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An elevated serum lactate level is associated with morbidity and mortality in patients with severe sepsis and septic shock. In patients with hepatic dysfunction, however an elevated serum lactate level may be due to either impaired lactate clearance or excessive production. Thus, we evaluated whether the initial serum lactate level was also associated with mortality in septic shock patients with hepatic dysfunction. A retrospective observational study enrolled 307 patients with septic shock admitted to the intensive care unit (ICU) between May 2007 and July 2009. Hepatic dysfunction was defined as a serum total bilirubin > 34.2 micromol/l (2 mg/dl). Selected patients were divided into high (> or = 4 mmol/l) and low (< 4 mmol/l) lactate groups, according to the initial serum lactate level. Of 307 patients with septic shock, 118 (38%) patients with hepatic dysfunction were eligible for this study. The median lactate levels were 5.9 (interquartile range 4.7 to 9.0) and 2.6 (interquartile range 1.7 to 3.2) mmol/l for the high and low lactate groups respectively (P < 0.001). The initial serum lactate level was strongly associated with in hospital mortality in a univariate analysis (P < 0.001). After adjusting for potential confounding factors, the initial serum lactate level remained significantly associated with in-hospital mortality (odds ratio 1.281, 95% confidence interval 1.097 to 1.496, P = 0.002). In conclusion, the serum lactate level could be useful in predicting the outcome of patients with septic shock regardless of hepatic dysfunction. [ABSTRACT FROM AUTHOR]

PURPOSES: The aim of this study was to evaluate the usefulness of the whole-blood interferon-gamma assay (enzyme-linked immunosorbent assay [ELISA]) and interferon-gamma enzyme-linked immunospot assay (ELISPOT) based on early secretory antigenic target 6 and culture filtrate protein 10 in the diagnosis of active pulmonary tuberculosis (TB) in routine clinical practice. METHOD: We conducted a prospective study enrolling 144 participants with suspected pulmonary TB in a tertiary referral hospital in Seoul, South Korea, to investigate the diagnostic sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of these tests. Clinical assessment, tuberculin skin test (TST), whole-blood interferon-gamma ELISA (QuantiFERON-TB Gold [QFT-G]; Cellestis Ltd; Victoria, Australia), and an ELISPOT assay (T SPOT.TB; Oxford Immunotec; Oxford, UK) were performed. Test results were compared with the final confirmed diagnoses. RESULTS: Active pulmonary TB was diagnosed in 67 of 144 participants (47%). Sensitivities of QFT-G and T SPOT.TB for active pulmonary TB were 89% (95% confidence interval [CI], 79 to 96%) and 92% (95% CI, 83 to 97%), respectively; and specificities were 49% (95% CI, 37 to 61%) and 47% (95% CI, 36 to 59%). NPVs of QFT-G (84%; 95% CI, 69 to 93%) and T SPOT.TB (87%; 95% CI, 73 to 96%) were higher than that of TST (64%; 95% CI, 51 to 76%) [p = 0.001 and p < 0.001, respectively]. CONCLUSION: High NPVs of QFT-G and T SPOT.TB for the diagnosis of active TB suggest the supplementary role of these tests for the diagnostic exclusion of active TB, although the low PPV limits their usefulness in routine clinical practice in South Korea, where the prevalence of latent TB infection is considerable. [ABSTRACT FROM AUTHOR]

Background: It remains uncertain how long pure ground-glass nodules (pGGNs) detected on low-dose CT (LDCT) imaging should be followed up. Further studies with longer follow-up periods are needed to determine the optimal follow-up duration for pGGNs., Research Question: What is the percentage of enlarging nodules among pGGNs that have remained stable for 10 years?, Study Design and Methods: This was a retrospective cohort study originating from participants with pGGNs detected on LDCT scans between 1997 and 2006 whose natural courses were reported in 2013. We re-analyzed all the follow-up data until July 2022. The study participants were followed up per our institutional guidelines until they were no longer a candidate for definitive treatment. The growth of the pGGNs was defined as an increase in the diameter of the entire nodule by ≥ 2 mm or the appearance of new solid portions within the nodules., Results: A total of 89 patients with 135 pGGNs were followed up for a median of 193 months. Of 135 pGGNs, 23 (17.0%) increased in size, and the median time to the first detection of a size change was 71 months. Of the 23 growing pGGNs, 122 were detected on the first LDCT scan and 13 were newly detected on the follow-up CT scan. An increase in size was observed within 5 years in 8 nodules (34.8%), between 5 and 10 years in 12 nodules (52.2%), and following 10 years in 3 nodules (13.0%). Fifteen nodules were histologically confirmed as adenocarcinoma by surgery. Among the 76 pGGNs stable for 10 years, 3 (3.9%) increased in size., Interpretation: Among pGGNs that remained stable for 10 years, 3.9% eventually grew, indicating that some pGGNs can grow even following a long period of stability. We suggest that pGGNs may need to be followed up for > 10 years to confirm growth., Competing Interests: Financial/Nonfinancial Disclosures None declared., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: This study was performed to investigate the detection rate of EGFR T790M mutation by repeated rebiopsy, to identify the clinical factors related to repeated rebiopsy, and to assess survival outcomes according to the methods and numbers of repeated rebiopsies in patients with lung adenocarcinoma who received sequential osimertinib after failure of previous 1st or 2nd generation EGFR-tyrosine kinase inhibitors., Methods: This retrospective study included patients with advanced-stage lung adenocarcinoma who were confirmed to have EGFR T790M mutation and to have received osimertinib from January 2020 to February 2021 at Samsung Medical Center. The presence of T790M mutation was assessed based on either plasma circulating tumor DNA (ctDNA) or tissue specimens. Results A total of 443 patients underwent rebiopsy, with 186 (42.0%) testing positive for the T790M mutation by the sixth rebiopsy. The final analysis included 143 eligible patients. Progression-free survival was not significantly different in terms of the methods (tissue: 13.3 months, 95% confidence interval [CI]: [9.4, 23.5] vs plasma: 11.1 months, 95% CI: [8.1, 19.4], p = 0.33) and numbers (one: 13.4 months, 95% CI: [9.4, 23.5] vs two or more: 11.0 months, 95% CI: [8.1, 14.8], p = 0.51) of repeated rebiopsies. Longer overall survival (OS) was found in patients in whom T790M was detected by tissue specimens rather than by plasma ctDNA (2-year OS rate: 81.7% for tissue vs 63.9% for plasma, p = 0.0038). Factors related to the lower numbers of rebiopsies included age and bone metastasis. Factor associated with T790M detection in tissue rather than in plasma was pleural metastasis, while advanced tumor stage was related to T790M confirmation in plasma rather than in tissue., Conclusions: Repeated rebiopsy for T790M detection in patients with NSCLC can increase the detection rate of the mutation. Detection of T790M by plasma ctDNA might be related to poor survival outcomes., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The aim of our retrospective study is to develop and assess an imaging-based model utilizing 18 F-FDG PET parameters for predicting the five-year survival in non-small-cell lung cancer (NSCLC) patients after curative surgery. A total of 361 NSCLC patients who underwent curative surgery were assigned to the training set ( n = 253) and the test set ( n = 108). The LASSO regression model was used to construct a PET-based risk score for predicting five-year survival. A hybrid model that combined the PET-based risk score and clinical variables was developed using multivariate logistic regression analysis. The predictive performance was determined by the area under the curve (AUC). The individual features with the best predictive performances were co-occurrence&#95;contrast (AUC = 0.675) and SUL peak (AUC = 0.671). The PET-based risk score was identified as an independent predictor after adjusting for clinical variables (OR 5.231, 95% CI 1.987-6.932; p = 0.009). The hybrid model, which integrated clinical variables, significantly outperformed the PET-based risk score alone in predictive accuracy (AUC = 0.771 vs. 0.696, p = 0.022), a finding that was consistent in the test set. The PET-based risk score, especially when integrated with clinical variables, demonstrates good predictive ability for five-year survival in NSCLC patients following curative surgery.

