early decline of CRP was significantly associated with a reduction in PFS risk (HR = 0.91, 95% CI: 0.83&ndash, 0.99, p = 0.036), respectively. Conclusion: These findings support the concept that CRP should be further explored by future prospective studies as a simple non-invasive biomarker for assessing treatment benefit during anti PD-(L)1 treatment in advanced NSCLC.

Beim Lungenkrebs werden verschiedene histologische Subtypen unterschieden. Im Wesentlichen sind dies das kleinzellige Karzinom, das Plattenepithel- und das Adenokarzinom. Beim Adenokarzinom wird seit einigen Jahren in internationalen Studien ein Anstieg der Inzidenz beobachtet. Dies wirft Fragen auf, da das relative Risiko fur dessen Entstehung durch Tabakrauchen als niedriger geschatzt wird als bei anderen Subtypen. Ziel der Arbeit war die Untersuchung der zeitlichen Trends der Lungenkrebsinzidenz bei Mannern und Frauen in Deutschland getrennt nach den histologischen Subtypen. Alle zwischen 2003 und 2012 neu diagnostizierten bosartigen Tumoren der Lunge und der Bronchien (ICD-10 C33-C34), die aus epidemiologischen Krebsregistern der deutschen Bundeslander mit einer durchschnittlichen Vollzahligkeit von mindestens 90 % gemeldet waren, wurden berucksichtigt und histologischen Gruppen zugeordnet. Insofern die Angabe zur Tumorhistologie nicht mikroskopisch verifiziert oder zu unspezifisch war, wurde mittels multipler Imputation die histologische Gruppe erganzt. Zwischen 2003 und 2012 ist bei Frauen ein deutlicher Anstieg der altersstandardisierten Lungenkrebsinzidenz (jahrliche prozentuale Anderung, APC = 2,7 %) zu beobachten, der insbesondere durch eine deutliche Zunahme der Adenokarzinome (APC = 4,7 %) verursacht ist. Bei Mannern sinkt im selben Zeitraum die Lungenkrebsinzidenz insgesamt (APC = −1,7 %), aber auch hier ist ein leichter Inzidenzanstieg der Adenokarzinome (APC = 1,0 %) zu beobachten. Die zunehmende Inzidenz des Adenokarzinoms der Lunge ist auch in Deutschland nachweisbar. Eine Ursachenanalyse ist anhand der Krebsregisterdaten nicht moglich. In der internationalen Diskussion wurde die Hypothese aufgeworfen, dass insbesondere die Einfuhrung der Filterzigaretten und die veranderte Zusammensetzung von Zigarettenrauch hierfur verantwortlich sind. Tiefergehende epidemiologische Studien sind dringend erforderlich.

ZusammenfassungZielgerichtete Therapien haben erfolgreich Einzug in die palliative Therapie des Lungenkarzinoms gehalten, da sie eine Individualisierung oder Personalisierung ermöglichen, die mit der Testung von prädiktiven Biomarkern einhergeht. Dadurch steigt die Zahl an prädiktiven molekularbiologischen und immunhistochemischen Untersuchungsmöglichkeiten zu verschiedenen Zeitpunkten der Therapie und damit der Bedarf an jeweils aktuellen Tumorgewebeproben. Diese sind jedoch oft nicht ohne unverhältnismäßig hohe Belastungen für den Patienten zu gewinnen. Daher stellen Verfahren der Diagnostik aus Blutproben, die mit dem aus dem Englischen stammenden Begriff „liquid biopsy“ zusammengefasst werden, eine Alternative bzw. Ergänzung zur klassischen Gewebebiopsie dar. Derzeit können in der klinischen Routine bereits aktivierende EGFR-Mutationen sowie die inhibitorische Mutation T790 M aus dem Blut detektiert werden. Dieser Artikel stellt den aktuellen Stellenwert der liquid biopsy in der Diagnostik, zur Prognose und zur Steuerung des Therapieverlaufs bei Lungenkarzinomen dar und gibt einen Ausblick auf zukünftige Möglichkeiten.

Purpose The purpose of this paper is the retrospective analysis of endovascular therapy for the treatment of superior vena cava syndrome (SVCS) of malignant cause. This study focuses on the effectiveness of the therapy regarding the duration of remission, symptom control and practicability. Materials and Methods From January 2003 to November 2012, therapeutic implantation of one or more stents was performed in 141 patients suffering from SVCS. The medical history was retrospectively researched using digitalized patient files. If those were incomplete, secondary research was conducted using the cancer registry of the General Hospital Nuremberg, the cancer registry of the tumor center at Friedrich-Alexander-University Erlangen-Nuremberg (FAU) or information given by physicians in private practice. This data was collected using Microsoft Office Excel® and statistically analyzed using IBM SPSS Statistics 22®. Results 168 stents were implanted in 141 patients (median age: 64.6 years; range: 36 – 84), 86 being male and 55 being female. In 121 patients, SVCS was caused by lung cancer (85.8 %), in 9 patients by mediastinal metastasis of an extrathoracic carcinoma (6.4 %), in 3 patients by mesothelioma of the pleura (2.1 %) and in 1 patient by Hodgkin’s disease (0.7 %). There was no histological diagnosis in 7 cases (4.9 %). The primary intervention was successful in 138 patients (97.9 %). Immediate thrombosis in the stent occurred in the remaining 3 cases. Recurrence of SVCS was observed in 22 patients (15.6 %), including 5 early and 17 late occlusions. Stent dislocation or breakage was not observed. As expected, the survival after implantation was poor. The median survival was 101 days, and the median occlusion-free survival was 80 days. Conclusion The symptomatic therapy of SVCS with endovascular stents is effective and safe. Despite effective symptom control and a low rate of recurrence, the patients' prognosis is poor. Key Points: Citation Format