Comparison of semiquantitative chest CT scoring systems to estimate severity in coronavirus disease 2019 (COVID-19) pneumonia.

OBJECTIVES: To compare the clinical usefulness among three different semiquantitative computed tomography (CT) severity scoring systems for coronavirus disease 2019 (COVID-19) pneumonia. METHODS: Two radiologists independently reviewed chest CT images in 108 patients to rate three CT scoring systems (total CT score [TSS], chest CT score [CCTS], and CT severity score [CTSS]). We made a minor modification to CTSS. Quantitative dense area ratio (QDAR: the ratio of lung involvement to lung parenchyma) was calculated using the U-net model. Clinical severity at admission was classified as severe (n = 14) or mild (n = 94). Interobserver agreement, interpretation time, and degree of correlation with clinical severity as well as QDAR were evaluated. RESULTS: Interobserver agreement was excellent (intraclass correlation coefficient: 0.952-0.970, p < 0.001). Mean interpretation time was significantly longer in CTSS (48.9-80.0 s) than in TSS (25.7-41.7 s, p < 0.001) and CCTS (27.7-39.5 s, p < 0.001). Area under the curve for differentiating clinical severity at admission was 0.855-0.842 in TSS, 0.853-0.850 in CCTS, and 0.853-0.836 in CTSS. All scoring systems correlated with QDAR in the order of CCTS (ρ = 0.443-0.448), TSS (ρ = 0.435-0.437), and CTSS (ρ = 0.415-0.426). CONCLUSIONS: All semiquantitative scoring systems demonstrated substantial diagnostic performance for clinical severity at admission with excellent interobserver agreement. Interpretation time was significantly shorter in TSS and CCTS than in CTSS. The correlation between the scoring system and QDAR was highest in CCTS, followed by TSS and CTSS. CCTS appeared to be the most appropriate CT scoring system for clinical practice. KEY POINTS: • Three semiquantitative scoring systems demonstrate substantial accuracy (area under the curve: 0.836-0.855) for diagnosing clinical severity at admission and (area under the curve: 0.786-0.802) for risk of developing critical illness. • Total CT score (TSS) and chest CT score (CCTS) were considered to be more appropriate in terms of clinical usefulness as compared with CT severity score (CTSS), given the shorter interpretation time in TSS and CCTS, and the lowest correlation with quantitative dense area ratio in CTSS. • CCTS is assumed to distinguish subtle from mild lung involvement better than TSS by adopting a 5% threshold in scoring the degree of severity.

Post-Progression Survival Influences Overall Survival among Patients with Advanced Non-Small Cell Lung Cancer Undergoing First-Line Pembrolizumab Monotherapy.

BACKGROUND: Among patients with non-small cell lung cancer (NSCLC), the impact of first-line treatment on overall survival (OS) may be influenced by subsequent therapies. Thus, using patient-level data, we assessed the relationships of progression-free survival (PFS) and post-progression survival (PPS) with OS among patients with high-programmed death-ligand 1 (PD-L1) expression undergoing first-line pembrolizumab monotherapy for NSCLC. METHODS: We reviewed data from 133 patients with high PD-L1 expression undergoing first-line pembrolizumab monotherapy for NSCLC at 6 Japanese centers between February 2017 and December 2018. The correlations of PFS and PPS with OS were evaluated at the patient level. RESULTS: Linear regression analyses and Spearman's rank correlation coefficient revealed that PPS was strongly correlated with OS (r = 0.76, p < 0.05, R2 = 0.65), while PFS was only moderately correlated with OS (r = 0.71, p < 0.05, and R2 = 0.4). Furthermore, PPS was significantly associated with performance status at the end of pembrolizumab monotherapy, as well as the use of platinum-based combination chemotherapy after pembrolizumab monotherapy (both p < 0.05). CONCLUSIONS: Among patients with high PD-L1 expression undergoing first-line pembrolizumab monotherapy for NSCLC, PPS was more strongly correlated with OS, relative to the relationship between PFS and OS. Therefore, subsequent treatment appears to significantly influence OS in patients with disease progression following first-line pembrolizumab monotherapy.