Background/aim: Although the importance of low-dose computed tomography (LDCT) screening is increasingly emphasized and implemented, many lung cancers continue to be incidentally detected during routine medical practices, and data on incidentally detected lung cancer (IDLC) remain scarce. This study aimed to investigate the clinical characteristics and prognosis of IDLCs by comparing them with screening-detected lung cancers (SDLCs)., Patients and Methods: In this retrospective study, subjects with cT1 (≤3 cm) pulmonary nodules detected on baseline computed tomography (CT), later pathologically confirmed as primary lung cancer in 2015, were included. Patients were categorized into IDLC and SDLC groups based on the setting of the first pulmonary nodule detection., Results: Out of 457 subjects, 129 (28.2%) were IDLCs and 328 (71.8%) were SDLCs. The IDLC group, consisted of older individuals with a higher prevalence of smokers and underlying pulmonary disease, compared to the SDLC group. Adenocarcinomas were more frequently detected in SDLCs (87.5%) than in IDLCs (76.7%, p<0.001). The time to treatment initiation (TTI) and 5-year overall survival (OS) rates were similar. Multivariate analyses revealed underlying interstitial lung disease, DLCO, solidity of nodules and TNM stage as independent risk factors associated with mortality. Less than 30% of study participants would have been eligible for the current lung cancer screening program., Conclusion: The IDLC group was associated with older age, higher rate of smokers, underlying pulmonary disease, and non-adenocarcinoma histology. However, prognosis was similar to that of the SDLC group, attributable to the similarity in TNM stage, strict adherence to guidelines, and short TTI. Furthermore, less than 30% of the participants would have been suitable for the existing lung cancer screening program, indicating a potential need to reconsider the scope for screening candidates., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: It is unclear whether performing endosonography first in non-small cell lung cancer (NSCLC) patients with radiological N1 (rN1) has any advantages over surgery without nodal staging. We aimed to compare surgery without endosonography to performing endosonography first in rN1 on the overall survival (OS) of patients with NSCLC., Materials and Methods: This is a retrospective analysis of patients with rN1 NSCLC between 2013 and 2019. Patients were divided into 'no endosonography' and 'endosonography first' groups. We investigated the effect of nodal staging through endosonography on OS using propensity score matching (PSM) and multivariable Cox proportional hazard regression analysis., Results: In the no endosonography group, pathologic N2 occurred in 23.0% of patients. In the endosonography first group, endosonographic N2 and N3 occurred in 8.6% and 1.6% of patients, respectively. Additionally, 51 patients were pathologic N2 among 249 patients who underwent surgery and mediastinal lymph node dissection (MLND) in endosonography first group. After PSM, the 5-year OSs were 68.1% and 70.6% in the no endosonography and endosonography first groups, respectively. However, the 5-year OS was 80.2% in the subgroup who underwent surgery and MLND of the endosonography first group. Moreover, in patients receiving surgical resection with MLND, the endosonography first group tended to have a better OS than the no endosonography group in adjusted analysis using various models., Conclusion: In rN1 NSCLC, preoperative endosonography shows better OS than surgery without endosonography. For patients with rN1 NSCLC who are candidates for surgery, preoperative endosonography may help improve survival through patient selection.

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., Competing Interests: All authors declare no competing interests., (© 2024 The Authors.)

Background: Paradoxical responses (PR) occur more frequently in lymph node tuberculosis (LNTB) than in pulmonary tuberculosis and present difficulties in differential diagnosis of drug resistance, new infection, poor patient compliance, and adverse drug reactions. Although diagnosis of mediastinal LNTB has become much easier with the development of endosonography, limited information is available. The aim of this study was to investigate the clinical course of mediastinal LNTB and the risk factors associated with PR., Methods: Patients diagnosed with mediastinal LNTB via endosonography were evaluated retrospectively between October 2009 and December 2019. Multivariable logistic regression was applied to evaluate the risk factors associated with PR., Results: Of 9,052 patients who underwent endosonography during the study period, 158 were diagnosed with mediastinal LNTB. Of these, 55 (35%) and 41 (26%) concurrently had pulmonary tuberculosis and extrapulmonary tuberculosis other than mediastinal LNTB, respectively. Of 125 patients who completed anti-tuberculosis treatment, 21 (17%) developed PR at a median of 4.4 months after initiation of anti-tuberculosis treatment. The median duration of anti-tuberculosis treatment was 6.3 and 10.4 months in patients without and with PR, respectively. Development of PR was independently associated with age < 55 years (adjusted odds ratio [aOR], 5.72; 95% confidence interval [CI], 1.81-18.14; P = 0.003), lymphocyte count < 800/μL (aOR, 8.59; 95% CI, 1.60-46.20; P = 0.012), and short axis diameter of the largest lymph node (LN) ≥ 16 mm (aOR, 5.22; 95% CI, 1.70-16.00; P = 0.004) at the time of diagnosis of mediastinal LNTB., Conclusion: As PR occurred in one of six patients with mediastinal LNTB during anti-tuberculosis treatment, physicians should pay attention to patients with risk factors (younger age, lymphocytopenia, and larger LN) at the time of diagnosis., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2023 The Korean Academy of Medical Sciences.)

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.

Background: Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer (NSCLC). Chemotherapy resistance is the main cause of chemotherapy failure. Cullin7 (Cul7) is highly expressed in LUAD and is associated with poor prognosis. Moreover, Cul7 is abnormally overexpressed in docetaxel-resistant LUAD cells. Therefore, further exploration of the role and molecular mechanism of Cul7 in LUAD docetaxel resistance is necessary., Methods: We established docetaxel-resistant cell lines (A549DTX and H358DTX cell lines) by exposing cells to gradually increasing concentrations of docetaxel. Cell (A549, A549DTX, H358, and H358DTX cell lines) sensitivity to docetaxel was determined via a 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymmethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assay. And then quantitative polymerase chain reaction (qPCR) and Western blotting were performed to measure the expression of Cul7 and Survivin in A549, A549DTX, H358, and H358DTX cell lines. Subsequently, we knocked down Cul7 in docetaxel-resistant cells and overexpressed Cul7 in parental cells via lentiviral transduction to further validate the correlation between Cul7 and docetaxel resistance, while exploring the molecular mechanism of docetaxel resistance it caused. Immunofluorescence and immunohistochemical (IHC) staining were also used to evaluate the expression and cellular localization of Cul7. To confirm the effect of Cul7 expression on cell apoptosis, we used flow cytometry to detect the apoptosis rate of A549 and A549DTX cells with the same drug concentration., Results: Cul7 was highly expressed in A549DTX and H358DTX cells. However, when Cul7 expression was knocked down in A549DTX and H358DTX cells, cell sensitivity to docetaxel was significantly increased. In addition, we found that Cul7 was coexpressed with Survivin . Silencing Survivin reversed the docetaxel insensitivity caused by Cul7 overexpression. High expression of Cul7 and Survivin in docetaxel-resistant LUAD cells inhibited the intrinsic apoptosis pathway and promoted cell proliferation. Therefore, the Cul7/Survivin axis may play a role in inducing LUAD docetaxel chemoresistance., Conclusions: Cul7 and Survivin were both highly expressed in docetaxel-resistant LUAD cells. Our results suggest that Cul7 may inhibit apoptosis and promote the proliferation of LUAD cells by increasing the Survivin protein level, which in turn contributes to docetaxel chemoresistance in LUAD., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1110/coif). XL is from GZ Runsheng CytoMed Technology Co. Ltd. The other authors have no conflicts of interest to declare., (2023 Journal of Thoracic Disease. All rights reserved.)

