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Background The use of immune checkpoint inhibitors (ICIs) in patients with advanced lung cancer is increasing. Despite ongoing studies to predict the efficacy of ICIs, its use in clinical practice remains difficult. Thus, we aimed to discover a predictive marker by analyzing blood cell characteristics and developing a scoring system for patients treated with ICIs. Methods This was a prospective multicenter study in patients with advanced nonsmall cell lung cancer (NSCLC) who received ICIs as second-line treatment from June 2021 to November 2022. Blood cell parameters in routine blood samples were evaluated using an automated hematology analyzer. Immune checkpoint inhibitor score (IChIS) was calculated as the sum of neutrophil count score and immature granulocyte score. Results A total of 143 patients from four institutions were included. The treatment response was as follows: partial response, 8.4%; stable disease, 37.1%; and progressive disease, 44.8%. Median progression-free survival and overall survival after ICI treatment was 3.0 and 8.3 months, respectively. Median progression-free survival in patients with an IChIS of 0 was 4.0 months, which was significantly longer than 1.9 months in patients with an IChIS of 1 and 1.0 month in those with an IChIS of 2 (p=0.001). The median overall survival in patients with an IChIS of 0 was 10.2 months, which was significantly longer than 6.8 and 1.8 months in patients with an IChIS of 1 and 2, respectively (p

Abstract The differentiation of naive CD8+ T cells into effector cells is important for establishing immunity. However, the effect of heterogeneous naive CD8+ T cell populations is not fully understood. Here, we demonstrate that steady-state naive CD8+ T cells are composed of functionally heterogeneous subpopulations that differ in their ability to differentiate into type 17 cytotoxic effector cells (Tc17) in a context of murine inflammatory disease models, such as inflammatory bowel disease and graft-versus-host disease. The differential ability of Tc17 differentiation is not related to T-cell receptor (TCR) diversity and antigen specificity but is inversely correlated with self-reactivity acquired during development. Mechanistically, this phenomenon is linked to differential levels of intrinsic TCR sensitivity and basal Suppressor of Mothers Against Decapentaplegic 3 (SMAD3) expression, generating a wide spectrum of Tc17 differentiation potential within naive CD8+ T cell populations. These findings suggest that developmental self-reactivity can determine the fate of naive CD8+ T cells to generate functionally distinct effector populations and achieve immense diversity and complexity in antigen-specific T-cell immune responses.

Abstract In this study, we aimed to investigate the feasibility of serum Krebs von den Lungen-6 (KL-6) as a potential biomarker for treatment-related ILD (TR-ILD) in lung cancer. We recruited patients with lung cancer in whom KL-6 was measured to differentiate between pneumonia and ILD (category 1), diagnose and assess the severity of suspicious ILD (category 2), or evaluate baseline levels before cancer treatment (category 3). Among 1,297 patients who underwent KL-6 testing, 422 had lung cancer, and TR-ILD was detected in 195 patients. In categories 1–2, median KL-6 level was higher in drug-induced ILD or acute exacerbation of underlying ILD than in no ILD or radiation-induced pneumonitis, and it was correlated with the severity of TR-ILD. High KL-6 level (cut-off: > 436U/mL) was an independent risk factor for severe TR-ILD, and low KL-6 level with high procalcitonin level (> 0.5 ng/mL) could exclude severe TR-ILD. Patients with severe TR-ILD had worse overall survival than those without, whereas high baseline KL-6 level was associated with worse survival, especially in patients without severe TR-ILD. Therefore, serum KL-6 may be a surrogate marker for predicting the occurrence and assessing the severity of TR-ILD at the time of suspected ILD and before lung cancer treatment.

Abstract Background Higher concentrations of particulate matter (PM) have been shown to cause deterioration of the symptoms of respiratory and cardiovascular disease in several regional studies. Here, we aimed to investigate the healthcare utilization of lung cancer patients associated with short‐term exposure to PM at the national level in Korea. Methods We extracted the data of 210 558 subjects over a period of 3 years (2015–2017), who were diagnosed with lung cancer before 2015 and benefited from the National Health Insurance Sharing Service. We performed the interpolation method using the geographic information system to calculate the estimated mean PM2.5 and PM10 concentrations by regions and classified three groups as high (upper 10%), intermediate (10%–90%), and low (bottom 10%) based on the mean PM mass concentrations of the month. Results The monthly average number of outpatient visits was significantly increased in high PM2.5 urban areas (46.296 vs. 50.646, p = 0.015). In high PM2.5 nationwide regions, the monthly average number of emergency admission was significantly increased (0.528 vs. 0.785, p = 0.001). The outpatient visits tended to change with PM2.5 concentration and correlated with PM10/PM2.5 concentrations in urban and nationwide areas. In high PM2.5 urban regions, there was a significant increase in bronchodilator prescriptions (3.102 vs. 3.758, p = 0.008). Concerning high PM2.5 nationwide regions, there were significantly increased prescriptions of antibiotics, steroids, bronchodilators, antihistamines, and mucolytics. Conclusions This study suggests that exposure to PM2.5 is significantly associated with hospital utilization and drug prescription in lung cancer patients.

