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Background: Telemonitoring-guided interventions can improve short-term positive airway pressure (PAP) therapy adherence, but long-term effects are unknown. This study investigated long-term PAP therapy termination in patients with sleep apnoea managed with standard care, telemonitoring-guided proactive care or telemonitoring-guided proactive care + patient engagement tool., Methods: German healthcare provider data were analysed retrospectively. Individuals aged 18-100 years who started PAP from 2014 to 2019 and had device type/interface data were included. Time-to-termination periods were analysed using Kaplan-Meier plots and Cox proportional hazards regression, adjusted for age, sex, insurance type, and device and mask type., Results: The per-protocol population (valid telemonitoring data) included 104 612 individuals (71% male; 95% aged >40 years). Mean follow-up was 3.3±2.0 years. The overall therapy termination rate was significantly lower in the telemonitoring-guided proactive care group versus standard care (20% versus 27%; p<0.001), and even lower in the telemonitoring-guided care + patient engagement tool group (11%; p<0.001 versus other treatment groups). Adjusted risk of therapy termination was lower versus standard care (hazard ratio 0.76, 95% confidence interval 0.74-0.78; and 0.41 (0.38-0.44) for telemonitoring-guided proactive care alone + patient engagement). Age <50 or >59 years and use of a nasal pillows or full-face mask were significant predictors of therapy termination; male sex, use of telemonitoring-guided proactive care (± patient engagement) and private insurance were significantly associated with lower therapy termination rates., Conclusions: Use of telemonitoring-guided proactive care and a patient engagement tool was associated with lower rates of PAP therapy termination., Competing Interests: Conflict of interest: H. Woerhle has received lecture/consulting fees from AstraZeneca, Allergopharma, Bioprojet, Boehringer Ingelheim, Chiesi, GSK, Novartis, Inspire, Jazz and ResMed, and research support from ResMed and Novartis. Conflict of interest: C. Schoebel has received grants from AstraZeneca, ResMed and Bayer, consulting fees from ResMed, Idorsia, Bristol-Myers Squibb and Astra Zeneca, and honoraria/lecture fees from Berlin Chemie, Takeda and Mementor; he also has unpaid roles as treasurer of the German Sleep Society, head of the Telemedicine Working Group of the German Society for Internal Medicine, and treasurer of the Sleep Apnea Working Group of the German Cardiac Society. Conflict of interest: J.H. Ficker has received grants and personal/lecture fees from ResMed and Inspire. Conflict of interest: A. Graml and J. Schnepf are employees of ResMed. Conflict of interest: I. Fietze reports support and grants from ResMed and Löwenstein Medical, personal fees from ResMed and Bioprojet, and has an unpaid role as director of the German Sleep Foundation. Conflict of interest: P. Young reports personal fees from Sanofi Genzyme, Biomarin, UCB Pharma, Medice, ResMed, Löwenstein Medical and Vanda, and grants from Lowensteinstiftung and the German Ministry of Education and Science (BMBF). Conflict of interest: M. Arzt has received grant support from ResMed, the ResMed Foundation, Philips Respironics and the Else-Kroehner Fresenisus Foundation, and lecture and/or consulting fees from ResMed, WITA Italia and Philips Respironics., (Copyright ©The authors 2024.)

Introduction: 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., Materials and Methods: 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)., Results: 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 the <70 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 the <70 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%)., Discussion: 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., Competing Interests: Declaration of Competing Interest Wolfgang M. Brueckl reports receiving lecture and educational event (personal) fees from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Chugai, Lilly, MSD, Pfizer, Roche Pharmaceuticals, and Takeda; receiving congress (personal) fees from Boehringer Ingelheim, AstraZeneca, and Roche Pharmaceuticals; and receiving advisory board fees (personal) from AstraZeneca, Boehringer Ingelheim, Novartis, Merck Sharp & Dohme, Lilly Pharma, Bristol Myers Squibb, and Roche. Martin Reck reports serving on advisory councils or committees and receiving consulting fees from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Lilly, Merck, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Sanofi; and receiving speaker honoraria from AbbVie, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Lilly, Merck, Merck Sharp & Dohme, Novartis, Pfizer, and Roche. Kai Neben reports receiving honoraria (personal fees) from Roche, Takeda, Amgen, Janssen, Pfizer, Bayer, Merck Sharp & Dohme, Bristol Myers Squibb, and Chugai. Frank Griesinger reports receiving support for scientific research from ASTRA, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Takeda, Siemens, Amgen, GlaxoSmithKline, and Janssen; receiving honoraria for presentations from ASTRA, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Takeda, Ariad, Abbvie, Siemens, Amgen, GlaxoSmithKline, Janssen, and Sanofi; and advisory board participation for ASTRA, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Takeda, Ariad, Abbvie, Siemens, GlaxoSmithKline, Janssen, and Sanofi. Justyna Rawluk reports serving on advisory councils or committees for AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Boehringer Ingelheim, Roche, and Takeda; and receiving consulting fees from AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Boehringer Ingelheim, Roche, and Takeda. Stefan Krüger reports receiving honoraria and grants or funds from Boehringer Ingelheim. Joachim H. Ficker reports receiving speaker honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi Aventis, and Bristol Myers Squibb. Miriam Möller reports receiving consulting fees (consulting or advisory role) from Boehringer Ingelheim and Roche; and receiving payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing or educational events from Boehringer Ingelheim, Roche, AstraZeneca, and Merck Sharp & Dohme. Andrea Schueler is an employee of Boehringer Ingelheim Pharma GmbH & Co KG. Eckart Laack, Konrad Kokowski and Harald Schäfer report no potential conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: 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., Competing Interests: Dr Franziska C Trudzinski reports personal fees from Novartis AG, non-financial support from CSL Behring, personal fees from Boehringer Ingelheim, personal fees from GlaxoSmithKline, personal fees from Chiesi, outside the submitted work. Professor Dr Robert Bals reports grants from BMBF, grants from Marburg University, during the conduct of the study; grants, personal fees from Various, outside the submitted work. Prof Dr Stefan Andreas reports grants from Boehringer, personal fees from Altana, Boehringer, AZ, GSK, Chiesi, GSK, Novartis, Menerini, outside the submitted work. Professor Dr Tobias Welte reports grants from German Ministry of Research and Education, during the conduct of the study. Dr Antonia Sassmann-Schweda reports Contractual payments for conduction of study visits; payments were made to Research Center Borstel, Center for Clinical Studies from Philipps University of Marburg, during the conduct of the study. Professor Dr Joachim H Ficker reports personal fees, non-financial support from CSL Behring, personal fees from Novartis, personal fees from AstraZeneca, personal fees from Boehringer, personal fees from Pfizer, outside the submitted work; Prof Dr Claus F Vogelmeier reports personal fees from Aerogen, grants, personal fees from AstraZeneca, grants, personal fees from Boehringer Ingelheim, grants, personal fees from CSL Behring, grants, personal fees from Chiesi, grants, personal fees from GlaxoSmithKline, grants, personal fees from Grifols, personal fees from Menarini, grants, personal fees from Novartis, personal fees from Nuvaira, personal fees from MedUpdate, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2022 Alter et al.)

Background: 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., Objectives: Plasma concentrations of isavuconazole were determined in critically ill ICU patients while considering different patients' characteristics., Methods: 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 (C max ), those 20-28 h after last dosing as trough levels (C min )., Results: Overall, 223 isavuconazole levels of 41 patients were analysed, divided into 141 peak levels and 82 trough levels. The overall median C max was 2.36 μg/ml (mean 2.43 μg/ml, range 0.41-7.79 μg/ml) and the overall median C min was 1.74 μg/ml (mean 1.77 μg/ml, range 0.24-4.96 μg/ml). In total, 31.7% of the C min values of the total cohort were below the plasma target concentrations of 1 μg/ml, defined as EUCAST antifungal clinical breakpoint for Aspergillus fumigatus. Both peak and trough plasma levels of isavuconazole were significantly lower among patients with a body mass index (BMI) ≥25. In addition, a significant correlation was observed between isavuconazole trough levels and sepsis-related organ failure assessment (SOFA) score., Conclusions: This 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., (© 2022 The Authors. Mycoses published by Wiley-VCH GmbH.)

