Molecular analysis of endobronchial ultrasound needle aspirates in patients with non-small cell lung cancer: Results from the SCOPE database.

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.

Patient perspectives on the use of indwelling pleural catheters in malignant pleural effusions.

BACKGROUND: Indwelling pleural catheters are an effective treatment option for patients with malignant pleural effusions. Despite their popularity, there remains a paucity of data on the patient experience and key patient-centred outcomes. OBJECTIVE: To investigate the experience of patients receiving an indwelling pleural catheter to better inform and identify potential areas for improvement in care. METHODS: This was a multicentre survey study at three academic, tertiary-care centres in Canada. Patients with a diagnosis of malignant pleural effusion who had an indwelling pleural catheter inserted were included. An adapted questionnaire specific to indwelling pleural catheters was used with responses recorded on a 4-point Likert scale. Patients completed the questionnaire in-person or by phone at 2-week and 3-month follow-up appointments. RESULTS: A total of 105 patients were enrolled in the study with 84 patients included in the final analysis. At the 2-week follow-up, patient-reported improvements in dyspnoea and quality of life from indwelling pleural catheter were high at 93% and 87%, respectively. The predominant issues identified were discomfort at time of insertion (58%), itching (49%), difficulty with sleeping (39%), discomfort with home drainage (36%) and the pleural catheter reminding patients of their disease (63%). Avoiding hospitalisation for the management of dyspnoea was important to 95% of patients. Findings were similar at 3 months. CONCLUSIONS: Indwelling pleural catheters are an effective intervention to directly improve dyspnoea and quality of life but have important disadvantages for some; clinicians and patients should be aware of these when making an informed decision regarding treatment.

Combination Tissue Plasminogen Activator and DNase for Loculated Malignant Pleural Effusions: A Single-center Retrospective Review.

BACKGROUND: Indwelling pleural catheters (IPCs) are frequently used for the management of malignant pleural effusions (MPEs), but drainage can be impaired by pleural loculations. We aimed to evaluate the safety and effectiveness of intrapleural tissue plasminogen activator (tPA) versus combination tPA-deoxyribonuclease (DNase) in the treatment of loculated MPE. METHODS: We performed a retrospective review of patients with confirmed or presumed MPEs requiring IPC insertion. We compared the efficacy of intrapleural tPA, tPA-DNase, and procedural intervention on pleural fluid drainage. Secondary endpoints included the need for future pleural procedures (eg, thoracentesis, IPC reinsertion, chest tube insertion, or surgical intervention), IPC removal due to spontaneous pleurodesis, and IPC-related complications. RESULTS: Among 437 patients with MPEs, loculations developed in 81 (19%) patients. Twenty-four (30%) received intrapleural tPA, 46 (57%) received intrapleural tPA-DNase, 4 (5%) underwent a procedural intervention, and 7 (9%) received ongoing medical management. tPA improved pleural drainage in 83% of patients, and tPA-DNase improved pleural drainage in 80% of patients. tPA alone may be associated with increased rates of spontaneous pleurodesis compared with tPA-DNase. There was no difference in complications when comparing tPA, combination tPA-DNase, procedural intervention, and no therapy. CONCLUSION: Both intrapleural tPA and combination tPA-DNase appear to be safe and effective in improving pleural fluid drainage in selected patients with loculated MPE, although further studies are needed.

Effect of chemotherapy, immunotherapy, and targeted therapies on removal of indwelling pleural catheters in non-small cell lung cancer patients with malignant pleural effusions.

BACKGROUND: Indwelling pleural catheters (IPCs) are a mainstay therapy for malignant pleural effusions (MPEs). Many patients treated with IPCs achieve pleurodesis. We aimed to identify the effect of systemic therapies for non-small cell lung cancer (NSCLC) on IPC removal in patients with associated MPEs. METHODS: We completed a retrospective cohort study of adult IPC recipients with metastatic NSCLC at the pleural effusion clinic at the Royal Alexandra Hospital from 2009 to 2020. We used logistic regression to assess the rates of IPC removal and Cox regression to assess the time to IPC removal. RESULTS: 232 patients met inclusion criteria with 248 IPCs reviewed. The overall pleurodesis rate was 42.7% with a median time to pleurodesis of 68 (IQR 38-140) days. In univariate analysis, chemotherapy (OR 1.86, CI 0.99-3.49) and epidermal growth factor receptor (EGFR) targeted therapy (OR 3.81, CI 1.86-7.79) were associated with higher rates of pleurodesis. In multivariate analysis, increased rates of pleurodesis were associated with an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of ≤2 (OR 4.82, CI 2.24-10.37) and EGFR targeted therapy (OR 3.87, CI 1.80-8.32). Earlier IPC removal was associated with EGFR targeted therapy in both univariate (HR 1.84, CI 1.20-2.83) and multivariate analysis (HR 1.86, CI 1.19-2.92). CONCLUSIONS: Treatment with EGFR targeted therapy is associated with increased rates and earlier removal of IPC in patients with NSCLC in our cohort. Further large cohort studies are required to determine if this relationship persists.

