Usefulness of diurnal variation of fractional exhaled nitric oxide for predicting early therapeutic response to asthma treatment.

OBJECTIVE: Fractional exhaled nitric oxide (FeNO) is considered to be an adjunct for asthma management, although its usefulness remains controversial. Therefore, it may be necessary for new approaches to use FeNO for asthma management. We evaluated whether diurnal variations of FeNO can predict response to asthma treatment. METHODS: This pilot study consisted of 22 uncontrolled asthmatics and 16 healthy subjects. FeNO and peak expiratory flow (PEF) were measured by themselves twice daily at home for three weeks (asthmatics) or two weeks (healthy subjects), and daily mean and diurnal variations of FeNO and PEF levels were calculated. In uncontrolled asthmatics, treatment was intensified a week after study entry, and then control status was reevaluated after three to four weeks. Asthmatics were then divided into two groups; good or poor responders. RESULTS: Diurnal variations of FeNO levels, as well as daily mean FeNO and PEF levels, in uncontrolled asthmatics before intensive treatment were significantly higher than those in healthy subjects, regardless of treatment response (p < 0.01). Furthermore, in the good responders, diurnal variations of FeNO levels were significantly decreased in the 1st week (p < 0.05) of intensive treatment, whereas the daily mean FeNO levels significantly dropped in the 2nd week (p < 0.05). In the poor responders, no such changes were observed in FeNO levels. In terms of PEF, only the daily mean levels were significantly elevated after the initiation of intensive treatment, regardless of treatment response. CONCLUSIONS: Diurnal variations of FeNO may contribute to predicting early therapeutic response to asthma treatment.

Hydrogen sulfide as a novel biomarker of asthma and chronic obstructive pulmonary disease.

Hydrogen sulfide (H2S) has recently been recognised as the third important gas-signalling molecule, besides nitric oxide and carbon monoxide. H2S has been reported to be produced by many cell types in mammalian tissues and organs throughout the actions of H2S-generating enzymes or redox reactions between the oxidation of glucose and element of sulfur. Although the pathological role of H2S has not yet been fully elucidated, accumulative data suggest that H2S may have biphasic effects. Briefly, it mainly has anti-inflammatory and antioxidant roles, although it can also have pro-inflammatory effects under certain conditions where rapid release of H2S in tissues occur, such as sepsis. To date, there have been several clinical studies published on H2S in respiratory disorders, including asthma and chronic obstructive pulmonary disease (COPD). According to previous studies, H2S is detectable in serum, sputum, and exhaled breath, although a gold standard method for detection has not yet been established. In asthma and COPD, H2S levels in serum and sputum can vary depending on the underlying conditions such as an acute exacerbation. Furthermore, sputum H2S in particular correlates with sputum neutrophils and the degree of airflow limitation, indicating that H2S has potential as a novel promising biomarker for neutrophilic airway inflammation for predicting current control state as well as future risks of asthma. In the future, concurrent measures of H2S with conventional inflammatory biomarkers (fractional exhaled nitric oxide, eosinophils etc) may provide more useful information regarding the identification of inflammatory phenotypes of asthma and COPD for personalised treatment.

Comparison of fractional exhaled nitric oxide levels measured by different analyzers produced by different manufacturers.

Objective: Fractional exhaled nitric oxide (FeNO) is widely used as a biomarker of allergic airway inflammation. At present, both stationary chemiluminescence and portable electrochemical analyzers produced by different manufacturers are available. However, it remains debatable whether those analyzers are comparable to each other. We compare FeNO levels obtained by different analyzers.Methods: For the first study, 153 subjects were enrolled to compare differences in FeNO levels measured using three analyzers (NA623NP®, NObreath®, and NIOX MINO®) which were produced by different manufacturers. For the second study, 30 subjects were recruited to compare FeNO levels obtained by the two analyzers (NIOX MINO® and NIOX VERO®) produced by the same manufacturer. FeNO was measured twice using each analyzer in random order.Results: FeNO levels obtained using the NIOX MINO® and NObreath® were more variable than those measured using the NA623NP®. There were strong positive correlations in FeNO levels measured by the NA623NP®, NIOX MINO®, and NObreath® (p < 0.001). The NA623NP® and NIOX MINO® provided the highest and lowest FeNO levels, respectively; whereas, those obtained by NObreath® were intermediate. No significant differences were observed in FeNO levels obtained using the NIOX MINO® and NIOX VERO®.Conclusions: FeNO levels measured by the NIOX MINO® and NIOX VERO®, both of which were produced by the same manufacturer, have comparability. However, significant differences in FeNO levels exist when measured by analyzers manufactured by different manufacturers. This should be taken into account for FeNO measurement.