Early detection of lung cancer is crucial for patient survival and treatment. Recent advancements in next-generation sequencing (NGS) analysis enable cell-free DNA (cfDNA) liquid biopsy to detect changes, like chromosomal rearrangements, somatic mutations, and copy number variations (CNVs), in cancer. Machine learning (ML) analysis using cancer markers is a highly promising tool for identifying patterns and anomalies in cancers, making the development of ML-based analysis methods essential. We collected blood samples from 92 lung cancer patients and 80 healthy individuals to analyze the distinction between them. The detection of lung cancer markers Cyfra21 and carcinoembryonic antigen (CEA) in blood revealed significant differences between patients and controls. We performed machine learning analysis to obtain AUC values via Adaptive Boosting (AdaBoost), Multi-Layer Perceptron (MLP), and Logistic Regression (LR) using cancer markers, cfDNA concentrations, and CNV screening. Furthermore, combining the analysis of all multi-omics data for ML showed higher AUC values compared with analyzing each element separately, suggesting the potential for a highly accurate diagnosis of cancer. Overall, our results from ML analysis using multi-omics data obtained from blood demonstrate a remarkable ability of the model to distinguish between lung cancer and healthy individuals, highlighting the potential for a diagnostic model against lung cancer.

Introduction: For patients with early stage EGFR-mutant-positive (EGFR-M+) NSCLC, curative surgery followed by adjuvant chemotherapy is considered the standard of care. This study evaluated the feasibility and efficacy of longitudinal monitoring of circulating tumor DNA (ctDNA) as a valuable biomarker for early detection of minimal residual disease (MRD) and provides identification of the group at high risk for recurrence in resected stages I to IIIA EGFR-M+ NSCLC., Methods: Between August 2015 and October 2017, a total of 278 patients with curative resected, stages I to IIIA (American Joint Committee on Cancer seventh version) common EGFR-M+ NSCLC were analyzed. Radiological follow-up was accompanied with longitudinal monitoring of ctDNA using a droplet-digital polymerase chain reaction from baseline (preoperative), 4 weeks after curative surgery, and follow-up per protocol until 5 years. The primary outcomes were disease-free survival (DFS) according to the status of ctDNA positivity at landmark points and the sensitivity of longitudinal monitoring of ctDNA., Results: Among 278 patients, preoperative baseline ctDNA was detected in 67 (24%) patients: 23% (stage IA), 18% (IB), 18% (IIA), 50% (IIB), and 42% (IIIA) (p = 0.06). Of patients with baseline ctDNA, 76% (51 of 67) had clearance at 4 weeks after surgery (postoperative). Patients were classified into the following three groups; group A, baseline ctDNA negative (n = 211) versus group B, baseline ctDNA positive but postoperative MRD negative (n = 51) versus group C, baseline ctDNA positive and postoperative MRD positive (n = 16). The 3-year DFS rate was significantly different among the three groups (84% for group A, 78% for group B, and 50% for group C, p = 0.02). After adjusting for clinicopathologic variables, ctDNA still remains an independent risk factor for DFS along with stage (p < 0.001) and micropapillary subtype (p = 0.02). With longitudinal monitoring of ctDNA, MRD was detected before radiological recurrence in 69% of patients with exon 19 deletion and in 20% with L858R mutation., Conclusions: These results suggest that patients with baseline ctDNA-positive or MRD-positive status were associated with poor DFS in curative resected stages I to IIIA EGFR-M+ NSCLC and that longitudinal monitoring of ctDNA, a noninvasive method, might be useful to detect early recurrence before radiological recurrence., (Copyright © 2023. Published by Elsevier Inc.)

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: NCT04253509) 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., (© 2023. Springer Nature Limited.)

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 (<1 cm in diameter), and NMPM was defined as the presence of ≤15 metastatic pulmonary nodules regardless of size. Baseline characteristics, genetic alterations and overall survival (OS) rates were compared between the two groups., Results: Twenty-six patients with MPM and 78 patients with NMPM were analyzed. The median number of patients who smoked was significantly lower in the MPM group than in the NMPM group (0 vs. 8 pack years, p = 0.030). The frequency of EGFR mutation was significantly higher in the MPM group (58%) than in the NMPM group (24%; p = 0.006). There was no significant difference in 5-year OS between the MPM and the NMPM group by the log-rank test (p = 0.900)., Conclusion: MPM in NSCLC were significantly related to EGFR mutation. The OS rate of the MPM group was not inferior to that of the NMPM group. The presence of EGFR mutations should be thoroughly evaluated for NSCLC patients with initial presentation of MPM., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

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.

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.

Background and Objective: The widespread use of chest computed tomography (CT) for lung cancer screening has led to increased detection of subsolid pulmonary nodules. The management of subsolid nodules (SSNs) is challenging since they are likely to grow slowly and a long-term follow-up is needed. In this review, we discuss the characteristics, natural history, genetic features, surveillance, and management of SSNs., Methods: PubMed and Google Scholar were searched to identify relevant articles published in English between January 1998 and December 2022 using the following keywords: "subsolid nodule", "ground-glass nodule (GGN)", and "part-solid nodule (PSN)"., Key Content and Findings: The differential diagnosis of SSNs includes transient inflammatory lesions, focal fibrosis, and premalignant or malignant lesions. Long-term CT surveillance follow-up is needed to manage SSNs that persist for >3 months. Although most SSNs have an indolent clinical course, PSNs may have a more aggressive clinical course than pure GGNs. The proportion of growth and the time to grow is higher and shorter in PSN than pure GGN. In lung adenocarcinoma manifesting as SSNs, EGFR mutations were the major driver mutations. Guidelines are available for the management of incidentally detected and screening-detected SSNs. The size, solidity, location, and number of SSNs are important factors in determining the need for surveillance and surgical resection, as well as the interval of follow-up. Positron emission tomography/CT and brain magnetic resonance imaging (MRI) are not recommended for the diagnosis of SSNs, especially for pure GGNs. Periodic CT surveillance and lung-sparing surgery are the main strategies for the management of persistent SSNs. Nonsurgical treatment options for persistent SSNs include stereotactic body radiotherapy (SBRT) and radiofrequency ablation (RFA). For multifocal SSNs, the timing of repeated CT scans and the need for surgical treatment are decided based on the most dominant SSN(s)., Conclusions: The SSN is a heterogeneous disease and a personalized medicine approach is required in the future. Future studies of SSNs should focus on their natural history, optimal follow-up duration, genetic features, and surgical and nonsurgical treatments to improve the corresponding clinical management. All these efforts will lead to the personalized medicine approach for the SSNs., Competing Interests: Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-5246/coif). SWU serves as an unpaid editorial board member of Annals of Translational Medicine from September 2022 to August 2024. The other author has no conflicts of interest to declare., (2023 Annals of Translational Medicine. All rights reserved.)

