Asthma control and quality of life in a real-life setting: a cross-sectional study of adult asthma patients in Japan (ACQUIRE-2).

Objective: The level of asthma control in adult asthma patients receiving treatment in clinical practice from allergy and/or respiratory specialists in Japan remains unclear. We conducted the ACQUIRE-2 study (NCT02640742) to evaluate level of asthma control, asthma symptoms, health-related quality of life (HR-QoL), and reliever medication use in this setting. Methods: This observational study was undertaken between December 2015 and June 2016 in 58 medical institutions across Japan. We enrolled outpatients aged ≥20 years diagnosed with asthma for ≥1 year who were being managed by specialists. Criteria to evaluate the level of asthma control were based on modified definitions of the Asthma Prevention and Management Guideline 2015, Japan (JGL 2015) and Global Initiative for Asthma (GINA) 2012. Asthma symptoms, HR-QoL, and reliever medication use were also evaluated. Results: Of 1250 enrolled patients, 1175 were analyzed, 62.9% of whom were women. Mean (± standard deviation) age and duration of asthma were 59.7 ± 14.5 years and 16.9 ± 14.0 years, respectively. Using JGL 2015-based criteria, 24.4%, 69.2%, and 6.5% of patients had well-controlled, insufficiently-controlled, and poorly-controlled asthma, respectively. Using GINA-based criteria, 35.1%, 49.8%, and 15.1% of patients had controlled, partly controlled, and uncontrolled asthma, respectively. Daytime and nighttime asthma symptoms were experienced by 51.5% and 44.9% of patients, respectively. The mean MiniAQLQ score was 5.8 ± 1.0 (7-point scale). Conclusions: Asthma was not well-controlled in the majority of patients in this study. To achieve better asthma control, improvements in symptom monitoring and management may be required.

Asthma exacerbations in patients with asthma and rhinitis: Factors associated with asthma exacerbation and its effect on QOL in patients with asthma and rhinitis.

BACKGROUND: The comorbidity of asthma and allergic rhinitis is remarkably high, but not much is known about the effects of this combined condition on the quality of life. We aimed to evaluate the factors associated with asthma exacerbations and the effect of the exacerbations on the quality of life (QOL) through a one-year, large-scale, observational study in Japanese patients with asthma and rhinitis. METHODS: A case survey by attending physicians and a patient survey was conducted at each assessment timepoint over a period of one year. Patients were divided into two groups according to the presence or absence of asthmatic attacks after enrollment and were matched using propensity scores to evaluate the factors associated with asthma exacerbations and the effect of the exacerbation on QOL. RESULTS: Potential factors associated with asthma exacerbations included high body mass index value, low forced expiratory flow 75% of forced vital capacity (FEF75%), severe rhinitis as determined based on ARIA (Allergic Rhinitis and its Impact on Asthma). Although patients with asthma exacerbations had significantly impaired quality of life at baseline as evidenced by the economic aspects, in addition to physical, mental, and social activities, no further reduction with the attacks was observed. CONCLUSIONS: This study suggested that higher body mass index (BMI) and severe asthma as well as severe rhinitis were factors associated with asthma exacerbations. Although patients with asthma exacerbations had impaired QOL, attacks caused no further reduction.

Helicobacter pylori infection is associated with favorable outcome in advanced gastric cancer patients treated with S-1 adjuvant chemotherapy.

BACKGROUND AND OBJECTIVES: Limited information exists regarding beneficial effects of Helicobacter pylori. To examine the effect in advanced gastric cancer, we compared survival for patients treated with surgery-only or adjuvant chemotherapy on the basis of H. pylori infection status. METHODS: A cohort of 491 patients who underwent R0 resection for locally advanced gastric cancer between 2000 and 2009 at 12 institutions in northern Japan was included. H. pylori infection status, was assessed from paraffin-embedded formalin-fixed samples. Overall survival (OS) and disease-free survival (DFS) in surgery-only (Surgery) and adjuvant chemotherapy (S-1) groups were analyzed. A propensity score matching was employed to correct for confounding factors by indication. RESULTS: H. pylori infection was positive in 175 patients and negative in 316 patients. H. pylori-positive patients showed significantly better survival than H. pylori-negative patients in both OS (hazard ratio [HR] 0.593, 95% confidence interval [CI] 0.417-0.843; P = 0.003]) and DFS (HR 0.679, 95%CI 0.492-0.937; P = 0.018). Propensity score matching further confirmed that S-1 was virtually only effective when tumors were H. pylori-positive. CONCLUSIONS: The favorable outcome of H. pylori-positive patients implies that the host immune system is modulated by H. pylori enhancing the chemotherapeutic efficacy.