Clinical Characteristics of Cough Frequency Patterns in Patients with and without Asthma.

BACKGROUND: Cough is a frequent symptom of asthma. Cough frequency (CoFr) monitoring devices are now available to objectively measure cough counts and offer a novel endpoint to assess asthma. However, little is known about CoFr in asthma. OBJECTIVE: The aims were, first, to determine whether unique features of CoFr exist in asthmatic and nonasthmatic patients and, secondly, to evaluate relationships between CoFr and pathophysiological parameters of asthma. METHODS: In the current study, 73 asthmatic and 63 nonasthmatic patients suffering from persistent cough were enrolled. At study entry, the Leicester Cough Questionnaire (LCQ health status), cough visual analog scale (VAS), Leicester Cough Monitor (LCM), fractional exhaled nitric oxide (FeNO) measurements, and spirometry were performed. In asthmatic patients, the bronchial hyperresponsiveness (BHR) test was conducted if applicable. In 28 asthmatic and 17 nonasthmatic patients, LCQ, VAS, and LCM were examined before and after treatment. RESULTS: CoFr during nighttime (asleep) was significantly higher in asthmatic patients than in nonasthmatic patients. Twenty-four-hour CoFr significantly decreased after appropriate treatment and was correlated with changes in VAS and LCQ in all patients. The improvement in cough in asthmatic patients was greater during nighttime than during daytime (awake). CoFr in asthmatic patients was significantly correlated with BHR, but not with FeNO. CONCLUSIONS: In asthmatic patients, nocturnal CoFr can be associated with BHR, was significantly higher before treatment, but improved more after treatment compared with nonasthmatic patients. Monitoring nocturnal CoFr may provide unique and valuable information on making an early prediction of therapeutic effects in asthma.

Brief report on similar mutational changes in neurofibromatosis type 2 gene in minute pulmonary meningothelial-like nodule and meningioma of the central nervous system.

INTRODUCTION: Minute Pulmonary Meningothelial-like Nodules (MPMNs) are usually detected incidentally adjacent to lung cancer tissue. The pathogenesis is unknown. MPMNs reportedly share the status of neurofibromatosis (NF)-2 gene with meningiomas of the central nervous system. RESULTS: Immunohistochemical staining of two MPMNs revealed they were positive for epithelial membrane antigen (EMA), vimentin, CD56, and progesterone. We identified deletion of the NF-2 gene in two MPMNs and one CNS meningioma. CONCLUSIONS: MPMN and CNS meningioma may develop via the same mechanism through NF-2 translocation. Further studies are required to elucidate the genetic similarities between these entities. METHODS: We used fluorescence in situ hybridization to explore the status of the NF-2 gene in MPMNs and compare it with that of CNS meningiomas. We used a commercially available locus-specific probe for the NF-2 region to analyze whole tissue sections of two MPMNs and two CNS meningiomas by fluorescence in situ hybridization.

Renin-producing germ cell tumor in the pineal apparatus and mediastinum: A rare case report.

Ectopic extrarenal renin-producing tumor is a rare disease with approximately 30 case reports in English literature. We herein present the first case of renin-producing germ cell tumors in the pineal apparatus and mediastinum. A 26-year-old man who had undergone craniotomy for the treatment of pineal tumor was found to have hypertension at a regular visit postoperatively. Laboratory findings revealed high plasma levels of renin activity and that of aldosterone concentration. Chest computed tomography demonstrated a large tumor in the mediastinum. The pathological findings revealed the mediastinal germ cell tumor positive for renin. The present case suggests that for young patients presenting with hypertension with a mediastinal tumor, the possibility of a renin-producing tumor should be considered.

A Serological Biomarker of Versican Degradation is Associated with Mortality Following Acute Exacerbations of Idiopathic Interstitial Pneumonia.

