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Summary: Background: Lung cancer diagnostic guidelines advocate for invasive mediastinal nodal staging (IMNS), but the survival benefits of this approach in patients with non-small cell lung cancer (NSCLC) without radiologic evidence of lymph node metastasis (rN0) remain uncertain. We aimed to investigate the impact of IMNS in patients with rN0 NSCLC by comparing the long-term survival between patients who underwent IMNS and those who did not (non-IMNS). Methods: In this retrospective cohort study, we included patients with NSCLC but without radiologic evidence of lymph node metastasis from the Registry for Thoracic Cancer Surgery and the clinical data warehouse at the Samsung Medical Centre, Republic of Korea between January 2, 2008 and December 31, 2016. We compared the 5-year overall survival (OS) rate as the primary outcome after propensity score matching between the IMNS and non-IMNS groups. The age, sex, performance statue, tumor size, centrality, solidity, lung function, FDG uptake in PET-CT, and histological examination of the tumor before surgery were matched. Findings: A total of 4545 patients (887 in the IMNS group and 3658 in the non-IMNS group) who received curative treatment for NSCLC were included in this study. By the mediastinal node dissection, the overall incidence of unforeseen mediastinal node metastasis (N2) was 7.2% (317/4378 patients). Despite the IMNS, 67% of pathological N2 was missed (61/91 patients with unforeseen N2). Based on propensity score matching, 866 patients each for the IMNS and non-IMNS groups were assigned. There was no significant difference in 5-year OS and recurrence-free survival (RFS) between two groups: 5-year OS was 73.9% (95% confidence interval, CI: 71%–77%) for IMNS and 71.7% (95% CI: 68.6%–74.9%; p = 0.23), for non-IMNS (hazard ratio, HR 0.90, 95% CI: 0.77–1.07), while 5-year RFS was 64.7% (95% CI: 61.5%–68.2%) and 67.5% (95% CI: 64.3%–70.9%; p = 0.35 (HR 1.08, 95% CI: 0.92–1.27), respectively. Moreover, the timing and locations of recurrence were similar in both groups. Interpretation: IMNS might not be required before surgery for patients with NSCLC without LN suspicious of metastasis. Further randomised trials are required to validate the findings of the present study. Funding: None.

Background Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment and significantly contribute to immune evasion. We investigated the effects of CAFs on the immune function of CD4+ and CD8+ T cells in non-small cell lung cancer (NSCLC). Methods We isolated CAFs and normal fibroblasts (NFs) from tumors and normal lung tissues of NSCLC patients, respectively. CAFs were co-cultured with activated T cells to evaluate their immune regulatory function. We investigated the effect of CAF conditioned medium (CAF-CM) on the cytotoxicity of T cells. CAFs were also co-cultured with activated peripheral blood mononuclear cells and further incubated with cyclooxygenase-2 (COX2) inhibitors to investigate the potential role of COX2 in immune evasion. Results CAFs and NFs were isolated from the lung tissues (n=8) and lymph nodes (n=3) of NSCLC patients. Immune suppressive markers, such as COX2 and programmed death-ligand 1 (PD-L1), were increased in CAFs after co-culture with activated T cells. Interestingly, CAFs promoted the expression of programmed death-1 in CD4+ and CD8+ T cells, and strongly inhibited T cell proliferation in allogenic and autologous pairs of CAFs and T cells. CAF-CM decreased the cytotoxicity of T cells. COX2 inhibitors partially restored the proliferation of CD4+ and CD8+ T cells, and downregulated the expression of COX2, prostaglandin E synthase, prostaglandin E2, and PD-L1 in CAFs. Conclusion CAFs promote immune evasion by suppressing the function of CD4+ and CD8+ T cells via their effects on COX2 and PD-L1 in NSCLC. The immunosuppressive function of CAFs could be alleviated by COX2 inhibitors.

Abstract Methylation patterns in cell-free DNA (cfDNA) have emerged as a promising genomic feature for detecting the presence of cancer and determining its origin. The purpose of this study was to evaluate the diagnostic performance of methylation-sensitive restriction enzyme digestion followed by sequencing (MRE-Seq) using cfDNA, and to investigate the cancer signal origin (CSO) of the cancer using a deep neural network (DNN) analyses for liquid biopsy of colorectal and lung cancer. We developed a selective MRE-Seq method with DNN learning-based prediction model using demethylated-sequence-depth patterns from 63,266 CpG sites using SacII enzyme digestion. A total of 191 patients with stage I–IV cancers (95 lung cancers and 96 colorectal cancers) and 126 noncancer participants were enrolled in this study. Our study showed an area under the receiver operating characteristic curve (AUC) of 0.978 with a sensitivity of 78.1% for colorectal cancer, and an AUC of 0.956 with a sensitivity of 66.3% for lung cancer, both at a specificity of 99.2%. For colorectal cancer, sensitivities for stages I–IV ranged from 76.2 to 83.3% while for lung cancer, sensitivities for stages I–IV ranged from 44.4 to 78.9%, both again at a specificity of 99.2%. The CSO model's true-positive rates were 94.4% and 89.9% for colorectal and lung cancers, respectively. The MRE-Seq was found to be a useful method for detecting global hypomethylation patterns in liquid biopsy samples and accurately diagnosing colorectal and lung cancers, as well as determining CSO of the cancer using DNN analysis. Trial registration: This trial was registered at ClinicalTrials.gov (registration number: NCT 04253509) for lung cancer on 5 February 2020, https://clinicaltrials.gov/ct2/show/NCT04253509 . Colorectal cancer samples were retrospectively registered at CRIS (Clinical Research Information Service, registration number: KCT0008037) on 23 December 2022, https://cris.nih.go.kr , https://who.init/ictrp . Healthy control samples were retrospectively registered.