Steroidogenesis in ovarian-like mesenchymal stroma of hepatic and pancreatic mucinous cystic neoplasms.

STEROIDOGENESIS IN HEPATIC MUCINOUS CYSTIC NEOPLASM: Aim Mucinous cystic neoplasms (MCNs) occur in the ovary, pancreas, and retroperitoneum but very rarely in the liver. Mucinous cystic neoplasms are known to harbor ovarian-like mesenchymal stroma (OLS) expressing progesterone and estrogen receptors. In this study we evaluated steroidogenesis in OLS of 25 hepatic MCNs and 24 pancreatic MCNs. Methods Both steroid receptors and steroidogenic factors were immunohistochemically evaluated using H-scores and results were compared with those in 15 ovarian MCNs and 10 normal ovaries. Results Androgen receptor (AR) H-scores in OLS were significantly higher in hepatic, pancreatic, and ovarian MCN than those in normal ovaries. H-scores of cytochrome P450 17α-hydroxylase/c17-20 lyase (P450c17) and 5α-reductase-1 (5αRED-1) in the stroma were significantly higher in OLS of hepatic and pancreatic MCN than in the stroma of ovarian MCN and normal ovary. In tumor epithelium, AR H-scores were significantly higher in hepatic and pancreatic MCN than in ovarian MCN. In both hepatic and pancreatic MCN, a significant positive correlation was detected between AR H-score in the epithelium and P450c17 H-score in OLS (hepatic MCN: Pearson's r = 0.446, P = 0.025; pancreatic MCN: r = 0.432, P = 0.035). In pancreatic MCN, a significantly positive correlation was detected between AR H-score in the tumor epithelium and 5αRED-1 H-score in OLS (Pearson's r = 0.458, P = 0.024). Conclusions These results indicated that locally produced androgens in OLS could be pivotal for tumorigenesis of both hepatic and pancreatic MCN and influence epithelial cells, possibly in a paracrine fashion, which could represent biological significance of OLS in these neoplasms.

Analysis of PIK3CA mutations and PI3K pathway proteins in advanced gastric cancer.

BACKGROUND: Although surgery and chemotherapy have extended advanced gastric cancer patient survival, some patients still experience relapse and metastasis. We postulated that PI3K pathway proteins could be prognostic biomarkers for the advanced gastric cancer patients. METHODS: A retrospective cohort of 160 advanced gastric cancer patients receiving potentially curative surgery with/without chemotherapy was investigated for PIK3CA mutation and PI3K pathway protein level in the context of overall survival and relapse-free survival. RESULTS: Thirteen patients (13 of 111, 11.7%) had PIK3CA mutations in codon 545, whereas one patient (1 of 94, 1.1%) had a mutation in PIK3CA codon 1047. PI3K pathway protein immunohistochemistry demonstrated that phosphorylated AKT positive [p-AKT (+)] patients in the surgery-only group had a good prognosis in terms of overall survival and relapse-free survival. No significant association between PIK3CA mutations and PI3K pathway protein level was seen. CONCLUSIONS: This study revealed that (1) PIK3CA hotspot mutations occurred with low frequency in gastric cancer; (2) PIK3CA hotspot mutations were not directly associated with PI3K pathway activation; and (3) p-AKT (+) may be a biomarker for better outcomes for gastric cancer patients undergoing gastrectomy regardless of the PIK3CA mutation status.

A STUDY OF INSPIRATORY RESISTANCE OF DRY POWDER INHALER OF AGENTS FOR ASTHMA CONTROL.