CysLT1 Receptor Is Protective against Oxidative Stress in a Model of Irritant-Induced Asthma.

The bronchoconstrictive and proinflammatory properties of cysteinyl leukotrienes (cysLTs) in allergic asthma mediate their effects predominantly through the cysLT1 receptor (cysLT1R). However, the role of cysLTs and cysLT1R in innate immune-triggered asthma is largely unexplored. We explored the synthesis of cysLTs and cysLT1R as determinants of airway responses in an oxidative stress-induced model of irritant asthma. Wild-type (WT) mice exposed to 100 ppm Cl2 for 5 min had airway neutrophilia, increased cysLT production, and pulmonary expression of cysLT-related biosynthetic genes. CysLT1R-deficient (CysLTr1(-/-)) mice that were exposed to Cl2 demonstrated airway hyperresponsiveness to inhaled methacholine significantly greater than in WT BALB/c mice. Compared to WT mice, airway neutrophilia and keratinocyte chemoattractant production levels were higher in CysLTr1(-/-) mice and airway hyperresponsiveness was ameliorated using a granulocyte depletion Ab. CysLTr1(-/-) mice also demonstrated prolonged bronchial epithelial cell apoptosis following Cl2 WT mice showed increased antioxidant and NF erythroid 2-related factor 2 (Nrf2) gene expression, Nrf2 nuclear translocation in bronchial epithelial cells, and increased reduced glutathione/oxidized glutathione following Cl2 exposure whereas CysLTr1(-/-) mice did not. Furthermore, CysLTr1(-/-) mice demonstrated increased pulmonary E-cadherin expression and soluble E-cadherin shedding compared with WT mice. Loss of a functional cysLT1R results in aberrant antioxidant response and increased susceptibility to oxidative injury, apparently via a cysLT1R-dependent impairment of Nrf2 function.

Neutrophils mediate airway hyperresponsiveness after chlorine-induced airway injury in the mouse.

Chlorine gas (Cl2) inhalation causes oxidative stress, airway epithelial damage, airway hyperresponsiveness (AHR), and neutrophilia. We evaluated the effect of neutrophil depletion on Cl2-induced AHR and its effect on the endogenous antioxidant response, and if eosinophils or macrophages influence Cl2-induced AHR. We exposed male Balb/C mice to 100 ppm Cl2 for 5 minutes. We quantified inflammatory cell populations in bronchoalveolar lavage (BAL), the antioxidant response in lung tissue by quantitative PCR, and nuclear factor (erythroid-derived 2)-like 2 (NRF2) nuclear translocation by immunofluorescence. In vitro, NRF2 nuclear translocation in response to exogenous hypochlorite was assessed using a luciferase assay. Anti-granulocyte receptor-1 antibody or anti-Ly6G was used to deplete neutrophils. The effects of neutrophil depletion on IL-13 and IL-17 were measured by ELISA. Eosinophils and macrophages were depleted using TRFK5 or clodronate-loaded liposomes, respectively. AHR was evaluated with the constant-phase model in response to inhaled aerosolized methacholine. Our results show that Cl2 exposure induced neutrophilia and increased expression of NRF2 mRNA, superoxide dismutase-1, and heme-oxygenase 1. Neutrophil depletion abolished Cl2-induced AHR in large conducting airways and prevented increases in antioxidant gene expression and NRF2 nuclear translocation. Exogenous hypochlorite administration resulted in increased NRF2 nuclear translocation in vitro. After Cl2 exposure, neutrophils occupied 22 ± 7% of the luminal space in large airways. IL-17 in BAL was increased after Cl2, although this effect was not prevented by neutrophil depletion. Neither depletion of eosinophils nor macrophages prevented Cl2-induced AHR. Our data suggest the ability of neutrophils to promote Cl2-induced AHR is dependent on increases in oxidative stress and occupation of luminal space in large airways.

[An Elderly Patient with Non-Small Cell Lung Cancer Who Responded to Salvage S-1 Monotherapy after Gefitinib Therapy].

