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Abstract Non-small cell lung cancer (NSCLC) is histologically classified into lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LSCC). However, some tumors are histologically ambiguous and other pathophysiological features or microenvironmental factors may be more prominent. Here we report integrative multiomics analyses using data for 229 patients from a Korean NSCLC cohort and 462 patients from previous multiomics studies. Histological examination reveals five molecular subtypes, one of which is a NSCLC subtype with PI3K-Akt pathway upregulation, showing a high proportion of metastasis and poor survival outcomes regardless of any specific NSCLC histology. Proliferative subtypes are present in LUAD and LSCC, which show strong associations with whole genome doubling (WGD) events. Comprehensive characterization of the immune microenvironment reveals various immune cell compositions and neoantigen loads across molecular subtypes, which predicting different prognoses. Immunological subtypes exhibit a hot tumor-enriched state and a higher efficacy of adjuvant therapy.

Abstract Background Lung cancer (LC) is an important comorbidity of interstitial lung disease (ILD) and has a poor prognosis. The clinical characteristics and outcome of each ILD subtype in LC patients have not been sufficiently investigated. Therefore, this study aimed to evaluate the difference between idiopathic pulmonary fibrosis (IPF) and non-IPF ILD as well as prognostic factors in patients with ILD-LC. Methods The medical records of 163 patients diagnosed with ILD-LC at Asan Medical Center from January 2018 to May 2023 were retrospectively reviewed. Baseline characteristics and clinical outcomes were compared between the IPF-LC and non-IPF ILD-LC groups, and prognostic factors were analyzed using the Cox proportional-hazard model. Results The median follow-up period was 11 months after the cancer diagnosis. No statistically significant differences were observed in clinical characteristics and mortality rates (median survival: 26 vs. 20 months, p = 0.530) between the groups. The independent prognostic factors in patients with ILD-LC were higher level of Krebs von den Lungen-6 (≥ 1000 U/mL, hazard ratio [HR] 1.970, 95% confidence interval [CI] 1.026-3.783, p = 0.025) and advanced clinical stage of LC (compared with stage I, HR 3.876 for stage II, p = 0.025, HR 5.092 for stage III, p = 0.002, and HR 5.626 for stage IV, p = 0.002). In terms of treatment, surgery was the significant factor for survival (HR 0.235; 95% CI 0.106-0.520; p

Abstract Understanding the degradation mechanism of organic light-emitting diodes (OLED) is essential to improve device performance and stability. OLED failure, if not process-related, arises mostly from chemical instability. However, the challenges of sampling from nanoscale organic layers and interfaces with enough analytical information has hampered identification of degradation products and mechanisms. Here, we present a high-resolution diagnostic method of OLED degradation using an Orbitrap mass spectrometer equipped with a gas cluster ion beam to gently desorb nanometre levels of materials, providing unambiguous molecular information with 7-nm depth resolution. We chemically depth profile and analyse blue phosphorescent and thermally-activated delayed fluorescent (TADF) OLED devices at different degradation levels. For OLED devices with short operational lifetimes, dominant chemical degradation mainly relate to oxygen loss of molecules that occur at the interface between emission and electron transport layers (EML/ETL) where exciton distribution is maximised, confirmed by emission zone measurements. We also show approximately one order of magnitude increase in lifetime of devices with slightly modified host materials, which present minimal EML/ETL interfacial degradation and show the method can provide insight for future material and device architecture development.

Abstract Background As the outcome of immunotherapy can be improved when concurrently or sequentially combined with cytotoxic chemotherapy or radiotherapy, we investigated the efficacy of immunotherapy maintenance following platinum‐based chemotherapy in epidermal growth factor receptor (EGFR)‐mutant non‐small cell lung cancer (NSCLC) after EGFR‐tyrosine kinase inhibitor (EGFR‐TKI) failure. Methods In this prospective, open‐label, single arm phase 2 trial, we enrolled patients aged 18 years or older with EGFR‐mutant NSCLC, which progressed after first‐ or second‐line EGFR‐TKI. Patients received platinum‐based chemotherapy followed by nivolumab maintenance therapy. They were intravenously administered 240 mg of nivolumab every 2 weeks for 3 months followed by 480 mg every 4 weeks until disease progression or unacceptable toxic effects occurred. The primary endpoint was progression‐free survival (PFS). Secondary outcomes were overall survival (OS) and incidence of grade 3–4 treatment‐related adverse events (AEs). Results We enrolled 26 patients between May 2020 and July 2021. The median PFS was 1.7 months (95% CI: 0.401–2.999 months). The median OS was 21.4 months (95% CI: 18.790–24.010 months) with 6‐ and 12‐month OS rates of 96.2% and 76.9%, respectively. The objective response rate was 7.7% (2/26) and disease control rate, 11.5% (3/26). The tumor mutational burden by next‐generation sequencing in blood was not related to the treatment outcomes. Grade 3–4 treatment‐related AEs occurred in four (15.4%) patients; the most frequent AE was increased alanine aminotransferase (7.7%). Conclusion Nivolumab maintenance following platinum‐based chemotherapy did not show clinical benefits after EGFR‐TKI failure in patients with EGFR‐mutant NSCLC.

