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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).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.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.Although it was not statistically significant, a trend to improvement in PFS was observed in patients with erlotinib plus bevacizumab compared to erlotinib alone.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.

Purpose 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% PD-L1 expression. Methods Patients received four cycles of CA-IT (C,500 mg/m2 and D, 50 mg/m2) every 3weeks. Nivolumab was given 360 mg every 3 weeks from the second cycle. After 4 cycles of CA-IT, nivolumab 480 mg was administered every 4 weeks. We collected blood samples for next-generation sequencing, fluorescence-activated Cell Sorting (FACS) to characterize immune cells, and liquid chromatography-tandem mass spectrometry to identify potential biomarkers. Results A total of 22 patients were enrolled. The median progression-free and overall survivals were 2.4 months (95% CI, 1.3–3.5) and 11.6 months (95% CI, 5.3–18.0), respectively. Two patients with a partial response received nivolumab for 2 years without disease progression. FACS revealed the lowest ratio of myeloid-derived suppressor cells (MDSCs) to CD8 + T-cell throughout the treatment in 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 (TRFC), which mediates ferroptosis and phagocytosis, was higher in responders than in non-responders before treatment. Conclusions CA-IT did not improve nivolumab efficacy in NSQ-NSCLCs with low PD-L1 expression. However, CA-IT induced deceasing MDSC resulted in durable response. Higher baseline TRFC levels may predict favorable response to nivolumab in NSCLC with low PD-L1 expression. Trial Registration: NCT03808480

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Purpose: Circulating cell-free DNA (CFDNA) was investigated as potential screening or prognostic markers in a variety of cancers. This study investigated its clinical significance in a homogeneous group of lung cancer patients.Experimental Design: We analyzed the blood samples of 134 never smokers with advanced lung adenocarcinoma, who were enrolled in a prospective randomized phase III study (First-SIGNAL) comparing gefitinib with gemcitabine plus cisplatin (GP) as first-line therapy. The amount of plasma CFDNA was measured by real-time quantitative PCR targeting the human ACTB genomic sequence. The patients were divided into three groups according to the tertiles of baseline plasma CFDNA.Results: Baseline plasma CFDNA did not correlate with primary tumor size (P = 0.961), whereas the number of metastatic sites correlated significantly with baseline plasma CFDNA (P = 0.015). In the GP arm, the low-CFDNA group showed a lower response rate than the middle- or high-CFDNA group (26.1%, 57.9%, and 60.9%, respectively; P = 0.035). However, in the gefitinib arm, there was no difference in response rate between the three CFDNA groups (57.1%, 47.4%, and 51.9%; respectively; P = 0.825). The high tertile CFDNA group showed a significantly shorter survival than the low tertile CFDNA group (median overall survival, 16.0 vs. 28.6 months, respectively; P = 0.030). The risk of death increased with increased baseline plasma CFDNA (HR = 1.23, 95% CI, 1.01–1.50; P = 0.045).Conclusion: High plasma CFDNA is associated with aggressive tumor behavior and poor survival outcomes in these patients. Clin Cancer Res; 17(15); 5179–87. ©2011 AACR.

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.

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. 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. 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 0.05). All agreement measures between radiologist-assessed 4X categorization and lung cancer diagnosis increased in session 2 (p < 0.05). Radiologist training can improve reader agreement on 4X categorization, leading to enhanced diagnostic performance for lung cancer. • 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.

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. 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. 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). 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. • 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.

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.

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. 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. 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). Lung-RADS, when reinforced with visual assessment–based categories, has a similar diagnostic performance to the Brock model for baseline CT scans. • 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).

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.

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. 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). 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

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. 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. 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

PurposeImmune 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 MethodsIn 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. ResultsPneumonitis 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).ConclusionSequential 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.