Background: COVID-19 is associated with acute respiratory distress and cytokine release syndrome. The Janus kinase (JAK)1/JAK2 inhibitor ruxolitinib reduces inflammatory cytokine concentrations in disorders characterised by cytokine dysregulation, including graft-versus-host disease, myelofibrosis, and secondary hemophagocytic lymphohistiocytosis. We assessed whether treatment with the JAK1/JAK2 inhibitor ruxolitinib would be beneficial in patients with COVID-19 admitted to hospital., Methods: RUXCOVID was an international, randomised, double-blind, phase 3 trial of ruxolitinib plus standard of care versus placebo plus standard of care in patients with COVID-19. Patients who were hospitalised but not on mechanical ventilation or in the intensive care unit [ICU] were randomly assigned (2:1) to oral ruxolitinib 5 mg twice per day or placebo for 14 days (14 additional days were allowed if no improvement). The primary endpoint was a composite of death, respiratory failure (invasive ventilation), or ICU care by day 29, analysed by logistic regression including region, treatment, baseline clinical status, age, and sex as covariates. This trial is registered with ClinicalTrials.gov, NCT04362137., Findings: Between May 4 and Sept 19, 2020, 432 patients were randomly assigned to ruxolitinib (n=287) or placebo (n=145) plus standard of care; the mean age was 56·5 years (SD 13·3), 197 (46%) were female, and 235 (54%) were male. The primary objective was not met: the composite endpoint occurred in 34 (12%) of 284 ruxolitinib-treated patients versus 17 (12%) of 144 placebo-treated patients (odds ratio 0·91, 95% CI 0·48-1·73; p=0·77). By day 29, nine (3%) of 286 ruxolitinib-treated patients had died compared with three (2%) of 145 placebo-treated patients; 22 (8%) of 286 ruxolitinib-treated patients had received invasive ventilation compared with ten (7%) of 145 placebo-treated patients; and 30 (11%) of 284 ruxolitinib-treated patients had received ICU care compared with 17 (12%) of 144 placebo-treated patients. In an exploratory analysis, median time to recovery was 1 day faster with ruxolitinib versus placebo (8 days vs 9 days; hazard ratio 1·10, 95% CI 0·89-1·36). Adverse events included headache (23 [8%] of 281 on ruxolitinib vs 11 [8%] of 143 on placebo) and diarrhoea (21 [7%] vs 12 [8%])., Interpretation: Ruxolitinib 5 mg twice per day showed no benefit in the overall study population. A larger sample is required to determine the clinical importance of trends for increased efficacy in patient subgroups., Funding: Novartis and Incyte., Competing Interests: IG, AG, ALB, AR, JS-O, FT, RT, and SS have no competing interests. MKH reports personal fees from GSK, AstraZeneca, Boehringer Ingelheim, Cipla, Chiesi, Novartis, Pulmonx, Teva, Verona, Merck, Mylan, Sanofi, DevPro, Aerogen, Polarian, Regeneron, United Therapeutics, UpToDate, Altesa Biopharma, Medscape, and Integrity. MKH has received either in kind research support or funds paid to the institution from the National Institutes of Health, Novartis, Sunovion, Nuvaira, Sanofi, AstraZeneca, Boehringer Ingelheim, Gala Therapeutics, Biodesix, the COPD Foundation, and the American Lung Association. MKH has participated in Data Safety Monitoring Boards for Novartis and Medtronic with funds paid to their institution. MKH has received stock options from Meissa Vaccines and Altesa Biopharma. MA has participated in clinical studies funded by AbbVie, AstraZeneca, EMS, Eurofarma, GSK, Humanigen, Janssen, Novartis, Sanofi Genzyme, Angion Biomedica Corporation, and Beigene; has received honoraria from Aché, AstraZeneca, Chiesi, Eurofarma, IPI ASAC Brasil, and Sanofi; has received meeting or travel support from AstraZeneca, GSK, Novartis, and Sanofi Genzyme; and has participated in data safety monitor boards or advisory boards, or both, for Sanofi Genzyme, Chiesi, AstraZeneca, Abbott, and Zambom. JHF has received research funding from Novartis; grants from Boehringer Ingelheim and CSL-Behring; consulting fees from Novartis, Boehringer Ingelheim, and CSL-Behring; honoraria from AstraZeneca, Boehringer Ingelheim, CSL-Behring, GSK, MSD, and Novartis; meeting or travel support from AstraZeneca, Boehringer Ingelheim, CSL-Behring, and Novartis; and materials from CSL-Behring; and has participated in data safety monitor boards or advisory boards, or both, for Boehringer Ingelheim and AstraZeneca. LB, DSB, JMF, BK, WC, TL, and ML are employees and stockholders of Novartis. XS was an employee of Novartis during the conduct of the study. PL is an employee of Incyte., (Published by Elsevier Ltd.)

Introduction: Specialized 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 " N uremberg I ntegrated P sychosomatic A cute Unit" (NIPA) has been developed to integrate treatment of both, psychosocial and physical impairments, in an acute somatic care setting., Method: NIPA 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)., Results: Data 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., Discussion: NIPA 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Köbler, Krauss-Köstler, Stein, Ficker, Wilhelm, Dechêne and Waller.)

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, < .001, respectively). In a nested reference model consisting of age, gender and body mass index, adding cardiac risk index but not apnea-hypopnea index or oxygen desaturation index significantly increased the area under the receiver operating characteristic curve (p = .012, .22 and .16, respectively). In a direct comparison of oxygen desaturation index and cardiac risk index, only the novel risk index had an independent effect on cardiovascular risk prediction (p CRI  < .001, p ODI  = .71). These results emphasize the association between nocturnal pulse wave and overall cardiovascular risk determined by an established risk matrix. Thus, pulse wave analysis during sleep provides a powerful approach for cardiovascular risk assessment in addition to conventional sleep study parameters., (© 2021 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

Background: 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., Competing Interests: Professor Joachim H Ficker reports personal fees from Boehringer-Ingelheim, AstraZeneca, and GSK; personal fees, non-financial support from CSL Behring and Novartis, outside the submitted work. Professor Jürgen Behr reports personal fees from Boehringer-Ingelheim, AstraZeneca, and Novartis, outside the submitted work. Professor Robert Bals reports COSYCONET is supported by the German Centre for Lung Research (DZL), grant number 82DZLI05A2 (COSYCONET), the BMBF, grant number 01GI0881 and also received unrestricted grants from AstraZeneca GmbH, Boehringer Ingelheim Pharma GmbH & Co. KG, GlaxoSmithKline GmbH&Co. KG, Grifols Deutschland GmbH, and Novartis Deutschland GmbH. Professor Bals also reports grants, and/or personal fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Grifols, Novartis, CSL Behring, German Federal Ministry of Education and Research (BMBF) Competence Network Asthma and COPD (ASCONET), Sander Stiftung, Schwiete Stiftung, Krebshilfe, and Mukoviszidose eV, outside the submitted work. Professor Claus F Vogelmeier reports personal fees, and/or grants from Aerogen, AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi, GlaxoSmithKline, Grifols, Menarini, Novartis, Nuvaira, and MedUpdate, outside the submitted work. The authors declare that they have no other competing interests., (© 2021 Kahnert et al.)

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., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/tlcr-21-587). The following authors received honoraria for lectures, presentation, speakers bureaus, manuscript writing or educational events: WMB from AstraZeneca, Boehringer, Novartis, MSD, BMS, Roche and Lilly; JHF from AstraZeneca, Boehringer, Novartis, MSD, BMS, Pfizer, Gilead and Roche; FPMR from Roche, Astra Zeneca and Chugai Pharma; SE from Roche. The following authors received support for attending meetings and/or travel: WMB from Boehringer, AstraZeneca and Roche; FPMR from Roche and Astra Zeneca; JHF from Boehringer and AstraZeneca. The following authors participated on a data safety monitoring board or an advisory board: WMB on AstraZeneca, Boehringer, Novartis, MSD, Lilly, BMS and Roche; JHF on AstraZenca; FPMR on Pfizer and Roche. The following authors receipt equipment, materials, drugs, medical writing, gifts or other services: WMB from Boehringer (for medical writing); JHF from Novartis (for medical writing); The following authors received consulting fees: AR from AbbVie, AstraZeneca, BMS, Boehringer, Lilly, MSD, Novartis, Pfizer and Roche. The following authors have patents planned, issued or pending: WMB, NFB, RMW and EV with Stratifyer. The following authors received support for the present manuscript: RMW and EV as employees to Stratifyer, WMB and JHF with an unrestricted grant from the W. Lutz Stiftung, Nuremberg, Germany. The following authors have stock or stock options related to the manuscript: RMW and SE (Stratifyer). The other authors have no conflicts of interest to declare., (2021 Translational Lung Cancer Research. All rights reserved.)

