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.

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.

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.

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.

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.

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.

The correlation of the International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) classification with prognosis and EGFR mutation in lung adenocarcinoma.

BACKGROUND: The purpose of this study was to validate the prognostic effect and the frequency of mutations in the gene expressing epidermal growth factor receptor (EGFR) in lung adenocarcinoma of Japanese patients, on the basis of the new adenocarcinoma classification proposed by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society. METHODS: The new classification was used to reclassify 486 adenocarcinomas. The percentage of each histopathologic subtype and the predominant pattern were determined. EGFR mutation was also investigated. The relationship between these results and clinicopathologic backgrounds was investigated statistically. RESULTS: No patients with adenocarcinoma in situ or minimally invasive adenocarcinoma died within the follow-up periods, followed by patients with lepidic predominant. Patients with papillary or acinar predominant, or invasive mucinous adenocarcinoma, showed almost similar overall survival (OS). The patients with solid predominant and micropapillary predominant showed the worst OS. Multivariate analysis showed that the new classification was an independent predictor of OS. The frequency of EGFR mutation was adenocarcinoma in situ (62%), minimally invasive adenocarcinoma (60%), lepidic (77%), acinar (49%), papillary (50%), solid (28%), micropapillary (43%), and invasive mucinous adenocarcinoma (0%). CONCLUSIONS: This new adenocarcinoma classification is a very useful predictive marker to plan and determine a therapeutic strategy for lung adenocarcinoma.

Positive intraoperative pleural lavage cytology is a predictive marker of disease recurrence in stage I lung adenocarcinoma.

OBJECTIVES: This study aimed at analysing the relationship between the pleural lavage cytology (PLC) status and clinicopathological characteristics, including the outcome of examined patients and tumour recurrence sites in surgically resected stage I non-small-cell lung carcinoma. METHODS: From April 2002 to August 2012, PLC was performed immediately after thoracotomy in 428 consecutive patients undergoing pulmonary resection for lung cancer. The relationship between clinicopathological characteristics and the PLC status was retrospectively analysed. RESULTS: The frequency of PLC-positive results was 4.4%, and larger tumour size, stage IB and pleural invasion were found more frequently in PLC-positive patients. Patients with a PLC-positive status had significantly worse disease-free survival (DFS) than those with a PLC-negative status (PLC positive versus PLC negative: hazard ratio [HR] = 2.79, 95% confidence interval [CI]: 1.4-5.57, P < 0.004; 5-year DFS: 46.6 vs 76.5%). With regard to the PLC status and histological type, adenocarcinoma was associated with a worse DFS in PLC-positive patients when compared with PLC-negative patients (5-year DFS: 38.1 vs 81.1%, P < 0.001). In multivariate analysis, PLC status remained significantly associated with DFS in patients with a PLC-positive status having an increased risk of recurrence, compared with PLC-negative patients (HR = 2.494, 95% CI: 1.241-5.011, P = 0.01) only in the case of adenocarcinoma. CONCLUSIONS: Our current study showed the clinicopathological characteristics associated with PLC status and demonstrated that PLC status was an independent predictor of increased recurrence in stage I lung adenocarcinoma.

[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.

Prognostic impact and initial recurrence site of lymphovascular and visceral pleural invasion in surgically resected stage I non-small-cell lung carcinoma.

OBJECTIVES: This study aimed to analyse and validate the prognostic impact and effect of the initial recurrence site of lymphovascular and visceral pleural invasion (VPI) on survival outcomes for Stage I non-small-cell lung carcinoma (NSCLC). METHODS: We retrospectively reviewed 433 patients undergoing resection of Stage I NSCLC. The relationship between the clinicopathological background and the pathological variables, lymphovascular invasion (LVI) and VPI, was evaluated by univariate and multivariate analyses. RESULTS: Lymphovascular and VPI was observed in 41 and 45 patients, respectively. On univariate analysis, the presence of LVI was associated with a significant decrease in relapse-free survival (RFS) (P < 0.001) and overall survival (OS) (P < 0.001). The RFS of the patients of Stage IB with LVI was worse than the RFS of those of Stage IIA (T2aN1 and T2bN0)/IIB (T3N0), and similar to the RFS of those of Stage IIB (T2bN1). The presence of VPI was also associated with a significant decrease in RFS (P < 0.001) and OS (P = 0.01). On multivariate analysis, LVI was found to be an independent predictor of both decreased RFS and decreased OS. However, VPI was not an independent predictor of both. Recurrence was seen in 68 patients. As an initial recurrence site, distant recurrence was seen in 32 patients and local recurrence, in 36. The proportion of local recurrence was significantly higher in the patients with VPI than in those without VPI compared with between the patients with LVI and those without LVI. CONCLUSIONS: We propose that LVI and/or VPI may be a candidate marker to determine adjuvant therapy or a more careful follow-up for these patients.

[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.

New IASLC/ATS/ERS classification and invasive tumor size are predictive of disease recurrence in stage I lung adenocarcinoma.

INTRODUCTION: The purpose of this study is to analyze and validate the prognostic impact of the new lung adenocarcinoma (ADC) classification proposed by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society and invasive tumor size in stage I lung ADC of Japanese patients. METHODS: We reclassified 191 stage I ADCs according to the new classification. The percentage of each histological subtype and the predominant type were determined. In addition, both total tumor size and invasive tumor size were examined. The relationship between these results and clinicopathological backgrounds was investigated statistically. RESULTS: The 5-year disease-free survival (DFS) of adenocarcinoma in situ and minimally invasive adenocarcinoma was 100%; lipidic-predominant ADCs, 94.9%; papillary-predominant ADCs, 85.4%; acinar-predominant ADCs, 89.7%; and solid-predominant ADCs, 54%. The predominant growth pattern was significantly correlated with DFS (p < 0.001, overall). With regard to tumor size, total tumor size was not correlated with DFS (p = 0.475, overall), however, invasive tumor size was significantly correlated with DFS (≤ 0.5 cm/ > 0.5 cm, ≤ 1 cm/ >1 cm, ≤ 2 cm/>2 cm, ≤ 3 cm/ >3 cm, 100%/91.5%/85.9%/80.8%/66.7%% in 5-year DFS) (p = 0.006, overall). A multivariate analysis showed solid-predominant and invasive tumor size were independent predictors of increased risk of recurrence (solid versus nonsolid: hazard ratio = 4.08, 95% confidence interval:1.59-10.5, p = 0.003; invasive tumor size: hazard ratio = 2.04, 95% confidence interval:1.14-3.63, p = 0.016). CONCLUSION: : The new International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society ADC classification and invasive tumor size are very useful predictors of recurrence of stage I ADCs in Japanese patients.

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.