Abstract Background Although acute exacerbation (AE) after treatment for lung cancer (LC) is a poor prognostic factor in patients with interstitial lung disease associated with lung cancer (ILD‐LC), the risk of AE according to cancer treatment type remains unclear. Therefore, in the present study, we aimed to investigate the association between AE and treatment received for LC in patients with ILD‐LC. Methods We conducted a retrospective study of patients with ILD‐LC who had undergone treatment for LC between January 2018 and December 2022. The primary study outcome was the incidence of AE within 12 months of treatment for LC according to treatment type. The association between AE and all‐cause mortality was evaluated as a secondary outcome. Results Among a total of 137 patients, 23 (16.8%) developed AE within 12 months of treatment for LC. The incidence of AE according to treatment type was 4.3% for surgery, 16.2% for radiotherapy, 15.6% for chemotherapy, and 54.5% for concurrent chemoradiation therapy (CCRT). Patients who received CCRT were more likely to develop AE, even after adjustment for covariables (hazard ratio [HR], 15.39; 95% confidence interval [CI]: 4.00–59.19; p

Leak detection in nuclear reactor coolant systems is crucial for maintaining the safety and operational integrity of nuclear power plants. Traditional leak detection methods, such as acoustic emission sensors and spectroscopy, face challenges in sensitivity, response time, and accurate leak localization, particularly in complex piping systems. In this study, we propose a novel leak detection approach that incorporates a rigid guide tube into the insulation layer surrounding reactor coolant pipes and combines this with an advanced detection criterion based on Frequency Center of Gravity shifts and Signal-to-Noise Ratio analysis. This dual-method strategy significantly improves the sensitivity and accuracy of leak detection by providing a stable transmission path for ultrasonic signals and enabling robust signal analysis. The rigid guide tube-based system, along with the integrated criteria, addresses several limitations of existing technologies, including the detection of minor leaks and the complexity of installation and maintenance. By enhancing the early detection of leaks and enabling precise localization, this approach contributes to increased reactor safety, reduced downtime, and lower operational costs. Experimental evaluations demonstrate the system’s effectiveness, focusing on its potential as a valuable addition to the current array of nuclear power plant maintenance technologies. Future research will focus on optimizing key parameters, such as the threshold frequency shift (Δf) and the number of randomly selected frequencies (N), using machine learning techniques to further enhance the system’s accuracy and reliability in various reactor environments.

Abstract Background Small cell lung cancer (SCLC) has an exceptionally poor prognosis; as most of the cases are initially diagnosed as extensive disease with hematogenous metastasis. Therefore, the early diagnosis of SCLC is very important and may improve its prognosis. Methods To investigate the feasibility of early diagnosis of SCLC, we examined exosomal microRNAs (miRNAs) present in serum obtained from patients with SCLC. First, exosomes were isolated in serum from patients with SCLC and healthy individuals and were characterized using particle size and protein markers. Additionally, miRNA array was performed to define SCLC-specific exosomal miRNAs. Second, the obtained miRNAs were further validated employing a large cohort. Finally, the ability to diagnose SCLC was estimated by area under the curve (AUC), and intracellular mRNA change patterns were verified through validated miRNAs. Results From the miRNA array results, we selected 51-miRNAs based on p-values and top 10 differentially expressed genes, and 25-miRNAs were validated using quantitative reverse transcription-polymerase chain reaction. The 25-miRNAs were further validated employing a large cohort. Among them, 7-miRNAs showed significant differences. Furthermore, 6-miRNAs (miR-3565, miR-3124-5p, miR-200b-3p, miR-6515, miR-3126-3p and miR-9-5p) were up-regulated and 1-miRNA (miR-92b-5p) was down-regulated. The AUC value of each miRNA sets between 0.64 and 0.76, however the combined application of 3-miRNAs (miR-200b-3p, miR-3124-5p and miR-92b-5p) remarkably improved the diagnostic value (AUC = 0.93). Gene ontology analysis revealed that the 3-miRNA panel is linked to various oncogene pathways and nervous system development. When the 3-miRNAs were introduced to cells, the resulting changes in total mRNA expression strongly indicated the presence of lung diseases, including lung cancer. In addition, the 3-miRNA panel was significantly associated with a poorer prognosis, although individual miRNAs have not been validated as prognostic markers. Conclusion Our study identified SCLC-specific exosomal miRNAs, and the 3-miRNAs panel (miR-200b-3p, miR-3124-5p and miR-92b-5p) may serve as a diagnostic and prognostic marker for SCLC. Graphical abstract

Abstract In this study, the potential of Chlorella sorokiniana JD1-1 for biodiesel production was evaluated using domestic wastewater (DWW) as a diluent for locally-generated livestock wastewater (LWW). This strategy aimed to provide sustainable wastewater treatment, reduce environmental impacts, enhance cost-effectiveness, and promote biodiesel production. LWW was diluted with tap water and DWW at ratios of 75%, 50%, and 25% (v/v), and the effects on microalgal growth, nutrient removal efficiency, and lipid yield were evaluated. Although the maximum biomass concentration was observed in the artificial growth medium (BG-11) (1170 mg L−1), 75% dilution using tap water (610 mg L−1) and DWW (780 mg L−1) yielded results comparable to the exclusive use of DWW (820 mg L−1), suggesting a potential for substitution. Total nitrogen (TN) removal rates were consistently high under all conditions, particularly in samples with higher concentrations of LWW. Conversely, total phosphorus (TP) concentrations decreased under most conditions, although some displayed large increases. Further studies are necessary to optimize the nutrient balance while maintaining economic feasibility and maximizing biodiesel production.

