Non‐invasive lung cancer diagnosis by detection ofGATA 6andNKX 2‐1isoforms in exhaled breath condensate
Aditi MehtaJulio CorderoStephanie DoberschAddi J. Romero-OlmedoRajkumar SavaiJohannes BodnerCho-Ming ChaoLudger FinkErnesto Guzmán‐DíazIndrabahadur SinghGergana DobrevaUlf R. RappStefan GüntherО. N. IlinskayaSavério BellusciReinhard DammannThomas BraunWerner SeegerStefan GattenlöhnerAchim TreschAndreas GüntherGuillermo Barreto
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Abstract Lung cancer ( LC ) is the leading cause of cancer‐related deaths worldwide. Early LC diagnosis is crucial to reduce the high case fatality rate of this disease. In this case–control study, we developed an accurate LC diagnosis test using retrospectively collected formalin‐fixed paraffin‐embedded ( FFPE ) human lung tissues and prospectively collected exhaled breath condensates ( EBC s). Following international guidelines for diagnostic methods with clinical application, reproducible standard operating procedures ( SOP ) were established for every step comprising our LC diagnosis method. We analyzed the expression of distinct mRNA s expressed from GATA 6 and NKX 2‐1 , key regulators of lung development. The Em/Ad expression ratios of GATA 6 and NKX 2‐1 detected in EBC s were combined using linear kernel support vector machines ( SVM ) into the LC score, which can be used for LC detection. LC score‐based diagnosis achieved a high performance in an independent validation cohort. We propose our method as a non‐invasive, accurate, and low‐price option to complement the success of computed tomography imaging ( CT ) and chest X‐ray ( CXR ) for LC diagnosis.Keywords:
Exhaled breath condensate
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Exhaled breath condensate (EBC) pH has been proposed as a biomarker of airway inflammation and oxidative stress in asthma. Cigarette smoking reduces EBC pH in mild asthma. The effects of smoking on EBC pH in more symptomatic asthmatic patients using inhaled corticosteroids (ICS) are unknown. We aimed to compare EBC pH in asthmatic smokers (AS) and non-smokers (ANS) with moderate to severe disease, who were taking ICS. We also investigated the relationship between EBC pH and biomarkers of airway inflammation and oxidative stress.AS (n = 18) and ANS (n = 17), who were using ICS, were recruited and EBC pH, sputum inflammatory cell counts and sputum supernatant 8-isoprostane concentrations were measured. Full lung function testing was performed.EBC pH was significantly lower in AS than in ANS (6.91 vs 7.41). In AS there was a significant inverse correlation between EBC pH and 8-isoprostane levels (r = -0.54, P = 0.03). There was no correlation between EBC pH and sputum neutrophil counts.EBC pH appears to be a biomarker of the level of oxidative stress in smokers with moderate to severe asthma. EBC pH may have applications for the longitudinal monitoring of the effects of smoking on the airways of asthmatic patients.
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Exhaled breath condensate (EBC) has been increasingly studied as a noninvasive research method for sampling the alveolar and airway space and is recognized as a promising source of biomarkers of lung diseases. Substances measured in EBC include oxidative stress and inflammatory mediators, such as arachidonic acid derivatives, reactive oxygen/nitrogen species, reduced and oxidized glutathione, and inflammatory cytokines. Although EBC has great potential as a source of biomarkers in many lung diseases, the low concentrations of compounds within the EBC present challenges in sample collection and analysis. Although EBC is viewed as a noninvasive method for sampling airway lining fluid (ALF), validation is necessary to confirm that EBC truly represents the ALF. Likewise, a dilution factor for the EBC is needed in order to compare across subjects and determine changes in the ALF. The aims of this paper are to address the characteristics of EBC; strategies to standardize EBC sample collection and review available analytical techniques for EBC analysis.
