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A cardiopulmonary exercise test (CPET) is essential for lung resection. However, performing a CPET can be challenging. This study aimed to develop a machine learning model to estimate maximal oxygen consumption (VO2max) using data collected through a patch-type single-lead electrocardiogram (ECG) monitoring device in candidates for lung resection. This prospective, single-center study included 42 patients who underwent a CPET at a tertiary teaching hospital from October 2021 to July 2022. During the CPET, a single-lead ECG monitoring device was applied to all patients, and the results obtained from the machine-learning algorithm using the information extracted from the ECG patch were compared with the CPET results. According to the Bland–Altman plot of measured and estimated VO2max, the VO2max values obtained from the machine learning model and the FRIEND equation showed lower differences from the reference value (bias: −0.33 mL·kg−1·min−1, bias: 0.30 mL·kg−1·min−1, respectively). In subgroup analysis, the developed model demonstrated greater consistency when applied to different maximal stage levels and sexes. In conclusion, our model provides a closer estimation of VO2max values measured using a CPET than existing equations. This model may be a promising tool for estimating VO2max and assessing cardiopulmonary reserve in lung resection candidates when a CPET is not feasible. [ABSTRACT FROM AUTHOR]

Simple Summary: Monoclonal antibodies targeting the programmed death 1 (PD-1) receptor and its ligand (PD-L1) have demonstrated improved clinical response and survival in non-small cell lung cancer (NSCLC). Although extrinsic immunologic factors play important roles in the regulation of PD-L1 and PD-1, tumor intrinsic factors, including genetic alterations, epigenetic alterations, oncogenic and tumor suppressor signals, and transcription factors also play important roles in PD-L1 expression. There is an urgent need to investigate the intrinsic transcriptional profiles affecting the clinical response to PD-1 inhibitors in patients with non-small cell lung cancer. In our study, PD-1 inhibitor-associated intrinsic gene patterns were very different between lung adenocarcinoma and squamous cell carcinoma. In lung adenocarcinoma, the intrinsic gene signature was a very good predictive or prognostic biomarker. Our findings prove for the first time that an intrinsic gene signature is well predictive of responsiveness to PD-1 inhibitors in lung adenocarcinoma. Using a machine learning method, we investigated the intrinsic and extrinsic transcriptional profiles that affect the clinical response to PD-1 inhibitors in 57 patients with non-small cell lung cancer (NSCLC). Among the top 100 genes associated with the responsiveness to PD-1 inhibitors, the proportion of intrinsic genes in lung adenocarcinoma (LUAD) (69%) was higher than in NSCLC overall (36%) and lung squamous cell carcinoma (LUSC) (33%). The intrinsic gene signature of LUAD (mean area under the ROC curve (AUC) = 0.957 and mean accuracy = 0.9) had higher predictive power than either the intrinsic gene signature of NSCLC or LUSC or the extrinsic gene signature of NSCLC, LUAD, or LUSC. The high intrinsic gene signature group had a high overall survival rate in LUAD (p = 0.034). When we performed a pathway enrichment analysis, the cell cycle and cellular senescence pathways were related to the upregulation of intrinsic genes in LUAD. The intrinsic signature of LUAD also showed a positive correlation with other immune checkpoint targets, including CD274, LAG3, and PDCD1LG2 (Spearman correlation coefficient > 0.25). PD-1 inhibitor-related intrinsic gene patterns differed significantly between LUAD and LUSC and may be a particularly useful biomarker in LUAD. [ABSTRACT FROM AUTHOR]

Background: Textbook outcome (TO) has been introduced as a novel composite measure for lung cancer surgery. We investigated TO after lobectomy for early‐stage non‐small cell lung cancer (NSCLC) in a Korean tertiary hospital and its prognostic implications for overall survival and recurrence. Methods: Between January 2012 and December 2017, 418 consecutive patients who underwent lobectomy for clinical stages I and II NSCLC were identified and retrospectively reviewed. TO was defined as complete resection (negative resection margins and sufficient lymph node dissection), no 30‐day or in‐hospital mortality, no reintervention within 30 days, no readmission to the intensive care unit, no prolonged hospital stay (<14 days), no hospital readmission within 30 days, and no major complications. Propensity score matching analysis was performed to investigate the association between TO, medical costs, and long‐term outcomes. Results: Of 418 patients, 277 (66.3%) achieved TO. The most common events leading to TO failure were prolonged air leakage (n = 54, 12.9%) and prolonged hospital stay (n = 53, 12.7%). Male sex (odds ratio [OR] = 2.148, p = 0.036) and low diffusing capacity for carbon monoxide (OR = 0.986, p = 0.047) were significant risk factors for failed TO in multivariate analysis. In matched cohorts, achieving TO was associated with lower medical costs and better overall survival but not cancer recurrence. Conclusions: TO is associated with low medical cost and favorable overall survival; thus, surgical teams and hospitals should make efforts to improve the quality of care and achieve TO. [ABSTRACT FROM AUTHOR]

