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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<0.001)., Conclusion: Baseline IChIS could be a potential biomarker for predicting survival benefit of immunotherapy in NSCLC.

In the last few decades, genome-wide association studies (GWAS) with more than 10,000 subjects have identified several loci associated with lung cancer and these loci have been used to develop novel risk prediction tools for cancer. The present study aimed to establish a lung cancer prediction model for Korean never-smokers using polygenic risk scores (PRSs); PRSs were calculated using a pruning-thresholding-based approach based on 11 genome-wide significant single nucleotide polymorphisms (SNPs). Overall, the odds ratios tended to increase as PRSs were larger, with the odds ratio of the top 5% PRSs being 1.71 (95% confidence interval: 1.31-2.23) using the 40%-60% percentile group as the reference, and the area under the curve (AUC) of the prediction model being of 0.76 (95% confidence interval: 0.747-0.774). The receiver operating characteristic (ROC) curves of the prediction model with and without PRSs as covariates were compared using DeLong's test, and a significant difference was observed. Our results suggest that PRSs can be valuable tools for predicting the risk of lung cancer., (© 2024 Wiley Periodicals LLC.)

Purpose: RUNX3 is a tumor suppressor gene, which is inactivated in approximately 70% of lung adenocarcinomas. Nicotinamide, a sirtuin inhibitor, has demonstrated potential in re-activating epigenetically silenced RUNX3 in cancer cells. This study assessed the therapeutic benefits of combining nicotinamide with first-generation EGFR-tyrosine kinase inhibitors (TKI) for patients with stage IV lung cancer carrying EGFR mutations., Patients and Methods: We assessed the impact of nicotinamide on carcinogen-induced lung adenocarcinomas in mice and observed that nicotinamide increased RUNX3 levels and inhibited lung cancer growth. Subsequently, 110 consecutive patients with stage IV lung cancer who had EGFR mutations were recruited: 70 females (63.6%) and 84 never-smokers (76.4%). The patients were randomly assigned to receive either nicotinamide (1 g/day, n = 55) or placebo (n = 55). The primary and secondary endpoints were progression-free survival (PFS) and overall survival (OS), respectively., Results: After a median follow-up of 54.3 months, the nicotinamide group exhibited a median PFS of 12.7 months [95% confidence interval (CI), 10.4-18.3], while the placebo group had a PFS of 10.9 months (9.0-13.2; P = 0.2). The median OS was similar in the two groups (31.0 months with nicotinamide vs. 29.4 months with placebo; P = 0.2). Notably, subgroup analyses revealed a significant reduction in mortality risk for females (P = 0.01) and never-smokers (P = 0.03) treated with nicotinamide., Conclusions: The addition of nicotinamide with EGFR-TKIs demonstrated potential improvements in PFS and OS, with notable survival benefits for female patients and those who had never smoked (ClinicalTrials.gov Identifier: NCT02416739)., (©2024 American Association for Cancer Research.)

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., (© 2024. The Author(s).)

Purpose: The addition of immune checkpoint inhibitors to chemotherapy has improved survival outcomes in patients with extensive-stage small cell lung cancer (ES-SCLC). However, their real-world effectiveness remains unknown. Therefore, we investigated the effectiveness of atezolizumab plus chemotherapy in ES-SCLC in actual clinical settings., Materials and Methods: In this multicenter prospective cohort study, patients with ES-SCLC receiving or scheduled to receive atezolizumab in combination with etoposide and carboplatin were enrolled between June 2021 and August 2022. The primary outcomes were progression-free survival (PFS) and the 1-year overall survival (OS) rate., Results: A total of 100 patients with ES-SCLC were enrolled from seven centers. Median age was 69 years, and 6% had an Eastern Cooperative Oncology Group performance status (ECOG PS) ≥ 2. The median PFS was 6.0 months, the 1-year OS rate was 62.2%, and the median OS was 13.5 months. An ECOG PS of 2-3 and progressive disease as the best response were poor prognostic factors for PFS, while an ECOG PS of 2-3 and brain metastasis were associated with poor prognosis for OS. In addition, consolidative thoracic radiotherapy was found to be an independent favorable prognostic factor for OS (hazard ratio, 0.336; p=0.021). Grade ≥ 3 treatment-related adverse events were observed in 7% of patients, with treatment-related deaths occurring in 2% of patients., Conclusion: We provided evidence of the favorable real-world effectiveness and safety of atezolizumab plus chemotherapy in ES-SCLC patients, including in the elderly and those with poor ECOG PS. Additional consolidative thoracic radiotherapy may also benefit ES-SCLC patients.

Background: The drive to improve surgical proficiency through advanced simulation-based training has gained momentum. This meta-analysis systematically evaluated evidence regarding the impact of plastic surgery-related simulation on the performance of residents., Methods: A systematic search of PubMed, Web of Science, and Cochrane Library and review of articles was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis protocol. An inverse-variance random-effects model was used to combine study estimates to account for between-study variability. Objective structured assessment of technical skills (OSATS) scores and subjective confidence scores were used to assess the impact of the simulation with positive changes from the baseline indicating better outcomes., Results: Eighteen studies pooling 367 trainees who participated in various simulations were included. Completion of simulation training was associated with significant improvement in subjective confidence scores with a mean increase of 1.44 units (95% CI: 0.93 to 1.94, P < 0.001), and in OSATS scores, with a mean increase of 1.24 units (95% CI: 0.87 to 1.62, P < 0.001), both on a 1-5 scale. Participants reported high satisfaction scores (mean = 4.76 units, 95% CI = 4.61 to 4.91, P = 0.006), also on a 1-5 scale., Conclusions: Participation in surgical simulation markedly improved objective and subjective scoring metrics for surgical trainees. Several simulation devices are available for honing surgical skills, with the potential for advancements. The evidence demonstrates the effectiveness of simulations; thus, incorporating simulation into training curricula should be a priority in the field of plastic surgery., (Copyright © 2024. Published by Elsevier Ltd.)

Real-world data on the use and outcomes of crizotinib in ROS1-rearranged non-small-cell lung cancer (NSCLC) are limited. This study aims to analyze the real-world efficacy of crizotinib in South Korea and explore the utilization of liquid biopsies that implement next-generation sequencing (NGS) using cell-free total nucleic acids. In this prospective multicenter cohort study, 40 patients with ROS1-rearranged NSCLC, either starting or already on crizotinib, were enrolled. Patients had a median age of 61 years, with 32.5% presenting brain/central nervous system (CNS) metastases at treatment initiation. At the data cutoff, 48.0% were still in treatment; four continued with it even after disease progression due to the clinical benefits. The objective response rate was 70.0%, with a median duration of response of 27.8 months. The median progression-free survival was 24.1 months, while the median overall survival was not reached. Adverse events occurred in 90.0% of patients, primarily with elevated transaminases, yet these were mostly manageable. The NGS assay detected a CD74-ROS1 fusion in 2 of the 14 patients at treatment initiation and identified emerging mutations, such as ROS1 G2032R, ROS1 D2033N, and KRAS G12D, during disease progression. These findings confirm crizotinib's sustained clinical efficacy and safety in a real-world context, which was characterized by a higher elderly population and higher rates of brain/CNS metastases. The study highlights the clinical relevance of liquid biopsy for detecting resistance mechanisms, suggesting its value in personalized treatment strategies.

