Causes of and Clinical Features Associated with Death in Tobacco Cigarette Users by Lung Function Impairment.

Rationale: Cigarette smoking contributes to the risk of death through different mechanisms. Objectives: To determine how causes of and clinical features associated with death vary in tobacco cigarette users by lung function impairment. Methods: We stratified current and former tobacco cigarette users enrolled in Genetic Epidemiology of Chronic Obstructive Pulmonary Disease (COPDGene) into normal spirometry, PRISm (Preserved Ratio Impaired Spirometry), Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1-2 COPD, and GOLD 3-4 COPD. Deaths were identified via longitudinal follow-up and Social Security Death Index search. Causes of death were adjudicated after a review of death certificates, medical records, and next-of-kin interviews. We tested associations between baseline clinical variables and all-cause mortality using multivariable Cox proportional hazards models. Measurements and Main Results: Over a 10.1-year median follow-up, 2,200 deaths occurred among 10,132 participants (age 59.5 ± 9.0 yr; 46.6% women). Death from cardiovascular disease was most frequent in PRISm (31% of deaths). Lung cancer deaths were most frequent in GOLD 1-2 (18% of deaths vs. 9-11% in other groups). Respiratory deaths outpaced competing causes of death in GOLD 3-4, particularly when BODE index ⩾7. St. George's Respiratory Questionnaire score ⩾25 was associated with higher mortality in all groups: Hazard ratio (HR), 1.48 (1.20-1.84) normal spirometry; HR, 1.40 (1.05-1.87) PRISm; HR, 1.80 (1.49-2.17) GOLD 1-2; HR, 1.65 (1.26-2.17) GOLD 3-4. History of respiratory exacerbations was associated with higher mortality in GOLD 1-2 and GOLD 3-4, quantitative emphysema in GOLD 1-2, and airway wall thickness in PRISm and GOLD 3-4. Conclusions: Leading causes of death vary by lung function impairment in tobacco cigarette users. Worse respiratory-related quality of life is associated with all-cause mortality regardless of lung function.

Longitudinal associations between exclusive, dual, and polytobacco use and asthma among US youth.

Little is known about the respiratory health effects of dual (two products) and polytobacco (three or more products) use among youth in the United States. Thus, we followed a longitudinal cohort of youth into adulthood using data from Waves 1-5 (2013-2019) of the Population Assessment of Tobacco and Health Study, examining incident asthma at each follow-up (Waves 2-5). We classified past 30-day tobacco use as 1) no products (never/former use), 2) exclusive cigarettes, 3) exclusive electronic nicotine delivery systems (ENDS), 4) exclusive other combustible (OC) tobacco products (cigars, hookah, pipe), 5) dual cigarettes/OC and ENDS, 6) dual cigarettes and OCs, and 7) polytobacco use (cigarettes, OCs, and ENDS). Using discrete time survival models, we analyzed the incidence of asthma across Waves 2-5, predicted by time-varying tobacco use lagged by one wave, and adjusted for potential baseline confounders. Asthma was reported by 574 of the 9141 respondents, with an average annual incidence of 1.44% (range 0.35% to 2.02%, Waves 2-5). In adjusted models, exclusive cigarette use (HR: 1.71, 95% CI: 1.11-2.64) and dual cigarette and OC use (HR: 2.78, 95% CI: 1.65-4.70) were associated with incident asthma compared to never/former use, while exclusive ENDS use (HR: 1.50, 95% CI: 0.92-2.44) and polytobacco use (HR: 1.95, 95% CI: 0.86-4.44) were not. To conclude, youth who use cigarettes with or without OCs had higher risk of incident asthma. Further longitudinal studies on the respiratory health effects of ENDS and dual/polytobacco use are needed as products continue to evolve.

Treatment capacity required for full-scale implementation of lung cancer screening in the United States.