CKLF-like MARVEL transmembrane domain containing 6 (CMTM6) plays a crucial role in the stability of the programmed death-ligand 1 (PD-L1). However, there has been no previous study of CMTM6 in non-small cell lung cancer (NSCLC) and its association with PD-L1 has not been confirmed. The aim of this study was to investigate the expression of CMTM6 and PD-L1 and to confirm their predictive roles for anti-PD-1 therapy in non-small cell lung cancer. CMTM6 and PD-L1 immunohistochemical expressions were evaluated in 35 advanced, treatment-refractory NSCLC patients who received PD-1 inhibitor therapy. The correlation between CMTM6 and PD-L1 expression was also determined based on immunohistochemistry and RNA-sequencing data obtained from The Cancer Genome Atlas (TCGA) database. CMTM6 expression was positively correlated with PD-L1 expression in immunohistochemical data (Pearson's r = 0.342 and p =.044). A positive correlation was also identified in the mRNA expression data. Using receiver operating characteristic curves, the levels of CMTM6 and PD-L1 expression which provided the best distinguishing point between responder versus non-responder to PD-1 inhibitors were 70 and 75 H-scores, respectively. The patients in the PD-1 inhibitor responder group had higher CMTM6 expressions in univariate logistic regression analysis (odds ratio (OR) = 5.333, p =.037). However, PD-L1 expression was not associated with response to PD-1 inhibitor (p =.288). In multivariate analysis, CMTM6 was also found to be an independent predictor of the response to PD-1 inhibitors (OR = 6.226, p =.032). CMTM6 expression can be a promising predictor useful for therapeutic decision-making regarding PD-1 inhibitors. [ABSTRACT FROM AUTHOR]

View large Download slide View large Download slide OBJECTIVES Anastomotic leakage after oesophageal cancer surgery is a serious complication. The purpose of this study was to evaluate the possibility of anastomotic leakage by repeatedly measuring amylase levels in the fluid obtained from the drainage tube inserted at the cervical anastomotic site. METHODS Ninety-nine patients who underwent oesophagectomy and cervical oesophagogastrostomy between April 2014 and March 2017 were retrospectively reviewed. A drainage tube was placed at the anastomotic site, and amylase levels were measured daily from postoperative day (POD) 1 until oral feeding or confirmation of anastomotic leakage. The amylase levels were analysed with a linear mixed model. RESULTS The mean age of the patients was 64.9 ± 9.0 years, and there were 89 (89%) male patients. Almost all pathologies (92%) were squamous cell carcinomas. The anastomotic methods were as follows: 63 (63%) circular stapled, 33 (33%) hand-sewn and 3 (3%) semistapled. Anastomotic leakage was confirmed in 10 (10%) patients. The amylase levels increased until POD 2 in both the leakage and non-leakage groups, but the levels subsequently decreased in the non-leakage group, whereas the levels peaked on POD 3 in the leakage group. On performing the linear mixed model analysis, anastomotic leakage was significantly associated with the trends in postoperative amylase levels in the drainage tube (P  < 0.001). Trends in the serum C-reactive protein levels and white blood cell count were not significantly associated with anastomotic leakage. CONCLUSIONS Amylase level trends measured in the cervical drain fluid can be a useful indicator of anastomotic leakage after cervical oesophagogastrostomy. [ABSTRACT FROM AUTHOR]

OBJECTIVES Elevated serum carcinoembryonic antigen (CEA) has been reported in lung transplant candidates with idiopathic pulmonary fibrosis, but its association with waitlist mortality is not known. In this study, we evaluated the ability of the serum CEA level to predict waitlist mortality in these patients. METHODS Fifty-nine patients with idiopathic pulmonary fibrosis who were enrolled as lung transplant candidates between January 2004 and December 2014 were retrospectively reviewed. Serum CEA was measured as part of routine evaluation. RESULTS Thirty-seven of the 59 patients underwent lung transplantation with a median waiting time of 91 days. Twenty-two patients died while on the waitlist. In univariable analysis, 6-min walking distance, lung allocation score and serum CEA level were identified as being significant prognostic factors. We constructed 2 multivariable models using forced vital capacity, CEA and 6-min walking distance (Model 1, concordance index 0.758) and CEA and lung allocation score (Model 2, concordance index 0.689). CEA was independently associated with waitlist mortality in Model 1 [hazard ratio 1.074, 95% confidence interval (CI)_ 1.004–1.137] and in Model 2 (hazard ratio 1.065, 95% CI 1.008–1.126). The cut-off values that best discriminated 30-day mortality and 6-month mortality by receiver-operating characteristic curve analysis were 8.55 ng/ml and 4.50 ng/ml, respectively. CONCLUSIONS There was a significant association between elevated serum CEA and increased risk of mortality in waitlisted transplant candidates with idiopathic pulmonary fibrosis. [ABSTRACT FROM AUTHOR]

In this study, we examined the repeatability of computed tomography (CT) lung volume measurements in healthy individuals and patients with obstructive and restrictive lung diseases. To do this, we retrospectively enrolled 200 healthy individuals (group 1), 100 patients with obstructive lung disease (group 2), and 100 patients with restrictive lung disease (group 3) who underwent two consecutive chest CT scans within a 1-year period. The CT lung volume was measured using a threshold-based, three-dimensional auto-segmentation technique at a default range from –200 to –1024 HU. The within-subject standard deviation, repeatability coefficient, within-subject coefficient variability, and intraclass correlation coefficient were evaluated. No significant differences were identified between the two consecutive CT lung volume measurements in any of the groups (p> 0.05). The within-subject standard deviations for groups 1, 2, and 3 were 441.1, 387.0, and 288.6, respectively, while the repeatability coefficients were 1222.6, 1072.6, and 800.1, respectively. The within-subject coefficient variabilities for groups 1, 2, and 3 were 0.097, 0.083, and 0.090, respectively, while the intraclass correlation coefficients were 0.818, 0.881, and 0.910, respectively. The two CT lung volume measurements showed excellent agreement in healthy individuals and patients with obstructive or restrictive lung disease. However, the repeatability was lower in healthy individuals than it was in patients with lung diseases. [ABSTRACT FROM AUTHOR]

