BACKGROUND:Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive procedure that allows for the evaluation of mediastinal and hilar lymph nodes. It has also been described in limited studies for the evaluation of central pulmonary lesions. OBJECTIVES:Our study aimed to describe the diagnostic performance of linear EBUS in pulmonary lesions, the sensitivity for malignancy, and its suitability as an adjunctive test for lung cancer. METHODS:We analyzed procedures from the Stather Canadian Outcomes Registry for Chest Procedures (SCOPE) database that included sampling of at least 1 intrapulmonary lesion with linear EBUS. Diagnostic yield (DY) and sensitivity were calculated using the standard definitions. Suitability for molecular testing was evaluated in the lung cancer cohort, in which lung lesion sampling was the only diagnostic site. RESULTS:Four hundred and 10 records were identified, one of which was excluded for lack of follow-up data. The most frequent final diagnosis was lung cancer in 346/409 cases (84.6%). DY for the lung EBUS-TBNA was 370/409 (90.5%), and sensitivity for malignancy was 358/372 (96.2%). The sensitivity of linear EBUS lung TBNA for lung cancer was 331/346 (95.7%). The data set did not record failed attempts at lung lesion localization with linear EBUS, during which no sample was collected. CONCLUSION:Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is an effective and safe diagnostic tool for lung lesions visible on ultrasound. Lesion size is associated with improved DY. Lung cancer ancillary testing is feasible in almost all cases.

Background:Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has been established as safe and effective in evaluating the mediastinum for malignant lymphadenopathy, with sensitivity reported at 92% to 95% with 21- and 22-gauge endobronchial ultrasound (EBUS) needles. Results for lymphoma and benign conditions such as sarcoidosis are significantly lower. Research Question:Does a 19-gauge EBUS needle increase diagnostic performance over smaller needles (21 or 22 gauge) in patients with a preprocedural diagnosis of suspected sarcoidosis, lymphoma, or mediastinal lymphadenopathy not yet diagnosed? Study Design and Methods:This study retrospectively examined patient records from the Stather Canadian Outcomes Registry for Chest Procedures database, and included patients who underwent EBUS-TBNA for a preprocedural diagnosis of suspected sarcoidosis, lymphoma, or mediastinal lymphadenopathy not yet diagnosed. Patients were separated into those who received EBUS-TBNA with a 19-gauge vs 21-/22-gauge needle. We performed a propensity score matching analysis with a 1:2 ratio and an inverse probability of treatment weighting approach, with diagnostic yield (DY) as the primary end point. Results:The data set was extracted from the Stather Canadian Outcomes Registry for Chest Procedures database on July 1, 2023, and included 1,810 procedures (19-gauge group: n = 195; 21-/22-gauge group: n = 1,615). The DY of EBUS-TBNA procedures with propensity score matching analysis was 230 of 316 (72.8%) in the 21-/22-gauge group vs 116 of 158 (73.4%) in the 19-gauge group (difference, 0.6%; 95% CI, -8.1 to 8.7%; P = .88). With the inverse probability of treatment weighting analysis, the DY was 1,117.8 of 1,606.7 (69.6%) in the 21-/22-gauge group vs 90.5 of 122.3 (74.0%) in the 19-gauge group (difference, 4.4%; 95% CI, -4.3 to 11.7%; P = .30). Interpretation:We did not identify a statistically significant difference in DY between the 19-gauge EBUS needles over the 21-/22-gauge needles in this patient population.

Background: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive procedure that allows for the evaluation of mediastinal and hilar lymph nodes. It has also been described in limited studies for the evaluation of central pulmonary lesions. Objectives: Our study aimed to describe the diagnostic performance of linear EBUS in pulmonary lesions, the sensitivity for malignancy, and its suitability as an adjunctive test for lung cancer. Methods: We analyzed procedures from the Stather Canadian Outcomes Registry for Chest Procedures (SCOPE) database that included sampling of at least 1 intrapulmonary lesion with linear EBUS. Diagnostic yield (DY) and sensitivity were calculated using the standard definitions. Suitability for molecular testing was evaluated in the lung cancer cohort, in which lung lesion sampling was the only diagnostic site. Results: Four hundred and 10 records were identified, one of which was excluded for lack of follow-up data. The most frequent final diagnosis was lung cancer in 346/409 cases (84.6%). DY for the lung EBUS-TBNA was 370/409 (90.5%), and sensitivity for malignancy was 358/372 (96.2%). The sensitivity of linear EBUS lung TBNA for lung cancer was 331/346 (95.7%). The data set did not record failed attempts at lung lesion localization with linear EBUS, during which no sample was collected. Conclusion: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is an effective and safe diagnostic tool for lung lesions visible on ultrasound. Lesion size is associated with improved DY. Lung cancer ancillary testing is feasible in almost all cases.