Abstract Background The prognosis of miliary pulmonary metastases (MPM), which are characterized as randomly disseminated, innumerable, and small metastatic nodules, has been considered as being poor. The purpose of this study was to evaluate the clinical characteristics and survival of MPM in patients with non‐small cell lung cancer (NSCLC). Methods This retrospective study included NSCLC patients with MPM and nonmiliary pulmonary metastases (NMPM) detected during staging evaluation between 2000 and 2020. MPM was defined as >50 bilaterally distributed metastatic pulmonary nodules (

Abstract Pulmonary lymphangitic carcinomatosis (PLC) is associated with a poor prognosis in patients with non-small cell lung cancer (NSCLC). We sought to determine prognostic value of pretherapeutic fluorine-18-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) in NSCLC with radiologically diagnosed PLC. We retrospectively reviewed 50 NSCLC patients with radiologically diagnosed PLC. Among eight clinical variables and five imaging parameters, metabolic PLC burden, which represents the overall tumor burden of PLC, and cPLC, which represents the location and extent of PLC in a three-grade system, were used. In multivariate analyses for progression-free survival, metabolic PLC burden (P = 0.0181), cPLC (P = 0.0401), and clinical stage (P = 0.0284) were identified as independent prognostic factors. High metabolic PLC burden had a worse prognosis, and the prognosis of cPLC3 was significantly worse than that of cPLC1 or cPLC2. In univariate analyses for overall survival, only age (P = 0.0073) was identified a prognostic factor. In conclusion, FDG PET/CT parameters were identified as independent prognostic factors in NSCLC with radiologically diagnosed PLC. Furthermore, a combination of anatomical and metabolic information about PLC obtained using FDG PET/CT provides insight into the overall tumor burden of PLC and is useful in predicting prognosis.

Abstract Background Lung cancer surgery is reported as a risk factor for chronic pulmonary aspergillosis (CPA). However, limited data are available on its clinical impact. We aimed to determine the effect of developed CPA after lung cancer surgery on mortality and lung function decline. Methods We retrospectively identified the development of CPA after lung cancer surgery between 2010 and 2016. The effect of CPA on mortality was evaluated using multivariable Cox proportional hazard analyses. The effect of CPA on lung function decline was evaluated using multiple linear regression analyses. Results During a median follow-up duration of 5.01 (IQR, 3.41–6.70) years in 6777 patients, 93 developed CPA at a median of 3.01 (IQR, 1.60–4.64) years. The development of CPA did not affect mortality in multivariable analysis. However, the decline in forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) were greater in patients with CPA than in those without (FVC, − 71.0 [− 272.9 to − 19.4] vs. − 10.9 [− 82.6 to 57.9] mL/year, p

Abstract Background Endobronchial ultrasound‐guided transbronchial needle aspiration (EBUS‐TBNA) is used to evaluate hilar/interlobar/lobar lymph nodes. This study aimed to assess the clinical utility of EBUS‐TBNA for station 10/11/12 lymph nodes (LNs) in patients with primary lung cancer. Methods This was a retrospective analysis of a prospectively collected database of patients with primary lung cancer who underwent EBUS‐TBNA for station 10/11/12 LNs from January 2015 to December 2019. Patients with benign results from EBUS‐TBNA who did not undergo surgical sampling/clinical follow‐up or who received radiotherapy/chemotherapy were excluded. Results The analyses were conducted on 889 LNs from 797 patients. The overall diagnostic sensitivity, specificity, accuracy, negative predictive value (NPV), and positive predictive value of EBUS‐TBNA were 95.7, 100, 97.3, 93.2, and 100%, respectively. Diagnostic sensitivity was significantly lower for LNs

BackgroundEpidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) showed potency as a non-invasive therapeutic approach in pure ground-glass opacity nodule (pGGN) lung adenocarcinoma. However, optimal methods of extracting information about EGFR mutation from pGGN lung adenocarcinoma images remain uncertain. We aimed to develop, validate, and evaluate the clinical utility of a deep learning model for predicting EGFR mutation status in lung adenocarcinoma manifesting as pGGN on computed tomography (CT).MethodsWe included 185 resected pGGN lung adenocarcinomas in the primary cohort. The patients were divided into training (n = 125), validation (n = 23), and test sets (n = 37). A preoperative CT-based deep learning model with clinical factors as well as clinical and radiomics models was constructed and applied to the test set. We evaluated the clinical utility of the deep learning model by applying it to 83 GGNs that received EGFR-TKI from an independent cohort (clinical validation set), and treatment response was regarded as the reference standard.ResultsThe prediction efficiencies of each model were compared in terms of area under the curve (AUC). Among the 185 pGGN lung adenocarcinomas, 122 (65.9%) were EGFR-mutant and 63 (34.1%) were EGFR-wild type. The AUC of the clinical, radiomics, and deep learning with clinical models to predict EGFR mutations were 0.50, 0.64, and 0.85, respectively, for the test set. The AUC of deep learning with the clinical model in the validation set was 0.72.ConclusionsDeep learning approach of CT images combined with clinical factors can predict EGFR mutations in patients with lung adenocarcinomas manifesting as pGGN, and its clinical utility was demonstrated in a real-world sample.