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., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/tlcr-21-197). Albrecht Stenzinger serves as an unpaid editorial board member of Translational Lung Cancer Research from Sep 2019 to Sep 2021. The following authors received honoraria for lectures, presentation, speakers bureaus, manuscript writing or educational events: WMB from AstraZeneca, Boehringer, Novartis, MSD, BMS, Roche and Lilly; MR from Amgen, AstraZeneca, BMS, Boehringer, Lilly, Minde, Merck, MSD, Novartis, Pfizer and Roche; AR from AbbVIe, AstraZeneca, BMS, Boehringer, Lilly, MSD, Novartis, Pfizer and Roche; CW from Boehringer, Lilly, MSD, Roche, AstraZeneca, BMS, Sanofi Aventis and Takeda; GHW from Boehringer, Lilly, MSD, Roche, AstraZeneca, BMS, Sanofi Aventis, Takeda, Glaxo and Berlin Chemie; PC from Roche, Takeda, AstraZeneca and Novartis; AS from Aignostics, Bayer, Thermo Fisher, Illumina, AstraZeneca, Novartis, Pfizer, Roche, Seattle Genetics, MSD, BMS, Takeda and Lilly; AT from GSK, Novartis, Amgen, BMS, MSD, Lilly, Pfizer, Boehringer, Roche, Takeda and Celgene; JHF from AstraZeneca, Boehringer, Novartis, MSD, BMS and Roche. The following authors received support for attending meetings and/or travel: WMB from Boehringer, AstraZeneca and Roche; CW from Boehringer, MSD, Roche, AstraZeneca and BMS; GW from Boehringer, MSD, Roche, AstraZeneca and Berlin Chemie; PC from AstraZeneca, Takeda, Novartis and Lilly; AT from GSK, Novartis, Amgen, MSD, BMS, Lilly, Pfizer, Boehringer, Roche, Takeda and Celgene; JHF from Boehringer and AstraZeneca. The following authors participated on a data safety monitoring board or an advisory board: WMB on AstraZeneca, Boehringer, Novartis, MSD, Lilly, BMS and Roche; JK on Roche, Boehringer, BMS, Merck, Amgen, Takeda and Lilly (all outside the submitted work and all without receiving any personal fees; CW on Boehringer, MSD, Roche, AstraZeneca and MBS; GHW on Boehringer, MSD, Roche, AstraZeneca and BMS; PC on Pfizer, Chugai, Boehringer and Roche; AT on GSK, Novartis, Amgen, MSD, BMS, Lilly, Pfizer, Boehringer, Roche, Takeda, Celgene and AIO Leadership Group; PH on Lilly, MSD, BMS, AstraZeneca, Takeda, Roche, Boehringer and Pfizer; JHF on AstraZenca. The following authors receipt equipment, materials, drugs, medical writing, gifts or other services: WMB from Boehringer (for medical writing); JHF from Novartis (for medical writing); the following authors received consulting fees: AR from AbbVie, AstraZeneca, BMS, Boehringer, Lilly, MSD, Novartis, Pfizer and Roche. The following authors received grants or contracts form any entity: PC from Roche, Takeda, AstraZeneca and Novartis (all research grants to the institution; AT from AstraZeneca (research grant). The other authors have no conflicts of interest to declare., (2021 Translational Lung Cancer Research. All rights reserved.)

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 ( EGFR m+). 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 EGFR m+ 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 EGFR m+ 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 <40 mg was received by 39 (25.7%) patients. Overall, the 12-month PFS rate was 50.2% while the median PFS was 12.2 months. The ORR was 74.6% and the median OS was 30.4 months. In patients with brain metastases and uncommon mutations, the median PFS was 10.5 and 10.7 months, and the ORR was 77.3% and 83.3%, respectively. Treatment effectiveness was similar in patients with a starting dose of <40 mg (median PFS: 16.4 months; ORR, 81.3%) and a starting dose of 40 mg (median PFS: 10.8 months; ORR, 72.1%). Adverse drug reactions were manageable and consistent with the known afatinib safety profile., 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 <40 mg afatinib starting dose, supporting patient-tailored dosing., Competing Interests: Conflict of interest statement: This study was supported by Boehringer Ingelheim. Wolfgang Brückl has received honoraria for consulting from AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Chugai, Lilly, MSD, Pfizer, Roche Pharmaceuticals and Takeda. Joachim Ficker has received speaker honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, GSK, MSD, Novartis, Pfizer, Roche, and Sanofi-Aventis. Frank Griesinger has served on advisory councils or committees for Boehringer Ingelheim, Roche, and AstraZeneca; and has received honoraria, consulting fees, and grants or funds, from Boehringer Ingelheim, Roche, and Astra Zeneca. Stefan Krüger has received honoraria, and grants or funds, from Boehringer Ingelheim. Justyna Rawluk has served on advisory councils or committees for AstraZeneca, BMS, MSD, Boehringer Ingelheim, Roche, and Takeda; and has received consulting fees from AstraZeneca, BMS, MSD, Boehringer Ingelheim, Roche, and Takeda. Martin Reck has served on advisory councils or committees for AbbVie, Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Lilly, Merck, MSD, Novartis, Pfizer, Roche, and Sanofi; received speaker honoraria from AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Lilly, Merck, MSD, Novartis, Pfizer, and Roche; and received consulting fees from AbbVie, Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Lilly, Merck, MSD, Novartis, Pfizer, Roche, and Sanofi. Christopher Hoffman and Andrea Schüler are employees of Boehringer Ingelheim. Stephan Budweiser, Tobias Gaska, Cornelius Kortsik, Konrad Kokowski, Eckart Laack, and Harold Schäfer have no potential conflicts of interest to declare., (© The Author(s), 2021.)

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., Competing Interests: Declaration of interests JB reports personal fees from Boehringer Ingelheim, Bristol Myers Squibb, Biogen, Galapagos, Promedior, Roche, and the German Center for Lung Research (DZL). SB reports personal fees and non-financial support from Roche, Bayer, Novartis, and Boehringer Ingelheim; personal fees from Merck Serono; and non-financial support from Teva, Gilead, Lucane Pharma, Actelion, CSL Behring, and Vertex. FB reports personal fees for consultancy, lecturing, and travel support from Boehringer Ingelheim and Roche. MC reports grants from DZL. JHF reports personal fees, grants, and non-financial support from Roche; and personal fees and non-financial support from Boehringer Ingelheim. AG reports grants from DZL, Boehringer Ingelheim, and Roche. MH reports grants from Actelion; honoraria for lectures from Actelion, Bayer Healthcare, Berlin Chemie, Boehringer Ingelheim, GlaxoSmithKline (GSK), Merck Sharp & Dohme (MSD), Novartis, OMT, Pfizer, and Roche; honoraria for advisory boards from Actelion, Bayer, Boehringer Ingelheim, GSK, MSD, and Roche; and honoraria for clinical trials from Actelion, Bayer, GSK, Pfizer, and United Therapeutics. NKn reports personal fees from Roche. DK reports personal fees from Roche; and personal fees and non-financial support from Boehringer Ingelheim. MK reports grants from DZL; and grants and personal fees from Boehringer Ingelheim and Roche. AP reports grants from DZL; grants, personal fees, and non-financial support from Boehringer Ingelheim and AstraZeneca; personal fees and non-financial support from Roche, Pliant, Chiesi Pharmaceuticals, and Nitto Denko; personal fees from Amgen; and non-financial support from Galapagos. KFR reports grants and personal fees from Boehringer Ingelheim and AstraZeneca; and personal fees from Novartis, Sanofi, Regeneron, Roche, and Chiesi Pharmaceuticals. TW reports grants from Roche; and personal fees from Boehringer Ingelheim, Roche, and Novartis. HWil reports personal fees for lectures or consultations from Actelion–Janssen, Bayer, Biotest, Boehringer Ingelheim, GSK, Pfizer, and Roche. HWir reports lecture fees from Roche. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Early discharge of patients with acute low-risk pulmonary embolism requires validation by prospective trials with clinical and quality-of-life outcomes., Methods: The 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., Results: The 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±sd PEmb-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% (p<0.0001). Improvement was consistent across all PEmb-QoL dimensions. The EQ-5D-5L was 0.89±0.12 at 3 weeks after enrolment and improved to 0.91±0.12 at 3 months (p<0.0001). Female sex and cardiopulmonary disease were associated with poorer disease-specific and generic quality of life; older age was associated with faster worsening of generic quality of life. The ACTS burden score improved from 40.5±6.6 points at 3 weeks to 42.5±5.9 points at 3 months (p<0.0001)., Conclusions: Our 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., Competing Interests: Conflict of interest: S. Barco reports personal fees from Biocompatibles Group UK, LEO Pharma, Bayer, nonfinancial support from Bayer HealthCare and Daiichi Sankyo, grants from Sanofi, outside the submitted work. Conflict of interest: I. Schmidtmann reports grants from Merck Serono, outside the submitted work. Conflict of interest: W. Ageno reports grants from Bayer, personal fees from Boehringer Ingelheim, Daiichi Sankyo and Bristol Myers Squibb/Pfizer, outside the submitted work. Conflict of interest: T. Anušić has nothing to disclose. Conflict of interest: R.M. Bauersachs reports personal fees for lectures and advisory board work from Bayer HealthCare, Bristol Myers Squibb/Pfizer and Daiichi Sankyo, during the conduct of the study. Conflict of interest: C. Becattini reports personal fees for consultancy and lectures from Bayer HealthCare, Daiichi Sankyo and Bristol Myers Squibb, outside the submitted work. Conflict of interest: E. Bernardi has nothing to disclose. Conflict of interest: J. Beyer-Westendorf reports patient fees from the Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, during the conduct of the study; grants and personal fees for advisory board work, lectures and travel support from Bayer, outside the submitted work. Conflict of interest: L. Bonacchini has nothing to disclose. Conflict of interest: J. Brachmann reports grants and personal fees from Medtronic, during the conduct of the study; grants from Medtronic, St Jude and Biotronik, outside the submitted work. Conflict of interest: M. Christ reports grants from the University of Mainz, during the conduct of the study. Conflict of interest: M. Czihal reports personal fees from Bayer HealthCare, Roche, AstraZeneca, MSD Sharp & Dohme and LEO Pharma, outside the submitted work. Conflict of interest: D. Duerschmied reports personal fees for lectures and nonfinancial support (travel costs) from Bayer, Pfizer, Daiichi Sankyo and CytoSorbents, outside the submitted work. Conflict of interest: K. Empen reports travel costs and personal fees for lectures from Bayer HealthCare, outside the submitted work. Conflict of interest: C. Espinola-Klein reports lecture fees from Bayer HealthCare, outside the submitted work. Conflict of interest: J.H. Ficker reports personal fees for lectures from Daiichi Sankyo, outside the submitted work. Conflict of interest: C. Fonseca reports personal fees for consultancy and lectures from Bayer, outside the submitted work Conflict of interest: S. Genth-Zotz has nothing to disclose. Conflict of interest: D. Jiménez has nothing to disclose. Conflict of interest: V-P. Harjola reports personal fees for lectures from Bayer, personal fees for lectures and advisory board work from Boehringer Ingelheim and Pfizer, personal fees for advisory board work from MSD, outside the submitted work. Conflict of interest: M. Held reports honoraria for advisory board work from Actelion, Bayer, Boehringer, MSD, Daiichi Sankyo and Roche, honoraria for lectures from Actelion, Bayer, Berlin-Chemie, Bristol Myers Squibb, MSD, Daichi Sankyo, Pfizer and OMT, grants from Actelion, outside the submitted work. Conflict of interest: L. Iogna Prat has nothing to disclose. Conflict of interest: T.J. Lange reports nonfinancial support for meeting attendance from the Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, during the conduct of the study; personal fees from Bayer and Pfizer, outside the submitted work. Conflict of interest: M. Lankeit reports personal fees for lectures and nonfinancial support (travel costs) from Actelion, Bayer and Daiichi Sankyo, personal fees for lectures from MSD and Bristol Myers Squibb/Pfizer, grants from BRAHMS – Thermo Fisher Scientific, outside the submitted work. Conflict of interest: A. Manolis has nothing to disclose. Conflict of interest: A. Meyer has nothing to disclose. Conflict of interest: T. Münzel has nothing to disclose. Conflict of interest: P. Mustonen reports personal fees for lectures and advisory board work from Boehringer Ingelheim, Bayer, Sanofi-Anetis, LEO Pharma, Bristol Myers Squibb/Pfizer and MSD, outside the submitted work. Conflict of interest: U. Rauch-Kroehnert reports grants from Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Interdisziplinäres Zentrum Klinische Studien (IZKS) during the conduct of the study; personal fees from Bayer Vital, outside the submitted work. Conflict of interest: P. Ruiz-Artacho reports personal fees from Bayer, Daiichi Sankyo, Sanofi, Pfizer, LEO Pharma and Rovi, outside the submitted work. Conflict of interest: S. Schellong reports personal fees for lectures and consultancy from Bayer, Boehringer Ingelheim, Daiichi Sankyo and Aspen, grants and personal fees for lectures and consultancy from Bristol Myers Squibb, outside the submitted work. Conflict of interest: M. Schwaiblmair has nothing to disclose. Conflict of interest: R. Stahrenberg has nothing to disclose. Conflict of interest: L. Valerio has nothing to disclose. Conflict of interest: P.E. Westerweel has nothing to disclose. Conflict of interest: P.S. Wild reports grants and personal fees from Boehringer Ingelheim, Sanofi-Aventis, Bayer Vital and Bayer HealthCare, grants from Philips Medical Systems and Daiichi Sankyo Europe, personal fees from AstraZeneca, personal fees and equipment provision from DiaSorin, equipment provision from IEM, outside the submitted work. Conflict of interest: S.V. Konstantinides reports grants and provision of study drug from Bayer, during the conduct of the study; grants and personal fees for consultancy and lectures from Boehringer Ingelheim, Daiichi Sankyo, Biocompatibles Group UK and MSD, personal fees for consultancy and lectures from Bayer and Bristol Myers Squibb/Pfizer, grants and personal fees for lectures from Actelion, grants from Servier, outside the submitted work., (Copyright ©ERS 2021.)

