Performance of the galactomannan test for the diagnosis of invasive pulmonary aspergillosis using non-invasive proximal airway samples.

OBJECTIVE: To diagnose invasive pulmonary aspergillosis (IPA), galactomannan (GM) detection in serum or bronchoalveolar lavage fluid (BALF) is widely used. However, the utility of proximal airway GM test (from induced sputum or tracheal aspirate) has not been well elucidated. METHODS: In this retrospective cohort study, we evaluated the diagnostic performance of proximal airway GM in diagnosis of IPA including COVID-19 associated pulmonary aspergillosis (CAPA). Between January 2022 and January 2023, patients who had been tested for GM with clinical suspicion or for surveillance from any specimen (serum, induced sputum, tracheal aspirate, and BALF) were screened. IPA was diagnosed using EORTC/MSGERC criteria, and CAPA was diagnosed following the 2020 ECMM/ISHAM consensus criteria. RESULTS: Of 624 patients with GM results, 70 met the criteria for proven/probable IPA and 427 had no IPA. The others included possible IPA and chronic form of aspergillosis. The sensitivities and specificities of serum, proximal airway, and BALF GM for proven/probable IPA versus no IPA were 78.9% and 70.6%, 93.1% and 78.7%, and 78.6% and 91.0%, respectively. Areas under the receiver operating characteristic curve (AUCs) were 0.742 for serum GM, 0.935 for proximal airway GM, and 0.849 for BALF GM (serum GM vs proximal airway GM, p = 0.014; proximal airway GM vs BALF GM, p = 0.334; serum GM vs BALF GM, p = 0.286). CONCLUSION: This study demonstrates that the performance of GM test from non-invasive proximal airway samples is comparable or even better than those from serum and distal airway sample (BALF).

Tumor Microenvironment Modulation by Neoadjuvant Erlotinib Therapy and Its Clinical Impact on Operable EGFR-Mutant Non-Small Cell Lung Cancer.

PURPOSE: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have greatly improved survival in EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC); however, their effects on the tumor microenvironment (TME) are unknown. We assessed the changes induced by neoadjuvant erlotinib therapy (NE) in the TME of operable EGFRm NSCLC. MATERIALS AND METHODS: This was a single-arm phase II trial for neoadjuvant/adjuvant erlotinib therapy in patients with stage II/IIIA EGFRm NSCLC (EGFR exon 19 deletion or L858R mutations). Patients received up to 2 cycles of NE (150 mg/day) for 4 weeks, followed by surgery and adjuvant erlotinib or vinorelbine plus cisplatin therapy depending on observed NE response. TME changes were assessed based on gene expression analysis and mutation profiling. RESULTS: A total of 26 patients were enrolled; the median age was 61, 69% were female, 88% were stage IIIA, and 62% had L858R mutation. Among 25 patients who received NE, the objective response rate was 72% (95% confidence interval [CI], 52.4 to 85.7). The median disease-free and overall survival (OS) were 17.9 (95% CI, 10.5 to 25.4) and 84.7 months (95% CI, 49.7 to 119.8), respectively. Gene set enrichment analysis in resected tissues revealed upregulation of interleukin, complement, cytokine, transforming growth factor ß, and hedgehog pathways. Patients with upregulated pathogen defense, interleukins, and T-cell function pathways at baseline exhibited partial response to NE and longer OS. Patients with upregulated cell cycle pathways at baseline exhibited stable/progressive disease after NE and shorter OS. CONCLUSION: NE modulated the TME in EGFRm NSCLC. Upregulation of immune-related pathways was associated with better outcomes.

Strategies to Improve Smoking Cessation for Participants in Lung Cancer Screening Program: Analysis of Factors Associated with Smoking Cessation in Korean Lung Cancer Screening Project (K-LUCAS).

PURPOSE: Smoking cessation intervention is one of the key components of successful lung cancer screening program. We investigated the effectiveness and related factors of smoking cessation services provided to the participants in a population-based lung cancer screening trial. MATERIALS AND METHODS: The Korean Lung Cancer Screening Project (K-LUCAS) is a nationwide, multi-center lung cancer screening trial that evaluates the feasibility of implementing population-based lung cancer screening. All 5,144 current smokers who participated in the K-LUCAS received a mandatory smoking cessation counseling. Changes in smoking status were followed up using a telephone survey in 6 months after lung cancer screening participation. The lung cancer screening's impact on smoking cessation is analyzed by variations in the smoking cessation interventions provided in screening units. RESULTS: Among 4,136 survey responders, participant's motivation to quit smoking increased by 9.4% on average after lung cancer screening. After 6 months from the initial screening, 24.3% of participants stopped smoking, and 10.6% of participants had not smoked continuously for at least 6 months after screening. Over 80% of quitters stated that participation in lung cancer screening motivated them to quit smoking. Low-cost public smoking cessation program combined with lung cancer screening increased the abstinence rates. The smokers were three times more likely to quit smoking when the smoking cessation counseling was provided simultaneously with low-dose computed tomography screening results than when provided separately. CONCLUSION: A mandatory smoking cessation intervention integrated with screening result counselling by a physician after participation in lung cancer screening could be effective for increasing smoking cessation attempts.