BACKGROUND: Full-scale implementation of lung cancer screening in the United States will increase detection of early stages. This study was aimed at assessing the capacity required for treating those cancers. METHODS: A well-established microsimulation model was extended with treatment data from the National Cancer Database. We assessed how treatment demand would change when implementing lung cancer screening in 2018. Three policies were assessed: 1) annual screening of current smokers and former smokers who quit fewer than 15 years ago, aged 55 to 80 years, with a smoking history of at least 30 pack-years (US Preventive Services Task Force [USPSTF] recommendations); 2) annual screening of current smokers and former smokers who quit fewer than 15 years ago, aged 55 to 77 years, with a smoking history of at least 30 pack-years (Centers for Medicare and Medicaid Services [CMS] recommendations); and 3) annual screening of current smokers and former smokers who quit fewer than 10 years ago, aged 55 to 75 years, with a smoking history of at least 40 pack-years (the most cost-effective policy in Ontario [Ontario]). The base-case screening adherence was a constant 50%. Sensitivity analyses assessed other adherence levels, including a linear buildup to 50% between 2018 and 2027. RESULTS: The USPSTF policy would require 37.0% more lung cancer surgeries in 2015-2040 than no screening, 2.2% less radiotherapy, and 5.4% less chemotherapy; 5.7% more patients would require any therapy. The increase in surgical demand would be 96.1% in 2018, 46.0% in 2023, 38.3% in 2028, and 24.9% in 2040. Adherence strongly influenced results. By 2018, surgical demand would range from 52,619 (20% adherence) to 96,121 (80%). With a gradual buildup of adherence, the increase in surgical demand would be 9.6% in 2018, 38.3% in 2023, 42.0% in 2028, and 24.4% in 2040. Results for the CMS and Ontario policies were similar, although the changes in comparison with no screening were smaller. CONCLUSIONS: Full-scale implementation of lung cancer screening causes a major increase in surgical demand, with a peak within the first 5 years. A gradual buildup of adherence can spread this peak over time. Careful surgical capacity planning is essential for successfully implementing screening.

RNAseq analysis of bronchial epithelial cells to identify COPD-associated genes and SNPs.

BACKGROUND: There is a need for more powerful methods to identify low-effect SNPs that contribute to hereditary COPD pathogenesis. We hypothesized that SNPs contributing to COPD risk through cis-regulatory effects are enriched in genes comprised by bronchial epithelial cell (BEC) expression patterns associated with COPD. METHODS: To test this hypothesis, normal BEC specimens were obtained by bronchoscopy from 60 subjects: 30 subjects with COPD defined by spirometry (FEV1/FVC < 0.7, FEV1% < 80%), and 30 non-COPD controls. Targeted next generation sequencing was used to measure total and allele-specific expression of 35 genes in genome maintenance (GM) genes pathways linked to COPD pathogenesis, including seven TP53 and CEBP transcription factor family members. Shrinkage linear discriminant analysis (SLDA) was used to identify COPD-classification models. COPD GWAS were queried for putative cis-regulatory SNPs in the targeted genes. RESULTS: On a network basis, TP53 and CEBP transcription factor pathway gene pair network connections, including key DNA repair gene ERCC5, were significantly different in COPD subjects (e.g., Wilcoxon rank sum test for closeness, p-value = 5.0E-11). ERCC5 SNP rs4150275 association with chronic bronchitis was identified in a set of Lung Health Study (LHS) COPD GWAS SNPs restricted to those in putative regulatory regions within the targeted genes, and this association was validated in the COPDgene non-hispanic white (NHW) GWAS. ERCC5 SNP rs4150275 is linked (D' = 1) to ERCC5 SNP rs17655 which displayed differential allelic expression (DAE) in BEC and is an expression quantitative trait locus (eQTL) in lung tissue (p = 3.2E-7). SNPs in linkage (D' = 1) with rs17655 were predicted to alter miRNA binding (rs873601). A classifier model that comprised gene features CAT, CEBPG, GPX1, KEAP1, TP73, and XPA had pooled 10-fold cross-validation receiver operator characteristic area under the curve of 75.4% (95% CI: 66.3%-89.3%). The prevalence of DAE was higher than expected (p = 0.0023) in the classifier genes. CONCLUSIONS: GM genes comprised by COPD-associated BEC expression patterns were enriched for SNPs with cis-regulatory function, including a putative cis-rSNP in ERCC5 that was associated with COPD risk. These findings support additional total and allele-specific expression analysis of gene pathways with high prior likelihood for involvement in COPD pathogenesis.

An official American Thoracic Society/American College of Chest Physicians policy statement: implementation of low-dose computed tomography lung cancer screening programs in clinical practice.

RATIONALE: Annual low-radiation-dose computed tomography (LDCT) screening for lung cancer has been shown to reduce lung cancer mortality among high-risk individuals and is now recommended by multiple organizations. However, LDCT screening is complex, and implementation requires careful planning to ensure benefits outweigh harms. Little guidance has been provided for sites wishing to develop and implement lung cancer screening programs. OBJECTIVES: To promote successful implementation of comprehensive LDCT screening programs that are safe, effective, and sustainable. METHODS: The American Thoracic Society (ATS) and American College of Chest Physicians (ACCP) convened a committee with expertise in lung cancer screening, pulmonary nodule evaluation, and implementation science. The committee reviewed the evidence from systematic reviews, clinical practice guidelines, surveys, and the experience of early-adopting LDCT screening programs and summarized potential strategies to implement LDCT screening programs successfully. MEASUREMENTS AND MAIN RESULTS: We address steps that sites should consider during the main three phases of developing an LDCT screening program: planning, implementation, and maintenance. We present multiple strategies to implement the nine core elements of comprehensive lung cancer screening programs enumerated in a recent ACCP/ATS statement, which will allow sites to select the strategy that best fits with their local context and workflow patterns. Although we do not comment on cost-effectiveness of LDCT screening, we outline the necessary costs associated with starting and sustaining a high-quality LDCT screening program. CONCLUSIONS: Following the strategies delineated in this policy statement may help sites to develop comprehensive LDCT screening programs that are safe and effective.