Abstract Background Necroptosis is a regulated inflammatory cell death which plays a significant role in cancer development and progression. In this study, we evaluated whether genetic variants in key regulators of necroptosis may affect survival outcome of non‐small cell lung cancer (NSCLC) patients after surgical resection. Methods A total of 674 patients who underwent curative surgery were included. Fifteen genetic variants in key regulators of necroptosis (RIPK1, RIPK3, and MLKL) were selected. The association of these variants with survival outcomes was evaluated. Results Two variants, RIPK1 rs17548629C > T and MLKL rs877375G > C, were associated with better overall survival and disease‐free survival in multivariate analyses. When the patients were divided according to histology, the associations were significant only in adenocarcinoma, but not in squamous cell carcinoma. RIPK1 rs17548629 C‐to‐T change was associated with significantly increased luciferase activity by modulating the binding of miR‐642a. Promoter assays showed a significantly increased promoter activity in MLKL rs877375C allele compared to G allele. Consistently, the mRNA expression level of RIPK1 and MLKL showed significant positive correlation with RIPK1 rs17548629C‐to‐T and MLKL rs877375G‐to‐C changes. Conclusion Two genetic variants in key regulators in necroptosis, RIPK1 rs17548629C > T and MLKL rs877375G > C, may be used as biomarkers to predict survival outcomes in surgically resected NSCLC patients.

Abstract Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (Pinteraction = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications.

Abstract Background Lung cancer is the leading cause of cancer-related deaths worldwide. The majority of lung cancers are non-small cell lung cancer (NSCLC), accounting for approximately 85% of all lung cancer types. The Cox proportional hazards model (CPH), which is the standard method for survival analysis, has several limitations. The purpose of our study was to improve survival prediction in patients with NSCLC by incorporating prognostic information from F-18 fluorodeoxyglucose positron emission tomography (FDG PET) images into a traditional survival prediction model using clinical data. Results The multimodal deep learning model showed the best performance, with a C-index and mean absolute error of 0.756 and 399 days under a five-fold cross-validation, respectively, followed by ResNet3D for PET (0.749 and 405 days) and CPH for clinical data (0.747 and 583 days). Conclusion The proposed deep learning-based integrative model combining the two modalities improved the survival prediction in patients with NSCLC.

Abstract Introduction The PACIFIC study demonstrated that durvalumab consolidation therapy significantly improved progression‐free survival (PFS) and overall survival (OS) in patients with unresectable stage III non‐small cell lung cancer (NSCLC) after concurrent chemoradiotherapy (CCRT). However, there was no clinical benefit in both PFS and OS in epidermal growth factor receptor (EGFR) mutation‐positive patient groups in a post hoc exploratory analysis. Moreover, the clinical effects of immune checkpoint inhibitors (ICIs) in EGFR mutation‐positive stage IV NSCLC were demonstrated to be poor. Personalized treatment according to the mutation status is also required in stage III NSCLC. Lazertinib, a third‐generation EGFR tyrosine kinase inhibitor (TKI), is newly developed and approved for use in Korea. Methods This prospective, open, single‐arm, multicenter, phase II clinical trial aims to evaluate the efficacy and safety of lazertinib as a consolidative therapy after CCRT treatment in unresectable, EGFR mutation‐positive NSCLC stage III patients. The primary endpoint of this study is PFS, and the secondary endpoints are OS, objective response rate (ORR), duration of response (DoR), time to death or distant metastasis (TTDM), and safety profiles. Discussion Our study may extend the indications for third‐generation EGFR‐TKIs to treat patients with stage III NSCLC. Moreover, using this drug to treat stage III NSCLC would emphasize the value of mutation analysis and personalized medicine.

BackgroundCancer recurrence remains a significant problem, and most postoperative recurrences of non-small cell lung cancer (NSCLC) develop within 5 years after resection. We present a rare case of ultra-late recurrence of NSCLC accompanying choroidal metastasis with KIF13A-RET fusion 14 years after the definitive surgery.Case descriptionA 48-year-old female patient who had never-smoked presented with decreased visual acuity. She had been treated with right upper lobe lobectomy followed by adjuvant chemotherapy 14 years prior. Fundus photographs revealed bilateral choroidal metastatic lesions. Positron emission tomography-computed tomography (PET-CT) scans showed extensive bone metastases and focal hypermetabolism in the left uterine cervix. An excision biopsy of the uterus showed primary lung adenocarcinoma with immunohistochemistry of TTF-1+. Plasma next-generation sequencing (NGS) identified the presence of KIF13A-RET fusion. After 6 months of selpercatinib therapy, PET-CT revealed a partial response for bone and uterine metastasis and stable disease for choroidal lesions.ConclusionIn this case report, we are reporting a rare case of ultra-late recurrence of NSCLC in a patient with choroidal metastasis. Furthermore, the diagnosis of NSCLC with RET fusion was based on liquid-based NGS rather than tissue-based biopsy. The patient showed a good response to selpercatinib, which supports the efficacy of selpercatinib as a treatment for RET-fusion-positive NSCLC with choroidal metastasis.