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., (© 2023. The Author(s).)

Electromagnetic navigation bronchoscopy (ENB) is one of the non-invasive methods used for lung nodule biopsy. We evaluated the efficacy of combining radial endobronchial ultrasound (R-EBUS)-guided transbronchial lung biopsy (TBLB) with ENB-guided TBLB or transbronchial needle aspiration (TBNA) for diagnosing lung nodules. Forty patients with a lung nodule underwent ENB-TBLB or TBNA, followed by R-EBUS-TBLB if available. The final diagnosis was benign or malignant, depending on the surgical pathology or 24-month follow-up computed tomography (CT). We compared the sensitivity, negative predictive value, and accuracy between combinations of procedures. The mean nodule size was 21.65 mm, and 60.0% of the nodules were solid. The bronchus was within the nodule in 67.5% and 65.0% of cases examined using CT and R-EBUS, respectively. The accuracies of ENB-TBLB alone, ENB-TBLB/TBNA, and R-EBUS-TBLB plus ENB-TBLB/TBNA were 74.4%, 82.5%, and 90.0%, respectively. The sensitivity levels of the aforementioned procedures were 69.8%, 78.8%, and 87.9%, respectively. Among 21 patients who underwent both ENB-TBLB and R-EBUS-TBLB, the latter revealed malignant cells in three of nine patients (33.3%) with benign ENB-TBLB results. Combined ENB-TBLB/TBNA and R-EBUS-TBLB had increased sensitivity and diagnostic accuracy for lung nodules. ENB and R-EBUS are complementary; using both modalities improves the sensitivity and accuracy of lung nodule diagnoses.

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 (FEV 1 ) 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 < 0.001; FEV 1 , - 52.9 [- 192.2 to 3.9] vs. - 20.0 [- 72.6 to 28.6] mL/year, p = 0.010). After adjusting for confounding factors, patients with CPA had greater FVC decline (β coefficient, - 103.6; 95% CI - 179.2 to - 27.9; p = 0.007) than those without CPA. However, the FEV 1 decline (β coefficient, - 14.4; 95% CI - 72.1 to 43.4; p = 0.626) was not significantly different., Conclusion: Although the development of CPA after lung cancer surgery did not increase mortality, the impact on restrictive lung function deterioration was profound., (© 2022. The Author(s).)

Background: Pulmonary sequestration (PS) is a rare congenital lung malformation that can be incidentally diagnosed in adulthood. The natural course of PS in adults is scarcely known., Methods: In this retrospective cohort study, medical records and imaging results of adult patients diagnosed with PS between 1994 and 2019 were reviewed. Diagnoses of PS were confirmed by histopathological findings in resected cases, while non-resected cases were diagnosed based on the presence of anomalous systemic arterial supply and abnormal lung parenchyma on enhanced chest computed tomography (CT)., Results: Among 104 patients with PS, the median age at diagnosis was 40.5 years, and 69 (66.3%) patients were asymptomatic. Patients in the surgery group were significantly younger (38.6 vs. 45.3 years, respectively, P=0.016), were more likely to be symptomatic initially (51.6% vs. 28.6%, respectively, P=0.015), and had larger PS (90.0 vs. 66.3 mm, respectively, P<0.001) than the non-surgery group. Of the patients in the surgery group, 29.0% (18/62) experienced postoperative complications. In the surgically resected cases, infections were only detected in intralobar PS, not in extralobar PS. Among 25 subjects without initial symptoms in the non-surgery group, 24 (96.0%) remained asymptomatic at the last follow-up., Conclusions: Adults with PS tended to undergo resection if they were young, symptomatic, and had large PS (a median diameter of 90.0 mm). Almost all subjects who were initially asymptomatic and did not undergo surgery remained asymptomatic at the last follow-up. Therefore, considering the indolent course of PS, initially asymptomatic adults with PS could be followed up without surgery., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-631/coif). The authors have no conflicts of interest to declare., (2022 Journal of Thoracic Disease. All rights reserved.)

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 real-world sample., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yoon, Choi, Kim, Um, Kang, Kim, Kim, Park and Lee.)

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 <10 mm than ≥10 mm in size (90.1% vs. 97.8%; p < 0.001). There was no significant difference in diagnostic performance according to the nodal station (10 vs. 11/12) and left- versus right-sided LNs. The diagnostic sensitivity (100 vs. 95.5%; p = 0.221) and specificity (100 vs. 100%) of N3 LNs was not significantly different from those of N1 LNs. In this study, eight (8/91, 8.8%) patients with cN1 NSCLC received neoadjuvant treatment based on the results of EBUS-TBNA., Conclusion: EBUS-TBNA accurately evaluates station 10/11/12 LNs of both N1 and N3 disease. The diagnostic performances of EBUS-TBNA for station 10/11/12 LNs seem to be comparable to those of EBUS-TBNA for mediastinal LNs., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

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.

Background: Classifying the progression pattern had been proved to be momentous for predicting efficacy and guiding treatment in the 1st/2nd generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), while lack evidence in the 3rd generation EGFR-TKIs. This study aimed to classify tumor progression of osimertinib in EGFR+ advanced non-small cell lung cancer (NSCLC), exploring the characteristics and the clinical significance of each progression pattern., Methods: After screening 1,125 lung cancer patients, 168 EGFR T790M+ advanced patients using osimertinib were enrolled and divided into two groups and five clinical progression models according to the time course of the tumor progression. The prognosis and characteristics, such as gender, age, metastases, of each model were analyzed and compared by Kaplan-Meier method, t- test, and linear regression., Results: Complete follow-up data were available for 117 of the 168 patients. Progressive disease (PD) occurred in 89 patients at an average onset of 6.59 months since using osimertinib, with 79.78% of patients experiencing enlargement of some preexisting lesions before PD. Among the five progression models, the 'Rapid Enlargement' (10.11%) model, the 'Rapid New Lesion' model (10.11%), the 'Delayed Enlargement' model (29.21%), the 'Delayed New Lesion' model (15.73%), and the 'Non-targeted Enlargement' model (34.83%), the 'Non-targeted Enlargement' model had the worst prognosis, with a median progression-free survival (mPFS) of 7.1 months (P=0.046). The mPFS of other models was similar, with the largest difference in the time interval between the beginning of osimertinib treatment to the first appearance of target lesion enlargement (T m-e ). Smoking history (P=0.046) and the location of the initial (P=0.048), enlarged (P=0.003), and progressive lesions (P=0.002) affected the progression models, while gender, age, and treatment lines had no effect. The T m-e was related to the overall disease control time with a correlation coefficient of 0.667 (P=0.000). The appearance of a malignant pleural effusion had an impact on progression., Conclusions: We tried to create a classification system for describing the failure of the third-generation EGFR-TKI osimertinib including two groups, subdivided into five progression models based on the time course of tumor lesion changes. The system might be conducive to predict the prognosis and be potential to assist in selecting subsequent treatment strategies., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-315/coif). KI reports personal fees from Boehringer Ingelheim, AstraZeneca, Pfizer, Eli Lilly, Chugai Pharmaceutical, Merk Sharp & Dohme (MSD), Ono Pharmaceutical, Takeda Pharmaceutical and Taiho Pharmaceutical. The other authors have no conflicts of interest to declare., (2022 Translational Lung Cancer Research. All rights reserved.)

