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Jeong Uk Lim,1 Hye Seon Kang,2 Chang Dong Yeo,3 Ju Sang Kim,4 Chan Kwon Park,1 Yong Hyun Kim,2 Jin Woo Kim,5 Seung Joon Kim,6,7 Sang Haak Lee3,7 1Division of Pulmonary, Critical Care and Allergy, Department of Internal Medicine, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 2Division of Pulmonary, Critical Care and Allergy, Department of Internal Medicine, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Bucheon, Republic of Korea; 3Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Eunpyeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 4Division of Pulmonary, Critical Care and Sleep Allergy, Department of Internal Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 5Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Uijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 6Division of Pulmonary, Critical Care and Allergy, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 7Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of KoreaCorrespondence: Yong Hyun KimDivision of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 327, Sosa-ro, Bucheon-si, Gyeonggi-do 14647, Republic of KoreaTel +82-32-340-7039Fax +82-32-340-2669Email kyh30med@catholic.ac.krBackground: In patients with non-small cell lung cancer (NSCLC), both chronic obstructive pulmonary disease (COPD) and systemic inflammatory biomarkers, such as neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR), have significant association with prognosis. NLR and PLR also predict mortality in patients with COPD alone. A combination of the two parameters may be helpful in a more individualized approach for predicting prognosis in NSCLC.Methods: Medical records of patients with stage IIIB and IV NSCLC from January 2012 to January 2018 in seven university hospitals were reviewed. Patients were categorized into four subgroups based on pulmonary function test results and cutoffs for NLR or PLR.Results: A total of 277 patients were evaluated and categorized into non-COPD and COPD groups; 194 patients were in the non-COPD group and 83 patients were in the COPD group. The non-COPD group showed significantly longer overall survival (OS) compared with the COPD group (P = 0.019). Median survival was significantly different between high/low PLR groups (P < 0.001), between high/low NLR groups (P = 0.001), and between high/low c-reactive protein (CRP) groups (P < 0.001). PLR, NLR and CRP showed significant correlations with each other. PLR showed a significant negative linear correlation with FVC (absolute) (r = − 0.149, P = 0.015), FVC (%) (r = − 0.192, P = 0.002), DLCO (absolute) (r = − 0.271, P < 0.001), DLCO (%) (r = − 0.139, P = 0.032), and NLR (r = 0.718, P < 0.001). In the multivariate analysis, the high PLR, COPD sub-group showed significantly higher risk for mortality (HR 2.066 (1.175– 3.633), P = 0.012) compared with the low-PLR non-COPD group. However, COPD-NLR subtype was not an independent predictor for OS.Conclusion: A combination of COPD status and PLR may be a cost-effective and readily available prognostic marker in patients with advanced NSCLC.Keywords: chronic obstructive pulmonary disease, non-small cell lung cancer, survival, platelet, lymphocyte, inflammation, biomarker

Jeong Uk Lim, Chang Dong Yeo, Chin Kook Rhee, Hye Seon Kang, Chan Kwon Park, Ju Sang Kim, Jin Woo Kim, Seung Joon Kim, Hyoung Kyu Yoon, Sang Haak LeeDivision of Pulmonology and Critical Care Medicine, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of KoreaObjectives: A significant proportion of non-small cell lung cancer (NSCLC) patients are never-smokers. However, the clinical impact of spirometrically diagnosed chronic obstructive pulmonary disease (COPD) on the prognosis of never-smoking NSCLC has not been evaluated in the context of treatment modalities and other cancer-related factors. In the present study, we evaluated the clinical impact of COPD in non-smoking NSCLC patients, and correlations between COPD and other previously unevaluated clinical variables.Materials and methods: Lung cancer patients (stages I to IV) diagnosed with NSCLC between January 2008 and December 2015 at six university hospitals were enrolled in the study cohort and retrospectively evaluated. Clinical parameters were compared between spirometrically diagnosed COPD and non-COPD groups. Correlations between COPD status and other variables were evaluated. In order to reduce the effect of potential confounders and selection bias, we performed adjustment for differences in baseline parameters by using propensity score matching (PSM). After PSM, clinical variables were evaluated for their effects on overall survival (OS).Results: Of the 345 patients enrolled in the study, 277 were categorized as non-COPD and 68 as COPD. Old age, male gender, and wild-type EGFR were significantly correlated with COPD. By univariate analysis of 218 patients in a propensity score matched cohort, not receiving active anticancer treatment, advanced stage, and COPD were significantly associated with shorter OS. Multivariate analysis showed that not receiving active anticancer treatment, advanced cancer stage, and COPD (P=0.044, HR: 1.526, 95% CI: 1.012–2.300) were significant predictors of shorter OS.Conclusion: In the present study, never-smoker NSCLC patients with COPD had shorter OS times, compared to non-COPD never-smoker NSCLC patients.Keywords: never smoker, overall survival, risk factor

Jeong Uk Lim, Chang Dong Yeo, Chin Kook Rhee, Yong Hyun Kim, Chan Kwon Park, Ju Sang Kim, Jin Woo Kim, Seung Joon Kim, Hyoung Kyu Yoon, Sang Haak Lee Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea Objectives: Focusing on the advanced non-small cell lung cancer (NSCLC) patients without driver mutations can elucidate the clinical impact of COPD on treatment outcomes. The present study evaluated the effects of COPD on the overall survival of driver mutation-negative NSCLC patients undergoing conventional chemotherapy as the first-line treatment. Patients and methods: Medical records of stage IIIB and IV NSCLC patients from January 2008 to December 2015 from six university hospitals were reviewed. Results: The total study population consisted of 197 patients; 92 (46.7%) were COPD patients and 105 (53.3%) were non-COPD patients. The median survival in the non-COPD group was 11.5 months, compared to 9.2 months in the COPD group. Univariate analysis showed that old age (>70 years), high Eastern Cooperative Oncology Group status score (2–3), squamous cell histology, and COPD were risk factors for mortality. The presence of COPD was a significant prognostic factor in univariate analysis (hazard ratio [HR], 1.402; p=0.037), but not in multivariate analysis (HR, 1.275; p=0.144). Subgroup analysis of 143 smokers showed that COPD was a significant prognostic factor on multivariate analysis (HR, 1.726; p=0.006). In 154 stage IV patients, COPD was also a prognostic factor in multivariate analysis (HR, 1.479; p=0.039). Conclusion: COPD had a negative impact on overall survival in the stage IV NSCLC and smoker NSCLC patients who underwent conventional chemotherapy. Keywords: non-small cell lung cancer, chronic obstructive pulmonary disease, smoker, overall survival

This study proposed an optimized histogel construction method for histological analysis by applying lung cancer patient-derived organoids (PDOs) to the developed histo-pillar strip. Previously, there is the cultured PDOs damage problem during the histogel construction due to forced detachment of the Matrigel spots from the 96-well plate bottom. To address this issue, we cultured PDO on the proposed Histo-pillar strips and then immersed them in 4% paraformaldehyde fixation solution to self-isolate PDO without damage. The 4 μ l patient-derived cell (PDC)/Matrigel mixtures were dispensed on the surface of a U-shaped histo-pillar strip, and the PDCs were aggregated by gravity and cultured into PDOs. Cultured PDOs were self-detached by simply immersing them in a paraformaldehyde fixing solution without physical processing, showing about two times higher cell recovery rate than conventional method. In addition, we proposed a method for embedding PDOs under conditions where the histogel temperature was maintained such that the histogel did not harden, thereby improving the problem of damaging the histogel block in the conventional sandwich histogel construction method. We performed histological and genotyping analyses using tumor tissues and PDOs from two patients with lung adenocarcinoma. Therefore, the PDO culture and improved histogel block construction method using the histo-pillar strip proposed in this study can be employed as useful tools for the histological analysis of a limited number of PDCs., (Creative Commons Attribution license.)