Simple Summary: It is important to be able to predict brain metastasis in lung adenocarcinoma patients; however, research in this area is still lacking. Much of the previous work on tumor microenvironments in lung adenocarcinoma with brain metastasis concerns the tumor immune microenvironment. The importance of the tumor nonimmune microenvironment (extracellular matrix (ECM), epithelial–mesenchymal transition (EMT) feature, and angiogenesis) has been overlooked with regard to brain metastasis. We evaluated tumor nonimmune-microenvironment-related gene expression signatures that could predict brain metastasis after the surgical resection of lung adenocarcinoma using a machine learning approach. We identified a tumor nonimmune-microenvironment-related 17-gene expression signature, and this signature showed high brain metastasis predictive power in four machine learning classifiers. The immunohistochemical expression of the top three genes of the 17-gene expression signature yielded similar results to NanoString tests. Our tumor nonimmune-microenvironment-related gene expression signatures are important biological markers that can predict brain metastasis and provide patient-specific treatment options. Using a machine learning approach with a gene expression profile, we discovered a tumor nonimmune-microenvironment-related gene expression signature, including extracellular matrix (ECM) remodeling, epithelial–mesenchymal transition (EMT), and angiogenesis, that could predict brain metastasis (BM) after the surgical resection of 64 lung adenocarcinomas (LUAD). Gene expression profiling identified a tumor nonimmune-microenvironment-related 17-gene expression signature that significantly correlated with BM. Of the 17 genes, 11 were ECM-remodeling-related genes. The 17-gene expression signature showed high BM predictive power in four machine learning classifiers (areas under the receiver operating characteristic curve = 0.845 for naïve Bayes, 0.849 for support vector machine, 0.858 for random forest, and 0.839 for neural network). Subgroup analysis revealed that the BM predictive power of the 17-gene signature was higher in the early-stage LUAD than in the late-stage LUAD. Pathway enrichment analysis showed that the upregulated differentially expressed genes were mainly enriched in the ECM–receptor interaction pathway. The immunohistochemical expression of the top three genes of the 17-gene expression signature yielded similar results to NanoString tests. The tumor nonimmune-microenvironment-related gene expression signatures found in this study are important biological markers that can predict BM and provide patient-specific treatment options. [ABSTRACT FROM AUTHOR]

Huntingtin-interacting protein 1-related protein (HIP1R) plays an important role in the regulation of programmed death-ligand 1 (PD-L1). The aim of this study was to investigate the expression of HIP1R and confirm its predictive or prognostic roles in anti-PD-1 therapy in nonsmall cell lung cancer (NSCLC) patients. HIP1R and PD-L1 immunohistochemical expression was examined in 52 refractory advanced NSCLC patients treated with anti-PD-1 inhibitors. We performed gene set enrichment analysis (GSEA) to detect HIP1R-specific gene sets. Patients in the PD-1 inhibitor responder group had lower HIP1R expression by univariate logistic regression analysis (odds ratio (OR) = 0.235, p = 0.015) and multivariate logistic regression analysis (OR = 0.209, p = 0.014). Patients with high HIP1R expression had poorer progression-free survival (PFS) than patients with low HIP1R expression in univariate analysis (p = 0.037) and multivariate Cox analysis (hazard ratio = 2.098, p = 0.019). The web-based mRNA dataset also showed that high HIP1R expression correlated with inferior overall survival in lung adenocarcinoma (p = 0.026). GSEA revealed that HIP1R levels correlate with a set of genes that reflect PD-L1-related immune pathways. HIP1R expression may be a promising predictor for determination of patient responses to anti-PD-1 treatment. [ABSTRACT FROM AUTHOR]

Brain metastasis (BM) is a prevalent prognostic event in the development of lung adenocarcinoma (LUAD) with a poor prognosis. Alterations in gene or protein expression during various phases of BM remain unclear. We performed gene expression and pathway analyses using a metastasis-related gene panel on 12 lung tissues from patients with confirmed BM, 12 lung tissues from patients without BM, and 12 matched brain tissues from patients with confirmed BM during follow-up after LUAD surgery. The results of the gene expression analysis were validated by immunohistochemistry. Cell interaction-related pathways (such as focal adhesion, extracellular matrix-receptor interaction, and proteoglycans in cancer) showed the greatest differences among the three groups. Expression of the cell interaction-related pathway was highest in the lung sample of BM group and lowest in the matched brain tissue. Using a machine learning model, a signature of 20 genes from cell interaction-related pathways accurately predicted BM (area under the curve score of 0.792 and an accuracy rate of 0.875). Immunohistochemical analysis showed higher expression of proteins associated with cell interaction-related genes and a mesenchymal phenotype in the lung sample of BM group than in those without BM or matched brain tissue. LUAD acquires the characteristics of the cell interaction-related pathway that leads to the development of BM, with a significant decrease in expression following brain colonization. [ABSTRACT FROM AUTHOR]