S-1 is one of the effective chemotherapy regimens for treating non-small cell lung cancer. We report of an elderly patient with non-small cell lung cancer who responded to S-1 monotherapy following gefitinib therapy. An 83-year-old woman was diagnosed with advanced adenocarcinoma of the lungs (cT3N3M1a, Stage IV). Considering her age, monotherapy with vinorelbine was administered as first-line chemotherapy. Despite the completion of four courses, she was diagnosed with progressive disease. Thereafter, after considering her status as a non-smoking woman, gefitinib was introduced as second-line chemotherapy, which resulted in significant tumor size reduction.Tumor regrowth was identified 16 months later, and gefitinib was switched to erlotinib, but the tumor kept increasing in size.S -1 monotherapy was introduced as fourth-line chemotherapy, and the tumor began to decrease in size again. A partial response was obtained after 10 months, without serious adverse effects. Gefitinib following S-1 monotherapy resulted in long-term tumor size control for a total of 27 months in an elderly patient with advanced non-small cell lung cancer.S -1 monotherapy might be one of the options for salvage therapy after gefitinib treatment becomes ineffective.

Superiority of nebulized corticosteroids over dry powder inhalers in certain patients with cough variant asthma or cough-predominant asthma.

BACKGROUND: The particle distribution might differ between nebulizer therapy and metered-dose inhaler (MDI) or dry powder inhaler (DPI) therapy because the particles repeatedly enter/re-enter the airways with the nebulizer. Inhaled corticosteroids (ICS) were administered with a nebulizer to assess the benefit of changes in the distribution of particles in patients with cough variant asthma (CVA) and cough-predominant asthma (CPA). METHODS: Patients whose symptoms were not controlled by their current therapy were enrolled. In patients receiving high-dose ICS by MDI or DPI (ICS-MDI/DPI), steroid therapy was switched to 1,320µg/day of nebulized dexamethasone (1,600µg as dexamethasone sodium phosphate) (chronic steroid-independent group). In patients receiving systemic steroids regardless of their ICS-MDI/DPI therapy, nebulized dexamethasone was added and any concurrent ICS-MDI/DPI therapy was halted to detect a steroid-sparing effect (chronic steroid-dependent group). In patients with acute exacerbation of CVA or CPA and persistent symptoms despite systemic corticosteroids, nebulized dexamethasone was added to assess its effect (acute group). RESULTS: Superior symptom control was achieved in 10 out of 12 steroid-independent patients, 3 out of 6 steroid-dependent patients, and all 7 acute patients. CONCLUSIONS: Delivery of ICS via a nebulizer has advantages over ICS-MDI/DPI in some patients with CVA or CPA.

Application of the advanced lung cancer inflammation index for patients with coronavirus disease 2019 pneumonia: Combined risk prediction model with advanced lung cancer inflammation index, computed tomography and chest radiograph.

The purpose of the present study was to evaluate the feasibility of applying the advanced lung cancer inflammation index (ALI) in patients with coronavirus disease 2019 (COVID-19) and to establish a combined ALI and radiologic risk prediction model for disease exacerbation. The present study included patients diagnosed with COVID-19 infection in our single institution from March to October 2020. Patients without clinical information and/or chest computed tomography (CT) upon admission were excluded. A radiologist assessed the CT severity score and abnormality on chest radiograph. The combined ALI and radiologic risk prediction model was developed via random forest classification. Among 79 patients (age, 43±19 years; male/female, 45:34), 72 experienced improvement and seven patients experienced exacerbation after admission. Significant differences were observed between the improved and exacerbated groups in the ALI (median, 47.6 vs. 13.2; P=0.011), frequency of chest radiograph abnormality (24.7 vs. 83.3%; P<0.001), and chest CT score (CCTS; median, 1 vs. 9; P<0.001). For the accuracy of predicting exacerbation, the receiver-operating characteristic curve analysis demonstrated an area under the curve of 0.79 and 0.92 for the ALI and CCTS, respectively. The combined ALI and radiologic risk prediction model had a sensitivity of 1.00 and a specificity of 0.81. Overall, ALI alone and CCTS alone modestly predicted the exacerbation of COVID-19, and the combined ALI and radiologic risk prediction model exhibited decent sensitivity and specificity.

