Table_1_Prognostic Value of Baseline Medications Plus Neutrophil-to-Lymphocyte Ratio in the Effectiveness of Nivolumab and Pembrolizumab in Patients With Advanced Non-Small-Cell Lung Cancer: A Retrospective Study.docx

BackgroundNivolumab and pembrolizumab are the standard treatments for patients with advanced non-small-cell lung cancer (NSCLC). While there are reports on several inflammatory indices and the prognosis of patients with cancer, no study has combined baseline medication with the neutrophil-to-lymphocyte ratio (NLR) to predict clinical outcomes. This study investigated the efficacy of baseline medications plus NLR to predict the effectiveness of nivolumab and pembrolizumab in a real-world clinical setting.MethodsWe conducted a single-center retrospective observational study of consecutive patients with advanced NSCLC who received nivolumab or pembrolizumab as first-line, second-line, or beyond treatment between December 2015 and November 2018 at the National Cancer Center Hospital in Japan. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method. The drug-based prognostic score for baseline medications plus NLR was weighed based on the regression β coefficients. The multivariable Cox proportional hazard model was used to assess the association between the prognostic score-stratified groups and survival outcomes.ResultsIn total, 259 patients were evaluated in this study. A prognostic score calculated from the baseline medications plus NLR was used to categorize the patients into good (score 0), intermediate (scores 1–2), and poor (scores 3–6) -prognosis groups. The multivariable Cox proportional hazard model revealed a significant association between the poor-prognosis group and reduced OS. The hazard ratio of OS was 1.75 (95% confidence interval: 1.07–2.99; P = 0.031). In contrast, no association between these prognosis groups and PFS was observed.ConclusionsThe findings suggest that the baseline medications with nivolumab or pembrolizumab plus NLR could lead to progressively shorter survival outcomes in patients with advanced NSCLC and could be used as a prognostic index for poor outcomes. However, to ascertain the clinical application of these findings, these concomitant medications need further validation in a large-scale multicenter study.</p

DataSheet_1_Increased Circulating Cell-Free DNA in Eosinophilic Granulomatosis With Polyangiitis: Implications for Eosinophil Extracellular Traps and Immunothrombosis.docx

BackgroundEndogenous DNA derived from nuclei or mitochondria is released into the blood circulation as cell-free DNA (cfDNA) following cell damage or death. cfDNA is associated with various pathological conditions; however, its clinical significance in antineutrophil cytoplasmic antibody-associated vasculitis (AAV) remains unclear. This study aimed to evaluate the clinical significance of cfDNA in AAV.MethodsWe enrolled 35 patients with AAV, including 10 with eosinophilic granulomatosis with polyangiitis (EGPA), 13 with microscopic polyangiitis, and 12 with granulomatosis with polyangiitis. Serum cf-nuclear DNA (cf-nDNA) and cf-mitochondrial DNA (cf-mtDNA) levels were measured by quantitative polymerase chain reaction before and after the initiation of immunosuppressive therapy. Tissue samples from EGPA patients were examined by immunofluorescence and transmission electron microscopy. The structure of eosinophil extracellular traps (EETs) and neutrophil extracellular traps (NETs) and stability against DNase were assessed in vitro. Platelet adhesion of EETs were also assessed.ResultsSerum cf-nDNA and cf-mtDNA levels were significantly higher in AAV than in healthy controls, with the highest levels in EGPA; however, serum DNase activities were comparable among all groups. cf-nDNA and cf-mtDNA decreased after treatment and were associated with disease activity only in EGPA. Blood eosinophil count and plasma D-dimer levels were significantly correlated with cf-nDNA in EGPA and cf-mtDNA. EGPA tissue samples showed lytic eosinophils and EETs in small-vessel thrombi. The structure of EETs showed bolder net-like chromatin threads in vitro and EETs showed greater stability against DNase than NETs. EETs provided a scaffold for platelet adhesion.ConclusioncfDNA was increased in EGPA, associated with disease activity. The presence of DNase-resistant EETs in small-vessel thrombi might contribute to higher concentration of cfDNA and the occurrence of immunothrombosis in EGPA.</p

Video_1_Increased Circulating Cell-Free DNA in Eosinophilic Granulomatosis With Polyangiitis: Implications for Eosinophil Extracellular Traps and Immunothrombosis.mp4

BackgroundEndogenous DNA derived from nuclei or mitochondria is released into the blood circulation as cell-free DNA (cfDNA) following cell damage or death. cfDNA is associated with various pathological conditions; however, its clinical significance in antineutrophil cytoplasmic antibody-associated vasculitis (AAV) remains unclear. This study aimed to evaluate the clinical significance of cfDNA in AAV.MethodsWe enrolled 35 patients with AAV, including 10 with eosinophilic granulomatosis with polyangiitis (EGPA), 13 with microscopic polyangiitis, and 12 with granulomatosis with polyangiitis. Serum cf-nuclear DNA (cf-nDNA) and cf-mitochondrial DNA (cf-mtDNA) levels were measured by quantitative polymerase chain reaction before and after the initiation of immunosuppressive therapy. Tissue samples from EGPA patients were examined by immunofluorescence and transmission electron microscopy. The structure of eosinophil extracellular traps (EETs) and neutrophil extracellular traps (NETs) and stability against DNase were assessed in vitro. Platelet adhesion of EETs were also assessed.ResultsSerum cf-nDNA and cf-mtDNA levels were significantly higher in AAV than in healthy controls, with the highest levels in EGPA; however, serum DNase activities were comparable among all groups. cf-nDNA and cf-mtDNA decreased after treatment and were associated with disease activity only in EGPA. Blood eosinophil count and plasma D-dimer levels were significantly correlated with cf-nDNA in EGPA and cf-mtDNA. EGPA tissue samples showed lytic eosinophils and EETs in small-vessel thrombi. The structure of EETs showed bolder net-like chromatin threads in vitro and EETs showed greater stability against DNase than NETs. EETs provided a scaffold for platelet adhesion.ConclusioncfDNA was increased in EGPA, associated with disease activity. The presence of DNase-resistant EETs in small-vessel thrombi might contribute to higher concentration of cfDNA and the occurrence of immunothrombosis in EGPA.</p