Background: Clinical sequencing data should be shared in order to achieve the sufficient scale and diversity required to provide strong evidence for improving patient care. A distributed research network allows researchers to share this evidence rather than the patient-level data across centers, thereby avoiding privacy issues. The Observational Medical Outcomes Partnership (OMOP) common data model (CDM) used in distributed research networks has low coverage of sequencing data and does not reflect the latest trends of precision medicine.Objective: The aim of this study was to develop and evaluate the feasibility of a genomic CDM (G-CDM), as an extension of the OMOP-CDM, for application of genomic data in clinical practice.Methods: Existing genomic data models and sequencing reports were reviewed to extend the OMOP-CDM to cover genomic data. The Human Genome Organisation Gene Nomenclature Committee and Human Genome Variation Society nomenclature were adopted to standardize the terminology in the model. Sequencing data of 114 and 1060 patients with lung cancer were obtained from the Ajou University School of Medicine database of Ajou University Hospital and The Cancer Genome Atlas, respectively, which were transformed to a format appropriate for the G-CDM. The data were compared with respect to gene name, variant type, and actionable mutations.Results: The G-CDM was extended into four tables linked to tables of the OMOP-CDM. Upon comparison with The Cancer Genome Atlas data, a clinically actionable mutation, p.Leu858Arg, in the EGFR gene was 6.64 times more frequent in the Ajou University School of Medicine database, while the p.Gly12Xaa mutation in the KRAS gene was 2.02 times more frequent in The Cancer Genome Atlas dataset. The data-exploring tool GeneProfiler was further developed to conduct descriptive analyses automatically using the G-CDM, which provides the proportions of genes, variant types, and actionable mutations. GeneProfiler also allows for querying the specific gene name and Human Genome Variation Society nomenclature to calculate the proportion of patients with a given mutation.Conclusions: We developed the G-CDM for effective integration of genomic data with standardized clinical data, allowing for data sharing across institutes. The feasibility of the G-CDM was validated by assessing the differences in data characteristics between two different genomic databases through the proposed data-exploring tool GeneProfiler. The G-CDM may facilitate analyses of interoperating clinical and genomic datasets across multiple institutions, minimizing privacy issues and enabling researchers to better understand the characteristics of patients and promote personalized medicine in clinical practice. [ABSTRACT FROM AUTHOR]

Background/aim: MicroRNAs (miRNAs) regulate programmed cell death ligand 1 (PD-L1) and play a crucial role in tumor immune response. However, the relationship between miRNA expression patterns and PD-L1 remains unclear in both lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). We investigated PD-L1-related miRNAs that can predict treatment response in patients treated with PD-L1/PD-1 inhibitors., Patients and Methods: We selected miRNAs that were correlated with PD-L1 expression within the LUAD and LUSC datasets obtained from The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC). We validated whether the miRNA profile could be used to predict the prognosis of patients treated with PD-L1/PD-1 inhibitors., Results: Based on four public datasets, we selected 66 and 23 miRNAs associated with PD-L1 expression in LUAD and LUSC, respectively. From the above miRNAs, we identified 5 miRNAs in LUSC and 1 miRNA in LUAD that could predict the response to PD-L1/PD-1 inhibitors in a validation set of patients treated with PD-L1/PD-1 inhibitors. In LUSC, the miRNA profile exhibited a high predictive capability for the response to PD-L1/PD-1 treatment [area under the curve (AUC)=0.963] and accurately predicted prognosis (p=0.031). In LUAD, the miRNA profile was relatively less predictive than in LUSC (AUC=0.691 and p=0.213). Additionally, we observed variations in the PD-L1-associated miRNA profiles, as well as in the associated pathways, between LUAD and LUSC., Conclusion: The PD-L1-associated miRNA profile may predict treatment response in LUSC patients treated with PD-L1/PD-1 inhibitors and help select the PD-L1/PD-1 inhibitor treatment group., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Ex vivo lung perfusion (EVLP) is a useful technique for evaluating and repairing donor lungs for transplantation. However, studies examining the effects of perfusate temperature on graft function are limited. Thus, this study aimed to examine these effects during EVLP on ischemic-reperfusion injury in the donor lung., Methods: Twenty-four male Sprague-Dawley rats were randomly divided into three groups, as follows: no treatment (sham group, n=5), normothermic EVLP (37 °C, n=5), and subnormothermic EVLP (30 °C, n=5). Lung function analyses, including oxygen capacity (OC), compliance, and pulmonary vascular resistance (PVR), were performed hourly during EVLP. Further, after 4 h of EVLP, histological evaluation of the right lobe was performed using the lung injury severity (LIS) scale. The expression levels of inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-18 were evaluated. Metabolomic analysis of left lung tissues was conducted using capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS) after 4 h of EVLP in the EVLP groups and after 1 h of cold preservation in the sham group., Results: Compared with those in the normothermic group, in the subnormothermic group, functional parameters during EVLP and subsequent histologic results were significantly superior, expression levels of inflammatory cytokines such as TNF-α, IL-1β, IL-6, and IL-18 were significantly lower, and glycolytic activity was significantly decreased. Furthermore, expression levels of mammalian target of rapamycin complex (mTORC), hypoxia-inducible factor (HIF) 1α, and nucleotide-binding domain, leucine-rich-containing family pyrin domain containing 3 (NLRP3) and its effector caspase-1 were significantly lower in the subnormothermic group than in the normothermic group., Conclusions: EVLP with subnormothermic perfusion improves lung graft function by reducing the expression of pro-inflammatory cytokines and glycolytic activity during EVLP. Additionally, EVLP can be a useful target for the improvement of graft function after transplantation., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1809/coif). The authors have no conflicts of interest to declare., (2024 Journal of Thoracic Disease. All rights reserved.)