Impact of inhaled ciclesonide on asymptomatic or mild COVID-19: A randomized trial.

The aim of this study was to determine the efficacy and safety of ciclesonide in the treatment of novel coronavirus disease 2019 (COVID-19) as gauged by pneumonia progression. This multi-center, open-label randomized trial was conducted with patients recruited from 22 hospitals across Japan. Participants were patients admitted with mild or asymptomatic COVID-19 without signs of pneumonia on chest X-rays. Asymptomatic participants were diagnosed after identification through contact tracing. Trial participants were randomized to either the ciclesonide or control arm. Participants in the treatment arm were administered 400 µg of ciclesonide three times a day over seven consecutive days. The primary endpoint was exacerbated pneumonia within seven days. Secondary outcomes were changes in clinical findings, laboratory findings, and changes over time in the amount of the viral genome. In the treatment group, 16 patients (39.0%) were classified as having exacerbated pneumonia compared to 9 (18.8%) in the control group. The risk ratio (RR) was 2.08 (95% confidence interval (CI): 1.15-3.75), indicating a worsening of pneumonia in the ciclesonide group. Significant differences were noted in participants with a fever on admission (RR: 2.62, 90% CI: 1.17-5.85, 95% CI: 1.00-6.82) and individuals 60 years of age or older (RR: 8.80, 90% CI: 1.76-44.06, 95% CI: 1.29-59.99). The current results indicated that ciclesonide exacerbates signs of pneumonia on images in individuals with mild or asymptomatic symptoms of COVID-19 without worsening clinical symptoms.

[A case of coexisting malignant mesothelioma and squamous cell carcinoma of the lung].

We experienced a case of malignant mesothelioma with squamous cell carcinoma of the lung concurrently. A 40-year-old man presented with dyspnea. A massive pleural effusion was found by X-ray in the right side of his chest. Transcutaneous pleural biopsy yielded a diagnosis of malignant mesothelioma(IMIG cT4N0M0, Stage IV ). At the same time, his chest CT revealed tumor in the right hilar lesion. Transbronchial lung biopsy yielded a diagnosis of squamous cell carcinoma of the lung (cT3N0M0, Stage III B). Our diagnosis was double cancer, malignant mesothelioma and lung cancer. Chemotherapy with carboplatin, gemcitabine and radiation therapy was performed, but the patient died from deterioration of his systemic condition. We encountered a rare case of double cancer. More attention must be paid in making a diagnosis of malignant mesothelioma and lung cancer.

Pretreatment Glasgow prognostic score predicts survival among patients with high PD-L1 expression administered first-line pembrolizumab monotherapy for non-small cell lung cancer.

BACKGROUND: There are no established biomarkers for predicting the efficacy of first-line pembrolizumab monotherapy in patients with high programmed death-ligand 1 (PD-L1) expression. In this study, we investigated whether the Glasgow prognostic score (GPS), neutrophil-to-lymphocyte ratio (NLR), and body mass index (BMI) can be used to evaluate the effect of first-line pembrolizumab monotherapy in patients with advanced non-small cell lung cancer (NSCLC) who express high levels of PD-L1. METHODS: We reviewed data from 142 patients with high PD-L1 expression who underwent first-line pembrolizumab monotherapy for NSCLC at six Japanese institutions between February 2017 and June 2019 and assessed the prognostic value of the GPS, NLR, and BMI. The Kaplan-Meier method and Cox proportional hazard models were used to examine differences in progression-free survival (PFS) and overall survival (OS). The GPS, NLR, and BMI were calculated using C-reactive protein and albumin concentrations, neutrophil and lymphocyte counts, and body weight and height, respectively. RESULTS: The GPS independently predicted the first-line pembrolizumab monotherapy efficacy, as a good GPS (GPS 0-1) was associated with a significantly better PFS and OS compared to a poor GPS (GPS 2) (PFS: 11.8 vs. 2.9 months, p < 0.0001; OS: not reached vs. 8.3 months, p < 0.0001). Furthermore, BMI independently predicted efficacy, as patients with high BMI (BMI ≥21.4) exhibited significantly better OS compared to those with low BMI (BMI <21.4) (OS: not reached vs. 14.1 months, p = 0.006). CONCLUSIONS: Among patients with high PD-L1 expression undergoing first-line pembrolizumab monotherapy for NSCLC, the GPS is significantly correlated with both PFS and OS, and BMI with OS, indicating that they could be used to predict treatment outcome in these patients. To the best of our knowledge, this is the first study to assess the relationship among the GPS, NLR, and BMI and survival among patients with high PD-L1 expression undergoing first-line pembrolizumab monotherapy for NSCLC.