BACKGROUND: Idiopathic interstitial pneumonia (IIP) is characterized by an increased rate of extracellular matrix (ECM) remodeling resulting in fibrosis. Acute exacerbations of IIP represent periods of increased disease activity, thus we hypothesized that ECM remodeling was altered during acute exacerbations and investigated this by serological neo-epitope biomarkers. METHODS: Patients who were sequentially admitted to the hospital with acute exacerbations of IIP were retrospectively analyzed for ECM remodeling at time of exacerbation (AE-IIP) and at clinical stability (S-IIP). Biomarkers released by matrix metalloproteinase-mediated degradation of collagen type I (C1M), III (C3M), IV (C4M), and VI (C6M), elastin (ELM7), versican (VCANM), biglycan (BGM), and C-reactive protein (CRPM) were assessed in serum by competitive ELISAs utilizing neo-epitope specific monoclonal antibodies. RESULTS: Sixty-eight patients at AE-IIP and 29 at S-IIP were included in this retrospective analysis. Of these, 28 and 11 patients, respectively, had idiopathic pulmonary fibrosis. At AE-IIP, serum levels of C4M (p = 0.002) and C6M (p = 0.024) were increased as compared with S-IIP, while ELM7 (p = 0.024) and VCANM (p < 0.0001) were decreased. Lower VCANM levels at AE-IIP were associated with increased risk of mortality (HR 0.64 [95% CI 0.43-0.94], p = 0.022). CONCLUSIONS: The ECM remodeling profile was significantly altered during acute exacerbations of IIP, and a biomarker of versican degradation was related to mortality outcome. These results indicate that biomarkers of ECM remodeling may be useful in the non-invasive evaluation of acute exacerbations of IIP. Especially versican degradation, as measured serologically by VCANM, may have prognostic potential and help guide treatment for acute exacerbations.

A Case of Eosinophilic Granulomatosis with Polyangiitis Complicated with A IgG4 Related Disease Like Symptoms.

We report a case of eosinophilic granulomatosis with polyangiitis (EGPA) complicated with a IgG4 related disease like symptoms presenting as eyelid swellings. In the present case, the serum level of IgG4 and the ratio of IgG4 to IgG were generally increased by the disease course of EGPA. Considering the course of clinical symptoms, there is a possibility that orbital manifestations were one of the clinical features during the disease course of EGPA while the histological features of right eyelid tissue and other ocular manifestations were consistent with the diagnosis of IgG4 related disease.

The clinical role of fractional exhaled nitric oxide in asthma control.

BACKGROUND: The potential role and characteristics of fractional exhaled nitric oxide (FeNO) remain unclear in the treatment of asthma. OBJECTIVE: To explore the clinical role of FeNO in asthmatic treatment. METHODS: We evaluated whether the mean or change of FeNO levels in the treatment period is associated with other conventional control parameters and predicted some clinical outcomes of asthma. We retrospectively analyzed the mean and percentage change of FeNO levels in the first 5 measurements at our hospital. RESULTS: The study found a significantly strong correlation between FeNO level at diagnosis and the largest changes of FeNO values from diagnosis. No significant correlations were observed between FeNO levels and other parameters (Asthma Control Test [ACT] score or forced expiratory volume in one second [FEV1]) in mean and percentage change of values under treatment of asthma; however, significant positive correlations were found between ACT scores and FEV1. The mean FeNO level revealed a significant negative correlation with an annual change in FEV1 in individuals with asthma who were followed up for more than 2 years. Both the mean ACT score and percent predicted FEV1 revealed a significant negative correlation with occasional use of systemic corticosteroids. CONCLUSION: During conventional treatment of asthma, the largest changes of FeNO values from diagnosis were strongly correlated with FeNO levels at diagnosis. As for the unlikely conventional parameters, no significant associations were observed between FeNO levels and deterioration of asthma during the treatment periods. An elevated mean FeNO level may be a marker of decreased lung function in individuals with asthma.

The efficacy of the Kampo medicine rikkunshito for chemotherapy-induced anorexia (RICH trial): study protocol for a randomized controlled trial.

