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Introduction Bronchodilators, including long-acting muscarinic antagonists (LAMA) and long-acting beta 2 agonists (LABA), are the main treatments for chronic obstructive pulmonary disease (COPD). The efficacy of triple therapy (inhaled corticosteroids/LAMA/LABA) has also been reported. However, the effect of triple therapy on patients with mild-to-moderate COPD has not yet been clarified. This study aims to investigate the safety and efficacy of triple therapy, compared with LAMA/LABA combination therapy, for lung function and health-related quality of life in patients with mild-to-moderate COPD and identify baseline characteristics and biomarkers to predict responders and non-responders to triple therapy.Methods and analysis This is a multicentre, prospective, open-label, randomised, parallel-group study. Mild-to-moderate patients with COPD will be randomised to receive fluticasone furoate/umeclidinium/vilanterol or umeclidinium/vilanterol for 24 weeks. A total of 668 patients will be enrolled from March 2022 to September 2023 from 38 sites in Japan. The primary endpoint is the change in the trough forced expiration volume in 1 s after 12 weeks of treatment. Secondary endpoints are responder rates based on the COPD assessment test score and the St. George’s Respiratory Questionnaire total score after 24 weeks of treatment. The safety endpoint is the occurrence of any adverse events. We will also investigate safety in terms of changes in microbial colonisation in sputum and antimycobacterium avium complex antibodies.Ethics and dissemination The study protocol and informed consent documents were approved by the Saga University Clinical Research Review Board (approval number: CRB7180010). Written informed consent will be obtained from all patients. Recruitment of the patients began in March 2022. The results will be disseminated through scientific peer-reviewed publications and domestic and international medical conferences.Trial registration numbers UMIN000046812 and jRCTs031190008.

Gastric subepithelial lesions (SEL) are usually found incidentally during esophagogastroduodenoscopy. Most gastric SELs are benign lesions, such as leiomyoma and pancreatic rests. However, neoplastic lesions including neuroendocrine tumors, gastrointestinal stromal tumors, and certain types of gastric adenocarcinoma (GA), such as the recently WHO-classified fundic gland type adenocarcinoma, may be found. The lack of simple and established diagnostic methods for SEL remains a clinical challenge. Standard biopsy is suboptimal for diagnosis due to the subepithelial location of lesions and is therefore often omitted. Furthermore, guideline-based algorithmic approaches for diagnosing SEL also differ between Japan and the USA. In this case series, we describe three cases of gastric SEL that were subsequently diagnosed as GA. Case 1 was a fundic gland type (chief cell predominant type) adenocarcinoma; Case 2 was a poorly differentiated GA; Case 3 was an advanced GA, found after 4 serial years of endoscopic follow-up for SEL. While standard biopsy led to successful diagnosis in the first 2 cases, no standard biopsy was performed during surveillance in Case 3, making its diagnostic effectiveness unclear. The third case highlights the importance of longitudinal observation for endoscopic mucosal alterations that may suggest certain types of GA. Clinicians should be aware that standard biopsy may play an important role in the evaluation of malignant gastric SEL-like lesions. It is crucial to remain vigilant for surface changes in SEL and not to summarily omit standard biopsy.

Abstract Mepolizumab, a humanized anti‐IL‐5 monoclonal antibody used for severe asthma, results in a reduced rate of asthma exacerbation, improved lung function, reduced oral corticosteroid use, and improved quality of life. A 62‐year‐old man using high‐dose inhaled corticosteroid visited our hospital because of poorly‐controlled asthma. He had eosinophilia in peripheral blood and sputum, and high levels of fraction of exhaled nitric oxide. Therefore, he was treated with mepolizumab for severe asthma. Mepolizumab treatment resulted in significantly improved pulmonary function and reduced frequencies of asthma exacerbations. Because of his good asthma control, mepolizumab treatment was discontinued after 3 years. Since discontinuing mepolizumab, his asthma control has remained without exacerbation. Previous studies suggest that mepolizumab should be continued to sustain clinical benefits. However, cases of long‐term controlled asthma have not been reported after mepolizumab withdrawal, and our case may be instructive.

Abstract Aims Studies detailing endoscopic findings and hemostatic interventions for upper gastrointestinal bleeding after cardiovascular surgery are scarce. We conducted this study to determine the frequency and findings of emergent esophagogastroduodenoscopy (EGD) after cardiovascular surgery and the effect of bleeding requiring hemostatic intervention on clinical outcomes. Methods and Results We retrospectively reviewed records of emergent EGD examinations conducted within 30 days after cardiovascular surgery at a tertiary referral center in Japan from April 2011 to March 2020. Of 1625 patients undergoing cardiovascular surgery, 47 underwent emergent EGD. Sources of bleeding were identified in 30 cases, including transesophageal echocardiogram (TEE)‐related injuries (8 patients), gastric ulcers (7 patients), and duodenal ulcers (7 patients). Patients who required endoscopic hemostatic intervention had more TEE‐related injuries (43% vs 3%, P = 0.005), gastric ulcers (35% vs 6%, P = 0.018), or ulcers in the first part of the duodenum (29% vs 0%, P = 0.006) than those who did not. Intraoperative TEE did not increase the need for endoscopic intervention (71% vs 64%, P = 0.435). Intraoperative TEE and the need for endoscopic intervention did not affect length of stay or all‐cause mortality. Only one death was associated with gastrointestinal bleeding. Conclusion Despite the potential severity of bleeding after cardiovascular surgery, most cases can be managed endoscopically with no increase in hospital stay or mortality.

