Clinical validation of a cell-free DNA fragmentome assay for augmentation of lung cancer early detection

Lung cancer screening via annual low-dose computed tomography has poor adoption. We conducted a prospective case-control study among 958 individuals eligible for lung cancer screening to develop a blood-based lung cancer detection test that when positive is followed by a low-dose computed tomography. Changes in genome-wide cell-free DNA fragmentation profiles (fragmentomes) in peripheral blood reflected genomic and chromatin characteristics of lung cancer. We applied machine learning to fragmentome features to identify individuals who were more or less likely to have lung cancer. We trained the classifier using 576 cases and controls from study samples and validated it in a held-out group of 382 cases and controls. The validation demonstrated high sensitivity for lung cancer and consistency across demographic groups and comorbid conditions. Applying test performance to the screening eligible population in a 5-year model with modest utilization assumptions suggested the potential to prevent thousands of lung cancer deaths. Significance: Lung cancer screening has poor adoption. Our study describes the development and validation of a novel blood-based lung cancer screening test utilizing a highly affordable, low-coverage genome-wide sequencing platform to analyze cell-free DNA fragmentation patterns. The test could improve lung cancer screening rates leading to substantial public health benefits. See related commentary by Haber and Skates, p. 2025

A common polymorphism in the intelectin-1 gene influences mucus plugging in severe asthma

By incompletely understood mechanisms, type 2 (T2) inflammation present in the airways of severe asthmatics drives the formation of pathologic mucus which leads to airway mucus plugging. Here we investigate the molecular role and clinical significance of intelectin-1 (ITLN-1) in the development of pathologic airway mucus in asthma. Through analyses of human airway epithelial cells we find that ITLN1 gene expression is highly induced by interleukin-13 (IL-13) in a subset of metaplastic MUC5A

Treatment of stage I lung cancer detected by computed tomography screening

INTRODUCTION: Reducing lung cancer deaths through early detection by computed tomography (CT) screening requires delivery of effective treatment. We performed this retrospective study to determine the types of treatment used for screen-detected stage I lung cancer at our academic center and to compare the demographic and clinical characteristics of patients by type of treatment. METHODS: All persons screened in the lung cancer screening program at our institution through June 16, 2021, were included. Those with screening CT findings needing follow-up were managed through a thoracic surgery clinic. Demographic and clinical characteristics of patients diagnosed with having stage I lung cancer through June 16, 2021, were compared by type of treatment, with follow-up through December 31, 2021. RESULTS: Stage I NSCLC was diagnosed in 54 of 2203 persons screened (2.5%), on the basis of biopsy in 37 and on imaging findings in 17 patients in whom a tissue diagnosis could not be obtained. Treatment was by lobectomy in 18, sublobar resection in 14, and stereotactic body radiation therapy (SBRT) in 22. Patients treated with SBRT had lower forced expiratory volume in 1 second ( CONCLUSIONS: Many patients with screen-detected stage I lung cancer are medically unfit for lobectomy, and a variety of treatments are being used. Assessment of treatment-based outcomes will be critical for ensuring an optimal balance of the risks and benefits of CT screening in a medically diverse population

Volumetric Measurements of Lung Nodules with Multi-Detector Row CT: Effect of Changes in Lung Volume

OBJECTIVE: To evaluate how changes in lung volume affect volumetric measurements of lung nodules using a multi-detector row CT. MATERIALS AND METHODS: Ten subjects with asthma or chronic bronchitis who had one or more lung nodules were included. For each subject, two sets of CT images were obtained at inspiration and at expiration. A total of 33 nodules (23 nodules > or =3 mm) were identified and their volume measured using a semiautomatic volume measurement program. Differences between nodule volume on inspiration and expiration were compared using the paired t-test. Percent differences, between on inspiration and expiration, in nodule attenuation, total lung volume, whole lung attenuation, and regional lung attenuation, were computed and compared with percent difference in nodule volume determined by linear correlation analysis. RESULTS: The difference in nodule volume observed between inspiration and expiration was significant (p or =3 mm. The volume of nodules was measured to be larger on expiration CT than on inspiration CT (28 out of 33 nodules; 19 out of 23 nodules > or =3 mm). A statistically significant correlation was found between the percent difference of lung nodule volume and lung volume or regional lung attenuation (p or =3 mm. CONCLUSION: Volumetric measurements of pulmonary nodules were significantly affected by changes in lung volume. The variability in this respiration-related measurement should be considered to determine whether growth has occurred in a lung nodule.Supported by in part NIH NHLBI, RO1 HL 69149 and by a grant from Electronics and Telecommunications Research Institute

Mucus Plugs and Emphysema in the Pathophysiology of Airflow Obstruction and Hypoxemia in Smokers.

Rationale: The relative roles of mucus plugs and emphysema in mechanisms of airflow limitation and hypoxemia in smokers with chronic obstructive pulmonary disease (COPD) are uncertain.Objectives: To relate image-based measures of mucus plugs and emphysema to measures of airflow obstruction and oxygenation in patients with COPD.Methods: We analyzed computed tomographic (CT) lung images and lung function in participants in the Subpopulations and Intermediate Outcome Measures in COPD Study. Radiologists scored mucus plugs on CT lung images, and imaging software automatically quantified emphysema percentage. Unadjusted and adjusted relationships between mucus plug score, emphysema percentage, and lung function were determined using regression.Measurements and Main Results: Among 400 smokers, 229 (57%) had mucus plugs and 207 (52%) had emphysema, and subgroups could be identified with mucus-dominant and emphysema-dominant disease. Only 33% of smokers with high mucus plug scores had mucus symptoms. Mucus plug score and emphysema percentage were independently associated with lower values for FEV1 and peripheral oxygen saturation (P < 0.001). The relationships between mucus plug score and lung function outcomes were strongest in smokers with limited emphysema (P < 0.001). Compared with smokers with low mucus plug scores, those with high scores had worse COPD Assessment Test scores (17.4 ± 7.7 vs. 14.4 ± 13.3), more frequent annual exacerbations (0.75 ± 1.1 vs. 0.43 ± 0.85), and shorter 6-minute-walk distance (329 ± 115 vs. 392 ± 117 m) (P < 0.001).Conclusions: Symptomatically silent mucus plugs are highly prevalent in smokers and independently associate with lung function outcomes. These data provide rationale for targeting patients with mucus-high/emphysema-low COPD in clinical trials of mucoactive treatments.Clinical trial registered with www.clinicaltrials.gov (NCT01969344)