Nivolumab after Induction Chemotherapy in Previously Treated Non-Small-Cell Lung Cancer Patients with Low PD-L1 Expression.

This study aimed to investigate whether cyclophosphamide (C) and adriamycin (A) induction therapy (IT) prior to nivolumab could enhance the efficacy of nivolumab in previously treated patients with non-squamous (NSQ) non-small-cell lung cancer (NSCLC) with less than 10% programmed death-ligand 1 (PD-L1) expression. Twenty-two enrolled patients received four cycles of CA-IT every 3 weeks. Nivolumab was given 360 mg every 3 weeks from the second cycle and 480 mg every 4 weeks after four cycles of CA-IT. The median progression-free survival (PFS) and overall survival (OS) were 2.4 months and 11.6 months, respectively. Fluorescence-activated cell sorting revealed the lowest ratio of myeloid-derived suppressor cells (MDSCs) to CD8+T-cells in the responders. Proteomic analysis identified a consistent upregulation of extracellular matrix-receptor interactions and phagosome pathways in the responders. Among the differentially expressed proteins, the transferrin receptor protein (TFRC) was higher in the responders before treatment (fold change > 1.2). TFRC validation with an independent cohort showed the prognostic significance of either OS or PFS in patients with low PD-L1 expression. In summary, CA-IT did not improve nivolumab efficacy in NSQ-NSCLCs with low PD-L1 expression; however, it induced decreasing MDSC, resulting in a durable response. Higher baseline TFRC levels predicted a favorable response to nivolumab in NSCLC with low PD-L1 expression.

Prediction Models for Mediastinal Metastasis and Its Detection by Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration in Potentially Operable Non-Small Cell Lung Cancer: A Prospective Study.

BACKGROUND: Prediction models for mediastinal metastasis and its detection by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) have not been developed using a prospective cohort of potentially operable patients with non-small cell lung cancer (NSCLC). RESEARCH QUESTION: Can mediastinal metastasis and its detection by EBUS-TBNA be predicted with prediction models in NSCLC? STUDY DESIGN AND METHODS: For the prospective development cohort, 589 potentially operable patients with NSCLC were evaluated (July 2016-June 2019) from five Korean teaching hospitals. Mediastinal staging was performed using EBUS-TBNA (with or without the transesophageal approach). Surgery was performed for patients without clinical N (cN) 2-3 disease by endoscopic staging. The prediction model for lung cancer staging-mediastinal metastasis (PLUS-M) and a model for mediastinal metastasis detection by EBUS-TBNA (PLUS-E) were developed using multivariable logistic regression analyses. Validation was performed using a retrospective cohort (n = 309) from a different period (June 2019-August 2021). RESULTS: The prevalence of mediastinal metastasis diagnosed by EBUS-TBNA or surgery and the sensitivity of EBUS-TBNA in the development cohort were 35.3% and 87.0%, respectively. In PLUS-M, younger age (< 60 years and 60-70 years compared with ≥ 70 years), nonsquamous histology (adenocarcinoma and others), central tumor location, tumor size (> 3-5 cm), cN1 or cN2-3 stage by CT, and cN1 or cN2-3 stage by PET-CT were significant risk factors for N2-3 disease. Areas under the receiver operating characteristic curve (AUCs) for PLUS-M and PLUS-E were 0.876 (95% CI, 0.845-0.906) and 0.889 (95% CI, 0.859-0.918), respectively. Model fit was good (PLUS-M: Hosmer-Lemeshow P = .658, Brier score = 0.129; PLUS-E: Hosmer-Lemeshow P = .569, Brier score = 0.118). In the validation cohort, PLUS-M (AUC, 0.859 [95% CI, 0.817-0.902], Hosmer-Lemeshow P = .609, Brier score = 0.144) and PLUS-E (AUC, 0.900 [95% CI, 0.865-0.936], Hosmer-Lemeshow P = .361, Brier score = 0.112) showed good discrimination ability and calibration. INTERPRETATION: PLUS-M and PLUS-E can be used effectively for decision-making for invasive mediastinal staging in NSCLC. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02991924; URL: www. CLINICALTRIALS: gov.

