Accumulation of plasmacytoid dendritic cell is associated with a treatment response to DNA-damaging treatment and favorable prognosis in lung adenocarcinoma

Introduction: Favorable responses to the treatment including immune checkpoint inhibitors (ICIs) have been consistently reported in lung cancer with smoking history. As the tumor microenvironment (TME) may be involved in the treatment response to ICIs, we aimed to investigate the TME of lung cancer with different smoking status. Methods: Lung adenocarcinoma (LUAD) tissue (Tu) and adjacent normal?appearing lung tissue (NL) from current and never smokers were investigated by single-cell RNA sequencing and immunofluorescence and immunohistochemical staining. The clinical implications of identified biomarkers were validated using open-source datasets. Results: The lungs of smokers had an increased proportion of innate immune cells in NL tissues, whereas Tu tissues had a lower proportion of these cells than those of non-smokers. Monocyte-derived macrophages (mono-Mc), CD163-LGMN macrophages, monocyte-derived dendritic cells (DCs), and plasmacytoid DCs (pDCs) were significantly enriched in smokers’ Tu. Among these clusters, pDCs, specifically enriched in the Tu of smokers. The expression of representative pDC markers, leukocyte immunoglobulin-like receptor A4 (LILRA4) and Toll-like receptor 9 (TLR9), was increased in the stromal cells of LUAD in patients with a smoking history. In an animal model of lung cancer, ionizing radiation induced robust TLR9 expressing immune cells in peritumoral area. Survival analysis using a TCGA-LUAD dataset indicated that patients overexpressing pDC markers exhibited superior clinical outcomes to age-, sex-, and smoking-matched control groups. Top 25% patients with high TLR9 expression exhibited significantly higher tumor mutational burden than that of low TLR9 expression group (bottom 25% patients) (5.81 mutations/Mb vs 4.36 mutations/Mb; P = 0.0059, Welch’s two-sample t-test) Conclusion: There is an increased pDC in the TME of smokers’ lung cancer, and the response of pDC to DNA damaging treatment would lead a conducive environment to ICIs containing regimens. These findings suggest that R&D that induces an increase in the activated pDC population is continuously required to enhance therapeutic effectiveness of ICIs-containing therapies in lung cancer.ope

Relationship between airway obstruction and incidence of metabolic syndrome in Korea: a community-based cohort study

Background: Although studies have examined the relationship between metabolic syndrome (MetS) and COPD, the incidence of MetS in individuals with COPD has not specifically been investigated. This study aimed to evaluate the incidence of MetS in subjects with airway obstruction using data from a community-based cohort. Patients and methods: Data representing 4 years of follow-up from the Ansung-Ansan cohort were analyzed; a total of 6,184 adults, who were ≥40 years of age and underwent spirometry, were enrolled in this study. Airway obstruction was defined as forced expiratory volume in 1 s/forced vital capacity ratio <70%, and MetS was determined according to the National Cholesterol Education Program Adult Treatment Panel III guidelines. Results: A total of 419 patients were newly diagnosed with MetS, based on the National Cholesterol Education Program Adult Treatment Panel III guidelines, during follow-up. MetS was more frequent in COPD subjects, relative to non-COPD subjects, in both sexes (14.7% vs 11.0% [men] and 14.7% vs 11.8% [women]). In men subjects, the risk for MetS was higher in subjects with airflow obstruction than in subjects without obstruction, after adjusting for age, body mass index, and smoking status. Conclusion: The incidence of MetS was higher in men with airflow obstruction than in healthy subjects.ope

New targeted therapies for non-small cell lung cancer

Background: Lung cancer is representative of a high frequency and high mortality disease and ranks at the top in incidence and mortality in Korea, when excluding thyroid cancer. In this manuscript, we focused on current targeted therapies for lung cancer used widely in the medical field. Current Concepts: The majority of patients with lung cancer cannot be treated with surgery only and require chemotherapeutics or radiation therapy. Currently, classical chemotherapeutic agents, targeted agents, and immune checkpoint inhibitors are the most widely used. Recently, the Research and Development of antibody drug conjugates is gaining attention, and this may become a more widely prescribed treatment in the future. Among the available treatment options, targeted therapy is becoming increasingly feasible and widespread for treating inoperable lung cancers, where driver mutations have been identified, and for adjuvant or neoadjuvant therapies. Next-generation sequencing (NGS) improves the ability to identify driver mutations that were previously difficult to detect and can also be performed on blood samples where no cancer tissue is available for testing. This makes it possible to identify therapeutic targets for targeted therapy more rapidly. Discussion and Conclusion: The most common type of lung cancer in Korea is adenocarcinoma, for which a driver mutation has been identified. Newly developed drugs target previously problematic mutations or cancer cell lines that have acquired resistance induced during the treatment process. The survival rate of patients with lung cancer is expected to improve with the development of tailored treatments for targets identified from the NGS data of the patient. This paper will help clinicians understand the current state of targeted therapies for lung cancer treatment.ope