Background: Recent evidences showed that resection of lung tumor post-targeted therapy has shown progression-free survival (PFS) benefits in initially unresectable patients. The aim of this study is to evaluate pathologic findings of resected lung tumor samples in patients who have undergone prior epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) treatment, and also to assess the prognostic factors related to outcomes after resection., Methods: The deidentified data of non-small cell lung cancer (NSCLC) patients admitted to seven university hospitals affiliated with the Catholic University of Korea were obtained from the Clinical Data Warehouse (CDW) database. Among screened patients, 40 individuals who had previously undergone targeted therapies and later received surgical resection of a primary lung tumor were evaluated for the study., Results: All 40 patients were diagnosed with adenocarcinoma. Of these, 36 with EGFR mutations received prior EGFR TKI treatment. Only one postoperative complication, atrial fibrillation, was observed. At the time of resection, 19 patients showed primary lung tumor size regressing or unchanged, while 21 patients showed primary lung tumor regrowth or new lesions being developed before the resection. The group with no programmed death-ligand 1 (PD-L1) expression from resected samples showed significantly better post-resection PFS when compared to the other group (P=0.01). In the Model II multivariate analysis for post-resection PFS, PD-L1 detection from the resected sample was significantly associated with PFS [P=0.03; hazard ratio (HR) =5.465; 95% confidence interval (CI): 1.200-24.885]. Furthermore, an increase in PD-L1 expression compared to the baseline value was associated with an increasing lung tumor burden at the time of resection (P=0.03)., Conclusions: Resected specimen following targeted therapy can provide valuable clinical information that can be used to predict the prognosis of patients with initially unresectable NSCLC., 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-24-215/coif). The authors have no conflicts of interest to declare., (2024 Translational Lung Cancer Research. All rights reserved.)

Background: Lazertinib is an oral, third-generation EGFR-TKI, which specifically targets the EGFR T790M mutation along with activating mutations Ex19del and L858R. More real-world data are needed to evaluate its efficacy and safety in treating locally advanced and metastatic non-small cell lung cancer (NSCLC) following prior EGFR TKI treatment., Methods: This multicenter retrospective study was conducted at seven university hospitals affiliated to the Catholic Medical Center (CMC) in Korea. A clinical data warehouse (CDW) platform was used to access and extract information., Results: A total of 48 patients were assessed. The majority were female (75%) and diagnosed with adenocarcinoma (95.8%). All patients had the EGFR mutation at diagnosis, 27 (56.3%) had the exon 19 deletion, 20 (41.7%) had the L858R mutation, and one (2.0%) had the exon 18 mutation. The median progression-free survival (PFS) was 15.4 months. At 6, 12, and 18 months, PFS rates were 79.1%, 53.6%, and 27.3%, respectively. When PFS was analyzed by prior TKI duration (<18 months vs. >18 months), significant differences were noted at the 6 and 9-month mark (p = 0.013 and p = 0.010, respectively). In multivariate analysis for PFS, only prior TKI duration and ECOG score showed statistical significance (p = 0.026 and p = 0.049, respectively). In the multivariate analysis for OS, ECOG score showed statistical significance (p = 0.006). Among 48 patients, 34 (70.8%) experienced adverse events (AEs) related to lazertinib. The most frequent AEs were skin reaction (29.8%), diarrhea (21.3%), and peripheral neuropathy (20.8%)., Conclusions: The results suggest that lazertinib is effective in second or more line settings, with tolerable safety profile. More patient data are necessary to find possible prognostic markers associated with patient outcome., (© 2024 The Author(s). Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

Hypoxia is a representative tumor characteristic associated with malignant progression in clinical patients. Engineered in vitro models have led to significant advances in cancer research, allowing for the investigation of cells in physiological environments and the study of disease mechanisms and processes with enhanced relevance. In this study, we propose a U-shape pillar strip for a 3D cell-lumped organoid model (3D-COM) to study the effects of hypoxia on lung cancer in a high-throughput manner. We developed a U-pillar strip that facilitates the aggregation of PDCs mixed with an extracellular matrix to make the 3D-COM in 384-plate array form. The response to three hypoxia-activated prodrugs was higher in the 3D-COM than in the 2D culture model. The protein expression of hypoxia-inducible factor 1 alpha (HIF-1α) and HIF-2α, which are markers of hypoxia, was also higher in the 3D-COM than in the 2D culture. The results show that 3D-COM better recapitulated the hypoxic conditions of lung cancer tumors than the 2D culture. Therefore, the U-shape pillar strip for 3D-COM is a good tool to study the effects of hypoxia on lung cancer in a high-throughput manner, which can efficiently develop new drugs targeting hypoxic tumors.

Patient-derived organoids (PDOs) are valuable in predicting response to cancer therapy. PDOs are ideal models for precision oncologists. However, their practical application in guiding timely clinical decisions remains challenging. This study focused on patients with advanced EGFR-mutated non-small cell lung cancer and employed a cancer organoid-based diagnosis reactivity prediction (CODRP)-based precision oncology platform to assess the efficacy of EGFR inhibitor treatments. CODRP was employed to evaluate EGFR-tyrosine kinase inhibitors (TKI) drug sensitivity. The results were compared to those obtained using area under the curve index. This study validated this index by testing lung cancer-derived organoids in 14 patients with lung cancer. The CODRP index-based drug sensitivity test reliably classified patient responses to EGFR-TKI treatment within a clinically suitable 10-day timeline, which aligned with clinical drug treatment responses. This approach is promising for predicting and analyzing the efficacy of anticancer, ultimately contributing to the development of a precision medicine platform., (© 2024. The Author(s).)

There have been previous studies conducted to predict postoperative lung function with pulmonary function tests (PFTs). Computing tomography (CT) can quantitatively measure small airway walls' thickness, lung volume, pulmonary vessel volume, and emphysema area, which reflect the severity of respiratory diseases. These measurements are considered imaging biomarkers. This study aimed to predict postoperative lung function with imaging biomarkers. A retrospective analysis of 79 patients with lung cancer who had undergone lung surgery was completed. Postoperative lung function measured by forced expiratory volume in one second (FEV 1 ) was defined as an outcome. Preoperative clinico-pathological parameters and imaging biomarkers representing airway walls' thickness, severity of emphysema, total lung volume, and pulmonary vessel volume were measured quantitatively in chest CT by an automated segmentation software, AVIEW COPD. Pi1 was defined as the first percentile along the histogram of lung attenuation that represents the degree of emphysema. Wafw was defined as the airway thickness, which was calculated by the full-width at half-maximum method. Logistic and linear regressions were used to assess these variables. If the actual postoperative FEV 1 was higher than the postoperative FEV 1 projected by a formula, the group was considered to be preserved. Among the 79 patients, 16 of the patients were grouped as a non-preserved group, and 63 of them were grouped as a preserved group. The patients in the preserved FEV 1 group had a higher vessel volume than the non-preserved group. Pi1 and Wafw were independent predictors of postoperative lung function. Imaging biomarkers can be considered significant variables in predicting postoperative lung function in patients with lung cancer.