Efficacy and safety of carboplatin with nab-paclitaxel versus docetaxel in older patients with squamous non-small-cell lung cancer (CAPITAL): a randomised, multicentre, open-label, phase 3 trial.

BACKGROUND: In Japan, docetaxel, a cytotoxic monotherapy, is the standard drug administered to older patients with advanced non-small-cell lung cancer (NSCLC). Carboplatin plus nab-paclitaxel has shown a high objective response rate in patients with squamous histology and was suggested to improve overall survival in patients aged 70 years and older. The CAPITAL trial aimed to assess the safety and efficacy of carboplatin plus nab-paclitaxel versus docetaxel as first-line therapy for patients aged 70 years and older with advanced squamous NSCLC. METHODS: This multicentre, open-label, randomised, phase 3 trial was carried out at 92 medical institutions in Japan. Eligible patients were aged 70 years and older, had advanced squamous NSCLC with no previous systemic chemotherapy, and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Using an electronic data capture system, patients were randomly assigned (1:1) to intravenous carboplatin (area under the concentration-time curve of 6 mg/mL per min for 30 min) on day 1 of a 21-day cycle and intravenous nab-paclitaxel (100 mg/m2 for 60 min) on days 1, 8, and 15 every 3 weeks or intravenous docetaxel (60 mg/m2 for 60 min) on day 1 every 3 weeks. Randomisation was computer-generated per participant and stratified by ECOG performance status, clinical stage, sex, age, and institution. The primary endpoint was overall survival, measured in the full analysis set and defined as the time from registration to the date of death due to any cause. Safety was assessed in all patients who received at least one dose of the trial treatment. This trial is registered with the UMIN Clinical Trials Registry, UMIN000019843, and the Japan Registry of Clinical Trials, jRCTs041180110. After the planned interim analysis in Aug 3, 2020, the independent data monitoring committee recommended that the trial be stopped early. This report represents the final analysis. FINDINGS: Between Feb 24, 2016, and Aug 11, 2020, 196 patients were enrolled and were randomly assigned to the carboplatin plus nab-paclitaxel group (n=98) or the docetaxel group (n=98). Of these patients, four (carboplatin plus nab-paclitaxel group, n=3; docetaxel group, n=1) did not receive any treatment and two patients in the docetaxel group were excluded from the full analysis set. Median overall survival in the full analysis set was 16·9 months (95% CI 12·6-25·4) in the carboplatin plus nab-paclitaxel group and 10·9 months (8·5-12·4) in the docetaxel group (hazard ratio 0·52 [90% CI 0·38-0·70]; p=0·0003). Grade 3-4 adverse events occurred in 79 (83%) patients in the carboplatin plus nab-paclitaxel group and 77 (79%) patients in the docetaxel group (p=0·63). The most common grade 3-4 adverse events in the carboplatin plus nab-paclitaxel group and the docetaxel group were leukopenia (44 [46%] vs 55 [57%]; p=0·20), neutropenia (60 [63%] vs 75 [77%]; p=0·046), febrile neutropenia (nine [10%] vs 19 [20%]; p=0·073), and anaemia (37 [39%] vs two [2%]; p<0·0001). Serious treatment-related adverse events of all grades occurred in 13 (14%) patients in the carboplatin plus nab-paclitaxel group and 11 (11%) patients in the docetaxel group. Treatment-related deaths occurred in two (2%; respiratory failure n=1, visceral arterial ischaemia n=1) patients in the carboplatin plus nab-paclitaxel group and one (1%; sepsis) patient in the docetaxel group. INTERPRETATION: Our study showed that overall survival was longer with carboplatin plus nab-paclitaxel than with docetaxel, suggesting that carboplatin plus nab-paclitaxel can be used as standard first-line treatment for patients aged 70 years and older with advanced squamous NSCLC. FUNDING: Taiho Pharmaceutical.