Association between Aortic Atheroma and Cerebral Small Vessel Disease in Patients with Ischemic Stroke

BACKGROUND AND PURPOSE: Cerebral small vessel disease (SVDs) are related with large artery atherosclerosis. However, the association between aortic atheroma (AA) and cerebral small vessel disease has rarely been reported. This study evaluated the relationship between presence and burden of AAs and those of SVDs in patients with acute ischemic stroke. METHODS: We included 737 consecutive patients who underwent transesophageal echocardiography (TEE) and brain magnetic resonance imaging (MRI) for evaluation of acute stroke. AA subtypes were classified as complex aortic plaque (CAP) and simple aortic plaque (SAP). Presence and burden of SVDs including cerebral microbleeds (CMBs), white matter hyperintensities (WMHs), perivascular spaces (PVSs), asymptomatic lacunar infarctions (ALIs), and total SVD score, were investigated. RESULTS: AA was found by TEE in 360 (48.8%) patients including 11.6% with CAP and 37.2% with SAP. One or more types of SVDs was found in 269 (36.4%) patients. In multivariable analysis, presence of CMBs (odds ratio [OR] 4.68), high-grade WMHs (OR 3.13), high-grade PVSs (OR 3.35), and ALIs (OR 4.24) were frequent in patients with AA than those without AA. Each 1-point increase in total SVD score increased the odds of presence of CAP (OR 1.94, 95% confidence interval (CI) 1.44-1.85) and SAP (OR 1.54, 95% CI 1.35-1.75). CONCLUSIONS: In this study, patients with AA frequently had cerebral SVDs. Larger burden of AA was associated with advanced cerebral SVDs. Our findings give an additional information for positive relationship with systemic atherosclerosis and coexisting cerebral SVDs in acute ischemic stroke patients.ope

Prevalence of pre-transplant anti-HLA antibodies and their impact on outcomes in lung transplant recipients

BACKGROUND: Previous studies have suggested that antibodies against human leukocyte antigen (HLA) are associated with worse outcomes in lung transplantation. However, little is known about the factors associated with outcomes following lung transplantation in Asia. Accordingly, we investigated the prevalence of anti-HLA antibodies in recipients before transplantation and assessed their impact on outcomes in Korea. METHODS: A single-center retrospective study was conducted. The study included 76 patients who received a lung transplant at a tertiary hospital in South Korea between January 2010 and March 2015. RESULTS: Nine patients (11.8%) had class I and/or class II panel-reactive antibodies greater than 50%. Twelve patients (15.8%) had anti-HLA antibodies with a low mean fluorescence intensity (MFI, 1000-3000), 7 (9.2%) with a moderate MFI (3000-5000), and 12 (15.8%) with a high MFI (> 5000). Ten patients (13.2%) had suspected donor-specific antibodies (DSA), and 60% (6/10) of these patients had antibodies with a high MFI. In an analysis of outcomes, high-grade (>/=2) primary graft dysfunction (PGD) was more frequent in patients with anti-HLA antibodies with moderate-to-high MFI values than in patients with low MFI values (39.4% vs. 14.0%, p = 0.011). Of 20 patients who survived longer than 2 years and evaluated for pBOS after transplant, potential bronchiolitis obliterans syndrome (pBOS) or BOS was more frequent in patients with anti-HLA antibodies with moderate-to-high MFI than in patients with low MFI, although this difference was not statistically significant (50.0% vs. 14.3%, p = 0.131). CONCLUSIONS: The prevalence of anti-HLA antibodies with high MFI was not high in Korea. However, the MFI was relatively high in patients with DSA. Anti-HLA antibodies with moderate-to-high MFI values were related to high-grade PGD. Therefore, recipients with high MFI before lung transplantation should be considered for desensitization and close monitoring.ope

Factors Associated with Lung Function Recovery at the First Year after Lung Transplantation

PURPOSE: Post-operative pulmonary function is an important prognostic factor for lung transplantation. The purpose of this study was to identify factors affecting recovery of forced expiratory volume in 1 second (FEV1) at the first year after lung transplantation. MATERIALS AND METHODS: We retrospectively reviewed the medical records of lung transplantation patients between October 2012 and June 2016. Patients who survived for longer than one year and who underwent pulmonary function test at the first year of lung transplantation were enrolled. Patients were divided into two groups according to whether they recovered to a normal range of FEV1 (FEV1 ≥80% of predicted value vs. <80%). We compared the two groups and analyzed factors associated with lung function recovery. RESULTS: Fifty-eight patients were enrolled in this study: 28 patients (48%) recovered to a FEV1 ≥80% of the predicted value, whereas 30 patients (52%) did not. Younger recipients [odds ratio (OR), 0.92; 95% confidence interval (CI), 0.87-0.98; p=0.010], longer duration of mechanical ventilator use after surgery (OR, 1.14; 95% CI, 1.03-1.26; p=0.015), and high-grade primary graft dysfunction (OR, 8.08; 95% CI, 1.67-39.18; p=0.009) were identified as independent risk factors associated with a lack of full recovery of lung function at 1 year after lung transplantation. CONCLUSION: Immediate postoperative status may be associated with recovery of lung function after lung transplantation.ope