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Abstract Exhaled breath condensate (EBC) pH appears to be a robust measure of asthma. However, the association between EBC pH and clinical factors and airway inflammatory markers remains unclear. The objectives of this study were to investigate the factors determining EBC pH in asthmatic children, and the reproducibility and effects of collection devices on EBC pH in nine healthy, nonsmoking adults. EBC was collected once from asthmatic children using EcoScreen, and from adults over 3 consecutive days using both RTubes and EcoScreen. EBC pH was measured immediately in non‐deaerated samples by microelectrode pH meter. Concentrations of 8‐isoprostane, cysteinyl leukotrienes (cys‐LT), and leukotriene B4 (LTB 4 ) were measured using enzyme immunoassay. Exhaled nitric oxide concentration (FeNO) was measured by chemiluminescence. Fifty‐eight asthmatics (16 intermittent, 12 mild persistent, and 30 moderate‐to‐severe persistent) were recruited. EBC pH was lower among patients with moderate‐to‐severe persistent than intermittent asthma ( P = 0.046). This marker correlated inversely with disease severity score (ρ = −0.276, P = 0.036), but not FeNO or other EBC biomarkers. Bland‐Altman analyses found pH but not other EBC biomarkers to be reproducible, which were confirmed by its low coefficient of variation (2.7%; range, 0.4–5.2%). There was poor correlation between pH in EBC collected by RTube and EcoScreen (ρ = 0.059, P = 0.784). Factor analysis selected four factors that explained 67.5% of the total variance, and EBC pH clustered with both cys‐LT and LTB 4 . In conclusion, our results suggest that pH in non‐deaerated EBC is influenced by asthma severity in children. EBC pH measurement is reproducible, but is dependent on the collection devices used. Pediatr Pulmonol. © 2005 Wiley‐Liss, Inc.
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The exhaled breath condensate (EBC) approach provides a convenient and noninvasive approach for sampling the pulmonary epithelial lining fluid (ELF). Increased EBC concentrations of more than a dozen inflammatory markers and hydrogen ions have been reported in lung diseases associated with inflammation. However, the usefulness of EBC is compromised by uncertainties concerning the sources of the EBC droplets and by the extreme and variable dilution of ELF droplets with condensed water vapor ( approximately 20,000-fold). Reported increases in EBC concentrations may reflect proportionate increases in the total volume rather than the concentration of ELF droplets in the collected samples. Conclusions regarding ELF concentrations can only be made if this dilution is estimated with a dilutional indicator (e.g., conductivity of lyophilized EBC). In normal EBC samples, pH is effectively set by oral contamination with NH(3), and EBC pH cannot provide reliable information regarding ELF pH in normal subjects. Acidification of EBC observed in asthma and other conditions may reflect acidification of ELF, decreases in NH(3) added to the EBC, and/or the presence of gastric droplets in the EBC.
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Summary Background Collection of exhaled breath condensate (EBC) is a simple, non‐invasive method of obtaining samples from the airways and it can be repeated in short intervals without side effects; therefore, it provides an opportunity to monitor the changes in concentration of inflammatory mediators in the airways. However, EBC analysis still has several unresolved issues. Objective To better understand the characteristics of EBC, we compared cysteinyl leukotriene (CysLT) concentrations between bronchoalveolar lavage fluid (BALF) and EBC. We also attempted to correct CysLT concentrations in BALF and EBC diluted with saline and water vapour using biological markers. Methods EBC was collected from 14 patients with idiopathic pulmonary fibrosis before bronchoscopy. We measured CysLT concentrations and also quantified tyrosine, urea and total protein as possible biomarkers for correcting dilution. Results (1) We have validated the quantification of CysLTs in EBC. (2) Although a significant correlation was observed among tyrosine and urea concentrations in BALF, urea and total protein concentrations were below the detection limit in EBC. (3) CysLT concentrations were higher in BALF than in EBC (median, 15.96 pg/mL vs. 5.5 pg/mL; P =0.001) and there was no correlation of CysLT concentrations in BALF with those in EBC. A significant correlation of the ratio of total CysLT concentration to tyrosine concentration (CysLT/Y) in EBC with that in BALF was observed ( r =0.547, P =0.043). (4) CysLT/Y in EBC correlated with serum KL‐6 concentration and total cell count in BALF, and CysLT/Y in BALF also correlated with exhaled NO concentration and %VC. Conclusions CysLT/Y in EBC significantly correlated with that in BALF and some clinical parameters correlated with CysLT/Y. Tyrosine concentration may be used to correct the dilution error for CysLT concentrations, and CysLT/Y in EBC can be a surrogate marker for CysLT concentrations in BALF.
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Introduction: Systematic analysis of markers from exhaled breath condensate (EBC) has become a more and more interesting tool for non-invasive diagnosis of lung and airway diseases. Standardization of EBC collection with respect to collection time and breathing pattern has been achieved by the development of ECoScreen and ECoVent. However, the issues on the pulmonary site in regard to the release of different markers remains still unclear. The aim of the study was to provide the technical tool to assess whether EBC markers are released from the conducting airways or the lung periphery.
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