Abstract Introduction Non‐small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation has a higher incidence of brain metastases than wild‐type EGFR mutations. Osimertinib, a third‐generation EGFR tyrosine kinase inhibitor (TKI), targets both EGFR‐TKI sensitizing and T790M‐resistance mutations and has a higher brain penetration rate relative to first‐ and second‐generation EGFR‐TKIs. Therefore, osimertinib has become a preferred first‐line therapy for advanced EGFR mutation‐positive NSCLC. However, lazertinib, an emerging EGFR‐TKI, has shown higher selectivity toward EGFR mutations and improved penetration of the blood–brain barrier compared to osimertinib in preclinical studies. This trial will evaluate the efficacy of lazertinib as a first‐line therapy in patients with EGFR mutation‐positive NSCLC who have brain metastases, with or without additional local therapy. Methods This is a single‐center, open‐label, single‐arm phase II trial. A total of 75 patients with advanced EGFR mutation‐positive NSCLC will be recruited. Eligible patients will receive oral lazertinib 240 mg, once daily until disease progression or intolerable toxicity is detected. Patients with moderate to severe symptoms related to brain metastasis will simultaneously receive local therapy for the brain. The primary endpoints are progression‐free survival and intracranial progression‐free survival. Discussion Lazertinib, in combination with local therapy for the brain, if necessary, is expected to improve the clinical benefit in advanced EGFR mutation‐positive NSCLC with brain metastases, as a first‐line treatment.

Objects adrift can cause considerable damage to coastal infrastructure and property during tsunami and storm surge events. Despite the potential for harm, the drifting behavior of these objects remains poorly understood, thereby hindering effective prediction and mitigation of collision damage. To address this gap, this study employed a motion analysis program to track a drifting container's location using images from an existing laboratory experiment. The container's trajectory and velocity were calculated based on the positions of five markers strategically placed at its four corners and center. Our findings indicate that the container's maximum drift velocity and distance are directly influenced by the scale of the solitary wave and inversely related to the container's weight. Specifically, heavier containers are less likely to be displaced by solitary waves, while larger waves can damage coastal structures more. This study offers new insights into container drift behavior induced by solitary waves, with implications for enhancing coastal infrastructure design and devising mitigation strategies to minimize the risk of collision damage.

Background Choosing treatments for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) patients with osimertinib resistance is challenging. We evaluated the safety and efficacy of SNK01 (autologous natural killer (NK) cells) in combination with cytotoxic chemotherapy and/or cetuximab (an anti-EGFR monoclonal antibody) in treating EGFR-mutated NSCLC in this non-clinical and phase I/IIa clinical trial.Methods We developed a cell line-derived xenograft-humanized mouse model with an osimertinib-resistant lung cancer cell line. The mice were divided into four groups based on treatment (no treatment, cetuximab, SNK01, and combination groups) and treated weekly for 5 weeks. In the clinical study, 12 patients with EGFR-mutated NSCLC who failed prior tyrosine kinase inhibitor (TKI) received SNK01 weekly in combination with gemcitabine/carboplatin (n=6) or cetuximab/gemcitabine/carboplatin (n=6) and dose escalation of SNK01 following the “3+3” design.Results In the non-clinical study, an increase in NK cells in the blood and enhanced NK cell tumor infiltration were observed in the SNK01 group. The volume of tumor extracted after treatment was the smallest in the combination group. In the clinical study, 12 patients (median age, 60.9 years; all adenocarcinoma cases) received SNK01 weekly for 7–8 weeks (4×109 cells/dose (n=6); 6×109 cells/dose (n=6)). The maximum feasible dose of SNK01 was 6×109 cells/dose without dose-limiting toxicity. Efficacy outcomes showed an objective response rate of 25%, disease control rate of 100%, and median progression-free survival of 143 days.Conclusion SNK01 in combination with cytotoxic chemotherapy, including cetuximab, for EGFR-mutated NSCLC with TKI resistance was safe and exerted a potential antitumor effect.Trial registration number NCT04872634.

This paper introduces the novel design and implementation of a low-power wireless monitoring system designed for nuclear power plants, aiming to enhance safety and operational efficiency. By utilizing advanced signal-processing techniques and energy-efficient technologies, the system supports real-time, continuous monitoring without the need for frequent battery replacements. This addresses the high costs and risks associated with traditional wired monitoring methods. The system focuses on acoustic and ultrasonic analysis, capturing sound using microphones and processing these signals through heterodyne frequency conversion for effective signal management, accommodating low-power consumption through down-conversion. Integrated with edge computing, the system processes data locally at the sensor level, optimizing response times to anomalies and reducing network load. Practical implementation shows significant reductions in maintenance overheads and environmental impact, thereby enhancing the reliability and safety of nuclear power plant operations. The study also sets the groundwork for future integration of sophisticated machine learning algorithms to advance predictive maintenance capabilities in nuclear energy management.

Abstract Background To validate a stratification method using an inverse of treatment decision rules that can classify non-small cell lung cancer (NSCLC) patients in real-world treatment records. Methods (1) To validate the index classifier against the TNM 7th edition, we analyzed electronic health records of NSCLC patients diagnosed from 2011 to 2015 in a tertiary referral hospital in Seoul, Korea. Predictive accuracy, stage-specific sensitivity, specificity, positive predictive value, negative predictive value, F1 score, and c-statistic were measured. (2) To apply the index classifier in an administrative database, we analyzed NSCLC patients in Korean National Health Insurance Database, 2002–2013. Differential survival rates among the classes were examined with the log-rank test, and class-specific survival rates were compared with the reference survival rates. Results (1) In the validation study (N = 1375), the overall accuracy was 93.8% (95% CI: 92.5–95.0%). Stage-specific c-statistic was the highest for stage I (0.97, 95% CI: 0.96–0.98) and the lowest for stage III (0.82, 95% CI: 0.77–0.87). (2) In the application study (N = 71,593), the index classifier showed a tendency for differentiating survival probabilities among classes. Compared to the reference TNM survival rates, the index classification under-estimated the survival probability for stages IA, IIIB, and IV, and over-estimated it for stages IIA and IIB. Conclusion The inverse of the treatment decision rules has a potential to supplement a routinely collected database with information encoded in the treatment decision rules to classify NSCLC patients. It requires further validation and replication in multiple clinical settings.