We aimed to identify blood lymphocytes as a prognostic factor for survival in patients with locally advanced stage III non-small cell lung cancer (NSCLC) treated with concurrent chemoradiotherapy (CCRT). This is a secondary study of 196 patients enrolled in the Korean Radiation Oncology Group 0903 phase III clinical trial to evaluate the prognostic significance of circulating blood lymphocyte levels. The median total lymphocyte count (TLC) reduction ratio during CCRT was 0.74 (range: 0.29-0.97). In multivariate analysis, patient age (p=0.014) and gross tumor volume (GTV, p=0.031) were significant factors associated with overall survival, while TLC reduction (p=0.018) and pretreatment neutrophil-to-lymphocyte ratio (NLR; p=0.010) were associated with progression-free survival (PFS). In multivariate logistic regression analysis, pretreatment NLR, GTV, and heart V20 were significantly associated with TLC reduction. Immunohistochemical analysis of programmed death ligand 1 and CD8 expression on T cells was performed on 84 patients. CD8 expression was not significantly associated with the pretreatment lymphocyte count (p=0.673), and PDL1 expression was not significantly associated with OS or PFS. Univariate analysis revealed that high CD8 expression in TILs was associated with favorable OS and was significantly associated with favorable PFS (p=0.032). TLC reduction during CCRT is a significant prognostic factor for PFS, and heart V20 is significantly associated with TLC reduction. Thus, in the era of immunotherapy, constraining the volume of the radiation dose to the whole heart must be prioritized for the better survival outcomes., Competing Interests: CONFLICT OF INTEREST STATEMENT: None declared., (© Chonnam Medical Journal, 2024.)

Background: Lung adenocarcinoma (LUAD) is the most common histological subtype of non-small cell lung cancer (NSCLC), with poor treatment outcomes worldwide. Dynamin-related protein 1 (DRP1), which is encoded by the dynamin 1-like ( DNM1L ) gene, acts as a regulator of mitochondrial fission and plays crucial roles in tumor initiation and progression. However, the clinical value and immune regulation of DNM1L in LUAD have not been explored., Methods: We comprehensively analyzed the expression of DNM1L in the LUAD cohort of the Human Protein Atlas (HPA) and the University of The ALabama at Birmingham CANcer data analysis Portal (UALCAN) databases. Kaplan-Meier plotter, in addition to the PrognoScan database, was used to estimate the correlation between DNM1L expression and survival outcome of LUAD patients. The association between the immune tumor microenvironment (TME) and DNM1L expression in LUAD was evaluated based on the Tumor IMmune Estimation Resource (TIMER)2.0 database. Finally, the functions of DNM1L were validated in vitro experiments, including reverse transcription-quantitative polymerase chain reaction (RT-qPCR), western blot, wound healing assays, and transwell assays., Results: DNM1L was overexpressed in LUAD compared to healthy control tissues and was regarded as an independent prognostic factor. Overexpression of DNM1L was significantly related to clinical variables and poor survival outcomes of LUAD patients. Moreover, DNM1L expression was positively associated with the expression of key genes involved in the regulation of immune cell subsets, including T helper (Th)2 cells, Th cells, B cells, CD8 T cells, dendritic cells, and mast cells. In contrast, DNM1L was negatively correlated with the infiltrating levels of myeloid dendritic cells and B cells. Furthermore, DNM1L may play a role in regulating immune cell infiltration and have prognostic value in LUAD patients. Finally, the in vitro experiments showed that increased DNM1L significantly promoted the proliferation and migration of LUAD cells., Conclusions: This study suggested that DNM1L may play an important role in regulating the proliferation and migration of LUAD cells as well as the infiltration of tumor-related immune cells, which suggests DNM1L was a potential therapeutic target in LUAD. Further studies are however warranted to define its exact mechanism of action and potential therapeutic significance in LUAD patients., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-685/coif). The authors have no conflicts of interest to declare., (2023 Translational Lung Cancer Research. All rights reserved.)

Background: Data from clinical trials and real-world studies show that afatinib is effective in treating non-small cell lung cancer (NSCLC) harboring activating mutations in the epidermal growth factor receptor ( EGFR ) gene. A previous analysis of patients enrolled in the Korean Academy of Tuberculosis and Respiratory Disease (KATRD) EGFR cohort showed that first-line afatinib was well tolerated and effectiveness results were encouraging. At the time of the previous analysis, survival data were not mature. Here we briefly present updated survival data from the cohort., Methods: The study was a retrospective, multicenter (15 sites) review of electronic records of Korean adult patients (aged >20 years) with advanced EGFR mutation-positive NSCLC who initiated first-line afatinib (N=421). Progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan-Meier survival curves., Results: Overall, median PFS was 20.2 months and median OS was 48.6 months. OS rates at 36 and 60 months were 60.1% and 42.3%, respectively. Presence vs . absence of baseline brain metastases was associated with significantly reduced median PFS (14.9 vs . 28.0 months; P<0.001) and median OS (32.2 vs . 65.6 months; P<0.001). The presence of common baseline EGFR mutations (Del19, L858R) was associated with significantly prolonged median OS (49.6 vs . 30.1 months; P=0.017). In patients stratified by the presence/absence of T790M EGFR mutation, the T790M mutation was associated with significantly reduced median PFS (P=0.0005) but there was no significant difference between groups in survival (P=0.263). There were no significant differences in PFS or OS for patients stratified by afatinib dose reduction or by age group (<70 vs . ≥70 years)., Conclusions: Afatinib was effective in Korean patients with EGFR mutation-positive NSCLC with median OS over 4 years. The presence of baseline brain metastases and/or uncommon EGFR mutations were associated with reduced survival. In the absence of baseline brain metastases, median OS was more than 5 years., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-383/coif). Y.S.C. declares being a stockholder in BicBio; Y.C.K. has received grants from AstraZeneca and honoraria from AstraZeneca, Merck Sharp & Dohme, Roche, Novartis, Janssen, Amgen, Ono Pharma, Bristol Myers Squibb, and Takeda; I.J.O. has received grants from AstraZeneca and Roche, personal fees from Gencurix, Janssen, Merck Sharp & Dohme, Ono Pharma, Panagene, Pfizer, Roche, and Yuhan, and honoraria from Amgen, AstraZeneca, Eli Lilly, Janssen, Menarini, Merck Sharp & Dohme, Novartis, Pfizer, and Yuhan; S.Y.L. has received honoraria from Boehringer Ingelheim; T.W.J. has received honoraria from Boehringer Ingelheim. The other authors have no conflicts of interest to disclose., (2023 Translational Lung Cancer Research. All rights reserved.)