OBJECTIVE: Because dry powder inhalers (DPI) aerosolize agents by means of inspiration of patients themselves, inspiratory resistance of DPI is an important factor for increasing inhalation efficiency. Therefore, we measured inspiratory resistance of DPI of agents for asthma control. METHODS: Using Flow/Volume Simulator, when setting flow rates at 6, 30, 60, 90, and 120L/min, we read off suction pressures and find inspiratory resistances by calculation (=suction pressure/flow rate) at each flow rate. RESULTS: In all DPI, inspiratory resistance increases with the increasing flow rate. To maintain flow rate of 60L/min, suction pressure of around 20-cmH2O for Diskus(®) and Ellipta(®), between 35- and 45-cmH2O for Turbuhaler (®), and about 60-cmH2O for Twisthaler(®) were needed. CONCLUSION: It is suggested that we should instruct patients to inhaler DPI based on inspiratory resistance of the DPI.

[A MULTICENTER STUDY ON CHILDHOOD ALLERGIC RHINITIS TREATMENT IN THE TOHOKU REGION].

BACKGROUND: We performed a multicenter study in order to clarify the present conditions of the childhood allergic rhinitis treatment in many departments of otorhinolaryngology and pediatrics/internal medicine in the Tohoku region, northern Japan. METHODS: We performed a questionnaire survey about patient backgrounds, nasal symptoms, QOL disturbance, and treatment agents, for childhood allergic rhinitis patients under age 12. RESULTS: The total number of cases was 814, the mean age of the patients seen in pediatrics/internal medicine departments was significantly lower than that in otorhinolaryngology. The merger rate of bronchial asthma of the patients seen in pediatrics/internal medicine was significantly higher, and nasal symptoms and QOL disturbance of the patients seen in otorhinolaryngology were significantly more severe. For therapeutic agents, antihistamines were most prescribed, and the combination of LT receptor antagonist and intranasal steroids was used for the cases in which nasal symptoms were severe. The nasal symptoms in the combination group were significantly improved compared with the antihistamine monotherapy group. CONCLUSION: It was indicated that the combination therapy was useful in the severe cases of childhood allergic rhinitis.

[Intravascular papillary endothelial hyperplasia of the lung].

We report a rare case of pulmonary intravascular papillary endothelial hyperplasia. The patient was a 63-year-old male. Multiple lung nodules were noted on chest computed tomography( CT) at preoperative check for gastric cancer. Metastatic lung tumor was suspected, and partial resection of the right lung was performed. Histopathologic examination revealed papillary proliferation lined by endothelial cells and a hematoma. Immunohistochemically, the endothelial cells were positive for CD31/CD34 and factor VIII related antigen.

Visual analog scale as a predictor of GINA-defined asthma control. The SACRA study in Japan.

OBJECTIVE: The assessment of asthma control is pivotal to treatment decisions. A questionnaire that assesses the Global Initiative for Asthma (GINA)-defined control requires four questions. A visual analog scale (VAS) to evaluate asthma control can be simply marked, but its correlation with GINA-defined control has been insufficiently evaluated. The purpose of this study is to evaluate whether VAS levels can predict GINA-defined asthma control with particular emphasis on the distinctions between "partly controlled" and "uncontrolled" and between "partly controlled" and "controlled" asthma, METHODS: A cross-sectional multicenter study was carried out throughout Japan (SACRA) from March to August 2009 among patients with a diagnosis and treatment of asthma. Asthma control was studied using the GINA questionnaire and a VAS measurement of asthma severity. Pulmonary function testing was not carried out, RESULTS: 1910 physicians enrolled 29,518 patients with asthma. 15,051 (51.0%) questionnaires were administered by physicians; patients filled out 14,076 (47.7%) questionnaires themselves. 28,225 (95.6%) of the patients were evaluable. VAS measurement of asthma symptoms was useful in predicting levels of GINA-defined control categories (the area under the receiver operating characteristic curve ranging from 0.704 to 0.837). Patients with "controlled," "partly controlled," and "uncontrolled" asthma were discriminated by VAS levels (1.50, 4.79, and 7.19). Similar results have been obtained with self- and physician-administered questionnaires showing the validity of results. CONCLUSION: Measurement of VAS levels is able to discriminate between patients with "controlled," "partly controlled," and "uncontrolled" asthma. The VAS score could be a simple guide in clinical situations requiring daily or regular evaluation of asthma control.

[Evaluation of airway narrowing by MostGraph and spirometry -examination using a reversibility test-].