Cough challenge tests involving mechanical stimulation of the cervical trachea in patients with cough as a leading symptom.

BACKGROUND AND OBJECTIVE: Challenge tests involving chemical stimulation by inhalation of capsaicin or citric acid are currently used to assess cough sensitivity. We investigated the clinical usefulness of cough challenge tests based on mechanical stimulation. METHODS: A total of 347 patients (126 men and 221 women) were enrolled in the study, including 161 patients with asthma, 116 with cough-variant asthma, 27 with acute upper respiratory tract viral infections, 25 with acute bronchitis, four with pneumonia, three with chronic bronchitis and 11 with cough of unknown aetiology. Three modes of mechanical stimulation were assessed: the cervical trachea was compressed softly with the fingers several times (tracheal compression test); the trachea was stretched by retroflexion of the neck for 5 s (tracheal stretch test); and a vibrating tuning fork was placed on the cervical trachea for 20 s (tuning fork test). The relationships between phonation-induced cough and the results of these tests were assessed. RESULTS: The cough detection rate was 27.7% with the tracheal compression test, 39.8% with the tracheal stretch test and 36.9% with the tuning fork test. An itchy sensation with or without cough was noted by about 50% of subjects undergoing each of the tests. Provocation of cough and an itchy sensation during each test was significantly more frequent in subjects with phonation-induced cough. Tests were usually negative after improvement of the cough with treatment. CONCLUSIONS: Mechanical stimulation of the cervical trachea is a feasible cough challenge test that may be useful for evaluating disease activity.

Retrospective Prognostic Study of Death at Home or Hospice Versus at a Hospital Among Patients With Advanced Non-Small Cell Lung Cancer.

BACKGROUND: Patients with advanced non-small cell lung cancer greatly care about where they will die. Most people in Japan preferred their location of death as their homes. But only 8.2% of patients with cancer spend their last days at home with palliative care in Japan. Many patients with cancer are still going to spend their last days at a hospital (81.7%). OBJECTIVE: We examined the survival times of such patients according to their place of death; that is, whether they died at home, at a hospice, or at a hospital, and investigated patient characteristics. RESULTS: Among the 313 patients recruited, 214 were analyzed in this study: 90, 49, and 75 received hospital-based, home-based, and hospice-based palliative care, respectively. The patients who died at a hospice exhibited significantly longer survival than those who died at hospital (estimated median survival time, 420 days [95% confidence interval [CI]: 325-612 days] versus 252 days [95% CI: 201-316 days]; P < .0001). The characteristics of patients did not differ significantly according to place of death. CONCLUSIONS: Patients who died at a hospice or at home exhibited significantly longer survival than those who died at a hospital for advanced non-small cell lung cancer.

Bilateral lung cancer showing various responses to immune checkpoint inhibitors: A case report.

BACKGROUND: Combination immune checkpoint inhibitor (ICI) therapy has become the mainstay in cancer treatment, and the various antitumor effects of ICIs are being observed. Synchronous multiple primary lung cancers (SMPLCs), which simultaneously involve tumors of different histologies, are often encountered in clinical settings. In standard lung cancer treatment, an anticancer drug, usually a platinum-based drug, is administered, and this first treatment provides some antitumor effect. Thus, the initial administration of platinum-based anticancer agent may mask the detection of SMPLCs. The following case represents different antitumor effects on two different primary lung lesions during treatment with ICIs. CASE PRESENTATION: A 72-year-old man was referred to our hospital for an abnormal chest shadow, and computed tomography showed masses in the left lower and right upper lungs. Transbronchial lung biopsy from the left lung tumor revealed an adenocarcinoma. Following the administration of pembrolizumab (200 mg/body over 3 weeks) as monotherapy, the tumor in the left lung rapidly reduced in size. However, the tumor in the right upper lung continued to grow. Finally, his disease was diagnosed as SMPLCs of adenocarcinoma and small cell lung cancer. CONCLUSION: Bilateral lung lesions considered to be intrapulmonary metastases have completely different responses to ICI treatment. It is necessary to consider a diagnosis of SMPLCs if lesions with different responses to antitumor therapy are observed.