Dynamics of disease progression during treatment with Osimertinib in patients with EGFR T790M-positive non-small cell lung cancer.

BACKGROUND: Patterns of treatment failure and subsequent treatment in non-small cell lung cancer (NSCLC) patients treated with osimertinib are scarcely known. We analyzed the disease progression during osimertinib treatment to identify potential treatment strategies. METHODS: We identified advanced NSCLC patients who commenced osimertinib treatment after progression on previous epidermal growth factor receptor (EGFR)-tyrosine-kinase inhibitor (TKI) from June 2014 to November 2018 from electronic records. Patients' tumor characteristics, efficacy outcomes, affected organs from radiology studies, and treatment modalities before and after osimertinib were analyzed. RESULTS: Eighty-four patients were included. At osimertinib initiation, bone (50.0%) and brain (41.9%) were the commonest single metastatic sites, whereas thoracic involvement (73.3%) was more frequent than bone (27.4%) or brain (20.2%) metastasis during disease progression on osimertinib. Oligo-progressive disease (PD) and central nervous system (CNS)-sanctuary PD were observed in 15 (17.9%) and 3 (3.6%) patients, respectively. Most patients without brain metastasis (BM) at osimertinib initiation remained BM-free (46/49, 93.9%), and 60% of patients (21/35) with pre-existing BM showed intracranial disease control despite extracranial PD. The resistance mechanisms to osimertinib were explored in 23 patients (27.4%), and T790M-loss was observed in 14 patients (60.9%) who had worse survival outcomes than those without T790M-loss (progression-free survival, 5.4 vs. 16.5 months, p = 0.02; overall survival, not reached, p = 0.03). CONCLUSION: PD during osimertinib treatment occurred preferentially in the thorax and pre-existing sites. Extracranial PD prevailed over intracranial PD regardless of baseline BM and prior brain radiation. These results support osimertinib's intracranial efficacy and may guide treatment strategies for EGFR-mutated NSCLC with BM.

A randomized Phase 2 study to compare erlotinib with or without bevacizumab in previously untreated patients with advanced non-small cell lung cancer with EGFR mutation.

BACKGROUND: This study evaluated whether an addition of bevacizumab to erlotinib improves clinical outcomes in patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC). METHODS: This is an open-label, multicenter, randomized Phase 2 study in South Korea. Chemonaïve patients with Stage IIIB/IV NSCLC with EGFR 19 deletion or L858R mutation were eligible. Asymptomatic brain metastasis (BM) was enrolled without local treatment. Patients received either erlotinib plus bevacizumab or erlotinib. RESULTS: Between December 2016 and March 2019, 127 patients were randomly assigned to receive erlotinib plus bevacizumab (n = 64) or erlotinib (n = 63). Fifty-nine (46.5%) patients had baseline BM. Fewer patients in the erlotinib plus bevacizumab arm received radiotherapy for BM than in the erlotinib arm (10.3% vs. 40.0%). A trend toward longer progression-free survival (PFS) was observed in the erlotinib plus bevacizumab arm compared with the erlotinib alone arm; however, it was not statistically significant (median PFS, 17.5 months vs. 12.4 months; hazard ratio [HR], 0.74; 95% CI, 0.51-1.08; p = .119). The unplanned subgroup analysis showed a longer PFS with erlotinib plus bevacizumab in patients with BM (median PFS, 18.6 months vs. 10.3 months; HR, 0.54; 95% CI, 0.31-0.95; p = .032). Grade 3 or worse adverse events occurred in 56.6% of the erlotinib plus bevacizumab arm and 20.6% of the erlotinib arm. CONCLUSIONS: Although it was not statistically significant, a trend to improvement in PFS was observed in patients with erlotinib plus bevacizumab compared to erlotinib alone. PLAIN LANGUAGE SUMMARY: A randomized Phase 2 study compared erlotinib with or without bevacizumab in previously untreated patients with advanced non-small cell lung cancer with EGFR mutation. The erlotinib plus bevacizumab failed to improve median progression-free survival compared with the erlotinib alone. However, the progression-free survival benefit from erlotinib plus bevacizumab was found in patients with brain metastasis with no severe hemorrhagic adverse effects.

Long-term Survival According to N Stage Diagnosed by Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration in Non-small Cell Lung Cancer.

BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is the main procedure for mediastinal staging. However, long-term survival analyses according to clinical nodal stage diagnosed by EBUS-TBNA (eN stage) have not been reported. The value of EBUS-TBNA has not been assessed through an analysis of survival in false-negative EBUS-TBNA cases. RESEARCH QUESTION: What is the prognostic impact of eN stage in non-small cell lung cancer (NSCLC)? What is the survival rate in false-negative EBUS-TBNA cases? STUDY DESIGN AND METHODS: We retrospectively (January 2006 to December 2011) reviewed the medical records of patients with NSCLC who underwent EBUS-TBNA (± transesophageal approach) for initial staging (N = 1,089). Mediastinoscopy was not performed for EBUS-TBNA-negative cases. We performed 5-year survival analyses according to eN stage and treatment modality. Survival in false-negative EBUS-TBNA cases was compared with that in patients with pN0-1, including 941 non-EBUS-TBNA cases, during the same period. RESULTS: Among the 1,089 patients undergoing EBUS-TBNA (eN0-1: n = 681; eN2: n = 314; eN3: n = 94), we observed significant differences in survival between the eN stages (eN0-1 vs eN2: P < .0001; eN2 vs eN3: P = .0118; estimated 5-year overall survival [5YOS] rate: eN0-1 = 57.4%, eN2 = 23.2%, eN3 = 12.8%). Surgery cases had better survival than nonsurgery cases among patients with eN0-1 and eN2 (eN0-1/surgery vs eN0-1/no surgery: P < .0001; eN2/surgery vs eN2/no surgery: P < .0001). Among the patients with eN0-1, there were 55 false-negative cases (eN0-1/pN2-3, pN2: n = 54; pN3: n = 1). The 5YOS rates of patients with pN0, pN1, and eN0-1/pN2-3 were 76.4%, 56.0%, and 56.4%, respectively. Patients with eN0-1/pN2-3 had worse survival than patients with pN0 (P = .0061), whereas there was no significant difference compared with patients with pN1 (P = .9191). INTERPRETATION: Long-term survival significantly differed according to eN stage in NSCLC, highlighting the importance of EBUS-TBNA in NSCLC staging. False-negative EBUS-TBNA cases had favorable survival which was similar to that of patients with pN1, which may provide a rationale for performing surgery after negative EBUS-TBNA results.

Effectiveness of radiologist training in improving reader agreement for Lung-RADS 4X categorization.

OBJECTIVES: To identify the agreement on Lung CT Screening Reporting and Data System 4X categorization between radiologists and an expert-adjudicated reference standard and to investigate whether training led to improvement of the agreement measures and diagnostic potential for lung cancer. METHODS: Category 4 nodules in the Korean Lung Cancer Screening Project were identified retrospectively, and each 4X nodule was matched with one 4A or 4B nodule. An expert panel re-evaluated the categories and determined the reference standard. Nineteen radiologists were asked to determine the presence of CT features of malignancy and 4X categorization for each nodule. A review was performed in two sessions, and training material was given after session 1. Agreement on 4X categorization between radiologists and the expert-adjudicated reference standard and agreement between radiologist-assessed 4X categorization and lung cancer diagnosis were evaluated. RESULTS: The 48 expert-adjudicated 4X nodules and 64 non-4X nodules were evenly distributed in each session. The proportion of category 4X decreased after training (56.4% ± 16.9% vs. 33.4% ± 8.0%; p < 0.001). Cohen's κ indicated poor agreement (0.39 ± 0.16) in session 1, but agreement improved in session 2 (0.47 ± 0.09; p = 0.03). The increase in agreement in session 2 was observed among inexperienced radiologists (p < 0.05), and experienced and inexperienced reviewers exhibited comparable agreement performance in session 2 (p > 0.05). All agreement measures between radiologist-assessed 4X categorization and lung cancer diagnosis increased in session 2 (p < 0.05). CONCLUSION: Radiologist training can improve reader agreement on 4X categorization, leading to enhanced diagnostic performance for lung cancer. KEY POINTS: • Agreement on 4X categorization between radiologists and an expert-adjudicated reference standard was initially poor, but improved significantly after training. • The mean proportion of 4X categorization by 19 radiologists decreased from 56.4% ± 16.9% in session 1 to 33.4% ± 8.0% in session 2. • All agreement measures between the 4X categorization and lung cancer diagnosis increased significantly in session 2, implying that appropriate training and guidance increased the diagnostic potential of category 4X.

Feasibility of implementing a national lung cancer screening program: Interim results from the Korean Lung Cancer Screening Project (K-LUCAS).