Abstract Chronic obstructive pulmonary disease (COPD), an established risk factor for lung cancer, remains largely undiagnosed and untreated before lung cancer surgery. We evaluated the effect of perioperative bronchodilator therapy on lung function changes in COPD patients who underwent surgery for non-small cell lung cancer (NSCLC). From a database including NSCLC patients undergoing lung resection, COPD patients were identified and divided into two groups based on the use of bronchodilator during the pre- and post-operative period. Changes in forced expiratory volume in 1 s (FEV1) and postoperative complications were compared between patients treated with and without bronchodilators. Among 268 COPD patients, 112 (41.8%) received perioperative bronchodilator, and 75% (84/112) were newly diagnosed with COPD before surgery. Declines in FEV1 after surgery were alleviated by perioperative bronchodilator even after adjustments for related confounding factors including surgical extent, surgical approach and preoperative FEV1 (adjusted mean difference in FEV1 decline [95% CI] between perioperative bronchodilator group and no perioperative bronchodilator group; − 161.1 mL [− 240.2, − 82.0], − 179.2 mL [− 252.1, − 106.3], − 128.8 mL [− 193.2, − 64.4] at 1, 4, and 12 months after surgery, respectively). Prevalence of postoperative complications was similar between two groups. Perioperative bronchodilator therapy was effective to preserve lung function, after surgery for NSCLC in COPD patients. An active diagnosis and treatment of COPD are required for surgical candidates of NSCLC.

Background Radial probe endobronchial ultrasound (R-EBUS), is effective for tissue diagnosis of lung lesions. We evaluated the diagnostic performance of R-EBUS both a guide-sheath and fluoroscopy and identified factors associated with accurate diagnosis. The feasibility of molecular and genetic testing, using specimens obtained by R-EBUS, was also investigated. Methods The study retrospectively reviewed 211 patients undergoing R-EBUS without a guide-sheath and fluoroscopy, June 2016-May 2017. After excluding 27 patients of which the target lesion was not reached, 184 were finally included. Multivariate logistic regression was used, to identify factors associated with accurate diagnosis. Results Among 184 patients, R-EBUS-guided biopsy diagnosed malignancy in 109 patients (59%). The remaining 75 patients (41%) with non-malignant results underwent additional work-ups, and 34 were diagnosed with malignancy. Based on final diagnosis, diagnostic accuracy was 80% (136/170), and sensitivity and specificity for malignancy were 76% (109/143) and 100% (27/27), respectively. In multivariate analysis, peripheral location (adjusted odds ratio [aOR], 3.925; 95% confidence interval [CI], 1.203–12.811; p=0.023), and central position of the probe (aOR, 2.435; 95% CI, 1.424–7.013; p=0.035), were associated with accurate diagnosis of malignancy. Molecular and genetic analyses were successful, in all but one case, with inadequate specimens. Conclusion R-EBUS-guided biopsy without equipment, is effective for tissue diagnosis. Peripheral location and central position of the radial probe, were crucial for accurate diagnosis. Performance of molecular and genetic testing, using samples obtained by R-EBUS, was satisfactory.

Abstract Background Endosonography with needle aspiration (EBUS/EUS-NA) is recommended as the first choice for mediastinal nodal assessment in non-small cell lung cancer (NSCLC). It is important to maintain adequate negative predictive value of the procedure to avoid unnecessary additional surgical staging, but there are few studies on the influence of operator-related factors including competency on false negative results. This study aims to compare the false negative rate of individual operators and whether it changes according to accumulation of experience. Methods This is a retrospective study of NSCLC patients who were N0/N1 by EBUS/EUS-NA and confirmed by pathologic staging upon mediastinal lymph node dissection (n = 705). Patients were divided into a false negative group (finally confirmed as pN2/N3) and a true negative group (pN0/N1). False negative rates of six operators and whether these changed according to accumulated experience were analyzed. Results There were 111 (15.7%) false negative cases. False negative rates among six operators ranged from 8.3 to 21.4%; however, there were no statistical differences before and after adjustment for patient characteristics and procedure-related factors (P = 0.346 and P = 0.494, respectively). In addition, false negative rates did not change as each operator accumulated experience (P for trend = 0.632). Conclusions Our data suggest that there would be no difference in false negative rates regardless of which operator performs the procedure assuming that the operators have completed a certain period of observation and have performed procedures under the guidance of an expert.

The aim of this study is to determine the cumulative incidence of, and the risk factors for, the development of nontuberculous mycobacteria pulmonary disease (NTM-PD) following lung cancer surgery. We retrospectively analyzed patients with non-small cell lung cancer who underwent surgical resection between 2010 and 2016. Patients who met all the diagnostic criteria in the NTM guidelines were defined as having NTM-PD. Additionally, we classified participants as NTM-positive when NTM were cultured in respiratory specimens, regardless of the diagnostic criteria. We followed 6503 patients for a median of 4.89 years, and NTM-PD and NTM-positive diagnoses occurred in 59 and 156 patients, respectively. The cumulative incidence rates of NTM-PD and NTM-positive were 2.8% and 5.9% at 10 years, respectively. Mycobacterium avium complex was the most commonly identified pathogen, and half of the NTM-PD patients had cavitary lesions. Several host-related factors (age > 65 years, body mass index ≤ 18.5 kg/m2, interstitial lung disease, bronchiectasis, and bronchiolitis) and treatment-related factors (postoperative pulmonary complications and neoadjuvant/adjuvant treatments) were identified as risk factors for developing NTM-PD and/or being NTM-positive after lung cancer surgery. The incidences of NTM-PD and NTM-positive diagnoses after lung cancer surgery were not low, and half of the NTM-PD patients had cavitary lesions, which are known to progress rapidly and often require treatment. Therefore, it is necessary to raise awareness of NTM-PD development after lung cancer surgery.