Development of pyogenic granuloma with strong vascular endothelial growth factor receptor-2 expression during ramucirumab treatment.

The angiogenesis inhibitor ramucirumab (IMC-1121B) is a fully humanised IgG1 monoclonal antibody targeting the extracellular domain of vascular endothelial growth factor receptor 2. Ramucirumab has been approved as a second-line treatment for lung cancer. Pyogenic granuloma is an acquired, benign vascular tumour of the skin or mucous membrane. We encountered a patient with pyogenic granuloma who was treated with ramucirumab. The patient was a 48-year-old Japanese woman with advanced lung cancer who had been heavily pretreated using several lines of chemotherapy. Ramucirumab was administered as the fifth-line treatment with docetaxel. After 10 days, a painless rice-coloured or pink papule appeared on her finger. One month later, it increased in size to 20 mm. We examined the pathological condition by immunostaining using the resected specimen diagnosed as pyogenic granuloma. Paradoxically, this vascular tumour arose during the administration of an angiogenesis inhibitor.

Cough related to swallowing in asthma patients.

BACKGROUND: Occurrence of cough during swallowing is common among asthma patients, but has not been investigated in detail. OBJECTIVE: We conducted an observational study to determine the prevalence of swallowing-related cough (SRC) and its characteristics in asthma patients. METHODS: Asthma patients attending our outpatient department between May 2005 and April 2007 were interviewed to investigate if they had ever experienced SRC, as well as postnasal drip or heartburn and cough related to these conditions. RESULTS: Among 417 patients who completed the questionnaire, 121 patients (29.0%) had experienced SRC. Spicy and sour foods were the most frequent tussigenic foods, causing cough in 76.0% and 53.7% of the 121 patients, respectively. In patients without SRC, the prevalence rates of postnasal drip and postnasal drip-induced cough were 35.8% (106 of 296) and 7.8% (23 of 296), respectively. The corresponding prevalence rates in patients with SRC were 50.4% (61 of 121) and 37.2% (45 of 121), which were both significantly higher than in patients without cough (p = 0.006 and p < 0.001 respectively). In patients without SRC, the prevalence rates of heartburn and heartburn-induced cough were 22.2% (66 of 296) and 2.4% (7 of 296), respectively. The corresponding prevalence rates in patients with SRC were 45.5% (55 of 121) and 16.5% (20 of 121), with both being significantly higher than in patients without cough (p = 0.002 and p < 0.001, respectively). CONCLUSION: SRC was frequent in asthma patients, and was closely related to postnasal drip and heartburn. Irritable larynx is one of the possible underlying mechanisms of SRC. This study was registered with the University Hospital Medical Information Network clinical trials registry (registration number: UMIN000017426).

Influence of oral care on fractional exhaled nitric oxide.

BACKGROUND: Fractional exhaled nitric oxide (FeNO) is an indicator of bronchial inflammation in asthma patients. However, nitric oxide is also produced in the oral cavity, with production depending on the local anaerobic flora and intraoral acidity. OBJECTIVE: To evaluate the influence of oral care on measurement of FeNO, to investigate the influence of sleep when the oral environment changes dramatically, and to assess the impact of oral care on FeNO in the real clinical setting. METHODS: FeNO was measured before and after oral care in 14 subjects on awakening and at bedtime on 2 consecutive days to investigate variation of nitric oxide derived from the oral cavity. It was also measured before and after oral care in 62 outpatients with asthma to assess the clinical relevance of oral cavity nitric oxide. RESULTS: On both days, FeNO was significantly decreased by oral care on awakening (day 1: decrease = 10.6 ± 12.4 ppb, p = 0.0020; day 2: decrease = 11.6 ± 23.7 ppb, p = 0.0009), and the decrease was larger than at bedtime. In addition, FeNO was significantly reduced by oral care in asthma outpatients (decrease = 1.73 ± 0.95 ppb, p = 0.0090), and older age was significantly correlated with the decrease (p = 0.0261). CONCLUSION: Oral care resulted in a decrease of FeNO, especially on awakening. While nitric oxide derived from the oral cavity generally has a limited impact in outpatients with asthma, its influence on measurement of FeNO may need to be considered, especially in elderly patients.