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., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

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.

Background: Antiangiogenic agents have been shown to stimulate the immune system and cause synergistic effects with chemotherapy. Effects might be even stronger after immune-checkpoint-inhibitor (ICI) therapy. The purpose of this analysis was to evaluate the efficacy of ramucirumab plus docetaxel (R + D) as third-line treatment after failure of a first-line platinum-based chemotherapy and a second-line ICI treatment in patients with non-small-cell lung cancer (NSCLC) stage IV., Methods: Retrospective data were collected from 9 German thoracic oncology centers. Only patients who had received at least 1 cycle of third-line R + D were included. The numbers of cycles, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were investigated., Results: Sixty-seven patients met the criteria for inclusion. Third-line treatment with R + D achieved an ORR of 36% and a disease control rate (DCR) of 69%. Median PFS for third-line therapy was 6.8 months with a duration of response (DOR) of 10.2 months. A median OS of 29 months was observed from the start of first-line therapy with a median OS of 11.0 months from the start of third-line treatment. No unexpected toxicities occurred., Conclusion: R + D is a highly effective and safe third-line treatment after failure of second-line programmed cell death protein 1/programmed cell death-ligand 1 (PD1/PD-L1)-derived ICI therapy irrespective of NSCLC histology. As there may be synergistic effects of second- and third-line treatments, this sequence is a very suitable option for patients not treated with first-line ICI. In addition, R + D should continue to be investigated as a second-line treatment option after failure of chemotherapy plus ICI in the palliative first-line treatment., Competing Interests: Declaration of Conflicting Interest:The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: W.M.B. and J.H.F. have received honoraria for consulting from Astra Zeneca, BMS, Boehringer Ingelheim, Celgene, Lilly, MSD, Pfizer, and Roche Pharma. P.C. reports consulting honoraria from Astra Zeneca, Boehringer Ingelheim, Chugai, Lilly, Novartis, Pfizer, Roche, and Takeda. P.H. has received honoraria for consulting from Boehringer Ingelheim, Pfizer, Takeda, Roche Pharma, Lilly, BMS, MSD, AstraZeneca, and Abbvie. F.R. has received honoraria for consulting from Astra Zeneca, Chugai Pharma, and Roche Pharma. C.W. and G.H.W. have received honoraria for consulting from Astra Zeneca, BMS, Boehringer Ingelheim, Lilly, MSD, Pfizer, and Roche Pharma. The other authors reported no conflict of interest., (© The Author(s) 2020.)

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: 1.16-1.63, p < 0.0001), worse OS (HR per doubling of baseline CRP = 1.42, 95% CI: 1.18-1.71, p < 0.0001) and a lower ORR ((odds ratio (OR) of ORR per doubling of baseline CRP = 0.68, 95% CI: 0.51-0.92, 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: 1.15-1.30, p < 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: 1.14-154.54, 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: 0.83-0.99, 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.

Aims: To investigate the efficacy and safety of early transition from hospital to ambulatory treatment in low-risk acute PE, using the oral factor Xa inhibitor rivaroxaban., Methods and Results: We conducted a prospective multicentre single-arm investigator initiated and academically sponsored management trial in patients with acute low-risk PE (EudraCT Identifier 2013-001657-28). Eligibility criteria included absence of (i) haemodynamic instability, (ii) right ventricular dysfunction or intracardiac thrombi, and (iii) serious comorbidities. Up to two nights of hospital stay were permitted. Rivaroxaban was given at the approved dose for PE for ≥3 months. The primary outcome was symptomatic recurrent venous thromboembolism (VTE) or PE-related death within 3 months of enrolment. An interim analysis was planned after the first 525 patients, with prespecified early termination of the study if the null hypothesis could be rejected at the level of α = 0.004 (<6 primary outcome events). From May 2014 through June 2018, consecutive patients were enrolled in seven countries. Of the 525 patients included in the interim analysis, three (0.6%; one-sided upper 99.6% confidence interval 2.1%) suffered symptomatic non-fatal VTE recurrence, a number sufficiently low to fulfil the condition for early termination of the trial. Major bleeding occurred in 6 (1.2%) of the 519 patients comprising the safety population. There were two cancer-related deaths (0.4%)., Conclusion: Early discharge and home treatment with rivaroxaban is effective and safe in carefully selected patients with acute low-risk PE. The results of the present trial support the selection of appropriate patients for ambulatory treatment of PE., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.)

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., Competing Interests: Joachim Ficker reports grants from the COSYCONET study supported by Bundesministerium fuer Bildung und Forschung BMBF, during the conduct of the study. He also received personal fees and nonfinancial support from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Grifols and Novartis, grants, personal fees and nonfinancial support from CSL Behring, outside the submitted work. Claus Vogelmeier reports personal fees from Almirall, grants and personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Grifols, Mundipharma, Novartis and Takeda, personal fees from Cipla, Berlin Chemie/Menarini, CSL Behring and Teva, grants from German Federal Ministry of Education and Research (BMBF) Competence Network Asthma and COPD (ASCONET), Bayer Schering Pharma AG, MSD and Pfizer, outside the submitted work. Robert Bals reports grants and personal fees from AstraZeneca, Novartis and Boehringer Ingelheim, personal fees from GlaxoSmithKline and Grifols and CSL Behring, grants from German Federal Ministry of Education and Research (BMBF) Competence Network Asthma and COPD (ASCONET), Sander Stiftung, Schwiete Stiftung and Krebshilfe from Mukoviszidose eV, outside the submitted work. Peter Alter reports grants from German Federal Ministry of Education and Research (BMBF) Competence Network Asthma and COPD (ASCONET), and AstraZeneca GmbH, grants and nonfinancial support from Bayer Schering Pharma AG, grants, personal fees and nonfinancial support from Boehringer Ingelheim Pharma GmbH & Co. KG, grants and nonfinancial support from Chiesi GmbH, grants from GlaxoSmithKline, Grifols Deutschland GmbH, and MSD Sharp & Dohme GmbH, grants and personal fees from Mundipharma GmbH, grants, personal fees and nonfinancial support from Novartis Deutschland GmbH, grants from Pfizer Pharma GmbH and Takeda Pharma Vertrieb GmbH & Co. KG, outside the submitted work. Johanna Lutter reports grants from Federal Ministry of Education and Research (grant number 01GI0881), during the conduct of the study. Tobias Welte reports grants from Boehringer, GSK, Novartis, AstraZeneca, during the conduct of the study; personal fees from AstraZeneca, Boehringer, GSK, Novartis, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2019 Königsdorfer et al.)