Abstract Background Interstitial lung abnormality (ILA) is closely related to lung cancer. This study aimed to assess whether the presence of ILA is associated with the clinicoradiological features of elderly patients (≥70 years) with early‐stage non‐small cell lung cancer (NSCLC). Methods Elderly patients who underwent surgical resection for stage I or II NSCLC with preserved lung function between 2012 and 2019 were retrospectively identified. ILA was evaluated using a three‐point scale. Univariate analyses were performed for clinicoradiological features based on the presence of ILA. Logistic and linear regression analyses were performed for cancer staging and tumor size, respectively. Results A total of 254 patients were evaluated. The presence of ILA (score = 2) was significantly associated with male sex, current or former smoker status, higher pack‐years of smoking, low forced expiratory volume in one second/forced vital capacity ratios and diffusing capacity of the lung for carbon monoxide, and presence of emphysema (≥5%). Tumor characteristics, such as lower lobe and outer one‐third location, squamous cell carcinoma, and higher cancer stage (stage II) were significantly associated with ILA. The presence of ILA independently predicted a higher cancer stage (adjusted odds ratio, 1.81; 95% confidence interval, 1.10–2.96; p = 0.02) and a larger tumor size in linear regression analysis (p = 0.04). Conclusions Patients with ILA showed clinicoradiological features similar to those of idiopathic pulmonary fibrosis in elderly patients with early‐stage NSCLC. Identifying the clinical implications of ILA in early‐stage lung cancer will guide clinicians in providing appropriate management for these patients.

Abstract Background We report a subgroup analysis of afatinib with respect to its efficacy, safety, and the long‐term survival of patients in a Named Patient Use program at a single institution. Methods We analyzed 60 patients with stage IV non‐small cell lung cancer (NSCLC) who had been treated with ≥1 line of platinum‐based chemotherapy and had activating epidermal growth factor receptor (EGFR) mutations or disease control for ≥6 months with prior EGFR inhibitors. Afatinib was started on a daily dose of 50 mg, which was decreased according to the adverse events and tolerability. Results A total of 13 patients achieved partial remission, whereas 33, 12, and two showed stable disease, had progression, and were not evaluable, respectively, resulting in an objective response rate and disease control rate of 21.7% and 76.7%, respectively. The median progression‐free survival (PFS) was 5.4 (95% confidence interval [CI]: 4.0–7.7) months and median overall survival (OS) was 10.1 (8.5–13.6) months. Toxicities leading to drug discontinuation were experienced by four patients (6.7%). Grade 3 diarrhea occurred in 10 patients (16.7%), and afatinib dose reductions were required in 35 patients. The PFS and OS were significantly longer for patients whose dose was reduced to 40 or 30 mg than for those without dose reduction (7.0 vs 3.1 months and 13.5 vs 8.1 months, respectively, p

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.

Abstract Background The Cox proportional hazards model is commonly used to predict hazard ratio, which is the risk or probability of occurrence of an event of interest. However, the Cox proportional hazard model cannot directly generate an individual survival time. To do this, the survival analysis in the Cox model converts the hazard ratio to survival times through distributions such as the exponential, Weibull, Gompertz or log-normal distributions. In other words, to generate the survival time, the Cox model has to select a specific distribution over time. Results This study presents a method to predict the survival time by integrating hazard network and a distribution function network. The Cox proportional hazards network is adapted in DeepSurv for the prediction of the hazard ratio and a distribution function network applied to generate the survival time. To evaluate the performance of the proposed method, a new evaluation metric that calculates the intersection over union between the predicted curve and ground truth was proposed. To further understand significant prognostic factors, we use the 1D gradient-weighted class activation mapping method to highlight the network activations as a heat map visualization over an input data. The performance of the proposed method was experimentally verified and the results compared to other existing methods. Conclusions Our results confirmed that the combination of the two networks, Cox proportional hazards network and distribution function network, can effectively generate accurate survival time.

