Takeo Endo

Regulation of endothelin-1 synthesis in cultured guinea pig airway epithelial cells by various cytokines

To study regulatory mechanisms influencing the synthesis and release of ET-1, a potent bronchoconstrictor, epithelial cells from guinea pig tracheas were cultured to test various cytokines for the synthesis of ET-1 and its precursor, big ET-1. Cytokines tested were divided into 4 groups, based on their potential modes of action. IL-8, TNF alpha and TGF beta transiently increased the synthesis of ET-1, while EGF, PDGF and GM/CSF promoted proliferation of ET-1 synthesizing cells. IL-1 enhanced the synthesis of ET-1 precursor without mitogenesis, whereas IL-2, IL-6 and IGF-1 induced both the synthesis of big ET-1 and mitogenesis. These observations suggest that cytokines involved in damage, inflammation and repair of the airway epithelial layer regulate the synthesis and release of ET-1 by multiple mechanisms, thereby influencing airway muscle tone.

ET-1 released histamine from guinea pig pulmonary but not peritoneal mast cells

Endothelin(ET)-1 triggered histamine release of mast cells from pulmonary tissue but not from the peritoneal cavity of guinea pigs. The observed difference in response to ET-1 was attributable to a quantitative difference in ET-1 binding sites between both cells. The concentrations of ET-1 required for half maximal release of histamine and half maximal binding of [125I]ET-1 were approximately 0.05 and 0.08 nM, respectively. The release of histamine by ET-1 was a Ca(2+)-dependent but not a cytotoxic process. These observations, taken together, suggest that ET-1 induces histamine release from mast cells in a receptor-dependent fashion.

Role of endogenous nitric oxide in allergen‐induced airway responses in guinea‐pigs

1 Endogenous nitric oxide (NO) can be detected in exhaled air and accumulates in inflamed airways. However its physiological role has not been fully elucidated. In this study, we investigated a role for endogenous NO in allergen‐induced airway responses. Sensitised guinea‐pigs were treated with NG‐nitro‐l‐arginine methyl ester l‐NAME (2.0 mm) or aminoguanidine (AG) (2.0 mm) 30 min before the allergen challenge, and 3 and 4 h after the challenge. Alternatively, l‐arginine (2.4 mm) treatment was performed 30 min before, and 2 and 3 h after the challenge. In all groups, ovalbumin (OVA) challenge (2 mg ml−1 for 2 min) was performed, and airway responses, NO production, infiltration of inflammatory cells, plasma exudation and histological details were examined. 2 Allergen‐challenged animals showed an immediate airway response (IAR) and a late airway response (LAR), which synchronised with an increase in exhaled NO. Treatment with l‐NAME and AG did not affect IAR while they significantly blocked LAR (72% and 80% inhibition compared to vehicle) and production of NO (35% and 40% inhibition). On the other hand, treatment with l‐arginine did not affect IAR but potentiated LAR (74% augmentation). 3 In bronchoalveolar lavage (BAL) fluid, allergen‐induced increases in eosinophils were reduced by 48% for l‐NAME treatment compared to vehicle, and increased by 56% for l‐arginine treatment. 4 Treatment with l‐NAME significantly decreased airway microvascular permeability to both Monastral blue (MB) and Evans blue (EB) dye (50.6% and 44% inhibition). 5 We conclude that allergen‐induced LAR is closely associated with NO production, and that NO plays a critical role in inflammatory cell infiltration and plasma exudation in the allergic condition.