A definitive surgical resection is the preferred treatment for early-stage non-small cell lung cancer (NSCLC). Research on genetic alterations, including epidermal growth factor receptor (EGFR) mutations, in early-stage NSCLC remains insufficient. We investigated the prevalence of genetic alterations in early-stage NSCLC and the association between EGFR mutations and recurrence after a complete resection. Between January 2019 and December 2021, 659 patients with NSCLC who underwent curative surgical resections at a single regional cancer center in Korea were recruited. We retrospectively compared the clinical and pathological data between the recurrence and non-recurrence groups. Among the 659 enrolled cases, the median age was 65.86 years old and the most common histology was adenocarcinoma (74.5%), followed by squamous cell carcinoma (21.7%). The prevalence of EGFR mutations was 43% (194/451). Among them, L858R point mutations and exon 19 deletions were 52.3% and 42%, respectively. Anaplastic lymphoma kinase (ALK) rearrangement was found in 5.7% of patients (26/453) and ROS proto-oncogene 1 (ROS1) fusion was found in 1.6% (7/441). The recurrence rate for the entire population was 19.7%. In the multivariate analysis, the presence of EGFR mutations (hazard ratio (HR): 2.698; 95% CI: 1.458-4.993; p = 0.002), stage II (HR: 2.614; 95% CI: 1.29-5.295; p = 0.008) or III disease (HR: 9.537; 95% CI: 4.825-18.852; p < 0.001) (vs. stage I disease), and the presence of a pathologic solid type (HR: 2.598; 95% CI: 1.405-4.803; p = 0.002) were associated with recurrence. Among the recurrence group, 86.5% of the patients with EGFR mutations experienced distant metastases compared with only 66.7% of the wild type ( p = 0.016), with no significant difference in median disease-free survival (52.21 months vs. not reached; p = 0.983). In conclusion, adjuvant or neoadjuvant targeted therapy could be considered more actively because EGFR mutations were identified as an independent risk factor for recurrence and were associated with systemic recurrence. Further studies on perioperative therapy for other genetic alterations are necessary.

Extracellular vesicles (EVs) are emerging as crucial materials for precision theragnostic applications. However, current separation methods are time-consuming, costly, and not scalable and deliver limited yields or purity. Here, we present EV precipitation by ionic strength modulation (ExoPRISM), a simple, low-cost, user-friendly, and readily adaptable approach for separating EVs in high yields without compromising their biological functions. Adding an electrolyte solution to blood plasma in small increments generates the sequential precipitation of proteins and EVs, allowing for fractional separation of EVs using low-speed centrifugation. The coprecipitated electrolytes are easily washed away, and the entire EV separation and washing process takes less than an hour. This approach successfully separates EVs from a broad range of volumes and types of biological fluids, including culture medium, urine, plasma, and serum, showing promise as a robust tool for next-generation liquid biopsies and regenerative medicine.

This study aimed to evaluate treatment outcomes and safety of afatinib in patients with squamous cell carcinoma of the lung (LSCC) who progressed after chemotherapy and immunotherapy. We recruited patients both retrospectively and prospectively and collected the outcomes and safety data. Additionally, we performed next-generation sequencing using tumor tissue and/or plasma to explore potential molecular biomarkers. Altogether, 42 patients were included in the final analysis. The median number of prior treatments was three (range 1-8), and the median TTF was 2.1 months. Objective response rate and disease control rate were 16.2% and 59.5%, respectively, and median duration of response was 4.0 months among response evaluable patients ( n = 37). Treatment-related adverse events (TRAEs, including diarrhea, stomatitis, and paronychia) occurred in 22 (52.3%) patients; however, most were grade 2 or lower, and only 5 cases were grade 3. TRAEs led to dose modification in 17 (40.5%) and discontinuation in 4 (9.5%) patients. The TTF in patients with ERBB2 mutations was significantly longer than that in patients without (6.8 vs. 2.1 months, p = 0.045). Our results highlight that afatinib is a reasonable treatment option in terms of effectiveness and safety, and ERBB2 mutation can be used as a predictive biomarker in clinical settings.

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., (© 2023. Springer Nature Limited.)

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., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

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 PM 2.5 and PM 10 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 PM 2.5 urban areas (46.296 vs. 50.646, p = 0.015). In high PM 2.5 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 PM 2.5 concentration and correlated with PM 10 /PM 2.5 concentrations in urban and nationwide areas. In high PM 2.5 urban regions, there was a significant increase in bronchodilator prescriptions (3.102 vs. 3.758, p = 0.008). Concerning high PM 2.5 nationwide regions, there were significantly increased prescriptions of antibiotics, steroids, bronchodilators, antihistamines, and mucolytics., Conclusions: This study suggests that exposure to PM 2.5 is significantly associated with hospital utilization and drug prescription in lung cancer patients., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Defining the molecular dynamics associated with T cell differentiation enhances our understanding of T cell biology and opens up new possibilities for clinical implications. In this study, we investigated the dynamics of CD5 expression in CD8 + T cell differentiation and explored its potential clinical uses. Using PBMCs from 29 healthy donors, we observed a stepwise decrease in CD5 expression as CD8 + T cells progressed through the differentiation stages. Interestingly, we found that CD5 expression was initially upregulated in response to T cell receptor stimulation, but diminished as the cells underwent proliferation, potentially explaining the differentiation-associated CD5 downregulation. Based on the proliferation-dependent downregulation of CD5, we hypothesized that relative CD5 expression could serve as a marker to distinguish the heterogeneous CD8 + T cell population based on their proliferation history. In support of this, we demonstrated that effector memory CD8 + T cells with higher CD5 expression exhibited phenotypic and functional characteristics resembling less differentiated cells compared to those with lower CD5 expression. Furthermore, in the retrospective analysis of PBMCs from 30 non-small cell lung cancer patients, we found that patients with higher CD5 expression in effector memory T cells displayed CD8 + T cells with a phenotype closer to the less differentiated cells, leading to favorable clinical outcomes in response to immune checkpoint inhibitor (ICI) therapy. These findings highlight the dynamics of CD5 expression as an indicator of CD8 + T cell differentiation status, and have implications for the development of predictive biomarker for ICI therapy., Competing Interests: Conflict of Interest: The authors declare no potential conflicts of interest., (Copyright © 2023. The Korean Association of Immunologists.)