A new method for enhanced expectoration of sputum by vibratory stimulation of the cervical trachea.

BACKGROUND: Expectoration of sputum can be difficult for patients with respiratory conditions such as chronic obstructive pulmonary disease, chronic bronchitis, or bronchiectasis because of the effects of decreased pulmonary function, respiratory muscle fatigue, altered sputum properties, and impaired ciliary function. We developed a new method for the vibratory stimulation of the cervical trachea and this study aimed to compare it with the Acapella (a current oscillation device) method. METHODS: Patients with chronic productive cough and difficulty with expectoration were recruited for the study. The tracheal vibration and Acapella methods were applied for 4 weeks each, according to a crossover design with an intervening 4-week washout period. To perform the tracheal vibration method, an electronic artificial larynx (Yourtone®) was applied to the cervical trachea for up to 5minutes. Patient preference for the two devices was determined from the performance scores recorded for each device and by using a visual analogue scale. RESULTS: Twelve patients were recruited in the study. According to the performance scores assigned by the subjects, the tracheal vibration method was effective in 9 patients, while the Acapella method was effective in 10 patients. Both methods were effective in 8 patients, among whom the tracheal vibration method was more effective in 5 patients. Both methods were found to be ineffective in 1 patient. CONCLUSIONS: The tracheal vibration method may be effective at removing central airway sputum and does not require repeated forced expiratory effort, which can otherwise cause exhaustion in patients with decreased lung function. Further investigation is required to confirm its use as a new oscillation technique.

Montelukast reduces inhaled chlorine triggered airway hyperresponsiveness and airway inflammation in the mouse.

BACKGROUND AND PURPOSE: Cysteinyl leukotrienes (CysLTs) are pro-inflammatory lipid mediators that exacerbate disease state in several asthma phenotypes including asthma induced by allergen, virus and exercise. However, the role of CysLTs in irritant-induced airway disease is not well characterized. The purpose of the current study was to investigate the effect of montelukast, a CysLT1 receptor antagonist, on parameters of irritant-induced asthma induced by inhalation of chlorine in the mouse. EXPERIMENTAL APPROACH: BALB/c mice were exposed to chlorine in air (100 ppm, for 5 min). Montelukast (3 mg·kg-1 ) or the vehicle (1% methylcellulose) was administered 24 and 1 h prior to chlorine exposure and 1 h prior to outcome measurements. Twenty-four hours after exposure, responses to inhaled aerosolized methacholine, cell composition and an array of cytokines/chemokines in bronchoalveolar lavage (BAL) fluid were measured. Neutralizing antibodies against IL-6 and VEGF were administered prior to exposures. KEY RESULTS: Montelukast reduced chlorine -induced airway hyperresponsiveness (AHR) to methacholine in the peripheral lung compartment as estimated from dynamic elastance, but not in large conducting airways. Montelukast treatment attenuated chlorine-induced macrophage influx, neutrophilia and eosinophilia in BAL fluid. Chlorine exposure increased VEGF, IL-6, the chemokines KC and CCL3 in BAL fluid. Montelukast treatment prevented chlorine-induced increases in VEGF and IL-6. Anti-IL-6 antibody inhibited chlorine-induced neutrophilia and reduced AHR. CONCLUSIONS AND IMPLICATIONS: Pre-treatment with montelukast attenuated chlorine-induced neutrophilia and AHR in mice. These effects are mediated, in part, via IL-6.