BACKGROUND: Cisplatin is a key drug in lung cancer therapy. However, cisplatin is also well known to induce gastrointestinal disorders, such as chemotherapy-induced nausea and vomiting, anorexia, and weight loss. These symptoms sometimes affect patients' quality of life and make continuation of chemotherapy difficult. Anorexia is a cause of concern for patients with cancer because a persistent loss of appetite progresses to cancer cachexia. Although evidence-based management for chemotherapy has recently been established, there is room for improvement. METHODS/DESIGN: This placebo-controlled, double-blind, randomized trial will aim to determine the efficacy of the traditional Japanese Kampo medicine rikkunshito (TJ-43) for preventing anorexia caused by cisplatin-including chemotherapy in patients with lung cancer. Patients with lung cancer who plan to receive cisplatin-including chemotherapy will be recruited. Patients who provide written consent will be randomly allocated to receive either TJ-43 (arm A) or placebo (arm B) for one course of chemotherapy (21 or 28 consecutive days). Investigators and patients will be masked to the treatment assignment throughout the trial. The primary endpoint will be evaluated as the change in dietary intake from day 0 (the day before the start of chemotherapy) to day 7 of cisplatin-including chemotherapy. The two arms of the trial will comprise 30 patients each. From November 2014, a total of 60 patients will be recruited, and recruitment for the study is planned to be complete by October 2017. DISCUSSION: This trial is designed to examine the efficacy of rikkunshito (TJ-43) for reducing anorexia and maintaining food intake caused by cisplatin-including chemotherapy in patients with lung cancer. TRIAL REGISTRATION: Japan Pharmaceutical Information Center Clinical Trials Information (JAPIC CTI), trial registration: JAPIC CTI-142747 . Registered on 15 December 2014; the RICH trial.

Involvement of midkine in the development of pulmonary fibrosis.

Midkine is a low-molecular-weight heparin-binding protein that is strongly expressed mainly in the midgestation period and has various physiological activities such as in development and cell migration. Midkine has been reported to be strongly expressed in cancer cells and in inflammation and repair processes, and to be involved in the pathogenesis of various diseases. However, its role in the lung is poorly understood. In this study, we analyzed the clinical characteristics of idiopathic pulmonary fibrosis patients in relation to midkine expression and used a mouse bleomycin-induced pulmonary fibrosis model to investigate the role of midkine in pulmonary fibrosis. In the idiopathic pulmonary fibrosis patients, the serum midkine level was significantly higher than in healthy subjects, and midkine levels in the serum and bronchoalveolar lavage (BAL) fluid correlated positively with the percentage of inflammatory cells in the BAL fluid. In wild-type mice, intratracheal bleomycin administration increased midkine expression in lung tissue. Additionally, compared with wild-type mice, midkine-deficient mice showed low expression of both collagen and α-smooth muscle actin, as well as a low value for the pathological lung fibrosis score after bleomycin administration. Furthermore, the total cell count and lymphocyte percentage in the BAL fluid, as well as TNF-α and transforming growth factor-ß expression in lung tissue, were significantly lower in the midkine-deficient mice compared with wild-type mice. These results suggest that midkine is involved in the development of pulmonary fibrosis by regulating inflammatory cell migration into the lung, and TNF-α and transforming growth factor-ß expression.

Baseline serum syndecan-4 predicts prognosis after the onset of acute exacerbation of idiopathic interstitial pneumonia.

BACKGROUND: Patients with idiopathic interstitial pneumonia can experience acute respiratory worsening, also known as acute exacerbation, with a large deterioration on prognosis. The precise mechanism remains unclear; however, syndecan-4 may be involved. Syndecan-4, a transmembrane heparan sulfate proteoglycan expressed in a variety of cells (e.g., epithelial cells, macrophages, fibroblasts, etc.), performs various biological roles by binding to several proteins through its heparan sulfate glycosaminoglycan side chains. The goal of this study was to clarify the role of syndecan-4 in acute exacerbation of idiopathic interstitial pneumonia. METHODS: Patients with idiopathic interstitial pneumonia who had been sequentially admitted to our hospital due to acute exacerbation were retrospectively analyzed. First, serum syndecan-4 levels in the acute exacerbation and clinically stable phases were compared. Second, the relationship between serum syndecan-4 levels and clinical parameters was analyzed. Third, the relationship between serum syndecan-4 levels and prognosis was evaluated. RESULTS: Serum syndecan-4 levels were significantly lower in patients with acute exacerbation of idiopathic interstitial pneumonia than in patients in the clinically stable phase. Serum syndecan-4 levels also showed a significant positive correlation with white blood cell count and a weak positive tendency with KL-6 and baseline %VC. Prognosis was significantly worse in patients with idiopathic interstitial pneumonia with high baseline serum syndecan-4 levels than with low baseline levels. Multiple logistic analysis indicated baseline serum syndecan-4 level as the only prognostic predictor following acute exacerbation. CONCLUSIONS: Baseline serum syndecan-4 is a possible prognostic biomarker after the onset of acute exacerbation of idiopathic interstitial pneumonia.