Background: Diagnosis of sarcoidosis often involves endobronchial biopsy (EBB), but studies have shown varying yields for EBB in suspected sarcoidosis, partly due to differences in identifying abnormal mucosa under white light (WL). Narrow band imaging (NBI) may assist in the visualization of abnormal mucosa, but its role in sarcoidosis remains to be characterized. Methods: Individuals referred for suspected sarcoidosis were considered for enrollment. Bronchoscopy with both WL and NBI was conducted, followed by EBB. The main objectives were to characterize NBI abnormalities in this patient population and determine the incremental yield of NBI-directed EBB. Results: In our cohort of 100 suspected sarcoidosis patients (66% male, median age 42), 88 were diagnosed with sarcoidosis, through cytopathology (n=78) or clinical evaluation (n=10). NBI high-grade lesions were more common than WL high-grade lesions (58% vs. 27%, difference 31%, 95% CI 18.3-42.5% P<0.001). High-grade WL EBB were more likely to be positive than low-grade WL biopsies [20/31 (65%) vs. 20/91 (22%), odds ratio (OR) 6.5, 95% CI 2.7-15.6, P<0.01]). Conversely, high-grade NBI lesions were no more likely to be positive than low-grade NBI lesions [23/63 (37%) vs. 17/59, (29%), OR 1.42, 95% CI 0.66-3.0, P=0.366]. EBB positivity and false-negative EBUS-TBNA were more common in patients with Scadding stage 2 or greater, suggesting that the chest radiography stage may help select patients more likely to benefit from adjunctive EBB. Conclusion: NBI abnormalities are common in patients with sarcoidosis, but unlike WL abnormalities, do not predict the finding of granulomatous inflammation on EBB. The chest radiography stage may be useful to identify patients more likely to benefit from EBB in addition to EBUS-TBNA.

BACKGROUND:The routine use of CT imaging and lung cancer screening has increased the identification of peripheral pulmonary lesions (PPLs). Sampling may be needed for some nodules. Many new technologies are available to improve the diagnostic performance of bronchoscopy for the sampling of PPLs, but few comparative trials exist. The objective of this study was to compare the diagnostic performance of bronchoscopy with radial endobronchial ultrasound (rEBUS) using an ultrathin bronchoscope (BF-MP190F; Olympus) with a non-ultrathin bronchoscope and to compare the diagnostic performance of bronchoscopy with and without rapid on-site evaluation (ROSE). RESEARCH QUESTION:Does diagnostic performance differ between ultrathin and non-ultrathin bronchoscopes with rEBUS, and what impact does ROSE have on diagnostic performance of rEBUS? STUDY DESIGN AND METHODS:This pragmatic, multicenter, 2 × 2 factorial, randomized controlled trial involved adult patients with PPLs (mean diameter < 5 cm) and radiographic stage N0 disease referred for bronchoscopy. The study was powered to detect a 20% improvement in the primary outcome of difference in diagnostic yield (DY) between ultrathin and non-ultrathin bronchoscopes and between procedures with and without ROSE. Secondary outcomes included sensitivity for malignancy, complications, and procedure duration. RESULTS:Of 215 patients assessed, 186 patients were randomized and 181 patients were analyzed. Malignancy prevalence was 84%. No significant differences in DY or sensitivity for malignancy were found between non-ultrathin and ultrathin bronchoscopes: 65.6% vs 58.2% (difference, -7.3%; P = .36) and 84.3% vs 74.3% (difference, -10.0%; P = .21), respectively. Similarly, no significant differences were observed with or without ROSE: 60.4% vs 63.5% (difference, -3.1%; P = .76) and 80.3% vs 78.3% (difference, 2.0%; P = .83), respectively. INTERPRETATION:We could not identify a difference in DY or sensitivity for malignancy for the diagnosis of PPLs between an ultrathin bronchoscope and a non-ultrathin bronchoscope and between ROSE and no ROSE. The study was underpowered to detect smaller but potentially clinically meaningful differences. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov; No.: NCT03809169; URL: www. CLINICALTRIALS:gov.

Intracavitary pulmonary aspergilloma is a persistent and life-threatening infection that carries a mortality rate of up to 15%. It occurs when Aspergillus species gain entry to an existing lung cavity. In the absence of definitive treatment, patients may succumb to severe complications such as massive hemoptysis, cachexia, or secondary infections. Aspergillomas often show limited response to antifungal medications, mainly due to insufficient drug concentrations within the cavities. Surgery is frequently the preferred treatment option, but it poses significant risks, and many individuals are ineligible due to underlying health issues. We present the most extensive non-surgical fungal ball cohort to date, managed using an innovative multimodal strategy that combines antifungal therapy before and after bronchoscopic debulking. This was a cross-sectional observational study. For those who cannot undergo surgery, our medical center has pioneered a multimodal approach to aspergilloma resection. This approach combines bronchoscopic endoscopy with antifungal therapy and has been applied successfully to more than 18 patients that are presented in this series. The median age of the cohort was 58 years (range: 32–73), with an equal sex distribution. The mean percent predicted FEV1 was 65.3%. The mean follow-up duration was 3.6 years (range: 0.5–10 years). The cohort receiving antifungals systematically prior to debridement showed a reduction of the pre-existing cavity (40.38 mm versus 34.02 mm, p = 0.021). Across the 18 patients during the follow-up period, 94% remained recurrence-free (defined by symptoms and radiology). Our study fills a critical knowledge gap regarding the significance of initiating antifungal treatment before bronchoscopic debulking and presents a viable approach in these cases for which there is a current unmet therapeutic need.