This study aimed to investigate the feasibility of blood-based biomarkers, including blood tumor mutation burden (bTMB), to predict atezolizumab efficacy in relapsed and advanced non-small cell lung cancer (NSCLC). Stage IV NSCLC patients who had previously received platinum-doublet chemotherapy were recruited and received 1200 mg of atezolizumab every three weeks. Blood was collected to obtain plasma cell-free DNA (cfDNA) before the first cycle (C0) and at the fourth cycle (C4). bTMB was measured by CT-ULTRA in patients with cfDNA over 10 ng. The objective response rate (ORR) of the enrolled 100 patients was 10%, and there was no difference in ORR according to bTMB (cutoff: 11.5 muts/Mb) at C0 (high bTMB: 8.1% vs. low bTMB: 11.1%). However, the C4/C0 bTMB ratio was significantly lower in the durable clinical benefit (DCB) patients. The cfDNA concentration at C0, the C4/C0 ratio of the cfDNA concentration, the highest variant allele frequency (hVAF), and the VAF standard deviation (VAFSD) were significantly lower in the DCB patients. In the multivariate analysis, a high cfDNA concentration at C0 (cutoff: 8.6 ng/mL) and a C4/C0 bTMB ratio greater than 1 were significantly associated with progression-free survival. These results suggest that baseline levels and dynamic changes of blood-based biomarkers (bTMB, cfDNA concentration, and VAFSD) could predict atezolizumab efficacy in previously treated NSCLC patients.

Abstract Background Mutation analysis of circulating tumor DNA (ctDNA) is used for diagnosing lung cancer. This trial aimed to assess the efficacy of afatinib in treatment‐naïve patients with lung cancer harboring epidermal growth factor receptor mutations (EGFRm, exon 19 deletions or exon 21 point mutations) detected based on ctDNA. Methods The primary objective was the objective response rate (ORR) in the response evaluable (RE) population. EGFRm analysis of ctDNA was performed using PANA Mutype. Of the 331 patients screened, ctDNA was positive in 21% (68/331) in the detection of activating EGFRm. Among 81 subjects with tumor EGFRm, 48 showed matched EGFRm in their ctDNA (59% sensitivity). Results Therapy with afatinib 40 mg was initiated in 21 (female, 17; adenocarcinoma, 20) patients (intention‐to‐treat, ITT); dose modifications were made in 15 (71%). The ORR was 74% in the RE population (14/19); 11 patients showed EGFRm only in ctDNA (Group A), whereas 10 exhibited the same EGFRm in their ctDNA and tumor DNA (Group B). There was no significant difference in ORR between Groups A and B (80% and 67% RE, respectively). Median progression‐free survival (PFS) was 12.0 months, and no significant difference was observed according to the final afatinib dose, type of EGFRm, and Group A versus B. After progression, T790M mutation was found in 40% (6/15) of patients, and osimertinib was used as a second‐line treatment. Conclusions Afatinib showed similar ORR and PFS in patients with lung cancer harboring EGFRm in their ctDNA regardless of tumor EGFRm results. Key points Significant findings of the study Afatinib showed favorable ORR and PFS regardless of the tumor EGFR mutation status results, similar to the findings of previous trials assessing afatinib as first‐line treatment of EGFR‐mutated non‐small cell lung cancer based on tumor genotyping. What this study adds Our findings emphasize that the survival benefit of afatinib treatment can be achieved not only by appropriate dose reduction with frequent and detailed monitoring of toxicities, but also by using noninvasive (ctDNA) assays in a real‐world setting.

Despite recent advances in precision medicine, lung cancer remains the leading cause of cancer-related mortality worldwide. To determine the prognosis of non-small cell lung cancer (NSCLC), which accounts for 85% of lung cancer, comprehensive analysis of various clinical factors are necessary. Artificial intelligence can help physician quickly identify key information from the vast amount of medical information including positron emission tomography (PET) scan. In this study, we compared image feature-extraction models and survival estimation models to determine an optimal model that effectively extracts features related to survival time. We collected PET image data of 2,685 patients who were diagnosed with NSCLC and received treatment at the Chonnam National University Hwasun Hospital in South Korea over a period of seven years. We compared four convolution neural network models, DenseNet, NFNet, EfficientNet, and ResNet, and two survival estimation models, CoxPH and CoxCC. The best model was determined based on criteria such as C-index, mean absolute error (MAE), classification accuracy for survival status, and learning time. The results show that DenseNet combined with CoxPH delivers superior performance for most of the criteria. In particular, the MAE for this combination was very low (391.50 days), and the model predicted survival days well; the five-year classification accuracy, which can indicate a cure for cancer, was high (95%). Extracted features were visualized using Score-CAM; thus, the learning process of the model could be understood without requiring expert knowledge of PET. In addition, the learning time for this model was short.