Endobronchial ultrasound-guided transbronchial needle aspiration for non-small cell lung cancer staging.

Real-time endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is an established technique for invasive mediastinal staging of non-small cell lung cancer (NSCLC). Needle-based techniques are now recommended as a first-line diagnostic modality for mediastinal staging. Accurate performance of systematic staging with EBUS-TBNA requires a detailed knowledge of mediastinal anatomy. This examination begins at the N3 lymph nodes, progressing through the N2 and N1 lymph node stations, unless a higher station lymph node is positive for malignant cells by rapid on-site cytologic examination. Objective methods of identifying EBUS-TBNA targets include sampling any lymph node station with a visible lymph node or with a lymph node greater than 5 mm in short axis. Three passes per station or the use of rapid on-site cytologic examination with identification of diagnostic material (tumor or lymphocytes) up to five passes are well-established techniques. Obtaining sufficient tissue for molecular profiling may require performing more than three passes. The operating characteristics of EBUS-TBNA are similar to mediastinoscopy. However, mediastinoscopy should be considered in the setting of a negative EBUS-TBNA and a high posterior probability of N2 or N3 involvement.

Phase II Trial Assessing Toxicity of Personalized Response-Based Radiation Treatment in Patients with Locally Advanced Non-Small Cell Lung Cancer.

INTRODUCTION: Local failure rates after treatment for locally advanced non-small-cell lung cancer (NSCLC) remain high. Efforts to improve local control with uniform dose-escalation or dose-escalation to mid-treatment PET-avid residual disease have been limited by heightened toxicity. This trial aimed to refine response-based adaptive radiation (RT) and minimize toxicity by incorporating FDG-PET and V/Q SPECT imaging mid-treatment. METHODS: 47 patients with Stage IIA-III unresectable NSCLC were prospectively enrolled in this single-institution trial (NCT02492867). Patients received concurrent chemoradiation with personalized response-based adaptive RT over 30 fractions incorporating V/Q SPECT and FDG-PET. The first 21 fractions (46.2Gy at 2.2 Gy/fraction) were delivered to the tumor while minimizing dose to SPECT-defined functional lung. The plan was then adapted for the final 9 fractions (2.2-3.8Gy/fraction) up to a total of 80.4Gy, based on mid-treatment FDG-PET tumor response to escalate dose to residual tumor while minimizing dose to SPECT-defined functional lung. Non-progressing patients received consolidative carboplatin/paclitaxel or durvalumab. The primary endpoint of the study was ≥ grade 2 lung and esophageal toxicities. Secondary endpoints included time to local progression, tumor response, and overall survival. RESULTS: At one year post-treatment, the rates of grade 2 and grade 3 pneumonitis were 21.3% and 2.1%, respectively, with no difference in pneumonitis rates among patients who received and did not receive adjuvant durvalumab (p=0.74). While there were no grade 3 esophageal-related toxicities, 66.0% of patients experienced grade 2 esophagitis. 1- and 2-year local control rates were 94.5% (95% CI, 87.4% - 100%) and 87.5% (95% CI, 76.7% - 100%), respectively. Overall survival was 82.8% (95% CI, 72.6% -94.4%) at 1 year and 62.3% (95% CI, 49.6%-78.3%) at 2 years. CONCLUSIONS: Response-based adaptive dose-escalation accounting for tumor change and normal tissue function during treatment provided excellent local control, comparable toxicity to standard chemoradiation, and did not increase toxicity with adjuvant immunotherapy.

Lung CD8+ T cells in COPD have increased expression of bacterial TLRs.