BACKGROUND AND OBJECTIVE: MostGraph is an apparatus for measuring respiratory resistance and respiratory reactance, using the forced oscillation technique. Because these parameters are measured during tidal breathing of subjects, measuring technique is easy with little burden on subjects. In the present study, we conducted spirometry and MostGraph at the same time and examined the clinical significance of parameters of MostGraph. METHODS: Subjects were 52 out-patients who underwent a reversibility test. Spirometry and MostGraph are simultaneously practiced both before and after short acting ß2 agonist (SABA) inhalation. RESULTS: Between each parameter of both methods before SABA inhalation, we confirmed significant correlations between many indexes of both manners. Above all, the strongest correlation was found between Fres and FEV1. In relationships between the percent changes of each parameter of both techniques by SABA inhalation, we also found a significant correlation between percent change of Fres and that of FEV1. In addition, there was a hyperbolic relation between change in Fres and that in FEV1 by SABA inhalation. CONCLUSION: We confirmed not only that airway narrowing itself significantly correlates with Fres, but also that elastic resistance of respiratory system changes in association with change of airway narrowing. Thus, our findings suggest that the percent change of Fres may provide a diagnostic criterion for a reversibility test in all parameters of MostGraph.

[Comparison of HER2 immunohistochemical results for advanced gastric cancer obtained on using 3 different antibodies].

We compared the results of immunohistochemical assessment of HER2 expression in 107 samples of advanced gastric cancer on using 3 currently used antibodies. Expression was scored as 0 to 3+, and equivocal or discordant cases were subjected to fluorescence in situ hybridization(FISH)analysis. HER2 scores of 2+or 3+were noted in 16.8% of cases(18/ 107)using SV2-61g, in 29.9% of cases(32/107)using Dako HercepTest, and in 34.6% of cases(37/107)using 4B5. The results of the HER2 test differed according to the antibodies used for immunohistochemistry preceding FISH analysis, and the HER2 positive rates after the FISH analysis were 14.0%(15/107)using SV2-61g, 19.6% (21/107)using Dako HercepTest, and 22.4% (24/107)using 4B5. Thus, therapeutic decisions might be considerably influenced by the antibody used for the HER2 test.

Peripheral T-cell lymphoma arising from an intraglandular lymph node in the parotid gland: a case report and literature review.

T/NK-cell lymphoma of the salivary gland is rare. A 58-year-old man complained of a tumor mass in the left parotid gland region and he was diagnosed to have a left parotid tumor. The tumor was subsequently resected, revealing a diffuse growth pattern of medium to large sized atypical cells. The tumor was surrounded by fibrous connective tissue in the form of a capsule, and those were positive for CD3, CD4, CD5 and CD30, but negative for Bcl2, CD8, CD10, CD15, CD20, CD25, CD56, CD79a, CD246, EMA, granzyme B, TdT and TIA-1. There was no molecular evidence of Epstein-Barr virus (EBV) infection. It was diagnosed as peripheral T-cell lymphoma (PTCL) arising from an intraglandular lymph node in the parotid gland. In conclusion, Only 17 cases of primary T/NK-cell lymphoma of the salivary glands have been recorded until now, and the characteristics of these are not clear yet. Additional study is needed.

Multiple carcinoid tumors of the rectum: report of two cases suggesting the origin of carcinoid tumors.

Two cases of multiple carcinoid tumors of the rectum with numerous micronests of carcinoid tumors are reported. The patients were 51- and 58-year-old males. Many carcinoid tumors and numerous carcinoid micronests were found in the resected rectum; the total number of carcinoid tumors, groups of micronests, and solitary micronests was 69 in the first case and 62 in the second case. The micronests, consisting of a few to many endocrine cells, were observed in the lamina propria, muscularis mucosa, and/or submucosa. Micronests increased in number, gathered and formed carcinoid tumors, which were up to 8 mm in diameter. It was found that a nest of the carcinoid tumors in the lamina propria showed continuity with the endocrine cells of a crypt in the different carcinoid tumors in both cases. The carcinoid tumor and micronest infiltrated the nerves and ganglions in the muscularis mucosa and submucosa. Nests of the carcinoid tumors and micronests were surrounded by S-100-positive cells. Lymph node metastases of the carcinoid tumor were found in both cases. Rectal carcinoid tumors may originate from endocrine cells of the crypts, and multiple carcinoid tumors may occur heterogeneously.