IntroductionThe maximum standardized uptake value (SUVmax) in 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) may be of prognostic significance for patients with malignant pleural mesothelioma (MPM). This retrospective study aimed to investigate the prognostic value of the SUVmax in patients with MPM.Materials and methodsMedical records were retrospectively reviewed for the patients who were diagnosed with histopathologically proven MPM between 2009 and 2018 at Samsung Medical Center. For each patient, SUVmax was calculated for the primary lesion on PET/CT. To determine optimal cutoff values for predicting mortality, receiver operating characteristic curves were used.ResultsAmong the 54 study patients, 34 (63.0%) had epithelioid subtype, 13 (24.1%) had sarcomatoid or biphasic subtype, and 7 (13.0%) had mesothelioma, not otherwise specified (NOS). The median overall survival (OS) was 8.7 months, and the median SUVmax was 9.9. The median values of SUVmax were 5.5 in patients with epithelioid subtype, 11.7 in those with sarcomatoid/biphasic subtype, and 13.3 in those with NOS subtype (P = 0.003). The optimal cutoff values of SUVmax to predict mortality were 10.1 in all patients, and 8.5 in patients with epithelioid subtype. In multivariate analysis, SUVmax was significantly associated with overall survival in all patients (P = 0.003) and in patients with epithelioid subtype (P = 0.012), but not in those with non-epithelioid subtype.ConclusionsSUVmax in PET/CT is an independent prognostic factor in patients with MPM, especially those with epithelioid subtype. The histologic subtype of MPM should be considered when evaluating the prognostic significance of SUVmax.

Abstract Background The objective of this study was to discover DNA methylation biomarkers for detecting non-small lung cancer (NSCLC) in bronchial washings and understanding the association between DNA methylation and smoking cessation. Methods DNA methylation was analyzed in bronchial washing samples from 70 NSCLCs and 53 hospital-based controls using Illumina HumanMethylation450K BeadChip. Methylation levels in these bronchial washings were compared to those in 897 primary lung tissues of The Cancer Genome Atlas (TCGA) data. Results Twenty-four CpGs (p

Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive procedure widely used for the diagnosis and staging of primary lung cancer. This review focuses on the role of EBUS-TBNA in minimally invasive mediastinal staging, restaging after induction therapy, and procedure-related issues. To better understand the role of EBUS-TBNA, one must consider issues of sedation and rapid onsite examination, sonographic features during the procedure, the number of aspirations per lymph node, and the thoroughness of the procedure. A literature review indicated that EBUS-TBNA showed equivalent or even superior performance to mediastinoscopy in the mediastinal staging of non-small cell lung cancer (NSCLC). Combining endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) or the transesophageal approach using an EBUS bronchoscope (EUS-B-FNA) with EBUS-TBNA can provide additional diagnostic benefits. A recent guideline recommended endosonography over mediastinoscopy as the initial procedure for mediastinal nodal staging in patients with NSCLC with abnormal mediastinal and/or hilar lymph nodes on chest computed tomography (CT) or positron emission tomography/CT. The diagnostic sensitivity of EBUS-TBNA for restaging after induction therapy in patients with stage IIIA-N2 NSCLC was lower than that of initial staging. It appears reasonable to perform EBUS-TBNA first for initial mediastinal staging and reserve mediastinoscopy for restaging after induction therapy.

Abstract Background This study was aimed at understanding whether bronchial biopsy specimen can be used as a surrogate for DNA methylation analysis in surgically resected lung cancer. Methods A genome-wide methylation was analyzed in 42 surgically resected tumor tissues, 136 bronchial washing, 12 sputum, and 8 bronchial biopsy specimens using the Infinium HumanMethylation450 BeadChip, and models for prediction of lung cancer were evaluated using TCGA lung cancer data. Results Four thousand seven hundred and twenty-six CpGs (P 0.05, Wilcoxon rank-sum test). However, their methylation levels were significantly different between paired bronchial biopsy and washing (P

Pulmonary actinomycosis frequently mimics lung malignancy on radiologic imaging studies. Positron emission tomography-computed tomography (PET-CT) is a useful diagnostic modality for differentiating lung malignancy from benign diseases. However, few studies evaluated PET-CT findings of pulmonary actinomycosis. Therefore, it is unclear whether PET-CT is helpful to distinguish lung malignancy from benign lung disease when pulmonary actinomycosis is clinically suspected. We investigated PET-CT findings in 11 patients with pathologically confirmed pulmonary actinomycosis. The median maximal standardized uptake value (SUV) on PET-CT of pulmonary actinomycosis was increased to 5.5 (interquartile range, 4.2–8.8), which was higher than the threshold value of 2.5 indicating malignancy. Pulmonary actinomycosis without central necrosis demonstrated higher maximal SUV of 7.5 (4.9–12.2) compared to 4.8 (3.2–5.6) of ones with central necrosis. PET-CT might be not helpful in differentiating lung malignancy from benign lesions when pulmonary actinomycosis is clinically suspected.