Air embolism is a rare, fatal complication of computed tomography (CT)‐guided transthoracic needle biopsy (TTNB) of the lung. Here, we report a patient who developed an air embolism after CT‐guided TTNB, which led to ST‐elevation myocardial infarction and acute cerebral ischemia. The patient recovered completely without critical sequelae and was diagnosed with adenocarcinoma harboring activating epidermal growth factor receptor (EGFR) mutation. The patient responded to subsequent treatment with gefitinib. Key points Signficant findings of the study Air embolism is a rare, fatal complication of CT‐guided transthoracic lung biopsy. Only a few cases have been previously reported where myocardial and cerebral infarction occurred after TTNB, demonstrated not only on CT scan, but also electrocardiogram and electroencephalogram. What this study adds Detection of driver gene mutation is crucial for planning lung cancer treatment. Despite the need for tissue biopsy, air embolism propagation to vital organs could result in severe end‐organ damage and multidisciplinary approaches are needed to improve initial outcomes.

Abstract Background The resistance of lung cancer to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is one of the unconquered frontiers in chemotherapy. Mitogen-inducible gene 6 (Mig-6) is known to inhibit the kinase activity of epidermal growth factor receptor (EGFR). Similarly, numerous studies of mouse models suggested tumor suppressive function of Mig-6 in lung cancer. On the contrary, the results of clinical investigations revealed that lung cancer patients with elevated expression of Mig-6 are associated with a poor prognosis. More recent work showed that unlike wild type (WT) EGFR, mutant EGFR phosphorylates Mig-6 and phosphorylated Mig-6 negatively regulates the degradation of EGFR mutants in lung adenocarcinoma. Here, we tried to untangle the controversies surrounding Mig-6 function as a protagonist or an antagonist of EGFR-TKI resistant lung cancer. Methods We compared the expression and phosphorylation status of Mig-6 in the EGFR-TKI resistant lung adenocarcinoma (PC9/GR cells) to EGFR-TKI sensitive lung adenocarcinoma (PC9 cells). We investigated the function of Mig-6 by either depletion or overexpression of Mig-6 in those cells and evaluated the efficacy of combining of Mig-6 knock-down and EGFR-TKI treatment in PC9/GR. The correlation between Mig-6 expressions and the prognoses of lung adenocarcinoma was examined by The Cancer Genome Atlas (TCGA) data and clinical samples. Results Our results indicated that the expression of Mig-6 was significantly increased in PC9/GR cells compared to that of PC9 cells. The significant portion of Mig-6 existed as a phosphorylated form in PC9 and PC9/GR cells. Moreover, overexpression of Mig-6 significantly increased the cell proliferation, invasion and epithelial mesenchymal transition (EMT) in PC9 cells. Combination of Mig-6 knock-down and EGFR-TKI treatment significantly overcame the EGFR-TKI resistance of PC9/GR cells. In addition, our analyses of clinical samples confirmed that high Mig-6 expressions positively correlate with a poor prognosis and EGFR-TKI resistance in lung adenocarcinoma. Conclusion Our findings reinforce scientific notion of Mig-6 as an oncoprotein in the context of EGFR-TKI resistant lung adenocarcinoma. We propose that targeting Mig-6 may be a promising strategy to overcome the EGFR-TKI resistance in lung cancer.

Abstract Background The concurrence of sarcoidosis and primary lung cancer is very rare. We report a very rare case with a delayed diagnosis of primary lung cancer due to its misdiagnosis as worsening of pulmonary sarcoidosis. Case presentation A 68-year-old man presented to the outpatient department for evaluation of a mass in the right hilar area with lymphadenopathies in subcarinal and both interlobar areas on chest computed tomography (CT). Sufficient core samples were obtained from subcarinal and bilateral interlobar lymph nodes using endobronchial ultrasonography (EBUS) guided transbronchial needle aspiration (TBNA). EBUS could not reach the right hilar lymph node due to its high angle. The pathologic findings were consistent with sarcoidosis. After 5 months, chest CT revealed aggravation of the right upper paratracheal lymphadenopathy. Assuming worsening of sarcoidosis, he was prescribed an oral corticosteroid for 5 months. However, follow-up chest CT showed a newly developed right lower paratracheal lymphadenopathy and worsening right hilar lymphadenopathy. Bronchoscopy and EBUS were performed once again. Transbronchial lung biopsy from the right upper lobe and EBUS-TBNA from the right lower paratracheal lymph node revealed adenocarcinoma from the lung. Conclusions Although coexistence of sarcoidosis and lung cancer is very rare, the clinician should consider the possibility of accompanying lung cancer in sarcoidosis patients who are not responding to initial corticosteroid therapy.