OBJECTIVE:Molecular subtyping of non-small cell lung cancer (NSCLC) is critical in the diagnostic evaluation of patients with advanced disease. This study aimed to examine whether samples from endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) of intrathoracic lymph nodes and/or lung lesions are adequate for molecular analysis across various institutions. METHODS:We retrospectively reviewed all cases of linear EBUS-TBNA with a final bronchoscopic diagnosis of NSCLC entered in the Stather Canadian Outcomes registry for chest ProcEdures database. The primary outcome was specimen inadequacy rate for each molecular target, as defined by the local laboratory or pathologist. RESULTS:A total of 866 EBUS-TBNA procedures for NSCLC were identified. Specimen inadequacy rates were 3.8% for EGFR, 2.5% for ALK-1 and 3.5% for PD-L1. Largest target size was not different between adequate and inadequate specimens, and rapid onsite evaluation did not increase specimen adequacy rates. One centre using next-generation sequencing for EGFR had lower adequacy rates than 2 others using matrix-assisted laser desorption/ionization time-of-flight mass spectrophotometry. CONCLUSION:EBUS-TBNA specimens have a very low-specimen inadequacy rate for molecular subtyping of non-small cell lung cancer.

Introduction: Lung cancer screening (LCS) for high-risk populations has been firmly established to reduce lung cancer mortality, but concerns exist regarding unintended downstream costs. Methods: Mean health care utilization and costs were compared in the Alberta Lung Cancer Screening Study in a cohort undergoing LCS versus a propensity-matched control group who did not. Results: A cohort of 651 LCS participants was matched to 336 unscreened controls. Over the study period (mean 3.6 y), a modest increase in the number of claims (22.4 versus 21.9 per person-year [PY]; D 0.50 [95% confidence interval: 0.15-0.86], p = 0.006) and outpatient visits (4.01 versus 3.50 per PY; D 0.51 [0.37-0.65], p <0.0001), but not in inpatient admissions, was noted in the screened cohort. Claims payments, inpatient costs, and cancer care costs were similar in the screening arm versus the unscreened. Outpatient encounter costs per participant were higher in the screened group ($2662.18 versus $2040.67 per PY; D-$621.51 [-1118.05 to-124.97], p = 0.014). Removing the additional computed tomography screening examinations rendered differences not significant. Mean total costs were not significantly different at $6461.10 per PY in the screening group and $6125.31 in the unscreened group (D-$335.79 [-2009.65 to 1338.07], p = 0.69). Conclusions: Modest increases in outpatient costs are noted in individuals undergoing LCS, in part attributable to the screening examinations, without differences in overall health care costs. Health care costs and utilization seem otherwise similar in individuals participating in LCS and those who do not. (c) 2023 The Authors. Published by Elsevier Inc. on behalf of the International Association for the Study of Lung Cancer. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/).

Background: Pulmonary aspergilloma is a chronic fungal infection and, without therapy, is often fatal. Death can occur from massive hemoptysis, cachexia, or secondary infection. Standard therapy is surgical resection, but unfortunately, many patients are not candidates due to poor lung function and comorbidities. Objectives:Aspergilloma removal via bronchoscopy may be an important, less invasive, and viable alternative therapy to the gold standard of surgical resection. Important considerations include patient selection, the use of antifungal treatment peri-procedure, optimization of procedure time, and the minimization of the risk of bleeding. We assessed whether this multi-modal approach to therapy may lead to overall benefits and reduced risk of recurrence. Methods: We describe a single-centre case series of 15 patients deemed non-surgical candidates selected for endoscopic procedure. All patients received a minimum of 3 months of appropriate antifungal therapy with no improvement in the size of the aspergilloma by radiographic measurements. The procedure was performed by an interventional pulmonologist. Blunt instruments were used to remove the fungus ball. Antifungal treatment was given for 1 to 3 months afterwards. Results: Across all patients (n=15), subjective symptomatic improvements occurred with no complications observed, including death or bleeding. Follow up time ranged from 6 months to 10 years. Only one patient severely immunocompromised post lung transplant had recurrence of the disease at 3 years. Conclusion: While further study is required to determine the optimal protocol, our proposed multi-modal approach to aspergilloma removal was viable, safe and effective.