Prognostic value of pre-transplant mean pulmonary arterial pressure in lung transplant recipients: a single-institution experience

Background: Currently, lung transplantation (LTX) is considered to be a curative treatment option in patients with end-stage lung disease. Although pulmonary hypertension (PH), confirmed by cardiac catheterization, is a prognostic factor in patients undergoing LTX, the prognostic value of PH in Asian lung transplant recipients remains uncertain. In this study, we aimed to determine whether PH before LTX may serve as a prognostic factor for survival in Asian patients. Methods: The medical records of 50 patients [male, 27; female, 23; mean age, 51.0 (41.0-60.0) years], who received preoperative right heart catheterization (RHC) and echocardiography before single or double LTX at Severance Hospital between January 2010 and December 2014, were reviewed. The relationship between 1-year survival after LTX and PH [mean pulmonary arterial pressure (mPAP) >/=25 mmHg at rest] was evaluated. Results: The mean right ventricular systolic pressure and mPAP were 48.5 (22.8) and 30.0 (24.0-40.0) mmHg. Of the 50 patients, 17 (34.0%) died within a year after LTX. The 1-year survival rate among patients with mPAP >/=25 mmHg (58.8%) was lower than the survival rate among patients with mPAP /=25 mmHg was associated with post-transplantation survival [hazard ratio (HR), 4.832; 95% confidence interval (CI), 1.080-21.608, P=0.039]. The presence of preoperative PH was also associated with an increased risk of postoperative complications. Conclusions: Confirmation of PH via preoperative cardiac catheterization was associated with the prognosis of the patient after LTX. Clinicians should consider the necessity for early transplantation surgery before the mPAP reaches >/=25 mmHg.ope