BACKGROUND: Lung cancer screening conducted in high-risk group using low-dose computer tomography (LDCT) has been reported as an effective method to reduce lung cancer mortality in two large randomized-control trials. However, the effectiveness is uncertain when lung cancer screening is expanded to a nationwide population-based program. METHODS: The Korean Lung Cancer Screening Project (K-LUCAS) is a single-arm cohort study that was conducted from February 2017 to evaluate the feasibility of implementing an organized national lung cancer screening program in Korea. High-risk population aged 55-74 years with more than a 30-pack-year smoking history was recruited. Smoking history was obtained from administering questionnaires at national health screening programs or public smoking cessation programs which are already established programs in Korea. The screening results were reported using the Lung Imaging Reporting and Data System (Lung-RADS), suggested by the American College of Radiology. K-LUCAS was performed by a network-based diagnosis supporting system using a computer-aided detection (CAD) program to maintain screening quality. Current smokers were provided with mandatory smoking counseling. RESULTS: Among 71,829 participants aged 50 years or older in the national health screening program, 5,975 (8.3%) were eligible for lung cancer screening. Among them, 1,062 (17.8%) refused to participate in K-LUCAS. Additionally, 779 participants were recruited in the smoking cessation program. Thus, a total of 5,692 eligible high-risk participants were recruited in this study. Among them, 865 (15.2%) had positive screening results, which requires a further examination; 529 (9.3%) had Lung-RADS category 3 (indeterminate), and 336 (5.9%) had category 4 (suspicious of lung cancer); 42 (0.7%) had confirmed lung cancer. Approximately 66.7% had early-stage lung cancer: 24 (57.1%), stage I and 4 (9.5%), stage II. Six (1.1%) patients developed complications at the time of diagnosis, including one death. The anxiety level related to cancer screening was low. Participation in screening encouraged motivation to quit smoking. CONCLUSIONS: K-LUCAS provided promising evidence supporting the implementation of a national lung cancer screening program to detect early stage lung cancer and promote smoking cessation for participants in Asian population.

Optimum diameter threshold for lung nodules at baseline lung cancer screening with low-dose chest CT: exploration of results from the Korean Lung Cancer Screening Project.

OBJECTIVES: To explore the optimum diameter threshold for solid nodules to define positive results at baseline screening low-dose CT (LDCT) and to compare two-dimensional and volumetric measurement of lung nodules for the diagnosis of lung cancers. METHODS: We included consecutive participants from the Korean Lung Cancer Screening project between 2017 and 2018. The average transverse diameter and effective diameter (diameter of a sphere with the same volume) of lung nodules were measured by semi-automated segmentation. Diagnostic performances for lung cancers diagnosed within 1 year after LDCT were evaluated using area under receiver-operating characteristic curves (AUCs), sensitivities, and specificities, with diameter thresholds for solid nodules ranging from 6 to 10 mm. The reduction of unnecessary follow-up LDCTs and the diagnostic delay of lung cancers were estimated for each threshold. RESULTS: Fifty-two lung cancers were diagnosed among 10,424 (10,141 men; median age 62 years) participants within 1 year after LDCT. Average transverse (0.980) and effective diameters (0.981) showed similar AUCs (p = .739). Elevating the average transverse diameter threshold from 6 to 9 mm resulted in a significantly increased specificity (91.7 to 96.7%, p < .001), a modest reduction in sensitivity (96.2 to 94.2%, p = .317), a 60.2% estimated reduction of unnecessary follow-up LDCTs, and a diagnostic delay in 1.9% of lung cancers. Elevating the threshold to 10 mm led to a significant reduction in sensitivity (86.5%, p = .025). CONCLUSIONS: Elevating the diameter threshold for solid nodules from 6 to 9 mm may lead to a substantial reduction in unnecessary follow-up LDCTs with a small proportion of diagnostic delay of lung cancers. KEY POINTS: • Elevation of the diameter threshold for solid nodules from 6 to 9 mm can substantially reduce unnecessary follow-up LDCTs with a small proportion of diagnostic delay of lung cancers. • The average transverse and effective diameters of lung nodules showed similar performances for the prediction of a lung cancer diagnosis.

Clinical Significance of Lung-RADS Category 3 Lesions in the National Lung Screening Trial.

