Molecular testing on bronchial washings for the diagnosis and predictive assessment of lung cancer.

Cytopathological analyses of bronchial washings (BWs) collected during fibre-optic bronchoscopy are often inconclusive for lung cancer diagnosis. To address this issue, we assessed the suitability of conducting molecular analyses on BWs, with the aim to improve the diagnosis and outcome prediction of lung cancer. The methylation status of RASSF1A, CDH1, DLC1 and PRPH was analysed in BW samples from 91 lung cancer patients and 31 controls, using a novel two-colour droplet digital methylation-specific PCR (ddMSP) technique. Mutations in ALK, BRAF, EGFR, ERBB2, KRAS, MAP2K1, MET, NRAS, PIK3CA, ROS1 and TP53 and gene fusions of ALK, RET and ROS1 were also investigated, using next-generation sequencing on 73 lung cancer patients and 14 tumour-free individuals. Our four-gene methylation panel had significant diagnostic power, with 97% sensitivity and 74% specificity (relative risk, 7.3; odds ratio, 6.1; 95% confidence interval, 12.7-127). In contrast, gene mutation analysis had a remarkable value for predictive, but not for diagnostic, purposes. Actionable mutations in EGFR, HER2 and ROS1 as well as in other cancer genes (KRAS, PIK3CA and TP53) were detected. Concordance with gene mutations uncovered in tumour biopsies was higher than 90%. In addition, bronchial-washing analyses permitted complete patient coverage and the detection of additional actionable mutations. In conclusion, BWs are a useful material on which to perform molecular tests based on gene panels: aberrant gene methylation and mutation analyses could be performed as approaches accompanying current diagnostic and predictive assays during the initial workup phase. This study establishes the grounds for further prospective investigation.

Idiopathic pulmonary fibrosis: prognostic impact of histologic honeycombing in transbronchial lung cryobiopsy.

BACKGROUND: Prognostic evaluation in idiopathic pulmonary fibrosis (IPF) may be important as it can guide management decisions, but the potential role of honeycomb changes in providing information about outcome and survival of patients with IPF, particularly if diagnosed using cryobiopsy, has not been evaluated. Aim of this study was to determinate whether a relationship exists between honeycombing on cryobiopsy and clinical/radiological picture and outcome in patients with IPF and to assess whether the same pathologic criteria that have been used to define the UIP pattern (usual interstitial pneumonia) for surgical biopsy can also be applied to cryobiopsy. METHODS: Sixty-three subjects with a multidisciplinary diagnosis of IPF and a UIP pattern on cryobiopsy were evaluated. Patients were classified into two sub-groups depending on the presence of honeycombing on histology. RESULTS: The presence of honeycombing on cryobiopsy did not identify a specific phenotype of patients as it did not correlate with radiological and clinical picture and it was not associated neither with the risk of death (p = 0.1192) or with the event-free survival (p = 0.827); a higher number of samples and the presence of pleura on biopsy were instead associated with an increase in the finding of honeycombing. CONCLUSIONS: The same pathologic criteria that have been used to define the UIP pattern in surgical biopsies (with honeycombing changes considered as non-mandatory for the definition of the pattern itself) can be applied to cryobiopsy samples, as the presence of these changes do not define different clinical or radiological phenotypes of patients with IPF.

Quality of life in idiopathic pulmonary fibrosis: The impact of sleep disordered breathing.

PURPOSE: the study aims at describing the role of sleep disordered breathing (SDB) on daytime symptoms, quality of sleep and quality of life (QoL) in patients with moderate-severe IPF. METHODS: we enrolled 34 consecutive room air breathing IPF outpatients who received a full-night polysomnography. The following questionnaires were administered: Epworth Sleepiness Score (ESS), Pittsburg Sleep Quality Index (PSQI), StGeorge's Questionnaire (StGQ). RESULTS: patients were classified in 3 groups:Group A (NO-SDB, 9 patients), Group B(OSAS without sleep-related hypoxemia, 17 patients), Group C(OSAS with sleep-related hypoxemia, 8 patients). Although sleep parameters showed no significant differences among the 3 groups, worse measures were found in group C. 50% of patients (17/34) reported a StGQ score indicating a reduced QoL and the StGQ score was significantly higher in group C patients compared to group A (p < 0.05). In the stepwise multiple regression analysis, 75% of StGQ score variability was significantly predicted by FVC(Forced Vital Capacity) %, DLco (diffusion lung capacity for carbon monoxide)%, PSQI and ESS. CONCLUSIONS: in patients with IPF both subjective and polysomnographic poor sleep quality are extremely common features, they are predicted by variables associated with SBD severity and are linked to low QoL. IPF with more severe SDB present poor sleep quality and a worse QoL compared to SDB-free or OSAS-only.

Effects of bronchodilation on biomarkers of peripheral airway inflammation in COPD.