한국인 지역사회코호트에서 폐기능 저하에 영향을 미치는 요인에 대한 분석

Background : Pulmonary function measures are traits that predict morbidity and mortality and define chronic obstructive pulmonary disease (COPD). Several studies have shown that some genetic variants associated with COPD have been identified in genome-wide association studies (GWASs), especially in patients with moderate to severe COPD; however, genetic susceptibility for lung function decline in the general population has not been widely studied. This study aims to investigate the factors associated lung function decline with or without airflow obstruction, using data from a community-based cohort. Methods : We evaluated characteristics of airflow obstruction and risk factors for the lung function decline of general population. We also conducted a genome-wide interaction study to identify the association between genetic variants and pulmonary function, and also examined how these variants relate to lung impairment in accordance with smoking status with amounts. Using community-based cohorts derived from the Korean Genome Epidemiology Study, we analyzed the association between genetic variants (single-nucleotide polymorphisms and haplotypes) and lung function (FEV1, FEV1/FVC ratio) using a linear mixed model for association and interaction to time effect. Results : A total of 8845 subjects were recruited from two community-based cohorts. When compared subjects with and without airflow obstruction clinical variable that such as age, sex, BMI, and smoking status were associated obstructive lung disease. We found annual mean FEV1 declines of 41.7 mL for men and 33.4 mL for women, and the annual rate of decline in FEV1 was fastest for current smokers. We also found a previously identified locus near FAM13, the most significant SNPs from the results of two LR tests for FEV1/FVC. These selected SNPs were located in the upstream region of FAM13 on chromosome 4 and had similar minor allele frequencies (MAFs). Furthermore, we found that certain SNPs tended to have lower FEV1/FVC values, and lung function decreased much faster with time interactions. The SNP most associated with lung function decline was the rs75679995 SNP on chromosome 7, and those SNPs located within the TAD of the DNAH11 region and the eQTL of rs9991425 revealed a higher expression of MFAP3L and AADAT genes. Conclusion: This is the first gene–time interaction study of lung function decline as a risk factor for COPD in the Korean population. In addition to replicating previously known signals for FAM13A, we identified two novel genomic regions (DNAH11, AADAT) involved in this gene-environmental interaction. 배경 및 목적: 폐기능은 만성폐쇄성폐질환과 같은 호흡기병으로의 이환율과 사망률을 예측할 수 있는 가장 중요한 호흡기계의 특성이다. 이전의 몇 가지 연구들에서 전장 유전체 분석을 통해 중등도 이상의 만성폐쇄성폐질환과 관련된 유전 변이들이 알려져 있다. 그러나 일반 인구 집단에서의 폐기능 저하와 관련된 유전적 감수성에 대해서는 널리 알려지지 않았다. 목적: 본 연구에서는 지역 사회 기반 코호트를 통해 일반인구에서의 폐기능 저하와 관련된 요인을 확인하고자 하였다. 방법: 우리는 폐기능 저하와 관련된 요인들을 분석하기 위해 지역사회 기반 코호트를 이용하여 임상적 표현형 및 특성과 함께 FEV1 및 FEV1/FVC등의 폐기능을 이용하여 관련된 유전자 변이와 (유전자 다형성과 일배체형) 함께 선형혼합모형을 이용하여 전장 유전체 연관성 분석을 통하여 확인하였다. 결과: 총 8845명의 참가자들이 분석에 포함되었다. 매년 평균 폐기능저하는 남성에서는 41.7 mL 그리고 여성에서는 33.4 mL 로 확인되었으며, 흡연자에서 폐기능저하의 속도가 가장 빠른 것이 확인 되었다. 기류 제한의 여부에 따라 환자를 분석하여 보았을 때 나이, 성별, 체질량 지수, 그리고 흡연력 등이 만성 폐쇄성 폐질환과 연관이 있었다. 우리는 전장 유전체 연관성 분석을 통해 이 임상적인 결과들과 함께 분석을 진행하였다. 이전에 밝혀져 있던 FAM13A 유전자와 연관된 유전 변이 지역을 확인하였으며, 이 부위는 염색체 4번에 존재하는 유전자로 비슷한 대립유전자형 빈도를 보였다. 게다가 우리는 FEV1/FVC값의 저하가 특정 유전 돌연변이와 연관되어 시간이 지날수록 빨리 감소한다는 것을 확인할 수 있었다. 폐기능 저하와 가장 연관된 단일 염기 다형성 부위는 염색체 7번에 있는 rs75679995와 그 단일 염기 다형성부위가 위치한 TAD 인 DNAH11 부위로 확인되었다. rs9991425 이MFAP3L와 AADAT 유전자 발현에 관여하는 것이 함께 확인 되었으며, 폐기능 저하 특히 FEV1/FVC값과 연관성이 있음이 확인되었다. 결론: 일반인구에서의 폐기능저하의 속도는 흡연과 관련이 있으며, 반복 측정한 폐기능과 선형혼합모형을 이용하여 전장 유전체 연관 분석을 시행하였을 때 염색체 4번에 있는 특정 단일 염기 다형성부위들과 관련된유전자 FAM13A와 염색체 7번에 특정 단일 염기 다형성부위들에 위치한 DNAH11, AADAT 유전자가 폐기능저하와 연관성이 있는 것이 확인 할 수 있었다.open박

Usefulness of the preoperative prognostic nutritional index score as a predictor of the outcomes of lung transplantation: A single-institution experience

BACKGROUND & AIMS: There is increasing evidence that preoperative nutritional status is a predictor of disease severity and mortality after lung transplantation (LTX). This study aimed to evaluate preoperative nutritional assessment as a predictor of LTX outcomes. METHODS: We included 132 patients who underwent single or double LTX at Severance Hospital, Yonsei University, between October 2010 and April 2016. The Prognostic Nutritional Index (PNI) scores were calculated as follows: 10 × serum albumin value (g/dL) + 0.005 × peripheral lymphocyte count (/mm3). The optimal cut-off PNI score for the prediction of postoperative overall survival was set at 41.15 using receiver operating characteristics analysis. The efficacies of PNI and other clinical factors in predicting LTX outcomes were determined using univariate and multivariate Cox proportional hazard analyses. RESULTS: Patients with PNI <41.15 (PNI-low group) were older, had higher preoperative C-reactive protein levels, and had lower nutritional status scores than did those in the PNI-high group (PNI ≥ 41.15). Based on Kaplan-Meier analysis, the overall survival rate was significantly better in the PNI-high group (78.3%) than in the PNI-low group (28.6%) (P < 0.001). Age, sex, body mass index, use of preoperative mechanical ventilation, C-reactive protein level, neutrophil-to-lymphocyte ratio, and PNI score were independent prognostic factors. Survival was significantly higher in the PNI-high group (hazard ratio: 0.220; P < 0.001) than in the PNI-low group, and incidence of complications ≥ grade IV was higher in the PNI-low group than in the PNI-high group (P < 0.001). Multivariate regression analysis showed that preoperative PNI score was significantly associated with postoperative survival, even after adjusting for other confounding factors. CONCLUSIONS: Our findings suggest that PNI is a useful prognostic marker for the identification of high-risk lung transplant recipients. Preoperative nutritional assessment using PNI may provide useful information for reducing postoperative morbidity and mortality.restrictio