Abstract Purpose This study aimed to investigate the differences in characteristics, clinical stages, treatment modalities, and survival outcomes in patients with non‐small‐cell lung cancer (NSCLC) based on sex differences using Korean nationwide registry data. Methods We analyzed the data of 8650 patients diagnosed with NSCLC between 2014 and 2017, obtained from the Korean Association for Lung Cancer Registry (KALC‐R). The Cox proportional hazard model was used to define the differences in survival based on sex. Propensity score matching was used to adjust for differences between men and women. Results Of a total of 10 943 patients, 8650 (79.1%) were diagnosed with NSCLC, of whom 68.7% were men and 31.3% were women. For NSCLC, the median age was higher (69.0 vs. 67.0, p

Abstract Background A previous trial showed that autologous ex‐vivo expanded NK cell (SNK01) treatment combined with pembrolizumab showed better efficacy than pembrolizumab monotherapy in advanced non‐small cell lung cancer (NSCLC). This study was a 2‐year follow‐up of that previous study to determine the long‐term efficacy of the combination treatment. Methods This trial included 20 patients with advanced NSCLC with a PD‐L1 tumor proportion score of 1% or greater who failed prior to front‐line platinum‐based therapy. The patients received pembrolizumab with low‐dose SNK01 (2 × 109 cells/dose) or high‐dose SNK01 (4 × 109 cells/dose), or pembrolizumab monotherapy. The primary study endpoint was overall survival (OS), and the secondary endpoint was progression‐free survival (PFS). Results Two patients were excluded following serious adverse events. Among the 11 patients who died, five were from the NK groups (41.6%, n = 5/12), and six received pembrolizumab monotherapy (100%, n = 6/6). The estimated 2‐year survival rate was 58.3% versus 16.7% (pembrolizumab plus SNK01 vs. pembrolizumab monotherapy). The hazard ratio of pembrolizumab plus SNK01 compared with pembrolizumab monotherapy was 0.32 (95% CI: 0.1, 1.08, p‐value: 0.066). Although the median PFS was significantly higher in the pembrolizumab plus SNK01 group than in the pembrolizumab alone group, OS and PFS did not differ statistically between patients who received low doses of NK cells and those who received high doses of NK cells. Conclusions Autologous NK cells can enhance the long‐term OS and PFS for NSCLC. A larger study is needed to confirm this result. Clinical Research Information Service number: KCT0003463.

Abstract Background This study was conducted to compare the reported adverse event (AE) profiles and unexpected use of medical services during chemotherapy between before and after the healthcare reimbursement of AE evaluation in patients with cancer. Patients and Methods Using the electronic medical record database system, extracted patients with breast, lung, gastric, and colorectal cancers receiving neoadjuvant or adjuvant chemotherapy between September 2013 and December 2016 at four centers in Korea were matched using the 1:1 greedy method: pre‐reimbursement group (n = 1084) and post‐reimbursement group (n = 1084). Unexpected outpatient department (OPD), emergency room (ER) visit, hospitalization rates, and chemotherapy completion rates were compared between the groups. Results The baseline characteristics were well‐balanced between the groups. By chemotherapy cycle, hospitalization (1.8% vs. 2.3%; p = 0.039), and ER visit rates (3.3% vs. 3.9%; p = 0.064) were lower in the post‐reimbursement group than that in the pre‐reimbursement group. In particular, since cycle 2, ER visit and hospitalization rates were significantly lower in the post‐reimbursement group than those in the pre‐reimbursement group (2.6% vs. 3.3%; p = 0.020 and 1.4% vs. 2.0%; p = 0.007, respectively), although no significant differences were observed during cycle 1. The OPD visit rates were similar between both groups, regardless of cycles. The post‐reimbursement group had a higher proportion of patients who completed chemotherapy as planned than the pre‐reimbursement group (93.5% vs. 90.1%; p = 0.006). Post‐reimbursement group had more AEs reported, including alopecia, fatigue, diarrhea, anorexia, and peripheral neuropathy, during cycle 1 than the pre‐reimbursement group, which significantly decreased after cycle 2. Conclusion The introduction of healthcare reimbursement for AE evaluation may help physicians capture and appropriately manage AEs, consequently, decreasing hospital utilization and increasing chemotherapy completion rates.

Abstract The emergence of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) with activating EGFR mutations is a major hindrance to treatment. We investigated the effects of p53 in primary sensitivity and acquired resistance to EGFR-TKIs in NSCLC cells. Changes in sensitivity to EGFR-TKIs were determined using p53 overexpression or knockdown in cells with activating EGFR mutations. We investigated EMT-related molecules, morphologic changes, and AXL induction to elucidate mechanisms of acquired resistance to EGFR-TKIs according to p53 status. Changes in p53 status affected primary sensitivity as well as acquired resistance to EGFR-TKIs according to cell type. Firstly, p53 silencing did not affect primary and acquired resistance to EGFR-TKIs in PC-9 cells, but it led to primary resistance to EGFR-TKIs through AXL induction in HCC827 cells. Secondly, p53 silencing in H1975 cells enhanced the sensitivity to osimertinib through the emergence of mesenchymal-to-epithelial transition, and the emergence of acquired resistance to osimertinib in p53 knockout cells was much slower than in H1975 cells. Furthermore, two cell lines (H1975 and H1975/p53KO) demonstrated the different mechanisms of acquired resistance to osimertinib. Lastly, the introduction of mutant p53-R273H induced the epithelial-to-mesenchymal transition and exerted resistance to EGFR-TKIs in cells with activating EGFR mutations. These findings indicate that p53 mutations can be associated with primary or acquired resistance to EGFR-TKIs. Thus, the status or mutations of p53 may be considered as routes to improving the therapeutic effects of EGFR-TKIs in NSCLC.