Introduction: This study aimed to investigate real-world evidence for efficacy and safety of durvalumab consolidation (DC) after chemoradiotherapy (CRT) in patients with unresectable stage III NSCLC., Methods: Patients with stage III NSCLC who started DC after CRT between September 2018 and December 2020 and were treated at five tertiary hospitals in the Republic of Korea were included. The primary end point was real-world progression-free survival (rwPFS). Secondary end points were overall survival, objective response rate, and adverse events including radiation pneumonitis (RP) and immune-related adverse events (irAEs)., Results: A total of 157 patients were enrolled. At the median follow-up of 19.1 months, median rwPFS of DC was 25.9 months (95% confidence interval: 16.5-35.4) and the 1-, 2-, and 3-year rwPFS rates were 59.4%, 51.8%, and 43.5%, respectively. The median overall survival was not mature, and objective response rate of DC was 51.0%. High programmed death-ligand 1 expression (≥50%) and development of RP requiring steroid treatment were significantly associated with longer (p = 0.043) and shorter rwPFS (p = 0.036), respectively. RP, RP requiring steroid treatment, and irAEs developed in 57 (36.3%), 42 (26.8%), and 53 (33.8%) patients, respectively. Among peripheral blood cell counts at the initiation of DC, a high derived monocyte-to-lymphocyte ratio was the most significant risk factor for the development of RP requiring steroid treatment (OR 44.76, 95% CI: 8.89-225.43, p < 0.001) and irAEs (OR 2.85, 95% CI: 1.27-6.41, p = 0.011)., Conclusions: Compared with the outcome of the PACIFIC trial, these real-world data revealed favorable survival benefits of DC after CRT in patients with unresectable stage III NSCLC. Blood-based biomarkers could predict higher-grade RP and irAEs before the initiation of DC., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

There has been controversy over whether to radiologically follow up or use local treatment for asymptomatic small-sized brain metastases from primary lung cancer. For brain tumors without local treatment, we evaluated potential factors related to the brain progression and whether systemic therapy controlled the tumor. We analyzed 96 patients with asymptomatic small-sized metastatic brain tumors from lung cancer. These underwent a radiologic follow-up every 2 or 3 months without local treatment of brain metastases. The pathologies of the tumors were adenocarcinoma ( n = 74), squamous cell carcinoma ( n = 11), and small cell carcinoma ( n = 11). The primary lung cancer was treated with cytotoxic chemotherapy ( n = 57) and targeted therapy ( n = 39). Patients who received targeted therapy were divided into first generation ( n = 23) and second or third generation ( n = 16). The progression-free survival (PFS) of brain metastases and the overall survival (OS) of patients were analyzed depending on the age, tumor pathology, number, and location of brain metastases, the extent of other organ metastases, and chemotherapy regimens. The median PFS of brain metastases was 7.4 months (range, 1.1-48.3). Targeted therapy showed statistically significant PFS improvement compared to cytotoxic chemotherapy ( p = 0.020). Especially, on univariate and multivariate analyses, the PFS in the second or third generation targeted therapy was more significantly improved compared to cytotoxic chemotherapy (hazard ratio 0.229; 95% confidence interval, 0.082-0.640; p = 0.005). The median OS of patients was 13.7 months (range, 2.0-65.0). Univariate and multivariate analyses revealed that the OS of patients was related to other organ metastases except for the brain ( p = 0.010 and 0.020, respectively). Three out of 52 patients with brain recurrence showed leptomeningeal dissemination, while the recurrence patterns of brain metastases were mostly local and/or distant metastases (94.2%). Of the 52 patients who relapsed, 25 patients received local brain treatment. There was brain-related mortality in two patients (2.0%). The intracranial anti-tumor effect was superior to cytotoxic chemotherapy in the treatment of asymptomatic small-sized brain metastases with targeted therapy. Consequently, it becomes possible to determine the optimal timing for local brain treatment while conducting radiological follow-up for these tumors, which do not appear to increase brain-related mortality. Furthermore, this approach has the potential to reduce the number of cases requiring brain local treatment.

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 (P interaction  = 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., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

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: We aimed to identify factors influencing smoking cessation success among cancer patients registered in an inpatient smoking cessation program at a single cancer center., Materials and Methods: The electronic medical records of enrolled patients with solid cancer were retrospectively reviewed. We evaluated factors associated with 6-month smoking cessation., Results: A total of 458 patients with cancer were included in this study. Their mean age was 62.9±10.3 years, and 56.3% of the participants had lung cancer. 193 (42.1%) had not yet begun their main treatment. The mean number of counseling sessions for the participants was 8.4±3.5, and 46 (10.0%) patients were prescribed smoking cessation medications. The 6-month smoking cessation success rate was 48.0%. Multivariate analysis showed that younger age (<65 years), cohabited status, early stage, and the number of counseling sessions were statistically significant factors affecting 6-month smoking cessation success ( p <0.05). Initiation of a cessation program before cancer treatment was significantly associated with cessation success (odds ratio, 1.66; 95% confidence interval, 1.02-2.70; p =0.040)., Conclusion: Smoking cessation intervention must be considered when establishing a treatment plan immediately after a cancer diagnosis among smokers., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Yonsei University College of Medicine 2023.)

Competing Interests: Conflicts of Interest: The authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2023-1/coif). All authors report that they received honoraria for presentations from AstraZeneca, Yuhan, Boehringer Ingelheim, MSD, Takeda, Ono BMS, Amgen, Novartis, Johnson and Johnson, and Pfizer. The authors have no other conflicts of interest to declare.

Purpose: We designed the Korean Radiation Oncology Group 09-03 phase III clinical trial to compare accelerated hypofractionated radiation therapy (RT) using a concomitant boost to the gross tumor volume (GTV) with conventionally fractionated 60-Gy RT in patients with stage III unresectable non-small cell lung cancer (NSCLC)., Methods and Materials: A conventionally fractionated RT group (arm 1; 124 patients) received a 2-Gy daily dose to a total cumulative dose of 44 Gy to the planning target volume (PTV) in 22 fractions and 60 Gy to the GTV in 30 fractions over 6 weeks. A hypofractionated RT group (arm 2; 142 patients) received a 1.8-Gy daily dose to the PTV with a synchronous boost of 0.6 Gy to the GTV, for total cumulative doses of 45 Gy to the PTV and 60 Gy to the GTV in 25 fractions over 5 weeks. All patients received concurrent weekly chemotherapy consisting of paclitaxel and cisplatin., Results: The objective response rate of all patients was 86.5% (arm 1, 84.6%; arm 2, 88.1%; P = .612). The median overall survival was 26 months (arm 1, 26 months; arm 2, 27 months; P = .508). The median progression-free survival was 11 months (arm 1, 10 months; arm 2, 13 months; P = .295). The local tumor control rates at 2 and 5 years were 58.3% and 50.7%, respectively (arm 1, 62.4% and 51.0%, respectively; arm 2, 54.0% and 48.6%, respectively; P = .615). There were no significant between-group differences in the cumulative incidence of grade ≥3 radiation pneumonitis (P = .134) or radiation esophagitis (P = .539)., Conclusions: This clinical trial did not confirm the superiority of accelerated 2.4-Gy hypofractionated RT compared with conventional 2-Gy fractionation in patients with unresectable stage III NSCLC undergoing concurrent chemoradiation therapy., (Copyright © 2022 Elsevier Inc. All rights reserved.)