Comparison of HER2 immunohistochemical results using a monoclonal antibody (SV2-61γ) and a polyclonal antibody (for Dako HercepTest) in advanced gastric cancer.

We compared a monoclonal antibody (SV2-61γ) and a polyclonal antibody (Dako HercepTest) in immunohistochemical assessments of human epidermal growth factor receptor 2 (HER2) expression in 73 samples of advanced gastric cancer. Results were scored as 0 to 3+, and equivocal or discordant (SV2-61γ/Dako HercepTest = 0/2+, 0/3+, 1+/3+ or 2+/3+) cases were subjected to fluorescence in situ hybridization (FISH) analysis. The frequencies of HER2 scores of 2+ or 3+ were 15.1% (11/73) using SV2-61γ and 38.4% (28/73) using Dako HercepTest. All of the equivocal or discordant cases with a HER2 score of 3+ using Dako HercepTest exhibited amplification of the HER2 gene regardless of the HER2 score determined with SV2-61γ. The results of the HER2 tests differed according to the antibodies used for immunohistochemistry that preceded FISH analysis, being 15.1% (11/73) using SV2-61γ and 23.3% (17/73) using Dako HercepTest. Thus, therapeutic decisions might be markedly influenced by the selection of antibody used in the HER2 test.

Transdermal tulobuterol patch, a long-actingß(2)-agonist.

Tulobuterol patch (HokunalinTM Tape), which contains a ß(2)-adrenergic agonist, is the first bronchodilator to be available as a transdermal patch. This drug delivery system ensures that the time at which the peak drug concentration in the blood is reached coincides with the morning dip in respiratory function. The use of the patch also prevents excessive increase in blood drug concentrations, thereby reducing the incidence of systemic adverse reactions. Since 1998, when it was first approved in Japan and worldwide, the tulobuterol patch has been used widely in the treatment of bronchial asthma and chronic obstructive pulmonary disease (COPD), and evidence collected since it was approved has confirmed its clinical efficacy and safety. Because the patch is easy to use and requires only once-daily application, treatment adherence of patients using the patch is good. In this article, we discuss the rationale behind the development of the tulobuterol patch, evaluate data on its clinical efficacy and safety in the treatment of asthma and COPD, and examine the treatment adherence in individuals using the patch.

In vitro evaluation of dry powder inhaler devices of corticosteroid preparations.

BACKGROUND: Although investigations of the drug aerosols generated from inhaled corticosteroid (ICS) preparations and combined drug preparations provide basic information about inhalation therapy, many clinicians have one-sided data about the precision of drug aerosols from the manufacturer. The present study was conducted to analyze and compare the performances of dry powder inhaler (DPI) devices of ICS and combined drug preparations. METHODS: The particle size of individual aerosols was measured according to the time-of-flight principle in terms of their aerodynamic diameter by using the aerodynamic particle sizer spectrometer Model 3321. Percent aerosolization was measured using only stage #0 and backup filters of the Andersen non-viable sampler model AN-200. RESULTS: The particle size distribution of aerosols generated from a Turbuhaler™ and Twisthaler™ showed a mono-modal distribution of less than 5 µm. In contrast, Diskus™ showed a polydisperse distribution, ranging from 0.5 to 20 µm. The percentages of DPI preparations converted into aerosols with a particle size less than 11 µm at a suction flow rate of 28.3 L/min were 5.7-6.2% for Diskus, 37.5-47.0% for Turbuhaler, and 19.8% for Twisthaler. At a suction flow rate of 60 L/min, the conversion percentages for DPI preparations into aerosols with a particle size less than 7.6 µm were 5.9-7.5%, 78.2-86.7%, and 43.5%, respectively. CONCLUSIONS: Because in vitro differences in the aerosolization among different DPI devices containing ICS and combined drug preparations were observed, prescribers of these preparations should consider whether the patients will benefit more from the treatment of the central airways versus the peripheral airways.

µ-opioid receptor-mediated alterations of allergen-induced immune responses of bronchial lymph node cells in a murine model of stress asthma.