Abstract Tumor-derived exosomes (TEXs) contain enriched miRNAs, and exosomal miRNAs can affect tumor growth, including cell proliferation, metastasis, and drug resistance through cell-to-cell communication. We investigated the role of exosomal miR-1260b derived from non-small cell lung cancer (NSCLC) in tumor progression. Exosomal miR-1260b induced angiogenesis by targeting homeodomain-interacting protein kinase-2 (HIPK2) in human umbilical vein endothelial cells (HUVECs). Furthermore, exosomal miR-1260b or suppression of HIPK2 led to enhanced cellular mobility and cisplatin resistance in NSCLC cells. In patients with NSCLC, the level of HIPK2 was significantly lower in tumor tissues than in normal lung tissues, while that of miR-1260b was higher in tumor tissues. HIPK2 and miR-1260b expression showed an inverse correlation, and this correlation was strong in distant metastasis. Finally, the expression level of exosomal miR-1260b in plasma was higher in patients with NSCLC than in healthy individuals, and higher levels of exosomal miR-1260b were associated with high-grade disease, metastasis, and poor survival. In conclusion, exosomal miR-1260b can promote angiogenesis in HUVECs and metastasis of NSCLC by regulating HIPK2 and may serve as a prognostic marker for lung cancers.

Abstract Background A primary pulmonary invasive mucinous adenocarcinoma (IMA) is a rare subtype of invasive adenocarcinoma of the lung. The prognosis of advanced IMA depending on chemotherapy regimen has not been fully investigated. Here, we compared the clinical outcomes of patients with advanced IMA treated with different palliative chemotherapies that included novel therapeutics. Methods This single-center retrospective study included a total of 79 patients diagnosed with IMA and treated with palliative chemotherapy. The primary outcome was the comparison of overall survival according to palliative chemotherapy type. Risk factors associated with death were evaluated as a secondary outcome. Results The study cohort of 79 patients comprised 27 progressive or recurrent cases and 52 initial metastatic patients. Thirteen patients (16.5%) received targeted therapy and 18 cases (22.8%) received immunotherapy. When we compared the survival outcomes of the different treatment regimens, patients with IMA treated by immunotherapy (undefined vs. non-immunotherapy 17.0 months, p

Abstract Background Electromagnetic navigation bronchoscopy (ENB) is a useful method to obtain tissue for peripheral lung nodules. We aimed to understand the diagnostic yield and safety profile in high‐risk pulmonary nodules that cannot be accessed by percutaneous transthoracic needle biopsy. Methods In this single‐center retrospective study, we reviewed patients who underwent ENB for high‐risk pulmonary nodules. All procedures were performed under moderate sedation using intravenous midazolam and fentanyl. Results A total of 100 pulmonary nodules in 90 patients were subjected to ENB between October 2018 and May 2020. The median age of the study population was 66 (59–73). The mean diameter of the lung nodules was 27.9 mm. The diagnostic yield of ENB‐guided biopsy was 53.0%. Although the nodule size (odds ratio: 1.055, p = 0.007) and positive bronchus sign (odds ratio: 2.918, p = 0.020) were associated with the diagnostic yield during univariate analysis, nodule size was the only independent variable on the multivariable analysis. Interestingly, the diagnostic yield showed an upward trend after 60 cases, from 45%–65%. Procedure‐related complications were reported in 16 cases; among these, pneumothorax occurred in three cases, and four cases experienced moderate bleeding. No instance of major bleeding or death was linked to ENB‐guided biopsy. Conclusion ENB‐guided biopsy for high‐risk pulmonary nodules demonstrated an acceptable diagnostic yield and good safety profile. Moreover, the diagnostic yield was associated with nodule size and procedure experience.

Introduction: The preferred first-line (1L) treatment for epidermal growth factor receptor (EGFR) mutation-positive (EGFRm) advanced/metastatic non-small lung cancer (NSCLC) are EGFR-tyrosine kinase inhibitors (TKIs). However, most patients treated with 1L first- or second-generation (1G/2G) EGFR-TKIs acquire resistance; the EGFR T790M mutation is observed in ~30–50% of patients. We report real-world NSCLC treatment and T790M testing patterns in South Korea and Taiwan. Methods: Retrospective medical record review of EGFRm advanced/metastatic NSCLC patients from routine practice. 1G/2G EGFR-TKI initiation 1 January 2015–31 December 2017 (follow-up end date: last available medical record or August 2019). Study measures: demographic/disease characteristics, 1L/2L treatment, T790M testing. Results: In South Korea, 70% (164/235) and in Taiwan 89% (89/100) experienced 1L disease progression (median [range] follow-up: 22 [2.3–50.7] months). Of those with disease progression, 68% (111/164) and 62% (55/89) had T790M testing in South Korea and Taiwan, respectively. In South Korea, 43% (48/111) were T790M-positive with 88% (n=42/48) receiving osimertinib (mostly 2L). In Taiwan, 18% (10/55) were T790M-positive; 100% received osimertinib. Overall, 73% (120/164) and 63% (63/100) in South Korea and Taiwan, respectively, received 2L therapy, predominantly pemetrexed-containing regimens. Among patients with disease progression, 9% (14/164) and 24% (21/89) died before receiving 2L therapy in South Korea and Taiwan, respectively. Conclusion: In both countries,