Recent studies have indicated that RRM2 plays a crucial part in the tumor immune microenvironment. According to the expression of RRM2, we evaluated immune cell infiltration, immunotherapy biomarkers, and the expression of immune checkpoint molecules in four lung adenocarcinoma (LUAD) datasets. We employed the Tumor Immune Dysfunction and Exclusion (TIDE) and CIBERSORTx algorithms to examine the patterns of immune cell distribution and evaluate the responses to anti-programmed death protein-1/programmed death ligand-1 (PD-1/PD-L1) therapy in three publicly available LUAD datasets. These findings were corroborated using a validation group comprising patients who received treatment with PD-1/PD-L1 inhibitors. Additionally, we conducted experiments using LUAD cell lines to investigate how RRM2 affects the expression of PD-L1. In comparison to the low RRM2 group, the high RRM2 group exhibited a high interferon gamma signature, high T-cell-inflamed signature, high CD274 expression, high CD8+ T cell levels, low cancer-associated fibroblasts, and low M2 macrophages, according to TIDE analysis in the three LUAD datasets. Analysis of the three LUAD datasets using CIBERSORTx confirmed a positive correlation between RRM2 and CD8+ T cells, and this finding was validated by immunohistochemistry in a separate validation set. In the three LUAD datasets without PD-1/PD-L1 inhibitor treatment, higher RRM2 expression was associated with a poorer prognosis. However, in the LUAD dataset treated with PD-1/PD-L1 inhibitors, higher RRM2 expression was associated with better prognosis. In the three datasets, the high-RRM2 group exhibited higher expression of inhibitory immune checkpoint molecules. In a LUAD cell line study, we discovered that RRM2 regulates PD-L1 expression through the ANXA1/AKT pathway. The expression of RRM2 shows promise as a predictive biomarker for PD-1/PD-L1 inhibitors in LUAD patients, and it may represent a new target to overcome resistance to PD-L1/PD-1 therapies., Competing Interests: None., (AJCR Copyright © 2023.)

Background: We examined the distributions of 22 immune cell types and the responses to PD-1/PD-L1 inhibitors according to EGFR mutation profile, in three independent datasets of lung adenocarcinoma (LUAD)., Methods: We used CIBERSORTx to analyze the distributions of immune cells, and tumor immune dysfunction and exclusion (TIDE) or tumor mutation burden (TMB) to analyze responses to anti-PD-1/PD-L1 therapy, in two public LUAD datasets. The results were verified with a validation set that included patients treated with PD-1/PD-L1 inhibitors., Results: Compared to EGFR mutants, EGFR wild-type carcinomas had higher numbers of CD8+ T cells, CD4 memory activated T cells and neutrophils, and lower numbers of resting dendritic cells and resting mast cells, in two of the datasets. In our subgroup analyses, CD8+ T cells and CD4 memory activated T cells were more numerous in EGFR rare variants than in wild-types, L858R mutants, and exon 19 deletion mutants. In our TIDE or TMB analyses, EGFR rare variants were predicted to respond better to PD-1/PD-L1 inhibitors than wild-types, L858R mutants, and exon 19 deletion mutants. In the validation set verified by immunohistochemical staining, levels of CD8+ T cells in the EGFR rare variant or wild-type groups were significantly higher than in the EGFR L858R and exon 19 deletion groups. In patients treated with PD-1/PD-L1 inhibitors, the survival rates of patients with EGFR wild-type and rare mutant carcinomas were higher than those with L858R and exon 19 deletion carcinomas., Conclusion: The EGFR rare mutation form of LUAD shows a higher immune activation state compared to wild-type, L858R, and exon 19 deletion variants, indicating it as a potential target for PD-1/PD-L1 inhibitor therapy., 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 Koh, Park, Jung, Han, Haam and Lee.)

Background: Pneumonia caused by severe acute respiratory syndrome coronavirus 2 can cause acute respiratory distress syndrome, often requiring prolonged mechanical ventilation and eventually tracheostomy. Both procedures occur in isolation units where personal protective equipment is needed. Additionally, the high bleeding risk in patients with extracorporeal membrane oxygenation (ECMO) places a great strain on surgeons. We investigated the clinical characteristics and outcomes of percutaneous dilatational tracheostomy (PDT) in patients with coronavirus disease 2019 (COVID-19) supported by ECMO, and compared the outcomes of patients with and without ECMO., Methods: This retrospective, single-center, observational study included patients with severe COVID-19 who underwent elective PDT (n=29) from April 1, 2020, to October 31, 2021. The patients were divided into ECMO and non-ECMO groups. Data were collected from electronic medical records at Ajou University Hospital in Suwon, Korea., Results: Twenty-nine COVID-19 patients underwent PDT (24 men [82.8%] and 5 women [17.2%]; median age, 61 years; range, 26-87 years; interquartile range, 54-71 years). The mean procedure time was 17±10.07 minutes. No clinically or statistically significant difference in procedure time was noted between the ECMO and non-ECMO groups (16.35±7.34 vs. 18.25±13.32, p=0.661). Overall, 12 patients (41.4%) had minor complications; 10 had mild subdermal bleeding from the skin incision, which was resolved with local gauze packing, and 2 (6.9%) had dislodgement. No healthcare provider infection was reported., Conclusion: Our PDT approach is safe for patients and healthcare providers. With bronchoscopy assistance, PDT can be performed quickly and easily even in isolation units and with acceptable risk, regardless of the hypo-coagulable condition of patients on ECMO.