The effects of calcitonin gene‐related peptide on tracheal smooth muscle of guinea‐pigs in vitro

1 The effect of calcitonin gene‐related peptide (CGRP) on airway smooth muscle is controversial. The aim of this study was to determine whether the action of CGRP on tracheal strips of guinea‐pigs is modulated by epithelium and whether this peptide‐induced action involves other mediators including nitric oxide (NO) and endothelin (ET)‐1. 2 CGRP produced a weak dose‐dependent increase in guinea‐pig tracheal tension in vitro (‐log EC50 = 8.5 ± 0.1, maximum contraction = 8.3 ± 1.2% of 50 mM KCl‐induced contraction, n = 6). In epithelium‐depleted preparations, CGRP (10−7 m)‐induced contraction was significantly potentiated from 9.0 ± 1.9% to 41.1 ± 6.0% (n = 6). 3 L‐NG‐nitro‐arginine methyl ester (L‐NAME, 10−4 m), which inhibits NO synthesis, enhanced the contractile response to CGRP from 9.0 ± 1.9% to 31.2 ± 1.1% (n = 6). Indomethacin (10−5 m) also enhanced the response to CGRP, although the effect was weak (13.4 ± 3.2%, n = 6). 4 Anti‐ET‐1 serum changed the CGRP‐induced contraction into a relaxation. After incubation of the trachea with ET‐1 (10−7 m) to attenuate ET‐1‐induced responses, the CGRP‐induced contraction also changed into a relaxation. BQ‐123 (an ETA receptor antagonist) and BQ‐788 (an ETB receptor antagonist) caused the same conversion of the CGRP response, from contraction to relaxation, although the relaxing effect elicited by BQ‐788 was more potent than that by BQ‐123. Maximum inhibitory responses were −31.0 ± 3.3% and −13.0 ± 2.3% of 50 mM KCl‐induced contraction, respectively (n = 6). 5 In primary culture, guinea‐pig tracheal epithelial cells released ET‐1, and CGRP (10−5 m) significantly increased the release of ET‐1. 6 These data suggest that the action of CGRP is modulated by airway epithelium and this mechanism involves the release of NO and ET‐1. Especially, the majority of contractile action elicited by CGRP consists of an action of ET‐1 via the predominant ETB receptor.

Epidermal Growth Factor Receptor Mutations: Effect on Volume Doubling Time of Non–Small-Cell Lung Cancer Patients

Background: The purpose of this study was to retrospectively compare the volume doubling time (VDT) on serial computed tomography (CT) of non–small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation with that of NSCLC without the mutation. Methods: One hundred and two pathologically proven NSCLCs, including 69 patients with lung adenocarcinoma, were reviewed with helical CT. Each tumor underwent at least two CT scans. The VDT was calculated using a modified Schwartz formula. EGFR mutations at exons 18–21 were determined by common fragment analysis and Cycleave method. Result: The median VDT of all the patients was 188 days. EGFR mutations were noted in 35 of the 102 patients. The VDT in the 35 patients with EGFR mutations (median 676 days) was longer than that in the 67 patients without EGFR mutations (median 139 days) (p <0.001). By histology subtype, the VDT of adenocarcinoma (305 days) was longer than that of squamous cell carcinoma (81 days) and other types (90 days; p <0.001). Conclusion: In NSCLC patients, positive EGFR mutation status may be associated with longer VDT, which seemed to have a slowly progressive and less-aggressive character. More accurate evaluation of VDT may be helpful for understanding the natural history of EGFR mutation–positive NSCLC and treatment with EGFR tyrosine kinase inhibitors.

Erlotinib for elderly patients with non-small-cell lung cancer: Subset analysis from a population-based observational study by the Ibaraki Thoracic Integrative (POSITIVE) Research Group.

The incidence and mortality of lung cancer have increased worldwide over the last decades, with an observed increased incidence particularly among elderly populations. It has not yet been determined whether erlotinib therapy exhibits the same efficacy and safety in elderly and younger patients with non-small-cell lung cancer (NSCLC). The aim of this retrospective subgroup analysis of data from a population-based observational study was to assess the efficacy and safety of erlotinib in an elderly (≥75 years, n=74) and a younger group of patients (<75 years, n=233) who received treatment for NSCLC. The time to treatment failure was similar in the elderly [median, 62 days; 95% confidence interval (95% CI): 44–80 days] compared with the younger group (median, 46 days; 95% CI: 35–53 days) (P=0.2475). The overall survival did not differ between the elderly and younger groups (median, 170 days; 95% CI: 142–239 days vs. median, 146 days; 95% CI: 114–185 days, respectively) (P=0.7642). The adverse events did not differ in incidence between the groups and were manageable, regardless of age. Among the NSCLC patients receiving erlotinib treatment, the outcomes of the elderly (≥75 years) and younger (<75 years) groups of patients were similar in our population-based observational study.

