Objectives: Exhaled breath analysis by electronic nose (eNose) has shown to be a potential predictive biomarker before start of anti-PD-1 therapy in patients with non-small cell lung carcinoma ... Show moreObjectives: Exhaled breath analysis by electronic nose (eNose) has shown to be a potential predictive biomarker before start of anti-PD-1 therapy in patients with non-small cell lung carcinoma (NSCLC). We hypothesized that the eNose could also be used as an early monitoring tool to identify responders more accurately at early stage of treatment when compared to baseline. In this proof-of-concept study we aimed to definitely discriminate responders from non-responders after six weeks of treatment. Materials and Methods: This was a prospective observational study in patients with advanced NSCLC eligible for anti-PD-1 treatment. The efficacy of treatment was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 at 3-month follow-up. We analyzed SpiroNose exhaled breath data of 94 patients (training cohort n = 62, validation cohort n = 32). Data analysis involved signal processing and statistics based on Independent Samples T-tests and Linear Discriminant Analysis (LDA) followed by Receiver Operating Characteristic (ROC) analysis. Results: In the training cohort, a specificity of 73% was obtained at a 100% sensitivity level to identify objective responders. The Area Under the Curve (AUC) was 0.95 (CI: 0.89-1.00). In the validation cohort, these results were confirmed with an AUC of 0.97 (CI: 0.91-1.00). Conclusion: Exhaled breath analysis by eNose early during treatment allows for a highly accurate, non-invasive and low-cost identification of advanced NSCLC patients who benefit from anti-PD-1 therapy. Show less
Disselhorst, M.J.; Vries, R. de; Quispel-Janssen, J.; Wolf-Lansdorf, M.; Sterk, P.J.; Baas, P. 2021
IntroductionRecent clinical trials with immune checkpoint inhibitors (ICIs) have shown that a subgroup of patients with malignant pleural mesothelioma (MPM) could benefit from these agents. However... Show moreIntroductionRecent clinical trials with immune checkpoint inhibitors (ICIs) have shown that a subgroup of patients with malignant pleural mesothelioma (MPM) could benefit from these agents. However, there are no accurate biomarkers to predict who will respond. The aim of this study was to assess the accuracy of exhaled breath analysis using electronic technology (eNose) for discriminating between responders to ICI and non-responders.MethodsThis proof-of-concept prospective observational study was part of an intervention study (INITIATE) in patients with recurrent MPM who were treated with nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA-4). At baseline and after six weeks of treatment, breath profiles were collected by an eNose. Modified Response Evaluation Criteria in Solid Tumors were used to assess efficacy at 6-month follow-up. For data processing and statistics, we used independent t-test analyses followed by linear discriminant and receiver-operating characteristic (ROC) analysis.ResultsExhaled breath data of 31 MPM patients who received nivolumab plus ipilimumab were available at baseline. There were 16 with and 15 without a response after 6 months of treatment. At baseline, breath profiles significantly differed between responders and non-responders, with a cross validation value of 71%. The ROC-AUC after internal cross-validation was 0.90 (confidence interval: 0.80–1.00).ConclusionAn eNose is able to discriminate at baseline between responders and non-responders to nivolumab plus ipilimumab in MPM, thereby potentially identifying a subgroup of patients that will benefit from ICI treatment. Show less
George, L.; Taylor, A.R.; Esteve-Codina, A.; Artigas, M.S.; Thun, G.A.; Bates, S.; ... ; EvA Study Team 2020
Background: Whether the clinical or pathophysiologic significance of the "treatable trait" high blood eosinophil count in COPD is the same as for asthma remains controversial. We sought to... Show moreBackground: Whether the clinical or pathophysiologic significance of the "treatable trait" high blood eosinophil count in COPD is the same as for asthma remains controversial. We sought to determine the relationship between the blood eosinophil count, clinical characteristics and gene expression from bronchial brushings in COPD and asthma.Methods: Subjects were recruited into a COPD (emphysema versus airway disease [EvA]) or asthma cohort (Unbiased BIOmarkers in PREDiction of respiratory disease outcomes, U-BIOPRED). We determined gene expression using RNAseq in EvA (n = 283) and Affymetrix microarrays in U-BIOPRED (n = 85). We ran linear regression analysis of the bronchial brushings transcriptional signal versus blood eosinophil counts as well as differential expression using a blood eosinophil > 200 cells/mu L as a cut-off. The false discovery rate was controlled at 1% (with continuous values) and 5% (with dichotomized values).Results: There were no differences in age, gender, lung function, exercise capacity and quantitative computed tomography between eosinophilic versus noneosinophilic COPD cases. Total serum IgE was increased in eosinophilic asthma and COPD. In EvA, there were 12 genes with a statistically significant positive association with the linear blood eosinophil count, whereas in U-BIOPRED, 1197 genes showed significant associations (266 positive and 931 negative). The transcriptome showed little overlap between genes and pathways associated with blood eosinophil counts in asthma versus COPD. Only CST1 was common to eosinophilic asthma and COPD and was replicated in independent cohorts.Conclusion: Despite shared "treatable traits" between asthma and COPD, the molecular mechanisms underlying these clinical entities are predominately different. Show less
The aim was to investigate whether microRNA (miRNA) expression is modulated by inhaled corticosteroid (ICS) treatmentWe performed genome-wide miRNA analysis on bronchial biopsies of 69 moderate... Show moreThe aim was to investigate whether microRNA (miRNA) expression is modulated by inhaled corticosteroid (ICS) treatmentWe performed genome-wide miRNA analysis on bronchial biopsies of 69 moderate/severe chronic obstructive pulmonary disease (COPD) patients at baseline and after 6- and 30-month treatment with the ICS fluticasone propionate or placebo. The effect of ICS on miRNA expression was validated in differentiated primary bronchial epithelial cultures, and functional studies were conducted in BEAS-2B cells. MiRNAs affected by ICS and their predicted targets were compared to an independent miRNA dataset of bronchial brushings from COPD patients and healthy controls.Treatment with ICS for both 6 and 30 months significantly altered the expression of four miRNAs, including miR-320d, which was increased during ICS treatment compared with placebo. The ICS-induced increase of miR-320d was confirmed in primary airway epithelial cells. MiR-320d negatively correlated targets were enriched for pro-inflammatory genes and were increased in the bronchial brushes of patients with lower lung function in the independent dataset. Overexpression of miR-320d in BEAS-2B cells dampened cigarette smoke extract-induced pro-inflammatory activity via inhibition of nuclear factor-kappa B.Collectively, we identified miR-320d as a novel mediator of ICS, regulating the pro-inflammatory response of the airway epithelium. Show less
Loymans, R.J.B.; Debray, T.P.A.; Honkoop, P.J.; Termeer, E.H.; Snoeck-Stroband, J.B.; Schermer, T.R.J.; ... ; Riet, G. ter 2018