Using a machine learning method, we investigated the intrinsic and extrinsic transcriptional profiles that affect the clinical response to PD-1 inhibitors in 57 patients with non-small cell lung cancer (NSCLC). Among the top 100 genes associated with the responsiveness to PD-1 inhibitors, the proportion of intrinsic genes in lung adenocarcinoma (LUAD) (69%) was higher than in NSCLC overall (36%) and lung squamous cell carcinoma (LUSC) (33%). The intrinsic gene signature of LUAD (mean area under the ROC curve (AUC) = 0.957 and mean accuracy = 0.9) had higher predictive power than either the intrinsic gene signature of NSCLC or LUSC or the extrinsic gene signature of NSCLC, LUAD, or LUSC. The high intrinsic gene signature group had a high overall survival rate in LUAD (p = 0.034). When we performed a pathway enrichment analysis, the cell cycle and cellular senescence pathways were related to the upregulation of intrinsic genes in LUAD. The intrinsic signature of LUAD also showed a positive correlation with other immune checkpoint targets, including CD274, LAG3, and PDCD1LG2 (Spearman correlation coefficient > 0.25). PD-1 inhibitor-related intrinsic gene patterns differed significantly between LUAD and LUSC and may be a particularly useful biomarker in LUAD.

Background: YTH domain-containing family protein 1 (YTHDF1) or YTHDF2 play crucial roles in cancer immunotherapy. We examine the expression of YTHDF1, YTHDF2, CD8, CD4, and FOXP3 to identify their prognostic or predictive role for PD-1/PD-L1 inhibitor in non-small cell lung cancer (NSCLC)., Methods: Immunohistochemical expression of YTHDF1, YTHDF2, CD8, CD4, and FOXP3 was investigated in 266 patients not receiving PD-1/PD-L1 inhibitors and in 59 patients receiving PD-1/PD-L1 inhibitors. Immunohistochemical results were verified using mRNA dataset obtained from The Cancer Genome Atlas (TCGA) database., Results: Immunohistochemical expression of YTHDF1 or YTHDF2 was negatively associated with CD8- and CD4-positive T cells; however, the same expression was positively associated with FOXP3-positive T cells. YTHDF1 or YTHDF2 mRNA expression was also negatively associated with CD8- and CD4-positive T cells. Gene set enrichment analysis revealed that low YTHDF1 was related to immune hot tumor gene sets. Expression of YTHDF1 or YTHDF2 was negatively associated with expression of most immune checkpoints. YTHDF1 and YTHDF2 were predictive markers of response to PD-1/PD-L1 inhibitors. YTHDF1 or YTHDF2 expression was associated with better prognosis. YTHDF1 has an immune hot profile in both cell types, whereas YTHDF2 is only seen in adenocarcinoma., Conclusion: Low YTHDF1 or YTHDF2 reflects an immune hot tumor signature and may serve as a predictor or prognostic marker., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Koh, Han, Haam and Lee.)

In lung transplantation surgery, the pulmonary veins are anastomosed by connecting each atrium of the donor and recipient. However, occasionally the recipient's left atrium is not suitable for anastomosis for various reasons. In these cases, several techniques for atrial anastomosis have been introduced, but these are somewhat complicated for an inexperienced surgeon. Here, we propose a new atrial anastomosis technique that is easier and safer than previously introduced techniques.

Ex vivo lung perfusion (EVLP) is a technique that enables active metabolism of the lung by creating an environment similar to that inside the body, even though the explanted lungs are outside the body. The EVLP system enables the use of lung grafts that do not satisfy the acceptance criteria for lung transplantation (LTx) by making it possible to evaluate the function of the lung grafts and repair lungs in poor condition, thereby reducing the waiting time of patients requiring LTx and consequently mortality.

The shortage of donor lungs has become a serious obstacle to implementing lung transplantation (LTx). Donation after circulatory death (DCD) donors are among the several donor pools utilized to overcome the problem posed by the shortage of donation after brain death (DBD) donors. The active use of DCD donors is expected to significantly reduce mortality on the waiting list for LTx, as LTx from DCD donors has comparable outcomes to LTx from DBD donors. Further studies on efforts to shorten the warm ischemic time and use uncontrolled DCD are required.

Purpose: End-stage lung diseases result in anatomical changes of the thoracic cavity. However, very few studies have assessed changes in the thoracic cavity after lung transplantation (LTx). This study aimed to evaluate the relationships between thoracic cavity volume (TCV) changes after LTx and underlying lung disease., Methods: We reviewed 89 patients who underwent a pre-LTx pulmonary function test (PFT), chest computed tomography (CT) scan, and 1-year follow-up CT after LTx. These patients were classified into two groups according to pre-LTx PFT as follows: obstructive group [forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio < 70%] and restrictive group (FEV1/FVC ratio > 70%). We measured TCV using CT scan before and at 1 year after LTx and compared the TCV change in the two groups., Results: In the restrictive group, TCV increased after LTx (preop: 2,347.8 ± 709.5 mL, 1-year postop: 3,224.4 ± 919.0 mL, p < 0.001). In contrast, in the obstructive group, it decreased after LTx (preop: 4,662.9 ± 1,296.3 mL, 1-year postop: 3,711.1 ± 891.7 mL, p < 0.001). We observed that restrictive lung disease, taller stature, lower body mass index, and larger donor lung were independently associated with increased TCV after LTx., Conclusion: The disease-specific chest remodeling caused by restriction and hyperinflation is at least, in part, reversible. After LTx, the chest remodeling appears to occur in the opposite direction to the disease-specific remodeling caused by the underlying lung disease in recipients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yu, Park, Paik, Lee, You, Shin, Jung and Haam.)