Background/aim: Acute lung injury (ALI) is associated with a high mortality rate and cancer patients who receive chemotherapy are at high risk of ALI during neutropenia recovery. Galantamine is a cholinesterase inhibitor used for Alzheimer's disease treatment. Previous studies have shown that galantamine reduced inflammatory response in lipopolysaccharide (LPS)-induced ALI in rats. Mer protein was negatively associated with inflammatory response. The aim of the study was to investigate whether galantamine is effective in LPS-induced ALI during neutropenia recovery and its effect on Mer tyrosine kinase (MerTK) expression in mice., Materials and Methods: Intraperitoneal cyclophosphamide was given to mice to induce neutropenia. After 7 days, LPS was administered by intratracheal instillation. Intraperitoneal galantamine was given once before LPS administration and in another group, galantamine was given twice before LPS administration., Results: Galantamine attenuated LPS-induced ALI in histopathological analysis. The neutrophil percentage was lower in the group where galantamine was injected once, compared to the LPS group (p=0.007). MerTK expression was also higher in the group where galantamine was injected once but did not reach statistical significance (p=0.101)., Conclusion: Galantamine attenuated inflammation in LPS-induced ALI during neutropenia recovery., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The subtype of eccrine carcinoma known as squamoid eccrine ductal carcinoma (SEDC) is rare; only 38 cases, including only 6 cases in the ear, have been documented in the literature. This may be the first case to focus on the fact that SEDC, located within the dermal and subcutaneous layers, spares the epidermis histopathologically, which can cause clinicians to confuse SEDC with acute perichondritis., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background/aim: Lung cancer is a major cause of cancer-related deaths worldwide, and chronic inflammation caused by cigarette smoke plays a crucial role in the development and progression of this disease. S100A8/9 and RAGE are associated with chronic inflammatory diseases and cancer. This study aimed to investigate the expression of S100A8/9, HMBG1, and other related pro-inflammatory molecules and clinical characteristics in patients with non-small cell lung cancer (NSCLC)., Patients and Methods: We obtained serum and bronchoalveolar lavage (BAL) fluid samples from 107 patients and categorized them as never or ever-smokers. We measured the levels of S100A8/9, RAGE, and HMGB1 in the collected samples using enzyme-linked immunosorbent kits. Immunohistochemical staining was also performed to assess the expression of S100A8/9, CD11b, and CD8 in lung cancer tissues. The correlation between the expression of these proteins and the clinical characteristics of patients with NSCLC was also explored., Results: The expression of S100A8/A9, RAGE, and HMGB was significantly correlated with smoking status and was higher in people with a history of smoking or who were currently smoking. There was a positive correlation between serum and BAL fluid S100A8/9 levels. The expression of S100A8/A9 and CD8 in lung tumor tissues was significantly correlated with smoking history in patients with NSCLC. Ever-smokers, non-adenocarcinoma histology, and high PD-L1 expression were significant factors predicting high serum S100A8/9 levels in multivariate analysis., Conclusion: The S100A8/9-RAGE pathway and CD8 expression were increased in smoking-related NSCLC patients. The S100A8/9-RAGE pathway could be a promising biomarker for chronic airway inflammation and carcinogenesis in smoking-related lung diseases., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Recently, cancer organoid-based drug sensitivity tests have been studied to predict patient responses to anticancer drugs. The area under curve (AUC) or IC 50 value of the dose-response curve (DRC) is used to differentiate between sensitive and resistant patient's groups. This study proposes a multi-parameter analysis method (cancer organoid-based diagnosis reactivity prediction, CODRP) that considers the cancer stage and cancer cell growth rate, which represent the severity of cancer patients, in the sensitivity test., Methods: On the CODRP platform, patient-derived organoids (PDOs) that recapitulate patients with lung cancer were implemented by applying a mechanical dissociation method capable of high yields and proliferation rates. A disposable nozzle-type cell spotter with efficient high-throughput screening (HTS) has also been developed to dispense a very small number of cells due to limited patient cells. A drug sensitivity test was performed using PDO from the patient tissue and the primary cancer characteristics of PDOs were confirmed by pathological comparision with tissue slides., Results: The conventional index of drug sensitivity is the AUC of the DRC. In this study, the CODRP index for drug sensitivity test was proposed through multi-parameter analyses considering cancer cell proliferation rate, the cancer diagnosis stage, and AUC values. We tested PDOs from eight patients with lung cancer to verify the CODRP index. According to the anaplastic lymphoma kinase (ALK) rearrangement status, the conventional AUC index for the three ALK-targeted drugs (crizotinib, alectinib, and brigatinib) did not classify into sensitive and resistant groups. The proposed CODRP index-based drug sensitivity test classified ALK-targeted drug responses according to ALK rearrangement status and was verified to be consistent with the clinical drug treatment response., Conclusions: Therefore, the PDO-based HTS and CODRP index drug sensitivity tests described in this paper may be useful for predicting and analyzing promising anticancer drug efficacy for patients with lung cancer and can be applied to a precision medicine platform., (© 2023. The Author(s).)

Objectives: To investigate the bidirectional association between sudden sensorineural hearing loss (SSNHL) and open-angle glaucoma (OAG) over a 12-year follow-up period using nationwide, population-based data., Methods: The study was conducted using the National Health Information Database of the National Health Insurance Service (NHIS-NHID), which covered 3.5 million individuals from 2008 to 2019. In Study 1, we evaluated the effect of OAG on SSNHL, and in Study 2, we evaluated the effect of SSNHL on OAG. Participants of the control group were enrolled through "greedy nearest-neighbor" 1:1 propensity score matching., Results: In Study 1, 26,777 people were included in each group. The hazard ratio (HR) for SSNHL of the OAG group was 1.27 (95% confidence interval [CI], 1.15-1.39). In subgroup analysis, there was significant HR value regarding (old age: 1.17, hyperlipidemia: 1.19). In Study 2, 15,433 people were included in each group. The HR for OAG of the SSNHL group was 1.18 (95% CI, 1.07-1.30). In subgroup analysis, the HRs were significant for old age (2.31), hypertension (1.17), diabetes (1.39), and hyperlipidemia (1.26)., Conclusion: Over the 12-year follow-up, we found a bidirectional association between SSNHL and OAG, suggesting a shared pathogenesis., Level of Evidence: N/A. Laryngoscope, 133:3169-3177, 2023., (© 2023 The American Laryngological, Rhinological and Otological Society, Inc.)

Background/aims: Obstructive sleep apnea (OSA) is prevalent in older patients with idiopathic pulmonary fibrosis (IPF); however, it is underrecognized. OSA is characterized by intermittent hypoxia (IH) and sleep fragmentation. In this study, we evaluated the effects of IH in an older mouse model of bleomycin-induced lung fibrosis., Methods: Bleomycin-induced mice (C57BL/6, female) were randomly divided into four groups of young vs. old and room air (RA)-exposed vs. IH-exposed. Mice were exposed to RA or IH (20 cycles/h, FiO2 nadir 7 ± 0.5%, 8 h/day) for four weeks. The mice were sacrificed on day 28, and blood, bronchoalveolar lavage (BAL) fluid, and lung tissue samples were obtained., Results: The bleomycin-induced IH-exposed (EBI) older group showed more severe inflammation, fibrosis, and oxidative stress than the other groups. The levels of inflammatory cytokines in the serum and BAL fluid increased in the EBI group. Hydroxyproline levels in the lung tissue increased markedly in the EBI group., Conclusion: This study demonstrates the possible harmful impact of OSA in an elderly mouse model of lung fibrosis. This study further suggests that older patients with IPF and OSA may be more of a concern than younger patients with IPF. Further research is required in this area.