Background We correlated the tumor proportion score (TPS) of programmed cell death ligand 1 (PD‐L1, SP263 or 22C3) expression with the disease control rate (DCR, partial remission and stable disease), and progression free survival (PFS) after nivolumab or pembrolizumab treatment. Methods A total of 70 case records (55 males, 15 females) of patients with non‐small cell lung cancer (NSCLC, 46 adenocarcinoma, 22 squamous cell carcinoma, and two others) were reviewed. The PD‐L1 expressions were divided into High (SP263 ≥ 30%, 22C3 ≥ 80%) and Low groups (SP263

ObjectivePulmonary arteriovenous malformation (PAVM) is a rare pulmonary disease. Although most patients with PAVMs are asymptomatic, cerebral complications associated with PAVMs are often fatal. This study aimed to evaluate the risk factors for cerebral complications in patients with PAVMs.MethodsWe retrospectively reviewed the medical charts of patients with PAVMs between 2003 and 2021 at two tertiary referral hospitals and one secondary hospital.ResultsFifty-five patients diagnosed with PAVMs were enrolled in this study. Most patients were female (89.1%), and the median age was 53 years. Thirty patients (54.5%) had incidentally detected PAVMs without symptoms. Twenty-four patients (43.7%) with PAVMs were treated with embolotherapy or surgery. Thirteen patients (23.6%) had cerebral complications. There was no significant difference in the development of cerebral complications according to treatment; however, older age (≥ 65 years) was associated with the development of new cerebral complications in untreated patients with PAVMs (odds ratio, 17.09; 95% confidence interval, 1.16-250.31; P = 0.038).ConclusionOlder age (≥ 65 years) was a risk factor for the development of cerebral complications in patients with PAVMs; therefore, treatment should be considered in older patients with PAVMs.

Here, we report a case of myasthenia gravis and myopathy in a patient treated with nivolumab. A 76‐year‐old man who had been treated with four doses of nivolumab because of non‐small cell lung cancer (NSCLC) presented with proximal‐dominant muscle weakness and fluctuating ptosis and diplopia. Serologic studies revealed increased levels of muscle enzymes including creatine phosphokinase (2934 U/L), and acetylcholine receptor antibody was positive (1.31 nmol/L). Following electrodiagnostic study, he was diagnosed with myasthenia gravis and active stage of myopathy. After discontinuation of nivolumab, he was treated with corticosteroids, intravenous immunoglobulin G, and pyridostigmine. The neuromuscular symptoms and serologic abnormalities of the patient markedly improved. Currently, he is taking oral steroids and pyridostigmine without further immunotherapy.

Background Programmed death-ligand 1 (PD-L1), a transmembrane protein, binds to the programmed death-1 (PD-1) receptor, and anti-PD-1 therapy enables immune responses against tumors. This study aimed to assess clinical characteristics of PD-L1 expression using immunohistochemistry among Korean patients with lung cancer. Methods We retrospectively reviewed the data of patients with pathologically proven lung cancer from a single institution. PD-L1 expression determined by Tumor Proportion Score (TPS) was detected using 22C3 pharmDx (Agilent Technologies) and SP263 (Ventana Medical Systems) assays. Results From July 2016 to July 2017, 267 patients were enrolled. The main histologic type was adenocarcinoma (69.3%). Most participants were smokers (67.4%) and had clinical stage IV disease (60.7%). In total, 116 (42%) and 58 (21%) patients had TPS ≥1% and ≥50%, respectively. The patients were significantly older in TPS ≥1% group than in TPS

Abstract Background Caveolin-1 (Cav-1) plays an important role in the development of various human cancers. We investigated the relationship between Cav-1 expression and non-small cell lung cancer (NSCLC) progression in the context of brain metastasis (BM). Methods Cav-1 expression was investigated in a series of 102 BM samples and 49 paired primary NSCLC samples, as well as 162 unpaired primary NSCLC samples with (63 cases) or without (99 cases) metastasis to distant organs. Human lung cancer cell lines were used for in vitro functional analysis. Results High Cav-1 expression in tumor cells was observed in 52% (38/73) of squamous cell carcinomas (SQCs) and 33% (45/138) of non-SQCs. In SQC, high Cav-1 expression was increased after BM in both paired and unpaired samples of lung primary tumors and BM (53% vs. 84% in paired samples, P = 0.034; 52% vs. 78% in unpaired samples, P = 0.020). Although the difference in median overall survival in patients NSCLC was not statistically significant, high Cav-1 expression in tumor cells (P = 0.005, hazard ratio 1.715, 95% confidence index 1.175–2.502) was independent prognostic factors of overall survival on multivariate Cox regression analyses, in addition to the presence of BM and non-SQC type. In vitro assays revealed that Cav-1 knockdown inhibited the invasion and migration of lung cancer cells. Genetic modulation of Cav-1 was consistently associated with SNAIL up- and down-regulation. These findings were supported by increased SNAIL and Cav-1 expression in BM samples of SQC. Conclusions Cav-1 plays an important role in the BM of NSCLC, especially in SQC. The mechanism may be linked to SNAIL regulation.