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.

Background: Plasma cell-free Deoxyribo nucleic acid epidermal growth factor receptor (EGFR) mutation tests are widely used at initial diagnosis and at progression in stage IV non-small cell lung cancer (NSCLC). We analyzed the factors associated with plasma EGFR mutation detection and the effect of plasma EGFR genotyping on the clinical outcomes of the patients with treatment-naïve stage IV NSCLC., Methods: In this retrospective cohort study, we included subjects with treatment-naïve stage IV NSCLC who underwent plasma EGFR genotyping between 2018 and 2020. The presence of plasma EGFR mutation was determined by real-time polymeric chain reaction., Results: The prevalence of EGFR mutation in this cohort was 52.7% (164/311). Among 164 EGFR mutant subjects, 34 (20.7%) were positive for the plasma EGFR mutation assay only. In multivariable analysis, the detection of plasma EGFR mutation was significantly related to higher serum carcinoembryonic antigen levels, never-smoker status, N3 stage, and brain or intrathoracic metastasis. The time to treatment initiation (TTI) of the plasma EGFR mutation-positive group (14 days) was shorter than that of the plasma EGFR mutation-negative group (21 days, p < 0.001). More patients received the 1st line EGFR-TKI in the plasma positive group compared with the tissue positive group., Conclusion: Smoking status and the factors reflecting tumor burden were associated with the detection of plasma EGFR mutation. The plasma EGFR mutation assay can shorten the TTI, and facilitate the 1st line EGFR-TKI therapy for patients with treatment-naïve stage IV NSCLC, especially in the region of high-prevalence of EGFR mutation.

This study aimed to understand aberrant methylation of SLITs genes as a biomarker for the early detection and prognosis prediction of non-small cell lung cancer (NSCLC). Methylation levels of SLITs were determined using the Infinium HumanMethylation450 BeadChip or pyrosequencing. Five CpGs at the CpG island of SLIT1 , SLIT2 or SLIT3 genes were significantly (Bonferroni corrected p < 0.05) hypermethylated in tumor tissues obtained from 42 NSCLC patients than in matched normal tissues. Methylation levels of these CpGs did not differ significantly between bronchial washings obtained from 76 NSCLC patients and 60 cancer-free patients. However, methylation levels of SLIT2 gene were significantly higher in plasma cell-free DNA of 72 NSCLC patients than in that of 61 cancer-free patients ( p = 0.001, Wilcoxon rank sum test). Prediction of NSCLC using SLIT2 methylation was achieved with a sensitivity of 73.7% and a specificity of 61.9% in a plasma test dataset ( N = 40). A Cox proportional hazards model showed that SLIT2 hypermethylation in plasma cell-free DNA was significantly associated with poor recurrence-free survival (hazards ratio = 2.19, 95% confidence interval = 1.21-4.36, p = 0.01). The present study suggests that aberrant methylation of SLIT2 in plasma cell-free DNA is a valuable biomarker for the early detection of NSCLC and prediction of recurrence-free survival. However, further research is needed with larger sample size to confirm results.

Background: The acinar- and papillary-predominant histological subtypes are the most common types of invasive lung adenocarcinoma and are considered "intermediate-grade" carcinomas with heterogeneous prognosis. This study investigated the prognostic significance of the lepidic and micropapillary/solid pathological patterns as minor components in patients with intermediate-grade lung adenocarcinomas., Methods: A total of 697 patients with pathological N0M0 acinar/papillary-predominant lung adenocarcinomas ≤3 cm in diameter, who underwent curative resection in our institution between June 1, 2014 and August 31, 2016, were retrospectively enrolled in this study. Acinar/papillary-predominant lung adenocarcinomas were classified into four subtypes according to the presence of the minor pathological components lepidic (Lep), micropapillary (MP), and solid (S). The subtypes were MP/S - Lep + , MP/S - Lep - , MP/S + Lep + , and MP/S + Lep - . The 5-year recurrence-free survival (RFS) and overall survival (OS) were recorded. Factors affecting survival were analyzed by Cox regression method., Results: Among 697 intermediate-grade lung adenocarcinomas, the distribution of patients was as follows: MP/S - Lep + type (n=314; 45.0%), MP/S - Lep - type (n=144; 20.7%), MP/S + Lep + type (n=133; 19.1%), and MP/S + Lep - type (n=106; 15.2%). The 5-year RFS rates were 98.7%, 94.4%, 94.0%, and 81.9%, respectively (P<0.001). The 5-year OS rates were 98.4%, 94.4%, 96.6%, and 87.7%, respectively (P<0.001). Multivariate analysis revealed that the MP/S + Lep - subtype was an independent poor prognostic factor of both RFS and OS., Conclusions: Acinar/papillary-predominant adenocarcinoma is an "intermediate-grade" carcinoma that can be further classified into subtypes according to the presence of lepidic and micropapillary/solid pathological patterns with significantly different prognosis. This classification may be useful in evaluating the recurrence risk and guiding adjuvant therapies in patients with acinar/papillary-predominant stage I lung adenocarcinoma., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-21-934/coif). The authors have no conflicts of interest to declare., (2022 Translational Lung Cancer Research. All rights reserved.)

Background: The eighth edition of the TNM classification for lung cancer does not provide a definite guideline for pulmonary lymphangitic carcinomatosis. The purpose of this retrospective case-control study is to evaluate the prognosis of pulmonary lymphangitic carcinomatosis in patients with non-small cell lung cancer compared with those with intrapulmonary metastases., Methods: Non-small cell lung cancer (NSCLC) patients with pulmonary lymphangitic carcinomatosis detected on chest computed tomography scan during staging evaluation between 2000 and 2016 were included. The extent of pulmonary lymphangitic carcinomatosis was classified as being around the primary tumor (cLy1), at a distance from the tumor but confined to the same lobe (cLy2), in other ipsilateral lobes (cLy3), or affecting the contralateral lung (cLy4). Overall survival rates of the subjects were compared with those with intrapulmonary metastases., Results: A total of 103 subjects with pulmonary lymphangitic carcinomatosis were analysed. The 5-year overall survival rates of the subjects with pulmonary lymphangitic carcinomatosis (n=103) and intrapulmonary metastases (n=111) were 33% and 21%, respectively. The 5-year overall survival rates of cLy1 (n=28), cLy2 (n=40), cLy3 (n=26) and cLy4 (n=9) were 54%, 35%, 12% and 11%, respectively. On multivariable analyses after adjusting for possible confounders, the subjects with cLy1 and cLy2 had better overall survival (adjusted hazard ratio for death, 0.34 and 0.49; 95% confidence interval, 0.24-0.73 and 0.30-0.80; P < 0.001 and 0.004, respectively) and the subjects with cLy4 had worse overall survival (adjusted hazard ratio, 2.21; 95% confidence interval, 1.03-4.70; P=0.040) compared with those with intrapulmonary metastases., Conclusions: The subjects with cLy1/2 had better overall survival than those with cLy3/4 or intrapulmonary metastases. cLy1/2 seems to be a T descriptor (T3/4) rather than an M1 descriptor., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/tlcr-21-677). MJA serves as an unpaid editorial board member of Translational Lung Cancer Research. The other authors have no conflicts of interest to declare., (2021 Translational Lung Cancer Research. All rights reserved.)