Endobronchial Ultrasound Transbronchial Needle Aspiration With a 19-Gauge Needle vs 21- and 22-Gauge Needles for Mediastinal Lymphadenopathy.

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 performed. 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.

Protocol for the Stather Canadian Outcomes Registry for Chest ProcedurEs (SCOPE).

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.

Organizing pneumonia associated with T-cell lymphoma.

A 61-year-old male with a history of coeliac disease was diagnosed with organizing pneumonia (OP) on transbronchial and transthoracic lung biopsies. He then developed refractory coeliac disease type II and haemophagocytic lymphohistiocytosis. Nine months after his initial diagnosis of OP and after multiple biopsies of the lung, duodenum, and bone marrow, he was diagnosed with enteropathy-associated T-cell lymphoma (EATL). Although OP in patients with lymphoma is most commonly attributed to chemotherapeutic agents or bone marrow transplant, it may be seen in the absence of prior anticancer treatment. The mechanism linking OP and lymphoma is unclear but OP could represent a syndrome of T-cell dysfunction or develop as a direct reaction to malignant infiltration of the lung. In patients with atypical presentations, exclusion of an alternate diagnosis must be pursued using surgical lung biopsy, wherever possible. This is the first reported case of OP associated with EATL.

Development of Learning Curves for Bronchoscopy: Results of a Multicenter Study of Pulmonary Trainees.

BACKGROUND: There are currently no reference standards for the development of competence in bronchoscopy. RESEARCH QUESTION: The aims of this study were to (1) develop learning curves for bronchoscopy skill development and (2) estimate the number of bronchoscopies required to achieve competence. STUDY DESIGN AND METHODS: Trainees from seven North American academic centers were enrolled at the beginning of their pulmonology training. Performance during clinical bronchoscopies was assessed by supervising physicians using the Ontario Bronchoscopy Assessment Tool (OBAT). Group-level learning curves were modeled using a quantile regression growth model, where the dependent variable was the mean OBAT score and the independent variable was the number of bronchoscopies performed at the time the OBAT was completed. RESULTS: A total of 591 OBAT assessments were collected from 31 trainees. The estimated regression quantiles illustrate significantly different learning curves based on trainees' performance percentiles. When competence was defined as the mean OBAT score for all bronchoscopies rated as being completed without need for supervision, the mean OBAT score associated with competence was 4.54 (95% CI, 4.47-4.58). Using this metric, the number of bronchoscopies required to achieve this score varied from seven to 10 for the 90th percentile of trainees and from 109 to 126 for the lowest 10th percentile of trainees. When competence was defined as the mean OBAT score for the first independent bronchoscopy, the mean was 4.40 (95% CI, 4.20-4.60). On the basis of this metric, the number of bronchoscopies required varied from one to 11 for the 90th percentile of trainees and from 83 to 129 for the lowest 10th percentile of trainees. INTERPRETATION: We were able to generate learning curves for bronchoscopy across a range of trainees and centers. Furthermore, we established the average number of bronchoscopies required for the attainment of competence. This information can be used for purposes of curriculum planning and allows a trainee's progress to be compared with an established norm.

Sarcoidosis: a prospective observational cohort from Northern Alberta.

INTRODUCTION: Sarcoidosis is a multi-system disease reported to occur with a higher incidence in Alberta than many other health jurisdictions within and outside of Canada. The reasons for this higher incidence are currently not known. Exposure to beryllium can result in a clinically and radiologically identical disease to sarcoidosis. The purpose of our study was to identify patterns with potential occupational or environmental exposures to beryllium amongst individuals with sarcoidosis in Alberta through a tertiary referral center. METHODS: A prospective observational study was carried out at the University of Alberta Hospital. Patients with confirmed sarcoidosis (stages 0-4) were recruited from subspecialty clinics (Respirology, Cardiology, Neurology and Occupational Health). A predetermined list of industries thought to involve potentially relevant exposures for the development of sarcoidosis was used to capture current and previous exposure history. Results were entered into a database and where possible verified by comparing with existing electronic medical records (including histories, physical examination, diagnostic imaging and physiology). RESULTS: A total of 45 patients were recruited, 25 men and 20 women. Of these, 84% of participants reported working in or being exposed to an industry/environment suspected of contributing to development of sarcoidosis over their lifetime. The most frequently reported exposures were within farming and agriculture (27%), oil and gas (20%), metalworking and handling animals (18%). CONCLUSIONS: Amongst this cohort, a high proportion reported working with a potentially relevant exposure. Individuals being assessed for sarcoidosis should have their most responsible physician elicit a detailed work and environmental history. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (4): e2020014).