INTRODUCTION: To determine the clinical significance of category 3 (CAT3) abnormalities and the necessity of a 6-month follow-up computed tomography (CT). We also explored features associated with increased lung cancer risk. METHODS: From the National Lung Screening Trial database, we identified participants with CAT3 lesions at prevalence screen. Rates of lung cancer and lung cancer-specific deaths (LSDs) were compared between those who underwent first follow-up CT before 6 months (early diagnostic group) and those who underwent annual screening (annual diagnostic group). We estimated the change in LSD if the 6-month CT was eliminated. Regression analysis was performed to identify features associated with participants with CAT3 who developed lung cancer. RESULTS: A total of 1763 CAT3s were identified (6.6% of all participants who had low-dose CT), with 108 lung cancers (6.1%) and 41 LSDs (2.3%) in a 7-year period. Rates of lung cancer (7.5% versus 3.1%) and LSD (4.0% versus 1.0%) were higher in the early diagnostic group than in the annual diagnostic group. We estimated an increase in LSD of 0.6% of all participants with CAT3 (24.4% of all LSDs) if the 6-month CT was not performed. Multivariate regression analysis found that increased age, emphysema, and a part-solid nodule greater than 5 mm were associated with participants with CAT3 who developed lung cancer. CONCLUSIONS: CAT3 lesions are uncommon, and eliminating the 6-month CT would potentially increase LSD by 0.6% of all patients with CAT3. Age, emphysema, and part-solid nodule greater than 5 mm may be useful in risk prediction models to determine which participants with CAT3 are more likely to develop lung cancer and suggest which patients may need more intense follow-up.

Variability in interpretation of low-dose chest CT using computerized assessment in a nationwide lung cancer screening program: comparison of prospective reading at individual institutions and retrospective central reading.

OBJECTIVES: To evaluate the degree of variability in computer-assisted interpretation of low-dose chest CTs (LDCTs) among radiologists in a nationwide lung cancer screening (LCS) program, through comparison with a retrospective interpretation from a central laboratory. MATERIALS AND METHODS: Consecutive baseline LDCTs (n = 3353) from a nationwide LCS program were investigated. In the institutional reading, 20 radiologists in 14 institutions interpreted LDCTs using computer-aided detection and semi-automated segmentation systems for lung nodules. In the retrospective central review, a single radiologist re-interpreted all LDCTs using the same system, recording any non-calcified nodules ≥ 3 mm without arbitrary rejection of semi-automated segmentation to minimize the intervention of radiologist's discretion. Positive results (requiring additional follow-up LDCTs or diagnostic procedures) were initially classified by the lung CT screening reporting and data system (Lung-RADS) during the interpretation, while the classifications based on the volumetric criteria from the Dutch-Belgian lung cancer screening trial (NELSON) were retrospectively applied. Variabilities in positive rates were assessed with coefficients of variation (CVs). RESULTS: In the institutional reading, positive rates by the Lung-RADS ranged from 7.5 to 43.3%, and those by the NELSON ranged from 11.4 to 45.0% across radiologists. The central review exhibited higher positive rates by Lung-RADS (20.0% vs. 27.3%; p < .001) and the NELSON (23.1% vs. 37.0%; p < .001), and lower inter-institution variability (CV, 0.30 vs. 0.12, p = .003 by Lung-RADS; CV, 0.25 vs. 0.12, p = .014 by the NELSON) compared to the institutional reading. CONCLUSION: Considerable inter-institution variability in the interpretation of LCS results is caused by different usage of the computer-assisted system. KEY POINTS: • Considerable variability existed in the interpretation of screening LDCT among radiologists partly from the different usage of the computerized system. • A retrospective reading of low-dose chest CTs in the central laboratory resulted in reduced variability but an increased positive rate.

Sequential Treatment with an Immune Checkpoint Inhibitor Followed by a Small-Molecule Targeted Agent Increases Drug-Induced Pneumonitis.

PURPOSE: Immune checkpoint inhibitors (ICI) and targeted small-molecule drugs are mainstay elements of lung cancer chemotherapy. However, they are associated with development of pneumonitis, a rare, but potentially life-threatening event. We analyzed lung cancer patients treated with ICI to evaluate the effect of sequential therapeutic administration on the incidence of pneumonitis. MATERIALS AND METHODS: In this retrospective study, 242 patients were included. Serial radiologic findings taken during and immediately after ICI treatment were reviewed. Factors that increased pneumonitis and the relationship between peri-ICI chemotherapy and the development of pneumonitis were evaluated. RESULTS: Pneumonitis developed in 23 patients (9.5%); severe pneumonitis (grade ≥ 3) occurred in 13 of 23 patients (56%); pneumonitis-related death occurred in six. High-dose thoracic radiation (≥ 6,000 cGy) revealed a tendency toward high risk of pneumonitis (odds ratio, 2.642; 95% confidence interval, 0.932 to 7.490; p=0.068). Among 149 patients followed for ≥ 8 weeks after the final ICI dose, more patients who received targeted agents within 8-weeks post-ICI experienced pneumonitis (3/16, 18.8%) compared with patients who received cytotoxic agents (4/54, 7.4%) or no chemotherapy (4/79, 5.1%) (p=0.162). Targeted therapy was associated with earlier-onset pneumonitis than treatment with cytotoxic agents (35 vs. 62 days post-ICI, p=0.007); the resulting pneumonitis was more severe (grade ≥ 3, 100% vs. 0%, p=0.031). CONCLUSION: Sequential administration of small-molecule targeted agents immediately after ICI may increase the risk of severe pneumonitis. The sequence of chemotherapy regimens that include ICI and targeted agents should be carefully planned to reduce the risk of pneumonitis in lung cancer patients.