This study aimed to add real-world evidence to the literature regarding the effectiveness and safety of durvalumab consolidation (DC) after concurrent chemoradiotherapy (CCRT) in the treatment of unresectable stage III non-small cell lung cancer (NSCLC). Using a hospital-based NSCLC patient registry and propensity score matching in a 2:1 ratio, we conducted a retrospective cohort study of patients with unresectable stage III NSCLC who completed CCRT with and without DC. The co-primary endpoints were 2-year progression-free survival and overall survival. For the safety evaluation, we evaluated the risk of any adverse events requiring systemic antibiotics or steroids. Of 386 eligible patients, 222 patients-including 74 in the DC group-were included in the analysis after propensity score matching. Compared with CCRT alone, CCRT with DC was associated with increased progression-free survival (median: 13.3 vs. 7.6 months, hazard ratio[HR]: 0.63, 95% confidence interval[CI]: 0.42-0.96) and overall survival (HR: 0.47, 95% CI: 0.27-0.82) without an increased risk of adverse events requiring systemic antibiotics or steroids. While there were differences in patient characteristics between the present real-world study and the pivotal randomized controlled trial, we demonstrated significant survival benefits and tolerable safety with DC after the completion of CCRT.

Background: While the central location is a known adverse prognostic factor in lung cancer, a precise definition of central lung cancer has not yet emerged., Purpose: To determine the prognostic significance of central lung cancer (defined by location index) in resected T1-sized early-stage non-small cell lung cancer (NSCLC)., Material and Methods: Patients with resected T1-sized early-stage NSCLC between 2010 and 2015 at a single tertiary cancer center were retrospectively reviewed. Central lung cancer was defined by a location index of the second tertile or less. Kaplan-Meier analysis with log-rank test and multivariable Cox regression analysis were performed to analyze the relationship between central lung cancer and the prognosis of relapse-free survival (RFS) and overall survival (OS). Inter-observer agreement was assessed using Cohen's kappa value and intraclass correlation coefficient (ICC)., Results: Overall, 289 patients (169 men; median age 65 years; interquartile range 58-70 years) were evaluated. Central lung cancer (defined by location index) was adversely associated with RFS ( P  = 0.005) and OS ( P  = 0.01). Multivariable Cox regression analysis showed that central lung cancer was independently associated with poor RFS (adjusted hazard ratio 1.91; 95% confidence interval [CI] 1.12-3.24; P  = 0.017) and OS (adjusted hazard ratio 1.69; 95% CI 1.04-2.74; P  = 0.033). Location index demonstrated excellent inter-observer agreement (Cohen's kappa value 0.88; 95% CI 0.82-0.93) with a high ICC (0.98; 95% CI 0.97-0.98)., Conclusion: Central lung cancer defined by a location index of the second tertile or lower is an independent adverse prognostic factor in resected T1-sized early-stage NSCLC.

Background: Immune checkpoint inhibitors (ICIs) possess remarkable clinical effectiveness in non-small cell lung cancer (NSCLC). Different immune profiles of tumors may play a key role in the efficacy of treatment with ICIs. This article aimed to determine the differential organ responses to ICI in individuals with metastatic NSCLC., Methods: This research analyzed data of advanced NSCLC patients receiving first-line treatment with ICIs. Major organs such as the liver, lung, adrenal glands, lymph nodes and brain were assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and RECIST-improved organ-specific response criteria., Results: A retrospective analysis was conducted on a total of 105 individuals with advanced NSCLC with programmed death ligand-1 (PD-L1) expression ≥50% who received single agent anti-programmed cell death protein 1 (PD-1)/PD-L1 monoclonal antibodies as first-line therapy. Overall, 105 (100%), 17 (16.2%), 15 (14.3%), 13 (12.4%), and 45 (42.8%) individuals showed measurable lung tumors and liver, brain, adrenal, and other lymph node metastases at baseline. The median size of the lung, liver, brain, adrenal gland, and lymph nodes were 3.4, 3.1, 2.8, 1.9, and 1.8 cm, respectively. The results recorded mean response times of 2.1, 3.4, 2.5, 3.1, and 2.3 months, respectively. Organ-specific overall response rates (ORRs) were 67%, 30.6%, 34%, 39%, and 59.1%, respectively, with the liver having the lowest remission rate and lung lesions having the highest remission rate. There were 17 NSCLC patients with liver metastasis at baseline, and 6 had different responses to ICI treatment, with remission in the primary lung site and progressive disease (PD) in the metastatic liver site. At baseline, the mean progression-free survival (PFS) of the 17 patients with liver metastasis and 88 patients without liver metastasis was 4.3 and 7 months, respectively (P=0.02, 95% CI: 0.691 to 3.033)., Conclusions: The liver metastases of NSCLC may be less responsive to ICIs than other organs. The lymph nodes respond most favorably to ICIs. Further strategies may include additional local treatment in case of oligoprogression in these organs in patients with otherwise sustained treatment benefit., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-83/coif). MP serves as an unpaid editorial board member of Translational Lung Cancer Research from October 2021 to September 2023. MP reports grants from BMS, AZ, MSD, Lilly, Janssen, Roche. In-Jae Oh reports consulting fees from Merck Sharp & Dohme, Ono Pharma, and Roche. The other authors have no conflicts of interest to declare., (2023 Translational Lung Cancer Research. All rights reserved.)

We recruited 50 patients with unresectable stage III NSCLC who received CCRT between March 2020 and March 2021. Durvalumab consolidation (DC) was administered to patients ( n = 23) without progression after CCRT and programmed death-ligand 1 (PD-L1) ≥ 1%. Blood samples were collected before (C0) and after CCRT (C1) to calculate PBC counts and analyze CTCs. CTCs, isolated by the CD-PRIME TM system, exhibited EpCAM/CK+/CD45- phenotype in BioViewCCBS TM . At median follow-up of 27.4 months, patients with residual CTC clusters at C1 had worse median PFS than those without a detectable CTC cluster (11.0 vs. 27.8 months, p = 0.032), and this trend was noted only in the DC group ( p = 0.034). Patients with high platelets at C1 (PLT hi , >252 × 10 3 /µL) had worse median PFS than those with low platelets (PLT lo ) (5.9 vs. 17.1 months, p < 0.001). In multivariable analysis, PLT hi and residual CTC clusters at C1 were independent risk factors for PFS, and DC group with PLT hi and residual CTC clusters at C1 showed the worst median PFS (2.6 months, HR 45.16, p = 0.001), even worse than that of the CCRT alone group with PLT hi (5.9 months, HR 15.39, p = 0.001). The comprehensive analysis of CTCs and PBCs before and after CCRT revealed that the clearance of CTC clusters and platelet counts at C1 might be potential biomarkers for predicting survival.

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., (© 2023. The Author(s).)

