Background: Cough hypersensitivity is a major factor mediating chronic persistent cough. Capsaicin inhalation cough challenge is a representative tool for assessing cough sensitivity. However, the normal ranges and determinants have not been investigated in healthy Korean adults. Methods: Healthy adult volunteers were recruited by public postings at a single tertiary medical institution. For every volunteer, four age-gender-matched patients with chronic cough (lasting more than 8 weeks) were included. Capsaicin cough challenge tests were performed by dose-response, tidal-breathing method (15 seconds) in 1 minute intervals and the concentration causing five or more coughs (C5) was determined. Results: A total of 65 volunteers (52 females and 13 males) with mean age of 35.5 ± 11.4 (SEM) were recruited. Age, gender, atopy, sputum eosinophilia did not influence capsaicin cough sensitivity. In healthy females, BMI showed moderate negative correlation to C5 (r= -0.353, p= 0.001). Healthy volunteers had significantly higher C5 values compared to the patients (median C5 (IQR): 32 (112) vs 16 (24) respectively; p-value= 0.000). However, in ROC curve analysis, C5 showed poor discriminating value (AUC= 0.329) in identifying clinical cough. Conclusions: Capsaicin cough reflex was examined in Korean adults. Chronic cough patients had significantly more sensitive capsaicin reflex; however, its wide overlap between volunteers and patients may limit its application in the diagnosis of cough patients. The significant relationship between capsaicin sensitivity and BMI in healthy females warrants further consideration in the interpretation of the results.
Staphylococcus aureus enterotoxin-specific immunoglobulin E (SE-sIgE) sensitization tends to increase with age and is known to be associated with asthma and severity in older adults. However, the long-term impact of SE-sIgE in the elderly remains unknown. This study aimed to examine the relationships between SE-sIgE and fixed airflow obstruction (FAO) in a cohort of elderly asthmatics.A total of 223 elderly asthmatics and 89 controls were analyzed. Patients were assessed for demographics, history of chronic rhinosinusitis (CRS), asthma duration, acute exacerbation frequency, and lung function at baseline and then were prospectively followed up for 2 years. Serum total IgE and SE-sIgE levels were measured at baseline. Airflow obstruction was defined as forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio < 0.7 at baseline and FAO was defined as FEV1/FVC ratio < 0.7 over the 2-year follow-up.At baseline, the prevalence of airflow obstruction was 29.1%. Patients with airflow obstruction were significantly more likely to be male, and have a positive smoking history, comorbid CRS, and higher levels of SE-sIgE than those without airflow obstruction. Multivariate logistic regression analysis showed that airflow obstruction was significantly associated with current smoking and SE-sIgE sensitization at baseline. After the 2-year follow-up, baseline SE-sIgE sensitization was consistently related to FAO. Meanwhile, the number of exacerbations per year was significantly correlated with SE-sIgE levels.Baseline SE-sIgE sensitization was significantly associated with the number of asthma exacerbations and FAO after the 2-year follow-up in elderly asthmatics. These findings warrant further investigation of the direct and mediating roles of SE-sIgE sensitization on airway remodeling.
The purpose of this study is to shed light on the importance of environmental cooperation in the water sector for the effective administration of a shared river management. Under the special relations between the two Koreas, environmental issues have had relatively less importance than political and military issues. Despite several recurrent problems, particularly flood damage and water pollution issues concerning the shared rivers, the countermeasures have always been temporary and variable according to the status of the inter-Korean relationship. For these reasons, this paper will mainly focus on environmental cooperation for such shared rivers as the Imjin River and the Bukhan River by comparison with Europe’s experience managing shared rivers through the adoption of the Water Framework Directive (WFD) in 2000 after a long tug-of-war negotiation process among the EU member states. In preparation for Korean reunification, this study will deal with the prospect of South-North environmental cooperation for shared river management and discuss ways toward reasonable utilization of the shared rivers based on lessons from the EU Water Framework Directive.