Implementation of the cloud-based computerized interpretation system in a nationwide lung cancer screening with low-dose CT: comparison with the conventional reading system.

OBJECTIVES: We aimed to compare the CT interpretation before and after the implementation of a computerized system for lung nodule detection and measurements in a nationwide lung cancer screening program. METHODS: Our screening program started in April 2017, with 14 participating institutions. Initially, all CTs were interpreted using interpretation systems in each institution and manual nodule measurement (conventional system). A cloud-based CT interpretation system, equipped with semi-automated measurement and CAD (computer-aided detection) for lung nodules (cloud-based system), was implemented during the project. Positive rates and performances for lung cancer diagnosis based on the Lung-RADS version 1.0 were compared between the conventional and cloud-based systems. RESULTS: A total of 1821 (M:F = 1782:39, mean age 62.7 years, 16 confirmed lung cancers) and 4666 participants (M:F = 4560:106, mean age 62.8 years, 31 confirmed lung cancers) were included in the conventional and cloud-based systems, respectively. Significantly more nodules were detected in the cloud-based system (0.76 vs. 1.07 nodule/participant, p < .001). Positive rate did not differ significantly between the two systems (9.9% vs. 11.0%, p = .211), while their variability across institutions was significantly lower in the cloud-based system (coefficients of variability, 0.519 vs. 0.311, p = .018). The Lung-RADS-based sensitivity (93.8% vs. 93.5%, p = .979) and specificity (90.9% vs. 89.6%, p = .132) did not differ significantly between the two systems. CONCLUSION: Implementation of CAD and semi-automated measurement for lung nodules in a nationwide lung cancer screening program resulted in increased number of detected nodules and reduced variability in positive rates across institutions. KEY POINTS: • Computer-aided CT reading detected more lung nodules than radiologists alone in lung cancer screening. • Positive rate in lung cancer screening did not change with computer-aided reading. • Computer-aided CT reading reduced inter-institutional variability in lung cancer screening.

External validation and comparison of the Brock model and Lung-RADS for the baseline lung cancer CT screening using data from the Korean Lung Cancer Screening Project.

OBJECTIVES: To validate and compare the performance of the Brock model and Lung CT Screening Reporting and Data System (Lung-RADS) on nodules detected by baseline CT screening. METHODS: We performed a secondary analysis of the Korean Lung Cancer Screening Project (K-LUCAS; ClinicalTrials.gov , NCT03394703), a nationwide, multicenter, prospective cohort study. From April 2017 to December 2018, low-dose CT screening was performed on high-risk subjects. Discrimination and calibration of Brock models 2a and 2b (i.e., full model without and with spiculation, respectively) were assessed, and discrimination was compared with that of Lung-RADS, which utilized subjective assessment categories 2b (b stands for benign) and 4X. RESULTS: Of the 13,150 subjects, 4578 were eligible (median age 62 years; 4458 men; 9929 nodules including 40 lung cancers). Areas under the receiver operating characteristic curve were 0.96 (IQR 0.92-0.99) for Brock model 2a, 0.96 (IQR 0.92-0.99) for Brock model 2b, and 0.95 (IQR 0.91-0.99) for Lung-RADS (p = 0.32 and p = 0.34, respectively). At an equivalent cutoff of 5%, Brock model 2b (sensitivity 87.5% [35/40]; specificity 93.6% [9259/9889]; positive predictive value [PPV] 5.3% [35/665]; negative predictive value [NPV] 99.9% [9259/9264]) and Lung-RADS (sensitivity 87.5% [35/40]; specificity 93.3% [9222/9889]; PPV 5.0% [35/702]; NPV 99.9% [9222/9227]) performed similarly well (all p > 0.05). The calibration performance of both Brock models 2a and 2b was poor (both p < 0.001). CONCLUSIONS: Lung-RADS, when reinforced with visual assessment-based categories, has a similar diagnostic performance to the Brock model for baseline CT scans. KEY POINTS: • Brock model 2b and Lung CT Screening Reporting and Data System (Lung-RADS) demonstrated a similar discrimination performance for lung cancer in the baseline CT screening (areas under the receiver operating characteristic curve 0.96 vs. 0.95; p = 0.34). • When visual assessment-based categories were removed from Lung-RADS, specificity and positive predictive value were lower than those of Brock model 2b (p = 0.001 and p = 0.02, respectively). • The Brock model showed poor calibration (p < 0.001).