Objectives: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has become a standard procedure, but little is known about its infectious complications. The aim of this study is to evaluate the incidence and risk factors of infectious complications of EBUS-TBNA and its clinical course, including effects on anti-cancer treatment., Methods: This is a nested case-control study of patients who received EBUS-TBNA and were followed for at least 2 months at Samsung Medical Center from August 2009 to April 2019. Patients with clinical symptoms of infection and correlating chest images were defined as the infection group (n = 33). The controls were randomly selected from patients without infectious complication. Multivariate logistic regression with backward selection was used to identify the risk factors of infectious complications., Results: Of the 6826 patients, 33 (0.48%) infectious complications were identified, comprising pneumonia (n = 20) and mediastinal infections (n = 13). Target lesions with necrotic features on chest computed tomography (CT) scan (adjusted odds ratio [aOR], 3.08; 95% confidence interval [CI], 1.49-6.40; P = 0.002) and procedures that were performed via the esophagus (aOR, 3.19; 95% CI, 1.47-6.88; P = 0.003) were independently associated with infectious complications. Among patients ultimately diagnosed with cancer, the infection group tended to refuse anti-cancer treatment compared to controls (32/459, 7.0% vs. 5/30, 16.7%; P = 0.066). However, among the patients who received anti-cancer treatment, there was no delay in onset of treatment., Conclusions: Infectious complications of EBUS-TBNA are rare; however, attention should be paid if the target lesion appears necrotic on chest CT or if the procedure is performed via the esophagus. Although it was not conclusive due to its rarity, patients with infectious complications tended not to receive anti-cancer treatment., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Radial endobronchial ultrasound-guided transbronchial biopsy (rEBUS-TBB) facilitates the diagnosis of peripheral lung lesions. However, methods to prevent infectious complications afterwards have not been well established. Therefore, we analyzed the efficacy of short-term oral antibiotics for preventing infectious complications., Methods: We retrospectively analyzed 484 patients. Patients who underwent rEBUS-TBB from March 2018 to March 2019 did not receive prophylactic antibiotics ("no prophylactic" group, n = 233), while patients who underwent rEBUS-TBB from April 2019 to March 2020 did receive prophylactics (oral amoxicillin/clavulanate for 3 days; "prophylactic" group, n = 251). Multivariable logistic regression was used to identify independent factors for infectious complications., Results: The median age was 66 years (IQR: 59-74 years), and 58.9% were male. Slightly over half of the patients (54.4%) were previous or current smokers. In 13% (n = 63) of patients, the procedure was performed using a guide sheath. Infectious complications occurred in 12 (5.2%) and 2 (0.8%) cases in the no prophylactic and prophylactic groups, respectively. In multivariable analysis, infectious complications were significantly associated with a cavity or low-density attenuation (LDA) of the lesion, and with obstructive pneumonic consolidation, but not with prophylactic antibiotics. In subgroup analysis, infectious complications occurred less often when prophylactic antibiotics were used in patients with at least one risk factor (22.4% vs. 0%, p = 0.005)., Conclusions: The risk factors for infectious complications were cavities, LDA in the lesion, and obstructive pneumonic consolidation. Use prophylactic antibiotics might reduce incidence of infectious complications in the presence of these risk factors., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Evidence suggests that there are substantial inconsistencies in the practice of anesthesia. There has not yet been a comprehensive summary of the anesthesia literature that can guide future knowledge translation interventions to move evidence into practice. As the first step toward identifying the most promising interventions for systematic implementation in anesthesia practice, this scoping review of multicentre RCTs aimed to explore and map the existing literature investigating perioperative anesthesia-related interventions and clinical patient outcomes., Methods: Multicenter randomized controlled trials were eligible for inclusion if they involved a tested anesthesia-related intervention administered to adult surgical patients (≥ 16 years old), with a control group receiving either another anesthesia intervention or no intervention at all. The electronic databases Embase (via OVID), MEDLINE, and MEDLINE in Process (via OVID), and Cochrane Central Register of Control Trials (CENTRAL) were searched from inception to February 26, 2021. Studies were screened and data were extracted by pairs of independent reviewers in duplicate with disagreements resolved through consensus or a third reviewer. Data were summarized narratively., Results: We included 638 multicentre randomized controlled trials (n patients = 615,907) that met the eligibility criteria. The most commonly identified anesthesia-related intervention theme across all studies was pharmacotherapy (n studies = 361 [56.6%]; n patients = 244,610 [39.7%]), followed by anesthetic technique (n studies = 80 [12.5%], n patients = 48,455 [7.9%]). Interventions were most often implemented intraoperatively (n studies = 233 [36.5%]; n patients = 175,974 [28.6%]). Studies typically involved multiple types of surgeries (n studies = 187 [29.2%]; n patients = 206 667 [33.5%]), followed by general surgery only (n studies = 115 [18.1%]; n patients = 201,028 [32.6%]) and orthopedic surgery only (n studies = 94 [14.7%]; n patients = 34,575 [5.6%]). Functional status was the most commonly investigated outcome (n studies = 272), followed by patient experience (n studies = 168), and mortality (n studies = 153)., Conclusions: This scoping review provides a map of multicenter RCTs in anesthesia which can be used to optimize future research endeavors in the field. Specifically, we have identified key knowledge gaps in anesthesia that require further systematic assessment, as well as areas where additional research would likely not add value. These findings provide the foundation for streamlining knowledge translation in anesthesia in order to reduce practice variation and enhance patient outcomes., (© 2021. The Author(s).)

Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/tlcr-21-634). Dr. IJO has grant from Roche; he also has received consulting fee from Roche, Ono, MSD, Pfizer, Boehringer-Ingelheim, AstraZeneca and Takeda. Dr. YT reports grants from JSPS KAKENHI grant number JP18K15928 and grants from Takeda Science Foundation outside the submitted work. Dr. SW reports grant and personal fee from AstraZeneca and Boehringer Ingelheim, personal fee from Chugai Pharma, Ono Pharmaceutical, Bristol-Myers, Eli Lilly, MSD, Taiho Pharmaceutical, Pfizer, Novartis, Daiichi Sankyo. Dr. RC has received consulting fees, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AZ, MSD, BMS, Roche, TAKEDA, Pfizer, janssen, Bayer, Novartis; Dr. RC has Participation on a Data Safety Monitoring Board or Advisory Board with AZ, MSD, BMS, Roche, TAKEDA, Pfizer, janssen, Bayer, Novartis; Dr. RC has received Support for attending meetings and/or travel from Roche, MSD, Takeda; Dr. RC declares stock ownership with The christie private care. Dr. KM reports medical education grant, Africa from Varian and Pfizer, Clinical trial grant from AstraZeneca and Novartis; travel and accommodations to a clinical trial meeting, 2019 from AstraZeneca; Dr. KM is an unpaid Board of Directors of Global Access to Cancer Care Foundation. Dr. JCS has grant support from National Institute of Health and the Noah’s Hope Foundation; she also has a family member that owns stock options and receives financial compensation from Vida Diagnostics. Dr. MF participated in advisory board for Astrazeneca, AbbVie and Beigene LLC. Dr. DDR reports grants from Bristol-Myers Squibb, grants from AstraZeneca, grants from Boehringer Ingelheim, from Philips, from Olink, from Celgene, from Seattle Genetics, from Roche/Genentech, from Merck/Pfizer, outside the submitted work. Dr. FC reports fees for membership of an advisory board from Roche, AstraZeneca, BMS, Pfizer, Takeda, Lilly, Bayer, Amgen, Sanofi, Pharmamar, Novocure and MSD. Dr NS obtained commercial research grants from Eli Lilly, Chugai Pharmaceutical, Taiho Pharmaceutical, Pfizer Japan, Ono Pharmaceutical, and Nippon Boehringer Ingelheim, and has received speaking honoraria from Eli Lilly, AstraZeneca, MSD Oncology, Chugai Pharmaceutical, Taiho Pharmaceutical, Pfizer Japan, Ono Pharmaceutical, Nippon Boehringer Ingelheim, and Bristol-Myers Squibb Japan. TH serves as an unpaid editorial board member of Translational Lung Cancer Research from Jan 2020 to Dec 2021. FC serves as an unpaid editorial board member of Translational Lung Cancer Research from Aug 2021 to Jul 2023. MF serves as an unpaid editorial board member of Translational Lung Cancer Research from Sep 2019 to Sep 2021. SY serves as an unpaid editorial board member of Translational Lung Cancer Research from Sep 2019 to Sep 2021. GM serves as an unpaid editorial board member of Translational Lung Cancer Research from Aug 2021 to Jul 2023. PH serves as an unpaid editorial board member of Translational Lung Cancer Research from Mar 2021 to Feb 2023. The other authors have no conflicts of interest to declare.

Objectives: We aimed to find the best machine learning (ML) model using 18 F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) for evaluating metastatic mediastinal lymph nodes (MedLNs) in non-small cell lung cancer, and compare the diagnostic results with those of nuclear medicine physicians., Methods: A total of 1329 MedLNs were reviewed. Boosted decision tree, logistic regression, support vector machine, neural network, and decision forest models were compared. The diagnostic performance of the best ML model was compared with that of physicians. The ML method was divided into ML with quantitative variables only (MLq) and adding clinical information (MLc). We performed an analysis based on the 18 F-FDG-avidity of the MedLNs., Results: The boosted decision tree model obtained higher sensitivity and negative predictive values but lower specificity and positive predictive values than the physicians. There was no significant difference between the accuracy of the physicians and MLq (79.8% vs. 76.8%, p = 0.067). The accuracy of MLc was significantly higher than that of the physicians (81.0% vs. 76.8%, p = 0.009). In MedLNs with low 18 F-FDG-avidity, ML had significantly higher accuracy than the physicians (70.0% vs. 63.3%, p = 0.018)., Conclusion: Although there was no significant difference in accuracy between the MLq and physicians, the diagnostic performance of MLc was better than that of MLq or of the physicians. The ML method appeared to be useful for evaluating low metabolic MedLNs. Therefore, adding clinical information to the quantitative variables from 18 F-FDG PET/CT can improve the diagnostic results of ML., Key Points: • Machine learning using two-class boosted decision tree model revealed the highest value of area under curve, and it showed higher sensitivity and negative predictive values but lower specificity and positive predictive values than nuclear medicine physicians. • The diagnostic results from machine learning method after adding clinical information to the quantitative variables improved accuracy significantly than nuclear medicine physicians. • Machine learning could improve the diagnostic significance of metastatic mediastinal lymph nodes, especially in mediastinal lymph nodes with low 18F-FDG-avidity.

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 (FEV 1 ) 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 FEV 1 after surgery were alleviated by perioperative bronchodilator even after adjustments for related confounding factors including surgical extent, surgical approach and preoperative FEV 1 (adjusted mean difference in FEV 1 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: Immune and stromal component evaluation is necessary to establish accurate prognostic markers for the prediction of clinical outcomes in lung adenocarcinoma (LUAD). We aimed to develop a gene signature based on the Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE)-stromal-immune score in LUAD., Methods: The transcriptomic profiles of patients with LUAD were obtained from The Cancer Genome Atlas (TCGA), and the immune and stromal scores were derived using the ESTIMATE algorithm. The prognostic signature genes were selected from the differentially expressed genes (DEGs) using the robust partial likelihood-based cox proportional hazards regression method. The negative log-likelihood and the Akaike Information Criterion (AIC) were used to identify the optimal gene signature. The validation was carried out in 2 independent datasets from the Gene Expression Omnibus (GSE68571 and GSE72094)., Results: Patients with high ESTIMATE, stromal, and immune scores had better overall survivals (P=0.0035, P=0.066, and P=0.0077). The expression of thirty-seven genes was related to ESTIMATE-stromal-immune score. A risk stratification model was developed based on a gene signature containing CD74, JCHAIN, and PTGDS. The ESTIMATE-stromal-immune risk score was revealed to be a prognostic factor (P=0.009) after multivariate analysis. Four groups were classified based on this risk stratification model, yielding increasing survival outcomes (log-rank test, P=0.0051). This risk stratification model and other clinicopathological factors were combined to generate a nomogram. The calibration curves showed perfect agreement between the nomogram-predicted outcomes and those actually observed. Similar observations were made in 2 independent cohorts., Conclusions: The gene signature based on the ESTIMATE-stromal-immune score could predict the prognosis of patients with LUAD., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr-21-223). The authors have no conflicts of interest to declare., (2021 Translational Lung Cancer Research. All rights reserved.)

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.

Background: To determine which components should be measured and which window settings are appropriate for computerized tomography (CT) size measurements of lung adenocarcinoma (ADC) and to explore interobserver agreement and accuracy according to the eighth edition of TNM staging., Methods: A total of 165 patients with surgically resected lung ADC earlier than stage 3A were included in this study. One radiologist and two pulmonologists independently measured the total and solid sizes of components of tumors on different window settings and assessed solidity. CT measurements were compared with pathologic size measurements., Results: In categorizing solidity, 25% of the cases showed discordant results among observers. Measuring the total size of a lung adenocarcinoma predicted pathologic invasive components to a degree similar to measuring the solid component. Lung windows were more accurate (intraclass correlation [ICC] = 0.65-0.81) than mediastinal windows (ICC = 0.20-0.72) at predicting pathologic invasive components, especially in a part-solid nodule. Interobserver agreements for measurement of solid components were good with little significant difference (lung windows, ICC = 0.89; mediastinal windows, ICC = 0.91). A high level of interobserver agreement was seen between the radiologist and pulmonologists and between residents (from the division of pulmonology and critical care) versus a fellow (from the division of pulmonology and critical care) on different windows., Conclusions: A considerable percentage (25%) of discrepancies was encountered in categorizing the solidity of lesions, which may decrease the accuracy of measurements. Lung window settings may be superior to mediastinal windows for measuring lung ADCs, with comparable interobserver agreement and moderate accuracy for predicting pathologic invasive components., Key Points: SIGNIFICANT FINDINGS OF THE STUDY: Lung window settings are better for evaluating part-solid lung adenocarcinoma (ADC), with comparable interobserver agreement and moderate accuracy for predicting pathologic invasive components. The considerable percentage (25%) of discrepancies in categorizing solidity of the lesions may also have decreased the accuracy of measurements., What This Study Adds: For accurate measurement and categorization of lung ADC, robust quantitative analysis is needed rather than a simple visual assessment., (© 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