BACKGROUND: Toll-like receptors (TLRs) on T cells can modulate their responses, however, the extent and significance of TLR expression by lung T cells, NK cells, or NKT cells in chronic obstructive pulmonary disease (COPD) is unknown. METHODS: Lung tissue collected from clinically-indicated resections (n = 34) was used either: (a) to compare the expression of TLR1, TLR2, TLR2/1, TLR3, TLR4, TLR5, TLR6 and TLR9 on lung CD8+ T cells, CD4+ T cells, NK cells and NKT cells from smokers with or without COPD; or (b) to isolate CD8+ T cells for culture with anti-CD3ε without or with various TLR ligands. We measured protein expression of IFN-γ, TNF-α, IL-13, perforin, granzyme A, granzyme B, soluble FasL, CCL2, CCL3, CCL4, CCL5, CCL11, and CXCL9 in supernatants. RESULTS: All the lung subsets analyzed demonstrated low levels of specific TLR expression, but the percentage of CD8+ T cells expressing TLR1, TLR2, TLR4, TLR6 and TLR2/1 was significantly increased in COPD subjects relative to those without COPD. In contrast, from the same subjects, only TLR2/1 and TLR2 on lung CD4+ T cells and CD8+ NKT cells, respectively, showed a significant increase in COPD and there was no difference in TLR expression on lung CD56+ NK cells. Production of the Tc1 cytokines IFN-γ and TNF-α by lung CD8+ T cells were significantly increased via co-stimulation by Pam3CSK4, a specific TLR2/1 ligand, but not by other agonists. Furthermore, this increase in cytokine production was specific to lung CD8+ T cells from patients with COPD as compared to lung CD8+ T cells from smokers without COPD. CONCLUSIONS: These data suggest that as lung function worsens in COPD, the auto-aggressive behavior of lung CD8+ T cells could increase in response to microbial TLR ligands, specifically ligands against TLR2/1.

Temporal Trends and Variation in Bronchoscopy Use for Acute Respiratory Failure in the United States.

BACKGROUND: National data on bronchoscopy for the evaluation of acute respiratory failure are lacking, and the limited available data suggest wide variation in use. RESEARCH QUESTION: How commonly is bronchoscopy performed among hospitalizations with acute respiratory failure? How has use changed over time and across hospitals? STUDY DESIGN AND METHODS: This was an observational cohort study of adult hospitalizations (2012-2018) treated with invasive mechanical ventilation (IMV) using the National Inpatient Sample, which represents 97% of all hospitalizations in the United States. We measured the proportion of hospitalizations treated with IMV who underwent bronchoscopy and assessed trends in bronchoscopy use over time. Multilevel linear regression models were used to quantify hospital-level variation, adjusting for differences in patient and hospital characteristics. RESULTS: We identified 6,101,070 IMV-treated hospitalizations (2012-2018), of whom 609,405 underwent bronchoscopy; among hospitalizations receiving bronchoscopy, mean age was 61 years, 41.8% were women, and in-hospital mortality was 30.8%. The percentage of IMV-treated hospitalizations receiving bronchoscopy increased from 9.5% (95% CI, 9.1%-9.9%) in 2012 to 10.8% (95% CI, 10.4%-11.2%) in 2018 (P < .001 for difference). In 2018, bronchoscopy use varied from 0% to 57.1% among 1,787 hospitals, and in multilevel models adjusted for patient and hospital characteristics, 16.0% of the variation was explained at the hospital level. The median OR was 2.13 (95% CI, 2.05-2.21), indicating 113% increased odds of receiving bronchoscopy if moving from a lower-use to a higher-use hospital. INTERPRETATION: Bronchoscopy use among hospitalizations treated with IMV has increased over time. The large variation in use of bronchoscopy across hospitals suggests potentially unwarranted practice variation and need for further studies to clarify which patients benefit from bronchoscopy.

Longitudinal Association Between Exclusive and Dual Use of Cigarettes and Electronic Nicotine Delivery Systems and Asthma Among U.S. Adolescents.

PURPOSE: Electronic Nicotine Delivery Systems (ENDS) use among adolescents has increased greatly over the past decade, but its impact on chronic respiratory health conditions, like asthma, is not fully understood. METHODS: We examined data from Waves 1-5 (2013-2019) of the Population Assessment of Tobacco and Health Study using discrete time hazard models to analyze the association between time-varying tobacco product use and incident diagnosed asthma among adolescents aged 12-17 years at baseline. We lagged the time-varying exposure variable by one wave and categorized respondents by current use status (1+ days in the past 30 days): never or non-current, exclusive cigarette, exclusive ENDS, and dual cigarette and ENDS use. We also controlled for sociodemographic (age, sex, race/ethnicity, parental education) and other risk factors (urban/rural setting, secondhand smoke exposure, household combustible tobacco use, body mass index). RESULTS: At baseline, over half the analytic sample (n = 9,141) was 15-17 years old (50.4%), female (50.2%), and non-Hispanic White (55.3%). Adolescents who exclusively smoked cigarettes had a statistically significant higher risk of incident diagnosed asthma at follow-up (adjusted Hazard Ratio (aHR): 1.68, 95% confidence interval (CI): 1.21-2.32) compared to those not currently using cigarettes or ENDS, but adolescents using ENDS exclusively (aHR: 1.25, 95% CI: 0.77-2.04) or in combination with cigarettes (aHR: 1.54, 95% CI: 0.92-2.57) did not. DISCUSSION: Short-term exclusive cigarette use was associated with a higher risk of incident diagnosed asthma over five years of follow-up among adolescents. We did not find conclusive evidence for an association between exclusive ENDS or dual use and incident diagnosed asthma.