Despite recent improvements, α 1 -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., Competing Interests: Conflict of interest: I. Horváth reports personal fees from AstraZeneca, GSK, Sandoz, Sager Pharma, Orion and Affidea, personal fees and non-financial support from Boehringer-Ingelheim, Berlin-Chemie, Novartis, CSL Behring, Roche and Teva, and non-financial support from MSD, outside the submitted work. Conflict of interest: J. Chlumský reports fees for lectures and consultancy from CSL Behring. Conflict of interest: J. Chorostowska-Wynimko reports grants, personal fees, nonfinancial support and other support from Grifols and CSL Behring, personal fees from Kamada, and other support from Shire, outside the submitted work. Conflict of interest: L. Corda reports personal fees from Grifols and CSL Behring for lectures, speakers’ bureaus and expert testimony. Conflict of interest: J.H. Ficker reports grants from CSL Behring during the conduct of the study; and personal fees from Grifols, and personal fees and non-financial support from CSL Behring, outside the submitted work. Conflict of interest: M. Kneussl has nothing to disclose. Conflict of interest: M. Miravitlles reports speaker's fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Menarini, Rovi, Bial, Zambon, CSL Behring, Grifols and Novartis, consulting fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Bial, Gebro Pharma, CSL Behring, Laboratorios Esteve, Mereo Biopharma, Verona Pharma, TEVA, pH Pharma, Novartis and Grifols, and grants from GlaxoSmithKline and Grifols, outside the submitted work. Conflict of interest: G. Thabut reports personal fees and non-financial support from CSL Behring, and grants, personal fees and non-financial support from LFB, outside the submitted work. Conflict of interest: A.M. Turner reports consultancy fees from CSL Behring, grants from Grifols Biotherapeutics, the Alpha 1 Foundation, the ATS Foundation and the Chest Foundation, grants, conference attendance and fees for clinical trial work as investigator paid to her institution from Arrowhead Inc., and fees for work as study investigator paid to her institution from Boehringer, outside the submitted work. Conflict of interest: N.G. McElvaney reports grants and personal fees from CSL Behring, grants, and personal fees and non-financial support from Grifols, outside the submitted work. Conflict of interest: E. Derom has nothing to disclose. Conflict of interest: E. van 't Wout has nothing to disclose. Conflict of interest: M. Canotilho has nothing to disclose. Conflict of interest: M. Sucena has nothing to disclose.

Background: There is a lack of robust data about factors predicting continuation (or termination) of positive airway pressure therapy (PAP) for sleep apnea. This analysis of big data from a German homecare provider describes patients treated with PAP, analyzes the therapy termination rate over the first year, and investigates predictive factors for therapy termination., Methods: Data from a German homecare service provider were analyzed retrospectively. Patients who had started their first PAP therapy between September 2009 and April 2014 were eligible. Patient demographics, therapy start date, and the date of and reason for therapy termination were obtained. At 1 year, patients were classified as having compliance-related therapy termination or remaining on therapy. These groups were compared, and significant predictors of therapy termination determined., Results: Of 98,329 patients included in the analysis, 11,702 (12%) terminated PAP therapy within the first year (after mean 171 ± 91 days). There was a U-shaped relationship between therapy termination and age; therapy termination was higher in the youngest (< 30 years, 15.5%) and oldest (≥ 80 years, 19.8%) patients, and lower in those aged 50-59 years (9.9%). Therapy termination was significantly more likely in females versus males (hazard ratio 1.48, 95% confidence interval 1.42-1.54), in those with public versus private insurance (1.75, 1.64-1.86) and in patients whose first device was automatically adjusting or fixed-level continuous positive airway pressure versus bilevel or adaptive servo-ventilation (1.28, 1.2-1.38)., Conclusions: This analysis of the largest dataset investigating PAP therapy termination identified a number of predictive factors. These can help health care providers chose the most appropriate PAP modality, identify specific patient phenotypes at higher risk of stopping PAP and target interventions to support ongoing therapy to these groups, as well as allow them to develop a risk stratification tool.

Background: Chronic obstructive pulmonary disease (COPD) is common around the world and carries a high morbidity and mortality. Symptom- and risk-oriented drug treatment is recommended, both in Germany and in other countries. It is not yet known to what extent the treatment that is actually delivered in Germany corresponds to the current recommendations in the guidelines., Methods: As recommended by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) in 2017, 2281 patients of the national COPD cohort COSYCONET (COPD and Systemic Consequences-Comorbidities Network) were classified into Gold classes A-D on the basis of disease-specific manifestations and the frequency of exacerbations. Moreover, the regular use of medications was documented and categorized according to active substance groups. For all groups, the documented treatment that was actually given was compared to the recommended treatment., Results: 67.6% of the patients received a combination of a long-acting anticholinergic drug (LAMA) and a long-acting beta-mimetic drug (LABA), while 65.8% received inhaled corticosteroids (ICS), 11.7% theophylline, and 12.6% oral corticosteroids (OCS). Despite recommendations to the contrary, 66% of the patients in Groups A and B (low exacerbation rates) were treated with ICS; some of these patients carried an additional diagnosis of bronchial asthma. There was evidence of undertreatment mainly in groups C and D (high exacerbation rate), because many of the patients in these groups were not treated with LAMA or LAMA/LABA as recommended., Conclusion: The observed deviations from the recommended treatment, some of which were substantial, might lead to suboptimal treatment outcomes as well as to avoidable side effects of medication.

Patients with COPD are often of advanced age and have a high number of medications due to their lung disease and comorbidities. Thus they are at risk for unwanted effects from drugs, either due to age or due to interactions between drugs. These issues are not clarified. We therefore assessed the number of medications and potential adverse effects in a large cohort of patients with COPD. The analysis was performed in 2741 patients of the German COPD cohort COSYCONET, using baseline data (visit 1) and follow-up data after about 1.5 years (visit 3). Spirometric GOLD grades 1-4 were found in 8/35/32/9% of patients and GOLD groups ABCD in 7/25/4/48% of patients, while the remaining patients (n = 450, 16.4%) could not be classified according to GOLD criteria. The compatibility of medication with age was evaluated via the PRISCUS list, drug interactions via the AiD clinic system, whereby only drug combinations occurring in at least 10 patients were considered (nine unwanted interactions, one wanted interaction). The median numbers of medications were 5 or more in all patient categories, among them 3 or more non-respiratory medications. In the total population there were 153 patients (10.2%) aged ≥65 years who had any medication of the PRISCUS list with intermediate or low risk. Serious adverse combinations of drugs according to AiD occurred in 114 patients (4.2%), while the number of unwanted but only potentially clinically relevant combinations was 175 (6.4%). The number of wanted combinations was 219 (8.0%). These numbers did not markedly change when restricting the analysis to patients of GOLD grades 1-4. Moreover, the results were similar for visit 1 and visit 3. We conclude that in a large cohort of COPD patients about 10% of patients aged at least 65 years had medications that could interfere with their age and that the proportions of patients with either unwanted or wanted drug interactions were both in the range of 8-10%. These results suggest that problems arising from the high number of medications were not very frequent in the COPD cohort analysed., (Copyright © 2018. Published by Elsevier Ltd.)

Background: In this prospective non-interventional study, the effectiveness and tolerability of erlotinib in elderly patients with non-small-cell lung cancer (NSCLC) after ≥1 platinum-based chemotherapy were assessed., Methods: A total of 385 patients ≥65 years of age with advanced NSCLC receiving erlotinib were observed over 12 months. The primary endpoint was the 1-year overall survival (OS) rate., Results: Patients were predominantly Caucasian (99.2%), a mean of 73 years old; 24.7% had an Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2. Most common tumor histologies were adenocarcinoma (64.9%) and squamous cell carcinoma (22.3%). Of 119 patients tested, 15.1% had an activating epidermal growth factor receptor gene (EGFR) mutation. The 1-year OS rate was 31% (95% CI 25-36) with a median OS of 7.1 months (95% CI 6.0-7.9). OS was significantly better in females than males (p = 0.0258) and in patients with an EGFR mutation compared to EGFR wild-type patients (p = 0.0004). OS was not affected by age (p = 0.3436) and ECOG PS (p = 0.5364). Patients with squamous NSCLC tended to live longer than patients with non-squamous EGFR wild-type tumors (median OS: 8.6 vs 5.5 months). Cough and dyspnea improved during the observation period. The erlotinib safety profile was comparable to that in previous studies with rash (45.2%) and diarrhea (22.6%) being the most frequently reported adverse events., Conclusions: Erlotinib represents a suitable palliative treatment option in further therapy lines for elderly patients with advanced NSCLC. The results obtained under real-life conditions add to our understanding of the benefits and risks of erlotinib in routine clinical practice., Trial Registration: BfArM ( https://www.bfarm.de ; ML23023); ClinicalTrials.gov (NCT01535729; 20 Feb 2012).