Background and Objectives: The application of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has been markedly increased over the past decade. EBUS-TBNA is known to be a very safe and accurate procedure; however, the incidence of bleeding complications in patients who are taking antithrombotic agents (ATAs) is not well established. Materials and Methods: We conducted a retrospective analysis of a prospectively registered EBUS-TBNA cohort in a single tertiary hospital from May 2009 to December 2016. The patients were divided into two groups: an insufficient discontinuation group, defined as having a prescription for ATAs on the procedure day or only interrupting them for a short period of time, and a sufficient discontinuation group, defined as having prescription for ATAs during 30 days prior to the procedure and interrupting them for a sufficient period of time. Results: During the study period, a total of 4271 patients, after excluding 3773 patients who did not take ATAs at all, 498 patients were classified into the insufficient discontinuation group (n = 102) and the sufficient discontinuation group (n = 396). The baseline characteristics of patients and examined lesions between two groups were not significantly different, except insufficient discontinuation group had longer prothrombin times than the sufficient discontinuation group. In the insufficient discontinuation group, the most common reasons for prescriptions of ATAs were ischemic heart disease (48.0%) and cerebral vascular disease (28.4%), and half of the patients were taking two or more ATAs. Eventually, only one bleeding complication in the insufficient discontinuation group (1/102, 1.0%) and one event in the sufficient discontinuation group (1/396, 0.3%) occurred (p = 0.368). Conclusions: EBUS-TBNA is considered a safe procedure in terms of bleeding complications, even in patients with insufficient stopping of ATAs.

Lung resection surgery for non-small-cell lung cancer (NSCLC) is reportedly a risk factor for developing chronic pulmonary aspergillosis (CPA). However, limited data are available regarding the development of CPA during long-term follow-up after lung cancer surgery. This study aimed to investigate the cumulative incidence and clinical factors associated with CPA development after lung cancer surgery. We retrospectively analyzed 3423 patients with NSCLC who (1) underwent surgical resection and (2) did not have CPA at the time of surgery between January 2010 and December 2013. The diagnosis of CPA was based on clinical symptoms, serological or microbiological evidences, compatible radiological findings, and exclusion of alternative diagnoses. The cumulative incidence of CPA and overall survival (OS) were estimated using the Kaplan–Meier method, and a multivariable Cox proportional hazard analysis was performed to identify factors associated with CPA development. Patients were followed-up for a median of 5.83 years with a 72.3% 5-year OS rate. Fifty-six patients developed CPA at a median of 2.68 years after surgery, with cumulative incidences of 0.4%, 1.1%, 1.6%, and 3.5% at 1, 3, 5, and 10 years, respectively. Lower body mass index (BMI), smoking, underlying interstitial lung disease, thoracotomy, development of postoperative pulmonary complications 30 days after surgery, and treatment with both chemotherapy and radiotherapy were independently associated with CPA development. The cumulative incidence of CPA after surgery was 3.5% at 10 years and showed a steadily increasing trend during long-term follow-up. Therefore, increased awareness regarding CPA development is needed especially in patients with risk factors.

Background: Although epidermal growth factor receptor (EGFR), v-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS), and anaplastic lymphoma kinase (ALK) mutations in non-small cell lung cancer (NSCLC) were thought to be mutually exclusive, some tumors harbor concomitant mutations. Discovering a driver mutation on the basis of morphologic features and therapeutic responses with mutation analysis can be used to understand pathogenesis and predict resistance in targeted therapy. Methods: In 6,637 patients with NSCLC, 12 patients who had concomitant mutations were selected and clinicopathologic features were reviewed. Clinical characteristics included sex, age, smoking history, previous treatment, and targeted therapy with response and disease-free survival. Histologic features included dominant patterns, nuclear and cytoplasmic features. Results: All patients were diagnosed with adenocarcinoma and had an EGFR mutation. Six patients had concomitant KRAS mutations and the other six had KRAS mutations. Five of six EGFR-KRAS mutation patients showed papillary and acinar histologic patterns with hobnail cells. Three of six received EGFR tyrosine kinase inhibitor (TKI) and showed partial response for 7–29 months. All six EGFR-ALK mutation patients showed solid or cribriform patterns and three had signet ring cells. Five of six EGFR-ALK mutation patients received EGFR TKI and/or ALK inhibitor and four showed partial response or stable disease, except for one patient who had acquired an EGFR mutation. Conclusions: EGFR and ALK mutations play an important role as driver mutations in double mutated NSCLC, and morphologic analysis can be used to predict treatment response.

We herein describe a 70-year-old woman who presented with respiratory failure due to extensive lung adenocarcinoma. Despite advanced disease, care in the intensive care unit with ventilator support was performed because she was a newly diagnosed patient and was considered to have the potential to recover after cancer treatment. Because prompt control of the cancer was needed to treat the respiratory failure, empirical treatment with an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor was initiated before confirmation of EGFR-mutant adenocarcinoma, and the patient was successfully treated. Later, EGFR-mutant adenocarcinoma was confirmed.

OBJECTIVE:Four commonly used clinical models for predicting the probability of malignancy in pulmonary nodules were compared. While three of the models (Mayo Clinic, Veterans Association [VA], and Brock University) are based on clinical and computed tomography (CT) characteristics, one model (Herder) additionally includes the 18F-fluorodeoxyglucose (FDG) uptake value among the positron emission tomography (PET) characteristics. This study aimed to compare the predictive power of these four models in the context of a population drawn from a single center in an endemic area for tuberculosis in Korea. METHODS:A retrospective analysis of 242 pathologically confirmed nodules (4-30 mm in diameter) in 242 patients from January 2015 to December 2015 was performed. The area under the receiver operating characteristic curve (AUC) was used to assess the predictive performance with respect to malignancy. RESULTS:Of 242 nodules, 187 (77.2%) were malignant and 55 (22.8%) were benign, with tuberculosis granuloma being the most common type of benign nodule (23/55). PET was performed for 227 nodules (93.8%). The Mayo, VA, and Brock models showed similar predictive performance for malignant nodules (AUC: 0.6145, 0.6042 and 0.6820, respectively). The performance of the Herder model (AUC: 0.5567) was not significantly different from that of the Mayo (vs. Herder, p = 0.576) or VA models (vs. Herder, p = 0.999), and there were no differences among the three models in determining the probability of malignancy of pulmonary nodules. However, compared with the Brock model, the Herder model showed a significantly lower ability to predict malignancy (adjusted p = 0.0132). CONCLUSIONS:In our study, the Herder model including the 18FDG uptake value did not perform better than the other models in predicting malignant nodules, suggesting the limited utility of adding PET/CT data to models predicting malignancy in populations within endemic areas for benign inflammatory nodules, such as tuberculosis.