Background We determined the clinical characteristics and predictive factors of long‐term response to pemetrexed maintenance therapy as first‐line treatment for non‐small cell lung cancer (NSCLC). Methods A total of 950 advanced NSCLC patients received pemetrexed (500 mg/m2) plus cisplatin (60 mg/m2) (Pem‐Cis) induction chemotherapy every three weeks as first‐line treatment between January 2010 and August 2018. Patients who did not show progression after four cycles of Pem‐Cis and received at least one cycle of pemetrexed maintenance were recruited (n = 199). Results Patients were divided into subgroups according to total cycles of pemetrexed: ≤ 10 (F10, n = 134) and > 10 (M10, n = 65). The M10 group had a higher proportion of patients with stage M1a (intrathoracic metastasis alone) and exhibited lower levels of thymidylate synthase (TS) than the F10 group (median H‐score 10.0% vs. 60.0%; P = 0.031). Further subgrouping identified extreme responders: ≤ 7 (F7, n = 101) and ≥ 20 (M20, n = 26) cycles. The M20 group showed lower mean serum CEA levels before (17.5 vs. 147.0; P = 0.099) and after (6.9 vs. 53.2; P = 0.001) Pem‐Cis treatment, and a higher incidence of normalization after Pem‐Cis (abnormal 41.7% vs. 68.5%; P = 0.015). M1a stage, normalization of CEA levels after Pem‐Cis, and lower TS H‐score were predictors of progression‐free survival in patients administered pemetrexed maintenance. Conclusion M1a stage and lower TS expression were predictors of long‐term response to pemetrexed maintenance. CEA normalization after Pem‐Cis could be an additional surrogate marker of positive response to long‐term treatment.

ObjectivePneumocystis jirovecii pneumonia (PCP) is a fatal respiratory infection, mostly associated with immunocompromised conditions. Several reports have described PCP development in patients who were not immunocompromised, but the clinical course and prognosis of PCP are not well understood. We compared the clinical characteristics and prognoses between patients with and without immunocompromised conditions who developed PCP.MethodsWe retrospectively analyzed patients who had been treated for PCP from three hospitals. We defined immunocompromised (IC) status as following: human immunodeficiency virus (HIV) infection; hematological malignancy; solid organ tumor under chemotherapy; rheumatic disease; medication with immunosuppressive agents. Patients without immunocompromised status were defined as being non-immunocompromised (non-IC).ResultsThe IC and non-IC groups comprised 173 and 14 patients. The median ages were 62.0 and 74.0 years in the IC and the non-IC group, respectively. The median interval between admission and anti-PCP treatment was significantly longer for patients in the non-IC group than that for patients in the IC group (7 vs. 2 days). The in-hospital mortality rates were significantly higher for patients in the non-IC group than that for patients in the IC group (71.4% vs. 43.9%; P = 0.047). A longer interval between admission and anti-PCP therapy was associated with increased 90-day mortality rate in patients with PCP (hazard ratio, 1.082; 95% confidence interval, 1.015-1.153; P = 0.016).ConclusionsPatients with PCP with no predisposing illnesses were older and had higher mortality rates than IC patients with PCP. Delayed anti-PCP treatment was associated with increased 90-day mortality.

ObjectiveThis study aimed to evaluate hypersensitivity reactions to anti-tuberculosis (TB) drugs.MethodsWe retrospectively compared the clinical manifestations and treatment outcomes of single and multiple drug hypersensitivity reactions (DHRs).ResultsTwenty-eight patients were diagnosed with anti-TB DHRs using oral drug provocation tests. Of these 28 patients, 17 patients (60.7%) had DHRs to a single drug and 11 (39.3%) had multiple DHRs. The median age of patients was 57.5 years (interquartile range [IQR], 39.2-73.2). Of the total patients, 18 patients (64.3%) were men. The median number of anti-TB drugs causing multiple DHRs was 2.0 (IQR 2.0-3.0). Rifampin was the most common drug that caused DHRs in both the single and multiple DHR groups (n = 8 [47.1%] and n = 9 [52.9%], respectively). The treatment success rate was lower in the multiple DHR group than in the single DHR group; however, the difference was not statistically significant (81.8% vs. 94.1%; P = 0.543).ConclusionsMultiple anti-TB DHRs were common in all patients who experienced DHRs, and rifampin was the most common causative drug. The treatment outcomes appeared to be poorer in patients with multiple DHRs than in those with single DHRs.