Background: Several randomized trials demonstrated have reduced lung cancer mortality with screening using computed tomography. However, there remains debate about the optimal approach for determining screening eligibility, and no evidence yet exists reporting lung cancer rates in those excluded from screening due to too low of a personalized risk.Methods: This study was based on the Alberta Lung Cancer Screening Study, which received 1737 applicants and enrolled 850 based on the NLST criteria or a PLCOM2012 risk >= 1.5%. We excluded 887 applicants who were interested in screening but deemed ineligible. We report lung cancer rates in the screened and unscreened cohorts. Results: We observed 30 and 8 lung cancers in the screened and unscreened groups, respectively. Only 1 of 8 lung cancers were among those considered too low risk (0.14%), while the remaining 7 were among those excluded for other reasons, including symptoms requiring more immediate workup. No NLST eligible but PLCO risk < 1.5% screened individual had a lung cancer detected as part of the study, so that of all applicants contacting the program with risk estimates less than 1.5%, only 1/857 (0.12%) developed lung cancer. Conclusion: Our findings indicate that a risk-based approach for screening eligibility is unlikely to miss many lung cancers.

Background Lung cancer is a major health problem. CT lung screening can reduce lung cancer mortality through early diagnosis by at least 20%. Screening high-risk individuals is most effective. Retrospective analyses suggest that identifying individuals for screening by accurate prediction models is more efficient than using categorical age-smoking criteria, such as the US Preventive Services Task Force (USPSTF) criteria. This study prospectively compared the effectiveness of the USPSTF2013 and PLCOm2012 model eligibility criteria. Methods In this prospective cohort study, participants from the International Lung Screening Trial (ILST), aged 55-80 years, who were current or former smokers (ie, had >= 30 pack-years smoking history or <= 15 quit-years since last permanently quitting), and who met USPSTF-2013 criteria or a PLCOm2012 risk threshold of at least 1.51% within 6 years of screening, were recruited from nine screening sites in Canada, Australia, Hong Kong, and the UK. After enrolment, patients were assessed with the USPSTF2013 criteria and the PLCOm-2012 risk model with a threshold of at least 1.70% at 6 years. Data were collected locally and centralised. Main outcomes were the comparison of lung cancer detection rates and cumulative life expectancies in patients with lung cancer between USPSTF2013 criteria and the PLCOm2012 model. In this Article, we present data from an interim analysis. To estimate the incidence of lung cancers in individuals who were USPSTF2013-negative and had PLCOm2012 of less than 1.51% at 6 years, ever-smokers in the Prostate Lung Colorectal and Ovarian Cancer Screening Trial (PLCO) who met these criteria and their lung cancer incidence were applied to the ILST sample size for the mean follow-up occurring in the ILST. This trial is registered at ClinicalTrials.gov, NCT02871856. Study enrolment is almost complete. Findings Between June 17, 2015, and Dec 29, 2020, 5819 participants from the International Lung Screening Trial (ILST) were enrolled on the basis of meeting USPSTF2013 criteria or the PLCOm2012 risk threshold of at least 1.51% at 6 years. The same number of individuals was selected for the PLCOm2012 model as for the USPSTF2013 criteria (4540 [78%] of 5819). After a mean follow-up of 2.3 years (SD 1.0), 135 lung cancers occurred in 4540 USPSTF2013positive participants and 162 in 4540 participants included in the PLCOm2012 of at least 1.70% at 6 years group (cancer sensitivity difference 15.8%, 95% CI 10.7-22.1%; absolute odds ratio 4.00, 95% CI 1.89-9.44; p<0.0001). Compared to USPSTF2013-positive individuals, PLCOm2012-selected participants were older (mean age 65.7 years [SD 5.9] vs 63.3 years [5.7]; p<0.0001), had more comorbidities (median 2 [IQR 1-3] vs 1 [1-2]; p<0.0001), and shorter life expectancy (13.9 years [95% CI 12.8-14.9] vs 14.8 [13.6-16.0] years). Model-based difference in cumulative life expectancies for those diagnosed with lung cancer were higher in those who had PLCOm2012 risk of at least 1.70% at 6 years than individuals who were USPSTF2013-positive (2248.6 years [95% CI 2089.6-2425.9] vs 2000.7 years [1841.2-2160.3]; difference 247.9 years, p=0.015). Interpretation PLCOm2012 appears to be more efficient than the USPSTF2013 criteria for selecting individuals to enrol into lung cancer screening programmes and should be used for identifying high-risk individuals who benefit from the inclusion in these programmes. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd.

BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is commonly used to evaluate mediastinal lymphadenopathy. Studies focusing on malignant lymphadenopathy have compared 21-and 22-gauge (21G and 22G, respectively) needles and have not identified an advantage of one needle size over the other in terms of diagnostic yield. RESEARCH QUESTION: Does the 19-gauge (19G) EBUS needle offer greater diagnostic yield and sensitivity vs the 21G and 22G EBUS needles for a diagnosis of sarcoidosis, lymphoma, or mediastinal lymphadenopathy not yet diagnosed? STUDY DESIGN AND METHODS: This study retrospectively examined records of 730 patients from the Stather Canadian Outcomes Registry for Chest Procedures (SCOPE) database who underwent EBUS-TBNA for a diagnosis of suspected sarcoidosis, lymphoma, or mediastinal lymphadenopathy not yet diagnosed. A propensity score analysis of two groups was per-formed. One group comprised patients undergoing EBUS-TBNA with a 19G needle, the other with a 21G or 22G needle. Cases for analysis were selected with a 1:2 ratio of 19G vs 21/ 22G using logistic regression and random matching with all eligible 19G cases included. RESULTS: There were 137 patients (312 targets) in the 19G group and 274 patients (631 targets) in the 21/22G group in the propensity score analysis. The diagnostic yield was 107 of 137 (78.1%) in the 19G group vs 194 of 274 (70.8%) in the 21/22G group (difference, 7.3%; 95% CI, -1.9 to 15.6; P = .116). The sensitivity of EBUS-TBNA for sarcoidosis was 80 of 83 (96.4%) in the 19G group vs 150 of 156 (96.2%) in the 21/22G group (difference, 0.24%; 95% CI, -6.6 to 85.1; P = .93). In patients with a final diagnosis of lymphoma, EBUS was diagnostic in 10 of 13 (76.9%) in the 19G group vs 12 of 12 (100%) in the 21/22G group (difference, 23.1%; 95% CI, -5.4 to 50.3; P = .08). INTERPRETATION: The study did not identify an advantage of the 19G EBUS needle over the 21/22G EBUS needles for diagnostic yield nor sensitivity for sarcoidosis or lymphoma.

BACKGROUND:Interpretation of Low Dose CT scans and protocol driven management of findings is a key aspect of lung cancer screening program performance. Reliable and reproducible methods are needed to communicate radiologists' interpretation to the screening program or clinicians driving management decision.METHODS:We performed an audit of a subset of dictated reports from the PANCAN study to assess for omissions. We developed an electronic synoptic reporting tool for radiologists embedded in a clinical documentation system software. The tool was then used for reporting as part of the Alberta Lung Cancer Screening Study and McGill University Health Centre Pilot Lung Cancer Screening Program.RESULTS:Fifty reports were audited for completeness. At least one omission was noted in 30 (70%) of reports, with a major omission (missing lobe, size, type of nodule in report or actionable incidental finding in recommendation section of report) in 24 (48%). Details of the reporting template and functionality such as automated nodule cancer risk assessment, Lung-RADS category assignment, auto-generated narrative type report as well as personalize participant results letter is provided. A description of the system's performance in its application in 2815 CT reports is then summarized.CONCLUSIONS:We found that narrative type radiologist reports for lung cancer screening CT examinations frequently lacked specific discrete data elements required for management. We demonstrate the successful implementation of a radiology synoptic reporting system for use in lung cancer screening, and the use of this information to drive program management and communications.

Background Subglottic stenosis (SGS) is a reportedly rare disease that causes recurrent severe airway obstruction. Etiologies reported for SGS include idiopathic, iatrogenic, autoimmune, congenital, and traumatic, with variable ratios among different centres. From empiric observation, southern and central Alberta was hypothesized to have a disproportionate distribution of SGS driven by increased idiopathic SGS (iSGS) compared to previous literature. Identification of causative agents of iSGS will help understand and guide future management options, so this study aimed to characterize the demographics of SGS subtypes, define prevalence and incidence rates of iSGS in southern Alberta, and geographically analyze for clustering of iSGS prevalence. Methods SGS patients from Alberta census divisions No. 1–9 and 15 were retrospectively reviewed. Patients were subtyped according to etiology of SGS and characterized. Idiopathic SGS prevalence and incidence was assessed; prevalence was further geographically segregated by census division and forward sortation area (FSA). Significant clustering patterns were assessed for using a Global Moran's I analysis. Results From 2010 to 2019 we identified 250 SGS patients, who were substantially overrepresented by idiopathic patients (80.4%) compared to autoimmune (10.0%), iatrogenic (7.6%), congenital (1.2%), and traumatic (0.8%). The total iSGS prevalence was 9.28/100,000 with a mean annual incidence rate of 0.71/100,000 per year. Significant clustering was observed (Moran's index 0.125; z-score 2.832; p = 0.0046) and the highest rates of prevalence were observed in southern Alberta and in rural communities heterogeneously dispersed around Calgary FSAs. Conclusion In southern and central Alberta, iSGS patients were disproportionately over-represented in contrast to other subtypes with the highest prevalence in southern Alberta. There was a three-fold higher annual incidence compared to previous literature demonstrating the highest rates of disease reported worldwide. Future research aims to expand the geographical scope and to assess for demographic or environmental differences within significant clusters that may contribute to disease pathophysiology. Level of evidence III. Graphical Abstract

