Misuse of corticosteroid metered-dose inhaler is associated with decreased asthma stability. V. Giraud, N. Roche. #ERS Journals Ltd 2002. ABSTRACT: This study assessed whether the improper use of pressurized metereddose inhalers (pMDIs) is associated with decreased asthma control in asthmatics treated by inhaled corticosteroids (ICS).General practitioners (GPs) included consecutive asthmatic outpatients treated by pMDI-administered ICS and on-demand, short-acting b 2 -agonists. They measured an asthma instability score (AIS) based on daytime and nocturnal symptoms, exerciseinduced dyspnoea, b 2 -agonist usage, emergency-care visits and global perception of asthma control within the preceding month; the inhalation technique of the patient also was assessed.GPs (n=915) included 4,078 adult asthmatics; 3,955 questionnaires were evaluable. pMDI was misused by 71% of patients, of which 47% was due to poor coordination. Asthma was less stable in pMDI misusers than in good users (AIS: 3.93 versus 2.86, pv0.001). Among misusers, asthma was less stable in poor coordinators (AIS: 4.38 versus 3.56 in good coordinators, pv0.001).To conclude, misuse of pressurized metered-dose inhalers, which is mainly due to poor coordination, is frequent and associated with poorer asthma control in inhaled corticosteroid-treated asthmatics. This study highlights the importance of evaluating inhalation technique and providing appropriate education in all patients, especially before increasing inhaled corticosteroid dosage or adding other agents. The use of devices which alleviate coordination problems should be reinforced in pressurized metered-dose inhaler misusers.

Poor inhaler technique is frequent in asthma, but its long-term consequences have been seldom assessed. Pharmacists are ideally positioned to teach inhaler technique. This prospective observational study evaluated the feasibility of inhaler training by pharmacists in patients receiving inhaled corticosteroids by pressurised metered-dose inhaler (pMDI) or breath-actuated MDI. In parallel, the relationships between inhaler technique, adherence, and asthma control, and their modulation one month after training were assessed. Of 727 patients receiving training at pharmacies (n=123), 61% were prescribed a pMDI; 35%, an Autohaler(®); and 5%, an Easi-Breathe(®) inhaler. Poor asthma control (Asthma Control Questionnaire score ≥ 1.5) at baseline was significantly (p<0.05) and independently associated with poor inhaler technique and poor self-reported adherence (Morisky score ≥ 3). The percentage of patients with optimal inhaler technique rose from 24% before to 79% after training (p<0.001). Median training session length was 6 min. At 1 month, mean (SD) ACQ score had improved from a baseline score of 1.8 (1.2) to 1.4 (1.1), (p<0.001). Importantly, greater change was observed in patients with improved inhaler technique versus those without. Similar results were observed for Morisky score. Inhaler technique is associated with adherence and influences asthma control. Inhaler training by pharmacists is feasible and seams to improve inhaler technique, asthma control and adherence.

Immune checkpoint inhibitors, as nivolumab, are used in advanced non-small cell lung cancer (NSCLC). However, no associated biomarker is validated in clinical practice with this drug. We investigated herein immune-related blood markers in patients with advanced NSCLC treated with nivolumab. Plasma of 43 consecutive patients were prospectively collected at time of the diagnosis of cancer, at the initiation of nivolumab and at the first tumour evaluation (2 months). Concentrations of PD-L1 (sPD-L1), soluble PD-L2 (sPD-L2), Interleukine-2 (sIl-2), Interferon-gamma (sIFN-γ), and Granzyme B (sGranB) were quantified by ELISA. Cell free RNA was quantified by Reverse Transcriptase -PCR), and plasmatic microRNAs (miRNAs) were evaluated by targeted sequencing. Expression of PD-L1 on tumour biopsies was performed by immunohistochemistry using E13LN. High sPD-L1 at 2 months and increase of sPD-L1 concentrations were associated with poor response and absence of clinical benefit (nivolumab treatment less than 6 months). The variation of sPD-L1 concentrations were confirmed by RNA quantification. sPD-L1 concentrations were not correlated with PD-L1 expression on corresponding tumour samples. Low sGranB at nivolumab initiation was also associated with poor response. High sPD-L1 and low sGranB were associated with poor progression-free survival (PFS) and overall survival (OS). Low sPD-L2, low sIl-2 and high sIFN-γ were associated with grade 3-4 toxicities. Finally, miRNA screening showed that patients with clinical benefit (n = 9) had down-expression of miRNA-320b and -375 compared to patients with early progression at 2 months (n = 9). In conclusion, our results highlight the interest of circulating biomarkers in patients treated with nivolumab.