Background: Lung cancer can be described by histological subtype, of which small cell, squamous cell and adenocarcinoma are the most common. International data show that adenocarcinoma is becoming the dominant histological subtype of lung cancer although the relative risk due to smoking has been found to be smaller than that for other histological subtypes., Objective: The aim of the analysis was to describe the time trends in incidence of lung cancer among women and men in Germany according to histological subtype., Materials and Methods: All lung cancer cases (ICD-10 C33-C34) newly diagnosed between 2003 and 2012 and collected by the epidemiologic cancer registries of the German federal states with average completeness of registration of at least 90% were considered and grouped into histologic subtypes. If data on tumor histology were not microscopically verified or unspecific, multiple imputation techniques were applied to estimate the histologic subtype., Results: Among women age-standardized lung cancer rates increased considerably between 2003 and 2012 (annual percent change APC = 2.7%), mostly driven by a rising adenocarcinoma incidence (APC = 4.7%). Among men overall lung cancer rates decreased during the same time (APC = -1.7%). Still, a slight increase in adenocarcinoma incidence was also observed in men (APC = 1.0%)., Conclusion: The rising incidence of adenocarcinoma of the lung is alarming. The cancer registry data do not allow risk factor analysis. In the international discussion, the introduction of filter cigarettes as well as the changing composition of cigarettes has been hypothesized as being responsible. Further epidemiologic studies are strongly needed.

Objective/background: This study investigated the addition of a real-time feedback patient engagement tool on positive airway pressure (PAP) adherence when added to a proactive telemedicine strategy., Patients/methods: Data from a German healthcare provider (ResMed Healthcare Germany) were retrospectively analyzed. Patients who first started PAP therapy between 1 September 2009 and 30 April 2014, and were managed using telemedicine (AirView™; proactive care) or telemedicine + patient engagement tool (AirView™ + myAir™; patient engagement) were eligible. Patient demographics, therapy start date, sleep-disordered breathing indices, device usage hours, and therapy termination rate were obtained and compared between the two groups., Results: The first 500 patients managed by telemedicine-guided care and a patient engagement tool were matched with 500 patients managed by telemedicine-guided care only. The proportion of nights with device usage ≥4 h was 77 ± 25% in the patient engagement group versus 63 ± 32% in the proactive care group (p < 0.001). Therapy termination occurred less often in the patient engagement group (p < 0.001). The apnea-hypopnea index was similar in the two groups, but leak was significantly lower in the patient engagement versus proactive care group (2.7 ± 4.0 vs 4.1 ± 5.3 L/min; p < 0.001)., Conclusions: Addition of a patient engagement tool to telemonitoring-guided proactive care was associated with higher device usage and lower leak. This suggests that addition of an engagement tool may help improve PAP therapy adherence and reduce mask leak., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Patients with intermediate-risk pulmonary embolism (PE) may, depending on the method and cut-off values used for definition, account for up to 60% of all patients with PE and have an 8% or higher risk of short-term adverse outcome. Although four non-vitamin K-dependent direct oral anticoagulants (NOACs) have been approved for the treatment of venous thromboembolism, their safety and efficacy as well as the optimal anticoagulation regimen using these drugs have not been systematically investigated in intermediate-risk PE. Moreover, it remains unknown how many patients with intermediate-high-risk and intermediate-low-risk PE were included in most of the phase III NOAC trials. The ongoing Pulmonary Embolism International Thrombolysis 2 (PEITHO-2) study is a prospective, multicentre, multinational, single-arm trial investigating whether treatment of acute intermediate-risk PE with parenteral heparin anticoagulation over the first 72 hours, followed by the direct oral thrombin inhibitor dabigatran over 6 months, is effective and safe. The primary efficacy outcome is recurrent symptomatic venous thromboembolism or death related to PE within the first 6 months. The primary safety outcome is major bleeding as defined by the International Society on Thrombosis and Haemostasis. Secondary outcomes include all-cause mortality, the overall duration of hospital stay (index event and repeated hospitalizations) and the temporal pattern of recovery of right ventricular function over the 6-month follow-up period. By applying and evaluating a contemporary risk-tailored treatment strategy for acute PE, PEITHO-2 will implement the recommendations of current guidelines and contribute to their further evolution., Competing Interests: Financial Support: PEITHO-2 is an independent, investigator-initiated trial. The study has an academic sponsor (University Medical Center Mainz, Germany) and is supported by public funding. In addition, the sponsor has obtained the study drug (dabigatran) and a grant from the market authorization holder of dabigatran, Boehringer Ingelheim. The authors are solely responsible for the design and conduct of the PEITHO-2 trial study, for all study analyses and for the drafting and editing of reports and publications and their final contents.

Background: Immunohistochemical (IHC) assessment of programmed death-ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC) has become important since the development of anti-PD-1/-PD-L1 directed drugs. Various PD-L1 antibodies and cut-offs have been used in different trials to predict response to these drugs, thus comparison of those studies is difficult. We compared PD-L1 mRNA expression measured by RT-qPCR with PD-L1 protein expression evaluated by IHC. Moreover, we investigated the impact of different tumour tissue acquisition methods on the reliability of PD-L1 measurement techniques., Materials and Methods: NSCLC cases (N=22), including n=9 mediastinal lymph node biopsies acquired by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and n=5 metastases, were evaluated prospectively for PD-L1 protein on tumor cells (TC) and immune cells (IC) using E1L3N and 28-8 antibodies and PD-L1 mRNA using the CheckPoint TYPER® assay., Results: In primary NSCLC tissues, agreement between PD-L1 mRNA and TC staining using the 28-8 antibody was excellent (ĸ=0.85, p=0.0002). Comparing both PD-L1 antibodies against each other showed a kappa value of 0.58 (p=0.0106). In EBUS-TBNA, PD-L1 mRNA correlated perfectly with the 28-8 antibody (ĸ=1.0, p=0.0023). PD-L1 mRNA levels significantly differed when comparing 28-8 TC staining of tumours >49% with 1-49% and 0% (p=0.0040; p=0.0081, respectively). In metastatic lesions, differences between PD-L1 mRNA and IHC became apparent (ĸ=0.2, p=0.2525)., Conclusion: Testing of PD-L1 mRNA and 28-8 IHC showed an excellent agreement in NSCLC samples including mediastinal lymph node biopsies. Since PD-L1 expression in >50% TC detected by 28-8 IHC can be reliably detected by RT-qPCR, quantitative PD-L1 mRNA determination should be considered as an alternative to IHC as there is no interobserver variability in RNA results., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

In this review, we summarize the rationale for combining long-acting bronchodilators in the management of chronic obstructive pulmonary disease (COPD), and the evidence for the long-acting bronchodilator combination indacaterol/glycopyrronium (IND/GLY). Clinical practice guidelines generally recommend the use of long-acting bronchodilators in the treatment of patients with all severities of COPD, either as a first-choice or alternative-choice therapy. Combining classes of long-acting bronchodilators can result in superior improvements in lung function and clinical outcomes compared with bronchodilator monotherapy, as observed in studies of free combinations of long-acting β 2 -agonists (LABAs) and long-acting muscarinic antagonists (LAMAs). LABA/LAMA fixed-dose combinations (FDCs) can also significantly improve lung function, dyspnea, symptoms and health status and reduce exacerbations and rescue medication use versus an inhaled corticosteroid/LABA, with a comparable safety profile and lower incidence of pneumonia. The LABA/LAMA FDC of IND/GLY is approved for use in the management of COPD. This review summarizes the evidence for IND/GLY, including its pharmacodynamic and pharmacokinetic profile, and published efficacy and safety data from clinical trials in patients with COPD. We also explore the unmet needs in COPD and discuss the potential future of COPD management., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Although hyperlipidemia is common in COPD, its relationship to comorbidities, risk factors and lung function in COPD has not been studied in detail. Using the baseline data of the COSYCONET cohort we addressed this question. Data from 1746 COPD patients (GOLD stage 1-4; mean age 64.6 y, mean FEV1%pred 57%) were evaluated, focusing on the comorbidities hyperlipidemia, diabetes and cardiovascular complex (CVC; including arterial hypertension, cardiac failure, ischemic heart disease). Risk factors comprised age, gender, BMI, and packyears of smoking. The results of linear and logistic regression analyses were implemented into a path analysis model describing the multiple relationships between parameters. Hyperlipidemia (prevalence 42.9%) was associated with lower intrathoracic gas volume (ITGV) and higher forced expiratory volume in 1 second (FEV1) when adjusting for its multiple relationships to risk factors and other comorbidities. These findings were robust in various statistical analyses. The associations between comorbidities and risk factors were in accordance with previous findings, thereby underlining the validity of our data. In conclusion, hyperlipidemia was associated with less hyperinflation and airway obstruction in patients with COPD. This surprising result might be due to different COPD phenotypes in these patients or related to effects of medication.