The association between risk of airflow limitation and serum uric acid measured at medical health check-ups.

The prevalence of COPD and asthma is increasing all over the world; however, their morbidities are thought to be greatly underestimated because of unawareness of patients' conditions and respiratory symptoms. Spirometry is useful for the early detection of COPD and asthma with airflow limitation (AL), although it is not yet widely used for screening in epidemiological and primary care settings. A simple predictive marker used in combination with spirometry for AL is expected to be established. In medical health check-ups, serum uric acid (s-UA) is measured when screening for gout and has recently been suggested to have an association with several respiratory disorders, including asthma and COPD. However, whether s-UA influences the development of AL remains unclear. Therefore, the aims of this study were to examine the relationship between AL and s-UA and to investigate s-UA as a potential auxiliary marker for predicting AL risk in medical health check-ups. A total of 8,662 subjects aged >40 years were included. They were administered a simple questionnaire and assessed using pulmonary function tests, blood pressure (BP) measurements, and blood samplings. One hundred and fifty-six subjects (1.8%) had AL, just 29% of whom had experienced respiratory symptoms. The subjects with AL had significantly higher s-UA levels compared with never-smoking subjects without AL. Forced expiratory volume in 1 second (FEV1) %predicted showed significant correlations with age, smoking index, body mass index (BMI), mean BP, white blood cells, hemoglobin A1c, s-UA, and high-density lipoprotein cholesterol. In multiple logistic regression analysis, s-UA, in addition to age, smoking index, respiratory symptoms, and BMI, was independently associated with AL. In conclusion, elevated s-UA levels, together with respiratory symptoms, high smoking index, and weight loss, may epidemiologically predict the development of AL risk.

Japanese guidelines for adult asthma 2017.

Adult bronchial asthma is characterized by chronic airway inflammation, and presents clinically with variable airway narrowing (wheezes and dyspnea) and cough. Long-standing asthma induces airway remodeling, leading to intractable asthma. The number of patients with asthma has increased; however, the number of patients who die of asthma has decreased (1.2 per 100,000 patients in 2015). The goal of asthma treatment is to enable patients with asthma to attain normal pulmonary function and lead a normal life, without any symptoms. A good relationship between physicians and patients is indispensable for appropriate treatment. Long-term management by therapeutic agents and elimination of the causes and risk factors of asthma are fundamental to its treatment. Four steps in pharmacotherapy differentiate between mild and intensive treatments; each step includes an appropriate daily dose of an inhaled corticosteroid, varying from low to high levels. Long-acting ß2-agonists, leukotriene receptor antagonists, sustained-release theophylline, and long-acting muscarinic antagonist are recommended as add-on drugs, while anti-immunoglobulin E antibody and oral steroids are considered for the most severe and persistent asthma related to allergic reactions. Bronchial thermoplasty has recently been developed for severe, persistent asthma, but its long-term efficacy is not known. Inhaled ß2-agonists, aminophylline, corticosteroids, adrenaline, oxygen therapy, and other approaches are used as needed during acute exacerbations, by choosing treatment steps for asthma in accordance with the severity of exacerbations. Allergic rhinitis, eosinophilic chronic rhinosinusitis, eosinophilic otitis, chronic obstructive pulmonary disease, aspirin-induced asthma, and pregnancy are also important issues that need to be considered in asthma therapy.

Immunohistochemical profiling of receptor tyrosine kinases, MED12, and TGF-ßRII of surgically resected small cell lung cancer, and the potential of c-kit as a prognostic marker.