Background/aim: Programmed death ligand-1 (PD-L1) expression is known to be a predictive biomarker for response to immunotherapy in non-small cell lung cancer (NSCLC). However, PD-L1 is not always a reliable predictive biomarker. In the present study, we aimed to compare responses to immunotherapy according to smoking status in NSCLC patients receiving immunotherapy in second line or further line treatment., Patients and Methods: The lung cancer registry database of the Catholic Medical Center, Seoul, Republic of Korea was used. Patients were eligible for this study if they were diagnosed with histologically confirmed NSCLC and received immune checkpoint inhibitors (ICIs) as second-line or further line therapy from January 2017 to December 2021., Results: Overall, 220 patients with NSCLC treated with ICIs were enrolled. There were 40 never smokers, 73 former smokers, and 107 current smokers. In multivariate analysis, smoking status, pathologic type, and PD-L1 expression were significant factors affecting PFS. Sex, ECOG performance status, pathologic type, and PD-L1 expression were significant factors affecting OS., Conclusion: Smoking status at diagnosis of lung cancer could be a predictive biomarker for response to ICIs in patients with advanced NSCLC., (Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Patients with locally advanced, unresectable, non-small cell lung cancer (NSCLC) receiving definitive concurrent chemoradiation therapy (CCRT) benefit from durvalumab consolidation therapy. However, predictive factors for early relapse during durvalumab maintenance have not yet been identified., Methods: The present study included the lung cancer cohort of the Catholic Medical Centers at the Catholic University of Korea from January 2018 to December 2021. A total of 51 NSCLC patients treated with durvalumab consolidation therapy after definitive CCRT were included in the analysis. Early relapse was defined as patients experiencing relapse within 6 months of starting initial durvalumab therapy., Results: Among the 51 patients, 15 (29.4%) relapsed during the study period. Median time from initial therapy of durvalumab to progression was 451.00 ± 220.87 days (95% confidence interval [CI]: 18.10-883.90) in overall patients. In multivariate analysis, younger age (adjusted odds ratio [aOR], 0.792; 95% CI: 0.642-0.977; p = 0.030), higher pack-years (aOR, 1.315; 95% CI: 1.058-1.635; p = 0.014), non-COPD (aOR, 0.004; 95% CI: 0.000-0.828; p = 0.004) and anemia (aOR, 234.30; 95% CI: 1.212-45280.24; p = 0.042), were independent predictive factors for early relapse during durvalumab consolidation therapy., Conclusion: Younger age, higher number of pack-years, non-COPD, and anemia were independent predictive factors for early relapse during durvalumab consolidation therapy in patients with unresectable stage III NSCLC after definitive CCRT. Careful patient selection and clinical attention are needed for high-risk individuals., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Purpose: Intermittent hypoxia and sleep fragmentation, two main features of sleep-disordered breathing (SDB), have been shown to increase the aggressiveness of lung cancer, mainly in animal and in vitro studies. However, the association between SDB and lung cancer has not been well described in human studies. In this study, we investigated the associations among SDB, sleep quality, and lung cancer in Korean patients., Methods: Patients with histologically diagnosed lung cancer performed a home sleep apnea test. Sleep questionnaires including the Epworth Sleepiness Scale (ESS), Insomnia Severity Index, and Pittsburgh Sleep Quality Index were also administered. Clinical information related to lung cancer was collected during the study., Results: Sixty-nine patients were enrolled, 31 of whom were poor sleepers. The overall prevalence of SDB was 57% and that of moderate to severe SDB was 27%. Underlying chronic obstructive pulmonary disease (COPD) and smoking history were significantly more frequent in patients with moderate to severe SDB compared to patients without or with mild SDB. No significant differences were observed in the apnea-hypopnea index (AHI), oxygen desaturation index (ODI), or time with oxygen saturation < 90% (T90) according to cancer cell types, mutations, stages, and survival. However, small-cell lung cancer patients showed a trend toward higher AHI, ODI, and T90 values., Conclusion: The prevalence of SDB and proportion of poor sleepers were high in Korean patients with lung cancer. Paying more attention to sleep status may be helpful for patients with COPD, a smoking history, and small-cell lung cancer., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Patients with lung cancer experience considerable symptom burden, which can decrease patients' QOL. Our aim was to investigate the association between QOL questionnaire at diagnosis and survival of lung cancer., Patients and Methods: This was a multicenter study of lung cancer patients at 7 medical centers of the Catholic University of Korea that responded to a quality of life questionnaire between December 1, 2017 and December 31, 2020. We analyzed 5 functional (physical, role, emotional, cognitive, and social functioning) and nine symptom (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties) scales and examined their associations with survival. A Cox proportional hazards model was used to evaluate the prognostic value., Results: In total, 1297 lung cancer patients were enrolled. The results of multivariable analysis showed that female, younger age, never smoker, stage I or II cancer, higher physical functioning, and emotional functioning were statistically significant favorable predictors for survival. On subgroup analysis according to early (stage I and II) or advanced (stage III or IV) stage, higher physical functioning and emotional functioning were each found to be favorable prognostic factors for survival. Meanwhile, fatigue, pain, insomnia, and financial difficulties were found to be associated with low scores on the emotional functioning scale; fatigue, pain, dyspnea, and financial difficulties were associated with low scores on the physical functioning scale., Conclusion: Assessing the physical functioning and emotional functioning scales of QOL questionnaire items at diagnosis can help clinicians predict the survival of patients with lung cancer., Competing Interests: Disclosure The authors have no conflicts of interest to disclose., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Surgical resection is the standard treatment for early-stage lung cancer. Since postoperative lung function is related to mortality, predicted postoperative lung function is used to determine the treatment modality. The aim of this study was to evaluate the predictive performance of linear regression and machine learning models., Methods: We extracted data from the Clinical Data Warehouse and developed three sets: set I, the linear regression model; set II, machine learning models omitting the missing data: and set III, machine learning models imputing the missing data. Six machine learning models, the least absolute shrinkage and selection operator (LASSO), Ridge regression, ElasticNet, Random Forest, eXtreme gradient boosting (XGBoost), and the light gradient boosting machine (LightGBM) were implemented. The forced expiratory volume in 1 second measured 6 months after surgery was defined as the outcome. Five-fold cross-validation was performed for hyperparameter tuning of the machine learning models. The dataset was split into training and test datasets at a 70:30 ratio. Implementation was done after dataset splitting in set III. Predictive performance was evaluated by R2 and mean squared error (MSE) in the three sets., Results: A total of 1,487 patients were included in sets I and III and 896 patients were included in set II. In set I, the R2 value was 0.27 and in set II, LightGBM was the best model with the highest R2 value of 0.5 and the lowest MSE of 154.95. In set III, LightGBM was the best model with the highest R2 value of 0.56 and the lowest MSE of 174.07., Conclusion: The LightGBM model showed the best performance in predicting postoperative lung function.

Background: Prostate cancer affects African American men disproportionately compared with men of other racial/ethnic groups. To identify biological bases for this health disparity, we sought to create a state-wide biobank of African American prostate cancer survivors in Florida., Methods: African American men diagnosed with prostate cancer between 2013 and 2017 and living in Florida at diagnosis were identified through the State of Florida's cancer registry. Individuals were approached via mail and telephone, assessed for eligibility, and asked for informed consent. χ2 and t tests were conducted to identify differences between eligible and reachable individuals (i.e., had valid contact information) versus consented participants., Results: Of the 5,960 eligible and reachable individuals, 3,904 were eligible and contacted at least once, and 578 consented [overall consent rate = 10% (578/5,960); adjusted consent rate = 15% (578/3,904)]. Statistically significant (Ps < 0.05) but small differences in demographic and clinical variables were observed. Consented participants were less likely to be older than 64 (35% vs. 41%) and less likely to have received radiotherapy (36% vs. 41%) and hormone therapy (16% vs. 21%), but more likely to have regional prostate cancer (13% vs. 11%) and have undergone surgery (44% vs. 39%). Consented participants did not differ from reachable individuals on other demographic and clinical factors (Ps > 0.05)., Conclusions: Recruiting African American prostate cancer survivors to biobanking research through a cancer registry is feasible. However, the consent rate was low, and existing challenges limit consent and participation., Impact: Strategies for overcoming barriers to informed consent and increasing participation in biospecimen research are needed to address cancer disparities., (©2023 American Association for Cancer Research.)

Background and Objective: Immune checkpoint inhibitors (ICI) were a major clinical advancement that provided an opportunity to improve the prognosis of patients with non-small cell lung cancer (NSCLC). However, programmed death-ligand-1 (PD-L1) expression does not sufficiently predict ICI efficacy in NSCLC patients. In recent studies, the tumor immune microenvironment (TIME) was shown to have a central role in lung cancer progression and to affect clinical outcome of patients diagnosed with lung cancer. As development of new therapeutic targets to overcome ICI resistance is a priority, understanding the TIME is important. Recently, a series of studies was conducted to target each component of TIME to improve efficacy of cancer treatment. In this review, important features related to TIME, its heterogeneity and current trends in treatment targeting the component of TIME are discussed., Methods: PubMed and PMC were searched from January 1st, 2012 to August 16th, 2022 using the following key words: "NSCLC", "Tumor microenvironment", "Immune", "Metastasis" and "Heterogeneity"., Key Content and Findings: Heterogeneity in the TIME can be either spatial or temporal. Subsequent to heterogeneous changes in the TIME, treatment of lung cancer can be more challenging because drug resistance is more likely to occur. In terms of the TIME, the main concept for increasing the chance of successful NSCLC treatment is to activate immune responses against tumor cells and inhibit immunosuppressive activities. In addition, relevant research is focused on normalizing an otherwise aberrant TIME in NSCLC patients. Potential therapeutic targets include immune cells, cytokine interactions, and non-immune cells such as fibroblasts or vessels., Conclusions: In management of lung cancer, understanding TIME and its heterogeneity is significant to treatment outcomes. Ongoing trials including various treatment modalities such as radiotherapy, cytotoxic chemotherapy, and anti-angiogenic treatment and regimens inhibiting other immunoinhibitory molecules are promising., 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-22-633/coif). SJK reports that this research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (No. 2019M3A9H2032425). The other authors have no conflicts of interest to declare., (2023 Translational Lung Cancer Research. All rights reserved.)

Background: Surgery is important treatment option for stage III non-small cell lung cancer (NSCLC) because of its curative potential. We investigated the characteristics of resectable patients, and compared the outcomes according to treatment modalities., Methods: Among 1,092 patients with NSCLC diagnosed between 2008 to 2020 from 7 university hospitals of Catholic Medical Center, we retrospectively analyzed 252 patients with clinical or pathological stage III. We compared survival outcomes among the groups according to resectability, first-line treatments, and the lung immune prognostic index (LIPI) score. Clinical N2 subgroup was analyzed using multi-parameter scoring system., Results: The resectable group consisted of less smokers, showed better pulmonary function and lower inflammatory markers, and tended to be diagnosed as earlier cancer stage than the unresectable group. The resectable group showed better progression-free survival (PFS) and overall survival (OS) than the unresectable group (P<0.001 and P<0.001, respectively). Regarding the first-line treatment, surgery showed the longest median PFS (33.70 months) and the highest 12-month OS rate (91.6%) than the other treatment modalities. OS was significantly different depending on the LIPI score in whole population, as well as in the unresectable group (P=0.004 and P=0.003, respectively). LIPI 0 group exhibited better OS than LIPI 1 and 2 in both populations. Eastern Cooperative Oncology Group (ECOG) 2-4, LIPI 1-2, and first-line treatment were independent prognostic factors for OS. Smoking, forced expiratory volume in the first second (FEV1) and more advanced cancer stage were associated with unresectability. In subgroup analysis of N2 disease, we attempted to create new scoring system combining lymph node (LN) status and LIPI score. This scoring system showed significant association with OS., Conclusions: The patients with resectable stage III NSCLC showed better PFS and OS than the patients with unresectable tumor. LIPI score exhibited possibility to be used as potential biomarker in stage III NSCLC. The multi-parameter scoring system using LN status and LIPI score was predictive of OS in the N2 subgroup., 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-22-642/coif). The authors have no conflicts of interest to declare., (2023 Translational Lung Cancer Research. All rights reserved.)