ObjectivesThe shape of the flow-volume (F-V) curve is known to change to showing a prominent plateau as stenosis progresses in patients with tracheal stenosis. However, no study has evaluated changes in the F-V curve according to the degree of bronchial stenosis in patients with unilateral main bronchial stenosis.MethodsWe performed an analysis of F-V curves in 29 patients with unilateral bronchial stenosis with the aid of a graphic digitizer between January 2005 and December 2011.ResultsThe primary diseases causing unilateral main bronchial stenosis were endobronchial tuberculosis (86%), followed by benign bronchial tumor (10%), and carcinoid (3%). All unilateral main bronchial stenoses were classified into one of five grades (I, ≤25%; II, 26%-50%; III, 51%-75%; IV, 76%-90%; V, >90% to near-complete obstruction without ipsilateral lung collapse). A monophasic F-V curve was observed in patients with grade I stenosis and biphasic curves were observed for grade II-IV stenosis. Both monophasic (81%) and biphasic shapes (18%) were observed in grade V stenosis. After standardization of the biphasic shape of the F-V curve, the breakpoints of the biphasic curve moved in the direction of high volume (x-axis) and low flow (y-axis) according to the progression of stenosis.ConclusionIn unilateral bronchial stenosis, a biphasic F-V curve appeared when bronchial stenosis was >25% and disappeared when obstruction was near complete. In addition, the breakpoint moved in the direction of high volume and low flow with the progression of stenosis.

Following publication of the original

Context: Bronchoscopic intervention can provide immediate relief from suffocation and an opportunity for additional treatment in patients with malignant airway obstruction. However, few studies have specifically identified prognostic factors affecting the survival of advanced lung or esophageal cancer patients receiving bronchoscopic intervention. Aims: We aimed to investigate prognostic factors influencing survival in these patients. Study Design: We conducted retrospective study. Methods: The clinical parameters were retrospectively reviewed in 51 patients (lung cancer: n = 35; esophageal cancer: n = 16) who underwent palliative bronchoscopic interventions due to malignant airway. Results: Bronchoscopic interventions, such as mechanical removal ( n = 26), stenting ( n = 31), laser cauterization ( n = 19), and ballooning ( n = 16), were performed on intraluminal ( n = 21, 41%), extrinsic ( n = 8, 16%), and combined lesions ( n = 22, 43%). Tracheal invasion was found in 24 patients (47%). Successful palliation was achieved in 49 patients (96%). After the intervention, additional anti-cancer treatment was followed in 24 patients (47%). The median survival time and overall survival rate were 3.4 months and 4%. Survival was increased with selected conditions, including a treatment-naοve status (hazard ratio [HR], 0.359; confidence interval [CI], 0.158-0.815; P = 0.01), an intact proximal airway (HR, 0.265; CI, 0.095-0.738; P = 0.01), and post-procedural additional treatment (HR, 0.330; CI, 0.166-0.657; P < 0.01). Conclusions: Brochoscopic intervention could provide immediate relief and survival improvement in advanced lung or esophageal cancer patients with selected conditions such as a treatment-naοve status, an intact proximal airway, and available post-procedural additional treatment.

Context: In patients with post-tuberculosis bronchial stenosis (PTBS), the severity of bronchial stenosis affects the restenosis rate after the silicone stent is removed. In PTBS patients with incomplete bronchial obstruction, who had a favorable prognosis, the timing of stent removal to ensure airway patency is not clear. Aims: We evaluated the time for silicone stent removal in patients with incomplete PTBS. Settings and Design: A retrospective study examined PTBS patients who underwent stenting and removal of a silicone stent. Methods: Incomplete bronchial stenosis was defined as PTBS other than total bronchial obstruction, which had a luminal opening at the stenotic segment on bronchoscopic intervention. The duration of stenting was defined as the interval from stent insertion to removal. The study included 44 PTBS patients and the patients were grouped at intervals of 6 months according to the duration of stenting. Results: Patients stented for more than 12 months had a significantly lower restenosis rate than those stented for less than 12 months (4% vs. 35%, P = 0.009). Multiple logistic regression revealed an association between stenting for more than 12 months and a low restenosis rate (odds ratio 12.095; 95% confidence interval 1.097-133.377). Moreover, no restenosis was observed in PTBS patients when the stent was placed more than 14 months previously. Conclusions: In patients with incomplete PTBS, stent placement for longer than 12 months reduced restenosis after stent removal.