The limited number of available treatments for patients with small-cell lung cancer (SCLC) has prompted us to further investigate the biology of SCLC by molecular profiling. We collected formalin-fixed paraffin-embedded tumor samples from 127 patients with SCLC, who had undergone surgery at 16 institutions between January 2003 and January 2013, and analyzed the association between disease-specific survival and protein expression of c-kit, c-Met, epidermal growth factor receptor, human EGFR-related 2, vascular endothelial growth factor receptor II, anaplastic lymphoma kinase, mediator complex subunit 12 (MED12), and transforming growth factor beta receptor II (TGF-ßRII) by immunohistochemistry (IHC). Of the 125 evaluable samples, all tumors expressed MED12, and 123 samples (98.4%) expressed TGF-ßRII. MED12 was highly expressed in the nucleus in 92% of the positive samples while TGF-ßRII was highly expressed in the cytoplasm in 55% of the positive samples. High c-kit expression was an independent favorable prognostic marker confirmed by multivariate analysis (hazard ratio: 0.543, 95% confidence interval: 0.310-0.953, p = 0.033). Both the relapse free-survival and overall survival of patients who underwent adjuvant chemotherapy were statistically longer in those with high c-kit expression (n = 38) than those with intermediate, low, or no c-kit expression (n = 19) (not reached vs 11.6 months, p = 0.021; not reached vs 25.9 months, p = 0.028). IHC for c-kit may offer a prognostic marker for early-stage SCLC, and the results for MED12 and TGF-ßRII may suggest the biological characteristics of SCLC. Further investigation of the roles of their related molecules in early stage SCLC is required.

Expression of Notch1 and Numb in small cell lung cancer.

Notch signaling in tumorigenesis functions as an oncogene or tumor suppressor according to the type of malignancy. Numb represses intracellular Notch signaling. Previous studies have demonstrated that Notch signaling suppresses the proliferation of small cell lung cancer (SCLC) cell lines. However, in SCLC, the association between Notch1 and Numb expression and clinicopathological factors or prognosis has remained unclear. In this study, we evaluated the expression of Notch1 and Numb in SCLC. We immunohistochemically assessed 125 SCLCs that were surgically resected at 16 institutions participating in either the Hokkaido Lung Cancer Clinical Study Group Trial (HOT) or the Fukushima Investigative Group for Healing Thoracic Malignancy (FIGHT) between 2003 and 2013. Correlations between Notch1 or Numb expression and various clinicopathological features were evaluated. Notch1 expression was associated with ECOG performance status. Numb expression was associated with age, sex, and pathological histology (SCLC or Combined SCLC). Analysis of cellular biological expression did not demonstrate a significant correlation between the expression of Notch1 and of Numb. Multivariate Cox regression analysis showed that high Notch1 expression was an independent favorable prognostic factor for SCLC(hazard ratio = 0.503, P = 0.023). High Notch1 expression, but not Numb expression, is associated with favorable prognosis in SCLC.

Identification of Clinical Phenotypes in Idiopathic Interstitial Pneumonia with Pulmonary Emphysema.

Objective Since the term "combined pulmonary fibrosis and emphysema" (CPFE) was first proposed, the co-existence of pulmonary fibrosis and pulmonary emphysema (PE) has drawn considerable attention. However, conflicting results on the clinical characteristics of patients with both pulmonary fibrosis and PE have been published because of the lack of an exact definition of CPFE. The goal of this study was thus to clarify the clinical characteristics and phenotypes of idiopathic interstitial pneumonia (IIP) with PE. Methods We retrospectively analyzed IIP patients who had been admitted to our hospital. Their chest high-resolution computed tomography images were classified into two groups according to the presence of PE. We then performed a cluster analysis to identify the phenotypes of IIP patients with PE. Results Forty-four (53.7%) out of 82 patients had at least mild emphysema in their bilateral lungs. The cluster analysis separated the IIP patients with PE into three clusters. The overall survival rate of one cluster that consisted of mainly idiopathic pulmonary fibrosis (IPF) patients was significantly worse than those of the other clusters. Conclusion Three different phenotypes can be identified in IIP patients with PE, and IPF with PE is a distinct clinical phenotype with a poor prognosis.