Purpose: Although osimertinib is the standard-of-care treatment of epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer, real-world evidence on the efficacy of osimertinib is not enough to reflect the complexity of the entire course of treatment. Herein, we report on the use of osimertinib in patients with EGFR T790M mutation-positive non-small cell lung cancer who had previously received EGFR tyrosine kinase inhibitor (TKI) treatment in Korea., Materials and Methods: Patients with confirmed EGFR T790M after disease progression of prior EGFR-TKI were enrolled and administered osimertinib 80 mg daily. The primary effectiveness outcome was progression-free survival, with time-to-treatment discontinuation, treatment and adverse effects leading to treatment discontinuation, and overall survival being the secondary endpoints., Results: A total of 558 individuals were enrolled, and 55.2% had investigator-assessed responses. The median progression-free survival was 14.2 months (95% confidence interval [CI], 13.0 to 16.4), and the median time-to-treatment discontinuation was 15.0 months (95% CI, 14.1 to 15.9). The median overall survival was 36.7 months (95% CI, 30.9 to not reached). The benefit with osimertinib was consistent regardless of the age, sex, smoking history, and primary EGFR mutation subtype. However, hepatic metastases at the time of diagnosis, the presence of plasma EGFR T790M, and the shorter duration of prior EGFR-TKI treatment were poor predictors of osimertinib treatment. Ten patients (1.8%), including three with pneumonitis, had to discontinue osimertinib due to severe adverse effects., Conclusion: Osimertinib demonstrated its clinical effectiveness and survival benefit for EGFR T790M mutation-positive in Korean patients with no new safety signals.

Context.—: The use of saliva samples for diagnosis of SARS-CoV-2 infection offers several advantages, including ease of sample collection, feasibility of self-collection, and minimization of medical staff exposure to infection. The emergence of new SARS-CoV-2 variants has had an impact on the viral load of specimens and the results of real-time reverse transcription-polymerase chain reaction (rRT-PCR)., Objective.—: To compare nasopharyngeal swab and saliva samples for the diagnosis of SARS-CoV-2 using rRT-PCR., Design.—: In this study, participants were recruited prospectively, and paired nasopharyngeal swab and saliva samples were collected simultaneously from each participant. After adding universal transport medium, RNA was extracted in an identical manner for both sample types, and samples were tested using rRT-PCR. In addition, samples with positive results were tested for SARS-CoV-2 variants., Results.—: Of the 338 paired samples, 100 nasopharyngeal swab and 101 saliva samples tested positive for SARS-CoV-2. The rRT-PCR results of the saliva and nasopharyngeal swab samples showed a positive percent agreement of 95.0% (95% CI, 88.7%-98.4%), a negative percent agreement of 97.9% (95% CI, 95.2%-99.3%), and an overall percent agreement of 96.8% (95% CI, 94.3%-98.4%). SARS-CoV-2 was detected in the saliva samples of 6 participants with negative nasopharyngeal sample results. In addition, the sensitivity of saliva samples was similar to that of nasopharyngeal samples for detecting various SARS-CoV-2 variants, including the Omicron variant., Conclusions.—: Saliva samples can be used as an alternative to nasopharyngeal samples for convenient and effective detection of various SARS-CoV-2 variants., Competing Interests: This work was supported by RapiGEN (Gyeonggi-do, Republic of Korea), Boditech Med Inc (Gang-won-do, Republic of Korea), PHC (Gyeonggi-do, Republic of Korea); they were not involved in study design or preparation of the manuscript., (© 2022 College of American Pathologists.)

Background: The phase III trial IMpower133 showed that platinum and etoposide plus atezolizumab was associated with improved overall survival (OS) and progression free-survival (PFS) when compared to the placebo group in treatment-naïve extensive stage (ES) small cell lung cancer (SCLC). Due to superiority in clinical outcomes, combination immunotherapy plus chemotherapy have become mainstay treatment modalities as first-line treatment in ES-SCLC. Nevertheless, real-world data are still lacking and the search for potential biomarkers is essential. This study aimed to evaluate potential predictive biomarkers applicable in ES-SCLC under combination therapy., Methods: Patients with ES-SCLC under etoposide-platinum-atezolizumab enrolled from seven university hospitals affiliated to the Catholic University of Korea were evaluated. Pretreatment clinical parameters were evaluated for association with OS and PFS. Adverse events (AEs) during induction and maintenance phases were also evaluated. p-values below 0.05 were considered statistically significant., Results: A total of 41 patients were evaluated. Six-month survival was 68.6%. As best response to treatment, 26 (63.4%) showed partial response, nine (22.0%) showed stable disease, and four (9.8%) showed progressive disease. During the induction phase, grade I-II AEs occurred in 22 (53.7%) patients, and grade III-IV AEs occurred in 26 (63.4%) patients. During the maintenance phase, nine out of 25 (36.0%) patients experienced any grade AEs. In multivariate analysis for OS, lactate dehydrogenase (LDH), c-reactive protein (CRP), and forced vital capacity (%) were significant factors. In multivariate analysis for PFS, sex, and LDH were significant., Conclusion: In ES-SCLC under etoposide-platinum-atezolizumab, pretreatment CRP, LDH and FVC (%) were independent predictive factors., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background/aim: Bronchiectasis has long been neglected, unlike chronic obstructive pulmonary disease (COPD) and asthma. Recent clinical trials have shown that long-term use of azithromycin or erythromycin reduce exacerbations of non-cystic fibrosis (non-CF) bronchiectasis. Because of this, we should actively try to treat patients susceptible to severe status., Patients and Methods: We enrolled patients who had been diagnosed with bronchiectasis at five branches of the Catholic Medical Center between January 2015 to December 2017. We retrospectively analyzed these patients for demographic characteristics such as sex, age, body mass index (BMI), history of smoking and tuberculosis, bacterial colonization, pulmonary function, hospitalizations, and other exacerbations., Results: Colonization was shown to have a statistically significant association with hospitalization. A three-year follow up period showed that the mean frequency of hospitalization in patients without colonization was 0.8 times, compared to 0.7 times and 1.9 times, respectively in patients with NTM colonization and with other bacterial colonization (p-value=0.03). Patients with a lower BMI also had an increased risk of hospitalization (p-value=0.024). Current smokers had increased risk of mortality as compared to those who had never smoked (HR=11.29, p-value 0.015). Patients with a high BMI also had low risk of mortality as compared to patients with a low BMI (HR=0.76, p-value 0.005)., Conclusion: Patients with bronchiectasis having chronic colonization, low BMI, or who are current smokers tend to be at greater risk for severe illness. Therefore, physicians should actively treat these patients to prevent exacerbations and mortality., (Copyright © 2022, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The diagnosis of pulmonary tuberculosis (TB) in patients suspected of lung cancer is difficult because of the similarities in signs, symptoms, and radiologic results. The clinical and radiologic characteristics of the co-occurrence of pulmonary TB and lung cancer have not been fully evaluated., Methods: Patients diagnosed with lung cancer and active pulmonary TB from January 2009 to December 2017 in four hospitals of the Catholic University of Korea were retrospectively reviewed. The clinical characteristics, including the TB diagnosis methods, lung cancer pathology, staging, initial radiographic features, and survival were analyzed and compared to 575 lung cancer patients without active pulmonary TB from the same hospitals., Results: Forty-eight (0.48%) of the 9,936 lung cancer patients had active pulmonary TB confirmed for M. tuberculosis at the time of the initial cancer diagnosis. The majority of the patients (95.9%) had non-small cell lung cancer and the most frequent findings were a mass-like lesion (79.2%) and separate nodules (75%). When compared to lung cancer patients without TB, the body mass index (BMI) was lower (21.4 vs. 23.1, P=0.001) and clinical stages were advanced in the lung cancer patients with TB; T3-4 (70.9% vs. 50.6%, P=0.002), N2-3 (85.2% vs. 55.6%, P<0.001); M1 (65.9% vs. 44.5%, P=0.007). Interestingly, lung cancer with TB was associated with lower mortality [hazard ratio (HR) =0.35, 95% CI: 0.21-0.60]., Conclusions: Rarely diagnosed concurrent active TB in lung cancer patients was associated with lower BMI and advanced clinical stages. Active investigation of and treatment for active pulmonary TB in lung cancer patients might possibly improve patient outcomes., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-22-272/coif). The authors have no conflicts of interest to declare., (2022 Translational Cancer Research. All rights reserved.)