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 χ

The essential micronutrient zinc plays regulatory roles in immune responses through its ability to affect signaling pathways. In activated monocytes/macrophages, signaling networks mediate metabolic reprogramming in order to meet the demands of participating in immune responses. Despite its known immunoregulatory roles, the effect of zinc on metabolic reprogramming in monocytes/macrophages remains unclear. Here, we demonstrate that cytoplasmic bioavailable zinc is essential for regulating IL-1β production in activated human monocytes/macrophages downstream of mTORC1-induced glycolysis. The cytoplasmic zinc level was influenced by extracellular zinc concentration through a zinc-specific importer, Zip8, which was markedly increased in monocytes of patients with rheumatoid arthritis (RA), a chronic inflammatory disease, and even in LPS-stimulated monocytes/macrophages of healthy individuals. Mechanically, phosphorylation of S6 kinase, a substrate of mTORC1, was significantly enhanced by zinc-mediated inhibition of PP2A, an S6 kinase phosphatase. As a result, IL-1β production was increased due to the activation of mTORC1-induced glycolysis. The expression of Zip8 and MT2A, a zinc-inducible gene, and the phosphorylation of S6 kinase by monocytes of RA patients was significantly enhanced compared with those of HCs and Zip8 levels positively correlated with RA clinical parameters, suggesting that Zip8-mediated zinc influx is related to inflammatory conditions. These results provide insight into the role of cytoplasmic bioavailable zinc in the metabolic reprogramming of human monocytes/macrophages which is an essential process for inflammatory responses.One Sentence SummaryCytoplasmic zinc regulates IL-1β production in monocytes/macrophages downstream of mTORC1-S6K-induced glycolysis via zinc-mediated inhibition of PP2A.

Purpose: Immune checkpoint inhibitor(ICI) therapies are a standard treatment for advanced non-small-cell lung cancer(NSCLC). However, the beneficial effects are limited to a small subset of patients. Primary resistance to ICIs has been attributed to various kinds of suppressive immune regulatory cells in tumor-microenvironment. Different strategies have thus been explored to escape from immune evasion by depleting and/or inactivating these regulatory cells. Given the immune-modulating effects of low doses of cyclophosphamide and adriamycin (CA), we assessed the efficacy of CA induction therapy to modulate the antitumor effect of the nivolumab in advanced NSCLC. Methods: This was a single center, open-label, single arm, phase II trial of nivolumab after CA induction therapy in previously treated advanced non-squamous NSCLC with PD-L1 Results: A total of 22 patients were enrolled; the median age, 61 years old; female, 81%; adenocarcinoma histology, 76.2%; and current or former smoker, 26.9%. The ORR and disease control rate (DCR) were 9.1% (95% confidence interval [CI], 1.9 -26.1)) and 22.7% (95% CI, 9.2-42.9) respectively. The median PFS and OS were 2.4 months (95% CI, 1.3-3.5) and 11.6 months (95% CI, 5.3-18.0) respectively. Though there were no significant safety signals during the trial, 72% of patients had grade 3 or 4 hematologic toxicities including neutropenia and anemia during CA combination. Regarding MDSC (HLA-DR-Lin-CD11b+CD33+) level, two patients with good response correlatively maintained the low ratio ( Conclusions: Our study didn’t meet the primary endpoint. However, CA induction prior to nivolumab showed an immune-modulating potential by decreasing MDSC in two responders. Further augmentation studies for enhancing ICIs response are warranted. As more patients gets ICIs, combination strategy with various immune modulator harbors great potential to eliminate the immunosuppressive mechanism within the tumor microenvironment architecture. Citation Format: Beung-Chul Ahn, Hyae Young Kim, Geon Kook Lee, Sang-Jin Lee, Ji-Eun Hwang, Kyoungsuk Kwon, Youngjoo Lee, Ji-Youn Han. Nivolumab after cyclophosphamide and doxorubicin induction therapy in previously treated advanced non-squamousl non-small cell lung cancer with PD-L1