Background: Pirfenidone, an antifibrotic medication approved for the treatment of idiopathic pulmonary fibrosis (IPF), often requires dose reduction owing to adverse events. In this study, we evaluated if pirfenidone's reduced dose has any impact on clinical outcomes in patients with IPF. Methods: We used the data of a prospective post-marketing study of pirfenidone conducted at 10 hospitals in South Korea from 2014 to 2017. Dose reduction was defined when the pirfenidone dose was temporarily or permanently reduced to manage adverse events or when the treatment dose failed to reach the standard dose. Study patients were classified based on the most frequently administered dose during 48-week follow-up-1800 mg, 1,200 mg, and <1,200 mg/days. The following clinical outcomes were compared between the groups: death, hospitalization, acute exacerbation, pulmonary function decline, and changes in severity of dyspnea and cough. Results: The median follow-up duration in all 143 patients was 11 months. During the study period, 70.6% experienced at least one dose reduction. Patients treated with standard-dose pirfenidone tended to be young and had the lowest diffusing capacity. Pulmonary function changes did not differ depending on the pirfenidone dose. The three groups were not significantly different in terms of the proportion of death, hospitalization, and acute exacerbation. The symptom changes were also similar between the groups. Conclusion: Reduced doses did not negatively impact clinical outcomes compared with the standard-dose pirfenidone in patients with IPF. Dose reduction may be a useful method to manage adverse events while maintaining therapeutic efficacy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kang, Chung, Park, Oh, Lee, Kim, Park, Uh, Kim, Jegal and Song.)

Objective: Pulmonary 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., Methods: We retrospectively reviewed the medical charts of patients with PAVMs between 2003 and 2021 at two tertiary referral hospitals and one secondary hospital., Results: Fifty-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)., Conclusion: Older 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., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Na et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Early detection is critical for minimizing mortality from cancer. Plasma cell-free DNA (cfDNA) contains the signatures of tumor DNA, allowing us to quantify the signature and diagnose early-stage tumors. Here, we report a novel tumor fragment quantification method, TOF (Tumor Originated Fragment) for the diagnosis of lung cancer by quantifying and analyzing both the plasma cfDNA methylation patterns and fragmentomic signatures. TOF utilizes the amount of ctDNA predicted from the methylation density information of each cfDNA read mapped on 6243 lung-tumor-specific CpG markers. The 6243 tumor-specific markers were derived from lung tumor tissues by comparing them with corresponding normal tissues and healthy blood from public methylation data. TOF also utilizes two cfDNA fragmentomic signatures: 1) the short fragment ratio, and 2) the 5' end-motif profile. We used 298 plasma samples to analyze cfDNA signatures using enzymatic methyl-sequencing data from 201 lung cancer patients and 97 healthy controls. The TOF score showed 0.98 of the area under the curve in correctly classifying lung cancer from normal samples. The TOF score resolution was high enough to clearly differentiate even the early-stage non-small cell lung cancer patients from the healthy controls. The same was true for small cell lung cancer patients., Competing Interests: Declaration of competing interest Jong Bhak is the CEO and a major shareholder of Clinomics Inc., Korea. Other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: We aimed to evaluate the efficacy of postoperative adjuvant pemetrexed plus cisplatin (Pem-Cis) in pathologic stage IB-IIIA lung adenocarcinoma (LUAD) patients., Methods: A prospective, phase II study was performed in seven institutions in South Korea. Patients with completely resected stage IB-IIIA LUAD received pemetrexed (500 mg/m 2 ) plus cisplatin (75 mg/m 2 ). Adjuvant treatments were administered every 3 weeks for 4 cycles. The primary endpoint was to prove the Pem-Cis's superiority in terms of 2-year disease-free survival rate (DFSR) compared with historical control without adjuvant chemotherapy (50%)., Results: Between August 2015 and February 2018, 105 patients were enrolled in this study. Approximately 31.4% (n=33), 43.8% (n=46), and 24.8% (n=26) of patients had pathologic stage IB, II, and IIIA, respectively. Most of the patients underwent lobectomy (n=98, 93.3%). Moreover, 41.1% and 12.1% of the patients had epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase rearrangement. Four cycles of Pem-Cis were administered in 99 patients (94.3%). At a median follow-up of 57.7 months, the 2-year DFSR was 78.1%. Multivariable analysis showed that pathologic stage IIIA and EGFR mutation were significant risk factors for DFS. Grade 3 adverse events occurred in 10 patients (9.5%), and leukopenia (n=3, 2.9%) was the most common adverse event., Conclusions: Adjuvant Pem-Cis is superior to historical control without adjuvant treatment in terms of 2-year DFSR; the proportion of patients with stage IB and driver mutations were higher than that of patients in previous trials. Pem-Cis showed favorable tolerability as adjuvant chemotherapy (clinicaltrial.gov; Identifier: NCT02498860)., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-183/coif). YCK reports a company funding from Shin Poong Pharm. Co., Ltd. for this study; grants from AstraZeneca and Boehringer Ingelheim; payments from AstraZeneca, MSD, Yuhan, Roche, Boehringer Ingelheim, Ono, BMS and Amgen. The other authors have no conflicts of interest to declare., (2022 Translational Lung Cancer Research. All rights reserved.)

Since it is a widely known fact that smoking cessation is beneficial physically and cognitively, efforts should be made to enable smokers to quit smoking through policy. Intensive care smoking cessation camps generally show a high smoking cessation success rate, but research is needed to determine which smokers should be admitted due to costeffectiveness. Although many studies have been conducted to find factors related to smoking cessation success, there is still controversy about the will and success rate of smoking cessation of elderly smokers. We performed this study to determine behavior characteristics and smoking cessation success rates in nonelderly and elderly smokers who participated in an intensive care smoking cessation camp. Heavy smokers participating in an intensive care smoking cessation camp at Chonnam National University Hospital between the August 2015 and December 2017 were classified into elderly (age ≥65 years old) or nonelderly (age <65 years old) groups after excluding missing data. Smokers were followed up at 4 weeks, 6 weeks, 12 weeks, and 6 months from the start of abstinence by self-report, measurement of carbon monoxide expiration levels or cotinine testing. A total of 351 smokers were enrolled in the study. At the 6-month follow-up, 56 of 107 (52.3%) elderly smokers and 109 of 244 (44.7%) nonelderly smokers continued to abstain from smoking. Elderly smokers showed a higher smoking cessation rate than that of nonelderly smokers, but it was not statistically significant (OR = 1.36, 95%CI: 0.862, 2.145). The most common causes of cessation failure in both groups were stress and temptation, followed by withdrawal symptoms. Smoking cessation rates in the elderly are comparable to that in the nonelderly after an intensive care smoking cessation camp. Intensive care smoking cessation camps can help both elderly and nonelderly smokers who intend to quit smoking by providing motivation, education and medication. Smoking cessation should be strongly recommended regardless of age., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: Identifying pretreatment interstitial lung abnormalities (ILAs) is important because of their predictive value for complications after lung cancer treatment. This study aimed to assess the predictive value of ILAs for postoperative pulmonary complications (PPCs) in elderly patients undergoing curative resection for early-stage non-small cell lung cancer (NSCLC)., Materials and Methods: Elderly patients (age ≥ 70 years) who underwent curative resection for pathologic stage I or II NSCLC with normal preoperative spirometry results (pre-bronchodilator forced expiratory volume in 1 s to forced vital capacity [FVC] ratio > 0.70 and FVC ≥ 80% of the predicted value) between January 2012 and December 2019 were retrospectively identified. Univariable and multivariable regression analyses were performed to assess risk factors for PPCs. The Kaplan-Meier method and log-rank test were used to analyze the relationship between ILAs and postoperative mortality. One-way analysis of variance was performed to assess the correlation between ILAs and hospital stay duration., Results: A total of 262 patients (median age, 73 [interquartile range, 71-76] years; 132 male) were evaluated. A multivariable logistic regression model revealed that, among several relevant risk factors, fibrotic ILAs independently predicted both overall PPCs (adjusted odds ratio [OR], 4.84; 95% confidence interval [CI], 1.35-17.38; p=0.016) and major PPCs (adjusted OR, 8.72; 95% CI, 1.71-44.38; p=0.009). Fibrotic ILAs were significantly associated with higher postoperative mortality and longer hospital stay (F=5.21, p=0.006)., Conclusion: Pretreatment fibrotic ILAs are associated with PPCs, higher postoperative mortality, and longer hospital stay.