INTRODUCTION:The Stather Canadian Outcomes registry for chest ProcedurEs (SCOPE registry) is a Canadian multicentre registry of chest procedures.METHODS AND ANALYSIS:The SCOPE registry is designed as a multicentre prospective database of specific bronchoscopic or other pulmonary procedures. Each procedure of interest will be associated with a registry module, and data capture designed to evaluate effectiveness of procedures on relevant patient outcomes. Participating physicians will be asked to enter data for all procedures performed in a given module. The anonymised dataset will be housed in a web-based electronic secure database. Specific modules included will be based on participating physician suggestions, capacity and consensus of the steering committee and relevance of hypotheses/research potential.ETHICS AND DISSEMINATION:The central registry is under approval from the Conjoint Health Research Ethics Board at the University of Calgary. We aim for registry data to lead to publication of manuscripts in international medical journals as the primary mode of dissemination. Data may also be used by local investigators for personal and/or institutional quality control purposes as well as to inform health policies. Data requests from non-participating investigators for use under ethics approved research protocols can be considered.

Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disorder characterized by alveolar accumulation of surfactant composed of lipids and proteins resulting in hypoxemic respiratory failure. Although spontaneous remission has been noted, whole lung lavage (WLL) is the standard of care in those requiring treatment. Pharmacologic treatments have been tried, most notably inhaled granulocyte-macrophage colony-stimulating factor (GM-CSF). Case series have shown improved gas exchange or pulmonary function parameters, and less need for WLL after therapy with inhaled GM-CSF.1–3 A more recent randomized trial however only showed minimal improvement in A-a gradient and no other significant benefits.4 Currently there are no Food and Drug Administraton approved pharmacologic treatments for aPAP. Peroxisome proliferator-activated receptor gamma (PPARγ) has been shown to play an important role in alveolar macrophage (AM) phospholipid and cholesterol efflux. PPARγ is present in the macrophages of healthy humans, and has been shown to be deficient in patients with aPAP and in an animal model of this disease which employs GM-CSF knockout (KO) mice.5–8 Upregulation of PPARγ leads to increased cholesterol efflux from AMs and decreased amounts of intracellular and extracellular phospholipids resulting in a decreased size of the AM compared with untreated mice.5 Administering PPARγ agonists to GM-CSF KO mice can reduce bronchoalveolar lavage (BAL) fluid turbidity and cholesterol levels,9 markers of disease severity in the mouse model. Although it is not known whether administering PPARγ agonists to humans with aPAP would lead to similar findings, PPARγ agonists, such as pioglitazone, may have potential in the clinical management of aPAP.5 We hypothesized that treatment of aPAP patients with pioglitazone would increase cholesterol efflux from AMs leading to a decrease in their size. We sought to measure the effect of pioglitazone on AMs in a patient treated with pioglitazone off-label for aPAP. CASE BACKGROUND A 52-year-old otherwise healthy male was diagnosed with aPAP in 2006 after presenting with hypoxic respiratory failure. A computed tomography scan showed a crazy paving pattern and BAL fluid demonstrated the typical milky appearance with Periodic-acid Schiff (PAS)-positive proteinaceous material on cytologic examination. Serum and BAL fluid were both positive for anti-GM-CSF antibodies (Mitogen Lab, Calgary, AB, Canada) confirming aPAP. He was treated with a WLL but was subsequently lost to follow-up until he returned with hypoxic respiratory failure again in 2009. He underwent several subsequent WLL in 2009 but continued to have refractory symptoms and hypoxemia and by January 2017 had undergone 42 unilateral WLL procedures using a technique similar to that described by Adbelmalak et al.10 Additional therapies included an 8-week course (24 sessions) of plasmapheresis as well as 8 months of inhaled GM-CSF. Neither produced any significant clinical improvement in pulmonary function testing or oxygen requirements. Despite the multiple WLLs by January 2017 the patient had gradually deteriorated and become oxygen dependent requiring 2 to 5 L via nasal prongs. There was diminishing benefit with subsequent WLLs as less proteinaceous material was removed compared with prior WLLs and improvement in oxygenation postprocedure was no longer noted. In addition, high resolution computed tomography scan of the lungs demonstrated progressive fibrosis (worsening reticulation with architectural distortion) with reduced ground glass and crazy paving. In view of limited options, progressive disease, and prior research showing the potential for reducing disease severity, a decision was made to treat with pioglitazone 30 mg daily. Institutional ethics were not obtained as it was a clinical decision to administer pioglitazone on an off-label, compassionate basis. Decision to pursue objective measurements pertaining to AMs was made after commencement of treatment to evaluate the effect of the medication. Patient consent was obtained for the off-label use of the medication as well as for the publication of this report. No adverse effects of the medication were noted while on treatment. METHODS BAL fluid was collected before initiation of pioglitazone therapy (January 2017) and after 9 months of treatment with no additional WLL performed in between. The fluid was