There are no accurate data on the diagnostic value of preoperative flexible bronchoscopy (FB) for persistent ground-glass nodule (GGN) of the lung. We evaluated the value of preoperative FB in patients with suspected GGN-type lung cancer. We retrospectively searched a database for subjects who had 'ground-glass opacity', 'non-solid nodule', 'part-solid nodule', or 'sub-solid nodule' on chest computed tomography reports between February 2004 and March 2012. Patients who had infiltrative ground-glass opacity lesions, mediastinal lymphadenopathy, or pleural effusion, focal ground-glass opacity lesions >3 cm, and were lost to follow-up were excluded. We assessed the diagnostic value of preoperative FB in patients with persistent GGNs who underwent surgical resection. In total, 296 GGNs were evaluated by FB in 264 patients with persistent GGNs who underwent preoperative FB and surgical resection. The median size of the GGNs was 18 mm; 135 (46%) were pure GGN and 161 (54%) were part-solid GGN. No visible tumor or unsuspected endobronchial metastasis was identified by preoperative FB. Only 3 (1%, 3/208) GGNs were identified preoperatively as malignant by bronchial washing cytology; all were part-solid GGNs. No other etiology was identified by FB. Of the GGNs, 271 (91%) were subsequently confirmed as malignant and 25 (9%) were confirmed as benign at surgical resection. Consequently, the overall diagnostic sensitivity and negative predictive value of preoperative FB on a per-nodule basis was 1% (3/271) and 8% (25/293), respectively. The preoperative FB did not change the surgical strategy. Preoperative FB did not add much to the evaluation of persistent GGNs of the lung. Routine preoperative FB may have limited value in surgical candidates with small persistent pure GGNs.

Patient- and procedure-related factors associated with postoperative pulmonary complications (PPCs) have changed over the last decade. Therefore, we sought to identify independent risk factors of PPCs and to develop a clinically applicable scoring system. We retrospectively analyzed clinical data from 2,059 patients who received preoperative evaluations from respiratory physicians between June 2011 and October 2012. A new scoring system for estimating PPCs was developed using beta coefficients of the final multiple regression models. Of the 2,059 patients studied, 140 (6.8%) had PPCs. A multiple logistic regression model revealed seven independent risk factors (with scores in parentheses): age ≥70 years (2 points), current smoker (1 point), the presence of airflow limitation (1 point), American Society of Anesthesiologists class ≥2 (1 point), serum albumin

We evaluated the utility of a combined approach using endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and transesophageal bronchoscopic ultrasound-guided fine-needle aspiration (EUS-FNA-B/E) for mediastinal staging of lung cancer.An EBUS-TBNA database was analyzed retrospectively. EUS-FNA-B/E was performed after EBUS-TBNA when mediastinal lymph nodes were not accessible using EBUS-TBNA or when tissue sampling using EBUS-TBNA alone was inadequate.During the study period, 44 patients were enrolled. EBUS-TBNA and EUS-FNA-B/E were performed on 79 and 52 lymph nodes, respectively. The sensitivity, specificity, and accuracy of mediastinal N-staging using EBUS-TBNA alone were 79%, 100%, and 84%, respectively. The sensitivity, specificity, and accuracy of mediastinal N-staging using a combination of EBUS-TBNA and EUS-FNA-B/E were 100%, 100%, and 100%, respectively. Significant differences in sensitivity (P = 0.008) and accuracy (P = 0.004) of mediastinal N-staging were evident when EBUS-TBNA alone and the combined procedure were compared. The nodal stage shifted higher after use of the EUS-FNA-B/E procedure in six cases (13%). No serious complication associated with the procedures was noted.Use of a combination of EBUS-TBNA and EUS-FNA-B/E can afford better sensitivity and accuracy of mediastinal N-staging compared with use of EBUS-TBNA alone. Such combined procedures should be considered for examination of lesions that are inaccessible or difficult to access by EBUS-TBNA.

Purpose This study aimed to investigate cumulative incidence and risk factors associated with chronic pulmonary infection (CPI) development after radiotherapy for lung cancer. Materials and Methods We retrospectively analyzed 1,872 patients with lung cancer who received radiotherapy for lung cancer from 2010-2014, had a follow-up period of = 3 months after radiotherapy, and did not have CPI at the time of radiotherapy. CPI was defined as pulmonary tuberculosis, non-tuberculous mycobacterial pulmonary disease, chronic pulmonary aspergillosis, or pulmonary actinomycosis. The cumulative incidence of CPI and overall survival (OS) were estimated using the Kaplan-Meier method, and a multivariable Cox proportional hazards analysis was performed to identify risk factors associated with CPI development. Results The median follow-up period was 2.3 years with OS rates of 55.6% and 37.6% at 2 and 5 years, respectively. CPI developed in 59 patients at a median of 1.8 years after radiotherapy, with cumulative incidence rates of 1.1%, 3.4%, 5.0%, and 6.8% at 1, 3, 5, and 7 years, respectively. A lower body mass index, interstitial lung disease, prior pulmonary tuberculosis, larger clinical target volume, history of lung cancer surgery or radiation pneumonitis, and use of inhaled corticosteroids were independent risk factors for CPI development. Conclusion The long-term survival rate of lung cancer patients receiving radiotherapy was not low, but the cumulative incidence of CPI gradually increased to 6.8% at 7 years after radiotherapy. Therefore, close monitoring of CPI development is required in surviving patients with risk factors. [ABSTRACT FROM AUTHOR]