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:   · Patients with SVCS of malignant cause have a poor prognosis.. · Lung cancer is the most common cause for SVCS.. · Endovascular therapy is safe and effective.. Citation Format · Büstgens FA, Loose R, Ficker JH et al. Stent Implantation for Superior Vena Cava Syndrome of Malignant Cause. Fortschr Röntgenstr 2017; 189: 423 - 430., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Adherence to positive airway pressure (PAP) therapy is essential for the benefits of therapy to be realised. Telemedicine-based strategies provide a new option for enhanced monitoring and intervention to promote adherence during PAP. This study investigated the impact of telemedicine-based proactive patient management on PAP therapy termination rates versus standard care., Methods: Observational data were obtained from ResMed Germany Healthcare, a German homecare provider. Patients were undergoing routine homecare using either a standard or proactive management strategy. The proactive strategy used data from AirView™, a cloud-based remote monitoring system, to prompt patient contact and information sharing/education. Patients receiving their first PAP therapy were included and analysed in matched pairs., Results: In all, 3401 patients were included in each group. In the first year of PAP therapy, overall therapy termination rate was significantly lower (5.4% vs 11.0%; p  < 0.001) and time to therapy termination was significantly longer (348 ± 58 vs 337 ± 76 days; p  < 0.05) in the proactive versus standard care group. Cox proportional hazard analysis revealed a significantly reduced risk of PAP termination in the proactive versus the standard care group (hazard ratio 0.48, 95% confidence interval 0.4-0.57). Findings were consistent in subanalyses according to gender, type of device and insurance status, and in patients aged ≥40 years. However, in the subgroup of patients aged younger than 40 years, the risk of PAP termination was similar in the proactive and standard groups., Conclusion: A telemedicine-based proactive management strategy compared with standard care of PAP patients was associated with a lower long-term therapy termination rate.

Background: Purified α1 proteinase inhibitor (A1PI) slowed emphysema progression in patients with severe α1 antitrypsin deficiency in a randomised controlled trial (RAPID-RCT), which was followed by an open-label extension trial (RAPID-OLE). The aim was to investigate the prolonged treatment effect of A1PI on the progression of emphysema as assessed by the loss of lung density in relation to RAPID-RCT., Methods: Patients who had received either A1PI treatment (Zemaira or Respreeza; early-start group) or placebo (delayed-start group) in the RAPID-RCT trial were included in this 2-year open-label extension trial (RAPID-OLE). Patients from 22 hospitals in 11 countries outside of the USA received 60 mg/kg per week A1PI. The primary endpoint was annual rate of adjusted 15th percentile lung density loss measured using CT in the intention-to-treat population with a mixed-effects regression model. This trial is registered with ClinicalTrials.gov, number NCT00670007., Findings: Between March 1, 2006, and Oct 13, 2010, 140 patients from RAPID-RCT entered RAPID-OLE: 76 from the early-start group and 64 from the delayed-start group. Between day 1 and month 24 (RAPID-RCT), the rate of lung density loss in RAPID-OLE patients was lower in the early-start group (-1·51 g/L per year [SE 0·25] at total lung capacity [TLC]; -1·55 g/L per year [0·24] at TLC plus functional residual capacity [FRC]; and -1·60 g/L per year [0·26] at FRC) than in the delayed-start group (-2·26 g/L per year [0·27] at TLC; -2·16 g/L per year [0·26] at TLC plus FRC, and -2·05 g/L per year [0·28] at FRC). Between months 24 and 48, the rate of lung density loss was reduced in delayed-start patients (from -2·26 g/L per year to -1·26 g/L per year), but no significant difference was seen in the rate in early-start patients during this time period (-1·51 g/L per year to -1·63 g/L per year), thus in early-start patients the efficacy was sustained to month 48., Interpretation: RAPID-OLE supports the continued efficacy of A1PI in slowing disease progression during 4 years of treatment. Lost lung density was never recovered, highlighting the importance of early intervention with A1PI treatment., Funding: CSL Behring., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objectives: Reflection of the finger pulse wave form is a valid measure of arterial stiffness, which may be continuously assessed during sleep. We investigated the relationships between sleep, sleep-disordered breathing, hypertension, and pulse propagation time (PPT) in patients with suspected sleep apnea., Methods: The digital photoplethysmographic signal derived from finger pulse oximetry was recorded during overnight sleep studies in 440 patients (64% men, age 55 ± 12 years, BMI 30 ± 6 kg/m, apnea-hypopnea index 19 ± 19 n/h). PPT, defined as the time interval between the systolic and diastolic peak of the finger pulse wave, was calculated. The influence of sleep stages on PPT were assessed in patients undergoing polysomnography. Generalized linear models were used to study predictors of PPT and hypertension., Results: Mean overnight PPT was independently associated with age (β = -1.34, P < 0.001), height (β = 0.47, P = 0.047), history of smoking (β = -9.44, P = 0.005), and apnea-hypopnea index (β = -0.18, P = 0.043). PPT was shorter in hypertensive patients compared with normotensive patients (160 ± 33 vs. 177 ± 47 ms, P < 0.001) and independently associated with a diagnosis of hypertension (P = 0.043). PPT was influenced by sleep stage (highest PPT during slow wave sleep compared with wake and all other sleep stages, all P < 0.001) and varied across sleep apnea severity groups in normotensive but not in hypertensive patients (P = 0.028 and 0.64, respectively)., Conclusion: Overnight PPT by oximetry was strongly associated with factors known to determine daytime vascular stiffness. In addition, PTT provides information on functional and structural vascular properties during sleep. This novel technique offers new opportunities to noninvasively monitor vascular function during the sleeping period.

Rationale: Endobronchial valves (EBVs) have been successfully used in patients with severe heterogeneous emphysema to improve lung physiology. Limited available data suggest that EBVs are also effective in homogeneous emphysema., Objectives: To evaluate the efficacy and safety of EBVs in patients with homogeneous emphysema with absence of collateral ventilation assessed with the Chartis system., Methods: Prospective, multicenter, 1:1 randomized controlled trial of EBV plus standard of care (SoC) or SoC alone. Primary outcome was the percentage change in FEV 1 (liters) at 3 months relative to baseline in the EBV group versus the SoC group. Secondary outcomes included changes in FEV 1 , St. George's Respiratory Questionnaire (SGRQ), 6-minute-walk distance (6MWD), and target lobe volume reduction., Measurements and Main Results: Ninety-three subjects (age, 63.7 ± 6.1 yr [mean ± SD]; FEV 1 , % predicted, 29.3 ± 6.5; residual volume, % predicted, 275.4 ± 59.4) were allocated to either the EBV group (n = 43) or the SoC group (n = 50). In the intention-to-treat population, at 3 months postprocedure, improvement in FEV 1 from baseline was 13.7 ± 28.2% in the EBV group and -3.2 ± 13.0% in the SoC group (mean between-group difference, 17.0%; P = 0.0002). Other variables demonstrated statistically and clinically significant changes from baseline to 3 months (EBV vs. SoC, respectively: SGRQ, -8.63 ± 11.25 vs. 1.01 ± 9.36; and 6MWD, 22.63 ± 66.63 m vs. -17.34 ± 52.8 m). Target lobe volume reduction at 3 months was -1,195 ± 683 ml (P < 0.0001). Of the EBV subjects, 97.2% achieved volume reduction in the target lobe (P < 0.0001). Procedure-related pneumothoraces occurred in 11 subjects (25.6%). Five subjects required removal/replacement of one or more valves. One subject experienced two valve migration events requiring removal/replacement of valves., Conclusions: EBV in patients with homogeneous emphysema without collateral ventilation results in clinically meaningful benefits of improved lung function, exercise tolerance, and quality of life.

Objective: In large cohort studies comorbidities are usually self-reported by the patients. This way to collect health information only represents conditions known, memorized and openly reported by the patients. Several studies addressed the relationship between self-reported comorbidities and medical records or pharmacy data, but none of them provided a structured, documented method of evaluation. We thus developed a detailed procedure to compare self-reported comorbidities with information on comorbidities derived from medication inspection. This was applied to the data of the German COPD cohort COSYCONET., Methods: Approach I was based solely on ICD10-Codes for the diseases and the indications of medications. To overcome the limitations due to potential non-specificity of medications, Approach II was developed using more detailed information, such as ATC-Codes specific for one disease. The relationship between reported comorbidities and medication was expressed by a four-level concordance score., Results: Approaches I and II demonstrated that the patterns of concordance scores markedly differed between comorbidities in the COSYCONET data. On average, Approach I resulted in more than 50% concordance of all reported diseases to at least one medication. The more specific Approach II showed larger differences in the matching with medications, due to large differences in the disease-specificity of drugs. The highest concordance was achieved for diabetes and three combined cardiovascular disorders, while it was substantial for dyslipidemia and hyperuricemia, and low for asthma., Conclusion: Both approaches represent feasible strategies to confirm self-reported diagnoses via medication. Approach I covers a broad spectrum of diseases and medications but is limited regarding disease-specificity. Approach II uses the information from medications specific for a single disease and therefore can reach higher concordance scores. The strategies described in a detailed and reproducible manner are generally applicable in large studies and might be useful to extract as much information as possible from the available data., Competing Interests: The authors have declared that no competing interests exist.