9107 Background: Synergistic anti-tumor effect of double blocking EGFR and VEGF pathways is proven by preclinical and clinical data. This study evaluated whether an addition of bevacizumab to erlotinib improves clinical outcomes in patients (pts) with untreated advanced EGFR-mutated NSCLC. Methods: This is an open-label, multi-center, randomized phase II study conducted in South Korea. Key eligibility was age ≥ 19 years old, untreated stage IIIB/IV NSCLC, EGFR exon 19 deletion or exon 21 L858R mutation, and ECOG performance status of 0 or 1. Asymptomatic brain metastasis (BM) was permitted without local treatment. Pts were randomly assigned to receive either oral erlotinib (E) 150 mg/day alone or erlotinib plus bevacizumab (E+B) at 15 mg/kg intravenously every 3 weeks. Primary endpoint was progression-free survival (PFS) with secondary endpoints including response rate (RR), overall survival (OS), and toxicity. Results: Between Dec 16, 2016, and Mar 8, 2019, a total of 127 pts were randomly assigned to receive E (n=63) or E+B (n=64). Median follow-up duration was 38.9 months. Fifty-nine (46.5%) pts had baseline BM. While the prevalence of baseline BM was similar between both arms (45.3% vs. 47.6%), more pts of the E arm received radiotherapy for BM before the study enrollment, compared to the E+B arm (40.0% vs. 10.3%). A trend toward improved PFS was observed with the E+B arm compared to the E arm (median PFS, 17.5 months vs 12.4 months; hazard ratio [HR] = 0.74 [95% confidence interval (CI), 0.51–1.08], P= 0.119). The RR was similar between both arms (85.9% vs. 83.9%; P= 0.746). The most significant PFS benefit from the E+B was found in the subgroup with baseline BM (median PFS, 18.6 months vs 10.3 months; HR = 0.54 [95% CI, 0.31–0.95], P= 0.032). The 12-month and 24-month cumulative central nervous system (CNS) progression rate was 4.4% and 6.8% in the E+B arm compared to 15.1% and 32.5% in the E arm. Thus, the E+B arm significantly reduced the risk for CNS progression than the E arm (HR = 0.33 [95% CI, 0.11–0.93], P= 0.035). Grade 3 or worse adverse events occurred in 56.6% of the E+B arm while 20.6% of the E arm. The E+B arm tended to increase the incidence or severity of some erlotinib-related adverse effects: grade 3 skin rash (17.2% vs. 4.8%) and any grade paronychia (60.9% vs. 46.0%), and oral mucositis (51.6% vs. 33.3). At the time of disease progression, more pts in the E arm showed EGFR T790M positivity (82% vs. 64%) and received 3rd generation EGFR tyrosine kinase inhibitor as the 2nd line therapy (58% vs. 22%) compared to the E+B arm. OS data are immature (events: 34%, HR = 1.24 [95% CI, 0.68–2.26]). Conclusions: A trend to improvement in PFS was observed with the combination of erlotinib and bevacizumab vs. erlotinib alone in advanced EGFR-mutated NSCLC. Especially, the PFS benefit from this combination was most significant in the pts with BM. Clinical trial information: NCT03126799.

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.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.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%; p0.001). 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 (p0.05), and experienced and inexperienced reviewers exhibited comparable agreement performance in session 2 (p0.05). All agreement measures between radiologist-assessed 4X categorization and lung cancer diagnosis increased in session 2 (p0.05).Radiologist training can improve reader agreement on 4X categorization, leading to enhanced diagnostic performance for lung cancer.• 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.

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.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.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).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.• 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.

Purpose To reduce lung cancer mortality, lung cancer screening was recommended using low-dose computed tomography (LDCT) to high-risk population. A protocol for multicenter lung cancer screening pilot project was developed to evaluate the effectiveness and feasibility of lung cancer screening to implement National Cancer Screening Program in Korea. Materials and methods Multidisciplinary expert committee was comprised to develop a standardized protocol for Korean Lung Cancer Screening Project (K-LUCAS). K-LUCAS is a population-based single arm trial that targets high-risk population aged 55-74 years with at least 30 pack-year smoking history. LDCT results are reported by Lung-RADS suggested by American Radiology Society. Network-based system using computer-aided detection program is prepared to assist reducing diagnostic errors. Smoking cessation counselling is provided to all currently smoking participants. A small pilot test was conducted to check the feasibility and compliance of the protocols for K-LUCAS. Results In pilot test, 256 were participated. The average age of participants was 63.2 years and only three participants (1.2%) were female. The participants had a smoking history of 40.5 pack-year on average and 53.9% were current smokers. Among them, 86.3% had willing to participate in lung cancer screening again. The average willingness to quit smoking among current smokers was 12.7% higher than before screening. In Lung-RADS reports, 10 (3.9%) were grade 3 and nine (3.5%) were grade 4. One participant was diagnosed as lung cancer. Conclusion The protocol developed by this study is assessed to be feasible to perform K-LUCAS in multicenter nationwide scale.

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.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).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.Considerable inter-institution variability in the interpretation of LCS results is caused by different usage of the computer-assisted system.• 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.

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.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.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.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.• 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.