<div>AbstractPurpose:<p>Neoadjuvant immunotherapy may improve the clinical outcome of regionally advanced operable melanoma and allows for rapid clinical and pathologic assessment of response. We examined neoadjuvant pembrolizumab and high-dose IFNα-2b (HDI) therapy in patients with resectable advanced melanoma.</p>Patients and Methods:<p>Patients with resectable stage III/IV melanoma were treated with concurrent pembrolizumab 200 mg i.v. every 3 weeks and HDI 20 MU/m<sup>2</sup>/day i.v., 5 days per week for 4 weeks, then 10 MU/m<sup>2</sup>/day subcutaneously 3 days per week for 2 weeks. Definitive surgery followed, as did adjuvant combination immunotherapy, completing a year of treatment. Primary endpoint was safety of the combination. Secondary endpoints included overall response rate (ORR), pathologic complete response (pCR), recurrence-free survival (RFS), and overall survival (OS). Blood samples for correlative studies were collected throughout. Tumor tissue was assessed by IHC and flow cytometry at baseline and at surgery.</p>Results:<p>A total of 31 patients were enrolled, and 30 were evaluable. At data cutoff (October 2, 2019), median follow-up for OS was 37.87 months (range, 33.2–43.47). Median OS and RFS were not reached. Radiographic ORR was 73.3% [95% confidence interval (CI): 55.5–85.8], with a 43% (95% CI: 27.3–60.1) pCR rate. None of the patients with a pCR have had a recurrence. HDI and pembrolizumab were discontinued in 73% and 43% of patients, respectively. Correlative analyses suggested that intratumoral PD-1/PD-L1 interaction and HLA-DR expression are associated with pCR (<i>P</i> = 0.002 and <i>P</i> = 0.008, respectively).</p>Conclusions:<p>Neoadjuvant concurrent HDI and pembrolizumab demonstrated promising clinical activity despite high rates of treatment discontinuation. pCR is a prognostic indicator.</p><p><i>See related commentary by Menzies et al., p. 4133</i></p></div>
Abstract Introduction: PD-1 inhibitors have shown limited efficacy in glioblastoma due to microenvironment immunosuppression and low tumor mutational burden. In GBM, PD-L1 expression is not a predictive marker for response to PD-1 or PD-L1 inhibitors. Multiplex immunostaining panel technology allows for detailed analyses of tumor microenvironment cells and their interaction. Methods: Pre-treatment tumor tissue was collected retrospectively from 27 patients at Columbia University Irving Medical Center with primary glioblastoma who were diagnosed within the past three years, had surgery here, and were either treated with SOC therapy (n= 8) or PD-1 inhibitors at recurrence (n= 19). Multiplex immunofluorescence panels included 1) CD11b/IDO1/HLADR/GFAP, 2) PD1/PD-L1/GFAP, and 3) CD4/CD8/CD25/FoxP3/Ki67/GFAP. Results: Multiplex immunofluorescence panels did not show any correlation with outcomes in patients treated with SOC therapy. Among the 19 patients treated with PD-1 inhibitors, those with more HLA-DR positive cells had worse outcomes (p= 0.02). PD-L1 expression on tumor cells was not predictive of outcomes. There was a correlation trend between PD-1/PD-L1 interaction score (p= 0.08) and outcomes. PTEN loss was correlated with higher Ki67 expression in both tumor cells (p= 0.05) and non-tumors cells (p= 0.03); however, this was not found in Ki67 in CD4+ cells, CD8+ cells, or CD4+CD8+ cells combined. Tumor-associated macrophages, myeloid-derived suppressor cells, CD8+ cells, and CD4+ cells were not significant predictive markers for outcome. Conclusion: Quantitative spatial profiling by multiplex immunofluorescence is feasible in FFPE glioblastoma tissue. More refined and extensive quantitative and spatial microenvironment analyses may allow for the development of biomarkers for immunotherapy in GBM.
Cough is an essential defence mechanism [1]. However, chronic cough is a significant cause of morbidity, seriously impairing quality of life [2]. Previously, chronic cough was considered a consequence of various diseases, such as asthma/eosinophilic bronchitis, rhinitis and gastro-oesophageal acid reflux disease [3, 4]. Recent evidence, however, suggests that chronic cough is a clinical syndrome with distinct intrinsic pathophysiology characterised by neuronal hypersensitivity [5–7]. Here, we estimated the worldwide epidemiological burden of chronic cough irrespective of putative diagnosis in general adult populations using a comprehensive systematic literature review. Chronic cough has a high global epidemiological burden. A standard definition would facilitate further studies. We gratefully acknowledge the help of GlaxoSmithKline (UK) in providing data translation assistance. We also wish to acknowledge the statistical advice from Soyeon Ahn (Division of Statistics, Medical Research Collaborating Center, Seoul National University Bundang Hospital, Seongnam, Korea).
Background: Fixed airway obstruction in asthma, which could be also called as asthma-chronic obstructive pulmonary disease (COPD) overlap, is associated with more morbidity and mortality burden, particularly in the elderly. However, risk factors for developing fixed airway obstruction are still under studied in elderly asthma patients. Objectives: We aimed to investigate risk factors of fixed airway obstruction among a group of elderly asthma patients. Methods: A total of 306 patients were included. Their lung function parameters during 3-year treatment period were collected, and fixed airway obstruction was defined if the best FEV1/FVC was less than 0.70 during the recent 1-year9s treatment period. Baseline parameters such as disease duration, smoking history, comorbidity, or serum IgE levels were analyzed for the associations with fixed airway obstruction. Results: The prevalence of fixed airway obstruction was 40.2% in our group of elderly asthma patients (mean age 71.3 years old). In univariate analyses, fixed airway obstruction was significantly associated with older age, male sex, smoking history, lower body mass index, and serum staphylococcal enterotoxin-specific IgE (SE-IgE) levels. In multiple logistic regression analyses, smoking history had the strong association with fixed airway obstruction. However, SE-IgE levels also had the significant relationships with fixed airway obstruction, independently of smoking history. Conclusions: Smoking history is a significant risk factor for fixed airway obstruction in elderly asthma. Our identification of SE-IgE sensitization as a potential risk factor for COPD overlap in elderly asthma warrants further investigation of its mechanism and clinical implication.
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