One essential step in radiotherapy treatment planning is the organ at risk of segmentation in Computed Tomography (CT). Many recent studies have focused on several organs such as the lung, heart, esophagus, trachea, liver, aorta, kidney, and prostate. However, among the above organs, the esophagus is one of the most difficult organs to segment because of its small size, ambiguous boundary, and very low contrast in CT images. To address these challenges, we propose a fully automated framework for the esophagus segmentation from CT images. The proposed method is based on the processing of slice images from the original three-dimensional (3D) image so that our method does not require large computational resources. We employ the spatial attention mechanism with the atrous spatial pyramid pooling module to locate the esophagus effectively, which enhances the segmentation performance. To optimize our model, we use group normalization because the computation is independent of batch sizes, and its performance is stable. We also used the simultaneous truth and performance level estimation (STAPLE) algorithm to reach robust results for segmentation. Firstly, our model was trained by k-fold cross-validation. And then, the candidate labels generated by each fold were combined by using the STAPLE algorithm. And as a result, Dice and Hausdorff Distance scores have an improvement when applying this algorithm to our segmentation results. Our method was evaluated on SegTHOR and StructSeg 2019 datasets, and the experiment shows that our method outperforms the state-of-the-art methods in esophagus segmentation. Our approach shows a promising result in esophagus segmentation, which is still challenging in medical analyses.

ObjectivesArgon plasma coagulation (APC) is a noncontact form of electrocautery that utilizes ionized argon as the electrical current. A rigid bronchoscopic use of APC for the management of central airway obstruction could be safe and rapidly effective. This study evaluated the usefulness of rigid bronchoscopy with APC for the management of central airway obstructions due to benign or malignant tumors.MethodsTwenty patients with obstructing central airway tumors were retrospectively reviewed from February 2008 to February 2013 at Chonnam National University Hospital. All patients received rigid bronchoscopic tumor removal under general anesthesia. APC was applied before and after tumor removal.ResultsThe median age of patients was 59 years (interquartile range [IQR], 51 to 67 years) and 70% were female. The causes of airway obstruction included malignancy (n=8) and benign tumor (n=12). Airway tumors comprised intraluminal lesions (n=11, 55%) and mixed intraluminal/extraluminal lesions (n=9, 45%). The median tumor size was 15 mm (IQR, 10 to 18 mm). The median degree of airway obstruction was significantly reduced after intervention (90% [IQR, 88% to 96%] vs. 10% [IQR, 0% to 20%], P

Glutathione peroxidase 3 (GPx3), a major scavenger of reactive oxygen species (ROS) in plasma, acts as a redox signal modulator. However, the mechanism underlying GPx3-mediated suppression of cancer cell growth is unclear. The aim of this study was to identify these mechanisms with respect to lung cancer. To enhance the redox modulating properties of GPx3, lung cancer cells were subjected to serum starvation for 12 h, resulting in ROS generation in the absence of oxidant treatment. We then investigated whether suppression of tumorigenesis under conditions of oxidative stress was dependent on GPx3. The results showed that GPx3 effectively suppressed proliferation, migration, and invasion of lung cancer cells under oxidative stress. In addition, GPx3 expression led to a significant reduction in ROS production by cancer cells and induced G2/M phase arrest. We also found that inactivation of cyclin B1 significantly suppressed by nuclear factor-κB(NF-κB) inactivation in lung cancer cells was dependent on GPx3 expression. To further elucidate the mechanism(s) underlying GPx3-medited suppression of tumor proliferation, we next examined the effect of GPx3-mediated redox signaling on the ROS-MKP3-extracellular signal-regulated kinase (Erk)-NF-κB-cyclin B1 pathway and found that GPx3 strongly suppressed activation of the Erk-NF-κB-cyclin B1 signaling cascade by protecting MKP3 (an Erk-specific phosphatase) from the effects of ROS. Thus, this study demonstrates for the first time that the GPx3 suppresses proliferation of lung cancer cells by modulating redox-mediated signals.

Identification and understanding of the pathogens responsible for pleural infection is critical for appropriate antibiotic treatment. This study sought to determine the microbiological characteristics of pleural infection and to identify potential predictive factors associated with mortality.In this retrospective study, we analyzed patient data from 421 cases of parapneumonic effusion. A total of 184 microorganisms were isolated from 164 patients, using two culture systems: a standard method and a method using pairs of aerobic and anaerobic blood culture bottles.The most frequently isolated microorganisms were streptococci (31.5%), followed by staphylococci (23.4%), gram-negative bacteria (18.5%) and anaerobes (10.3%). Streptococci were the main microorganisms found in standard culture (41.9%) and community-acquired infections (52.2%), and were susceptible to all antimicrobial agents in drug sensitivity testing. Staphylococci were the most frequently isolated pathogens in blood cultures (30.8%) and hospital-acquired infections (38.3%), and were primarily multidrug-resistant (61.8%). In multivariate analysis, the following were significant predictive factors for 30-day mortality among the total population: CURB-65 ≥ 2 (aOR 5.549, 95% CI 2.296-13.407, p