Background and Aims: Currently there is no Food and Drug Administration-approved drug to treat NAFLD and NASH, the rates of which are increasing worldwide. Although NAFLD/NASH are highly complex and heterogeneous conditions, most pharmacotherapy pipelines focus on a single mechanistic target. Considering the importance of the gut-liver axis in their pathogenesis, we investigated the therapeutic effect of a long-acting dual agonist of glucagon-like peptide (GLP)-1 and GLP-2 receptors in mice with NAFLD/NASH., Approach and Results: C57BL/6J mice were fed a choline-deficient high-fat diet/high fructose and sucrose solution. After 16 weeks, mice were randomly allocated to receive vehicle, GLP1-Fc, GLP2-Fc, or GLP1/2-Fc fusion (GLP1/2-Fc) subcutaneously every 2 days for 4 weeks. Body weight was monitored, insulin/glucose tolerance tests were performed, feces were collected, and microbiome profiles were analyzed. Immobilized cell systems were used to evaluate direct peptide effect. Immunohistochemistry, quantitative PCR, immunoblot analysis, tunnel assay, and biochemical assays were performed to assess drug effects on inflammation, hepatic fibrosis, cell death, and intestinal structures. The mice had well-developed NASH phenotypes. GLP1/2-Fc reduced body weight, glucose levels, hepatic triglyceride levels, and cellular apoptosis. It improved liver fibrosis, insulin sensitivity, and intestinal tight junctions, and increased microvillus height, crypt depth, and goblet cells of intestine compared with a vehicle group. Similar effects of GLP1/2-Fc were found in in vitro cell systems. GLP1/2-Fc also changed microbiome profiles. We applied fecal microbiota transplantation (FMT) gain further insight into the mechanism of GLP1/2-Fc-mediated protection. We confirmed that FMT exerted an additive effect on GLP1-Fc group, including the body weight change, liver weight, hepatic fat accumulation, inflammation, and hepatic fibrosis., Conclusions: A long-acting dual agonist of GLP-1 and GLP-2 receptors is a promising therapeutic strategy to treat NAFLD/NASH., (© 2021 American Association for the Study of Liver Diseases.)

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., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: The incidence of bone metastases in non-small cell lung cancer (NSCLC) patients is about 30-40% and bone-related events can seriously affect quality of life. Immune checkpoint inhibitor (ICI) therapy has become the standard treatment for advanced NSCLC patients. However, the specific efficacy of ICIs in NSCLC patients with bone metastases remains unclear. The aim of the present study was to explore the prognosis of immunotherapy in this population and to find potential biomarkers., Methods: In this retrospective study, a total of 110 advanced NSCLC patients with bone metastases who received pembrolizumab therapy were enrolled. Patient characteristics; palliative bone radiotherapy or bone-targeted therapy; serum levels of lactate dehydrogenase (LDH), and the neutrophil-to-lymphocyte ratio (NLR) at baseline were assessed. The correlation of these factors with progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) was analyzed., Results: The ORR of the total population was 29.1%, and PFS and OS were 7.0 and 14.8 months, respectively. Fifty-eight patients (52.7%) received pembrolizumab treatment as first-line therapy, and 52 patients (47.3%) as second-line therapy or beyond [ORR: 41.4% vs. 15.4%, P=0.011; PFS: 9.0 vs. 4.0 months, P=0.004; OS: not reached (NR) vs. 11.5 months, P<0.0001]. Bone therapy, including palliative bone radiotherapy and bone-targeted therapy, increased the ORR (34.9% vs. 11.1%, P<0.0001) and prolonged PFS (8.5 vs. 2.0 months, P=0.002). Eastern Cooperative Oncology Group performance status score of 0-1 [OS: hazard ratio (HR) =0.117, P<0.0001] and first-line pembrolizumab therapy (OS: HR =0.372, P=0.004) were independent predictors of OS. Patients whose baseline serum LDH level was ≤240.5 IU/L (NR vs. 10.0 months, P<0.0001) or NLR ≤5.55 (NR vs. 18.0 months, P=0.039) showed longer OS., Conclusions: The efficacy of Pembrolizumab therapy is confirmed in advanced NSCLC patients with bone metastases, particularly when palliative bone radiotherapy or bone-targeted therapy is delivered. Baseline serum LDH level ≤240.5 IU/L and NLR ≤5.55 might predict the prognosis of patients with bone metastases from advanced NSCLC treated with immunotherapy., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-21-1033/coif). Dr. AA reports that he received personal fees for attending advisory from Bristol‐MyersSquibb, AstraZeneca, Roche, Pfizer, Merck Sharp and Dohme, Astella, Eli Lilly and Boehringer‐Ingelheim and received fees for speaking bureau for Eli Lilly, AstraZeneca, MSD for work performed outside of the current study. Dr. GLB has received consulting fees from AstraZeneca, and payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from AstraZeneca and Astellas. Dr. IJO has received research funding from Roche, and consulting fees from Roche, Ono, MSD, Pfizer, Boehringer-Ingelheim, AstraZeneca and Takeda. The other authors have no conflicts of interest to declare., (2022 Translational Lung Cancer Research. All rights reserved.)

Background: We investigated the clinical characteristics and treatment outcomes of Korean patients receiving first-line afatinib for advanced epidermal growth factor receptor mutation-positive ( EGFR m + ) non-small cell lung cancer (NSCLC) in a real-world setting., Methods: Electronic case reports were retrospectively reviewed from patients across 15 sites in South Korea. Outcome measures included baseline characteristics, overall response rate (ORR), time-to-treatment discontinuation (TTD), and overall survival (OS). Subgroups were: presence/absence of brain metastases at baseline, dose reductions, and baseline EGFR mutation category., Results: Among 422 patients, 39.8% had brain metastases and 59.0%/25.1%/10.0%/5.0% had Del19/L858R/compound/uncommon EGFR mutations at baseline. ORR was 62.6% overall; responses were observed across all EGFR mutation categories, including against compound mutations. Median TTD was 17.8 months; median OS was not reached (NR). Median TTD and OS were longer in patients without versus with brain metastases (TTD: 22.9 vs. 14.8 months, P=0.001; OS: NR vs. 40.3 months, P=0.0009) and patients with versus without dose reductions (TTD: 22.2 vs. 14.2 months, P=0.0004; OS: NR vs. 40.3 months, P=0.0117). Median OS was 30.5/37.7 months in patients receiving chemotherapy/osimertinib as subsequent therapy. The most common treatment-related adverse events (TRAEs; any grade/grade ≥3) were diarrhea (31.3%/8.5%) and rash (23.0%/8.1%). Overall, 34 patients (8.1%) discontinued afatinib due to AEs., Conclusions: Afatinib was well tolerated with no new safety signals, and efficacy was encouraging in Korean patients with EGFR m + NSCLC, including those with baseline brain metastases and/or uncommon EGFR mutations. AE management with dose reductions facilitated a long TTD, prolonging the chemotherapy-free period for many patients., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/tlcr-21-501). YCK reports receiving research grant and honorarium from AstraZeneca, research grant from Boehringer Ingelheim, and honorarium from Roche outside the submitted work. TWJ reports receiving honoraria and grants or funds from BI outside the submitted work. The other authors have no conflicts of interest to declare., (2021 Translational Lung Cancer Research. All rights reserved.)