Currently, the settlement of soft ground is measured using instruments operated by on-site workers. However, this method is expensive and inefficient in terms of data consistency, costeffectiveness, and utility. On the other hand, surveying using unmanned aerial vehicle (UAV) light detection and ranging (LiDAR) is used in various fields. However, studies on its utility in soft ground are insufficient. Therefore, in this study, we examined the optimal method for creating digital elevation models (DEMs) for estimating the settlement of soft ground using UAV LiDAR survey data. This method involved selecting a coastal construction site as the study area and acquiring data through UAV LiDAR surveying. The acquired data were used to create DEMs through preprocessing and postprocessing. Settlement measurements obtained from onsite instruments and settlement estimates derived from DEMs created using various interpolation methods and grid sizes were compared and analyzed. Additionally, the utility of the created time-series DEMs in the settlement estimation of soft ground was evaluated. We proposed the optimal method for creating DEMs for estimating the settlement of soft ground and suggested methods to utilize the proposed time-series DEMs. Our research results show that the use of UAV LiDAR survey data can lead to the economical and efficient settlement estimation of soft ground. [ABSTRACT FROM AUTHOR]

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.

Background The establishment of biomarkers that can be used to predict the response to immunotherapy for malignancy is extremely important. In particular, noninvasive analysis of immune cells from peripheral blood before treatment has gained increased attention, and natural killer (NK) cell activity has been shown to be related to treatment response. Here, we aimed to confirm the relationship between the response to immunotherapy and NK cell activity. Methods In this prospective observational study, patients with advanced NSCLC who were scheduled for immunotherapy from October 2018 to December 2019 were enrolled. Baseline NK cell activity was compared according to the best clinical response to immunotherapy. Results A total of 54 patients with advanced NSCLC were enrolled, and 34 patients were analyzed. The baseline NK cell activity was significantly higher in the non‐PD group than in the PD group (P = 0.002). At the cutoff level of ≥1200 pg/mL, baseline NK cell activity yielded a sensitivity of 80% and a specificity of 68.4% in predicting the response to immunotherapy (AUC = 0.8, P

Abstract Background We investigated the risk factors for leptomeningeal carcinomatosis (LMC) and compared clinical efficacies of various treatment modalities including intrathecal (IT) chemotherapy in patients with lung adenocarcinoma harboring epidermal growth factor receptor (EGFR) mutations. Methods Using clinical research data from the Asan Medical Center, we retrospectively analyzed data of patients diagnosed with LMC, confirmed via cerebrospinal fluid (CSF) analysis from January 2008 to December 2017. Results We identified 1189 patients with lung adenocarcinoma harboring EGFR mutations. Among these, 9.8% had a median duration of 13.5 (interquartile range [IQR] 6.8–23.6) months from the initial lung cancer diagnosis to LMC occurrence. Younger age (hazard ratio [HR] 1.043, P

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.

Purpose: This study aimed to assess the real-world clinical outcomes of consolidative durvalumab in patients with unresectable locally advanced non-small cell lung cancer (LA-NSCLC) and to explore the role of radiotherapy in the era of immunotherapy. Materials and Methods: This retrospective study assessed 171 patients with unresectable LA-NSCLC who underwent concurrent chemoradiotherapy (CCRT) with or without consolidative durvalumab at Asan Medical Center between May 2018 and May 2021. Primary outcomes included freedom from locoregional failure (FFLRF), distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival (OS). Results: Durvalumab following CCRT demonstrated a prolonged median PFS of 20.9 months (p=0.048) and a 3-year FFLRF rate of 57.3% (p=0.008), compared to 13.7 months and 38.8%, respectively, with CCRT alone. Furthermore, the incidence of in-field recurrence was significantly greater in the CCRT-alone group compared to the durvalumab group (26.8% vs. 12.4%, p=0.027). While median OS was not reached with durvalumab, it was 35.4 months in patients receiving CCRT alone (p=0.010). Patients positive for programmed cell death ligand 1 (PD-L1) expression showed notably better outcomes, including FFLRF, DMFS, PFS, and OS. Adherence to PACIFIC trial eligibility criteria identified 100 patients (58.5%) as ineligible. The use of durvalumab demonstrated better survival regardless of eligibility criteria. Conclusion The use of durvalumab consolidation following CCRT significantly enhanced locoregional control and OS in patients with unresectable LA-NSCLC, especially in those with PD-L1-positive tumors, thereby validating the role of durvalumab in standard care. [ABSTRACT FROM AUTHOR]

Background Although chemical pleurodesis is a useful treatment option for malignant pleural effusion, little is known about the effects of intrapleural docetaxel therapy. Objectives This study aimed to evaluate the effects of medical thoracoscopy‐guided intrapleural docetaxel therapy in patients with lung cancer. Methods Patients with lung cancer who diagnosed malignant pleural effusion were enrolled in this single‐center prospective pilot study. The clinical response and toxicity were evaluated at two, six and 12 weeks post‐treatment. Results Medical thoracoscopy‐guided intrapleural docetaxel therapy was conducted in four patients between June 2016 and August 2017. The control rate of malignant pleural effusion was 100% (4/4), and the progression‐free duration of effusion was 527 ± 109 days. No serious adverse events were observed, but only mild‐to‐moderate adverse events were observed and well controlled by conservative management. Although the overall quality of life assessed using questionnaires did not show significant improvement, symptom burden due to dyspnea was significantly improved. Conclusions Intrapleural docetaxel therapy with medical thoracoscopy showed good clinical responses, relieving dyspnea symptoms and providing tolerable safety profiles in patients with non‐small cell lung cancer (NSCLC) with malignant pleural effusion. A further prospective trial is warranted to evaluate the clinical effects of intrapleural docetaxel therapy in order to compare it with other treatment modalities.