First-iGAP: A Randomized Placebo-Controlled Phase II Study of First-line Intercalated Gefitinib and Pemetrexed-Cisplatin Chemotherapy for Never-Smoker Lung Adenocarcinoma Patients.

BACKGROUND: We aimed to evaluate whether intercalated combination of EGFR tyrosine kinase inhibitor gefitinib and chemotherapy improves survival outcomes in never-smokers with advanced lung adenocarcinoma. PATIENTS AND METHODS: Never-smokers with chemo-naive stage IIIB/IV lung adenocarcinoma were randomly assigned to receive either gefitinib or placebo on days 5 to 18 of a 3-weekly cycle of pemetrexed and cisplatin. Chemotherapy was given up to 9 cycles, after which gefitinib or placebo was given daily. Patients in the placebo arm who had progression were crossed over to receive gefitinib. RESULTS: Between June 2012 and December 2014, 76 patients with median age of 58.0 years were randomized, 39 on gefitinib and 37 on the placebo arm. EGFR mutation was positive in 34 (44.7%) patients. Baseline characteristics were well balanced between the 2 arms. The gefitinib arm had a better response rate (79.5% vs. 51.4%, P = .010) and median progression-free survival (PFS) (12.4 vs. 6.7 months, hazard ratio [HR] 0.49, P = .005) than the placebo arm; however, there was no statistically significant difference in median overall survival between the 2 arms (31.8 vs. 22.9 months, HR 0.78, P = .412). The PFS benefit of intercalated use of gefitinib over placebo was more apparent for patients with EGFR-mutant tumors (13.3 vs. 7.8 months, P = .025) than those with EGFR-wild-type tumors (8.2 vs. 6.6 months, P = .063). Overall, there was no difference in the frequency of severe adverse effect between the 2 arms. CONCLUSIONS: Intercalated combination of gefitinib with pemetrexed and cisplatin was well tolerated and improved PFS in never-smoker patients with lung adenocarcinoma.

Lung Cancer CT Screening and Lung-RADS in a Tuberculosis-endemic Country: The Korean Lung Cancer Screening Project (K-LUCAS).

Background Low-dose CT screening for lung cancer in a tuberculosis-endemic country may be less effective because of false-positive results caused by tuberculosis sequelae. Purpose To evaluate the impact of tuberculosis sequelae at CT screening according to the American College of Radiology Lung CT Screening Reporting and Data System (Lung-RADS) using data from the Korean Lung Cancer Screening Project (K-LUCAS). Materials and Methods This is a secondary analysis of K-LUCAS (ClinicalTrials.gov identifier NCT03394703), a nationwide Asian population-based, multicenter, prospective cohort study. Participants at high risk for lung cancer were enrolled between April 2017 and December 2018. Associations of tuberculosis sequelae with a positive screening result for lung cancer (defined as Lung-RADS categories 3 or 4) and diagnosis of lung cancer were analyzed with multivariable logistic regression. The diagnostic performance of Lung-RADS in predicting lung cancer was compared between participants with and participants without tuberculosis sequelae by using the χ2 test. Results A total of 11 394 participants (median age, 62 years; interquartile range, 58-67 years; 11 098 men) were evaluated. Positive screening results were found in 1868 of the 11 394 participants (16%); lung cancer was diagnosed in 65 of the 11 394 participants (0.6%). Tuberculosis sequelae were identified in 1509 of the 11 394 participants (13%) on the basis of CT scans. Tuberculosis sequelae were associated with positive CT screening results (odds ratio [OR] with one nodule, 1.22; 95% confidence interval [CI]: 1.02, 1.45; P = .03), but no evidence was found of an association with lung cancer (OR, 0.9; 95% CI: 0.4, 1.6; P = .64). Specificity of Lung-RADS was higher for participants without tuberculosis sequelae (85% [8327 of 9829 participants]; 95% CI: 84.0%, 85.4%) than for those with tuberculosis sequelae (80% [1198 of 1500 participants]; 95% CI: 77.7%, 82%; P < .001). Sensitivity was not different between participants with tuberculosis sequelae (100% [nine of nine participants]; 95% CI: 62.9%, 100%) and those without tuberculosis sequelae (98% [55 of 56 participants]; 95% CI: 89.2%, 99.9%; P > .99). Conclusion In an at-risk population, tuberculosis sequelae resulted in a reduced specificity of CT screening for lung cancer using the Lung CT Screening Reporting and Data System. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Ketai in this issue.