Background: Patients with high-risk (HR) operable non-small cell lung cancer (NSCLC) may have unique prognostic factors. This study aimed to evaluate surgical outcomes in HR patients and to investigate prognostic factors in HR patients versus standard-risk (SR) patients., Methods: In total, 471 consecutive patients who underwent curative lung resection for NSCLC between January 2012 and December 2017 were identified and reviewed retrospectively. Patients were classified into HR (n=77) and SR (n=394) groups according to the American College of Surgeons Oncology Group criteria (Z4099 trial). Postoperative complications were defined as those of grade 2 or higher by the Clavien-Dindo classification., Results: The HR group comprised more men and older patients, had poorer lung function, and had more comorbidities than the SR group. The patients in the HR group also experienced more postoperative complications (p≤0.001). More HR patients died without disease recurrence. The postoperative complication rate was the only significant prognostic factor in multivariable Cox regression analysis for HR patients but not SR patients. HR patients without postoperative complications had a survival rate similar to that of SR patients., Conclusion: The overall postoperative survival of HR patients with NSCLC was more strongly affected by postoperative complications than by any other prognostic factor. Care should be taken to minimize postoperative complications, especially in HR patients.

Video-assisted thoracic surgery (VATS) for lobectomy or segmentectomy is considered a favorable alternative to thoracotomy because of its usefulness and safety; it reduces postoperative pain, lowers morbidity, and shortens the hospital stay. However, despite these advantages of VATS, it has been difficult to perform VATS pneumonectomy due to the high morbidity and mortality rate of pneumonectomy. Recently, as VATS techniques have been developed and the usefulness of VATS pneumonectomy has continued to be reported, the frequency of VATS pneumonectomy is gradually increasing at large-volume centers. This article describes VATS pneumonectomy with a focus on the surgical technique.

Background: Lung adenocarcinoma (LUAD) with brain metastasis (BM) occurs frequently and has a poor prognosis. In this study, we aimed to assess the correlation between gene expression signatures and the development of BM after surgical resection of LUAD., Methods: We analyzed the immune-related gene expression profiles of 72 LUADs with and without BM after surgery and verified them using NanoString method and immunohistochemistry (IHC). We matched the Tumor, Node, Metastasis (TNM) stage in the groups with and without BM to minimize the effect of TNM stage. Pathway enrichment studies were also performed., Results: In the NanoString results, we identified 11 upregulated immune-related gene signature that correlated specifically with BM in the discovery and validation sets [area under the curve (AUC) =0.750 and 0.787, respectively]. The discovery set achieved 94% sensitivity and 62% specificity and the validation set displayed 100% sensitivity and 50% specificity. Eight out of the 11 genes were verified by IHC and had profiles similar to the gene expression profile results (AUC =0.844 for the discovery set and AUC =0.795 for the validation set). Subgroup analysis revealed that 11 immune-related gene signature enabled prediction of BM at all TNM stages. There were no differences in the 11 immune-related gene expression signatures between the primary LUAD samples and the matched brain samples. Pathway enrichment analysis revealed that the cytokine-cytokine receptor interaction pathway was closely correlated with BM., Conclusions: The 11 identified immune-related gene expression signatures may be potentially clinically useful predictors for BM and can provide patient-specific treatment options., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at: http://dx.doi.org/10.21037/tlcr-20-1056). The authors have no conflicts of interest to declare., (2021 Translational Lung Cancer Research. All rights reserved.)

Regulatory T cells (Treg) are targeted for cancer immunotherapy because they suppress antitumor immunity. Although the importance of neuropilin-1 (NRP1) in the stability and function of intratumoral Tregs is well-documented, targeting of NRP1 + Tregs for anticancer immunotherapy has not been well explored. Here, we found that an NRP1 antagonist [Fc(AAG)-TPP11], generated by fusion of the NRP1-specific binding peptide TPP11 with the C-terminus of an effector function-deficient immunoglobulin Fc(AAG) variant, inhibits intratumoral NRP1 + Treg function and stability. Fc(AAG)-TPP11 triggered the internalization of NRP1, reducing its surface expression on Tregs and thereby inhibiting the suppressive function of Tregs. In two murine syngeneic tumor models, Fc(AAG)-TPP11 retarded tumor growth, comparable with a Treg-depleting anti-CTLA-4 antibody, without noticeable toxicity. Fc(AAG)-TPP11 inhibited NRP1-dependent Treg function, inducing unstable intratumoral Tregs, with reduced expression of Foxp3 and enhanced production of IFNγ, which subsequently increased the functionality and frequency of intratumoral CD8 + T cells. We also observed selective expression of NRP1 on Tregs isolated from human tumors, but not from the blood of healthy donors and patients with cancer, as well as ex vivo inhibition of intratumoral NRP1 + Treg function by Fc(AAG)-TPP11. Our results suggest that the NRP1 antagonist Fc(AAG)-TPP11 has therapeutic potential for the inhibition of intratumoral NRP1 + Tregs with limited unfavorable effects on peripheral Tregs., (©2019 American Association for Cancer Research.)