Purpose Because of growing concerns about lung cancer in female never smokers, chest low-dose computed tomography (LDCT) screening is often performed although it has never shown clinical benefits. We examinewhether or not female never smokers really need annual LDCT screening when the initial LDCT showed negative findings. Materials and methods This retrospective cohort study included 4,365 female never smokers aged 40 to 79 years who performed initial LDCT from Aug 2002 to Dec 2007. Lung cancer diagnosis was identified from the Korea Central Cancer Registry Database registered until December 31, 2013. We calculated the incidence, cumulative probability, and standardized incidence ratio (SIR) of lung cancer by Lung Imaging Reporting and Data System (Lung-RADS) categories showed on initial LDCT. Results After median follow-up of 9.69 years, 22 (0.5%) had lung cancer. Lung cancer incidence for Lung-RADS category 4 was 1,848.4 (95% confidence interval [CI], 1,132.4 to 3,017.2) per 100,000 person-years and 16.4 (95% CI, 7.4 to 36.4) for categories 1, 2, and 3 combined. The cumulative probability of lung cancer for category 4 was 10.6% at 5 years and 14.8% at 10 years while they were 0.07% and 0.17% when categories 1, 2, and 3 were combined. The SIR for subjects with category 4 was 43.80 (95% CI, 25.03 to 71.14), which was much higher than 0.47 (95% CI, 0.17 to 1.02) for categories 1, 2, and 3 combined. Conclusion Considering the low risk of lung cancer development in female never smokers, it seems unnecessary to repeat annual LDCT screening for at least 5 years or even longer unless the initial LDCT showed Lung-RADS category 4 findings.

We report the first case of a 62-year-old man with a sclerosing pneumocytoma (SP) combined with a typical carcinoid (TC) and pulmonary adenocarcinoma in different lung lobes. Computed tomography revealed two nodules. The radiological diagnosis was primary lung cancer and a metastatic nodule; however, no enlarged lymph nodes were observed. Histological and immunohistochemical analyses defined the 1.7 cm nodule in the right upper lobe as adenocarcinoma and the 1.3 cm nodule in the left lower lobe as SP combined with TC. This case is noteworthy because of the rarity of SP combined with TC, the comprehensive examination of frozen and permanent sections, and the clinical implications of the differential diagnosis of lung nodules.

Background & Aim Respiratory mucosa defect results airway obstruction and infection. Functional recovery of respiratory epithelium, including ciliary movement and mucus secretion, is mandatory. Since site-specific extracellular matrix (ECM) facilitates restoration of the organ function by helping cellular migration and engraftment, a decellularized trachea was considered as ideal ECM in previous studies. However, incomplete removal of cells in cartilage and destruction of mucosal architecture were frequently reported. This results due to the different susceptibility of tissues to various decellularizing agent. To address this issue, the idea of conducting the individual decellularization protocol for separated respiratory mucosa and cartilage was raised. Methods, Results & Conclusion Porcine tracheas were obtained from adult market-sized pig. The trachea was divided into six groups according to their decellularization protocol as follows; native mucosa(N), freezing-thawing(FT), freezing-thawing-DNase/Perasafe™-based chemical agents before separation (tFTD/tFTP) and after separation(mFTD/mFTP). Decelluarization efficacy was evaluated using DNA quantification and H&E stain. ECM contents of the scaffold were evaluated by histological evaluation, glycosaminoglycan(GAG)/collagen assay. Biocompatibility was accessed by cell viability assay and in vivo transplantation. The scaffolds from chemical agent protocols showed low DNA contents ( When comparing the differences by chemical agents, GAG and collagen content was higher in DNase groups than Perasafe™ groups. Laminin and fibronectin were preserved more in mFTP groups. The Cells remained viable when seeded upon the mFTP scaffolds in vitro, and in vivo host response showed a pattern of constructive remodeling when the mFTP scaffolds were implanted. Xenogenic acellular respiratory mucosa matrix which was fabricatied using Perasafe as chemical decellularizing agent on separated porcine tracheal mucosa demonstrated suitable biocompatibility as a scaffold material for respiratory mucosa engineering.