Purpose Guidelines recommend that non-small cell lung cancer (NSCLC) patients with suspected hilar lymph node (LN) metastases should undergo invasive mediastinal LN staging prior to surgical treatment via endosonography. We evaluated the diagnostic performance of endosonography for detecting occult mediastinal metastases (OMM) and determined the factors associated with OMM in NSCLC patients with radiological N1. Materials and Methods Patients with confirmed primary NSCLC with radiological N1 who underwent endosonography for nodal staging assessment from January 2013 to December 2019 were retrospectively analyzed. Results The prevalence of OMM was found to be 83/279 (29.7%) and only 38.6% (32/83) were diagnosed via endosonography. However, five of them were confirmed as N3 by endosonography. The overall diagnostic sensitivity, negative predictive value, accuracy, and area under the curve of endosonography were 38.6%, 79.4%, 81.7%, and 0.69, respectively. In multivariable analysis, central tumor (adjusted odds ratio [aOR], 2.05; 95% confidence interval [CI], 1.15 to 3.68; p=0.016), solid tumor (aOR, 10.24; 95% CI, 1.32 to 79.49; p=0.026), and adenocarcinoma (aOR, 3.01; 95% CI, 1.63 to 5.55; p < 0.001) were related to OMM in radiological N1 NSCLC patients. Conclusion Although the sensitivity of endosonography for detecting OMM was only 40%, the prevalence of OMM was not low (30%) and some cases even turned out to be N3 diseases. Clinicians should be aware that OMM may be more likely in patients with central, solid, and adenocarcinomatous tumor when performing nodal staging in radiological N1 NSCLC via endosonography. [ABSTRACT FROM AUTHOR]

Background: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) showed potency as a non-invasive therapeutic approach in pure ground-glass opacity nodule (pGGN) lung adenocarcinoma. However, optimal methods of extracting information about EGFR mutation from pGGN lung adenocarcinoma images remain uncertain. We aimed to develop, validate, and evaluate the clinical utility of a deep learning model for predicting EGFR mutation status in lung adenocarcinoma manifesting as pGGN on computed tomography (CT). Methods: We included 185 resected pGGN lung adenocarcinomas in the primary cohort. The patients were divided into training (n=125), validation (n=23), and test sets (n = 37). A preoperative CT-based deep learning model with clinical factors as well as clinical and radiomics models was constructed and applied to the test set. We evaluated the clinical utility of the deep learning model by applying it to 83 GGNs that received EGFR-TKI from an independent cohort (clinical validation set), and treatment response was regarded as the reference standard. Results: The prediction efficiencies of each model were compared in terms of area under the curve (AUC). Among the 185 pGGN lung adenocarcinomas, 122 (65.9%) were EGFR-mutant and 63 (34.1%) were EGFR-wild type. The AUC of the clinical, radiomics, and deep learning with clinical models to predict EGFR mutations were 0.50, 0.64, and 0.85, respectively, for the test set. The AUC of deep learning with the clinical model in the validation set was 0.72. Conclusions: Deep learning approach of CT images combined with clinical factors can predict EGFR mutations in patients with lung adenocarcinomas manifesting as pGGN, and its clinical utility was demonstrated in a realworld sample. [ABSTRACT FROM AUTHOR]

Purpose The role of epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR-TKIs) in the management of persistent subsolid nodules (SSNs) is unclear. This study aimed to investigate the impact of EGFR-TKIs on concurrent SSNs in patients with stage IV non–small cell lung cancer (NSCLC). Materials and Methods Patients who received an EGFR-TKI for at least 1 month for stage IV NSCLC and had concurrent SSN(s) that had existed for at least 3 months on chest computed tomography were included in this retrospective study. Size change of each nodule before and after EGFR-TKI therapies were evaluated using a cutoff value of 2 mm; increase (≥ 2 mm), decrease (≤ –2 mm), and no change (–2 mm < size change < +2 mm). Results A total of 77 SSNs, 51 pure ground-glass (66.2%) and 26 part-solid nodules (33.8%), were identified in 59 patients who received gefitinib (n=45) and erlotinib (n=14). Among 58 EGFR mutation analysis performed for primary lung cancer, 45 (77.6%) were EGFR mutant. The proportions of decrease group were 19.5% (15/77) on per-nodule basis and 25.4% (15/59) on per-patient basis. Four SSNs (5.2%) disappeared completely. On per-patient based multivariable analysis, EGFR exon 19 deletion positivity for primary lung cancer was associated with a decrease after initial EGFR-TKI therapy (adjusted odds ratio, 4.29; 95% confidence interval, 1.21 to 15.29; p=0.025). Conclusion Approximately 20% of the concurrent SSNs decreased after the initial EGFR-TKI therapy. EGFR exon 19 deletion positivity for primary lung cancer was significantly associated with the size change of concurrent SSNs. [ABSTRACT FROM AUTHOR]

Purpose: The diagnosis of pulmonary fungal infections is challenging due to the difficulty of obtaining sufficient specimens. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) needle rinse fluid has become an emerging diagnostic material. This study evaluated the role of routine fungal culture from EBUS-TBNA needle rinse fluid, in addition to histopathologic examination and fungal culture of EBUS-TBNA core tissue, in the diagnosis of pulmonary fungal infections. Materials and Methods: Among patients who underwent EBUS-TBNA, those with results for at least one of three tests (histopathologic examination, fungal culture of EBUS-TBNA core tissue or needle rinse fluid) were included. Patients with a positive test were divided into two groups (clinical fungal infection and suspected fungal contamination) according to their clinical assessment and therapeutic response to antifungal. Results: Of 6072 patients, 41 (0.7%) had positive fungal tests and 9 (22%) were diagnosed as clinical fungal infection. Of the 5222 patients who were evaluated using a fungal culture from EBUS-TBNA needle rinse fluid, 35 (0.7%) had positive results. However, only 4 out of 35 (11.4%) were classified as clinical fungal infection. Positive results were determined in 4 of the 68 (5.9%) evaluated by a fungal culture of EBUS-TBNA core tissue, and all were diagnosed as clinical fungal infection. Conclusion: Routine fungal culture of EBUS-TBNA needle rinse fluid is not useful due to the low incidence of fungal infection and high rate of contamination. However, fungal culture of EBUS-TBNA core tissue and needle rinse fluid should be considered in patients with clinically suspected fungal infection. [ABSTRACT FROM AUTHOR]