Background: Direct insertion of a double-lumen endobronchial tube (DLT) over a fibreoptic bronchoscope (FOB) is considered more difficult and traumatic than that of a single-lumen tube (SLT). We hypothesized that time to intubation over an FOB using a silicone left DLT would be non-inferior to that using a polyvinyl chloride (PVC) SLT., Methods: Eighty patients were enrolled in this open-label, randomized controlled, non-inferiority trial. Patients were randomly allocated to fibreoptic tracheal intubation with either a silicone DLT or PVC SLT (DLT and SLT groups, respectively). Time to tracheal intubation [time to insertion of FOB plus railroading (advancement over the FOB) time]; total time for correct tube and bronchial blocker positioning; difficulty of railroading; and the incidence of sore throat, swallowing difficulty, and hoarseness were compared between groups., Results: The median time to intubation over the FOB was 20 s in the DLT group and 23 s in the SLT group. The upper limit of the confidence interval of this difference was below the non-inferiority margin of 10 s (median difference: -2 s; 95% confidence interval: -4 to 0 s). Railroading time was significantly shorter in the DLT group than in the SLT group (median time: 10 vs . 11 s; median difference: -1 s; 95% confidence interval: -3 to 0 s; P=0.03). Railroading over the FOB (rated on a four-point scale) was less difficult in the DLT group than in the SLT group (P<0.01)., Conclusions: Tracheal intubation using an FOB can be achieved at least as fast using the silicone DLT as using the PVC SLT. The silicone DLT exhibited superior railroading performance to the PVC SLT., Competing Interests: Conflicts of Interest: This study was presented as a poster presentation at the 12th Asian Society of Cardiothoracic Anaesthesiologists, Scientific meeting at Hong Kong, in 2017.

Background: Although a decrease in the psoas muscle area (PMA) has been reported as a risk factor for survival after esophagectomy in esophageal cancer, no previous studies have focused on the change in the PMA after surgery. We investigated the prognostic role of PMA changes in patients with surgically treated esophageal cancer., Methods: Fifty-eight patients with esophageal cancer who underwent surgical resection and complete lymph node dissection were reviewed retrospectively. The PMA was measured at the level of the L3 vertebrae on preoperative and one-year postoperative follow-up computed tomography images. The percentage change of the PMA was calculated as follows: delta (%) = (postoperative PMA - preoperative PMA) / (preoperative PMA × 100)., Results: The study patients included 54 (93.1%) males and 4 females (mean age, 60.59±9.16 years), of whom 17 (29.3%) were pathological Stage I, 18 (31.0%) were Stage II, and 23 (39.7%) were Stage III. The mean change of the PMA was -10.17% and the postoperative PMA was decreased significantly compared with the preoperative PMA (P<0.001). The PMA was increased in 13 (22.4%) patients, whereas it was decreased in 45 (77.6%). Multivariate analysis revealed that the change of the PMA (hazard ratio, HR =0.688; P=0.001) and the pathologic stage (Stage III vs . Stage I, HR =3.388; P=0.016) were risk factors for overall survival (OS). The 3-year OS in patients with a PMA decrease of more than 10%, and those with a PMA decrease of less than 10% or an increase, were 18.9% and 59.5%, respectively (P=0.049)., Conclusions: The decrease in the PMA had a negative prognostic effect on OS in patients with surgically treated esophageal cancer., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Objectives: Although a decrease in psoas muscle area (PMA) has been reported as a risk factor for survival in several malignancies, there have been few studies regarding its prognostic value in oesophageal cancer. We investigated the prognostic role of PMA and its F-18 fluorodeoxyglucose uptake in patients who had surgically treated oesophageal cancer., Methods: From 2004 to 2013, 131 patients who underwent surgical resection and complete lymph node dissection for oesophageal cancer were retrospectively reviewed. The PMA and mean standardized uptake value (SUVmean) of the psoas muscle were measured at the L3 spine level on preoperative positron emission tomography/computed tomography images., Results: The mean age was 63.38 ± 8.47 years and male patients were 125 (95.4%). The pathological stage I, II and III were 38 (29.0%), 41 (31.3%) and 52 (39.7%), respectively. The mean body mass index (BMI), PMA and SUVmean of the psoas muscle were 59.50 ± 10.14, 14.42 ± 4.30 and 1.51 ± 0.27, respectively. Operative mortality occurred in 7 (5.3%) patients. The BMI and PMA were lower in patients with operative mortality than in patients who survived. The median follow-up time was 32.52 months. A multivariate analysis revealed that PMA was an adverse risk factor for overall survival (OS) (hazard ratio, HR = 0.930; P= 0.004), whereas BMI was related to OS. The 3-year OS rates were 64.9% in high-PMA (≥15.8) patients; however, it was only 37.1% in low-PMA (less than 15.8) patients (P= 0.002). Akaike information criterion was the lowest by including PMA in the multivariate model., Conclusions: Decreased PMA was an adverse significant prognostic factor for OS in patients with oesophageal cancer., (© The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)