T helper type 2 cells (Th2 cells) and group 2 innate lymphoid cells (ILC2s) play an important role in the pathophysiology of asthma, including airway eosinophilic inflammation. ILC2s are activated by epithelial-derived cytokines [interleukin-25 (IL-25), IL-33, and thymic stromal lymphopoietin (TSLP)] from airway epithelial cells, leading to the release of high amounts of type 2 cytokines, such as IL-5 and IL-13. ILC2s induce airway inflammation in an antigen-independent manner, and ILC2s are considered to be involved in the pathogenesis of asthma exacerbation. Furthermore, ILC2 activation might also confer steroid resistance. Many recent studies in humans and mice are increasingly demonstrating that the function of ILC2s is regulated not just by epithelial-derived cytokines but by a variety of cytokines and mediators derived from innate immune cells. Furthermore, the biologics targeting these cytokines and/or their receptors have been shown to reduce asthma exacerbations and improve lung function and quality of life in asthmatics. This article reviews the current treatment landscape for type 2 airway inflammation in asthma and discusses the therapeutic potential for targeting ILC2s.

Abstract Background and Aim Endoscopic band ligation (EBL), used for the treatment of colonic diverticular bleeding, has a lower rebleeding rate than endoscopic clipping. However, different devices are used in Japan and the Western countries; no animal studies have been conducted to elucidate the safety of such devices. We compared two EBL devices, the first used in Japan and the second used in Western countries. Methods and Results The Japanese and Western EBL devices were compared by assessing the EBL safety at 40 sites in an animal model with a normal colon that is anatomically similar to the human colon. Macroscopic and pathological examinations were performed to evaluate the layer ligated by the band and the presence of perforation. The findings on day 1 and day 7 after EBL were compared. The ligated layer was the muscularis propria at 39 sites; the layer was not evaluated at one site where the band was unintentionally removed during the endoscopic procedure. Pathologically, there was no perforation at any of the assessed sites. There was no statistical difference in any of the pathological variables between the two devices or between days 1 and 7 after EBL. The total procedure time was significantly shorter with the Western EBL device. Conclusions In this animal study, both evaluated devices were safe for EBL, without differences in the macroscopic and pathological variables after EBL. Ligation of the muscularis propria layer did not result in perforation.

Asthma is a heterogeneous disease characterized by chronic airway inflammation. Group 2 innate lymphoid cells (ILC2) play an important role in the pathogenesis of asthma. ILC2s lack antigen-specific receptors and respond to epithelial-derived cytokines, leading to the induction of airway eosinophilic inflammation in an antigen-independent manner. Additionally, ILC2s might be involved in the mechanism of steroid resistance. Numerous studies in both mice and humans have shown that ILC2s induce airway inflammation through inflammatory signals, including cytokines and other mediators derived from immune or non-immune cells. ILC2s and T helper type 2 (Th2) cells collaborate through direct and indirect interactions to organize type 2 immune responses. Interestingly, the frequencies or numbers of ILC2 are increased in the blood and bronchoalveolar lavage fluid of asthma patients, and the numbers of ILC2s in the blood and sputum of severe asthmatics are significantly larger than those of mild asthmatics. These findings may contribute to the regulation of the immune response in asthma. This review article highlights our current understanding of the functional role of ILC2s in asthma.

A 64-year-old Japanese man with no significant medical history presented with epigastric discomfort of 2-weeks’ duration. He was diagnosed with metastatic HER2-positive gastric cancer. Chemotherapy with capecitabine, oxaliplatin, and trastuzumab was initiated. During the eighth cycle, he suddenly complained of electric shock-like pain in both legs upon neck flexion, consistent with Lhermitte’s sign. Oxaliplatin was discontinued, and Lhermitte’s sign resolved after 3 months. Neurotoxicity is commonly observed in platinum-based chemotherapy, but Lhermitte’s sign is rare. This is the first report of oxaliplatin-induced Lhermitte’s sign in a gastric cancer patient.

Endoscopic stenting with self-expandable metallic stents is widely accepted for the treatment of malignant colorectal obstruction. Generally, stenting is performed as a bridge-to-surgery for primary colorectal cancer (CRC). Furthermore, palliative colonic stenting is performed for extraparenteral malignant tumors (EPMTs). However, predictive factors for improving clinical outcomes after colonic stenting for EPMTs remain unclear. This study is aimed at evaluating patients with EPMTs who underwent colonic stenting and investigating factors influencing clinical improvement after the stenting procedure. Twenty-one patients with colorectal obstruction by EPMTs were treated using self-expandable metallic stents over a period of 8 years. We divided the enrolled patients into the clinically improved and nonimproved groups after colonic stenting. Variables, including age; sex; type of primary cancer; serum albumin level; location of the obstruction; stent type, length, and diameter; prior chemotherapy treatment; ascites; Eastern Cooperative Oncology Group performance status (PS); technical and clinical success rates; stent-related adverse events; and mortality rates, were evaluated. Technical failure was not observed in all cases. Clinical success, defined as the passage of stool and improvement in the colorectal obstruction scoring system (CROSS) without adverse events, was observed in the 14 patients. Univariate analyses revealed no significant differences in factors other than PS before stenting (P=0.04) between the improved and nonimproved groups. Colonic stenting for EPMTs was effective. PS may be an independent risk factor of clinical outcomes after stenting.