centrifuged in a Shandon CytoSpin 3 cytocentrifuge (Thermo Fisher Scientific, Waltham, MA) at 1000 RPM for 3 minutes and cytospins prepared. The slides were stained with Wright-Giemsa stain and consisted mainly of AMs (∼99%). For assessment of mean AM diameter, a total of 75 AMs randomly selected in each cytospin were photographed ×200 magnification and then measured with ImageJ 1.51s software (https://imagej.nih.gov/ij/), blinded as to whether it was collected before or after treatment with pioglitazone. The longest diameter of the AM and the diameter orthogonal to this was measured. The average of these 2 measurements was considered the cell diameter. In addition, qualitative assessment of PAS-positive material and neutral lipids within the cell were performed. For these assessments, at least 100 AMs were assessed before and after pioglitazone treatment. Oil Red O was used to determine lipid content,5 and AMs were designated either positive or negative for stain. With respect to PAS, AMs were designated as having no/minimal, moderate, or strong positivity. A semiquantitative Histochemical score (H-score) was calculated for the PAS stain using methods previously described.11 A t test was performed on the mean diameters of the AMs before and after pioglitazone therapy, as well as the H-score before and after treatment (IBM SPSS Statistics 24.0.0.0). χ2 analysis was performed on the results of the Oil Red O staining. RESULTS The mean AM diameter decreased from 25.64 to 22.38 μm after therapy, representing a 12.7% decrease (P=0.002) (Fig. 1). There was a reduction in number of strongly PAS-positive AMs from 31.8% to 22.2% and increase in number of AMs with no/minimal PAS-positive material from 38.2% to 41.7%, but this did not meet statistical significance (Fig. 2). H-score for the PAS stain was 193.6 before pioglitazone, and decreased to 180.5 after treatment, however, this did not meet statistical significance (P=0.234) (Fig. 2). There was a nonsignificant reduction in proportion of AMs staining Oil Red O positive from 9.9% to 7.5% (P=0.427).FIGURE 1: Graphical representation of cell diameter prepioglitazone and postpioglitazone therapy. Each circle in the scatter plot signifies an individual cell size measurement. The horizontal line demonstrates the mean for the respective sample. AM indicates alveolar macrophage.FIGURE 2: Assessments of AM intracellular glycoprotein content. Clustered bar chart demonstrating fraction of AMs prepioglitazone and postpioglitazone therapy of different PAS stain grade. No statistical difference by H-score. AM indicates alveolar macrophage; H-score, Histochemical score; PAS, Periodic-acid Schiff.DISCUSSION AM size is a simple, although imperfect, marker of the total lipoproteinaceous material that has accumulated in patients with aPAP. We inferred that a significant decrease in the size of AMs may correlate with decrease in accumulation of lipid material within the cells and might therefore represent a decrease in disease severity. In this patient with refractory aPAP, a reduction in AM size was shown after 9 months of treatment with a PPARγ agonist. We believe the decreased AM size was due to improved cholesterol efflux from the cell as this would be consistent with previously published data of PPARγ agonist therapy in a mouse model of PAP.9 It should be noted that both prepioglitazone and postpioglitazone AM size was larger than the previously reported mean size for never-smokers (17.1 µm),12 consistent with aPAP. Despite the decrease in mean cell diameter, no significant change was seen in degree of intracellular PAS-positive material, or lipids seen with Oil Red O stain between samples. Previously rates of Oil Red O positivity of >90% in aPAP has been reported.5 The low proportion of cells staining positive for Oil Red O both pretreatment and posttreatment raises the possibility that the lipoproteinaceous material accumulation was not severe and therefore the fibrosis was the more clinically significant factor. There was neither clinical improvement nor deterioration in the patient’s oxygenation, pulmonary function testing, or subjective reporting of symptoms during this time frame. Starting therapy late after development of significant fibrosis may have minimized the potential for clinical improvement. Whether treatment earlier in his disease course would have led to clinical improvement is unknown. Similarly, it is unknown if pioglitazone prevented this patient from deteriorating further although this remains a possibility. Our paper has several limitations. Only one subject was evaluated and therefore we do not know if this could be reproduced in others. In addition, we do not know the expected changes in mean AM diameter on serial bronchoscopy and the decrease may have been due to normal intertest variability, although we feel this is less likely due to the number of AMs examined. The optimal dose of pioglitazone is not known for this situation, nor if a different dose would have yielded different results. Whether pioglitazone would lead to clinical improvement if used in other patients or at earlier stages of disease is not known. This medication’s use was off-label and no recommendations regarding routine use in aPAP can be made from this data. This report is the first to describe a reduction in AM size in a human patient with aPAP following the administration of a PPARγ agonist. Findings are consistent with prior laboratory and animal research and support the hypothesis that pioglitazone could potentially reduce disease severity in humans with aPAP. A phase 1 study of this drug in humans is underway (ClinicalTrials.gov Identifier: NCT03231033) and should give even more information about this drug as a potential therapy.