Lung cancer: Immune suppressant protein promotes tumor growth An immune suppressant protein expressed by non-small cell lung cancer cells (NSCLC) to facilitate tumor growth could be a valuable therapeutic target. NSCLC is often diagnosed at advanced stages, making treatment challenging. Therapies that inhibit an immune suppressant protein called programmed cell death ligand-1 (PD-L1) have shown promise for other cancers, but how PD-L1 interacts with host and tumor cells in NSCLC needs clarification. In experiments on human cell lines and mice, Jae Cheol Lee and Jin Kyung Rho at the University of Ulsan in Seoul, South Korea, and co-workers found that microvesicles (or ‘exosomes’) released by NSCLC cells carry PD-L1, which interacts with tumor-infiltrating immune cells, inhibiting their activity. The amount of PD-L1 in exosomes directly correlates with PD-L1 expression levels on tumor cell surfaces, providing a useful indication of disease activity.

Afatinib, a second-generation, irreversible pan-HER inhibitor, shows better suppression of T790M-positive lung cancer cells than gefitinib in preclinical studies. However, whether the effect of afatinib on T790M acquisition differs from that of gefitinib when used clinically as first-line therapy remains unclear. To reaffirm the preclinical efficacy of afatinib on T790M-positive lung cancer cells, H1975 cells and established PC-9 cells resistant to gefitinib and erlotinib by T790M were used. In total, 398 patients with second biopsy at progression with stage IIIB/IV non–small cell lung cancer with EGFR mutation, treated with afatinib or gefitinib as first-line therapy, were retrospectively reviewed. Propensity score matching was used to balance covariates. Afatinib inhibited the growth of lung cancer cells with low T790M allele frequencies, which are resistant to gefitinib, but not those with high T790M allele frequencies. Afatinib and gefitinib showed similar efficacy in terms of progression-free survival (PFS) (11.5 vs 13.4 months, P = .08) and overall survival (OS) (29.3 vs 28.5 months, P = .76). T790M patients had better PFS and OS than those without T790M. There was no significant difference in the cumulative T790M acquisition ratio over time between afatinib and gefitinib (48.8% vs 59.3%, P = .317). The median time to acquire T790M was 12.9 months for afatinib and 15.7 months for gefitinib (P = .342). Although afatinib inhibited the growth of lung cancer cells with low T790M allele frequencies in preclinical studies, this could not be translated into clinical efficacy in terms of lowering the rate or delaying the time of T790M acquisition.

Background Radiation pneumonitis is one of the most harmful and clinically significant complications of radiotherapy. This study investigated the benefits of nebulized acetylcysteine for lung cancer patients diagnosed with radiation pneumonitis after radiotherapy. Methods We prospectively enrolled and followed 25 patients with radiation pneumonitis who used nebulized acetylcysteine three times a day for 12 weeks. We also reviewed the medical records of 106 control patients who had undergone radiotherapy for lung cancer but had not used acetylcysteine. We evaluated the effects of nebulized acetylcysteine by comparing visits 1 and 4 among nebulizer users and by comparing the acetylcysteine group with the control group. Results Twenty‐five acetylcysteine group patients and 101 control group patients were included in the analyses. The mean patient‐rated severity score associated with sputum production decreased in the acetylcysteine group between visits 1 and 4 (from 1.10 to 0.95; P = 0.08). None of the patients used additional expectorant agents after using nebulized acetylcysteine and critical adverse events were not reported. The acetylcysteine group had a shorter mean duration of expectorant use among patients whose radiation pneumonitis required steroid therapy and covered > 10% of a single lung field on computed tomography (37.2 vs. 78.1 days, respectively; P = 0.07). Conclusions The beneficial effects of nebulized acetylcysteine for patients with radiation pneumonitis included relieving sputum severity and minimizing expectorant use, especially in severe cases. Further investigation is required to clarify and expand on the benefits of nebulized acetylcysteine for patients with radiation pneumonitis.

Central nervous system (CNS) metastasis is one of the serious complications of epidermal growth factor receptor (EGFR)‐mutant lung cancer, which arises due to poor penetration of the brain–blood barrier by EGFR‐tyrosine kinase inhibitors (EGFR‐TKIs). Although osimertinib, a third‐generation EGFR‐TKI, has efficacy against CNS metastases, further treatment modalities are still needed as some of these lesions do not respond to osimertinib, or undergo progression after an initial response to this drug if radiotherapy has already been conducted. Here, we investigated the efficacy of water‐soluble erlotinib (NUFS‐sErt) against these metastases. This agent was synthesized using a nano‐particulation platform technology utilizing fat and supercritical fluid (NUFS™) to resolve the low solubility problem that typically prevents the creation of injectable forms of EGFR‐TKIs. The average NUFS‐sErt particle size was 236.4 nm, and it showed time‐dependent dissolution in culture media. The effects of NUFS‐sErt were similar to those of conventional erlotinib in terms of inhibiting the proliferation of EGFR‐mutant lung cancer cells and suppressing EGFR signaling. In an intraperitoneal xenograft model of HCC827 cells, intraperitoneal administration of NUFS‐sErt produced a dose‐dependent inhibition of tumor growth and enhanced survival rate. Notably, the injection of NUFS‐sErt into the brain ventricle caused significant tumor growth inhibition in an intracranial xenograft model. Hence, our current findings indicate that NUFS‐sErt is a novel, water‐soluble form of erlotinib that can be administered using intraventricular or intrathecal injections. The target cases would be patients with a progressive CNS metastasis and no other therapeutic options. This drug could also be given intravenously to patients with swallowing difficulties or an inability to ingest due to a medical condition.