Background: The aim of this study was to investigate the characteristics and clinical outcomes of patients with nonsmoking small cell lung cancer (SCLC) using a nationwide registry in Korea., Methods: The Korean Association for Lung Cancer developed a registry in cooperation with the Korean Central Cancer Registry (KCCR) and surveyed approximately 10% of recorded lung cancer cases., Results: From 2014 to 2016, the KCCR registered 1,043 patients newly diagnosed with SCLC among a total of 8,110 lung cancer patients. In subgroup analysis, Kaplan meier survival analysis showed that the overall survival (OS) was significantly shorter in the nonsmoking subgroup than the ever-smoking subgroup of SCLC patients with extensive disease (6.99 vs. 9.68 months; P = 0.016). Among SCLC patients with limited disease, OS was also shorter in the nonsmoking subgroup, without statistical significance (19.4 vs. 23.5 months; P = 0.247). In a multivariate analysis using a Cox regression model, never smoking was not associated with shorter OS, but older age, extensive stage, poor performance status (Eastern Cooperative Oncology Group grade ≥ 2), male sex, no prophylactic cranial irradiation, and no active treatment (chemotherapy and/or radiotherapy) were associated with poor prognosis., Conclusion: This evaluation of an unbiased nationwide survey dataset revealed that a significant proportion of Korean SCLC patients were never-smokers. No history of smoking appeared to be a significant prognostic factor according to the univariate analysis but was confirmed to be statistically insignificant through a multivariate analysis of the total population. Reasons for a poor prognosis may include the possibility that a high rate of the elderly population is composed of nonsmokers who did not receive active treatment., (© 2022. The Author(s).)

Study Objectives: To evaluate the risk of insomnia in patients with sudden sensorineural hearing loss (SSNHL)., Methods: A retrospective propensity score-matched cohort study was conducted using a nationwide representative sample from the National Sample Cohort 2002-2013 data from the Korea National Health Insurance Service. The SSNHL group (n = 631) included patients diagnosed with SSNHL between January 2002 and December 2005. The comparison group (4 controls for every patient with SSNHL, n = 2,524) was selected using propensity score matching, according to sociodemographic factors and the year of enrollment. Each patient was monitored until 2013. Survival analysis, log-rank test, and Cox proportional hazards regression models were used to calculate the incidence, survival rate, and hazard ratio (HR) of insomnia for each group., Results: Among the 3,155 individuals included in the study population (male, 48.6%), the overall incidence of insomnia during the 11-year follow-up was 1.4-fold higher in the SSNHL group than in the non-SSNHL group (106.3 vs 138.3 per 10,000 person-years; adjusted HR, 1.38; 95% confidence interval [CI], 1.08-1.78). Moreover, the adjusted HRs for developing insomnia (depression, 3.33 [95% CI, 2.22-5.01]; anxiety, 1.78 [95% CI, 1.27-2.53]; tinnitus, 1.56 [95% CI, 1.2-2.03]; dizziness, 1.76 [95% CI, 1.27-2.44]) were higher in patients with comorbidities., Conclusions: This observational study suggests that SSNHL is associated with an increased incidence of insomnia. Specifically, findings from this study show that patients with tinnitus, depression, anxiety, and dizziness had a higher risk of developing insomnia than those without tinnitus, depression, anxiety, and dizziness., Citation: Yeo CD, Yeom SW, You YS, Kim JS, Lee EJ. Association of sudden sensorineural hearing loss with increased risk of insomnia: a nationwide population-based cohort study. J Clin Sleep Med . 2022;18(5):1335-1342., (© 2022 American Academy of Sleep Medicine.)

Background: This study aimed to investigate the outcome of using the human acellular dermal allograft patch compared with the conven- tional paper patch in traumatic tympanic membrane perforation., Methods: This was a retrospective study including 41 patients (42 ears) treated with 22 human acellular dermal allografts and 20 paper patches for acute traumatic tympanic membrane perforation from April 2013 to June 2020. The procedure was performed by applying human acellular dermal allograft or paper patches after trimming of perforation margins under local anesthesia. Patient's age, sex, cause, duration, side, location, size of perforation, and the result of healing was analyzed. The audiologic or computed tomography data were also investigated when available., Results: There was no significant difference in sex, age, affected side ratio, size and duration of perforation, recovery confirmation time, and audiogram results between the two groups. There was no significant difference in the size or duration of perforation between the success and failure groups. The human acellular dermal allograft and paper-patch groups showed no significant difference in the recovery confirmation time (70.7 ± 42.3 vs. 89.9 ± 119.4 days, P = .486) and recovery rate (95.5% vs. 85.0%, P = .333). However, the patch maintenance time of the human acellular dermal allograft group was statistically longer than the paper-patch group (32.9 ± 14.9 vs. 15.6 ± 19.9 days, P = .001). On multivariable regression analysis, patch material was the only parameter associated with patch maintenance time (P = .002)., Conclusion: Treatment outcomes of traumatic tympanic membrane perforation using human acellular dermal allograft showed better or similar therapeutic efficacy compared to paper patch. The important advantage of this material is to stay in situ for a sufficient time without being detached until successful healing.

Background: Local treatment (LT) such as radiotherapy and metastasectomy on metastatic sites may improve outcomes in oligometastatic NSCLC patients, but more data are necessary to support LT in oligometastatic diseases. Patients with single extrathoracic metastatic lesion are more likely to benefit from local therapy. In this study, we evaluated the impact of LT in NSCLC patients with a single extrathoracic metastatic lesion., Methods: Data were obtained from the Korean Association for Lung Cancer Registry (KALC-R), a database created using a retrospective sampling survey by the Korean Central Cancer Registry (KCCR) and the Lung Cancer Registration Committee., Results: A total of 787 NSCLC patients with a single extrathoracic metastatic lesion were evaluated. In the multivariate analysis for OS, age, female sex, poor performance score, squamous histological subtype, LT, and initial treatment modality showed significant associations. Regarding LT, groups that underwent curative LT were significantly associated with better OS compared to groups that did not undergo LT (p = 0.011, HR 0.448, 95% CI: 0.242-0.829). In the multivariate analysis of patients who underwent LT, poor performance score, initial treatment modality, and T stage were independently associated with poor OS. Compared to the T1 stage, T3 stage showed an HR of 2.470 (95% CI: 1.309-4.663; p = 0.005) and T4 stage showed an HR of 2.063 (95% CI: 1.093-3.904; p = 0.026)., Conclusion: In NSCLC with a single extrathoracic metastatic lesion, LT, especially for curative purposes, has an independent association with OS. Moreover, among the patients who received LT, factors such as T stage, poor performance score, and initial treatment modality were significantly associated with OS., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