Background and aims: Endoscopic band ligation (EBL) has been used to achieve hemostasis in patients with colonic diverticular bleeding. The safety and effectiveness of EBL when performed by non-expert endoscopists have not been sufficiently verified. This study aimed to elucidate the feasibility of the EBL technique when performed by non-expert endoscopists and of considering EBL as a standard treatment for colonic diverticular bleeding. Patients and methods: A retrospective cohort study was conducted in a tertiary referral center in Tokyo, Japan, between June 2009 and October 2014. A total of 95 patients treated with EBL were included in the study and were divided into two groups according to whether they had been treated by expert or non-expert endoscopists. Comorbidities, medications, shock index, hemoglobin level on admission, location of the bleeding diverticula, rate of bowel preparation, procedure time, and EBL-associated adverse events were evaluated in each group. Multivariate linear regression analyses were used to investigate factors related to EBL procedure time, which is the time elapsed between marking the site of bleeding with hemoclips and completion of the band release. Results: A total of 47 (49.5 %) procedures were performed by expert endoscopists. In a bivariate analysis, the median EBL procedure times in the expert and non-expert groups were 15 minutes (range 4 – 45) and 11 minutes (range 4 – 36), respectively (P = 0.03). When a multivariate linear regression model was used, EBL for right-sided diverticula was the factor most significantly affecting EBL procedure time. No adverse events were encountered. Conclusion: EBL can be safely and effectively performed by non-expert endoscopists. A right-sided location of diverticula was the factor most significantly affecting EBL procedure time.

Background and study aims: Long-term outcomes of endoscopic band ligation (EBL) for colonic diverticular hemorrhage have not been reported to date. The aim of this study was to determine the long-term outcomes of EBL and to retrospectively compare them with those of endoscopic clipping (EC) in the treatment of colonic diverticular hemorrhage. Patients and methods: The study included patients with colonic diverticular hemorrhage who were treated with EBL or EC from January 2004 to November 2014 and followed up more than 1 year (61 patients in the EBL group and 39 patients in the EC group). Time-to-event analysis of rebleeding was performed with the Kaplan-Meier method. A follow-up colonoscopy was performed to confirm the disappearance of the banded diverticula in the EBL group. Results: Rebleeding occurred in 21 patients in the EBL group and in 26 patients in the EC group. The cumulative incidence of rebleeding at 1, 12, 24, and 36 months after first treatments was 14 %, 23 %, 26 %, and 41 % in the EBL group and 38 %, 49 %, 59 %, and 68 % in the EC group, respectively. Time-to-event analysis revealed statistically significant data (Log-rank test, P = 0.0036). Scar formation with fold convergence at the previously banded site was observed in 11 of 24 patients who underwent follow-up colonoscopy (46 %). However, late rebleeding (rebleeding more than 30 days after EBL) occurred in five of these 11 cases. Conclusions: EBL was superior to EC in the treatment of colonic diverticular hemorrhage. However, the risk of rebleeding was not avoided even after the diverticula had been resolved using EBL.

Background and study aims: Endoscopic band ligation (EBL) has been used for hemostasis of colonic diverticular hemorrhage. However, early rebleeding (

Asparagine-linked glycosylation (N-glycosylation) of proteins in the cancer secretome has been gaining increasing attention as a potential biomarker for cancer detection and diagnosis. Small extracellular vesicles (sEVs) constitute a large part of the cancer secretome, yet little is known about whether their N-glycosylation status reflects known cancer characteristics. Here, we investigated the N-glycosylation of sEVs released from small-cell lung carcinoma (SCLC) and non–small-cell lung carcinoma (NSCLC) cells. We found that the N-glycans of SCLC-sEVs were characterized by the presence of structural units also found in the brain N-glycome, while NSCLC-sEVs were dominated by typical lung-type N-glycans with NSCLC-associated core fucosylation. In addition, lectin-assisted N-glycoproteomics of SCLC-sEVs and NSCLC-sEVs revealed that integrin αV was commonly expressed in sEVs of both cancer cell types, while the epithelium-specific integrin α6β4 heterodimer was selectively expressed in NSCLC-sEVs. Importantly, N-glycomics of the immunopurified integrin α6 from NSCLC-sEVs identified NSCLC-type N-glycans on this integrin subunit. Thus, we conclude that protein N-glycosylation in lung cancer sEVs may potentially reflect the histology of lung cancers. [ABSTRACT FROM AUTHOR]