Sarcopenia in Resected NSCLC: Effect on Postoperative Outcomes

Introduction: Skeletal muscle depletion, referred to as sarcopenia, has recently been identified as a risk factor for poor outcomes in various malignancies. However, the prognostic significance of sarcopenia in patients with NSCLC after surgery has not been adequately determined. This study investigated the impact of sarcopenia in patients undergoing pulmonary resection for lung cancer. Methods: This retrospective study consisted of 328 patients with pathologically confirmed NSCLC who underwent curative resection between January 2005 and April 2017. Preoperative computed tomography imaging at the third lumbar vertebrae level was assessed to measure the psoas muscle mass index (PMI, cm2/m2). Sarcopenia was defined as a cutoff value of PMI less than 6.36 cm2/m2 for males and 3.92 cm2/m2 for females, based on PMI values from “healthy” subjects. Results: The median patient age was 71 years and 59% were male. Sarcopenia was present in 183 (55.8%) and was significantly related with increasing age (p < 0.001), being male (p < 0.001), smoking habit (p < 0.001), lower body mass index (p < 0.001), and postoperative major complication (Clavien‐Dindo grade ≥3, p = 0.036). The prevalence of sarcopenia was higher in men than in women, and the prevalence increased with age in men, whereas the prevalence did not increase in females older than 70 years. The 5‐year survival rate was 61% in patients with sarcopenia and 91% in those without. Multivariate analysis revealed that sarcopenia was an independent unfavorable prognostic factor (p = 0.019). Conclusions: Sarcopenia as determined using preoperative computed tomography could be used to predict postoperative major complication and prognosis in patients with resected NSCLC. Our results may provide some important information for preoperative management.

A Case of Seasonal Influenza Vaccine-induced Pneumonitis Presenting with Multiple Pulmonary Nodules

A 39-year-old woman received a seasonal influenza vaccine in November 2015 and subsequently experienced malaise, low-grade fever, and chest discomfort. A chest X-ray performed 2 weeks after vaccination showed multiple nodular shadows in both lungs and ground-glass shadows in both lower lung fields. Her bronchoalveolar lavage fluid contained an unusually high number of lymphocytes, and a drug-induced lymphocyte stimulation test for seasonal influenza vaccine was positive. Transbronchial lung biopsy revealed the presence of granulomatous inflammation. Thereafter her abnormal chest shadow spontaneously improved. Based on these findings, the patient was diagnosed with drug-induced pneumonitis due to an influenza vaccine.

Real Clinical Practice of Using Afatinib Therapy in NSCLC Patients with an Acquired EGFR T790M Mutation

Background/Aim: To describe real clinical outcomes when using afatinib therapy to treat non-small cell lung cancer patients who have an acquired EGFR T790M mutation. Materials and Methods: A retrospective chart review was conducted from January 2013 to November 2017 sourced from 15 medical institutes that cover a population of three million people. Results: There were 74 patients who met the above-mentioned criteria. Treatment outcomes with afatinib, in patients with or without tyrosine kinase inhibitor (TKI) therapy prior to afatinib, were similar to previously reported clinical trials. Stratification of patients by the presence or absence of TKI pretreatment before afatinib, and the presence or absence of an acquired T790M mutation found no statistical difference in overall survival. Conclusion: This population-based study found that the disadvantages of pretreatment before afatinib, and absence of an acquired T790M EGFR mutation, could be overcome by an appropriate treatment strategy in clinical practice.