Abstract Tumor cells shed an abundance of extracellular vesicles (EVs) to body fluids containing bioactive molecules including DNA, RNA, and protein. Investigations in the field of tumor-derived EVs open a new horizon in understanding cancer biology and its potential as cancer biomarkers as well as platforms for personalized medicine. This study demonstrates that successfully isolated EVs from plasma and bronchoalveolar lavage fluid (BALF) of non-small cell lung cancer (NSCLC) patients contain DNA that can be used for EGFR genotyping through liquid biopsy. In both plasma and BALF samples, liquid biopsy results using EV DNA show higher accordance with conventional tissue biopsy compared to the liquid biopsy of cfDNA. Especially, liquid biopsy with BALF EV DNA is tissue-specific and extremely sensitive compared to using cfDNA. Furthermore, use of BALF EV DNA also demonstrates higher efficiency in comparison to tissue rebiopsy for detecting p.T790 M mutation in the patients who developed resistance to EGFR-TKIs. These finding demonstrate possibility of liquid biopsy using EV DNA potentially replacing the current diagnostic methods for more accurate, cheaper, and faster results.

In patients with epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) with brain metastases, it remains controversial whether the use of EGFR-tyrosine kinase inhibitor (TKI) alone without radiotherapy (RT) is an optimal approach. Here, we investigated the clinical outcomes according to the use of upfront RT as well as the subsequent therapy following intracranial progression. This single-centre retrospective study included a total of 173 patients who were treated with EGFR-TKI alone (TKI alone group) or with upfront whole-brain RT (WBRT) or stereotactic radiosurgery (SRS) followed by EGFR-TKI (RT plus TKI group). Clinical outcomes according to initial and subsequent therapies following intracranial progression were analysed. There was no significant difference in OS according to the use of upfront RT (TKI alone group, 24.5 months vs. WBRT group, 20.0 months vs. SRS group, 17.8 months; P = 0.186). Intracranial progression was found in 35 (32.7%) of 107 patients in the TKI alone group. Among them, 19 patients who received salvage RT had the better prognosis than others [median overall survival (OS); 28.6 vs. 11.2 months; P = 0.041]. In the RT plus TKI group, 12 (18.1%) of the 66 patients experienced intracranial progression and 3 of them received salvage RT (median OS; 37.4 vs. 20.0 months; P = 0.044). In multivariate analysis, upfront WBRT was associated with trends towards a lower probability of intracranial progression, whereas upfront SRS was found to be an independent risk factor for poor OS. In conclusion, using EGFR-TKI alone for brain metastasis in EGFR-mutant lung cancer patients showed outcomes comparable to those using upfront RT followed by EGFR-TKI. Patients who could not receive salvage RT following intracranial progression had the worst survival regardless of the type of initial treatment.

Background Immune checkpoint inhibitors (ICI) have become an important treatment option for non-small cell lung cancer (NSCLC). We aimed to evaluate the clinical impact of pseudoprogression (PsP) and treatment beyond RECIST1.1-defined progressive disease (TBP) on outcome in NSCLC patients treated with ICI. Methods NSCLC patients treated with ICI between Mar 2016 and July 2018 were recruited in a consecutive manner. Response was assessed every 8–12 weeks using RECIST1.1 and iRECIST. Based on iRECIST, PsP was defined as progressive disease (PD) on RECIST1.1 subsequently reset to non-PD categories. Using log-rank test, progression-free survival (PFS) was compared between patients with and without PsP, and overall survival (OS) was compared between patients treated with and without TBP. The impact of TBP on OS was evaluated through multivariate Cox proportional hazard models. Results Of the 189 patients, seven (3.7%) experienced PsP which mostly occurred approximately 3 months after baseline. The median PFS was significantly longer in patients with PsP (not reached) than those without PsP (3.8 months, P = .02). Among patients who demonstrated PD according to RECIST1.1, median OS was significantly longer in patients with TBP (17.2 months) than those without TBP (7.4 months, P

BACKGROUND: The aim of this study was to investigate the association between epidermal growth factor receptor (EGFR) mutation and thyroid cancer in female patients with nonsmall-cell lung cancer (NSCLC). METHODS: In a retrospective study, we examined 835 female patients who were diagnosed with NSCLC and underwent an EGFR mutation test between June 2003 and August 2013. The associations of EGFR mutation with thyroid cancer and a family history of thyroid cancer were evaluated using logistic regression models. RESULTS: EGFR mutation was found in 378 of 835 patients. In addition to adenocarcinoma (P < 0.001), EGFR mutations were positively associated with a personal history of thyroid cancer (5.8% versus 2.6%; P = 0.020), while showing a trend toward inverse association with a personal history of nonthyroid cancer (5.8% vs. 9.0%; P = 0.086). Likewise, the incidence of EGFR mutations was associated with a family history of thyroid cancer (2.9% vs. 0.9%; P = 0.028), while showing a trend toward inverse association with a family history of nonthyroid cancer (27.8% vs. 33.7%; P = 0.066). Multivariate logistic regression showed that the incidence of EGFR mutations was different in women with thyroid or nonthyroid cancer (P = 0.035) and in women with a family history of thyroid or nonthyroid cancer (P = 0.023). CONCLUSIONS: Our data suggest that thyroid cancer and a family history of thyroid cancer are associated with EGFR-mutated NSCLC in female patients. The differences in the incidence of thyroid cancer and a family history of thyroid cancer by EGFR mutational status provide new insight into pathogenesis of this genetic change.