BACKGROUND: Psychological stress has a recognized association with asthma symptoms. Using a murine model of allergic asthma, we recently demonstrated the involvement of µ-opioid receptors (MORs) in the central nervous system in the stress-induced exacerbation of airway inflammation. However, the involvement of MORs on neurons and immunological alterations in the stress asthma model remain unclear. METHODS: MOR-knockout (MORKO) mice that express MORs only on noradrenergic and adrenergic neurons (MORKO/Tg mice) were produced and characterized for stress responses. Sensitized mice inhaled antigen and were then subjected to restraint stress. After a second antigen inhalation, bronchoalveolar lavage cells were counted. Before the second inhalation, bronchial lymph node (BLN) cells and splenocytes from stressed and non-stressed mice were cultured with antigen, and cytokine levels and the proportions of T cell subsets were measured. RESULTS: Stress-induced worsening of allergic airway inflammation was observed in wild-type and MORKO/Tg mice but not MORKO mice. In wild-type stressed mice, IFN-γ/IL-4 ratios in cell culture supernatants and the proportion of regulatory T cells in BLN cell populations were significantly lower than those in non-stressed mice. These differences in BLN cells were not observed between the stressed and non-stressed MORKO mice. Restraint stress had no effect on cytokine production or T cell subsets in splenocytes. CONCLUSIONS: Restraint stress aggravated allergic airway inflammation in association with alterations in local immunity characterized by greater Th2-associated cytokine production and a reduced development of regulatory T cells, mediated by MORs.

[A case of curatively resected locally advanced cancer of the pancreatic body treated by distal pancreatectomy with en bloc celiac axis resection after neoadjuvant chemotherapy].

A 68-year-old man with locally advanced pancreatic body cancer invading the celiac axis(CA, including common hepatic artery)and in contact with the superior mesenteric artery(SMA)underwent 2 courses of neoadjuvant chemotherapy(NAC); gemcitabine hydrochloride(GEM 1,000 mg/m / / 2, on day 1 and 15)and S-1(100mg/m2day, 2-weeks of continuous administration followed by 1-week rest). The tumor volume and the contact area to SMA were greatly diminished. All tumor markers were reduced. He underwent R0 resection by distal pancreatectomy with en bloc celiac axis resection(DP-CAR). After the surgery, he could continue adjuvant chemotherapy; (GEM 1,000 mg/m2)only twice because of malnutrition. Nine months later CT revealed local recurrence and multiple lung metastases. The patient died 371 days after surgery. Appropriate NAC can contribute to R0 resection in locally advanced pancreatic cancer.

Helicobacter pylori Modulated Host Immunity in Gastric Cancer Patients With S-1 Adjuvant Chemotherapy.

BACKGROUND: Paradoxically, Helicobacter pylori-positive (HP+) advanced gastric cancer patients have a better prognosis than those who are HP-negative (HP-). Immunologic and statistical analyses can be used to verify whether systemic mechanisms modulated by HP are involved in this more favorable outcome. METHODS: A total of 658 advanced gastric cancer patients who underwent gastrectomy were enrolled. HP infection, mismatch repair, programmed death-ligand 1 (PD-L1) and CD4/CD8 proteins, and microsatellite instability were analyzed. Overall survival (OS) and relapse-free survival (RFS) rates were analyzed after stratifying clinicopathological factors. Cox proportional hazards regression analysis was performed to identify independent prognostic factors. RESULTS: Among 491 patients that were analyzed, 175 (36%) and 316 (64%) patients were HP+ and HP-, respectively. Analysis of RFS indicated an interaction of HP status among the subgroups for S-1 dose (Pinteraction = .049) and PD-L1 (P = .02). HP+ patients in the PD-L1- group had statistically higher 5-year OS and RFS than HP- patients (81% vs 68%; P = .0011; hazard ratio [HR] = 0.48, 95% confidence interval [CI] = 0.303 to 0.751, and 76% vs 63%; P = .001; HR = 0.508, 95% CI = 0.335 to 0.771, respectively). The 5-year OS and RFS was also statistically higher for HP+ compared with HP- patients in the "PD-L1- and S-1-r educed" group (86% vs 46%; P = .001; HR = 0.205, 95% CI = 0.07 to 0.602, and 83% vs 34%; P = .001; HR = 0.190, 95% CI = 0.072 to 0.498, respectively). Thus, HP status was identified as one of the most potentially important independent factors to predict prolonged survival. CONCLUSION: This retrospective study suggests that an HP-modulated host immune system may contribute to prolonged survival in the absence of immune escape mechanisms of gastric cancer.