Cardiovascular disease is the main cause of death in Europe, and early detection of increased cardiovascular risk (CR) is of clinical importance. Pulse wave analysis based on pulse oximetry has proven useful for the recognition of increased CR. The current study provides a detailed description of the pulse wave analysis technology and its clinical application. A novel matching pursuit-based feature extraction algorithm was applied for signal decomposition of the overnight photoplethysmographic pulse wave signals obtained by a single-pulse oximeter sensor. The algorithm computes nine parameters (pulse index, SpO2 index, pulse wave amplitude index, respiratory-related pulse oscillations, pulse propagation time, periodic and symmetric desaturations, time under 90 % SpO2, difference between pulse and SpO2 index, and arrhythmia). The technology was applied in 631 patients referred for a sleep study with suspected sleep apnea. The technical failure rate was 1.4 %. Anthropometric data like age and BMI correlated significantly with measures of vascular stiffness and pulse rate variability (PPT and age r = -0.54, p < 0.001, PR and age r = -0.36, p < 0.01). The composite biosignal risk score showed a dose-response relationship with the number of CR factors (p < 0.001) and was further elevated in patients with sleep apnea (AHI ≥ 15n/h; p < 0.001). The developed algorithm extracts meaningful parameters indicative of cardiorespiratory and autonomic nervous system function and dysfunction in patients suspected of SDB.

Introduction: Afatinib is a tyrosine kinase inhibitor (TKI), that has been approved for treating patients with epidermal growth factor receptor (EGFR) mutated advanced non-small-cell lung cancer (NSCLC). Stevens-Johnson syndrome (SJS) related to EGFR directed TKIs is a rare adverse event., Case Presentation: We report a case of a 79-year-old white female with EGFR-mutated, metastatic non-small-cell lung cancer treated with afatinib as first-line palliative treatment, who developed a SJS after two months of treatment. Discontinuation of the TKI and systemic glucocorticoid treatment led to improvement of symptoms and recovery., Conclusion: Severe adverse cutaneous drug reactions that predominantly involve the skin and mucous membranes during treatment with afatinib should alert clinicians to suspect SJS and react appropriately., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Lung volume reduction of emphysematous lobes results in clinical improvement for patients with severe emphysema. However, some segments within a lobe are often substantially more diseased than others, thereby warranting a more targeted approach of the emphysematous parts of a lobe. We therefore did a study to assess whether or not selective sequential treatment of the more diseased upper lobe segments with bronchoscopic vapour ablation led to clinical improvement., Methods: For the multicentre, parallel-group, randomised, controlled, open-label Sequential Staged Treatment of Emphysema with Upper Lobe Predominance (STEP-UP) trial, adult patients aged 45-75 years with severe, upper lobe-predominant emphysema with a forced expiratory volume in 1 s (FEV1) between 20% and 45%, substantial hyperinflation, and post-rehabilitation 6-min walk test (6MWT) greater than 140 m were enrolled from 13 hospital sites in Europe (ten sites) and Australia (three sites). A computer-generated blocked randomisation scheme (block size three per site based on a random table from an independent biostatistician) stratified by site was used to randomly assign enrolled patients 2:1 to segmental vapour ablation (treatment group) or standard medical management (control group). Patients and investigators were not masked to group assignment. The primary efficacy endpoints were statistically significant changes in FEV1 and St George's Respiratory Questionnaire (SGRQ-C) scores between trial groups at 6 months, analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01719263., Findings: Between June 30, 2013, and Oct 1, 2014, 134 patients were screened and 70 were enrolled and randomly assigned: 46 to the treatment group and 24 to the control group. One patient in the treatment group did not receive treatment because of physician decision post-randomisation; this patient is excluded from all analyses. The mean relative improvement in FEV1 between the treatment group versus the control group was 14·7% (95% CI 7·8-21·5%; p<0·0001) and in SGRQ-C was -9·7 points (95% CI -15·7 to -3·7; p=0·0021). COPD exacerbation was the most common serious adverse event, occurring in 11 (24%) of 45 patients in the treatment group and one (4%) of 24 in the control group. One exacerbation resulted in a patient death 84 days after treatment; this was judged by the data and safety monitoring board to be possibly related to treatment. No pneumothorax occurred within 30 days of treatment., Interpretation: Compared with standard medical management, targeted thermal vapour ablation of more diseased segments and preservation of less diseased segments resulted in clinically meaningful and statistically significant improvements in lung function and quality of life at 6 months, with an acceptable safety profile., Funding: Uptake Medical., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Sleep-related breathing disorders may promote cardiovascular (CV) diseases. A novel and differentiated approach to overnight photoplethysmographic pulse wave analysis, which includes risk assessment and measurement of various pulse wave characteristics, has been evaluated in obstructive sleep apnea (OSA)., Objectives: The purpose of this study was to assess if and which of the differentiated pulse wave characteristics might be influenced by OSA treatment with positive airway pressure (PAP)., Methods: The study included two protocols. In the case-control study (group A), pulse wave-derived CV risk indices recorded during PAP therapy were compared with those obtained in age, body mass index, and CV risk class-matched patients with untreated OSA (n = 67/67). In the prospective PAP treatment study (group B), 17 unselected patients undergoing a full-night sleep test at baseline and after 23 ± 19 weeks of treatment were analyzed., Results: In untreated OSA patients (group A), the overnight hypoxic load was increased (SpO2 index 38.7 ± 17.5 vs. 24.0 ± 11.1, p < 0.001) and the pulse wave attenuation index (PWA-I) was lower (29.4 ± 9.2 vs. 33.5 ± 11.8, p = 0.022) than in treated patients. In group B, PAP therapy reduced the hypoxic load and increased the PWA-I significantly. The composite CV risk index was slightly but not significantly reduced., Conclusions: PAP therapy modified the hypoxic load and pulse wave-derived markers. The PWA-I - associated with sympathetic vascular tone - was most prominently modified by PAP. This novel approach to markers of CV function should be further evaluated in prospective studies., (© 2016 S. Karger AG, Basel.)

Post-translational modifications of chromatin components are significantly involved in the regulation of tumor suppressor gene and oncogene expression. Connective tissue growth factor (CTGF) is an epigenetically regulated growth factor with functions in angiogenesis and cell-matrix interactions and plays a pivotal role in hepatocellular carcinoma (HCC). The pharmacologic inhibition of histone and protein deacetylases represents a new approach to interfere with pathways of apoptosis and angiogenesis. We investigated the effect of the pan-deacetylase inhibitor panobinostat (LBH589) on human HCC cell lines HepG2 (p53wt) and Hep3B (p53null) and in a subcutaneous xenograft model and explored the influence on angiogenesis. Specimens were characterized by quantitative real-time PCR. Protein was separated for western blotting against CTGF, VEGF, VEGF receptor-1 (VEGFR-1/FLT-1), VEGF receptor-2 (VEGFR-2/KDR), MAPK and phospho-MAPK. In vivo, HepG2 cells were xenografted to NMRI mice and treated with daily i.p. injections of 10 mg/kg panobinostat. After 1, 7 and 28 days, real-time PCR was performed. Immunohistochemistry and western blotting were examined after 28 days. An increased significant expression of CTGF was only seen after 24 h treatment with 0.1 µM panobinostat in HepG2 cells and Hep3B cells, whereas after 72 h treatment CTGF expression clearly decreased. In the xenografts, treatment with panobinostat showed a minimal CTGF expression after 1 day and 4 weeks, respectively. In vitro as well as in vivo, VEGF was not affected by panobinostat treatment at any time. In conclusion, panobinostat influences extracellular signaling cascades via CTGF-dependent pathways.

Objectives: Conventional methods for cardiovascular disease risk stratification are based on quantification of recognized risk factors or assessment of biomarkers during the wake period. We evaluated an algorithm on the basis of a photoplethysmographic pulse wave recording during sleep for cardiovascular risk assessment., Methods: Five hundred and twenty individuals (346 men, age 55.0 ± 13.4 years, BMI 29.9 ± 6.  kg/m) with suspected sleep apnoea were randomly recruited at five sleep centres. Individual cardiovascular risk scores were calculated in accordance with established cardiovascular risk matrixes (ESH/ESC, Framingham, SCORE, PROCAM scores). A digital photoplethysmographic pulse wave signal was continuously recorded during the night using an oximeter sensor. An algorithm based on eight separate hypoxic and pulse wave derived parameters was trained in 130 individuals and validated in 390 individuals for low/high cardiovascular risk classification., Results: All derived parameters were associated with elevated ESH/ESC risk in univariate analysis and five in the multiple logistic regression model [discrimination index C = 0.8, Chi-square (7) = 69, P < 0.0001]. The combined algorithm detected high-risk patients (validation set, ESH/ESC risk classes 4 and 5) with a sensitivity, specificity, positive predictive value and negative predictive value of 74.5, 76.4, 69.0 and 81.0%, respectively. Significant associations were also found for the Framingham, SCORE and PROCAM scores. The computed risk scores in individuals with/without (n = 34/356) a previous history of cardiovascular event (myocardial infarction, transitory ischemic attack or stroke) were 0.71 ± 0.27 and 0.42 ± 0.34 (P < 0.001), respectively., Conclusion: Parameters derived from modified pulse oximetry during sleep may provide information on cardiovascular function. Combined signal analysis may be used for recognition of individuals with established cardiovascular risk in a sleep laboratory cohort.