Cigarettes, ENDS Use, and Chronic Obstructive Pulmonary Disease Incidence: A Prospective Longitudinal Study.

INTRODUCTION: Understanding the relationship between ENDS use and chronic obstructive pulmonary disease (COPD) and other respiratory conditions is critical. However, most previous studies have not fully adjusted for cigarette smoking history. METHODS: Using Waves 1-5 of the U.S. Population Assessment of Tobacco and Health study, the association between ENDS use and self-reported incident COPD was examined among adults aged 40+ years using discrete-time survival models. Current ENDS use was measured as a time-varying covariate, lagged by 1 wave, defined as established daily or some days of use. Multivariable models were adjusted for baseline demographics (age, sex, race/ethnicity, education), health characteristics (asthma, obesity, exposure to second-hand smoke), and smoking history (smoking status and cigarette pack years). Data were collected between 2013 and 2019, and the analysis was conducted in 2021-2022. RESULTS: Incident COPD was self-reported by 925 respondents during the 5-year follow-up. Before adjusting for other covariates, time-varying ENDS use appeared to double COPD incidence risk (hazard ratio=1.98, 95% CI=1.44, 2.74). However, ENDS use was no longer associated with COPD (adjusted hazard ratio=1.10, 95% CI=0.78, 1.57) after adjusting for current cigarette smoking and cigarette pack years. CONCLUSIONS: ENDS use did not significantly increase the risk of self-reported incident COPD over a 5-year period once current smoking status and cigarette pack years were included. Cigarette pack years, by contrast, remained associated with a net increase in COPD incidence risk. These findings highlight the importance of using prospective longitudinal data and adequately controlling for cigarette smoking history to assess the independent health effects of ENDS.

ENDS, Cigarettes, and Respiratory Illness: Longitudinal Associations Among U.S. Youth.

INTRODUCTION: ENDS use is highly prevalent among U.S. youth, and there is concern about its respiratory health effects. However, evidence from nationally representative longitudinal data is limited. METHODS: Using youth (aged 12-17 years) data from Waves 1-5 (2013-2019) of the Population Assessment of Tobacco and Health Study, multilevel Poisson regression models were estimated to examine the association between ENDS use; cigarettes; and diagnosed bronchitis, pneumonia, or chronic cough. Current product use was lagged by 1 wave and categorized as (1) never/noncurrent use, (2) exclusive cigarette use, (3) exclusive ENDS use, and (4) dual ENDS/cigarette use. Multivariable models adjusted for age, sex, race and ethnicity; parental education; asthma; BMI; cannabis use; secondhand smoke exposure; and household use of combustible products. Data analysis was conducted in 2022-2023. RESULTS: A total of 7.4% of respondents were diagnosed with bronchitis, pneumonia, or chronic cough at follow-up. In the multivariable model, exclusive cigarette use (incident rate ratio=1.85, 95% CI=1.29, 2.65), exclusive ENDS use (incident rate ratio=1.49, 95% CI=1.06, 2.08), and dual use (incident rate ratio=2.70, 95% CI=1.61, 3.50) were associated with a higher risk of diagnosed bronchitis, pneumonia, or chronic cough than never/noncurrent use. CONCLUSIONS: These results suggest that ENDS and cigarettes, used exclusively or jointly, increased the risk of diagnosed bronchitis, pneumonia, or chronic cough among U.S. youth. However, dual use was associated with the highest risk. Targeted policies aimed at continuing to reduce cigarette smoking and ENDS use among youth, especially among those with dual use, are needed.

Cytotoxic potential of lung CD8(+) T cells increases with chronic obstructive pulmonary disease severity and with in vitro stimulation by IL-18 or IL-15.