Introduction: Smoking cessation activities incorporated into lung cancer screening programs have been broadly recommended, but studies to date have not exhibited increased quit rates associated with cessation programs in this setting. We aimed to determine the long-term effectiveness of smoking cessation counseling in smokers presenting for lung cancer screening. Methods: This was a randomized control trial of an intensive, telephone-based smoking cessation counseling intervention incorporating lung cancer screening results versus usual care (information pamphlet). This analysis reports on the long-term impact (24-mo) of the intervention on abstinence from smoking. Results: A total of 337 active smokers who participated in the screening study were randomized to active smoking cessation counseling (n = 171) or control arm (n = 174) and completed a 24-month assessment. The 30-day smoking abstinence rates at 24 months postrandomization was 18.3% and 21.4% in the control and intervention arms, respectively—a 3.1% difference (95% confidence interval: −5.4 to 11.6, p = 0.48). No statistically significant differences in the 7-day abstinence, the use of pharmacologic cessation aids, nicotine replacement therapies, nor intent to quit in the following 30 days were noted (p > 0.05). The abstinence rates at 24-months were higher overall than at 12-months (19.9% versus 13.3%, p < 0.001), and smoking intensity was lower than at baseline for ongoing smokers. Conclusions: A telephone-based smoking cessation counseling intervention incorporating lung cancer screening results did not result in increased long-term cessation rates versus written information alone in unselected smokers undergoing lung cancer screening. Overall, quit rates were high and continued to improve throughout participation in the screening program. (ClinicalTrials.gov NCT02431962).

Background Proper staging of the mediastinum is an essential component of lung cancer evaluation. Positron emission tomography–computed tomography (PETCT) and endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) are an integral part of this process. False-positive PETCT results can occur following surgical procedures but has not been demonstrated following EBUS-TBNA. We aimed to determine whether false-positive PETCT rates increase when EBUS-TBNA is performed prior to PETCT. Study design and methods A retrospective review was carried out of clinical cases that underwent both PETCT and EBUS-TBNA within 30 days for the suspected malignancy. The impact of test sequence on the PETCT false-positive rate (FPR) was determined using Generalised Estimating Equation logistic regression analysis. Results A total of 675 lymph node stations were sampled and imaged on PETCT. Overall, 332 (49.2%) nodes were sampled by EBUS-TBNA before PETCT, and 343 (50.8%) afterwards, with the interval between EBUS and subsequent PETCT being a mean±sd of 11.6±6.8 days (range 1–29). The FPR on qualitative PETCT for the EBUS first group was 41 (23.2%) out of 164, and for PETCT first it was 57 (29.0%) out of 193 for a difference of 5.8% (95% CI −3.4–14.7, p=0.22). In the regression model, EBUS as the first test was associated with a lower FPR when using the clinical PETCT interpretation. Interpretation The performance of EBUS-TBNA sampling did not influence the FPR of PETCT when bronchoscopy took place in the 30 days prior to testing. Test sequence should be selected based on other clinical considerations.

ObjectivesThe impact of lung cancer screening with low-dose chest CT (LDCT) on participants’ anxiety levels and health-related quality of life (HRQoL) is an important consideration in the implementation of such programmes. We aimed to describe changes in anxiety and HRQoL in a high-risk Canadian cohort undergoing LDCT lung cancer screening.Methods2537 subjects who had 2% or greater lung cancer risk over 6 years using a risk prediction tool were recruited from eight centres across Canada in the Pan-Canadian Early Detection of Lung Cancer Study (2008–2010). We compared HRQoL and anxiety levels before and after screening of 1237 participants with LDCT (excluding a subset of 1300 participants who also underwent autofluorescence bronchoscopy screening), as well as after investigations performed because of a positive screening examination. The 12-item short-form Physical and Mental Component Scales (SF-12), EQ-5D-3L scores and State Trait Anxiety Inventory-State anxiety were used at each assessment.ResultsOverall, there were no clinically significant differences in HRQoL outcomes between baseline and each of the survey time points following initial screening. No mean change in anxiety in the overall cohort was noted following baseline LDCT, but more participants had clinically significant increase in anxiety versus decrease after baseline screening (increase >minimal clinically important difference (MCID) (n=180) vs decrease >MCID (n=50), p<0.001). This finding persisted but to a lesser degree at the 12 month time point (increase >MCID (n=146) vs decrease >MCID (n=87), p<0.001).ConclusionsCT screening for lung cancer has no major overall impact on HRQoL among participants, although a minority of participants (number-needed-to-harm=7 after baseline screening and 18 at 1 year) demonstrated clinically significant increased anxiety levels.Trialregistration numberNCT00751660; Results.