In patients with completely resected non-small cell lung cancer (NSCLC), postoperative adjuvant chemotherapy has been associated with improvement in survival by minimizing the risk of recurrence. For years, systemic chemotherapy including platinum based regimen has been a mainstay treatment modality of adjuvant treatment after complete resection. ADAURA study showed that among completely resected IB to IIIA NSCLC, disease-free survival was significantly better in patients under adjuvant osimertinib than a placebo group. After the advent of a variety of new treatment regimens, such as third generation TKI and immunotherapy, the landscape of postoperative adjuvant treatment has been changing. In this review, we discuss some key issues regarding choice of adjuvant treatment after complete resection in NSCLC, and provide further updates on recent advances in treatment modalities., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background/aim: Little is known about the prognostic role of the Glasgow prognostic score (GPS) in non-small cell lung cancer (NSCLC) patients treated with immunotherapy after platinum-based cytotoxic chemotherapy., Patients and Methods: This study used a lung cancer cohort of the Catholic Medical Center of Korea between January 2018 and September 2020., Results: A total of 78 patients with NSCLC treated with immunotherapy as second or further-line therapy were included. Higher GPS values were significant predictors of shorter immune-related progression-free survival (irPFS) and overall survival (OS). The hazard ratios for irPFS were 0.249 for programmed death-ligand 1 (PD-L1) expression ≥50% and 9.73 for a GPS of 2. Older age, lower PD-L1 expression and higher GPS values were independently associated with shorter OS., Conclusion: Higher GPS values were identified as a poor prognostic factor for OS and irPFS in NSCLC patients who received immunotherapy as second or further-line therapy., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Chronic obstructive pulmonary disease (COPD) is one of the most frequently occurring concomitant diseases in patients with non-small cell lung cancer (NSCLC). It is characterized by small airways and the hyperinflation of the lung. Patients with hyperinflated lung tend to have more reserved lung function than conventionally predicted after lung cancer surgery. The aim of this study was to identify other indicators in predicting postoperative lung function after lung resection for lung cancer. Patients with NSCLC who underwent curative lobectomy with mediastinal lymph node dissection from 2017 to 2019 were included. Predicted postoperative FEV 1 (ppoFEV 1 ) was calculated using the formula: preoperative FEV 1 × (19 segments-the number of segments to be removed) ÷ 19. The difference between the measured postoperative FEV 1 and ppoFEV 1 was defined as an outcome. Patients were categorized into two groups: preserved FEV 1 if the difference was positive and non-preserved FEV 1 , if otherwise. In total, 238 patients were included: 74 (31.1%) in the FEV 1 non-preserved group and 164 (68.9%) in the FEV 1 preserved group. The proportion of preoperative residual volume (RV)/total lung capacity (TLC) ≥ 40% in the FEV 1 non-preserved group (21.4%) was lower than in the preserved group (36.1%) ( p = 0.03). In logistic regression analysis, preoperative RV/TLC ≥ 40% was related to postoperative FEV1 preservation. (adjusted OR, 2.02, p = 0.041). Linear regression analysis suggested that preoperative RV/TLC was positively correlated with a significant difference. ( p = 0.004) Preoperative RV/TLC ≥ 40% was an independent predictor of preserved lung function in patients undergoing curative lobectomy with mediastinal lymph node dissection. Preoperative RV/TLC is positively correlated with postoperative lung function.

The present study evaluated the impact of prior radiotherapy (RT) on patients with advanced non-small cell lung cancer (NSCLC) receiving therapy with immune checkpoint inhibitors (ICIs) and further assessed the prognostic factors in patients receiving both RT and ICI. Patients diagnosed with NSCLC at the Catholic Medical Center and Asan Medical Center between January 2016 and October 2020 and who received immunotherapy were retrospectively reviewed. Among 240 patients, poor Eastern Cooperative Oncology Group (ECOG) score, high PD-L1 expression, and ICI-related adverse events (AE) were significantly associated with progression-free survival (PFS) (HR, 2.654; 95% CI, 1.484-4.749; p = 0.001; HR, 0.645; 95% CI, 0.449-0.926, p = 0.017; HR, 0.430; 95% CI, 0.229-0.808; p = 0.009, respectively). Among patients who received both RT and immunotherapy, poor ECOG status, squamous cell carcinoma, and ICI-related AE were significant factors associated with poor PFS (HR, 2.430; 95% CI, 1.464-4.034; p = 0.001; HR, 0.667; 95% CI, 0.455-0.978, p = 0.038; HR, 0.520; 95% CI, 0.284-0.953, p = 0.034, respectively). The present study showed that prior RT showed no significant independent association with primary outcomes in patients with advanced NSCLC receiving immunotherapy. In patients who received both RT and immunotherapy, clinical parameters, including ICI-related AEs, were independently predictive of PFS.

Abstract: This study aimed to evaluate the risk of developing chronic otitis media with effusion (OME) in individuals with gastroesophageal reflux disease (GERD).A retrospective propensity score-matched cohort study was performed using data from the Korea National Health Insurance Service. The GERD group (n = 3532) included certain individuals who had been diagnosed with GERD between January 2002 and December 2005. A comparison control group (n = 14,128) was calculated by 1:4 propensity score matching considering age, sex, and comorbidities and year of enrollment. Each patient was monitored until 2013. Survival analysis, the Log-rank test, and Cox proportional hazard regression models were used to calculate the incidence, survival rate, and hazard ratio (HR) of chronic OME for each group.Among the 17,660 individuals included in the study population (53.2% men), the overall incidence of chronic OME during the 11-year follow-up was 1.84-fold higher in the GERD group than in the non-GERD group (1.8 vs 3.0 per 1000 person-year; adjusted HR 1.84; 95% confidence interval [CI], 1.46-2.31). Moreover, the adjusted HRs of developing chronic OME (allergic rhinitis, 1.69 [95% CI, 1.37-2.10]; asthma, 1.29 [95% CI, 1.02-1.64]; chronic rhinosinusitis, 1.61 [95% CI, 1.26-2.05]) were greater in study population with comorbidities.From long-term follow-up, the prevalence of chronic OME in adults was 1.84 times higher in the GERD group compared with the non-GERD group. Specifically, it found that allergic rhinitis, asthma, or chronic rhinosinusitis showed increase the risk of developing chronic OME than those without these conditions., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: As association between systemic inflammation and disease progression has been suggested, early changes in neutrophil-to-lymphocyte ratio (NLR) and derived NLR (dNLR) may have accurate predictability for prognosis in non-small cell lung cancer (NSCLC) treated with ICI therapy., Methods: Complete blood count (CBC) was measured immediately before the first and second cycles of ICI therapy in patients with advanced NSCLC. Differences in NLR and dNLR were measured. When the increase in NLR was ≥1, the patient was classified into the increased NLR group. Similarly, when the increase in dNLR was ≥1, the patient was classified into the increased dNLR group; otherwise, they were classified into the non-increased NLR or dNLR group., Results: A total of 89 patients was selected for evaluation. Median progression-free survival (PFS) was significantly shorter in the increased NLR group than in the non-increased NLR group (2.6 vs. 9.5 months, P<0.001). The increased dNLR group showed significantly shorter median PFS than the non-increased dNLR group (4.2 vs. 9.2 months, P=0.001). Association with PFS was analyzed using the Cox regression model. In model 1, increase ≥1 in NLR showed significant association (HR =3.085, 95% CI, 1.657-5.742, P<0.001). In model 2, increase ≥1 in dNLR showed significant association (HR =2.826, 95% CI, 1.436-5.561, P=0.003)., Conclusions: Early changes in dNLR were shown to have prognostic value in patients undergoing immunotherapy. It can be an accurate and a comprehensive biomarker for predicting ICI response., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jtd-20-3416). The authors have no conflicts of interest to declare., (2021 Journal of Thoracic Disease. All rights reserved.)

Background/aim: Preoperative fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET-CT) is a non-invasive and useful diagnostic tool to evaluate mediastinal lymph node (LN) metastasis in lung cancer. However, there are often false-positive LN cases in FDG PET-CT. This study aimed to explore the clinical characteristics and outcome of pathologic N0 non-small cell lung cancer patients with false-positive mediastinal LN on FDG PET-CT., Patients and Methods: We enrolled 147 patients who underwent preoperative FDG PET-CT scan and mediastinal LN dissection. These patients were re-evaluated for post-operative pathologic nodal metastasis and divided into a false-positive group and a group of others., Results: Among 40 patients diagnosed with clinical N1-3 on FDG PET-CT, 19 (47.5%) patients were pathologic N0, meaning false-positive LN by PET-CT. Preoperative absolute platelet count and platelet-lymphocyte ratio were significantly higher in patients with pathologic N0. The presence of lymphatic invasion was significantly lower in patients with pathologic N0 than in the group of others. Recurrence-free survival was significantly shorter in patients with false positive LN than in patients with true positive LN or true negative LN at the same pathologic stage., Conclusion: Higher absolute platelet count and PLR, lower proportion of lymphatic invasion and shorter recurrence-free survival were associated with false positive mediastinal LN on preoperative FDG PET-CT., (Copyright© 2021, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

MRI has the advantages of having excellent soft-tissue contrast and providing functional information without any harmful ionizing radiation. Although previous technical limitations restricted the use of chest MRI, recent technological advances and expansion of insurance coverage are increasing the demand for chest MRI. Recognizing the need for guidelines on appropriate use of chest MRI in Korean clinical settings, the Korean Society of Radiology has composed a development committee, working committee, and advisory committee to develop Korean chest MRI justification guidelines. Five key questions were selected and recommendations have been made with the evidence-based clinical imaging guideline adaptation methodology. Recommendations are as follows. Chest MRI can be considered in the following circumstances: for patients with incidentally found anterior mediastinal masses to exclude non-neoplastic conditions, for pneumoconiosis patients with lung masses to differentiate progressive massive fibrosis from lung cancer, and when invasion of the chest wall, vertebrae, diaphragm, or major vessels by malignant pleural mesothelioma or non-small cell lung cancer is suspected. Chest MRI without contrast enhancement or with minimal dose low-risk contrast media can be considered for pregnant women with suspected pulmonary embolism. Lastly, chest MRI is recommended for patients with pancoast tumors planned for radical surgery., Competing Interests: Conflicts of Interest: The authors have no potential conflicts of interest to disclose., (Copyrights © 2021 The Korean Society of Radiology.)

