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Introduction: Risk prediction of gastric cancers is important to implement appropriate screening procedures. Although aberrant DNA methylation is deeply involved in gastric carcinogenesis, its induction by Helicobacter pylori, a strong gastric carcinogen, is unclear. Here, we analyzed the effect of H. pylori infection on the quantity of methylated DNA molecules in noncancerous gastric mucosae and examined its association with gastric cancer risk.Experimental Design: Gastric mucosae were collected from 154 healthy volunteers (56 H. pylori negative and 98 H. pylori positive) and 72 cases with differentiated-type gastric cancers (29 H. pylori negative and 43 H. pylori positive) by endoscopy. The numbers of DNA molecules methylated and unmethylated for eight regions of seven CpG islands (CGI) were quantified by quantitative PCR after bisulfite modification, and fractions of methylated molecules (methylation levels) were calculated.Results: Among healthy volunteers, methylation levels of all the eight regions were 5.4- to 303-fold higher in H. pylori positives than in H. pylori negatives (P < 0.0001). Methylation levels of the LOX, HAND1, and THBD promoter CGIs and p41ARC exonic CGI were as high as 7.4% or more in H. pylori–positive individuals. Among H. pylori–negative individuals, methylation levels of all the eight regions were 2.2- to 32-fold higher in gastric cancer cases than in age-matched healthy volunteers (P ≤ 0.01). Among H. pylori–positive individuals, methylation levels were highly variable, and that of only HAND1 was significantly increased in gastric cancer cases (1.4-fold, P = 0.02).Conclusions: It was indicated that H. pylori infection potently induces methylation of CGIs to various degrees. Methylation levels of specific CGIs seemed to reflect gastric cancer risk in H. pylori–negative individuals.

Supplementary Table S1 from High Levels of Aberrant DNA Methylation in Helicobacter pylori–Infected Gastric Mucosae and its Possible Association with Gastric Cancer Risk

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.

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 ACQUI...

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.

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.

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.

Background and Aims: The Japanese Asthma Prevention and Management Guideline 2015 (JGL 2015) recommends managing asthma patients to become “well-controlled” as the treatment goal. The aims of this study were to investigate the asthma control level, symptoms, QOL, and reliever usage among adult asthma patients managed by specialists in a real life setting. Methods: This was a cross-sectional, multi-centered observational study. Adult physician-diagnosed asthma outpatients, who started treatment with an asthma controller at least one year prior to enrollment, were recruited by respiratory specialists. Patients were asked to complete a one week asthma symptoms diary, ACQ-5 and mini AQLQ. Data including asthma exacerbation history, medication and laboratory tests were collected from medical records retrospectively. Patients who were free of symptoms, reliever usage, activity limitation and exacerbation were defined as ‘well-controlled’, which approximately aligns with JGL 2015. Results: A total of 1,175 patients (62.9 % female; mean age 59.7 years) were included in the analysis set. 24.4 % of the patients were classified as “well-controlled”. 51.5 % and 44.9 % of the patients recorded daytime and nighttime asthma symptoms in their diary, respectively. Mean ACQ and mini AQLQ scores were 0.7±0.9 and 5.8±1.0, respectively. Conclusion: The majority of adult asthma patients managed by specialists (about 75%) suffered from asthma symptoms and were not “well-controlled”. This suggests a more frequent and thorough review of the current asthma control level based on patient symptoms and adjustment of pharmacological treatment is needed.

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.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.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.It is suggested that we should instruct patients to inhaler DPI based on inspiratory resistance of the DPI.

4043Background: The beneficial and deleterious effects of Helicobacter pylori (H. pylori) infection remain to be fully elucidated. A clear understanding of the infectious mechanism is crucial since...

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.We performed a questionnaire survey about patient backgrounds, nasal symptoms, QOL disturbance, and treatment agents, for childhood allergic rhinitis patients under age 12.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.It was indicated that the combination therapy was useful in the severe cases of childhood allergic rhinitis.