Purpose We examined the efficacy of poziotinib, a second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) in patients with lung adenocarcinoma with activating EGFR mutations, who developed acquired resistance (AR) to EGFR-TKIs. Materials and methods This single-arm phase II study included EGFR-mutant lung adenocarcinoma with AR to erlotinib or gefitinib based on the Jackman criteria. Patients received poziotinib 16 mg orally once daily in a 28-day cycle. The primary endpoint was progression-free survival (PFS). Prestudy tumor biopsies and blood samples were obtained to determine resistance mechanisms. Results Thirty-nine patients were treated. Tumor genotyping was determined in 37 patients; 19 EGFR T790M mutations and two PIK3CA mutations were detected in the prestudy tumors, and seven T790M mutations were detected in the plasma assay. Three (8%; 95% confidence interval [CI], 2 to 21) and 17 (44%; 95% CI, 28 to 60) patients had partial response and stable disease, respectively. The median PFS and overall survival were 2.7 months (95% CI, 1.8 to 3.7) and 15.0 months (95% CI, 9.5 to not estimable), respectively. A longer PFS was observed for patients without T790M or PIK3CA mutations in tumor or plasma compared to those with these mutations (5.5 months vs. 1.8 months, p=0.003). The most frequent grade 3 adverse events were rash (59%), mucosal inflammation (26%), and stomatitis (18%). Most patients required one (n=15) or two (n=15) dose reductions. Conclusion Low activity of poziotinib was detected in patients with EGFR-mutant non-small cell lung cancer who developed AR to gefitinib or erlotinib, potentially because of severe-toxicityimposed dose limitation.

Ahead of Print article withdrawn by publisher.

PURPOSE Paclitaxel (P) and gemcitabine (G) are clinically synergistic in small cell lung cancer (SCLC). We evaluated the efficacy of PG as a salvage treatment for SCLC patients whose disease progressed after a platinum-containing regimen. MATERIALS AND METHODS Eligibility included histologically confirmed SCLC, one dimensionally measurable disease, Eastern Cooperative Oncology Group performance status 0-2, and progressive disease after platinum-based chemotherapy. Treatment consisted of P (80 mg/m(2)) and G (1,000 mg/m(2)) on days 1 and 8 of each cycle of 21 days until disease progression. RESULTS Thirty-three patients seen between December 2005 and February 2009 were selected into this study. Thirty patients (91%) had received irinotecan-platinum, and three had received etoposide-platinum. Sixteen patients (49%) had a treatment-free interval of less than 3 months. The overall response rate was 30.3% (29.4% in sensitive relapse and 31.3% in refractory relapse). The median time to progression was 12.0 weeks and median overall survival (OS) 31.0 weeks, with a 1-year OS rate of 30.3%. Toxicities were moderate and manageable with 18.2% grade (G) 4 neutropenia, 24.2% G3 thrombocytopenia, 6.1% G3 sensory neuropathy, and 3% G3 asthenia. One patient developed febrile neutropenia. CONCLUSION Second-line paclitaxel and gemcitabine were well-tolerated and moderately active in SCLC patients previously treated with platinum-based chemotherapy.

BACKGROUND Data are insufficient regarding the survival benefit of surveillance for hepatocellular carcinoma (HCC). AIM To investigate the effectiveness of HCC surveillance in a hepatitis B-endemic population. METHODS This retrospective cohort study included 1402 consecutive patients who were newly diagnosed with HCC between 2005 and 2012 at a single tertiary hospital in Korea. The primary endpoint was overall survival. Lead-time and length-time biases were adjusted (sojourn time = 140 days) and sensitivity analyses were performed. RESULTS The most common aetiology was hepatitis B (80.4%). Cirrhosis was present in 78.2%. HCC was diagnosed during regular surveillance (defined as mean interval of ultrasonography

BACKGROUND: Falls are among the most frequent critical health problems for older adults over 65 years of age and often result in consequential injuries. AIM: This study developed a guideline covering risk factors and interventions for falls in order to prevent them from occurring in long-term care facilities. METHODS: This study was grounded in the methodological approach of the Scottish Intercollegiate Guideline Network for establishing evidence-based guidelines: (1) establishment of the target population and scope of the guideline, (2) systematic literature review and critical analysis, (3) determination of the recommendation grade, (4) development of a draft nursing intervention guideline and algorithm, (5) expert evaluation of the draft nursing intervention guideline, and (6) confirmation of the final intervention guideline and completion of the algorithm. RESULTS: The resulting evidence-based fall prevention guideline consists of a three-step factor assessment and a three-step intervention approach. LIMITATIONS: The resulting guideline was based on the literature and clinical experts. Further research is required to test the guideline's feasibility in across long term care facilities. CONCLUSION: This guideline can be used by nurses to screen patients who are at a high risk of falling to provide patient interventions to help prevent falls. IMPLICATIONS FOR NURSING AND HEALTH POLICY: Considering the high rate of falls at long-term care facilities and the absence of evidence-based guidelines to prevent them, additional studies on falls at long-term care facilities are necessary. Meanwhile, given prior research that indicates the importance of human resources in the application of such guidelines, continuous investigations are needed as to whether the research outcomes are actually conveyed to nurses. Language: en