This study suggests that air pollution has a negative impact on IPF outcomes, corroborating the role of ozone on AEs and establishing, for the first time, the potential role of long-term exposure to PM and PM on overall mortality.

No abstract

Idiopathic interstitial pneumonias (IIPs) comprise a heterogeneous group of rare lung parenchyma disorders with high morbidity and mortality, which can occur at all ages. In adults, the most common form of IIPs, idiopathic pulmonary fibrosis (IPF), has been associated with an increased frequency of lung cancer. The molecular basis of IIPs remains unknown in most cases. This study investigates IIP pathophysiology in 12 families affected by IPF and lung cancer. We identified, in a multigenerational family, nine members carrying a heterozygous missense mutation with evidence of pathogenicity in SFTPA1 that encodes the surfactant protein (SP)-A1. The mutation (p.Trp211Arg), which segregates with a disease phenotype characterized by either isolated IIP/IPF, or IPF associated with lung adenocarcinoma, is located in the carbohydrate recognition domain (CRD) of SP-A1 and involves a residue invariant throughout evolution, not only in SP-A1, but also in its close paralog SP-A2 and other CRD-containing proteins. As shown through functional studies, the p.Trp211Arg mutation impairs SP-A1 secretion. Immunohistochemistry studies on patient alveolar epithelium showed an altered SP-A expression pattern. Overall, this first report of a germline molecular defect in SFTPA1 unveils the key role of SP-A1 in the occurrence of several chronic respiratory diseases, ranging from severe respiratory insufficiency occurring early in life to the association of lung fibrosis and cancer in adult patients. These data also clearly show that, in spite of their structural and functional similarities, SP-A1 and SP-A2 are not redundant.

No abstract

Nivolumab is an anti-PD1 antibody, given in second-line or later treatment in advanced non-small cell lung cancer (NSCLC). The objective of this study was to describe the predictive value of circulating tumor DNA (ctDNA) on the efficacy of nivolumab in advanced NSCLC. We prospectively included all consecutive patients with advanced NSCLC treated with nivolumab in our Department between June 2015 and October 2016. Plasma samples were obtained before the first injection of nivolumab and at the first tumor evaluation with nivolumab. ctDNA was analyzed by Next-Generation Sequencing (NGS), and the predominant somatic mutation was followed for each patient and correlated with tumor response, clinical benefit (administration of nivolumab for more than 6 months), and progression-free survival (PFS). Of 23 patients, 15 had evaluable NGS results at both times of analysis. ctDNA concentration at the first tumor evaluation and ctDNA change correlated with tumor response, clinical benefit and PFS. ROC curve analyses showed good diagnostic performances for tumor response and clinical benefit, both for ctDNA concentration at the first tumor evaluation (tumor response: positive predictive value (PPV) at 100.0% and negative predictive value (NPV) at 71.0%; clinical benefit: PPV at 83.3% and NPV 77.8%) and the ctDNA change (tumor response: PPV 100.0% and NPV 62.5%; clinical benefit: PPV 100.0% and NPV 80.0%). Patients without ctDNA concentration increase >9% at 2 months had a long-term benefit of nivolumab. In conclusion, NGS analysis of ctDNA allows the early detection of tumor response and long-term clinical benefit with nivolumab in NSCLC.