Lung CD8(+) T cells might contribute to progression of chronic obstructive pulmonary disease (COPD) indirectly via IFN-gamma production or directly via cytolysis, but evidence for either mechanism is largely circumstantial. To gain insights into these potential mechanisms, we analyzed clinically indicated lung resections from three human cohorts, correlating findings with spirometrically defined disease severity. Expression by lung CD8(+) T cells of IL-18R and CD69 correlated with severity, as did mRNA transcripts for perforin and granzyme B, but not Fas ligand. These correlations persisted after correction for age, smoking history, presence of lung cancer, recent respiratory infection, or inhaled corticosteroid use. Analysis of transcripts for killer cell lectin-like receptor G1, IL-7R, and CD57 implied that lung CD8(+) T cells in COPD do not belong to the terminally differentiated effector populations associated with chronic infections or extreme age. In vitro stimulation of lung CD8(+) T cells with IL-18 plus IL-12 markedly increased production of IFN-gamma and TNF-alpha, whereas IL-15 stimulation induced increased intracellular perforin expression. Both IL-15 and IL-18 protein expression could be measured in whole lung tissue homogenates, but neither correlated in concentration with spirometric severity. Although lung CD8(+) T cell expression of mRNA for both T-box transcription factor expressed in T cells and GATA-binding protein 3 (but not retinoic acid receptor-related orphan receptor gamma or alpha) increased with spirometric severity, stimulation of lung CD8(+) T cells via CD3epsilon-induced secretion of IFN-gamma, TNF-alpha, and GM-CSF, but not IL-5, IL-13, and IL-17A. These findings suggest that the production of proinflammatory cytokines and cytotoxic molecules by lung-resident CD8(+) T cells contributes to COPD pathogenesis.

Prevalence and consequences of non-adherence to an evidence-based approach for incidental pulmonary nodules.

IMPORTANCE: Distinguishing benign from malignant pulmonary nodules is challenging. Evidence-based guidelines exist, but their impact on patient-centered outcomes is unknown. OBJECTIVE: To understand if the evaluation of incidental pulmonary nodules that follows an evidence-based management strategy is associated with fewer invasive procedures for benign lesions and/or fewer delays in cancer diagnosis. DESIGN: Retrospective cohort study. SETTING: Large academic medical center. PARTICIPANTS: Adults (≥18 years age) with an incidental pulmonary nodule discovered between January 2012 and December 2014. Patients with calcified nodules, prior nodules, prior diagnosis of cancer, high suspicion for pulmonary metastasis, or limited life expectancy were excluded. EXPOSURE: Nodule management strategy (pre-specified based on evidence-based practices). OUTCOME: Composite of any invasive procedure for a benign nodule or delay in diagnosis in patients with cancer (>3 month delay once probability of cancer was >15%). RESULTS: Of 314 patients that met inclusion criteria, median age was 61, 46.5% were men, and 66.5% had current or former tobacco use. The mean nodule size was 10.3 mm, mean probability of cancer was 11.8%, and 14.3% of nodules were malignant. Evaluation followed an evidence-based strategy in 245 patients (78.0%), and deviated in 69 patients (22%). The composite outcome occurred in 26 (8.3%) patients. Among patients whose nodule evaluation was concordant with an evidence-based evaluation, 6.1% (15/245) experienced the composite outcome versus 15.9% (11/69) of patients with an evaluation that deviated from evidence-based recommendations (P<0.01). CONCLUSIONS AND RELEVANCE: At a large academic medical center, more than 1 in 5 patients with an incidental pulmonary nodule underwent evaluation that deviated from evidence-based practice recommendations. Nodule evaluation that deviated from an evidence-based strategy was associated with biopsy of benign lesions and delays in cancer diagnosis, suggesting a need to improve guideline uptake.

Management of Stage III Non-Small-Cell Lung Cancer: ASCO Guideline.

PURPOSE: To provide evidence-based recommendations to practicing clinicians on management of patients with stage III non-small-cell lung cancer (NSCLC). METHODS: An Expert Panel of medical oncology, thoracic surgery, radiation oncology, pulmonary oncology, community oncology, research methodology, and advocacy experts was convened to conduct a literature search, which included systematic reviews, meta-analyses, and randomized controlled trials published from 1990 through 2021. Outcomes of interest included survival, disease-free or recurrence-free survival, and quality of life. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. RESULTS: The literature search identified 127 relevant studies to inform the evidence base for this guideline. RECOMMENDATIONS: Evidence-based recommendations were developed to address evaluation and staging workup of patients with suspected stage III NSCLC, surgical management, neoadjuvant and adjuvant approaches, and management of patients with unresectable stage III NSCLC.Additional information is available at www.asco.org/thoracic-cancer-guidelines.

NAVIGATE 24-Month Results: Electromagnetic Navigation Bronchoscopy for Pulmonary Lesions at 37 Centers in Europe and the United States.