Objective: The effectiveness of gamma knife radiosurgery (GKR) in the treatment of brain metastases is well established. The aim of this study was to evaluate the efficacy and safety of maximizing the radiation dose in GKR and the factors influencing tumor control in cases of small and medium-sized brain metastases from non-small cell lung cancer (NSCLC)., Methods: We analyzed 230 metastatic brain tumors less than 5 mL in volume in 146 patients with NSCLC who underwent GKR. The patients had no previous radiation therapy for brain metastases. The pathologies of the tumors were adenocarcinoma (n=207), squamous cell carcinoma (n=18), and others (n=5). The radiation doses were classified as 18, 20, 22, and 24 Gy, and based on the tumor volume, the tumors were categorized as follows : small-sized (less than 1 mL) and medium-sized (1-3 and 3-5 mL). The progression-free survival (PFS) of the individual 230 tumors and 146 brain metastases was evaluated after GKR depending on the pathology, Eastern Cooperative Oncology Group (ECOG) performance score (PS), tumor volume, radiation dose, and anti-cancer regimens. The radiotoxicity after GKR was also evaluated., Results: After GKR, the restricted mean PFS of individual 230 tumors at 24 months was 15.6 months (14.0-17.1). In small-sized tumors, as the dose of radiation increased, the tumor control rates tended to increase (p=0.072). In medium-sized tumors, there was no statistically difference in PFS with an increase of radiation dose (p=0.783). On univariate analyses, a statistically significant increase in PFS was associated with adenocarcinomas (p=0.001), tumors with ECOG PS 0 (p=0.005), small-sized tumors (p=0.003), radiation dose of 24 Gy (p=0.014), synchronous lesions (p=0.002), and targeted therapy (p=0.004). On multivariate analyses, an improved PFS was seen with targeted therapy (hazard ratio, 0.356; 95% confidence interval, 0.150-0.842; p=0.019). After GKR, the restricted mean PFS of brain at 24 months was 9.8 months (8.5-11.1) in 146 patients, and the pattern of recurrence was mostly distant within the brain (66.4%). The small and medium-sized tumors treated with GKR showed radiotoxicitiy in five out of 230 tumors (2.2%), which were controlled with medical treatment., Conclusion: The small-sized tumors were effectively controlled without symptomatic radiation necrosis as the radiation dose was increased up to 24 Gy. The medium-sized tumors showed potential for symptomatic radiation necrosis without signifcant tumor control rate, when greater than 18 Gy. GKR combined targeted therapy improved the tumor control of GKR-treated tumors.

Background: CD8 + tumor-infiltrating lymphocytes (TILs) comprise phenotypically and functionally heterogeneous subpopulations. Of these, effector memory CD45RA re-expressing CD8 + T cells (Temra) have been discovered and characterized as the most terminally differentiated subset. However, their exact ontogeny and physiological importance in association with tumor progression remain poorly understood., Methods: We analyzed primary tumors and peripheral blood samples from 26 patients with non-small cell lung cancer and analyzed their phenotypes and functional characteristics using flow cytometry, RNA-sequencing, and bioinformatics., Results: We found that tumor-infiltrating Temra (tilTemra) cells largely differ from peripheral blood Temra (pTemra), with distinct transcriptomes and functional properties. Notably, although majority of the pTemra was CD27 - CD28 - double-negative (DN), a large fraction of tilTemra population was CD27 + CD28 + double-positive (DP), a characteristic of early-stage, less differentiated effector cells. Trajectory analysis revealed that CD8 + TILs undergo a divergent sequence of events for differentiation into either DP or DN tilTemra. Such a differentiation toward DP tilTemra relied on persistent expression of CD27 and CD28 and was associated with weak T cell receptor engagement. Thus, a higher proportion of DP Temra was correlated with lower immunogenicity of tumor antigens and consequently lower accumulation of CD8 + TILs., Conclusions: These data suggest a complex interplay between CD8 + T cells and tumors and define DP Temra as a unique subset of tumor-specific CD8 + TILs that are produced in patients with relatively low immunogenic cancer types, predicting immunogenicity of tumor antigens and CD8 + TIL counts, a reliable biomarker for successful cancer immunotherapy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

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

Purpose: Although immune-checkpoint inhibitors have become a new therapeutic option for recurrent/metastatic non-small cell lung cancers (R/M-NSCLC), its clinical benefit in the real-world is still unclear., Methods: We investigated 1181 Korean patients with programmed death-1 ligand 1 (PD-L1)-positive [tumor proportion score (TPS) ≥ 10% by the SP263 assay or ≥ 50% by the 22C3 assay] R/M-NSCLC treated with pembrolizumab or nivolumab after failure of platinum-based chemotherapy., Results: The median age was 67 years, 13% of patients had ECOG-PS ≥ 2, and 27% were never-smokers. Adenocarcinoma was predominant (61%) and 18.1% harbored an EGFR activating mutation or ALK rearrangement. Pembrolizumab and nivolumab were administered to 51.3% and 48.7, respectively, and 42% received them beyond the third-line chemotherapy. Objective response rate (ORR) was 28.6%. Pembrolizumab group showed numerically higher ORR (30.7%) than the nivolumab group (26.4%), but it was comparable with that of the nivolumab group having PD-L1 TPS ≥ 50% (32.4%). Median progression-free survival (PFS) and overall survival (OS) were 2.9 (95% CI 0-27.9) and 10.7 months (95% CI 0-28.2), respectively. In multivariable analysis, concordance of TPS ≥ 50% in both PD-L1 assays and the development of immune-related adverse events (irAEs) were two significant predictors of better ORR, PFS, and OS. EGFR mutation could also predict significantly worse OS outcomes., Conclusion: The real-world benefit of later-line anti-PD1 antibodies was comparable to clinical trials in patients with R/M-NSCLC, although patients generally were more heavily pretreated and had poorer ECOG-PS. Concordantly high PD-L1 TPS ≥ 50% and development of irAE could independently predict better treatment outcomes, while EGFR mutation negatively affected OS.

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.