In patients with lung cancer acquiring resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), an intrapatient heterogeneity in response to retreatment with EGFR-TKIs remains to be elucidated.Records were retrospectively reviewed for 68 patients with advanced non-small-cell lung cancer who received second EGFR-TKIs after systemic progression that followed durable response to the first EGFR-TKIs. All tumor lesions identified on radiologic images before second EGFR-TKIs were categorized into organs. Tumor response to EGFR-TKIs was assessed per patient and per organ. Mixed response (MR) was defined as the coexistence of at least 2 responsive and progressive organs.Tumor lesions were detected in 244 organs. The response rate (RR) and median time to progression (TTP) to second EGFR-TKIs for patients were 26.5% and 11.6 weeks (95% CI, 8.5-14.7 weeks), and the RR and median TTP for organs were 38.8% and 17.3 weeks (95% CI, 14.8-19.8 weeks). Of 35 patients categorized to progressive disease, 22 (62.8%) showed MR. Among organs, the RR was highest for the central nervous system (CNS) and lowest for the liver (CNS vs. others vs. liver: 77.8%, 36.9%, 17.6%; P.001). Multivariate analysis confirmed the organ type and prior drug sensitivity at the time of stopping first EGFR-TKIs as predictors for the risk of progression to second EGFR-TKIs in organs.Intrapatient heterogeneity in response to second EGFR-TKIs is not a rare event. The organ type and prior drug sensitivity at the failure time of first EGFR-TKIs may predict the efficacy of second EGFR-TKIs in individual organs.

Purpose Gefitinib has shown high response rate and improved progression-free survival (PFS) in never-smokers with lung adenocarcinoma (NSLAs). We compared efficacy of gefitinib with gemcitabine and cisplatin (GP) chemotherapy in this group of patients as first-line therapy. Patients and Methods In this randomized phase III trial, a total of 313 Korean never-smokers with stage IIIB or IV lung adenocarcinoma, Eastern Cooperative Oncology Group performance status 0 to 2, and adequate organ function were randomly assigned to receive either gefitinib (250 mg daily) or GP chemotherapy (gemcitabine 1,250 mg/m2 on days 1 and 8; cisplatin 80 mg/m2 on day 1 every 3 weeks, for up to nine courses). The primary objective was to demonstrate better overall survival (OS) for gefitinib compared with GP in chemotherapy-naive NSLAs. Results Three hundred nine patients were analyzed per protocol (gefitinib arm, n = 159; GP arm, n = 150). Gefitinib did not show better OS compared with GP (hazard ratio [HR], 0.932; 95% CI, 0.716 to 1.213; P = .604; median OS, 22.3 v 22.9 months, respectively). The 1-year PFS rates were 16.7% with gefitinib and 2.8% with GP (HR, 1.198; 95% CI, 0.944 to 1.520). Response rates were 55% with gefitinib and 46% with GP (P = .101). Myelosuppression, renal insufficiency, and fatigue were more common in the GP arm, but skin toxicities and liver dysfunction were more common in the gefitinib arm. Two patients (1.3%) in the gefitinib arm developed interstitial lung disease and died. Conclusion Gefitinib failed to demonstrate superior OS compared with GP as first-line therapy for NSLAs.

Sarcoidosis is an inflammatory disease involving multiple-organs with an unknown cause. The new onset of sarcoidosis associated with therapeutic agents has been observed in 3 clinical settings; tumor necrosis factor antagonists in autoimmune rheumatologic diseases, interferon alpha with or without ribavirin in patients with chronic hepatitis C or melanoma, and antineoplastic agent-associated sarcoidosis in patients with hematologic malignancies. Here, we report a female patient who developed sarcoidosis after capecitabine treatment as an adjuvant chemotherapy for sigmoid colon cancer. To our knowledge, this is the first report of a capecitabine-induced sarcoidosis.