INTRODUCTION: Electromagnetic navigation bronchoscopy (ENB) is a minimally invasive, image-guided approach to access lung lesions for biopsy or localization for treatment. However, no studies have reported prospective 24-month follow-up from a large, multinational, generalizable cohort. This study evaluated ENB safety, diagnostic yield, and usage patterns in an unrestricted, real-world observational design. METHODS: The NAVIGATE single-arm, pragmatic cohort study (NCT02410837) enrolled subjects at 37 academic and community sites in seven countries with prospective 24-month follow-up. Subjects underwent ENB using the superDimension navigation system versions 6.3 to 7.1. The prespecified primary end point was procedure-related pneumothorax requiring intervention or hospitalization. RESULTS: A total of 1388 subjects were enrolled for lung lesion biopsy (1329; 95.7%), fiducial marker placement (272; 19.6%), dye marking (23; 1.7%), or lymph node biopsy (36; 2.6%). Concurrent endobronchial ultrasound-guided staging occurred in 456 subjects. General anesthesia (78.2% overall, 56.6% Europe, 81.4% United States), radial endobronchial ultrasound (50.6%, 4.0%, 57.4%), fluoroscopy (85.0%, 41.7%, 91.0%), and rapid on-site evaluation use (61.7%, 17.3%, 68.5%) differed between regions. Pneumothorax and bronchopulmonary hemorrhage occurred in 4.7% and 2.7% of subjects, respectively (3.2% [primary end point] and 1.7% requiring intervention or hospitalization). Respiratory failure occurred in 0.6%. The diagnostic yield was 67.8% (range: 61.9%-70.7%; 55.2% Europe, 69.8% United States). Sensitivity for malignancy was 62.6%. Lung cancer clinical stage was I to II in 64.7% (55.3% Europe, 65.8% United States). CONCLUSIONS: Despite a heterogeneous cohort and regional differences in procedural techniques, ENB demonstrates low complications and a 67.8% diagnostic yield while allowing biopsy, staging, fiducial placement, and dye marking in a single procedure.

Lung Cancer Screening Knowledge, Perceptions, and Decision Making Among African Americans in Detroit, Michigan.

INTRODUCTION: Previously, a web-based, patient-facing decision aid for lung cancer screening, shouldiscreen.com, was developed and evaluated. An initial evaluation was completed before the Medicare coverage decision and recruited a nondiverse sample of mostly former smokers, limiting the understanding of the potential effectiveness of the tool among diverse populations. This study evaluates shouldiscreen.com among African Americans in Metro Detroit. METHODS: Using insights obtained from participatory workshops in this population, content changes to shouldiscreen.com were implemented, and this modified version was evaluated with a before-after study. Measures included knowledge of lung cancer screening, decisional conflict, and concordance between individual preference and screening eligibility. Surveys occurred between April and July 2018. Participants were contacted 6 months after the survey to assess subsequent screening behaviors. Analysis took place in 2019. RESULTS: Data were collected from 74 participants aged 45-77 years, who were current/former smokers with no history of lung cancer. The average knowledge score increased by 25% from 5.7 (SD=1.94) before to 7.1 (SD=2.30) after (out of 13 points). Decisional conflict was halved between before and after. Concordance between individual preference and eligibility for screening increased from 22% (SD=41) to 35% (SD=47). Half of the participants felt uncomfortable answering surveys electronically and requested paper versions. CONCLUSIONS: The use of the tool led to small improvements in lung cancer screening knowledge and increased concordance with current recommendations. Additional design modifications and modes of information delivery of these decision aids should be considered to increase their efficacy in helping populations with lower educational attainment and computer literacy.

Quantitative Emphysema on Low-Dose CT Imaging of the Chest and Risk of Lung Cancer and Airflow Obstruction: An Analysis of the National Lung Screening Trial.