Tobacco use and motivation to stop smoking among long-term smokers who are ineligible for lung cancer screening.

BACKGROUND: The importance of smoking cessation interventions in lung cancer screening participants has been highlighted. This study aimed to describe the smoking habits of individuals who were ineligible for lung cancer screening and to investigate whether this encounter may represent an opportunity to reduce tobacco use. METHODS: Ever smokers between the ages of 55 and 80 and ≥1.5% lung cancer risk over 6 years or having smoked ≥30 pack-years and with no more than 15 years of smoking abstinence were eligible to participate in the Alberta Lung Cancer Screening Program (ALCSP). A baseline questionnaire exploring tobacco use was administered to all interested individuals as part of the eligibility determination for the program. RESULTS: Among 504 individuals, 254 (50.4%) met the criteria for the ALCSP and 250 (49.6%) were non-eligible for screening. Non-eligible individuals were slightly younger (mean=60.2 vs. 63.1 years, p-value <0.001), and less likely to be current smokers (26.0% vs. 48.8%, p-value <0.001). Non-eligible smokers had a lower degree of addiction compared to eligible group, as measured by the Fagerström Test of Nicotine Dependence (Median=4.0 vs 6.0, p-value=0.001), but still in the "moderately dependent" range for this test. There were no significant differences in motivation to quit (98.5% vs. 97.6%, p-value=0.689), or motivation to receive help with their quit attempt (89.2% vs. 90.3%, p-value=0.813) between these two groups. Only 7.7% of non-eligible and 2.4% of eligible current smokers were currently in a smoking cessation program. CONCLUSION: A significant proportion of individuals applying to, but not qualifying for a lung cancer screening program are active smokers with significant nicotine dependence. Very few are currently participating in active smoking cessation programs but almost all are interested in quitting and in receiving help with quit attempts. Future studies need to investigate the most effective approaches for smoking cessation in this substantial group of older, long-term smokers, capitalizing on their motivation to receive cessation assistance.

The role of steric effects in the direct mutagenicity of N-acyloxy-N-alkoxyamides.

Electrophilic N-acyloxy-N-alkoxyamides are mutagenic in Salmonella typhimurium TA100 without the need for S9 metabolic activation and they react with DNA at guanine-N7 at physiological pH. Since these are direct-acting mutagens, structural factors influence binding and reactivity with DNA. Mutagenicity in TA100 can be predicted by a QSAR incorporating hydrophobicity (logP), stability to substitution reactions at nitrogen (pK(a) of the leaving acid) and steric effects of para-aryl substituents (E(s)). A number of mutagens exhibit activities that deviate markedly from the predicted values and they fall into two classes: di-tert-butylated N-benzoyloxy-N-benzyloxybenzamides, which--because of their size--are most probably excluded from the major groove or are unable to achieve a transition state for reaction with DNA, and N-benzoyloxy-N-butoxyalkylamides with branching alpha-to the amide carbonyl, which are resistant to S(N)2 reactions at the amide nitrogen.

Crystal structures and properties of mutagenic N-acyloxy-N-alkoxyamides--"most pyramidal" acyclic amides.

X-Ray data for two N-acyloxy-N-alkoxyamides, a class of direct-acting mutagens, indicate extreme pyramidalisation at the amide nitrogen in keeping with spectroscopic and theoretically determined properties of amides with bisoxosubstitution at nitrogen. The combined electronegativity of two oxygens leads to average angles at nitrogen of 107.8 and 108.1 degrees and [chiN] of 66 degrees and 65 degrees. The sp3 nature of nitrogen results in negligible amide resonance as evidenced by long N-C(O) bonds, high IR carbonyl stretch frequencies, carbonyl 13C NMR data and very low amide isomerisation barriers. In addition, conformations in the solid state support a strong n(O)-sigma*(NOAc), anomeric interaction as predicted by molecular orbital theory. HF/6-31G* calculations on formamide, N-methoxyformamide and N-formyloxy-N-methoxyformamide support these findings.