The next diagnostic step in cases of indeterminate radial probe endobronchial ultrasound (radial EBUS)-guided biopsy results remains uncertain. This study aimed to identify risk factors for malignancy based on clinical findings, chest computed tomography (CT), and radial EBUS images, and to estimate the risk of malignancy in lung nodules that showed indeterminate radial EBUS-guided biopsy results by constructing a nomogram. This retrospective study included 157 patients with indeterminate results on an initial radial EBUS biopsy performed at the Samsung Medical Center from January 2017 to December 2018, but with a definitive final diagnosis. Medical records, chest CT, radial EBUS images, and the final diagnoses were reviewed. Patients were randomly divided into training and validation sets. Factors related to malignancy were identified through logistic regression analysis, and a nomogram was constructed using the training set and subsequently applied to the validation set. Six factors in univariable and multivariable analyses, including upper lobe location, spiculation, satellite nodules, echogenicity, presence of dots or linear arcs, and patency of vessels and bronchi predicted malignancy. A nomogram was constructed based on these predictors. The area under the curve (AUC) value of the nomogram was 0.858 using the chest CT factors, which improved to 0.952 when radial EBUS factors were added. The calibration curve showed good agreement between the actual and nomogram-predicted malignancy outcomes. The utility of radial EBUS images for revealing risk factors of malignancy was confirmed. Furthermore, our nomogram was able to predict the probability of malignancy in lung nodules with indeterminate radial EBUS-guided biopsy results.

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: We investigated the clinicoradiopathological features and prognosis according to genomic alterations in patients with surgically resected lung adenocarcinoma., Methods: Patients who underwent surgical resection for pathologic stage I, II, or IIIA lung adenocarcinoma between 2009 and 2016 and for whom results regarding EGFR mutation, ALK immunohistochemistry (IHC), and KRAS mutation were available were included. Clinicoradiopathological characteristics, genomic alterations, and disease-free survival were analyzed retrospectively., Results: Of 164 patients, 86 (52.4%) were female and 94 (57.3%) were never-smokers. The most common imaging patterns were part-solid lesion (67.7%) followed by solid (26.2%) and non-solid (6.1%) lesions. EGFR mutation, ALK IHC, and KRAS mutation were positive in 95 (57.9%), 9 (5.5%), and 11 (6.7%) patients, respectively. EGFR mutation positivity was associated with female sex, never-smoker, subsolid pattern on radiological examination, and acinar or papillary predominant histologic subtype. ALK IHC positivity was associated with longer maximal diameter, advanced stage, solid pattern on radiological examination, solid predominant histologic subtype, and distant metastasis during follow-up. KRAS mutation positivity was associated with male sex, smoker, solid pattern on radiological examination, and invasive mucinous adenocarcinoma on histologic analysis. In multivariable analysis, ALK IHC positivity and lymph node involvement were independently associated with recurrence. However, solidity was not an independent risk factor for recurrence., Conclusions: Genomic alterations are associated with clinicoradiopathologic features in patients with resected lung adenocarcinoma. Identifying genomic alterations could help to predict the prognosis of early-stage lung adenocarcinoma., Competing Interests: Conflicts of Interests: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jtd-20-1716). The authors have no conflicts of interest to declare., (2020 Journal of Thoracic Disease. All rights reserved.)

Objectives: Primary pulmonary salivary gland-type tumors (PSGT) are rare among all types of lung cancer. The purpose of this study was not only to evaluate the clinical outcomes and prognostic factors after treatment, but also to assess the role for bronchoscopic intervention in PSGT., Methods: We analyzed the medical data of 181 PSGT patients who were treated between 1995 and 2018. Patients were divided into three groups according to the initial treatment, as follows: surgical resection with/without adjuvant therapy including bronchoscopic intervention (surgery group, n = 116); bronchoscopic intervention without surgical resection (bronchoscopic intervention group, n = 51); and other treatments group (n = 14). A multivariable Cox proportional hazard regression analysis was used to identify the independent prognostic factors associated with overall survival (OS) and progression free survival (PFS) after the first treatment. In addition, subgroup analysis was performed according to the clinical stage., Results: Among the 181 patients, 104 (57.5%) patients were diagnosed with adenoid cystic carcinoma (ACC), 71 (39.2%) with mucoepidermoid carcinoma, and 6 (3.3%) with epithelial-myoepithelial carcinoma. In the surgery group, 21 patients underwent bronchoscopic intervention as a bridge therapy before surgery because of respiratory distress. Poor OS was associated with older age, the existence of other malignancy, higher clinical stages, larger tumor size, and non-surgical treatments. Lower PFS was associated with ACC, larger tumor size, and non-surgical treatments. The surgery group had the best OS and PFS among all treatment groups. However, there was no significant difference in the OS between the surgery and bronchoscopic intervention groups (p = 0.66) in patients at high clinical stages., Conclusions: Surgical resection was the best initial treatment choice. However, bronchoscopic intervention may be useful as the initial treatment in patients at high clinical stage and as a bridge therapy prior to surgery., Competing Interests: Declarations of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

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., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Yonsei University College of Medicine 2020.)

Background/aim: Although it has been suggested that circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) might be used in a complementary manner in lung cancer diagnosis, limited confirmatory data are available. In this prospective study, we evaluated the diagnostic performance of each assay separately and in combination., Patients and Methods: From March 2018 to January 2019, patients with suspected primary lung cancer, who underwent routine lung cancer work-up and peripheral blood sampling, were prospectively enrolled in the study. Epithelial cell adhesion molecule and cytokeratin served as markers of CTCs. In terms of ctDNA analysis, single-nucleotide variants were evaluated via next-generation sequencing., Results: We analyzed 111 patients, including 99 with primary lung cancer and 12 with benign pulmonary disease. The median number of CTCs in 10 ml of blood was 3. The most frequently detected single nucleotide variants of ctDNA were TP53, CDKN2A, and EGFR. The diagnostic sensitivity of conventional tumor marker (combination of carcinoembryonic antigen/CYFRA 21-1/neuron-specific enolase) was 66.7%, while those of the ctDNA and CTC assays were 72.7% and 65.7%, respectively. The sensitivity of the CTC/ctDNA combination (95.0%) was significantly greater than those of the CTC (p<0.001), ctDNA (p<0.001), or conventional tumor marker (p<0.001) alone. Subgroup analysis revealed that the sensitivity of the combination assay was greater than those of the CTC or ctDNA assays alone, regardless of tumor stage or histopathology type., Conclusion: The CTC/ctDNA combination assay enhanced the sensitivity of primary lung cancer diagnosis. The combination assay strategy may be clinically useful and could enhance the early detection of lung cancer (ClinicalTrials.gov number: NCT03479099)., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)