BACKGROUND: Lung cancer risk prediction models do not routinely incorporate imaging metrics available on low-dose CT (LDCT) imaging of the chest ordered for lung cancer screening. RESEARCH QUESTION: What is the association between quantitative emphysema measured on LDCT imaging and lung cancer incidence and mortality, all-cause mortality, and airflow obstruction in individuals who currently or formerly smoked and are undergoing lung cancer screening? STUDY DESIGN AND METHODS: In 7,262 participants in the CT arm of the National Lung Screening Trial, percent low attenuation area (%LAA) was defined as the percentage of lung volume with voxels less than -950 Hounsfield units on the baseline examination. Multivariable Cox proportional hazards models, adjusting for competing risks where appropriate, were built to test for association between %LAA and lung cancer incidence, lung cancer mortality, and all-cause mortality with censoring at 6 years. In addition, multivariable logistic regression models were built to test the cross-sectional association between %LAA and airflow obstruction on spirometry, which was available in 2,700 participants. RESULTS: The median %LAA was 0.8% (interquartile range, 0.2%-2.7%). Every 1% increase in %LAA was independently associated with higher hazards of lung cancer incidence (hazard ratio [HR], 1.02; 95% CI, 1.01-1.03; P = .004), lung cancer mortality (HR, 1.02; 95% CI, 1.00-1.05; P = .045), and all-cause mortality (HR, 1.01; 95% CI, 1.00-1.03; P = .042). Among participants with spirometry, 892 had airflow obstruction. The likelihood of airflow obstruction increased with every 1% increase in %LAA (odds ratio, 1.07; 95% CI, 1.06-1.09; P < .001). A %LAA cutoff of 1% had the best discriminative accuracy for airflow obstruction in participants aged > 65 years. INTERPRETATION: Quantitative emphysema measured on LDCT imaging of the chest can be leveraged to improve lung cancer risk prediction and help diagnose COPD in individuals who currently or formerly smoked and are undergoing lung cancer screening.

The Impact of Biopsy Tool Choice and Rapid On-Site Evaluation on Diagnostic Accuracy for Malignant Lesions in the Prospective: Multicenter NAVIGATE Study.

BACKGROUND: The diagnostic yield of electromagnetic navigation bronchoscopy (ENB) is impacted by biopsy tool strategy and rapid on-site evaluation (ROSE) use. This analysis evaluates usage patterns, accuracy, and safety of tool strategy and ROSE in a multicenter study. METHODS: NAVIGATE (NCT02410837) evaluates ENB using the superDimension navigation system (versions 6.3 to 7.1). The 1-year analysis included 1215 prospectively enrolled subjects at 29 United States sites. Included herein are 416 subjects who underwent ENB-aided biopsy of a single lung lesion positive for malignancy at 1 year. Use of a restricted number of tools (only biopsy forceps, standard cytology brush, and/or bronchoalveolar lavage) was compared with an extensive multimodal strategy (biopsy forceps, cytology brush, aspirating needle, triple needle cytology brush, needle-tipped cytology brush, core biopsy system, and bronchoalveolar lavage). RESULTS: Of malignant cases, 86.8% (361/416) of true positive diagnoses were obtained using extensive multimodal strategies. ROSE was used in 300/416 cases. The finding of malignancy by ROSE reduced the total number of tools used. A malignant ROSE call was obtained in 71% (212/300), most (88.7%; 188/212) by the first tool used (49.5% with aspirating needle, 20.2% with cytology brush, 17.0% with forceps). True positive rates were highest for the biopsy forceps (86.9%) and aspirating needle (86.6%). Use of extensive tool strategies did not increase the rates of pneumothorax (5.5% restricted, 2.8% extensive) or bronchopulmonary hemorrhage (3.6% restricted, 1.1% extensive). CONCLUSION: These results suggest that extensive biopsy tool strategies, including the aspirating needle, may provide higher true positive rates for detecting lung cancer without increasing complications.

Lung dendritic cell expression of maturation molecules increases with worsening chronic obstructive pulmonary disease.

RATIONALE: Dendritic cells (DCs) have not been well studied in chronic obstructive pulmonary disease (COPD), yet their integral role in activating and differentiating T cells makes them potential participants in COPD pathogenesis. OBJECTIVES: To determine the expression of maturation molecules by individual DC subsets in relationship to COPD stage and to expression of the acute activation marker CD69 by lung CD4(+) T cells. METHODS: We nonenzymatically released lung leukocytes from human surgical specimens (n = 42) and used flow cytometry to identify three DC subsets (mDC1, mDC2, and pDC) and to measure their expression of three costimulatory molecules (CD40, CD80 and CD86) and of CD83, the definitive marker of DC maturation. Spearman nonparametric correlation analysis was used to identify significant correlations between expression of DC maturation molecules and COPD severity. MEASUREMENTS AND MAIN RESULTS: Expression of CD40 by mDC1 and mDC2 and of CD86 by mDC2 was high regardless of GOLD stage, but CD80 and CD83 on these two DC subsets increased with disease progression. pDC also showed significant increases in expression of CD40 and CD80. Expression of all but one of the DC molecules that increased with COPD severity also correlated with CD69 expression on lung CD4(+) T cells from the same patients, with the exception of CD83 on mDC2. CONCLUSIONS: This cross-sectional study implies that COPD progression is associated with significant increases in costimulatory molecule expression by multiple lung DC subsets. Interactions with lung DCs may contribute to the immunophenotype of CD4(+) T cells in advanced COPD. Clinical trial registered with www.clinicaltrials.gov (NCT00281229).