Background: Complementary and alternative medicine (CAM) has been used frequently, and its use continues to increase in lung cancer patients, despite insufficient scientific of its efficacy. To investigate this situation, we analyzed the current awareness and use of CAM in Korean lung-cancer patients., Methods: This prospective survey-based study was performed at seven medical centers in South Korea between August and October 2019. The survey assessed general patient characteristics and the awareness and use of CAM. We analyzed differences in the clinical parameters of patients aware and not aware of CAM and of CAM non-users and users., Results: Of the 434 patients included in this study, 68.8% responded that they were aware of CAM and 30.9% said they had experienced it. In univariate analysis, the patients aware of CAM were younger with poor performance status, had advanced-stage lung cancer, received more systemic therapy, and received concurrent chemoradiation therapy (CCRT). By multiple logistic regression, younger age, poor performance status, advanced stage, and prior CCRT were identified as independent risk factors for CAM awareness. There were no significant differences in the general characteristics and cancer-associated clinical parameters of CAM non-users and users., Conclusion: Specific clinical parameters were associated with patients' awareness of CAM, although there were no significantly different characteristics between CAM users and non-users.

Background: Obstructive sleep apnea (OSA) is associated with pulmonary fibrosis. Chronic intermittent hypoxia (CIH) is considered to be a surrogate of OSA. However, its exact role in pulmonary fibrosis remains uncertain. Therefore, we investigated the mechanism underlying CIH-induced pulmonary fibrosis and the role of the anti-fibrotic agent in bleomycin (BLE) induced lung injury., Methods: Mice were divided into eight groups: the normoxia (NOR), CIH, NOR plus BLE, CIH plus BLE, NOR plus pirfenidone (PF), CIH plus PF, NOR plus BLE and PF, and CIH plus BLE and PF groups. BLE was administered intratracheally on day 14 following CIH or NOR exposure. Subsequently, the mice were exposed to CIH or NOR for an additional 4 weeks. PF was administered orally on day 5 after BLE instillation once daily for 3 weeks., Results: In the BLE-treated groups, CIH-induced more collagen deposition in lung tissues than NOR, and significantly increased hydroxyproline and transforming growth factor-β expression. The CIH and BLE-treated groups showed increased lung inflammation compared to NOR or CIH groups. Following CIH with BLE treatment, nuclear factor-κB (NF-κB) protein expression was significantly increased, whereas nuclear factor-erythroid-related factor 2 (Nrf2) and heme oxygenase-1 protein levels were decreased. After PF treatment, NF-κB and Kelch-like ECH-associated protein 1 expression were suppressed, and Nrf2 expression was increased., Conclusion: CIH accelerated lung fibrosis in BLE-induced lung injury in mice, potentially by regulating the NF-κB/Nrf2 signaling pathway. Our results implicate PF as a potential therapeutic agent for treating pulmonary fibrosis in individuals with OSA and idiopathic pulmonary fibrosis.

Aim of the Study: Obstructive sleep apnea (OSA) is a common disease associated with significant morbidity and mortality. Sleep quality is an important issue; some patients with acute lung injury (ALI) have underlying OSA. However, the potential influences of OSA on ALI have not been reported until now. In this study, we evaluated the impact of preceding intermittent hypoxia (IH), a typical characteristic of OSA, on lipopolysaccharide (LPS)-induced ALI in a mouse model., Methods: C57BL/6J mice were randomly divided into four groups: room air-control (RA-CTL), intermittent hypoxia-control (IH-CTL), room air-lipopolysaccharide (RA-LPS), and intermittent hypoxia-lipopolysaccharide (IH-LPS) groups. The mice were exposed to RA or IH (20 cycles/h, FiO 2 nadir 7 ± 0.5%, 8 h/day) for 30 days. The LPS groups received intratracheal LPS on day 28., Results: The IH-LPS group tended to exhibit more severe inflammation, fibrosis, and oxidative stress compared to the other groups, including the RA-LPS group. Total cell, neutrophil, and eosinophil counts in bronchoalveolar lavage fluid increased significantly in the IH-LPS group compared to the RA-LPS group. Compared to the RA-LPS group, the hydroxyproline level increased significantly in the IH-LPS group. In addition, the IH-LPS group exhibited significantly more terminal deoxynucleotidyl transferase dUTP nick end labeled-positive cells compared to the RA-LPS group., Conclusions: We found that prior IH may negatively impact LPS-induced ALI in a mouse model. This result suggests that ALI in patients with OSA may be more of a concern. Further research into the mechanisms underlying the effects of IH on ALI is needed.

Approximately 10%-20% of patients with clinically localized clear cell renal cell carcinoma (ccRCC) at time of surgery will subsequently experience metastatic progression. Although considerable progression was seen in the systemic treatment of metastatic ccRCC in last 20 years, once ccRCC spreads beyond the confines of the kidney, 5-year survival is less than 10%. Therefore, significant clinical advances are urgently needed to improve overall survival and patient care to manage the growing number of patients with localized ccRCC. We comprehensively evaluated expression of 388 candidate genes related with survival of ccRCC by using TCGA RNAseq (n = 515), Total Cancer Care (TCC) expression array data (n = 298), and a well characterized Moffitt RCC cohort (n = 248). We initially evaluated all 388 genes for association with overall survival using TCGA and TCC data. Eighty-one genes were selected for further analysis and tested on Moffitt RCC cohort using NanoString expression analysis. Expression of nine genes (AURKA, AURKB, BIRC5, CCNE1, MK167, MMP9, PLOD2, SAA1, and TOP2A) was validated as being associated with poor survival. Survival prognostic models showed that expression of the nine genes and clinical factors predicted the survival in ccRCC patients with AUC value: 0.776, 0.821 and 0.873 for TCGA, TCC and Moffitt data set, respectively. Some of these genes have not been previously implicated in ccRCC survival and thus potentially offer insight into novel therapeutic targets. Future studies are warranted to validate these identified genes, determine their biological mechanisms and evaluate their therapeutic potential in preclinical studies., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Lung cancer is a frequent comorbidity of chronic obstructive pulmonary disease (COPD). However, the local risk of developing lung cancer related to regional emphysema distribution and clinical outcome has not been investigated. Our aim was to evaluate the impact of regional emphysema score (RES) on tumor location and prognosis in non-small cell lung cancer (NSCLC) patients., Methods: We enrolled 457 patients who underwent curative surgery for NSCLC at seven hospitals at The Catholic University of Korea from 2014 to 2018. Emphysema was visually assessed for each lobe, with the lingula as a separate lobe. Semi-quantitative emphysema scoring was classified as follows: 0 = none, 0.5 = 1 to 10%, 1 = 11 to 25%, 2 = 26 to 50%, 3 = 51 to 75%, and 4 = 76 to 100%. An RES was given to each of the six lung zone: the upper, middle, and lower lobes in the right and left lungs., Results: There were 145 patients in the high RES (≥ 3) group and 312 in the low RES (< 3) group. The mean RES in each lobe with cancer was significantly higher than that in other lobes without cancer (0.51 vs. 0.37, P <  0.001). This group showed significantly shorter disease-free survival (P <  0.001), in addition, presence of COPD, low diffusing capacity of the lung for carbon monoxide (< 80), smoking status, and poor differentiation were more frequent in this group. Also, cancer in a lobe with a higher RES (odds ratio (OR) = 1.56; 95% confidence interval (CI:1.01-2.42; P = 0.04), pathologic stage ≥ III (OR = 2.23; 95% CI: 1.28-3.89; P <  0.001), and poor differentiation (OR = 1.99; 95% CI: 1.22-3.21; P <  0.001) were independent factors for tumor recurrence., Conclusions: The regional severity of emphysema by visual qualification was associated with the location of lung cancer, and was an independently poor prognostic factor for tumor recurrence in completely resected NSCLC patients.