Peripheral airway inflammation and dysfunction are key elements in the pathogenesis of COPD. The exhaled alveolar fraction of nitric oxide (CANO) is an indirect biomarker of lung peripheral inflammation. We tested whether inhaled long-acting bronchodilators (LABA) can affect CANO and we evaluated correlations with lung mechanics in patients with COPD. Two-centre, randomised, double blind, crossover study including COPD patients with moderate-to-severe airflow obstruction. Following a pharmacological washout, multi-flow exhaled fraction of NO (FENO), plethysmography, lung diffusion (DLCO), single breath nitrogen washout test and dyspnoea were measured in a crossover manner at baseline and 30, 60 and 180 min following administration of salmeterol (Sal) or formoterol fumarate (FF). (ClinicalTrials.gov, number NCT01853787). Fort-five patients were enrolled (median age: 71.8 years; 84.4% males). At baseline, CANO correlated with airway resistances (r = 0.422), residual volume/total lung capacity (RV/TLC; r = 0.375), transfer factor (r= -0.463) and forced expiratory volume in 1 s (FEV1; r= -0.375, all P < 0.01). After LABA administration, we found a significant reduction of FENO that reached statistical significance at 180'; no difference was found between FF and S. Consistently, a significant reduction of CANO was documented at 60' and 180' compared to baseline for both FF and S (P < 0.01 and P < 0.05, respectively). Changes in CANO were correlated with changes in vital capacity (r=-44; P < 0.001) and RV/TLC (r = 0.56; P < 0.001), but not FEV1. In COPD, direct correlations were found between the levels of CANO and the magnitude of peripheral airway dysfunction. LABA reduced CANO levels. The reduction was associated with improvement in functional parameters reflecting air trapping.

Predischarge screening for chronic obstructive pulmonary disease in patients with acute coronary syndrome and smoking history.

BACKGROUND: Several studies suggested that chronic obstructive pulmonary disease (COPD) is largely underdiagnosed in patients with acute coronary syndrome (ACS) contributing to further affect clinical outcome. Our aim was to validate a screening procedure to identify, in ACS patients, those with negligible risk of undiagnosed COPD. METHODS: From December 2014 to August 2015, 169 ACS patients with smoking history underwent screening procedure. Screening procedure combined peak expiratory flow rate (PEFR, defined as positive if <80% of predicted) and respiratory health status questionnaire (RHSQ, defined as positive if >19.5 points). The screening was considered negative if both tests provided negative results, positive if both were positive, uncertain in presence of discrepancy. Spirometry was planned after 2months to identify or not the presence of irreversible airflow obstruction (undiagnosed COPD). The primary endpoint was the negative predictive value of screening for undiagnosed COPD. RESULTS: Overall, 137 (81%) patients received spirometry (final study population). Screening was negative, uncertain and positive in 58 (42%), 46 (34%) and 33 (24%) patients, respectively. We found undiagnosed COPD in 39 (29%) patients. Only 3 patients with negative screening showed undiagnosed COPD. Negative screening showed the best ability to discriminate patients without COPD (negative predictive value 95%). Two-month health status in patients with undiagnosed COPD was significantly poor. CONCLUSIONS: Undiagnosed COPD is relatively frequent in ACS patients with smoking history and a simple screening procedure including PEFR and RHSQ can be administered before hospital discharge to discriminate those at negligible risk of undiagnosed COPD (ClinicalTrials.gov, NCT02324660).

Chronic obstructive pulmonary disease and ischemic heart disease comorbidity: overview of mechanisms and clinical management.

In the last few years, many studies focused their attention on the relationship between chronic obstructive pulmonary disease (COPD) and ischemic heart disease (IHD), showing that these diseases are mutually influenced. Many different biological processes such as hypoxia, systemic inflammation, endothelial dysfunction, heightened platelet reactivity, arterial stiffness and right ventricle modification interact in the development of the COPD-IHD comorbidity, which therefore deserves special attention in early diagnosis and treatment. Patients with COPD-IHD comorbidity have a worst outcome, when compared to patients with only COPD or only IHD. These patients showed a significant increase on risk of adverse events and of hospital readmissions for recurrent myocardial infarction, heart failure, coronary revascularization, and acute exacerbation of COPD. Taken together, these complications determine a significant increase in mortality. In most cases death occurs for cardiovascular cause, soon after an acute exacerbation of COPD or a cardiovascular adverse event. Recent data regarding incidence, mechanisms and prognosis of this comorbidity, along with the development of new drugs and interventional approaches may improve the management and long-term outcome of COPD-IHD patients. The aim of this review is to describe the current knowledge on COPD-IHD comorbidity. Particularly, we focused our attention on underlying pathological mechanisms and on all treatment and strategies that may improve and optimize the clinical management of COPD-IHD patients.